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Abbruzzese, James

Overview:

My research interests include the clinical study and treatment of pancreatic cancer.

Positions:

Charles Johnson, M.D. Professor of Medicine

Medicine, Medical Oncology
School of Medicine

Professor of Medicine

Medicine, Medical Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Chief, Division of Medical Oncology

Medicine, Medical Oncology
School of Medicine

Education:

M.D. 1978

M.D. — University of Chicago

News:

Grants:

Preclinical and Human Correlative Studies of a Novel Bruton Tyronsine Kinase Inhibitor in Pancreatic Cancer

Administered By
Medicine, Medical Oncology
AwardedBy
Department of Defense
Role
Co Investigator
Start Date
September 30, 2016
End Date
September 29, 2019

Topic Refinement, Task order 9 Topic Briefs

Administered By
Duke Clinical Research Institute
AwardedBy
Patient-Centered Outcomes Research Institute
Role
Co Investigator
Start Date
August 29, 2016
End Date
November 16, 2016

Publications:

Sequential Validation of Blood-Based Protein Biomarker Candidates for Early-Stage Pancreatic Cancer.

CA19-9, which is currently in clinical use as a pancreatic ductal adenocarcinoma (PDAC) biomarker, has limited performance in detecting early-stage disease. We and others have identified protein biomarker candidates that have the potential to complement CA19-9. We have carried out sequential validations starting with 17 protein biomarker candidates to determine which markers and marker combination would improve detection of early-stage disease compared with CA19-9 alone.Candidate biomarkers were subjected to enzyme-linked immunosorbent assay based sequential validation using independent multiple sample cohorts consisting of PDAC cases (n = 187), benign pancreatic disease (n = 93), and healthy controls (n = 169). A biomarker panel for early-stage PDAC was developed based on a logistic regression model. All statistical tests for the results presented below were one-sided.Six out of the 17 biomarker candidates and CA19-9 were validated in a sample set consisting of 75 PDAC patients, 27 healthy subjects, and 19 chronic pancreatitis patients. A second independent set of 73 early-stage PDAC patients, 60 healthy subjects, and 74 benign pancreatic disease patients (combined validation set) yielded a model that consisted of TIMP1, LRG1, and CA19-9. Additional blinded testing of the model was done using an independent set of plasma samples from 39 resectable PDAC patients and 82 matched healthy subjects (test set). The model yielded areas under the curve (AUCs) of 0.949 (95% confidence interval [CI] = 0.917 to 0.981) and 0.887 (95% CI = 0.817 to 0.957) with sensitivities of 0.849 and 0.667 at 95% specificity in discriminating early-stage PDAC vs healthy subjects in the combined validation and test sets, respectively. The performance of the biomarker panel was statistically significantly improved compared with CA19-9 alone (P < .001, combined validation set; P = .008, test set).The addition of TIMP1 and LRG1 immunoassays to CA19-9 statistically significantly improves the detection of early-stage PDAC.

Authors
Capello, M; Bantis, LE; Scelo, G; Zhao, Y; Li, P; Dhillon, DS; Patel, NJ; Kundnani, DL; Wang, H; Abbruzzese, JL; Maitra, A; Tempero, MA; Brand, R; Brennan, L; Feng, E; Taguchi, I; Janout, V; Firpo, MA; Mulvihill, SJ; Katz, MH; Hanash, SM
MLA Citation
Capello, M, Bantis, LE, Scelo, G, Zhao, Y, Li, P, Dhillon, DS, Patel, NJ, Kundnani, DL, Wang, H, Abbruzzese, JL, Maitra, A, Tempero, MA, Brand, R, Brennan, L, Feng, E, Taguchi, I, Janout, V, Firpo, MA, Mulvihill, SJ, Katz, MH, and Hanash, SM. "Sequential Validation of Blood-Based Protein Biomarker Candidates for Early-Stage Pancreatic Cancer." Journal of the National Cancer Institute 109.4 (April 2017).
PMID
27986802
Source
epmc
Published In
Journal of the National Cancer Institute
Volume
109
Issue
4
Publish Date
2017

Preoperative Therapy and Pancreatoduodenectomy for Pancreatic Ductal Adenocarcinoma: a 25-Year Single-Institution Experience.

The purpose of this study was to evaluate a single-institution experience with delivery of preoperative therapy to patients with pancreatic ductal adenocarcinoma (PDAC) prior to pancreatoduodenectomy (PD).Consecutive patients (622) with PDAC who underwent PD following chemotherapy and/or chemoradiation between 1990 and 2014 were retrospectively reviewed. Preoperative treatment regimens, clinicopathologic characteristics, operative details, and long-term outcomes in four successive time periods (1990-1999, 2000-2004, 2005-2009, 2010-2014) were evaluated and compared.The average number of patients per year who underwent PD following preoperative therapy as well as the proportion of operations performed for borderline resectable and locally advanced (BR/LA) tumors increased over time. The use of induction systemic chemotherapy, as well as postoperative adjuvant chemotherapy, also increased over time. Throughout the study period, the mean EBL decreased while R0 margin rates and vascular resection rates increased overall. Despite the increase in BR/LA resections, locoregional recurrence (LR) rates remained similar over time, and overall survival (OS) improved significantly (median 24.1, 28.1, 37.3, 43.4 months, respectively, p < 0.0001).Despite increases in case complexity, relatively low rates of LR have been maintained while significant improvements in OS have been observed. Further improvements in patient outcomes will likely require disruptive advances in systemic therapy.

Authors
Cloyd, JM; Katz, MHG; Prakash, L; Varadhachary, GR; Wolff, RA; Shroff, RT; Javle, M; Fogelman, D; Overman, M; Crane, CH; Koay, EJ; Das, P; Krishnan, S; Minsky, BD; Lee, JH; Bhutani, MS; Weston, B; Ross, W; Bhosale, P; Tamm, EP; Wang, H; Maitra, A; Kim, MP; Aloia, TA; Vauthey, J-N; Fleming, JB; Abbruzzese, JL; Pisters, PWT; Evans, DB; Lee, JE
MLA Citation
Cloyd, JM, Katz, MHG, Prakash, L, Varadhachary, GR, Wolff, RA, Shroff, RT, Javle, M, Fogelman, D, Overman, M, Crane, CH, Koay, EJ, Das, P, Krishnan, S, Minsky, BD, Lee, JH, Bhutani, MS, Weston, B, Ross, W, Bhosale, P, Tamm, EP, Wang, H, Maitra, A, Kim, MP, Aloia, TA, Vauthey, J-N, Fleming, JB, Abbruzzese, JL, Pisters, PWT, Evans, DB, and Lee, JE. "Preoperative Therapy and Pancreatoduodenectomy for Pancreatic Ductal Adenocarcinoma: a 25-Year Single-Institution Experience." Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract 21.1 (January 2017): 164-174.
PMID
27778257
Source
epmc
Published In
Journal of Gastrointestinal Surgery
Volume
21
Issue
1
Publish Date
2017
Start Page
164
End Page
174
DOI
10.1007/s11605-016-3265-1

FGF21-FGFR1 Coordinates Phospholipid Homeostasis, Lipid Droplet Function, and ER Stress in Obesity

Authors
Ye, M; Lu, W; Wang, X; Wang, C; Abbruzzese, JL; Liang, G; Li, X; Luo, Y
MLA Citation
Ye, M, Lu, W, Wang, X, Wang, C, Abbruzzese, JL, Liang, G, Li, X, and Luo, Y. "FGF21-FGFR1 Coordinates Phospholipid Homeostasis, Lipid Droplet Function, and ER Stress in Obesity." Endocrinology 157.12 (December 2016): 4754-4769.
Source
crossref
Published In
Endocrinology
Volume
157
Issue
12
Publish Date
2016
Start Page
4754
End Page
4769
DOI
10.1210/en.2016-1710

Interim Acute Toxicity Analysis and Surgical Outcomes of Neoadjuvant Gemcitabine/nab-Paclitaxel and Hypofractionated Image Guided Intensity Modulated Radiation Therapy in Resectable and Borderline Resectable Pancreatic Cancer (ANCHOR) Study

Authors
Palta, M; Czito, B; Abbruzzese, J; Uronis, H; Duffy, EA; Blazer, DT; Willett, CG
MLA Citation
Palta, M, Czito, B, Abbruzzese, J, Uronis, H, Duffy, EA, Blazer, DT, and Willett, CG. "Interim Acute Toxicity Analysis and Surgical Outcomes of Neoadjuvant Gemcitabine/nab-Paclitaxel and Hypofractionated Image Guided Intensity Modulated Radiation Therapy in Resectable and Borderline Resectable Pancreatic Cancer (ANCHOR) Study." October 1, 2016.
Source
wos-lite
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
96
Issue
2
Publish Date
2016
Start Page
S204
End Page
S205

Interim Acute Toxicity Analysis and Surgical Outcomes of Neoadjuvant Gemcitabine/nab-Paclitaxel and Hypofractionated Image Guided Intensity Modulated Radiation Therapy in Resectable and Borderline Resectable Pancreatic Cancer (ANCHOR) Study.

Authors
Palta, M; Czito, B; Abbruzzese, J; Uronis, H; Duffy, EA; Blazer, DT; Willett, CG
MLA Citation
Palta, M, Czito, B, Abbruzzese, J, Uronis, H, Duffy, EA, Blazer, DT, and Willett, CG. "Interim Acute Toxicity Analysis and Surgical Outcomes of Neoadjuvant Gemcitabine/nab-Paclitaxel and Hypofractionated Image Guided Intensity Modulated Radiation Therapy in Resectable and Borderline Resectable Pancreatic Cancer (ANCHOR) Study." International journal of radiation oncology, biology, physics 96.2S (October 2016): S204-S205.
PMID
27675789
Source
epmc
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
96
Issue
2S
Publish Date
2016
Start Page
S204
End Page
S205
DOI
10.1016/j.ijrobp.2016.06.509

Development of a Novel c-MET-Based CTC Detection Platform.

Amplification of the MET oncogene is associated with poor prognosis, metastatic dissemination, and drug resistance in many malignancies. We developed a method to capture and characterize circulating tumor cells (CTC) expressing c-MET using a ferromagnetic antibody. Immunofluorescence was used to characterize cells for c-MET, DAPI, and pan-CK, excluding CD45(+) leukocytes. The assay was validated using appropriate cell line controls spiked into peripheral blood collected from healthy volunteers (HV). In addition, peripheral blood was analyzed from patients with metastatic gastric, pancreatic, colorectal, bladder, renal, or prostate cancers. CTCs captured by c-MET were enumerated, and DNA FISH for MET amplification was performed. The approach was highly sensitive (80%) for MET-amplified cells, sensitive (40%-80%) for c-MET-overexpressed cells, and specific (100%) for both c-MET-negative cells and in 20 HVs. Of 52 patients with metastatic carcinomas tested, c-MET CTCs were captured in replicate samples from 3 patients [gastric, colorectal, and renal cell carcinoma (RCC)] with 6% prevalence. CTC FISH demonstrated that MET amplification in both gastric and colorectal cancer patients and trisomy 7 with gain of MET gene copies in the RCC patient. The c-MET CTC assay is a rapid, noninvasive, sensitive, and specific method for detecting MET-amplified tumor cells. CTCs with MET amplification can be detected in patients with gastric, colorectal, and renal cancers.This study developed a novel c-MET CTC assay for detecting c-MET CTCs in patients with MET amplification and warrants further investigation to determine its clinical applicability. Mol Cancer Res; 14(6); 539-47. ©2016 AACR.

Authors
Zhang, T; Boominathan, R; Foulk, B; Rao, C; Kemeny, G; Strickler, JH; Abbruzzese, JL; Harrison, MR; Hsu, DS; Healy, P; Li, J; Pi, C; Prendergast, KM; Hobbs, C; Gemberling, S; George, DJ; Hurwitz, HI; Connelly, M; Garcia-Blanco, MA; Armstrong, AJ
MLA Citation
Zhang, T, Boominathan, R, Foulk, B, Rao, C, Kemeny, G, Strickler, JH, Abbruzzese, JL, Harrison, MR, Hsu, DS, Healy, P, Li, J, Pi, C, Prendergast, KM, Hobbs, C, Gemberling, S, George, DJ, Hurwitz, HI, Connelly, M, Garcia-Blanco, MA, and Armstrong, AJ. "Development of a Novel c-MET-Based CTC Detection Platform." Molecular cancer research : MCR 14.6 (June 2016): 539-547.
Website
http://hdl.handle.net/10161/11944
PMID
26951228
Source
epmc
Published In
Molecular cancer research : MCR
Volume
14
Issue
6
Publish Date
2016
Start Page
539
End Page
547
DOI
10.1158/1541-7786.mcr-16-0011

Utility of a molecular prescreening program in advanced colorectal cancer for enrollment on biomarker-selected clinical trials.

Incorporation of multiple enrichment biomarkers into prospective clinical trials is an active area of investigation, but the factors that determine clinical trial enrollment following a molecular prescreening program have not been assessed.Patients with 5-fluorouracil-refractory metastatic colorectal cancer at the MD Anderson Cancer Center were offered screening in the Assessment of Targeted Therapies Against Colorectal Cancer (ATTACC) program to identify eligibility for companion phase I or II clinical trials with a therapy targeted to an aberration detected in the patient, based on testing by immunohistochemistry, targeted gene sequencing panels, and CpG island methylation phenotype assays.Between August 2010 and December 2013, 484 patients were enrolled, 458 (95%) had a biomarker result, and 157 (32%) were enrolled on a clinical trial (92 on biomarker-selected and 65 on nonbiomarker selected). Of the 458 patients with a biomarker result, enrollment on biomarker-selected clinical trials was ninefold higher for predefined ATTACC-companion clinical trials as opposed to nonpredefined biomarker-selected clinical trials, 17.9% versus 2%, P < 0.001. Factors that correlated positively with trial enrollment in multivariate analysis were higher performance status, older age, lack of standard of care therapy, established patient at MD Anderson, and the presence of an eligible biomarker for an ATTACC-companion study. Early molecular screening did result in a higher rate of patients with remaining standard of care therapy enrolling on ATTACC-companion clinical trials, 45.1%, in contrast to nonpredefined clinical trials, 22.7%; odds ratio 3.1, P = 0.002.Though early molecular prescreening for predefined clinical trials resulted in an increase rate of trial enrollment of nonrefractory patients, the majority of patients enrolled on clinical trials were refractory to standard of care therapy. Within molecular prescreening programs, tailoring screening for preidentified and open clinical trials, temporally linking screening to treatment and optimizing both patient and physician engagement are efforts likely to improve enrollment on biomarker-selected clinical trials.The study NCT number is NCT01196130.

Authors
Overman, MJ; Morris, V; Kee, B; Fogelman, D; Xiao, L; Eng, C; Dasari, A; Shroff, R; Mazard, T; Shaw, K; Vilar, E; Raghav, K; Shureiqi, I; Liang, L; Mills, GB; Wolff, RA; Hamilton, S; Meric-Bernstam, F; Abbruzzese, J; Morris, J; Maru, D; Kopetz, S
MLA Citation
Overman, MJ, Morris, V, Kee, B, Fogelman, D, Xiao, L, Eng, C, Dasari, A, Shroff, R, Mazard, T, Shaw, K, Vilar, E, Raghav, K, Shureiqi, I, Liang, L, Mills, GB, Wolff, RA, Hamilton, S, Meric-Bernstam, F, Abbruzzese, J, Morris, J, Maru, D, and Kopetz, S. "Utility of a molecular prescreening program in advanced colorectal cancer for enrollment on biomarker-selected clinical trials." Annals of oncology : official journal of the European Society for Medical Oncology 27.6 (June 2016): 1068-1074.
Website
http://hdl.handle.net/10161/11946
PMID
27045102
Source
epmc
Published In
Annals of Oncology
Volume
27
Issue
6
Publish Date
2016
Start Page
1068
End Page
1074
DOI
10.1093/annonc/mdw073

The effects of curcumin (diferuloylmethane) on body composition of patients with advanced pancreatic cancer.

Curcumin is a natural product that is often explored by patients with cancer. Weight loss due to fat and muscle depletion is a hallmark of pancreatic cancer and is associated with worse outcomes. Studies of curcumin's effects on muscularity show conflicting results in animal models.Retrospective matched 1:2 case-control study to evaluate the effects of curcumin on body composition (determined by computerized tomography) of 66 patients with advanced pancreatic cancer (22 treated,44 controls). Average age (SEM) was 63(1.8) years, 30/66(45%) women, median number of prior therapies was 2, median (IQR) time from advanced pancreatic cancer diagnosis to baseline image was 7(2-13.5) months (p>0.2, all variables). All patients lost weight (3.3% and 1.3%, treated vs. control, p=0.13). Treated patients lost more muscle (median [IQR] percent change -4.8[-9.1,-0.1] vs. -0.05%[-4.2, 2.6] in controls,p<0.001) and fat (median [IQR] percent change -6.8%[-15,-0.6] vs. -4.0%[-7.6, 1.3] in controls,p=0.04). Subcutaneous fat was more affected in the treated patients. Sarcopenic patients treated with curcumin(n=15) had survival of 169(115-223) days vs. 299(229-369) sarcopenic controls(p=0.024). No survival difference was found amongst non-sarcopenic patients.Patients with advanced pancreatic cancer treated with curcumin showed significantly greater loss of subcutaneous fat and muscle than matched untreated controls.

Authors
Parsons, HA; Baracos, VE; Hong, DS; Abbruzzese, J; Bruera, E; Kurzrock, R
MLA Citation
Parsons, HA, Baracos, VE, Hong, DS, Abbruzzese, J, Bruera, E, and Kurzrock, R. "The effects of curcumin (diferuloylmethane) on body composition of patients with advanced pancreatic cancer." Oncotarget 7.15 (April 2016): 20293-20304.
Website
http://hdl.handle.net/10161/11945
PMID
26934122
Source
epmc
Published In
Oncotarget
Volume
7
Issue
15
Publish Date
2016
Start Page
20293
End Page
20304
DOI
10.18632/oncotarget.7773

RECQ1 A159C Polymorphism Is Associated With Overall Survival of Patients With Resected Pancreatic Cancer: A Replication Study in NRG Oncology Radiation Therapy Oncology Group 9704.

To confirm whether a previously observed association between RECQ1 A159C variant and clinical outcome of resectable pancreatic cancer patients treated with preoperative chemoradiation is reproducible in another patient population prospectively treated with postoperative chemoradiation.Patients were selected, according to tissue availability, from eligible patients with resected pancreatic cancer who were enrolled on the NRG Oncology Radiation Therapy Oncology Group 9704 trial of 5-fluorouacil (5-FU)-based chemoradiation preceded and followed by 5-FU or gemcitabine. Deoxyribonucleic acid was extracted from paraffin-embedded tissue sections, and genotype was determined using the Taqman method. The correlation between genotype and overall survival was analyzed using a Kaplan-Meier plot, log-rank test, and multivariate Cox proportional hazards models.In the 154 of the study's 451 eligible patients with evaluable tissue, genotype distribution followed Hardy-Weinberg equilibrium (ie, 37% had genotype AA, 43% AC, and 20% CC). The RECQ1 variant AC/CC genotype carriers were associated with being node positive compared with the AA carrier (P=.03). The median survival times (95% confidence interval [CI]) for AA, AC, and CC carriers were 20.6 (16.3-26.1), 18.8 (14.2-21.6), and 14.2 (10.3-21.0) months, respectively. On multivariate analysis, patients with the AC/CC genotypes were associated with worse survival than patients with the AA genotype (hazard ratio [HR] 1.54, 95% CI 1.07-2.23, P=.022). This result seemed slightly stronger for patients on the 5-FU arm (n=82) (HR 1.64, 95% CI 0.99-2.70, P=.055) than for patients on the gemcitabine arm (n=72, HR 1.46, 95% CI 0.81-2.63, P=.21).Results of this study suggest that the RECQ1 A159C genotype may be a prognostic or predictive factor for resectable pancreatic cancer patients who are treated with adjuvant 5-FU before and after 5-FU-based chemoradiation. Further study is needed in patients treated with gemcitabine to determine whether an association exists.

Authors
Li, D; Moughan, J; Crane, C; Hoffman, JP; Regine, WF; Abrams, RA; Safran, H; Liu, C; Chang, P; Freedman, GM; Winter, KA; Guha, C; Abbruzzese, JL
MLA Citation
Li, D, Moughan, J, Crane, C, Hoffman, JP, Regine, WF, Abrams, RA, Safran, H, Liu, C, Chang, P, Freedman, GM, Winter, KA, Guha, C, and Abbruzzese, JL. "RECQ1 A159C Polymorphism Is Associated With Overall Survival of Patients With Resected Pancreatic Cancer: A Replication Study in NRG Oncology Radiation Therapy Oncology Group 9704." International journal of radiation oncology, biology, physics 94.3 (March 2016): 554-560.
PMID
26725729
Source
epmc
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
94
Issue
3
Publish Date
2016
Start Page
554
End Page
560
DOI
10.1016/j.ijrobp.2015.10.062

Clinical Insights Into the Biology and Treatment of Pancreatic Cancer.

Pancreatic cancer is a devastating disease with a universally poor prognosis. In 2015, it is estimated that there will be 48,960 new cases of pancreatic cancer and that 40,560 people will die of the disease. The 5-year survival rate is 7.2% for all patients with pancreatic cancer; however, survival depends greatly on the stage at diagnosis. Unfortunately, 53% of patients already have metastatic disease at diagnosis, which corresponds to a 5-year survival rate of 2.4%. Even for the 9% of patients with localized disease confined to the pancreas, the 5-year survival is still modest at only 27.1%. These grim statistics highlight the need for ways to identify cohorts of individuals at highest risk, methods to screen those at highest risk to identify preinvasive pathologic precursors, and development of effective systemic therapies. Recent clinical and translational progress has emphasized the relationship with diabetes, the role of the stroma, and the interplay of each of these with inflammation in the pathobiology of pancreatic cancer. In this article, we will discuss these relationships and how they might translate into novel management strategies for the treatment of this disease.

Authors
Mettu, NB; Abbruzzese, JL
MLA Citation
Mettu, NB, and Abbruzzese, JL. "Clinical Insights Into the Biology and Treatment of Pancreatic Cancer." Journal of oncology practice 12.1 (January 2016): 17-23. (Review)
Website
http://hdl.handle.net/10161/11572
PMID
26759461
Source
epmc
Published In
Journal of Oncology Practice
Volume
12
Issue
1
Publish Date
2016
Start Page
17
End Page
23
DOI
10.1200/jop.2015.009092

From Protocols to Publications: A Study in Selective Reporting of Outcomes in Randomized Trials in Oncology.

The decision by journals to append protocols to published reports of randomized trials was a landmark event in clinical trial reporting. However, limited information is available on how this initiative effected transparency and selective reporting of clinical trial data.We analyzed 74 oncology-based randomized trials published in Journal of Clinical Oncology, the New England Journal of Medicine, and The Lancet in 2012. To ascertain integrity of reporting, we compared published reports with their respective appended protocols with regard to primary end points, nonprimary end points, unplanned end points, and unplanned analyses.A total of 86 primary end points were reported in 74 randomized trials; nine trials had greater than one primary end point. Nine trials (12.2%) had some discrepancy between their planned and published primary end points. A total of 579 nonprimary end points (median, seven per trial) were planned, of which 373 (64.4%; median, five per trial) were reported. A significant positive correlation was found between the number of planned and nonreported nonprimary end points (Spearman r = 0.66; P < .001). Twenty-eight studies (37.8%) reported a total of 65 unplanned end points; 52 (80.0%) of which were not identified as unplanned. Thirty-one (41.9%) and 19 (25.7%) of 74 trials reported a total of 52 unplanned analyses involving primary end points and 33 unplanned analyses involving nonprimary end points, respectively. Studies reported positive unplanned end points and unplanned analyses more frequently than negative outcomes in abstracts (unplanned end points odds ratio, 6.8; P = .002; unplanned analyses odd ratio, 8.4; P = .007).Despite public and reviewer access to protocols, selective outcome reporting persists and is a major concern in the reporting of randomized clinical trials. To foster credible evidence-based medicine, additional initiatives are needed to minimize selective reporting.

Authors
Raghav, KPS; Mahajan, S; Yao, JC; Hobbs, BP; Berry, DA; Pentz, RD; Tam, A; Hong, WK; Ellis, LM; Abbruzzese, J; Overman, MJ
MLA Citation
Raghav, KPS, Mahajan, S, Yao, JC, Hobbs, BP, Berry, DA, Pentz, RD, Tam, A, Hong, WK, Ellis, LM, Abbruzzese, J, and Overman, MJ. "From Protocols to Publications: A Study in Selective Reporting of Outcomes in Randomized Trials in Oncology." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 33.31 (November 2015): 3583-3590. (Review)
PMID
26304898
Source
epmc
Published In
Journal of Clinical Oncology
Volume
33
Issue
31
Publish Date
2015
Start Page
3583
End Page
3590
DOI
10.1200/jco.2015.62.4148

FGF21 Delays Pancreatic Cancer Formation and Prevents Liver Metastasis in Oncogenic Kras Expressing Mice Fed on High-Fat Diet

Authors
Lu, W; Yang, Y; Luo, Y; Liu, Y; Wang, X; Liu, M; Wolff, RA; Abbruzzese, JL; Logsdon, CD
MLA Citation
Lu, W, Yang, Y, Luo, Y, Liu, Y, Wang, X, Liu, M, Wolff, RA, Abbruzzese, JL, and Logsdon, CD. "FGF21 Delays Pancreatic Cancer Formation and Prevents Liver Metastasis in Oncogenic Kras Expressing Mice Fed on High-Fat Diet." PANCREAS 44.8 (November 2015): 1393-1393.
Source
wos-lite
Published In
Pancreas
Volume
44
Issue
8
Publish Date
2015
Start Page
1393
End Page
1393

ABO non-O type as a risk factor for thrombosis in patients with pancreatic cancer.

ABO blood type has previously been identified as a risk factor for thrombosis and pancreatic cancer (PC). The aim of the study is to demonstrate the associations between ABO blood type and other clinical factors with the risk of thromboembolism (TE) in patients with PC. We conducted a retrospective study in 670 patients with pathologically confirmed pancreatic adenocarcinoma at the University of Texas MD Anderson Cancer Center. Clinical information was retrieved from medical records. ABO blood type was determined serologically and/or genetically. Logistic regression models, Kaplan-Meier plot, log-rank test, and Cox proportional hazard regression models were employed in data analysis. The incidence of TE was 35.2% in 670 patients who did not have TE prior to cancer diagnosis. Pulmonary embolism (PE) and deep vein thrombosis (DVT) consisted 44.1% of the TE events. Non-O blood type, pancreatic body/tail tumors, previous use of antithrombotic medication, and obesity (body mass index >30 kg/m(2) ) were significant predictors for TE in general. Blood type A and AB, low hemoglobin level (≤ 10 g/dL), obesity, metastatic tumor, and pancreatic body/tail tumors were significant predictors for PE and DVT. Patients with metastatic tumor or pancreatic body/tail tumors had a much higher frequency of early TE events (≤ 3 months after cancer diagnosis); and early TE occurrence was a significant independent predictor for increased risk of death. These observations suggest that ABO non-O blood type is an independent predictor for TE in PC. A better understanding of the risk factors for TE in PC may help to identify patients who are most likely to benefit from prophylactic anticoagulation therapy.

Authors
Li, D; Pise, MN; Overman, MJ; Liu, C; Tang, H; Vadhan-Raj, S; Abbruzzese, JL
MLA Citation
Li, D, Pise, MN, Overman, MJ, Liu, C, Tang, H, Vadhan-Raj, S, and Abbruzzese, JL. "ABO non-O type as a risk factor for thrombosis in patients with pancreatic cancer." Cancer medicine 4.11 (November 2015): 1651-1658.
PMID
26275671
Source
epmc
Published In
Cancer Medicine
Volume
4
Issue
11
Publish Date
2015
Start Page
1651
End Page
1658
DOI
10.1002/cam4.513

Family history as a marker of platinum sensitivity in pancreatic adenocarcinoma.

Metastatic pancreatic adenocarcinoma is considered a uniformly fatal disease with a median survival of 1 year with modern chemotherapy. While a subset of patients achieve prolonged survival, few of the factors that define this group of patients are known.For the determination of overall survival (OS), 549 patients with histologically confirmed metastatic pancreatic adenocarcinoma were evaluated. Emphasis was placed on treatment history and family history of breast, ovarian, and pancreatic cancers. To ensure a uniform metastatic population, patients treated with prior locoregional therapies (i.e., surgery or radiotherapy) were excluded as were patients with a prior history of stage I-III disease.Patients with family history or pedigree history of cancer had superior OS. This was especially true in patients with three or more relatives with either breast, ovarian, or pancreatic cancers [hazard ratio (HR) 0.49, 95 % confidence interval (CI) 0.30-0.80, p = 0.003]. First-line platinum chemotherapy was associated with a poor survival (hazard ratio for death 1.74, 95% CI 1.12-2.71, p = 0.01) for patients without a family history of these cancers but not for those without such a history (p = 0.31). In fact, as the number of relatives with these cancers increased, the OS survival improved for individuals receiving first-line platinum therapy (HR 0.76, 95 % CI 0.65-0.89, p = 0.0004), which was not the case for those receiving other therapies (p = 0.98).Treatment with platinum chemotherapy in patients with a family history of breast, ovarian, or pancreatic cancers was associated with a longer survival, whereas platinum use in patients without such a family history of cancer was associated with poor survival. These findings suggest that family history may serve as a predictive marker for platinum use in patients with metastatic pancreatic adenocarcinoma.

Authors
Fogelman, D; Sugar, EA; Oliver, G; Shah, N; Klein, A; Alewine, C; Wang, H; Javle, M; Shroff, R; Wolff, RA; Abbruzzese, JL; Laheru, D; Diaz, LA
MLA Citation
Fogelman, D, Sugar, EA, Oliver, G, Shah, N, Klein, A, Alewine, C, Wang, H, Javle, M, Shroff, R, Wolff, RA, Abbruzzese, JL, Laheru, D, and Diaz, LA. "Family history as a marker of platinum sensitivity in pancreatic adenocarcinoma." Cancer chemotherapy and pharmacology 76.3 (September 2015): 489-498.
PMID
26126726
Source
epmc
Published In
Cancer Chemotherapy and Pharmacology
Volume
76
Issue
3
Publish Date
2015
Start Page
489
End Page
498
DOI
10.1007/s00280-015-2788-6

Abstract 891: FGF21 prevents high fat diet-induced pancreatic cancer in mice expressing oncogenic Kras

Authors
Lu, W; Yang, Y; Wang, X; Liu, Y; Luo, Y; Wolff, RA; Abbruzzese, JL; Logsdon, CD
MLA Citation
Lu, W, Yang, Y, Wang, X, Liu, Y, Luo, Y, Wolff, RA, Abbruzzese, JL, and Logsdon, CD. "Abstract 891: FGF21 prevents high fat diet-induced pancreatic cancer in mice expressing oncogenic Kras." August 1, 2015.
Source
crossref
Published In
Cancer Research
Volume
75
Issue
15 Supplement
Publish Date
2015
Start Page
891
End Page
891
DOI
10.1158/1538-7445.AM2015-891

Phase II study of saracatinib (AZD0530) in patients with previously treated metastatic colorectal cancer.

Src has a critical role in tumor cell migration and invasion. Increased Src activity has been shown to correlate with disease progression and poor prognosis, suggesting Src could serve as a therapeutic target for kinase inhibition. Saracatinib (AZD0530) is a novel selective oral Src kinase inhibitor.Metastatic colorectal cancer patients who had received one prior treatment and had measurable disease were enrolled in this phase 2 study. Saracatinib was administered at 175 mg by mouth daily for 28 day cycles until dose-limiting toxicity or progression as determined by staging every 2 cycles. The primary endpoint was improvement in 4 month progression-free survival. Design of Thall, Simon, and Estey was used to monitor proportion of patients that were progression free at 4 months. The trial was opened with plan to enroll maximum of 35 patients, with futility assessment every 10 patients.A total of 10 patients were enrolled between January and November 2007. Further enrollment was stopped due to futility. Median progression-free survival was 7.9 weeks, with all 10 patients showing disease progression following radiographic imaging. Median overall survival was 13.5 months. All patients were deceased by time of analysis. Observed adverse events were notable for a higher than expected number of patients with grade 3 hypophosphatemia (n = 5).Saracatinib is a novel oral Src kinase inhibitor that was well tolerated but failed to meet its primary endpoint of improvement in 4 month progression-free survival as a single agent in previously treated metastatic colorectal cancer patients.

Authors
Reddy, SM; Kopetz, S; Morris, J; Parikh, N; Qiao, W; Overman, MJ; Fogelman, D; Shureiqi, I; Jacobs, C; Malik, Z; Jimenez, CA; Wolff, RA; Abbruzzese, JL; Gallick, G; Eng, C
MLA Citation
Reddy, SM, Kopetz, S, Morris, J, Parikh, N, Qiao, W, Overman, MJ, Fogelman, D, Shureiqi, I, Jacobs, C, Malik, Z, Jimenez, CA, Wolff, RA, Abbruzzese, JL, Gallick, G, and Eng, C. "Phase II study of saracatinib (AZD0530) in patients with previously treated metastatic colorectal cancer." Investigational new drugs 33.4 (August 2015): 977-984.
PMID
26062928
Source
epmc
Published In
Investigational New Drugs
Volume
33
Issue
4
Publish Date
2015
Start Page
977
End Page
984
DOI
10.1007/s10637-015-0257-z

Cyclopamine-loaded core-cross-linked polymeric micelles enhance radiation response in pancreatic cancer and pancreatic stellate cells.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. Cyclopamine (CPA), a potent inhibitor for sonic hedgehog pathway (SHH), shows great promises in PDAC treatment, including the disruption of tumor-associated stroma, and enhancement of radiation therapy. However, CPA is insoluble in water and therefore requires a nanometric delivery platform to achieve satisfactory performance. We herein encapsulated CPA in a core-cross-linked polymeric micelle system (M-CPA). M-CPA was combined with Cs-137 radiation and evaluated in vitro in PDAC cell lines and a human pancreatic stellate cell line. The results showed that M-CPA had higher cytotoxicity than CPA, abolished Gli-1 expression (a key component of SHH), and enhanced the radiation therapy of Cs-137. M-CPA radiosensitization correlated with its ability to disrupt the repair of radiation-induced DNA damage. These findings indicate that the combination therapy of M-CPA and radiation is an effective strategy to simultaneously treat pancreatic tumors and tumor-associated stroma.

Authors
Zhao, J; Wu, C; Abbruzzese, J; Hwang, RF; Li, C
MLA Citation
Zhao, J, Wu, C, Abbruzzese, J, Hwang, RF, and Li, C. "Cyclopamine-loaded core-cross-linked polymeric micelles enhance radiation response in pancreatic cancer and pancreatic stellate cells." Molecular pharmaceutics 12.6 (June 2015): 2093-2100.
PMID
25936695
Source
epmc
Published In
Molecular Pharmaceutics
Volume
12
Issue
6
Publish Date
2015
Start Page
2093
End Page
2100
DOI
10.1021/mp500875f

Evaluation of a novel c-MET based circulating tumor cell (CTC) biomarker in patients with gastrointestinal (GI) and genitourinary (GU) malignancies.

Authors
Zhang, T; Boominathan, R; Foulk, B; Connelly, MC; Rao, C; Kemeny, G; Strickler, JH; Abbruzzese, JL; Harrison, MR; George, DJ; Hurwitz, H; Garcia-Blanco, MA; Armstrong, AJ
MLA Citation
Zhang, T, Boominathan, R, Foulk, B, Connelly, MC, Rao, C, Kemeny, G, Strickler, JH, Abbruzzese, JL, Harrison, MR, George, DJ, Hurwitz, H, Garcia-Blanco, MA, and Armstrong, AJ. "Evaluation of a novel c-MET based circulating tumor cell (CTC) biomarker in patients with gastrointestinal (GI) and genitourinary (GU) malignancies." May 20, 2015.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
33
Issue
15
Publish Date
2015

Impacts of new-onset and long-term diabetes on clinical outcome of pancreatic cancer

Patients with pancreatic cancer have a high frequency of concurrent diabetes. This study is aimed to demonstrate the impact of diabetes on clinical outcome of pancreatic cancer. Clinical and epidemiological information was collected from medical records or by personal interview in 1328 patients with pancreatic ductal adenocarcinoma. Diabetes was defined by a known medical history, or abnormal fasting blood glucose (FBG) and HbA1c levels within three months of the cancer diagnosis. Duration of ≤3 years was used as the cutoff to arbitrarily define the new-onset and long-term diabetes. Logistic regression, Kaplan-Meier plot, log-rank test and Cox regression models were employed in the data analysis. Elevated level of FBG or HbA1c was observed in 24.7% and 11.5% of the patients without a known diabetes history, respectively. The prevalence of DM was 44.4% and was comparable by strata of tumor stage. New-onset diabetes was a significant independent predictor for risk of death in metastatic patients (HR=1.35, 95% CI=1.11-1.63, P=0.002) and in all patients (HR=1.23, 95% CI=1.09-1.40, P=0.001). Both new-onset and long term diabetes were significantly associated with older age, obesity, hypertension and coronary artery disease as well as weight loss. New-onset diabetes was also significantly related to larger tumors and elevated level of CA19-9 but not to tumor site and presence of biliary obstruction. Diabetes in general and new-onset diabetes in particular, is associated with poor outcome of pancreatic cancer. New-onset and long-term diabetes share common risk factors for type 2 diabetes.

Authors
Li, D; Mao, Y; Chang, P; Liu, C; Hassan, MM; Yeung, SJ; Abbruzzese, JL
MLA Citation
Li, D, Mao, Y, Chang, P, Liu, C, Hassan, MM, Yeung, SJ, and Abbruzzese, JL. "Impacts of new-onset and long-term diabetes on clinical outcome of pancreatic cancer." American Journal of Cancer Research 5.10 (January 1, 2015): 3260-3269.
Source
scopus
Published In
American Journal of Cancer Research
Volume
5
Issue
10
Publish Date
2015
Start Page
3260
End Page
3269

Intra-tumoral heterogeneity of gemcitabine delivery and mass transport in human pancreatic cancer.

There is substantial heterogeneity in the clinical behavior of pancreatic cancer and in its response to therapy. Some of this variation may be due to differences in delivery of cytotoxic therapies between patients and within individual tumors. Indeed, in 12 patients with resectable pancreatic cancer, we previously demonstrated wide inter-patient variability in the delivery of gemcitabine as well as in the mass transport properties of tumors as measured by computed tomography (CT) scans. However, the variability of drug delivery and transport properties within pancreatic tumors is currently unknown. Here, we analyzed regional measurements of gemcitabine DNA incorporation in the tumors of the same 12 patients to understand the degree of intra-tumoral heterogeneity of drug delivery. We also developed a volumetric segmentation approach to measure mass transport properties from the CT scans of these patients and tested inter-observer agreement with this new methodology. Our results demonstrate significant heterogeneity of gemcitabine delivery within individual pancreatic tumors and across the patient cohort, with gemcitabine DNA incorporation in the inner portion of the tumors ranging from 38 to 74% of the total. Similarly, the CT-derived mass transport properties of the tumors had a high degree of heterogeneity, ranging from minimal difference to almost 200% difference between inner and outer portions of the tumor. Our quantitative method to derive transport properties from CT scans demonstrated less than 5% difference in gemcitabine prediction at the average CT-derived transport value across observers. These data illustrate significant inter-patient and intra-tumoral heterogeneity in the delivery of gemcitabine, and highlight how this variability can be reproducibly accounted for using principles of mass transport. With further validation as a biophysical marker, transport properties of tumors may be useful in patient selection for therapy and prediction of therapeutic outcome.

Authors
Koay, EJ; Baio, FE; Ondari, A; Truty, MJ; Cristini, V; Thomas, RM; Chen, R; Chatterjee, D; Kang, Y; Zhang, J; Court, L; Bhosale, PR; Tamm, EP; Qayyum, A; Crane, CH; Javle, M; Katz, MH; Gottumukkala, VN; Rozner, MA; Shen, H; Lee, JE; Wang, H; Chen, Y; Plunkett, W; Abbruzzese, JL; Wolff, RA; Maitra, A; Ferrari, M; Varadhachary, GR; Fleming, JB
MLA Citation
Koay, EJ, Baio, FE, Ondari, A, Truty, MJ, Cristini, V, Thomas, RM, Chen, R, Chatterjee, D, Kang, Y, Zhang, J, Court, L, Bhosale, PR, Tamm, EP, Qayyum, A, Crane, CH, Javle, M, Katz, MH, Gottumukkala, VN, Rozner, MA, Shen, H, Lee, JE, Wang, H, Chen, Y, Plunkett, W, Abbruzzese, JL, Wolff, RA, Maitra, A, Ferrari, M, Varadhachary, GR, and Fleming, JB. "Intra-tumoral heterogeneity of gemcitabine delivery and mass transport in human pancreatic cancer." Physical biology 11.6 (November 26, 2014): 065002-.
PMID
25427073
Source
epmc
Published In
Physical Biology
Volume
11
Issue
6
Publish Date
2014
Start Page
065002
DOI
10.1088/1478-3975/11/6/065002

Hepatobiliary/Pancreas Pathology: SY11-3 PANCREATIC DUCTAL ADENOCARCINOMA: NEOADJUVANT THERAPIES AND PATHOLOGY.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies with less than 5% five-year survival rate. Despite significant improvements in medical and surgical oncology and postoperative mortality rate, the overall survival for patients with pancreatic cancer has not changed significantly in the last four decades. Neoadjuvant chemoradiation therapy (NCT) is increasingly used to treat patients with potentially resectable PDAC, especially for patients with borderline resectable disease. However, analysis of prognostic factors is limited for patients with PDAC treated with NCT and pancreaticoduodenectomy. We systemically examined the pancreaticoduodenectomy specimens from 240 consecutive patients with PDAC who received NCT and pancreaticoduodenectomy between 1999 and 2007 at our institution. We found that posttreatment pathologic stage, pathologic tumor response grading, tumor involvement of the superior mesenteric/portal vein, tumor invasion into the muscular vessels, and perineural invasion are significant prognostic factors in our patient population. Therefore careful pathologic evaluation of the pancreatectomy specimens plays a key role in predicting prognosis of patients with PDAC who received NCT and pancreaticoduodenectomy.

Authors
Wang, H; Estrella, JS; Chatterjee, D; Katz, MH; Rashid, A; Wang, H; Wolff, RA; Varadhachary, GR; Lee, JE; Pisters, PW; Abbruzzese, JL; Fleming, JB
MLA Citation
Wang, H, Estrella, JS, Chatterjee, D, Katz, MH, Rashid, A, Wang, H, Wolff, RA, Varadhachary, GR, Lee, JE, Pisters, PW, Abbruzzese, JL, and Fleming, JB. "Hepatobiliary/Pancreas Pathology: SY11-3 PANCREATIC DUCTAL ADENOCARCINOMA: NEOADJUVANT THERAPIES AND PATHOLOGY." Pathology 46 Suppl 2 (October 2014): S25-.
PMID
25188109
Source
epmc
Published In
Pathology
Volume
46 Suppl 2
Publish Date
2014
Start Page
S25
DOI
10.1097/01.pat.0000454135.19954.47

New option for the initial management of metastatic pancreatic cancer?

Authors
Abbruzzese, JL; Hess, KR
MLA Citation
Abbruzzese, JL, and Hess, KR. "New option for the initial management of metastatic pancreatic cancer?." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 32.23 (August 2014): 2405-2407.
PMID
24982449
Source
epmc
Published In
Journal of Clinical Oncology
Volume
32
Issue
23
Publish Date
2014
Start Page
2405
End Page
2407
DOI
10.1200/jco.2013.54.4155

Development and validation of insulin-like growth factor-1 score to assess hepatic reserve in hepatocellular carcinoma.

Child-Turcotte-Pugh (CTP) score is the standard tool to assess hepatic reserve in hepatocellular carcinoma (HCC), and CTP-A is the classic group for active therapy. However, CTP stratification accuracy has been questioned. We hypothesized that plasma insulin-like growth factor 1 (IGF-1) is a valid surrogate for hepatic reserve to replace the subjective parameters in CTP score to improve its prognostic accuracy.We retrospectively tested plasma IGF-1 levels in the training set (n = 310) from MD Anderson Cancer Center. Recursive partitioning identified three optimal IGF-1 ranges that correlated with overall survival (OS): greater than 50 ng/mL = 1 point; 26 to 50 ng/mL = 2 points; and less than 26 ng/mL = 3 points. We modified the CTP score by replacing ascites and encephalopathy grading with plasma IGF-1 value (IGF-CTP) and subjected both scores to log-rank analysis. Harrell's C-index and U-statistics were used to compare the prognostic performance of both scores in both the training and validation cohorts (n = 155). All statistical tests were two-sided.Patients' stratification was statistically significantly stronger for IGF-CTP than CTP score for the training (P = .003) and the validation cohort (P = .005). Patients reclassified by IGF-CTP relative to their original CTP score were better stratified by their new risk groups. Most important, patients classified as A by CTP but B by IGF-CTP had statistically significantly worse OS than those who remained under class A by IGF-CTP in both cohorts (P = .03 and P < .001, respectively, from Cox regression models). AB patients had a worse OS than AA patients in both the training and validation set (hazard ratio [HR] = 1.45, 95% confidence interval [CI] = 1.03 to 2.04, P = .03; HR = 2.83, 95% CI = 1.65 to 4.85, P < .001, respectively).The IGF-CTP score is simple, blood-based, and cost-effective, stratified HCC better than CTP score, and validated well on two independent cohorts. International validation studies are warranted.

Authors
Kaseb, AO; Xiao, L; Hassan, MM; Chae, YK; Lee, J-S; Vauthey, J-N; Krishnan, S; Cheung, S; Hassabo, HM; Aloia, T; Conrad, C; Curley, SA; Vierling, JM; Jalal, P; Raghav, K; Wallace, M; Rashid, A; Abbruzzese, JL; Wolff, RA; Morris, JS
MLA Citation
Kaseb, AO, Xiao, L, Hassan, MM, Chae, YK, Lee, J-S, Vauthey, J-N, Krishnan, S, Cheung, S, Hassabo, HM, Aloia, T, Conrad, C, Curley, SA, Vierling, JM, Jalal, P, Raghav, K, Wallace, M, Rashid, A, Abbruzzese, JL, Wolff, RA, and Morris, JS. "Development and validation of insulin-like growth factor-1 score to assess hepatic reserve in hepatocellular carcinoma." Journal of the National Cancer Institute 106.5 (May 9, 2014).
PMID
24815863
Source
epmc
Published In
Journal of the National Cancer Institute
Volume
106
Issue
5
Publish Date
2014
DOI
10.1093/jnci/dju088

Aberrant expression of p53, p21, cyclin D1, and Bcl2 and their clinicopathological correlation in ampullary adenocarcinoma.

Previous studies on the molecular alterations in ampullary adenocarcinoma (AA) are limited, and little is known about their clinical implications. The objective of this study is to examine the expression of p53, p21, cyclin D1, and Bcl2 and their clinical significance in patients with AA. Tissue microarrays were constructed using archival tissue from 92 patients with AA who underwent pancreaticoduodenectomy at our institution. Each tumor was sampled in triplicate with a 1.0-mm punch from representative areas. The expression of p53, p21, cyclin D1, and Bcl2 was evaluated by immunohistochemistry, and the staining results were correlated with clinicopathological features and survival. Among 92 cases studied, overexpression of p53, p21, cyclin D1, and Bcl2 was observed in 58.7%, 39.2%, 71.7%, and 5.4% of tumors, respectively. Patients whose tumor showed high level of cyclin D1 expression had higher risk of disease recurrence (P = .02) and worse recurrence-free and overall survivals after pancreaticoduodenectomy than did those with no or low cyclin D1 expression (P = .027 and P = .02, respectively). In multivariate analysis, cyclin D1 expression was an independent prognostic factor for both recurrence-free and overall survival (P < .05). However, there was no significant correlation between p53, p21, or Bcl2 expression and survival (P > .05). Our study showed that p53, p21, and cyclin D1, but not Bcl2, are frequently overexpressed in AAs. Cyclin D1 overexpression is associated with increased risk of disease recurrence and worse survival in patients with AA after resection.

Authors
Guo, R; Overman, M; Chatterjee, D; Rashid, A; Shroff, S; Wang, H; Katz, MH; Fleming, JB; Varadhachary, GR; Abbruzzese, JL; Wang, H
MLA Citation
Guo, R, Overman, M, Chatterjee, D, Rashid, A, Shroff, S, Wang, H, Katz, MH, Fleming, JB, Varadhachary, GR, Abbruzzese, JL, and Wang, H. "Aberrant expression of p53, p21, cyclin D1, and Bcl2 and their clinicopathological correlation in ampullary adenocarcinoma." Human pathology 45.5 (May 2014): 1015-1023.
PMID
24746206
Source
epmc
Published In
Human Pathology
Volume
45
Issue
5
Publish Date
2014
Start Page
1015
End Page
1023
DOI
10.1016/j.humpath.2013.12.016

Transport properties of pancreatic cancer describe gemcitabine delivery and response.

The therapeutic resistance of pancreatic ductal adenocarcinoma (PDAC) is partly ascribed to ineffective delivery of chemotherapy to cancer cells. We hypothesized that physical properties at vascular, extracellular, and cellular scales influence delivery of and response to gemcitabine-based therapy.We developed a method to measure mass transport properties during routine contrast-enhanced CT scans of individual human PDAC tumors. Additionally, we evaluated gemcitabine infusion during PDAC resection in 12 patients, measuring gemcitabine incorporation into tumor DNA and correlating its uptake with human equilibrative nucleoside transporter (hENT1) levels, stromal reaction, and CT-derived mass transport properties. We also studied associations between CT-derived transport properties and clinical outcomes in patients who received preoperative gemcitabine-based chemoradiotherapy for resectable PDAC.Transport modeling of 176 CT scans illustrated striking differences in transport properties between normal pancreas and tumor, with a wide array of enhancement profiles. Reflecting the interpatient differences in contrast enhancement, resected tumors exhibited dramatic differences in gemcitabine DNA incorporation, despite similar intravascular pharmacokinetics. Gemcitabine incorporation into tumor DNA was inversely related to CT-derived transport parameters and PDAC stromal score, after accounting for hENT1 levels. Moreover, stromal score directly correlated with CT-derived parameters. Among 110 patients who received preoperative gemcitabine-based chemoradiotherapy, CT-derived parameters correlated with pathological response and survival.Gemcitabine incorporation into tumor DNA is highly variable and correlates with multiscale transport properties that can be derived from routine CT scans. Furthermore, pretherapy CT-derived properties correlate with clinically relevant endpoints.Clinicaltrials.gov NCT01276613.Lustgarten Foundation (989161), Department of Defense (W81XWH-09-1-0212), NIH (U54CA151668, KCA088084).

Authors
Koay, EJ; Truty, MJ; Cristini, V; Thomas, RM; Chen, R; Chatterjee, D; Kang, Y; Bhosale, PR; Tamm, EP; Crane, CH; Javle, M; Katz, MH; Gottumukkala, VN; Rozner, MA; Shen, H; Lee, JE; Wang, H; Chen, Y; Plunkett, W; Abbruzzese, JL; Wolff, RA; Varadhachary, GR; Ferrari, M; Fleming, JB
MLA Citation
Koay, EJ, Truty, MJ, Cristini, V, Thomas, RM, Chen, R, Chatterjee, D, Kang, Y, Bhosale, PR, Tamm, EP, Crane, CH, Javle, M, Katz, MH, Gottumukkala, VN, Rozner, MA, Shen, H, Lee, JE, Wang, H, Chen, Y, Plunkett, W, Abbruzzese, JL, Wolff, RA, Varadhachary, GR, Ferrari, M, and Fleming, JB. "Transport properties of pancreatic cancer describe gemcitabine delivery and response." The Journal of clinical investigation 124.4 (April 2014): 1525-1536.
PMID
24614108
Source
epmc
Published In
Journal of Clinical Investigation
Volume
124
Issue
4
Publish Date
2014
Start Page
1525
End Page
1536
DOI
10.1172/jci73455

Molecular Pathogenesis of Pancreatic Adenocarcinoma

Authors
Shroff, RT; Abbruzzese, JL
MLA Citation
Shroff, RT, and Abbruzzese, JL. "Molecular Pathogenesis of Pancreatic Adenocarcinoma." The Molecular Basis of Cancer: Fourth Edition. March 1, 2014.
Source
scopus
Publish Date
2014
DOI
10.1016/B978-1-4557-4066-6.00035-4

SOX9: a useful marker for pancreatic ductal lineage of pancreatic neoplasms.

Previous studies showed that SOX9 plays a critical role in pancreatic ductal development. The aim of this study was to evaluate SOX9 as a marker for pancreatic ductal lineage. SOX9 expression was evaluated by immunohistochemistry in 146 benign pancreas (BP), 136 pancreatic ductal adenocarcinomas, 47 pancreatic intraepithelial neoplasia (PanIN), 21 intraductal papillary mucinous neoplasms (IPMNs), 14 mucinous cystic neoplasms, 10 serous cystadenomas, 39 pancreatic neuroendocrine tumors, 9 acinar cell carcinomas, and 23 solid pseudopapillary neoplasms. Nuclear expression of SOX9 was detected in the centroacinar cells and ductal cells, but not in acinar or endocrine cells in 100% BP. Focal or diffuse SOX9 expression was detected in 100% PanINs, 100% IPMNs, 100% mucinous cystic neoplasms, 100% serous cystadenomas, 89.0% pancreatic ductal adenocarcinomas, 2.6% pancreatic neuroendocrine tumors, 11.1% acinar cell carcinomas, and 0% solid pseudopapillary neoplasms. SOX9 expression was lower in PanIN2 and PanIN3 than in PanIN1 lesions (P < .01). Compared with BP, IPMN had lower SOX9 expression (P < .05). No correlation between SOX9 expression and other clinicopathologic parameters was identified. Our study showed that SOX9 is expressed in centroacinar and ductal epithelial cells of BP and is a useful marker for pancreatic ductal lineage of pancreatic neoplasms.

Authors
Shroff, S; Rashid, A; Wang, H; Katz, MH; Abbruzzese, JL; Fleming, JB; Wang, H
MLA Citation
Shroff, S, Rashid, A, Wang, H, Katz, MH, Abbruzzese, JL, Fleming, JB, and Wang, H. "SOX9: a useful marker for pancreatic ductal lineage of pancreatic neoplasms." Human pathology 45.3 (March 2014): 456-463.
PMID
24418153
Source
epmc
Published In
Human Pathology
Volume
45
Issue
3
Publish Date
2014
Start Page
456
End Page
463
DOI
10.1016/j.humpath.2013.10.008

Solid pseudopapillary neoplasm of the pancreas: clinicopathologic and survival analyses of 64 cases from a single institution.

Although solid pseudopapillary neoplasms (SPNs) are considered tumors of low malignant potential, patients may present with aggressive disease (ie, liver metastasis/invasion into adjacent organs) and, rarely, die from disease. Although the clinicopathologic features associated with aggressive SPNs have been reported, important prognostic factors of survival remain unclear. We systematically reviewed 64 cases of SPN resected at our institution for tumor size, extent of invasion, margin status, presence of lymphovascular, muscular vessel, and perineural invasion, and lymph node and distant metastases. Clinicopathologic characteristics were correlated with the presence of metastasis/recurrence and disease-specific survival. Five (8%) patients presented with stage IV disease. During follow-up, 5 (13%) of 39 patients with stage I-II disease had recurrences. Patients with metastatic/recurrent SPNs had significantly larger tumor size (P<0.001) and more frequent tumor invasion into muscular vessels (P=0.02). In a median follow-up of 76 months, only 2 died of disease (1 who presented with extensive peritoneal tumor involvement who died 2.5 mo after surgery, and 1 unusual case who presented with multiple liver metastasis and peritoneal seeding who died 19 mo after surgery), and 5 were alive with disease. The 10-year disease-specific survival rate was 96%. Muscular vessel invasion (P=0.001), tumor (T) stage by European Neuroendocrine Tumors Society (ENETS) classification (P<0.001), ENETS stage grouping (P<0.001), and stage grouping by the American Joint Committee on Cancer (AJCC stage, P<0.001) were important predictors of disease-specific survival in patients with SPN. Our study highlights the importance of pathologic evaluation in risk assessment in patients with SPNs.

Authors
Estrella, JS; Li, L; Rashid, A; Wang, H; Katz, MH; Fleming, JB; Abbruzzese, JL; Wang, H
MLA Citation
Estrella, JS, Li, L, Rashid, A, Wang, H, Katz, MH, Fleming, JB, Abbruzzese, JL, and Wang, H. "Solid pseudopapillary neoplasm of the pancreas: clinicopathologic and survival analyses of 64 cases from a single institution." The American journal of surgical pathology 38.2 (February 2014): 147-157.
PMID
24418850
Source
epmc
Published In
American Journal of Surgical Pathology
Volume
38
Issue
2
Publish Date
2014
Start Page
147
End Page
157
DOI
10.1097/pas.0000000000000141

The CUL7/F-box and WD repeat domain containing 8 (CUL7/Fbxw8) ubiquitin ligase promotes degradation of hematopoietic progenitor kinase 1.

HPK1, a member of mammalian Ste20-like serine/threonine kinases, is lost in >95% pancreatic cancer through proteasome-mediated degradation. However, the mechanism of HPK1 loss has not been defined. The aims of this study are to identify the ubiquitin ligase and to examine the mechanisms that targets HPK1 degradation. We found that the CUL7/Fbxw8 ubiquitin ligase targeted HPK1 for degradation via the 26 S proteasome. The ubiquitination of HPK1 required its kinase activity and autophosphorylation. Wild-type protein phosphatase 4 (PP4), but not the phosphatase-dead PP4 mutant, PP4-RL, inhibits the interaction of Fbxw8 with HPK1 and Fbxw8-mediated ubiquitination of HPK1. In addition, we showed that Thr-355 of HPK1 is a key PP4 dephosphorylation site, through which CUL7/Fbxw8 ubiquitin ligase and PP4 regulates HPK1 stability. Knockdown of Fbxw8 restores endogenous HPK1 protein expression and inhibits cell proliferation of pancreatic cancer cells. Our study demonstrated that targeted degradation of HPK1 by the CUL7/Fbxw8 ubiquitin ligase constitutes a negative-feedback loop to restrain the activity of HPK1 and that CUL7/Fbxw8 ubiquitin ligase promotes pancreatic cancer cell proliferation. CUL7/Fbxw8 ubiquitin ligase-mediated HPK1 degradation revealed a direct link and novel role of CUL7/Fbxw8 ubiquitin ligase in the MAPK pathway, which plays a critical role in cell proliferation and differentiation.

Authors
Wang, H; Chen, Y; Lin, P; Li, L; Zhou, G; Liu, G; Logsdon, C; Jin, J; Abbruzzese, JL; Tan, T-H; Wang, H
MLA Citation
Wang, H, Chen, Y, Lin, P, Li, L, Zhou, G, Liu, G, Logsdon, C, Jin, J, Abbruzzese, JL, Tan, T-H, and Wang, H. "The CUL7/F-box and WD repeat domain containing 8 (CUL7/Fbxw8) ubiquitin ligase promotes degradation of hematopoietic progenitor kinase 1." The Journal of biological chemistry 289.7 (February 2014): 4009-4017.
PMID
24362026
Source
epmc
Published In
The Journal of biological chemistry
Volume
289
Issue
7
Publish Date
2014
Start Page
4009
End Page
4017
DOI
10.1074/jbc.m113.520106

Solid Pseudopapillary Neoplasm of the Pancreas: Clinicopathologic and Survival Analyses of 64 Cases from a Single Institution

Authors
Estrella, J; Li, L; Rashid, A; Wang, H; Katz, MH; Fleming, JB; Abbruzzese, JL; Wang, H
MLA Citation
Estrella, J, Li, L, Rashid, A, Wang, H, Katz, MH, Fleming, JB, Abbruzzese, JL, and Wang, H. "Solid Pseudopapillary Neoplasm of the Pancreas: Clinicopathologic and Survival Analyses of 64 Cases from a Single Institution." February 2014.
Source
wos-lite
Published In
Modern Pathology
Volume
27
Publish Date
2014
Start Page
448A
End Page
449A

Reassessing hepatocellular carcinoma staging in a changing patient population.

Hepatocellular carcinoma (HCC) staging systems were developed using data predominantly from patients who had hepatitis and cirrhosis. Given the recent change in prevalence of viral hepatitis and cirrhosis at oncology centers, which has altered the natural history of HCC, we aimed at comparing the accuracy of HCC staging systems in patients with or without hepatitis and cirrhosis.A total of 438 patients were enrolled. Baseline clinicopathologic parameters, Barcelona Clinic Liver Cancer stage, Cancer of the Liver Italian Program score, TNM (6th edition) stage, Okuda stage, and Chinese University Prognostic Index score were prospectively obtained for all patients, and retrospectively analyzed. Kaplan-Meier analysis was used to determine overall survival (OS), Cox regression analyses were performed, and Harrell's Correspondence Index compared the staging systems' ability to predict OS duration. Subgroup analyses of patients with or without hepatitis or cirrhosis were performed.Median patient OS was 13.9 months; 165 patients (37.7%) had no cirrhosis and 256 patients (58.4%) had no hepatitis. Overall, all staging systems were significantly less predictive of OS in patients who did not have cirrhosis or hepatitis.Our results advocate the need to further stratify HCC based on cirrhosis and hepatitis status, which may change patient risk-stratification and, ultimately, treatment decisions.

Authors
Kaseb, AO; Shah, NN; Hassabo, HM; Morris, JS; Xiao, L; Abaza, YM; Soliman, K; Lee, J-S; Vauthey, J-N; Wallace, M; Aloia, TA; Curley, S; Abbruzzese, JL; Hassan, MM
MLA Citation
Kaseb, AO, Shah, NN, Hassabo, HM, Morris, JS, Xiao, L, Abaza, YM, Soliman, K, Lee, J-S, Vauthey, J-N, Wallace, M, Aloia, TA, Curley, S, Abbruzzese, JL, and Hassan, MM. "Reassessing hepatocellular carcinoma staging in a changing patient population." Oncology 86.2 (January 8, 2014): 63-71.
PMID
24401634
Source
epmc
Published In
Oncology
Volume
86
Issue
2
Publish Date
2014
Start Page
63
End Page
71
DOI
10.1159/000356573

Development and validation of insulin-like growth factor-1 score to assess hepatic reserve in hepatocellular carcinoma.

Child-Turcotte-Pugh (CTP) score is the standard tool to assess hepatic reserve in hepatocellular carcinoma (HCC), and CTP-A is the classic group for active therapy. However, CTP stratification accuracy has been questioned. We hypothesized that plasma insulin-like growth factor 1 (IGF-1) is a valid surrogate for hepatic reserve to replace the subjective parameters in CTP score to improve its prognostic accuracy. We retrospectively tested plasma IGF-1 levels in the training set (n = 310) from MD Anderson Cancer Center. Recursive partitioning identified three optimal IGF-1 ranges that correlated with overall survival (OS): greater than 50 ng/mL = 1 point; 26 to 50 ng/mL = 2 points; and less than 26 ng/mL = 3 points. We modified the CTP score by replacing ascites and encephalopathy grading with plasma IGF-1 value (IGF-CTP) and subjected both scores to log-rank analysis. Harrell's C-index and U-statistics were used to compare the prognostic performance of both scores in both the training and validation cohorts (n = 155). All statistical tests were two-sided. Patients' stratification was statistically significantly stronger for IGF-CTP than CTP score for the training (P = .003) and the validation cohort (P = .005). Patients reclassified by IGF-CTP relative to their original CTP score were better stratified by their new risk groups. Most important, patients classified as A by CTP but B by IGF-CTP had statistically significantly worse OS than those who remained under class A by IGF-CTP in both cohorts (P = .03 and P < .001, respectively, from Cox regression models). AB patients had a worse OS than AA patients in both the training and validation set (hazard ratio [HR] = 1.45, 95% confidence interval [CI] = 1.03 to 2.04, P = .03; HR = 2.83, 95% CI = 1.65 to 4.85, P < .001, respectively). The IGF-CTP score is simple, blood-based, and cost-effective, stratified HCC better than CTP score, and validated well on two independent cohorts. International validation studies are warranted. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Authors
Kaseb, AO; Xiao, L; Hassan, MM; Chae, YK; Lee, JS; Vauthey, JN; Krishnan, S; Cheung, S; Hassabo, HM; Aloia, T; Conrad, C; Curley, SA; Vierling, JM; Jalal, P; Raghav, K; Wallace, M; Rashid, A; Abbruzzese, JL; Wolff, RA; Morris, JS
MLA Citation
Kaseb, AO, Xiao, L, Hassan, MM, Chae, YK, Lee, JS, Vauthey, JN, Krishnan, S, Cheung, S, Hassabo, HM, Aloia, T, Conrad, C, Curley, SA, Vierling, JM, Jalal, P, Raghav, K, Wallace, M, Rashid, A, Abbruzzese, JL, Wolff, RA, and Morris, JS. "Development and validation of insulin-like growth factor-1 score to assess hepatic reserve in hepatocellular carcinoma." Journal of the National Cancer Institute 106.5 (January 1, 2014).
Source
scopus
Published In
Journal of the National Cancer Institute
Volume
106
Issue
5
Publish Date
2014

Evaluating physician performance in oncology: moneyball becomes impactball.

Authors
Fisch, MJ; Abbruzzese, JL; Hong, WK
MLA Citation
Fisch, MJ, Abbruzzese, JL, and Hong, WK. "Evaluating physician performance in oncology: moneyball becomes impactball." Journal of oncology practice 10.1 (January 2014): 79-81.
PMID
24443736
Source
epmc
Published In
Journal of Oncology Practice
Volume
10
Issue
1
Publish Date
2014
Start Page
79
End Page
81
DOI
10.1200/jop.2013.001218

Treatment sequencing for resectable pancreatic cancer: influence of early metastases and surgical complications on multimodality therapy completion and survival.

Barriers to multimodality therapy (MMT) completion among patients with resectable pancreatic adenocarcinoma include early cancer progression and postoperative major complications (PMC). We sought to evaluate the influence of these factors on MMT completion rates of patients treated with neoadjuvant therapy (NT) and surgery-first (SF) approaches. We evaluated all operable patients treated for clinically resectable pancreatic head adenocarcinoma at our institution from 2002 to 2007. Rates of MMT completion, 90-day PMC, and overall survival (OS) were evaluated. Ninety-five of 115 (83 %) NT and 29/50 (58 %) SF patients completed MMT. Patients who completed MMT lived longer than those who did not (36 vs. 11 months, p < 0.001). The most common reason that NT (11 %) and SF (26 %) patients failed to complete MMT was early disease progression. The rates of PMC among NT and SF patients were similar. Among SF patients, 69 % with no PMC completed MMT versus 29 % after PMC (p = 0.040). PMC were associated with decreased OS in SF patients but not in NT patients. The impact of early cancer progression and PMC upon completion of MMT is reduced by delivery of nonoperative therapies prior to pancreaticoduodenectomy. NT sequencing is a practical treatment strategy, particularly for patients at high biological or perioperative risk.

Authors
Tzeng, C-WD; Tran Cao, HS; Lee, JE; Pisters, PWT; Varadhachary, GR; Wolff, RA; Abbruzzese, JL; Crane, CH; Evans, DB; Wang, H; Abbott, DE; Vauthey, J-N; Aloia, TA; Fleming, JB; Katz, MHG
MLA Citation
Tzeng, C-WD, Tran Cao, HS, Lee, JE, Pisters, PWT, Varadhachary, GR, Wolff, RA, Abbruzzese, JL, Crane, CH, Evans, DB, Wang, H, Abbott, DE, Vauthey, J-N, Aloia, TA, Fleming, JB, and Katz, MHG. "Treatment sequencing for resectable pancreatic cancer: influence of early metastases and surgical complications on multimodality therapy completion and survival." Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract 18.1 (January 2014): 16-24.
PMID
24241967
Source
epmc
Published In
Journal of Gastrointestinal Surgery
Volume
18
Issue
1
Publish Date
2014
Start Page
16
End Page
24
DOI
10.1007/s11605-013-2412-1

Morbidity and mortality after pancreaticoduodenectomy in patients with borderline resectable type C clinical classification.

We previously described the clinical classification of patients with resectable pancreatic tumor anatomy but marginal performance status (PS) or reversible comorbidities as "borderline resectable type C" (BR-C). This study was designed to analyze the incidence and risk factors for post-pancreaticoduodenectomy (PD) morbidity/mortality in a multi-institutional cohort of BR-C patients.Elective PDs were evaluated from the 2005-10 ACS-NSQIP database. BR-C was defined as age ≥ 80, poor PS, weight loss > 10 %, pulmonary disease, recent myocardial infarction/angina, stroke history, and/or preoperative sepsis. Variables associated with 30-day postoperative major complications (PMC) and mortality were analyzed.A total of 3,033/8,266 (36.7 %) patients were BR-C. BR-C patients were more likely to suffer PMC (31.3 vs. 26.2 %) and mortality (4.1 vs. 2.3 %). BR-C patients with PMC suffered 50 % higher mortality versus non-BR-C patients with PMC (11.5 vs. 7.7 %) (all p < 0.001). For BR-C patients, multivariate analysis identified the following risk factors for PMC or mortality: albumin < 3.5 g/dL, dyspnea, preoperative sepsis, age ≥ 80, poor PS, anesthesia score ≥ 4, and intraoperative transfusion ≥ 4 units.Nationwide, one third of patients undergoing PD are medically borderline. These BR-C patients are at higher risk for and less able to be rescued from PMC. Surgeons should identify and optimize comorbidities and utilize prehabilitation to address functional deficits before elective PD.

Authors
Tzeng, C-WD; Katz, MHG; Fleming, JB; Lee, JE; Pisters, PWT; Holmes, HM; Varadhachary, GR; Wolff, RA; Abbruzzese, JL; Vauthey, J-N; Aloia, TA
MLA Citation
Tzeng, C-WD, Katz, MHG, Fleming, JB, Lee, JE, Pisters, PWT, Holmes, HM, Varadhachary, GR, Wolff, RA, Abbruzzese, JL, Vauthey, J-N, and Aloia, TA. "Morbidity and mortality after pancreaticoduodenectomy in patients with borderline resectable type C clinical classification." Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract 18.1 (January 2014): 146-155.
PMID
24129825
Source
epmc
Published In
Journal of Gastrointestinal Surgery
Volume
18
Issue
1
Publish Date
2014
Start Page
146
End Page
155
DOI
10.1007/s11605-013-2371-6

Clinicopathologic features and prognosis of duodenal adenocarcinoma and comparison with ampullary and pancreatic ductal adenocarcinoma.

Because of the rarity of duodenal adenocarcinoma (DAC), the clinicopathologic features and prognostication data for DAC are limited. There are no published studies directly comparing the prognosis of DAC to that of ampullary adenocarcinoma (AA) and of pancreatic ductal adenocarcinoma (PDA) after resection. In this study, we examined the clinicopathologic features of 68 patients with DAC, 92 patients with AA, and 126 patients with PDA who underwent resection. Patient clinicopathologic and survival information were extracted from medical records. Statistical analysis was performed using Statistical Package for the Social Sciences with 2-sided significance level of .05. Patients with DAC had higher American Joint Committee on Cancer (AJCC) stage than AA patients (P = .001). Lymph node metastasis (P = .013) and AJCC stage (P = .02) correlated with overall survival in DAC patients. Patients with DAC or AA had lower frequencies of lymph node metastasis and positive margin and better survival than those with PDA (P < .05). However, no differences in nodal metastasis, margin status, or survival were observed between DAC patients and those with AA. Our study showed that lymph node metastasis and AJCC stage are important prognostic factors for overall survival in DAC patients. Patients with DAC had less frequent nodal metastasis and better prognosis than those with PDA. There was no significant difference in prognosis between DAC and AA.

Authors
Zenali, M; Overman, MJ; Rashid, A; Broaddus, RB; Wang, H; Katz, MH; Fleming, JB; Abbruzzese, JL; Wang, H
MLA Citation
Zenali, M, Overman, MJ, Rashid, A, Broaddus, RB, Wang, H, Katz, MH, Fleming, JB, Abbruzzese, JL, and Wang, H. "Clinicopathologic features and prognosis of duodenal adenocarcinoma and comparison with ampullary and pancreatic ductal adenocarcinoma." Human pathology 44.12 (December 2013): 2792-2798.
PMID
24139211
Source
epmc
Published In
Human Pathology
Volume
44
Issue
12
Publish Date
2013
Start Page
2792
End Page
2798
DOI
10.1016/j.humpath.2013.07.030

Pancreatic intraepithelial neoplasia and histological changes in non-neoplastic pancreas associated with neoadjuvant therapy in patients with pancreatic ductal adenocarcinoma.

To study the histological changes in non-neoplastic pancreas and the effects on pancreatic intraepithelial neoplasia (PanIN) after neoadjuvant chemoradiation therapy (NCRT) for pancreatic ductal adenocarcinoma (PDAC).We reviewed the archival H&E slides from 218 patients with PDAC who completed NCRT and pancreaticoduodenectomy. Sixty-five patients who underwent pancreaticoduodenectomy for PDAC without NCRT were used as controls. Various histological features were reviewed and correlated with NCRT and survival. The NCRT group had lower densities of PanIN2 (P = 0.004) and PanIN3 (P = 0.02) than the control group. The extent of fibrosis, the frequency of neuroma-like nerve proliferation and the frequency of islet cell aggregation were significantly higher in the NCRT group than in the control group (P < 0.05). The intensity of inflammation was less in the NCRT group than in the control group (P = 0.02). In the NCRT group, patents with moderate to severe fibrosis or grade 2 inflammation had poorer survival than those with mild fibrosis (P = 0.04) or those with grade 0 or grade 1 inflammation (P = 0.003), respectively.Non-neoplastic pancreatic tissue from patients who received NCRT had a reduced density of high-grade PanIN lesions, more pancreatic fibrosis, and higher frequencies of neuroma-like nerve proliferation and islet cell aggregation, but less inflammation, compared to tissue from those who did not receive NCRT.

Authors
Chatterjee, D; Katz, MH; Rashid, A; Estrella, JS; Wang, H; Varadhachary, GR; Wolff, RA; Lee, JE; Pisters, PW; Abbruzzese, JL; Fleming, JB; Wang, H
MLA Citation
Chatterjee, D, Katz, MH, Rashid, A, Estrella, JS, Wang, H, Varadhachary, GR, Wolff, RA, Lee, JE, Pisters, PW, Abbruzzese, JL, Fleming, JB, and Wang, H. "Pancreatic intraepithelial neoplasia and histological changes in non-neoplastic pancreas associated with neoadjuvant therapy in patients with pancreatic ductal adenocarcinoma." Histopathology 63.6 (December 2013): 841-851.
PMID
24111684
Source
epmc
Published In
Histopathology
Volume
63
Issue
6
Publish Date
2013
Start Page
841
End Page
851
DOI
10.1111/his.12234

The cost-effectiveness of neoadjuvant chemoradiation is superior to a surgery-first approach in the treatment of pancreatic head adenocarcinoma.

In treating pancreatic cancer, there is no clearly defined optimal sequence of chemotherapy, radiation therapy and surgery. Therefore, cost-effectiveness should be considered. The objective of this study was to compare cost and outcomes between a surgery-first approach versus neoadjuvant chemoradiation followed by surgery for resectable pancreatic head cancer.A decision analytic model was constructed to compare the 2 approaches. Data from the National Cancer Database, National Surgical Quality Improvement Program, and literature populated the surgery-first arm. Data from our prospectively maintained institutional pancreatic cancer database populated the neoadjuvant arm. Costs were estimated by Medicare payment (2011 U.S. dollars). Survival was reported in quality-adjusted life-months (QALMs).The neoadjuvant chemoradiation arm consisted of 164 patients who completed preoperative therapy. Of these, 36 (22 %) did not proceed to surgery; 12 (7 %) underwent laparotomy but had unresectable disease; and 116 (71 %) underwent definitive resection. The surgery-first approach cost $46,830 and yielded survival of 8.7 QALMs; the neoadjuvant chemoradiation approach cost $36,583 and yielded survival of 18.8 QALMs. In the neoadjuvant arm, costs and survival times for patients not undergoing surgery, those with unresectable disease at laparotomy, and those completing surgery were $12,401 and 7.7 QALMs, $20,380 and 7.1 QALMs, and $45,673 and 23.4 QALMs, respectively.Neoadjuvant chemoradiation for pancreatic cancer identifies patients with early metastases or poor performance status, who can be spared an ineffective or prohibitively morbid operation, and is associated with improved survival at significantly lower cost than a surgery-first approach. Neoadjuvant chemoradiation followed by surgery is a strategy that provides more cost-effective care than a surgery-first approach.

Authors
Abbott, DE; Tzeng, C-WD; Merkow, RP; Cantor, SB; Chang, GJ; Katz, MH; Bentrem, DJ; Bilimoria, KY; Crane, CH; Varadhachary, GR; Abbruzzese, JL; Wolff, RA; Lee, JE; Evans, DB; Fleming, JB
MLA Citation
Abbott, DE, Tzeng, C-WD, Merkow, RP, Cantor, SB, Chang, GJ, Katz, MH, Bentrem, DJ, Bilimoria, KY, Crane, CH, Varadhachary, GR, Abbruzzese, JL, Wolff, RA, Lee, JE, Evans, DB, and Fleming, JB. "The cost-effectiveness of neoadjuvant chemoradiation is superior to a surgery-first approach in the treatment of pancreatic head adenocarcinoma." Annals of surgical oncology 20 Suppl 3 (December 2013): S500-S508.
PMID
23397153
Source
epmc
Published In
Annals of Surgical Oncology
Volume
20 Suppl 3
Publish Date
2013
Start Page
S500
End Page
S508
DOI
10.1245/s10434-013-2882-0

The expression of pten is associated with improved prognosis in patients with ampullary adenocarcinoma after pancreaticoduodenectomy

Context.- Phosphatase and tensin homolog (PTEN) is one of the most frequently inactivated tumor suppressor genes in sporadic cancers. Somatic mutations of PTEN occur in many tumors including those of the gastrointestinal and hepatobiliary tracts. Loss of PTEN expression is associated with poor prognosis in patients with metastatic colonic adenocarcinoma, gastroesophageal junction adenocarcinoma, gastric adenocarcinoma, and pancreatic ductal adenocarcinoma. Objective.- To study the expression of PTEN and its significance in ampullary adenocarcinoma (AA). Design.- We constructed tissue microarrays by using archival tissue from 92 patients (55 males, 37 females; median age, 63 years; age range, 37 to 87 years) with previously untreated AA who underwent pancreaticoduodenectomy at our institution. PTEN expression was evaluated by immunohistochemistry, scored semiquantitatively (based on staining intensity and percentage positive tumor cells), and correlated with clinicopathologic features and survival. Results.- Of 92 cases, 23 (25.0%) were PTEN negative. Loss of PTEN expression correlated with lymph node metastasis (P=.004), advanced American Joint Committee on Cancer (AJCC) stage (P = .02), and higher frequency of recurrence (P = .03). Patients with PTEN-negative tumors had shorter disease-free survival (DFS, mean: 89.0 ± 20.8 months) and overall survival (OS, mean: 93.1 ± 19.1 months) than those with PTEN-positive tumors (DFS, mean: 161.4 ± 11.7 months, P = .01; OS, mean: 175.4 ± 11.0 months, P = .001). In multivariate analyses, PTEN expression was a prognostic factor for both DFS and OS, independent of AJCC stage, lymph node status, pathologic tumor (pT) stage, and differentiation. Conclusions.- Loss of PTEN expression is associated with poor DFS and OS in patients with AA after curative surgery. PTEN expression may be used as a prognostic marker for patients with resected AA.

Authors
Stuti, S; Shroff, S; Overman, MJ; Rashid, A; Shroff, RT; Wang, H; Chatterjee, D; Katz, MH; Lee, JE; Wolff, RA; Abbruzzese, JL; Fleming, JB; Wang, H
MLA Citation
Stuti, S, Shroff, S, Overman, MJ, Rashid, A, Shroff, RT, Wang, H, Chatterjee, D, Katz, MH, Lee, JE, Wolff, RA, Abbruzzese, JL, Fleming, JB, and Wang, H. "The expression of pten is associated with improved prognosis in patients with ampullary adenocarcinoma after pancreaticoduodenectomy." Archives of Pathology and Laboratory Medicine 137.11 (November 1, 2013): 1619-1626.
Source
scopus
Published In
Archives of Pathology and Laboratory Medicine
Volume
137
Issue
11
Publish Date
2013
Start Page
1619
End Page
1626
DOI
10.5858/arpa.2012-0418-OA)

The expression of PTEN is associated with improved prognosis in patients with ampullary adenocarcinoma after pancreaticoduodenectomy.

Phosphatase and tensin homolog (PTEN) is one of the most frequently inactivated tumor suppressor genes in sporadic cancers. Somatic mutations of PTEN occur in many tumors including those of the gastrointestinal and hepatobiliary tracts. Loss of PTEN expression is associated with poor prognosis in patients with metastatic colonic adenocarcinoma, gastroesophageal junction adenocarcinoma, gastric adenocarcinoma, and pancreatic ductal adenocarcinoma.To study the expression of PTEN and its significance in ampullary adenocarcinoma (AA).We constructed tissue microarrays by using archival tissue from 92 patients (55 males, 37 females; median age, 63 years; age range, 37 to 87 years) with previously untreated AA who underwent pancreaticoduodenectomy at our institution. PTEN expression was evaluated by immunohistochemistry, scored semiquantitatively (based on staining intensity and percentage positive tumor cells), and correlated with clinicopathologic features and survival.Of 92 cases, 23 (25.0%) were PTEN negative. Loss of PTEN expression correlated with lymph node metastasis (P = .004), advanced American Joint Committee on Cancer (AJCC) stage (P = .02), and higher frequency of recurrence (P = .03). Patients with PTEN-negative tumors had shorter disease-free survival (DFS, mean: 89.0 ± 20.8 months) and overall survival (OS, mean: 93.1 ± 19.1 months) than those with PTEN-positive tumors (DFS, mean: 161.4 ± 11.7 months, P = .01; OS, mean: 175.4 ± 11.0 months, P = .001). In multivariate analyses, PTEN expression was a prognostic factor for both DFS and OS, independent of AJCC stage, lymph node status, pathologic tumor (pT) stage, and differentiation.Loss of PTEN expression is associated with poor DFS and OS in patients with AA after curative surgery. PTEN expression may be used as a prognostic marker for patients with resected AA.

Authors
Shroff, S; Overman, MJ; Rashid, A; Shroff, RT; Wang, H; Chatterjee, D; Katz, MH; Lee, JE; Wolff, RA; Abbruzzese, JL; Fleming, JB; Wang, H
MLA Citation
Shroff, S, Overman, MJ, Rashid, A, Shroff, RT, Wang, H, Chatterjee, D, Katz, MH, Lee, JE, Wolff, RA, Abbruzzese, JL, Fleming, JB, and Wang, H. "The expression of PTEN is associated with improved prognosis in patients with ampullary adenocarcinoma after pancreaticoduodenectomy." Archives of pathology & laboratory medicine 137.11 (November 2013): 1619-1626.
PMID
24168499
Source
epmc
Published In
Archives of Pathology and Laboratory Medicine
Volume
137
Issue
11
Publish Date
2013
Start Page
1619
End Page
1626
DOI
10.5858/arpa.2012-0418-oa

Genetic variation in the PNPLA3 gene and hepatocellular carcinoma in USA: risk and prognosis prediction.

Nonalcoholic fatty liver disease (NAFLD) is an emerging epidemic with high prevalence in Western countries. Genome-wide association studies had reported that a variation in the patatin-like phospholipase domain containing 3 (PNPLA3) gene is associated with high susceptibility to NAFLD. However, the relationship between this variation and hepatocellular carcinoma (HCC) has not been well established. We investigated the impact of PNPLA3 genetic variation (rs738409: C>G) on HCC risk and prognosis in the United States by conducting a case-control study that included 257 newly diagnosed and pathologically confirmed Caucasian patients with HCC (cases) and 494 healthy controls. Multivariate logistics and Cox regression models were used to control for the confounding effects of HCC risk and prognostic factors. We observed higher risk of HCC for subjects with a homozygous GG genotype than for those with CC or CG genotypes, the adjusted odds ratio (OR) was 3.21 (95% confidence interval [CI], 1.68-6.41). We observed risk modification among individuals with diabetes mellitus (OR = 19.11; 95% CI, 5.13-71.20). The PNPLA3 GG genotype was significantly associated with underlying cirrhosis in HCC patients (OR = 2.48; 95% CI, 1.05-5.87). Moreover, GG allele represents an independent risk factor for death. The adjusted hazard ratio of the GG genotype was 2.11 (95% CI, 1.26-3.52) compared with CC and CG genotypes. PNPLA3 genetic variation (rs738409: C>G) may determine individual susceptibility to HCC development and poor prognosis. Further experimental investigations are necessary for thorough assessment of the hepatocarcinogenic role of PNPLA3.

Authors
Hassan, MM; Kaseb, A; Etzel, CJ; El-Serag, H; Spitz, MR; Chang, P; Hale, KS; Liu, M; Rashid, A; Shama, M; Abbruzzese, JL; Loyer, EM; Kaur, H; Hassabo, HM; Vauthey, J-N; Wray, CJ; Hassan, BS; Patt, YZ; Hawk, E; Soliman, KM; Li, D
MLA Citation
Hassan, MM, Kaseb, A, Etzel, CJ, El-Serag, H, Spitz, MR, Chang, P, Hale, KS, Liu, M, Rashid, A, Shama, M, Abbruzzese, JL, Loyer, EM, Kaur, H, Hassabo, HM, Vauthey, J-N, Wray, CJ, Hassan, BS, Patt, YZ, Hawk, E, Soliman, KM, and Li, D. "Genetic variation in the PNPLA3 gene and hepatocellular carcinoma in USA: risk and prognosis prediction." Molecular carcinogenesis 52 Suppl 1 (November 2013): E139-E147.
PMID
23776098
Source
epmc
Published In
Molecular Carcinogenesis
Volume
52 Suppl 1
Publish Date
2013
Start Page
E139
End Page
E147
DOI
10.1002/mc.22057

Carcinoma of Unknown Primary

Authors
Varadhachary, GR; Lenzi, R; Raber, MN; Abbruzzese, JL
MLA Citation
Varadhachary, GR, Lenzi, R, Raber, MN, and Abbruzzese, JL. "Carcinoma of Unknown Primary." Abeloff's Clinical Oncology: Fifth Edition. October 22, 2013. 1792-1803.e2.
Source
scopus
Publish Date
2013
Start Page
1792
End Page
1803.e2
DOI
10.1016/B978-1-4557-2865-7.00094-1

The addition of erlotinib to gemcitabine and cisplatin does not appear to improve median survival in metastatic pancreatic cancer.

Metastatic pancreatic cancer carries a poor prognosis, with median survival on the order of several months. There is evidence that combining gemcitabine with either erlotinib or cisplatin may be superior to single agent gemcitabine in patients with good performance (PS 0-1). We retrospectively compared outcomes of patients treated with either the three drug regimen of gemcitabine, cisplatin, and erlotinib (GCE) or the doublet of gemcitabine and cisplatin (GC) in order to assess the potential benefit of erlotinib. We also evaluated the role of erlotinib among smokers and non-smokers. We retrospectively analyzed 145 patients who presented between 2006 and 2009 with previously untreated metastatic pancreatic cancer initially treated at the M.D. Anderson cancer center with either GC or GCE. Information on tumor characteristics and overall survival time (OS) was collected by medical record review. Kaplan-Meier curves were used to estimate OS. Log rank tests were used to compare OS between groups. The Cox proportional hazards regression model was used to evaluate the ability of patient prognostic variables or treatment group to predict OS. A total of 71 patients were treated with GC, while 74 were treated with GCE. Cox analyses found no significant difference in overall survival (median 5.5 vs. 8.0 months, respectively, p-value=0.1). Small sampling numbers may have contributed to this result. One year survival was 23 % in the GCE group and 13 % in the GC group. Patients with poor performance status (PS=2-3) had worse survival as compared to patients with better performance status (PS=0-1, p=0.001). As in earlier studies, patients treated with more lines of therapy tended to have better survival (p <0.0001), and CA19-9 was found to be a significant predictor for OS (p=0.001). No statistical evidence of a survival difference was found between smokers and non-smokers in both treatment groups (p=0.72). In conclusion, though there was a trend towards improved survival with the addition of erlotinib to gemcitabine and cisplatin, this does not reach statistical significance.

Authors
Khalil, MA; Qiao, W; Carlson, P; George, B; Javle, M; Overman, M; Varadhachary, G; Wolff, RA; Abbruzzese, JL; Fogelman, DR
MLA Citation
Khalil, MA, Qiao, W, Carlson, P, George, B, Javle, M, Overman, M, Varadhachary, G, Wolff, RA, Abbruzzese, JL, and Fogelman, DR. "The addition of erlotinib to gemcitabine and cisplatin does not appear to improve median survival in metastatic pancreatic cancer." Investigational new drugs 31.5 (October 2013): 1375-1383.
PMID
23645398
Source
epmc
Published In
Investigational New Drugs
Volume
31
Issue
5
Publish Date
2013
Start Page
1375
End Page
1383
DOI
10.1007/s10637-013-9967-2

Modified cisplatin/interferon α-2b/doxorubicin/5-fluorouracil (PIAF) chemotherapy in patients with no hepatitis or cirrhosis is associated with improved response rate, resectability, and survival of initially unresectable hepatocellular carcinoma.

The purpose of this study was to evaluate the factors associated with response rate, resectability, and survival after cisplatin/interferon α-2b/doxorubicin/5-fluorouracil (PIAF) combination therapy in patients with initially unresectable hepatocellular carcinoma.The study included 2 groups of patients treated with conventional high-dose PIAF (n = 84) between 1994 and 2003 and those without hepatitis or cirrhosis treated with modified PIAF (n = 33) between 2003 and 2012. Tolerance of chemotherapy, best radiographic response, rate of conversion to curative surgery, and overall survival were analyzed and compared between the 2 groups, and multivariate and logistic regression analyses were applied to identify predictors of response and survival.The modified PIAF group had a higher median number of PIAF cycles (4 versus 2, P = .049), higher objective response rate (36% versus 15%, P = .013), higher rate of conversion to curative surgery (33% versus 10%, P = .004), and longer median overall survival (21.3 versus 10.6 months, P = .002). Multivariate analyses confirmed that positive hepatitis B serology (hazard ratio [HR] = 1.68; 95% confidence interval [CI] = 1.08-2.59) and Eastern Cooperative Oncology Group performance status ≥ 2 (HR = 1.75; 95% CI = 1.04-2.93) were associated with worse survival whereas curative surgical resection after PIAF treatment (HR = 0.15; 95% CI = 0.07-0.35) was associated with improved survival.In patients with initially unresectable hepatocellular carcinoma, the modified PIAF regimen in patients with no hepatitis or cirrhosis is associated with improved response, resectability, and survival.

Authors
Kaseb, AO; Shindoh, J; Patt, YZ; Roses, RE; Zimmitti, G; Lozano, RD; Hassan, MM; Hassabo, HM; Curley, SA; Aloia, TA; Abbruzzese, JL; Vauthey, J-N
MLA Citation
Kaseb, AO, Shindoh, J, Patt, YZ, Roses, RE, Zimmitti, G, Lozano, RD, Hassan, MM, Hassabo, HM, Curley, SA, Aloia, TA, Abbruzzese, JL, and Vauthey, J-N. "Modified cisplatin/interferon α-2b/doxorubicin/5-fluorouracil (PIAF) chemotherapy in patients with no hepatitis or cirrhosis is associated with improved response rate, resectability, and survival of initially unresectable hepatocellular carcinoma." Cancer 119.18 (September 2013): 3334-3342.
PMID
23821538
Source
epmc
Published In
Cancer
Volume
119
Issue
18
Publish Date
2013
Start Page
3334
End Page
3342
DOI
10.1002/cncr.28209

Correction: Gene Expression Profiling of Ampullary Carcinomas Classifies Ampullary Carcinomas into Biliary-Like and Intestinal-Like Subtypes That Are Prognostic of Outcome

Authors
Overman, MJ; Zhang, J; Kopetz, S; Davies, M; Jiang, Z-Q; Stemke-Hale, K; Rümmele, P; Pilarsky, C; Grützmann, R; Hamilton, S; Hwang, R; Abbruzzese, JL; Varadhachary, G; Broom, B; Wang, H
MLA Citation
Overman, MJ, Zhang, J, Kopetz, S, Davies, M, Jiang, Z-Q, Stemke-Hale, K, Rümmele, P, Pilarsky, C, Grützmann, R, Hamilton, S, Hwang, R, Abbruzzese, JL, Varadhachary, G, Broom, B, and Wang, H. "Correction: Gene Expression Profiling of Ampullary Carcinomas Classifies Ampullary Carcinomas into Biliary-Like and Intestinal-Like Subtypes That Are Prognostic of Outcome." Ed. J-S Lee. PLoS ONE 8.7 (July 3, 2013).
Source
crossref
Published In
PloS one
Volume
8
Issue
7
Publish Date
2013
DOI
10.1371/annotation/6afdd046-e1a7-4421-b7ec-0c9492ce2544

Frequency and intensity of postoperative surveillance after curative treatment of pancreatic cancer: a cost-effectiveness analysis.

Few data exist to guide oncologic surveillance following curative treatment of pancreatic cancer. We sought to identify a rational, cost-effective postoperative surveillance strategy.We constructed a Markov model to compare the cost-effectiveness of 5 postoperative surveillance strategies. No scheduled surveillance served as the baseline strategy. Clinical evaluation and carbohydrate antigen (CA) 19-9 testing without/with routine computed tomography and chest X-ray at either 6- or 3-month intervals served as the 4 comparison strategies of increasing intensity. We populated the model with symptom, recurrence, treatment, and survival data from patients who had received intensive surveillance after multimodality treatment at our institution between 1998 and 2008. Costs were based on Medicare payments (2011 US dollars).The baseline strategy of no scheduled surveillance was associated with a postoperative overall survival (OS) of 24.6 months and a cost of $3837/patient. Clinical evaluation and CA 19-9 assay every 6 months until recurrence was associated with a 32.8-month OS and a cost of $7496/patient, with an incremental cost-effectiveness ratio (ICER) of $5364/life-year (LY). Additional routine imaging every 6 months incrementally increased total cost by $3465 without increasing OS. ICERs associated with clinic visits every 3 months without/with routine imaging were $127,680 and $294,696/LY, respectively. Sensitivity analyses changed the strategies' absolute costs but not the relative ranks of their ICERs.Increasing the frequency and intensity of postoperative surveillance of patients after curative therapy for pancreatic cancer beyond clinical evaluation and CA 19-9 testing every 6 months increases cost but confers no clinically significant survival benefit.

Authors
Tzeng, C-WD; Abbott, DE; Cantor, SB; Fleming, JB; Lee, JE; Pisters, PWT; Varadhachary, GR; Abbruzzese, JL; Wolff, RA; Ahmad, SA; Katz, MHG
MLA Citation
Tzeng, C-WD, Abbott, DE, Cantor, SB, Fleming, JB, Lee, JE, Pisters, PWT, Varadhachary, GR, Abbruzzese, JL, Wolff, RA, Ahmad, SA, and Katz, MHG. "Frequency and intensity of postoperative surveillance after curative treatment of pancreatic cancer: a cost-effectiveness analysis." Annals of surgical oncology 20.7 (July 2013): 2197-2203.
PMID
23408126
Source
epmc
Published In
Annals of Surgical Oncology
Volume
20
Issue
7
Publish Date
2013
Start Page
2197
End Page
2203
DOI
10.1245/s10434-013-2889-6

Loss of phosphatase and tensin homolog expression is associated with recurrence and poor prognosis in patients with pancreatic ductal adenocarcinoma.

Phosphatase and tensin homolog (PTEN) is a tumor suppressor in the AKT/mTOR pathway. Animal model studies have shown that loss of PTEN function is involved in the progression of pancreatic cancer. However, the prognostic significance of loss of PTEN expression in pancreatic cancer is unclear. PTEN expression was evaluated by immunohistochemistry on tissue microarrays consisting of multiple cores of 133 resected stage II pancreatic ductal adenocarcinomas. A PTEN expression score was calculated as the product of the percentage of positive tumor cells and the intensity of PTEN staining. We categorized PTEN expression for each tumor as retained (PTEN score >5) or lost (PTEN score ≤5). Thirty-four (25.6%) patients had tumors with loss of PTEN expression, and 99 (74.4%) had tumors with retained PTEN expression. Recurrence/Metastasis was observed in 88.2% (30/34) of patients whose tumors showed loss of PTEN compared with 68.7% (68/99) of patients whose tumors showed retained PTEN (P = .03). Patients whose tumors showed loss of PTEN had a shorter overall survival (median, 19.9 ± 3.6 months) than did patients whose tumors had retained PTEN (32.7 ± 5.0 months, P = .03). In a multivariate analysis, loss of PTEN expression was an independent prognostic factor for poor overall survival in patients with stage II pancreatic ductal adenocarcinoma. No significant correlations between loss of PTEN expression and other clinicopathologic parameters were observed (P > .05). Assessment of PTEN expression may be used as a prognostic marker for patients with resected pancreatic ductal adenocarcinoma.

Authors
Foo, WC; Rashid, A; Wang, H; Katz, MH; Lee, JE; Pisters, PW; Wolff, RA; Abbruzzese, JL; Fleming, JB; Wang, H
MLA Citation
Foo, WC, Rashid, A, Wang, H, Katz, MH, Lee, JE, Pisters, PW, Wolff, RA, Abbruzzese, JL, Fleming, JB, and Wang, H. "Loss of phosphatase and tensin homolog expression is associated with recurrence and poor prognosis in patients with pancreatic ductal adenocarcinoma." Human pathology 44.6 (June 2013): 1024-1030.
PMID
23260327
Source
epmc
Published In
Human Pathology
Volume
44
Issue
6
Publish Date
2013
Start Page
1024
End Page
1030
DOI
10.1016/j.humpath.2012.09.001

Deciphering the mechanisms of tumorigenesis in human pancreatic ductal epithelial cells.

The most common genetic lesions in pancreatic ductal adenocarcinoma (PDAC) have been identified. However, significant gaps still exist in our understanding of how such genetic alterations act in concert to induce PDAC development. In this study, we investigated the mechanism of tumorigenic transformation in the immortalized human pancreatic ductal epithelial (HPDE) cell line by sequentially introducing PDAC signature alterations into this cell line.The phenotype for stable expression of mutant K-ras, Her2, p16/p14shRNA, and Smad4shRNA in HPDE cells was examined by assays for cell proliferation, migration, invasion, soft agar, and orthotopic tumorigenesis. The mechanisms of tumorigenic transformation were further explored by gene expression profiling and pathway analyses.The transformed cells exhibited enhanced proliferation, migration, and invasion, displayed anchorage-independent growth in soft agar, and grew orthotopic tumors with some histopathologic features of PDAC. We found that Smad4 played key roles in the tumorigenic transformation of HPDE cells. We further found that MDM2 and Bmi-1 were overexpressed in the tumorigenic HPDE cells and that Bmi-1 overexpression was regulated by Smad4. Ingenuity Pathway Analysis software analysis of microarray data revealed that dysregulation of integrin-linked kinase signaling and the cell cycle were the most significant changes involved in tumorigenic transformation. Altogether, this cell culture model closely recapitulated human pancreatic carcinogenesis from gene lesions, activation of specific signaling pathways, and some histopathologic features.The combination of activated K-ras and Her2 with inactivated p16/p14 and Smad4 was sufficient and essential to transform HPDE cells, thus revealing the potential tumorigenic mechanism.

Authors
Chang, Z; Li, Z; Wang, X; Kang, Y; Yuan, Y; Niu, J; Wang, H; Chatterjee, D; Fleming, JB; Li, M; Abbruzzese, JL; Chiao, PJ
MLA Citation
Chang, Z, Li, Z, Wang, X, Kang, Y, Yuan, Y, Niu, J, Wang, H, Chatterjee, D, Fleming, JB, Li, M, Abbruzzese, JL, and Chiao, PJ. "Deciphering the mechanisms of tumorigenesis in human pancreatic ductal epithelial cells." Clinical cancer research : an official journal of the American Association for Cancer Research 19.3 (February 2013): 549-559.
PMID
23340292
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
19
Issue
3
Publish Date
2013
Start Page
549
End Page
559
DOI
10.1158/1078-0432.ccr-12-0032

Solid pseudopapillary neoplasm of the pancreas with prominent atypical multinucleated giant tumour cells.

Solid pseudopapillary neoplasm of the pancreas (SPN) is a rare low-grade malignant neoplasm. To our knowledge, SPN with prominent atypical multinucleated giant tumour cells (MNGTCs) has not yet been reported.We identified four cases of SPN with prominent atypical MNGTCs in a cohort of 62 cases of SPN (6.5%). The MNGTCs contained multiple enlarged, hyperchromatic, irregular nuclei with ample eosinophilic cytoplasm, typically present in the solid area of the tumour. The MNGTCs had an immunohistochemical profile typical of the conventional SPN and were positive for vimentin, β-catenin, CD10 and progesterone receptor, but negative for pan-cytokeratin, chromogranin, synaptophysin, trypsin, Ki-67 and CD68 in all four cases. Patients of SPN with prominent MNGTCs were older than those with conventional SPN (P = 0.01); tumours were discovered incidentally by imaging studies for an unrelated disease in all four cases, and with a female to male ratio of 1:1. The proliferation index (Ki-67) was <1% in all four cases. None of the three patients for whom information was available developed recurrence during follow-up of 2.7, 3.8 and 5.0 years.The presence of MNGTCs in SPN most probably represents degenerative change of the tumour cells and does not seem to affect the prognosis.

Authors
Li, L; Othman, M; Rashid, A; Wang, H; Li, Z; Katz, MH; Lee, JE; Pisters, PW; Abbruzzese, JL; Fleming, JB; Wang, H
MLA Citation
Li, L, Othman, M, Rashid, A, Wang, H, Li, Z, Katz, MH, Lee, JE, Pisters, PW, Abbruzzese, JL, Fleming, JB, and Wang, H. "Solid pseudopapillary neoplasm of the pancreas with prominent atypical multinucleated giant tumour cells." Histopathology 62.3 (February 2013): 465-471.
PMID
23134473
Source
epmc
Published In
Histopathology
Volume
62
Issue
3
Publish Date
2013
Start Page
465
End Page
471
DOI
10.1111/his.12023

BSTA promotes mTORC2-mediated phosphorylation of Akt1 to suppress expression of FoxC2 and stimulate adipocyte differentiation.

Phosphorylation and activation of Akt1 is a crucial signaling event that promotes adipogenesis. However, neither the complex multistep process that leads to activation of Akt1 through phosphorylation at Thr³⁰⁸ and Ser⁴⁷³ nor the mechanism by which Akt1 stimulates adipogenesis is fully understood. We found that the BSD domain-containing signal transducer and Akt interactor (BSTA) promoted phosphorylation of Akt1 at Ser⁴⁷³ in various human and murine cells, and we uncovered a function for the BSD domain in BSTA-Akt1 complex formation. The mammalian target of rapamycin complex 2 (mTORC2) facilitated the phosphorylation of BSTA and its association with Akt1, and the BSTA-Akt1 interaction promoted the association of mTORC2 with Akt1 and phosphorylation of Akt1 at Ser⁴⁷³ in response to growth factor stimulation. Furthermore, analyses of bsta gene-trap murine embryonic stem cells revealed an essential function for BSTA and phosphorylation of Akt1 at Ser⁴⁷³ in promoting adipocyte differentiation, which required suppression of the expression of the gene encoding the transcription factor FoxC2. These findings indicate that BSTA is a molecular switch that promotes phosphorylation of Akt1 at Ser⁴⁷³ and reveal an mTORC2-BSTA-Akt1-FoxC2-mediated signaling mechanism that is critical for adipocyte differentiation.

Authors
Yao, Y; Suraokar, M; Darnay, BG; Hollier, BG; Shaiken, TE; Asano, T; Chen, C-H; Chang, BH-J; Lu, Y; Mills, GB; Sarbassov, D; Mani, SA; Abbruzzese, JL; Reddy, SAG
MLA Citation
Yao, Y, Suraokar, M, Darnay, BG, Hollier, BG, Shaiken, TE, Asano, T, Chen, C-H, Chang, BH-J, Lu, Y, Mills, GB, Sarbassov, D, Mani, SA, Abbruzzese, JL, and Reddy, SAG. "BSTA promotes mTORC2-mediated phosphorylation of Akt1 to suppress expression of FoxC2 and stimulate adipocyte differentiation." Science signaling 6.257 (January 8, 2013): ra2-.
PMID
23300339
Source
epmc
Published In
Science Signaling
Volume
6
Issue
257
Publish Date
2013
Start Page
ra2
DOI
10.1126/scisignal.2003295

Deficiency of metabolic regulator FGFR4 delays breast cancer progression through systemic and microenvironmental metabolic alterations.

BACKGROUND: Endocrine FGF21 and FGF19 target adipocytes and hepatocytes through betaKlotho (KLB) and FGFR tyrosine kinases effecting glucose, lipid and energy metabolism. Both factors alleviate obesity and metabolic abnormalities which are contributing factors to breast tumor progression. Genomic manipulation of hepatic FGFR4 has uncovered roles of endocrine FGF signaling in both metabolic and cellular homeostasis. Here we determined whether systemic and microenvironmental metabolic alterations caused by the FGFR4 deficiency affect tumorigenesis in breast where FGFR4 is negligible. Breast tumors were induced in the bigenic mice with ablation of FGFR4 and overexpression of TGFα that activates Her2 in the ductal and lobular epithelium surrounded by adipocytes. Mammary tumorigenesis and alterations in systemic and breast microenvironmental metabolic parameters and regulatory pathways were analyzed. RESULTS: Ablation of FGFR4 had no effect on cellular homeostasis and Her2 activity of normal breast tissue. However, the absence of FGFR4 reduced TGFα-driven breast tumor incidence and progression and improved host survival. Notable increases in hepatic and serum FGF21, ileal FGF15/19, adiponectin and adipsin, and decreases in systemic Fetuin A, IGF-1, IGFBP-1, RBP4 and TIMP1 were observed. The ablation affected adipogenesis and secretory function of adipocytes as well as lipogenesis, glycolysis and energy homeostasis associated with the functions of mitochondria, ER and peroxisomes in the breast and tumor foci. Treatment with a chemical inhibitor of NAMPT involved in the pathways inhibited the growth and survival of breast tumor cells and tumor-initiating cell-containing spheres. The FGFR4 ablation also caused elevation of inflammatory factors in the breast. CONCLUSIONS: Although the primary role of FGFR4 in metabolism occurs in hepatocytes, its ablation results in a net inhibitory effect on mammary tumor progression. We suggest that the tumor-delaying effect of FGFR4 deficiency may be in large part due to elevated anti-obesogenic FGF21 that triggers tumor-suppressing signals from both peripheral and breast adipocytes. The predominant changes in metabolic pathways suggested roles of metabolic effects from both peripheral and breast adipocytes on metabolic reprogramming in breast epithelial cells that contribute to the suppression of tumor progression. These results provide new insights into the contribution of systemic and microenvironmental metabolic effects controlled by endocrine FGF signaling to breast carcinogenesis.

Authors
Luo, Y; Yang, C; Ye, M; Jin, C; Abbruzzese, JL; Lee, M-H; Yeung, S-CJ; McKeehan, WL
MLA Citation
Luo, Y, Yang, C, Ye, M, Jin, C, Abbruzzese, JL, Lee, M-H, Yeung, S-CJ, and McKeehan, WL. "Deficiency of metabolic regulator FGFR4 delays breast cancer progression through systemic and microenvironmental metabolic alterations." Cancer & metabolism 1.1 (January 2013): 21-.
PMID
24279986
Source
epmc
Published In
Cancer and Metabolism
Volume
1
Issue
1
Publish Date
2013
Start Page
21
DOI
10.1186/2049-3002-1-21

Prognostic indicators and treatment outcome in 94 cases of fibrolamellar hepatocellular carcinoma.

Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare variant of HCC. We report an analysis of the clinicopathologic features, treatment outcomes, and prognostic indicators of 94 cases.We retrospectively collected clinicopathologic and treatment outcome data from 94 FLHCC patients (48 males and 46 females). Median overall survival (OS) and recurrence-free survival (RFS) were calculated using Kaplan-Meier curves, and survival rates were compared by the log-rank test. The Cox proportional hazard model was used for univariate and multivariate estimation of hazard risk ratios and 95% confidence intervals (CI) for factors that correlated with survival and disease recurrence after resection.Median age was 23 years (14-75); median OS was 57.2 months (95% CI, 36.4-77.9), and median RFS was 13.9 months (95% CI, 8.8-18.9). White race, female gender, early tumor stage, and tumor resection including metastasectomy were positively associated with longer OS, while female gender was the only significant positive predictor of longer RFS. Finally, the 5-fluorouracil-interferon combination was the most frequently used systemic therapy.Our analyses indicate that surgical approaches including metastasectomy as the first-line treatment in FLHCC correlated with better outcome. Multimodality approaches, including neoadjuvant and adjuvant therapies, prolonged patient survival.

Authors
Kaseb, AO; Shama, M; Sahin, IH; Nooka, A; Hassabo, HM; Vauthey, J-N; Aloia, T; Abbruzzese, JL; Subbiah, IM; Janku, F; Curley, S; Hassan, MM
MLA Citation
Kaseb, AO, Shama, M, Sahin, IH, Nooka, A, Hassabo, HM, Vauthey, J-N, Aloia, T, Abbruzzese, JL, Subbiah, IM, Janku, F, Curley, S, and Hassan, MM. "Prognostic indicators and treatment outcome in 94 cases of fibrolamellar hepatocellular carcinoma." Oncology 85.4 (January 2013): 197-203.
PMID
24051705
Source
epmc
Published In
Oncology
Volume
85
Issue
4
Publish Date
2013
Start Page
197
End Page
203
DOI
10.1159/000354698

Gene expression profiling of ampullary carcinomas classifies ampullary carcinomas into biliary-like and intestinal-like subtypes that are prognostic of outcome.

Adenocarcinomas of the ampulla of Vater are classified as biliary cancers, though the exact epithelium of origin for these cancers is not known. We sought to molecularly classify ampullary adenocarcinomas in comparison to known adenocarcinomas of the pancreas, bile duct, and duodenum by gene expression analysis.We analyzed 32 fresh-frozen resected, untreated periampullary adenocarcinomas (8 pancreatic, 2 extrahepatic biliary, 8 duodenal, and 14 ampullary) using the Affymetrix U133 Plus 2.0 genome array. Unsupervised and supervised hierarchical clustering identified two subtypes of ampullary carcinomas that were molecularly and histologically characterized.Hierarchical clustering of periampullary carcinomas segregated ampullary carcinomas into two subgroups, which were distinctly different from pancreatic carcinomas. Non-pancreatic periampullary adenocarcinomas were segregated into two subgroups with differing prognoses: 5 year RFS (77% vs. 0%, p = 0.007) and 5 year OS (100% vs. 35%, p = 0.005). Unsupervised clustering analysis of the 14 ampullary samples also identified two subgroups: a good prognosis intestinal-like subgroup and a poor prognosis biliary-like subgroup with 5 year OS of 70% vs. 28%, P = 0.09. Expression of CK7+/CK20- but not CDX-2 correlated with these two subgroups. Activation of the AKT and MAPK pathways were both increased in the poor prognostic biliary-like subgroup. In an independent 80 patient ampullary validation dataset only histological subtype (intestinal vs. pancreaticobiliary) was significantly associated with OS in both univariate (p = 0.006) and multivariate analysis (P = 0.04).Gene expression analysis discriminated pancreatic adenocarcinomas from other periampullary carcinomas and identified two prognostically relevant subgroups of ampullary adenocarcinomas. Histological subtype was an independent prognostic factor in ampullary adenocarcinomas.

Authors
Overman, MJ; Zhang, J; Kopetz, S; Davies, M; Jiang, Z-Q; Stemke-Hale, K; Rümmele, P; Pilarsky, C; Grützmann, R; Hamilton, S; Hwang, R; Abbruzzese, JL; Varadhachary, G; Broom, B; Wang, H
MLA Citation
Overman, MJ, Zhang, J, Kopetz, S, Davies, M, Jiang, Z-Q, Stemke-Hale, K, Rümmele, P, Pilarsky, C, Grützmann, R, Hamilton, S, Hwang, R, Abbruzzese, JL, Varadhachary, G, Broom, B, and Wang, H. "Gene expression profiling of ampullary carcinomas classifies ampullary carcinomas into biliary-like and intestinal-like subtypes that are prognostic of outcome." PloS one 8.6 (January 2013): e65144-.
PMID
23776447
Source
epmc
Published In
PloS one
Volume
8
Issue
6
Publish Date
2013
Start Page
e65144
DOI
10.1371/journal.pone.0065144

Use of research biopsies in clinical trials: are risks and benefits adequately discussed?

PURPOSE: Although the incorporation of research biopsies into clinical trials is increasing, limited information is available about how study protocols and informed consents integrate and describe their use. METHODS: All therapeutic clinical trials in which image-guided research biopsies were performed from January 1, 2005, to October 1, 2010, were identified from an interventional radiology database. Data from study protocols and informed consents were extracted and analyzed. Procedural complications were recorded. RESULTS: A total of 57 clinical trials were identified, of which 38 (67%) contained at least one mandatory biopsy. The analysis of the research biopsy tumor tissue was a study end point in 95% of trials. The primary indication for a research biopsy was for integral biomarker analysis in 32% and for correlative science in 68% of trials. A statistical analytic plan for the correlative science research biopsy tumor tissue was mentioned in 26%, described as exploratory in 51%, and not mentioned in 23% of trials. For studies with mandatory biopsies, biopsy was an eligibility criterion in 71% of trials, and a statistical justification for the research biopsy sample size was present in 50% of trials. A total of 745 research biopsies were performed on 576 patients. Overall and major complication rates were 5.2% (39 of 745 biopsies) and 0.8% (six of 745 biopsies), respectively. Complication rates for intrathoracic and abdominal/pelvic solid organ biopsies were 17.1% (36 of 211 biopsies) and 1.6% (three of 189 biopsies), respectively. Site-stratified research biopsy-related risks were discussed in five consents. CONCLUSION: A better representation of the risks and benefits of research biopsies in study protocols and informed consents is needed.

Authors
Overman, MJ; Modak, J; Kopetz, S; Murthy, R; Yao, JC; Hicks, ME; Abbruzzese, JL; Tam, AL
MLA Citation
Overman, MJ, Modak, J, Kopetz, S, Murthy, R, Yao, JC, Hicks, ME, Abbruzzese, JL, and Tam, AL. "Use of research biopsies in clinical trials: are risks and benefits adequately discussed?." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 31.1 (January 2013): 17-22.
PMID
23129736
Source
epmc
Published In
Journal of Clinical Oncology
Volume
31
Issue
1
Publish Date
2013
Start Page
17
End Page
22
DOI
10.1200/jco.2012.43.1718

Response of borderline resectable pancreatic cancer to neoadjuvant therapy is not reflected by radiographic indicators.

Experience with preoperative therapy for other cancers has led to an assumption that borderline resectable pancreatic cancers can be converted to resectable cancers with preoperative therapy. In this study, the authors sought to determine the rate at which neoadjuvant therapy is associated with a reduction in the size or stage of borderline resectable tumors.Patients who had borderline resectable pancreatic cancer and received neoadjuvant therapy before potentially undergoing surgery at the authors' institution between 2005 and 2010 were identified. The patients' pretreatment and post-treatment pancreatic protocol computed tomography images were rereviewed to determine changes in tumor size or stage using modified Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1) and standardized anatomic criteria.The authors identified 129 patients who met inclusion criteria. Of the 122 patients who had their disease restaged after receiving preoperative therapy, 84 patients (69%) had stable disease, 15 patients (12%) had a partial response to therapy, and 23 patients (19%) had progressive disease. Although only 1 patient (0.8%) had their disease downstaged to resectable status after receiving neoadjuvant therapy, 85 patients (66%) underwent pancreatectomy. The median overall survival duration for all 129 patients was 22 months (95% confidence interval, 14-30 months). The median overall survival duration for the patients who underwent pancreatectomy was 33 months (95% confidence interval, 25-41 months) and was not associated with RECIST response (P = .78).Radiographic downstaging was rare after neoadjuvant therapy, and RECIST response was not an effective treatment endpoint for patients with borderline resectable pancreatic cancer. The authors concluded that these patients should undergo pancreatectomy after initial therapy in the absence of metastases.

Authors
Katz, MHG; Fleming, JB; Bhosale, P; Varadhachary, G; Lee, JE; Wolff, R; Wang, H; Abbruzzese, J; Pisters, PWT; Vauthey, J-N; Charnsangavej, C; Tamm, E; Crane, CH; Balachandran, A
MLA Citation
Katz, MHG, Fleming, JB, Bhosale, P, Varadhachary, G, Lee, JE, Wolff, R, Wang, H, Abbruzzese, J, Pisters, PWT, Vauthey, J-N, Charnsangavej, C, Tamm, E, Crane, CH, and Balachandran, A. "Response of borderline resectable pancreatic cancer to neoadjuvant therapy is not reflected by radiographic indicators." Cancer 118.23 (December 2012): 5749-5756.
PMID
22605518
Source
epmc
Published In
Cancer
Volume
118
Issue
23
Publish Date
2012
Start Page
5749
End Page
5756
DOI
10.1002/cncr.27636

Overexpression of protein phosphatase 4 correlates with poor prognosis in patients with stage II pancreatic ductal adenocarcinoma.

Protein phosphatase 4 (PP4) has been reported to be overexpressed in breast and lung cancers. PP4 plays an important role in the regulation of centrosome maturation, DNA repair, NF-κB, and c-jun-NH(2)-kinase (JNK) signaling pathways. However, the expression and functions of PP4 in pancreatic cancer have not been studied.We examined the expression of PP4 catalytic subunit (PP4C) protein in 133 patients with stage II pancreatic ductal adenocarcinoma (PDAC) and their paired benign pancreatic samples (N = 113) by immunohistochemistry. To confirm the immunohistochemical results, we measured PP4C protein and mRNA levels by Western blotting and real-time reverse transcriptase PCR. Using univariate and multivariate analysis, we correlated PP4C expression with survival and other clinicopathologic features.PP4C was overexpressed in 75 of 133 (56.4%) stage II PDAC samples, which was significantly higher than the paired benign pancreatic tissue (15%, 17 of 113). PP4C mRNA expression levels were also higher in PDAC samples than the paired benign pancreatic tissue. Overexpression of PP4C in PDAC samples was associated with higher frequencies of distant metastasis (P = 0.02) and poor disease-free and overall survivals in patients with stage II PDAC (P = 0.006 and 0.02) independent of tumor size, margin status, and lymph node status (stage).Our study showed that PP4C is overexpressed in PDAC. Overexpression of PP4C in PDAC samples is associated with poor prognosis in patients with stage II PDAC. Therefore, targeting PP4 signaling pathway may represent a new approach for the treatment of PDAC.Our study showed that PP4C is an independent prognostic factor in patients with stage II PDAC.

Authors
Weng, S; Wang, H; Chen, W; Katz, MH; Chatterjee, D; Lee, JE; Pisters, PW; Gomez, HF; Abbruzzese, JL; Fleming, JB; Wang, H
MLA Citation
Weng, S, Wang, H, Chen, W, Katz, MH, Chatterjee, D, Lee, JE, Pisters, PW, Gomez, HF, Abbruzzese, JL, Fleming, JB, and Wang, H. "Overexpression of protein phosphatase 4 correlates with poor prognosis in patients with stage II pancreatic ductal adenocarcinoma." Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 21.8 (August 2012): 1336-1343.
PMID
22665577
Source
epmc
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
21
Issue
8
Publish Date
2012
Start Page
1336
End Page
1343
DOI
10.1158/1055-9965.epi-12-0223

Histologic tumor involvement of superior mesenteric vein/portal vein predicts poor prognosis in patients with stage II pancreatic adenocarcinoma treated with neoadjuvant chemoradiation.

Studies have shown that superior mesenteric vein (SMV)/portal vein (PV) resection with pancreaticoduodenectomy (PD) is safe and feasible for patient with pancreatic adenocarcinoma (PAC). However, the prognostic significance of tumor involvement of the resected vein in patients who received neoadjuvant therapy is unclear.The authors evaluated 225 consecutive patients with stage II PAC who received neoadjuvant therapy and PD with or without SMV/PV resection. The resected SMV/PV was entirely submitted for histologic assessment and reviewed in all cases. Tumor involvement of the SMV/PV was correlated with clinicopathologic features and survival.Among the 225 patients, SMV/PV resection was performed in 85 patients. Histologic tumor involvement of the resected SMV/PV was identified in 57 patients. Histologic tumor involvement of the SMV/PV was associated with larger tumor size, higher rates of positive margin, and local/distant recurrence. By multivariate analysis, tumor involvement of the SMV/PV was an independent predictor of both disease-free survival (DFS) and overall survival (OS). However, addition of venous resection to PD itself had no impact on either DFS or OS compared with those with PD alone.Histologic tumor involvement of the SMV/PV is an independent predictor of both DFS and OS in patients with stage II PAC treated with neoadjuvant therapy and PD. Complete histologic evaluation of the resected SMV/PV is important for the prognosis in patients with PAC who received neoadjuvant therapy and PD.

Authors
Wang, J; Estrella, JS; Peng, L; Rashid, A; Varadhachary, GR; Wang, H; Lee, JE; Pisters, PWT; Vauthey, J-N; Katz, MH; Gomez, HF; Evans, DB; Abbruzzese, JL; Fleming, JB; Wang, H
MLA Citation
Wang, J, Estrella, JS, Peng, L, Rashid, A, Varadhachary, GR, Wang, H, Lee, JE, Pisters, PWT, Vauthey, J-N, Katz, MH, Gomez, HF, Evans, DB, Abbruzzese, JL, Fleming, JB, and Wang, H. "Histologic tumor involvement of superior mesenteric vein/portal vein predicts poor prognosis in patients with stage II pancreatic adenocarcinoma treated with neoadjuvant chemoradiation." Cancer 118.15 (August 2012): 3801-3811.
PMID
22180096
Source
epmc
Published In
Cancer
Volume
118
Issue
15
Publish Date
2012
Start Page
3801
End Page
3811
DOI
10.1002/cncr.26717

Multimodality therapy offers a chance for cure in patients with pancreatic adenocarcinoma deemed unresectable at first operative exploration.

Patients identified at surgical exploration with unresectable pancreatic ductal adenocarcinoma receive palliative, noncurative therapy. We hypothesized that accurate radiographic restaging, multimodality treatment, and advanced surgical technique can offer patients deemed unresectable at previous exploration the possibility for curative salvage pancreatectomy.Review of a prospectively maintained pancreatic ductal adenocarcinoma database identified all patients (1990 to 2010) evaluated after being deemed unresectable at first exploration elsewhere. Referring hospitals were categorized per National Cancer Data Base criteria as academic, community, or international. Patients were restaged using objective imaging (CT) criteria and classified based on anatomic resectability. Clinicopathologic factors and cancer-related outcomes were assessed.We evaluated 88 patients who underwent previously unsuccessful resection attempts at academic (n = 50), community (n = 25), and international (n = 13) centers. Radiographic restaging confirmed that 7 (8%) patient tumors were locally advanced and unresectable, but 81 (92%) were resectable (n = 61) or borderline resectable (n = 20). Using a surgery first (9%) or preoperative chemoradiation (91%) approach, successful reoperative pancreatectomy was performed in 66 (81%) patients, with 94% receiving R0 resections. Vascular resection/reconstruction was required in 30 (46%) patients and 50 (76%) required complex revision of previously created biliary/gastrointestinal bypass. The major complication rate was 20% and 3 (4.5%) patients died perioperatively. Median overall survival was 29.6 months for successfully resected patients vs 10.6 and 5.1 months (p < 0.0001) for those patients with locally advanced unresectable disease at initial referral or in whom metastatic disease developed before resection, respectively.In this very selected cohort of high-risk patients, the majority had anatomically resectable tumors on restaging. Accurate radiographic restaging, a multimodality treatment strategy, and advanced surgical techniques can provide an opportunity for cure in a substantial proportion of select patients who were deemed unresectable at exploration.

Authors
Truty, MJ; Thomas, RM; Katz, MH; Vauthey, J-N; Crane, C; Varadhachary, GR; Wolff, RA; Abbruzzese, JL; Lee, JE; Fleming, JB
MLA Citation
Truty, MJ, Thomas, RM, Katz, MH, Vauthey, J-N, Crane, C, Varadhachary, GR, Wolff, RA, Abbruzzese, JL, Lee, JE, and Fleming, JB. "Multimodality therapy offers a chance for cure in patients with pancreatic adenocarcinoma deemed unresectable at first operative exploration." Journal of the American College of Surgeons 215.1 (July 2012): 41-51.
PMID
22608401
Source
epmc
Published In
Journal of The American College of Surgeons
Volume
215
Issue
1
Publish Date
2012
Start Page
41
End Page
51
DOI
10.1016/j.jamcollsurg.2012.03.024

Histologic grading of the extent of residual carcinoma following neoadjuvant chemoradiation in pancreatic ductal adenocarcinoma: a predictor for patient outcome.

Several grading schemes for the extent of residual tumor in posttreatment pancreaticoduodenectomy (PD) specimens have been proposed. However, the prognostic significance of these grading schemes is unknown.Histopathologic slides of 223 cases who received neoadjuvant chemoradiation and PD were reviewed. The extent of residual tumor was graded using both the College of American Pathologists (CAP) and the Evans grading systems. The grading results were correlated with clinicopathological parameters and survival.Among the 223 patients, 6 patients (2.7%) showed pathologic complete response (pCR; CAP grade 0 or Evans grade IV), 36 cases (16.1%) had minimal residual tumor (CAP grade 1 or Evans grade III), 124 cases (55.6%) had moderate response (CAP grade 2 or Evans grade IIb), and 57 cases (25.6%) had poor response (CAP grade 3, where 18 had Evans grade I and 39 had Evans grade IIa response). Patients with pCR or minimal residual tumor (response group 1) had better survival rates than those with moderate and poor response (response group 2). Response group 1 patients had lower posttherapy tumor and American Joint Committee on Cancer stages and lower rates of lymph node metastasis, positive resection margin, and recurrence and/or metastasis. Grading the extent of residual tumor is an independent prognostic factor for overall survival in multivariate analysis.pCR or minimal residual tumor in posttreatment PD specimens correlate with better survival in patients with pancreatic ductal adenocarcinoma who received neoadjuvant therapy and PD. Histologic grading of the extent of residual tumor in PD specimen is an important prognostic factor in patients with pancreatic ductal adenocarcinoma who received neoadjuvant therapies.

Authors
Chatterjee, D; Katz, MH; Rashid, A; Varadhachary, GR; Wolff, RA; Wang, H; Lee, JE; Pisters, PWT; Vauthey, J-N; Crane, C; Gomez, HF; Abbruzzese, JL; Fleming, JB; Wang, H
MLA Citation
Chatterjee, D, Katz, MH, Rashid, A, Varadhachary, GR, Wolff, RA, Wang, H, Lee, JE, Pisters, PWT, Vauthey, J-N, Crane, C, Gomez, HF, Abbruzzese, JL, Fleming, JB, and Wang, H. "Histologic grading of the extent of residual carcinoma following neoadjuvant chemoradiation in pancreatic ductal adenocarcinoma: a predictor for patient outcome." Cancer 118.12 (June 2012): 3182-3190.
PMID
22028089
Source
epmc
Published In
Cancer
Volume
118
Issue
12
Publish Date
2012
Start Page
3182
End Page
3190
DOI
10.1002/cncr.26651

DNA mismatch repair network gene polymorphism as a susceptibility factor for pancreatic cancer.

DNA repair plays a critical role in human cancers. We hypothesized that DNA mismatch repair gene variants are associated with risk of pancreatic cancer. We retrospectively genotyped 102 single-nucleotide polymorphisms (SNPs) of 13 mismatch repair related genes in 706 patients with pancreatic cancer and 706 cancer-free controls using the mass spectroscopy-based MassArray method. Association of genotype with pancreatic cancer risk was tested by multivariate logistic regression models. A significance level of P ≤ 0.0015 was set at the false discovery rate (FDR) <1% using the Beta-Uniform Mixture method. We found 28 SNPs related to altered pancreatic cancer risk (P < 0.05). Adjusting for multiple comparisons, MGMT I143V AG/GG, PMS2 IVS1-1121C > T TC/TT, and PMS2L3 Ex1 + 118C > T CT/TT genotypes showed significant main effects on pancreatic cancer risk at FDR <1% with OR (95% CI) of 0.60 (0.46-0.80), 1.44 (1.14-1.81), and 5.54 (2.10-14.61), respectively (P ≤ 0.0015). To demonstrate genotype-phenotype association, we measured O(6)-ethylguanosine (O(6)-EtGua) adduct levels in vitro by immunoslot blot assay in lymphocytes treated with N-ethyl-N-nitrosourea (ENU) in 297 case/control subjects. MGMT I143V GG, MGMT K178R GG, MSH6 G39E AG/AA, PMS2L3 IVS3 + 9A > G GA and TP73 IVS1-7449G > C CG/CC genotypes correlated with a higher level of ENU-induced DNA adducts. Haplotypes of MGMT, MSH6, PMS2, PMS2L3, and TP73 were significantly associated with pancreatic cancer risk (P ≤ 0.0015). Our findings suggest that mismatch repair gene variants may affect susceptibility to pancreatic cancer.

Authors
Dong, X; Li, Y; Chang, P; Hess, KR; Abbruzzese, JL; Li, D
MLA Citation
Dong, X, Li, Y, Chang, P, Hess, KR, Abbruzzese, JL, and Li, D. "DNA mismatch repair network gene polymorphism as a susceptibility factor for pancreatic cancer." Molecular carcinogenesis 51.6 (June 2012): 491-499.
PMID
21681824
Source
epmc
Published In
Molecular Carcinogenesis
Volume
51
Issue
6
Publish Date
2012
Start Page
491
End Page
499
DOI
10.1002/mc.20817

A population-based comparison of adenocarcinoma of the large and small intestine: insights into a rare disease.

Because of its rarity, adenocarcinoma of the small intestine is frequently compared to adenocarcinoma of the colon, although the validity of this comparison is not known.Patients with small and large bowel adenocarcinoma (SBA and LBA) diagnosed between 1988 and 2007 were identified from the Surveillance, Epidemiology, and End Results registry. Age-standardized incidence and mortality rates were determined. Cancer-specific survival (CSS) stratified by stage and by number of assessed lymph nodes was calculated.A total of 4518 and 261,521 patients with SBA and LBA, respectively, were identified. In comparison to LBA, patients with SBA were younger and presented with disease of higher stage and histologic grade. The age-standardized incidence rates decreased for LBA (-1.24% per year) but increased for SBA (+1.47% per year). Although age-standardized mortality rates decreased for both LBA and SBA, the decreases were more pronounced for LBA. Five-year CSS was worse for resected SBA compared with resected LBA, although this difference diminished when comparing cases having eight or more lymph nodes assessed. The relative reduction in CSS when selecting eight or more lymph nodes was much greater for duodenal as opposed to jejunal/ileal subsite of the small bowel. With nodal selection the absolute difference in CSS between LBA and SBA for stages I, II, and III was 13, 15.9, and 18.5%, respectively.Adequate nodal assessment is much less common in SBA than LBA; and it appears that SBA, in particular duodenal adenocarcinoma, is understaged. Even after corrections to minimize the effect of stage migration and inadequate lymph node evaluation, SBA demonstrated distinctly worse CSS than LBA.

Authors
Overman, MJ; Hu, C-Y; Kopetz, S; Abbruzzese, JL; Wolff, RA; Chang, GJ
MLA Citation
Overman, MJ, Hu, C-Y, Kopetz, S, Abbruzzese, JL, Wolff, RA, and Chang, GJ. "A population-based comparison of adenocarcinoma of the large and small intestine: insights into a rare disease." Annals of surgical oncology 19.5 (May 2012): 1439-1445.
PMID
22187121
Source
epmc
Published In
Annals of Surgical Oncology
Volume
19
Issue
5
Publish Date
2012
Start Page
1439
End Page
1445
DOI
10.1245/s10434-011-2173-6

Cetuximab plus cisplatin, irinotecan, and thoracic radiotherapy as definitive treatment for locally advanced, unresectable esophageal cancer: a phase-II study of the SWOG (S0414).

The specific aims of the study were to evaluate the 2-year overall survival (OS) and progression-free survival (PFS), toxicity profile, and best objective response rate in patients with locally advanced, clinically unresectable esophageal cancer receiving cetuximab, cisplatin, irinotecan, and thoracic radiotherapy (TRT) within a multi-institutional cooperative-group setting.Eligible patients (cT4 M0 or medically unresectable, biopsy proven, and noncervical esophageal cancer) were to receive four 21-day cycles of cetuximab 400 mg/m (day 1, cycle 1), cetuximab 250 mg/m (day 8, 15, cycle 1; then days 1, 8, and 15 for subsequent cycles), cisplatin 30 mg/m (days 1 and 8, all cycles), and irinotecan 65 mg/m (days 1 and 8, all cycles). TRT was administered at 1.8 Gy in 28 daily fractions to a total dose of 50.4 Gy, to begin with on day 1 of cycle 3. The primary endpoint was 2-year OS, with an accrual goal of 75 patients with adenocarcinoma.The study was closed because of slow accrual, with 21 eligible patients (11 squamous, 10 adenocarcinoma) enrolled from May 2005 to September 2007. Two-year OS and PFS (95% confidence interval [CI]) were 33.3% (14.6-57.0%) and 23.8% (8.2-47.2%), respectively. Kaplan-Meier estimates of median (95% CI) OS and PFS were 11.2 (6.4-43.6) and 6.4 (3.7-12.0) months, respectively. The overall response rate (95% CI) among 17 evaluable patients was 17.6% (3.8-43.4%), including 6% confirmed complete responders and 12% unconfirmed partial responders. Two deaths resulted from protocol treatment (sudden death and gastrointestinal necrosis). Ten (47.6%) and 6 (28.6%) patients had grade-3 or -4 toxicity, respectively: 52.4% were hematologic, 23.8% had fatigue, 19.0% had nausea, 19.0% had dehydration, and 19.0% had anorexia.Concomitant cetuximab, cisplatin, irinotecan, and TRT were poorly tolerated in the first North American cooperative group trial testing this regimen for locally advanced esophageal cancer as treatment-related mortality approached 10%. Single-institution phase-II cetuximab-based combined modality trials have yielded encouraging results in preliminary analyses. The SWOG GI Committee endorses enrollment to open clinical trials to clarify the therapeutic ratio of cetuximab-based combined modality approaches for esophageal cancer.

Authors
Tomblyn, MB; Goldman, BH; Thomas, CR; Benedetti, JK; Lenz, H-J; Mehta, V; Beeker, T; Gold, PJ; Abbruzzese, JL; Blanke, CD
MLA Citation
Tomblyn, MB, Goldman, BH, Thomas, CR, Benedetti, JK, Lenz, H-J, Mehta, V, Beeker, T, Gold, PJ, Abbruzzese, JL, and Blanke, CD. "Cetuximab plus cisplatin, irinotecan, and thoracic radiotherapy as definitive treatment for locally advanced, unresectable esophageal cancer: a phase-II study of the SWOG (S0414)." Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 7.5 (May 2012): 906-912.
PMID
22481235
Source
epmc
Published In
Journal of Thoracic Oncology
Volume
7
Issue
5
Publish Date
2012
Start Page
906
End Page
912
DOI
10.1097/jto.0b013e31824c7bed

A phase I study to determine the safety and pharmacokinetics of intravenous administration of TAS-106 once per week for three consecutive weeks every 28 days in patients with solid tumors.

BACKGROUND: The nucleoside 3'-c-ethynylcytidine (TAS-106) was designed to inhibit RNA synthesis which occurs throughout the cell cycle except for the M phase. TAS-106 is incorporated into cells, is rapidly phosphorylated to a monophosphate form, and is preferentially distributed into malignant cells. Preclinical studies showed that TAS-106 has a wide antitumor spectrum against human cancer xenografts. This phase I study was conducted in order to determine the recommended phase II dose of TAS-106 administered once per week for three consecutive weeks, every 28 days in patients with solid tumors. PATIENTS AND METHODS: Patients were enrolled in cohorts of three, starting at 0.22 mg/m(2)/dose. Patients received at least two doses in order to be evaluable in each dose cohort. Dose escalation was stopped if two or more patients experienced dose limiting toxicity at any dose level. RESULTS: In 20 evaluable patients, TAS-106 was given at the following dose levels (mg/m(2)/dose): 0.22 (3 pts), 0.33 (3 pts), 0.66 (3 pts), 0.99 (1 pt), 1.32 (3 pts), 2.64 (3 pts) and 3.96 (1 pt). Three additional patients were evaluated at 2.64 mg/m(2)/dose for further characterization of toxicity and safety. A total of 16 patients completed courses 1 and 2. All 21 patients enrolled experienced at least one adverse event. The AE attributed to the study drug was grade 2 peripheral neuropathy characterized by peripheral sensory neuropathy, numbness, tremor, pain, and hyperesthesia involving the fingers, hands, toes, and feet. CONCLUSION: Due to neurotoxicity the MTD was the 2.64 mg/m(2)/dose for the study schedule. No suggested phase II dose was determined. However, at the 1.32 mg/m(2)/dose level, no patients experienced DLTs during course 1 or 2. This could be further studied to determine its viability as a potential phase II dosage.

Authors
Friday, B; Lassere, Y; Meyers, CA; Mita, A; Abbruzzese, JL; Thomas, MB
MLA Citation
Friday, B, Lassere, Y, Meyers, CA, Mita, A, Abbruzzese, JL, and Thomas, MB. "A phase I study to determine the safety and pharmacokinetics of intravenous administration of TAS-106 once per week for three consecutive weeks every 28 days in patients with solid tumors." Anticancer research 32.5 (May 2012): 1689-1696.
PMID
22593447
Source
epmc
Published In
Anticancer research
Volume
32
Issue
5
Publish Date
2012
Start Page
1689
End Page
1696

Metformin use is associated with better survival of diabetic patients with pancreatic cancer.

Accumulating evidence suggests that metformin has antitumor activity. The aim of this study was to determine whether metformin use has a survival benefit in patients with pancreatic cancer.We conducted a retrospective study of patients with diabetes and pancreatic cancer treated at The University of Texas MD Anderson Cancer Center (Houston, TX). Information on diabetes history, including treatment modalities and clinical outcome of pancreatic cancer, was collected using personal interviews and medical record review. Survival analysis was carried out using a Kaplan-Meier plot, log-rank test, and Cox proportional hazards regression models.Among the 302 patients identified, there were no significant differences in demographic or major clinical characteristics between the patients who had received metformin (n = 117) and those who had not (n = 185). The 2-year survival rate was 30.1% for the metformin group and 15.4% for the non-metformin group (P = 0.004; χ(2) test). The median overall survival time was 15.2 months for the metformin group, and 11.1 months for the non-metformin group (P = 0.004, log-rank test). Metformin users had a 32% lower risk of death; the HR (95% confidence interval) was 0.68 (0.52-0.89) in a univariate model (P = 0.004), 0.64 (0.48-0.86) after adjusting for other clinical predictors (P = 0.003), and 0.62 (0.44-0.87) after excluding insulin users (P = 0.006). Metformin use was significantly associated with longer survival in patients with nonmetastatic disease only.Our finding that metformin use was associated with improved outcome of patients with diabetes and pancreatic cancer should be confirmed in independent studies. Future research should prospectively evaluate metformin as a supplemental therapy in this population.

Authors
Sadeghi, N; Abbruzzese, JL; Yeung, S-CJ; Hassan, M; Li, D
MLA Citation
Sadeghi, N, Abbruzzese, JL, Yeung, S-CJ, Hassan, M, and Li, D. "Metformin use is associated with better survival of diabetic patients with pancreatic cancer." Clinical cancer research : an official journal of the American Association for Cancer Research 18.10 (May 2012): 2905-2912.
PMID
22465831
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
18
Issue
10
Publish Date
2012
Start Page
2905
End Page
2912
DOI
10.1158/1078-0432.ccr-11-2994

Increased CDC20 expression is associated with pancreatic ductal adenocarcinoma differentiation and progression.

Cell division cycle 20 (CDC20) homolog is an anaphase-promoting complex activator that is essential for cell division, but whether its expression in pancreatic ductal adenocarcinoma (PDAC) is significant is unknown. In this retrospective study, we determined whether aberrant CDC20 expression can be used as a biomarker in pancreatic ductal adenocarcinoma (PDAC) tumorigenesis and whether its expression reflects clinical progression.We compared CDC20 expression levels in normal, cancerous, and inflamed pancreatic tissues from stage II PDAC patients with clinical outcomes and determined CDC20 levels in seven PDAC cell lines. CDC20 was identified using a cDNA microarray database containing gene expression profiles for PDAC tissues and cell lines and chronic pancreatitis and normal pancreas tissues. Its expression was confirmed by real-time quantitative reverse-transcriptase-polymerase chain reaction (qRT-PCR). An immunohistochemical analysis of tissue microarrays from resected PDAC tumors and paired benign pancreatic tissues was done and CDC20 levels were correlated with clinical outcome.Fifty-six patients were included in this study. A microarray analysis revealed 5-fold higher CDC20 expression in PDAC tissue than in chronic pancreatitis tissue. A qRT-PCR analysis confirmed a mean 20-fold higher CDC20 level in PDAC tissue than in normal pancreas and pancreatitis tissue. RNA and protein CDC20 expression was detected in several PDAC cell lines. An immunohistochemical analysis revealed higher CDC20 protein expression levels in PDAC tissue than in normal pancreas tissue, and high CDC20 expression was associated with poor differentiation (P = 0.020) and a significantly lower 5-year recurrence-free survival rate (P = 0.039); we also found a trend toward a shorter overall survival duration.Aberrant CDC20 expression may play an important role in PDAC tumorigenesis and progression and may thus be useful as a marker of disease progression and prognosis and as a therapeutic target.

Authors
Chang, DZ; Ma, Y; Ji, B; Liu, Y; Hwu, P; Abbruzzese, JL; Logsdon, C; Wang, H
MLA Citation
Chang, DZ, Ma, Y, Ji, B, Liu, Y, Hwu, P, Abbruzzese, JL, Logsdon, C, and Wang, H. "Increased CDC20 expression is associated with pancreatic ductal adenocarcinoma differentiation and progression." Journal of hematology & oncology 5 (April 4, 2012): 15-.
PMID
22475564
Source
epmc
Published In
Journal of Hematology and Oncology
Volume
5
Publish Date
2012
Start Page
15
DOI
10.1186/1756-8722-5-15

Tumor invasion of muscular vessels predicts poor prognosis in patients with pancreatic ductal adenocarcinoma who have received neoadjuvant therapy and pancreaticoduodenectomy.

Lymphovascular invasion (LVI) is a prognostic factor in many types of human malignancies, including pancreatic ductal adenocarcinoma (PDAC). However, the prognostic significance of LVI in patients with PDAC who have received neoadjuvant therapy and pancreaticoduodenectomy is unclear. In this study, we analyzed LVI in 212 patients who had received neoadjuvant chemoradiation and subsequent pancreaticoduodenectomy at our institution between January 1999 and December 2007. LVI was present in 61.8% (131/212) of the patients. Of the 131 patients who were positive for LVI, 67 (31.6%) had tumor invasion into lymphovascular spaces without muscle layer (nonmuscular lymphovascular spaces), and 64 (30.2%) had tumor invasion into muscular vessels. Tumor invasion into muscular vessels correlated with higher frequencies of positive resection margin, lymph node metastasis, and locoregional/distant recurrence. Patients with tumor invasion into muscular vessels had significantly shorter disease-free survival and overall survival than did patients who had no LVI or who had tumor invasion of nonmuscular lymphovascular spaces (P<0.01). Tumor invasion into muscular vessels is an independent prognostic factor in patients with PDAC who have received neoadjuvant therapies. Our results showed that tumor invasion into muscular vessels plays an important role in the progression of PDAC and in predicting prognosis in this group of patients.

Authors
Chatterjee, D; Rashid, A; Wang, H; Katz, MH; Wolff, RA; Varadhachary, GR; Lee, JE; Pisters, PW; Gomez, HF; Abbruzzese, JL; Fleming, JB; Wang, H
MLA Citation
Chatterjee, D, Rashid, A, Wang, H, Katz, MH, Wolff, RA, Varadhachary, GR, Lee, JE, Pisters, PW, Gomez, HF, Abbruzzese, JL, Fleming, JB, and Wang, H. "Tumor invasion of muscular vessels predicts poor prognosis in patients with pancreatic ductal adenocarcinoma who have received neoadjuvant therapy and pancreaticoduodenectomy." The American journal of surgical pathology 36.4 (April 2012): 552-559.
PMID
22301496
Source
epmc
Published In
American Journal of Surgical Pathology
Volume
36
Issue
4
Publish Date
2012
Start Page
552
End Page
559
DOI
10.1097/pas.0b013e318240c1c0

Insulin-like growth factor axis gene polymorphisms modify risk of pancreatic cancer.

Insulin-like growth factor (IGF)-axis genes plays a critical role in cancer development and progression via their impact on the RAS/MAPK/ERK and PI3K/AKT/mTOR signaling pathways. We hypothesized that IGF-axis genetic variants modify individual susceptibility to pancreatic cancer.We retrospectively genotyped 41 single-nucleotide polymorphisms of 10 IGF-axis genes (IGF1, IGF2, IGF1R, IGF2R, IGFBP1, IGFBP3, IGFBP5, IRS1, IRS2, and IRS4) in 706 pancreatic cancer patients and 706 cancer-free controls using Sequenom and TaqMan technology. The association between genotype and pancreatic cancer risk was evaluated using multivariate logistic regression. A P value ≤.007 at a false discovery rate of 10% was set as the significance level.We observed that the IGF1 *10212C>A and Ex4+2776G>A and IGF1R IVS2-70184A>G and IVS2+46329T>C variant genotypes were significantly associated with decreased pancreatic cancer risk (odds ratio [OR] range, 0.60-0.75) and that IGFBP1 Ex4+111A>G (I253M) was significantly associated with increased pancreatic cancer risk (OR=1.46) after adjusted for other risk factors and multiple comparisons (P≤.007). IGF2R and IGFBP3 variant haplotypes were associated with increased and decreased pancreatic cancer risk, respectively (P<.001). We also observed a weak interaction of the IGF1R IVS2+46329T>C and IGF2R Ex45+11C>T (L2222L) genotypes with diabetes (P(interaction)=.05) and interaction of IGF2R and IRS1 genotypes with alcohol consumption (P(interaction)=.03 and .019, respectively) on increased pancreatic cancer risk.These findings support our hypothesis that polymorphic variants of IGF-axis genes act alone or jointly with other risk factors to affect susceptibility to pancreatic cancer.

Authors
Dong, X; Li, Y; Tang, H; Chang, P; Hess, KR; Abbruzzese, JL; Li, D
MLA Citation
Dong, X, Li, Y, Tang, H, Chang, P, Hess, KR, Abbruzzese, JL, and Li, D. "Insulin-like growth factor axis gene polymorphisms modify risk of pancreatic cancer." Cancer epidemiology 36.2 (April 2012): 206-211.
PMID
21852217
Source
epmc
Published In
Cancer Epidemiology: the international journal of cancer epidemiology, detection and prevention
Volume
36
Issue
2
Publish Date
2012
Start Page
206
End Page
211
DOI
10.1016/j.canep.2011.05.013

Reply to A. Goyal et al

Authors
Kaseb, AO; Morris, JS; Hassan, MM; Abbruzzese, JL
MLA Citation
Kaseb, AO, Morris, JS, Hassan, MM, and Abbruzzese, JL. "Reply to A. Goyal et al." Journal of Clinical Oncology 30.9 (March 20, 2012): 1019-1020.
Source
crossref
Published In
Journal of Clinical Oncology
Volume
30
Issue
9
Publish Date
2012
Start Page
1019
End Page
1020
DOI
10.1200/JCO.2011.40.9375

Perineural and intraneural invasion in posttherapy pancreaticoduodenectomy specimens predicts poor prognosis in patients with pancreatic ductal adenocarcinoma.

Perineural invasion (PNI) is one of the established prognostic factors in pancreatic ductal adenocarcinoma (PDAC). However, the prognostic significance of PNI in patients with PDAC who received neoadjuvant therapy and pancreaticoduodenectomy is not clear. In this study, we performed a detailed examination of neural invasion in pancreaticoduodenectomy specimens from 212 patients with PDAC who received neoadjuvant chemoradiation (treated group) and in 60 untreated patients at our institution between January 1999 and December 2007. The frequency of PNI was higher in the untreated group (80%, 48/60) than in the treated group (58%, 123/212). For the 123 treated cases that were positive for PNI, extratumoral PNI, intratumoral PNI, intrapancreatic PNI only, extrapancreatic PNI, and intraneural invasion were identified in 86 (69.9%), 37 (30.1%), 11 (8.9%), 112 (91.1%), and 35 cases (28.5%), respectively. The presence of PNI correlated with tumor size, margin status, lymph node metastasis, pathologic tumor, and American Joint Committee on Cancer stages in the treated group. Tumor involvement of nerves >0.8 mm correlated with higher frequency of positive margin compared with tumors with PNI involving nerves ≤0.8 mm but not with other clinicopathologic parameters and survival. In the treated group, the presence of PNI or intraneural invasion correlated significantly with shorter disease-free survival and overall survival compared with no PNI or PNI only, respectively. PNI was an independent prognostic factor for both disease-free survival and overall survival in multivariate analysis. Our results showed that PNI plays an important role in the progression of PDAC and in predicting prognosis in this group of patients.

Authors
Chatterjee, D; Katz, MH; Rashid, A; Wang, H; Iuga, AC; Varadhachary, GR; Wolff, RA; Lee, JE; Pisters, PW; Crane, CH; Gomez, HF; Abbruzzese, JL; Fleming, JB; Wang, H
MLA Citation
Chatterjee, D, Katz, MH, Rashid, A, Wang, H, Iuga, AC, Varadhachary, GR, Wolff, RA, Lee, JE, Pisters, PW, Crane, CH, Gomez, HF, Abbruzzese, JL, Fleming, JB, and Wang, H. "Perineural and intraneural invasion in posttherapy pancreaticoduodenectomy specimens predicts poor prognosis in patients with pancreatic ductal adenocarcinoma." The American journal of surgical pathology 36.3 (March 2012): 409-417.
PMID
22301497
Source
epmc
Published In
American Journal of Surgical Pathology
Volume
36
Issue
3
Publish Date
2012
Start Page
409
End Page
417
DOI
10.1097/pas.0b013e31824104c5

The use of GTX as second-line and later chemotherapy for metastatic pancreatic cancer: a retrospective analysis.

There are limited data regarding the role of second-line treatment for metastatic pancreatic cancer (mPC) after the failure of initial chemotherapy. No data exist on the use of GTX after the failure of first-line therapy.We identified patients who were given GTX chemotherapy for a diagnosis of mPC after the failure of initial therapy. Demographic features, progression-free (PFS) and overall survival (OS), response to treatment, and toxicities were recorded.The 59 evaluable patients received a median of 2 prior therapies. Three had no prior gemcitabine. Median PS was 1. Median survival was 22 weeks; progression-free survival was 9.9 weeks. Survival did not correlate with the number of prior regimens but trended with PS. There were no radiologic responses; those with stable disease (n = 21) had a better survival than those with progression (n = 29) or unevaluable patients (n = 9). Median survival was 38.3, 15.0, and 7.4 weeks, respectively. Grade 3 and 4 toxicities included leucopenia (n = 14), anemia (n = 7), and thrombocytopenia (n = 6). Hospitalizations were required in 21 patients, for febrile neutropenia (n = 7), non-neutropenic infection (n = 3), pulmonary embolus (n = 2), anemia or failure to thrive (n = 9). A 75% drop or more in CA 19-9 correlated with improved survival.GTX is an active regimen in patients previously treated with gemcitabine for mPC. Better performance status and >75% drop in pretreatment CA 19-9 were associated with longer survival. The number of prior regimens did not predict for survival duration.

Authors
Dakik, HK; Moskovic, DJ; Carlson, PJ; Tamm, EP; Qiao, W; Wolff, RA; Abbruzzese, JL; Fogelman, DR
MLA Citation
Dakik, HK, Moskovic, DJ, Carlson, PJ, Tamm, EP, Qiao, W, Wolff, RA, Abbruzzese, JL, and Fogelman, DR. "The use of GTX as second-line and later chemotherapy for metastatic pancreatic cancer: a retrospective analysis." Cancer chemotherapy and pharmacology 69.2 (February 2012): 425-430.
PMID
21850466
Source
epmc
Published In
Cancer Chemotherapy and Pharmacology
Volume
69
Issue
2
Publish Date
2012
Start Page
425
End Page
430
DOI
10.1007/s00280-011-1705-x

Phase I and pharmacokinetic study of 3'-C-ethynylcytidine (TAS-106), an inhibitor of RNA polymerase I, II and III,in patients with advanced solid malignancies.

TAS-106 is a novel nucleoside analog that inhibits RNA polymerases I, II and II and has demonstrated robust antitumor activity in a wide range of models of human cancer in preclinical studies. This study was performed to principally evaluate the feasibility of administering TAS-106 as a bolus intravenous (IV) infusion every 3 weeks.Patients with advanced solid malignancies were treated with escalating doses of TAS-106 as a single bolus IV infusion every 3 weeks. Plasma and urine sampling were performed during the first course to characterize the pharmacokinetic profile of TAS-106 and assess pharmacodynamic relationships.Thirty patients were treated with 66 courses of TAS-106 at eight dose levels ranging from 0.67-9.46 mg/m(2). A cumulative sensory peripheral neuropathy was the principal dose-limiting toxicity (DLT) of TAS-106 at the 6.31 mg/m(2) dose level, which was determined to be the maximum tolerated dose (MTD). Other mild-moderate drug-related toxicities include asthenia, anorexia, nausea, vomiting, myelosuppression, and dermatologic effects. Major objective antitumor responses were not observed. The pharmacokinetics of TAS-106 were dose-proportional. The terminal elimination half-life (t(1/2)) averaged 11.3 ± 3.3 h. Approximately 71% of TAS-106 was excreted in the urine as unchanged drug. Pharmacodynamic relationships were observed between neuropathy and: C(5min;) AUC(0-inf;) and dermatologic toxicity.The recommended phase II dose of TAS-106 is 4.21 mg/m(2). However, due to a cumulative drug-related peripheral sensory neuropathy that proved to be dose-limiting, further evaluation of this bolus every 21 day infusion schedule will not be pursued and instead, an alternate dosing schedule of TAS-106 administered as a continuous 24-hour infusion will be explored to decrease C(max) in efforts to minimize peripheral neuropathy and maximize antitumor activity.

Authors
Hammond-Thelin, LA; Thomas, MB; Iwasaki, M; Abbruzzese, JL; Lassere, Y; Meyers, CA; Hoff, P; de Bono, J; Norris, J; Matsushita, H; Mita, A; Rowinsky, EK
MLA Citation
Hammond-Thelin, LA, Thomas, MB, Iwasaki, M, Abbruzzese, JL, Lassere, Y, Meyers, CA, Hoff, P, de Bono, J, Norris, J, Matsushita, H, Mita, A, and Rowinsky, EK. "Phase I and pharmacokinetic study of 3'-C-ethynylcytidine (TAS-106), an inhibitor of RNA polymerase I, II and III,in patients with advanced solid malignancies." Investigational new drugs 30.1 (February 2012): 316-326.
PMID
20839029
Source
epmc
Published In
Investigational New Drugs
Volume
30
Issue
1
Publish Date
2012
Start Page
316
End Page
326
DOI
10.1007/s10637-010-9535-y

Efficacy of bevacizumab plus erlotinib for advanced hepatocellular carcinoma and predictors of outcome: final results of a phase II trial.

OBJECTIVE: A phase II study was performed to evaluate the efficacy and tolerability of bevacizumab and erlotinib in advanced hepatocellular carcinoma (HCC) patients, and to investigate clinical and molecular predictors of outcome. METHODS: 59 patients with advanced HCC received 10 mg/kg i.v. of bevacizumab every 14 days and 150 mg p.o. of erlotinib daily. The primary endpoint was progression-free survival (PFS) at 16 weeks. Clinical characteristics and plasma biomarkers expression levels were analyzed. RESULTS: PFS at 16 weeks was 64% (95% CI 51-76): 14 patients achieved partial response (24%), 33 had stable disease (56%), 6 progressed (10%), and 6 were not evaluable (10%). Median overall survival was 13.7 months (95% CI 9.6-19.7), and median PFS was 7.2 months (95% CI 5.6-8.3). Grade 3-4 adverse events included fatigue (30%), diarrhea (17%), hypertension (14%), elevated transaminases (12%), and gastrointestinal hemorrhage (10%). High plasma angiopoietin-2, epidermal growth factor receptor, and endothelin-1, and lack of acneiform rash were associated with poor outcome. CONCLUSIONS: The combination of bevacizumab with erlotinib achieved encouraging results in patients with advanced HCC. Current correlatives may help to guide future HCC studies.

Authors
Kaseb, AO; Garrett-Mayer, E; Morris, JS; Xiao, L; Lin, E; Onicescu, G; Hassan, MM; Hassabo, HM; Iwasaki, M; Deaton, FL; Abbruzzese, JL; Thomas, MB
MLA Citation
Kaseb, AO, Garrett-Mayer, E, Morris, JS, Xiao, L, Lin, E, Onicescu, G, Hassan, MM, Hassabo, HM, Iwasaki, M, Deaton, FL, Abbruzzese, JL, and Thomas, MB. "Efficacy of bevacizumab plus erlotinib for advanced hepatocellular carcinoma and predictors of outcome: final results of a phase II trial." Oncology 82.2 (January 2012): 67-74.
PMID
22327795
Source
epmc
Published In
Oncology
Volume
82
Issue
2
Publish Date
2012
Start Page
67
End Page
74
DOI
10.1159/000335963

Pathologic complete response to neoadjuvant therapy in patients with pancreatic ductal adenocarcinoma is associated with a better prognosis.

In patients with pancreatic ductal adenocarcinoma (PDA) who received neoadjuvant therapy and pancreatectomy, pathologic complete response (pCR) is rarely observed and the prognostic significance of pCR is not clear. In this study, we identified 11 patients with pCR (2.5%) from 442 patients with PDA who received neoadjuvant treatment and pancreatectomy from 1995 to 2010. There were 6 men and 5 women, with a median age of 61 years. Four patients had either synchronous or history of extrapancreatic cancer. Five patients received neoadjuvant chemotherapy followed by chemoradiation, and 6 received chemoradiation alone. Ten patients had pancreaticoduodenectomy, and 1 had distal pancreatectomy. Scar and chronic pancreatitis consistent with therapy effect were present in all cases (100%). Pancreatic intraepithelial neoplasia (PanIN) 3/carcinoma in situ was present in 5 cases, and PanIN1 and PanIN2 in 5 cases. However, no residual invasive carcinoma or lymph node metastasis was identified in all cases. Follow-up information was available in 10 patients. Follow-up time ranges from 6 to 194 months (median, 63 months). During the follow-up, 3 patients died of other causes, and 1 developed a second primary PDA in the tail of the pancreas at 84 months after the initial pancreaticoduodenectomy and died at 105 months after the initial diagnosis of PDA. The other 6 patients were alive with no evidence of disease. Patients with pCR had a better survival than did those who had posttherapy stage I or IIA disease (P < .001). Patients with PDA who received neoadjuvant therapy and had pCR in pancreatectomy are rare but have a better prognosis.

Authors
Zhao, Q; Rashid, A; Gong, Y; Katz, MH; Lee, JE; Wolf, R; Balachandran, A; Varadhachary, GR; Pisters, PW; Wang, H; Gomez, HF; Abbruzzese, JL; Fleming, JB; Wang, H
MLA Citation
Zhao, Q, Rashid, A, Gong, Y, Katz, MH, Lee, JE, Wolf, R, Balachandran, A, Varadhachary, GR, Pisters, PW, Wang, H, Gomez, HF, Abbruzzese, JL, Fleming, JB, and Wang, H. "Pathologic complete response to neoadjuvant therapy in patients with pancreatic ductal adenocarcinoma is associated with a better prognosis." Annals of diagnostic pathology 16.1 (January 2012): 29-37.
PMID
22050964
Source
epmc
Published In
Annals of Diagnostic Pathology
Volume
16
Issue
1
Publish Date
2012
Start Page
29
End Page
37
DOI
10.1016/j.anndiagpath.2011.08.005

Effect of neoadjuvant chemoradiation and surgical technique on recurrence of localized pancreatic cancer.

To determine the influence of neoadjuvant chemoradiation and standardized dissection of the superior mesenteric artery upon the oncologic outcome of patients with localized pancreatic adenocarcinoma.One hundred ninety-four patients with pancreatic adenocarcinoma who underwent pancreaticoduodenectomy between 2004 and 2008 were evaluated. The retroperitoneal dissection was performed directly along the superior mesenteric artery in all cases. A standard histopathologic protocol that measured the "superior mesenteric artery (SMA) margin distance" between cancer cells and the superior mesenteric artery was employed.Seventy-six percent of patients received neoadjuvant chemoradiation. The SMA margin was positive in 4% of patients but an additional 22% of patients with a negative margin had a SMA margin distance of ≤1 mm. Preoperative CT images overestimated the SMA margin distance in 73% of cases. Patients who received chemoradiation had longer SMA margin distances than those who did not. Patients who received chemoradiation and had a SMA margin of >1 mm had the lowest recurrence rates. Administration of neoadjuvant chemoradiation and lower estimated blood loss were independently associated with longer progression-free survival on multivariate analysis.Preoperative chemoradiation and meticulous dissection of the superior mesenteric artery maximize the distance between cancer cells and the SMA margin and may influence locoregional control.

Authors
Katz, MHG; Wang, H; Balachandran, A; Bhosale, P; Crane, CH; Wang, X; Pisters, PWT; Lee, JE; Vauthey, J-N; Abdalla, EK; Wolff, R; Abbruzzese, J; Varadhachary, G; Chopin-Laly, X; Charnsangavej, C; Fleming, JB
MLA Citation
Katz, MHG, Wang, H, Balachandran, A, Bhosale, P, Crane, CH, Wang, X, Pisters, PWT, Lee, JE, Vauthey, J-N, Abdalla, EK, Wolff, R, Abbruzzese, J, Varadhachary, G, Chopin-Laly, X, Charnsangavej, C, and Fleming, JB. "Effect of neoadjuvant chemoradiation and surgical technique on recurrence of localized pancreatic cancer." Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract 16.1 (January 2012): 68-78.
PMID
22065318
Source
epmc
Published In
Journal of Gastrointestinal Surgery
Volume
16
Issue
1
Publish Date
2012
Start Page
68
End Page
78
DOI
10.1007/s11605-011-1748-7

Post-therapy pathologic stage and survival in patients with pancreatic ductal adenocarcinoma treated with neoadjuvant chemoradiation.

Neoadjuvant chemoradiation before surgery is an emerging treatment modality for pancreatic ductal adenocarcinoma (PDAC). However, analysis of prognostic factors is limited for patients with PDAC treated with neoadjuvant chemoradiation and pancreaticoduodenectomy (PD).The study population was comprised of 240 consecutive patients with PDAC who received neoadjuvant chemoradiation and PD and was compared with 60 patients who had no neoadjuvant therapy between 1999 and 2007. Clinicopathologic features were correlated with disease-free survival (DFS) and overall survival (OS).Among the 240 treated patients, the 1-year and 3-year DFS rates were 52% and 32%, with a median DFS of 15.1 months. The 1-year and 3-year OS rates were 95% and 47%, with a median OS of 33.5 months. By univariate analysis, DFS was associated with age, post-therapy tumor stage (ypT), lymph node status (ypN), number of positive lymph nodes, and American Joint Committee on Cancer (AJCC) stage, whereas OS was associated with intraoperative blood loss, margin status, ypT, ypN, number of positive lymph nodes, and AJCC stage. By multivariate analysis, DFS was independently associated with age, number of positive lymph nodes, and AJCC stage, and OS was independently associated with differentiation, margin status, number of positive lymph nodes, and AJCC stage. In addition, the treated patients had better OS and lower frequency of lymph node metastasis than those who had no neoadjuvant therapy.In patients with PDAC who received neoadjuvant chemoradiation and subsequent PD, post-therapy pathologic AJCC stage and number of positive lymph nodes are independent prognostic factors.

Authors
Estrella, JS; Rashid, A; Fleming, JB; Katz, MH; Lee, JE; Wolf, RA; Varadhachary, GR; Pisters, PWT; Abdalla, EK; Vauthey, J-N; Wang, H; Gomez, HF; Evans, DB; Abbruzzese, JL; Wang, H
MLA Citation
Estrella, JS, Rashid, A, Fleming, JB, Katz, MH, Lee, JE, Wolf, RA, Varadhachary, GR, Pisters, PWT, Abdalla, EK, Vauthey, J-N, Wang, H, Gomez, HF, Evans, DB, Abbruzzese, JL, and Wang, H. "Post-therapy pathologic stage and survival in patients with pancreatic ductal adenocarcinoma treated with neoadjuvant chemoradiation." Cancer 118.1 (January 2012): 268-277.
PMID
21735446
Source
epmc
Published In
Cancer
Volume
118
Issue
1
Publish Date
2012
Start Page
268
End Page
277
DOI
10.1002/cncr.26243

Bevacizumab plus gemcitabine and oxaliplatin as first-line therapy for metastatic or locally advanced pancreatic cancer: a phase II trial.

PURPOSE: The gemcitabine and oxaliplatin (GEMOX) has yielded among the longest progression-free survival durations in patients with advanced pancreatic cancer (APC). We postulated that adding bevacizumab would increase the effectiveness of GEMOX. METHODS: Eligible patients had stage III or IV pancreatic cancer, ECOG PS 0-2, and no prior gemcitabine. Treatment included 1,000 mg/m(2) intravenous gemcitabine over 100 min on day 1, 10 mg/kg intravenous bevacizumab on day 1, and 100 mg/m(2) oxaliplatin given on day 2. Cycles were repeated every 2 weeks. CT imaging was performed every 6 weeks. RESULTS: Fifty patients were enrolled: 14 had stage III disease, the remainder stage IV. Median age was 59 years. Fourty-five patients were ECOG 0-1. The grade 3-4 toxicity rate was 94%; fatigue (47%) and nausea (40%) were frequent. One patient died after a bowel perforation; a second died of a CVA. The median PFS was 4.9 months; median survival was 11.9 months; 1 year survival was 42%. Locally advanced patients lived 12.8 months; metastatic patients lived 10.2 months. Patients developing grade 3 hypertension were more likely to have a radiologic response (P = .012); survival among the top and bottom quintiles of hypertension was 14.7 and 6.2 months, respectively. Survival correlated with baseline CA 19-9 (P = .004) and radiologic response. The overall response rate was 36%; 34% demonstrated stable disease. CONCLUSIONS: The GEMOX/bevacizumab regimen demonstrated an excellent median overall survival but did not meet our objective of a 14 month median survival. Toxicity was significant. We do not recommend further evaluation of this regimen.

Authors
Fogelman, D; Jafari, M; Varadhachary, GR; Xiong, H; Bullock, S; Ozer, H; Lin, E; Morris, J; Cunningham, P; Bennett, B; Abbruzzese, JL; Wolff, RA
MLA Citation
Fogelman, D, Jafari, M, Varadhachary, GR, Xiong, H, Bullock, S, Ozer, H, Lin, E, Morris, J, Cunningham, P, Bennett, B, Abbruzzese, JL, and Wolff, RA. "Bevacizumab plus gemcitabine and oxaliplatin as first-line therapy for metastatic or locally advanced pancreatic cancer: a phase II trial." Cancer chemotherapy and pharmacology 68.6 (December 2011): 1431-1438.
PMID
21479635
Source
epmc
Published In
Cancer Chemotherapy and Pharmacology
Volume
68
Issue
6
Publish Date
2011
Start Page
1431
End Page
1438
DOI
10.1007/s00280-011-1601-4

Mast cells in tumor microenvironment promotes the in vivo growth of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer death. No effective therapy is currently available for PDAC because of the lack of understanding of the mechanisms leading to its growth and development. Inflammatory cells, particularly mast cells, have been shown to play key roles in some cancers. We carried out this study to test the hypothesis that mast cells in the tumor microenvironment are essential for PDAC tumorigenesis.The presence of inflammatory cells at various stages of PDAC development was determined in a spontaneous mouse model of PDAC (K-ras(G12V)). The importance of mast cells was determined using orthotopically implanted PDAC cells in mast cell-deficient Kit(w-sh/w-sh) mice and further confirmed by reconstitution of wild-type bone marrow-derived mast cells. Clinical relevance was assessed by correlating the presence of mast cells with clinical outcome in patients with PDAC.In the spontaneous mouse model of PDAC (K-ras(G12V)), there was an early influx of mast cells to the tumor microenvironment. PDAC tumor growth was suppressed in mast cell-deficient Kit(w-sh/w-sh) mice, but aggressive PDAC growth was restored when PDAC cells were injected into mast cell-deficient mice reconstituted with wild-type bone marrow-derived mast cells. Mast cell infiltration into the tumor microenvironment was predictive of poor prognosis in patients with PDAC.Mast cells play an important role in PDAC growth and development in mouse models and are indicative of poor prognosis in humans, which makes them a potential novel therapeutic target.

Authors
Chang, DZ; Ma, Y; Ji, B; Wang, H; Deng, D; Liu, Y; Abbruzzese, JL; Liu, Y-J; Logsdon, CD; Hwu, P
MLA Citation
Chang, DZ, Ma, Y, Ji, B, Wang, H, Deng, D, Liu, Y, Abbruzzese, JL, Liu, Y-J, Logsdon, CD, and Hwu, P. "Mast cells in tumor microenvironment promotes the in vivo growth of pancreatic ductal adenocarcinoma." Clinical cancer research : an official journal of the American Association for Cancer Research 17.22 (November 2011): 7015-7023.
PMID
21976550
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
17
Issue
22
Publish Date
2011
Start Page
7015
End Page
7023
DOI
10.1158/1078-0432.ccr-11-0607

Clinical and prognostic implications of plasma insulin-like growth factor-1 and vascular endothelial growth factor in patients with hepatocellular carcinoma.

Cirrhosis and hepatocellular carcinoma (HCC) together form a two-disease state that affects survival of patients with HCC and dictates treatment decisions and prognostic stratification of patients in clinical trials. The study objective was to improve prognostic stratification of patients with HCC.We prospectively collected plasma samples and baseline clinicopathologic features from 288 new patients with HCC, and plasma insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF) levels were tested. We applied Cox regression and log-rank tests to assess association of IGF-1 and VEGF with overall survival (OS), Kaplan-Meier curves to estimate OS, and recursive partitioning to determine optimal cutoff points for IGF-1 and VEGF. Prognostic ability of conventional and molecular Barcelona Clinic Liver Cancer classifications was compared using the c-index.Lower plasma IGF-1 and higher plasma VEGF levels significantly correlated with advanced clinicopathologic parameters and poor OS, with optimal cut points of 26 ng/mL and 450 pg/mL, respectively. The combination of low IGF-1 and high VEGF predicted median OS of 2.7 months compared with 19 months for patients with high IGF-1 and low VEGF (P < .001), further refining the prognostic ability of conventional HCC staging (P < .001).Baseline levels of plasma IGF-1 and VEGF correlated significantly with survival in patients with HCC. Integrating IGF-1 and VEGF into HCC staging significantly enhanced prognostic stratification of patients. If validated, these results may prove to be useful in designing strategies to personalize management approaches among these patients.

Authors
Kaseb, AO; Morris, JS; Hassan, MM; Siddiqui, AM; Lin, E; Xiao, L; Abdalla, EK; Vauthey, J-N; Aloia, TA; Krishnan, S; Abbruzzese, JL
MLA Citation
Kaseb, AO, Morris, JS, Hassan, MM, Siddiqui, AM, Lin, E, Xiao, L, Abdalla, EK, Vauthey, J-N, Aloia, TA, Krishnan, S, and Abbruzzese, JL. "Clinical and prognostic implications of plasma insulin-like growth factor-1 and vascular endothelial growth factor in patients with hepatocellular carcinoma." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 29.29 (October 2011): 3892-3899.
PMID
21911725
Source
epmc
Published In
Journal of Clinical Oncology
Volume
29
Issue
29
Publish Date
2011
Start Page
3892
End Page
3899
DOI
10.1200/jco.2011.36.0636

Anti-VEGF treatment-resistant pancreatic cancers secrete proinflammatory factors that contribute to malignant progression by inducing an EMT cell phenotype.

The resistance of tumors to antiangiogenic therapies is becoming increasingly relevant. There are currently no validated predictive biomarkers for selecting which cancer patients will benefit from antiangiogenic therapy. Also lacking are resistance biomarkers that can identify which escape pathways should be targeted after tumors develop resistance to VEGF treatment. Recent studies showed that anti-VEGF treatment can make tumor cells more aggressive and metastatic. However, the mechanisms and mediators of this are unidentified. Therefore, we aimed this study at directly identifying the tumor cell-initiated mechanisms responsible for the resistance of pancreatic cancer to anti-VEGF treatment.We established and validated two murine models of human pancreatic cancer resistant to the VEGF-specific antibody bevacizumab in vivo. We used a genome-wide analysis to directly identify which tumor-secreted factors were overexpressed by pancreatic cancer cells that were resistant to anti-VEGF treatment.Rather than direct proangiogenic factors, we identified several proinflammatory factors that were expressed at higher levels in cells resistant to anti-VEGF treatment than in treatment-sensitive control cells. These proinflammatory factors acted in a paracrine manner to stimulate the recruitment of CD11b(+) proangiogenic myeloid cells. Also, we found that secreted factors overexpressed by anti-VEGF treatment-resistant pancreatic cancer cells acted in an autocrine manner to induce epithelial-to-mesenchymal transition (EMT) and were thus responsible for increased aggressiveness of bevacizumab-resistant pancreatic tumors.Our results identified proinflammatory factors and EMT markers as potential biomarkers for selecting patients with pancreatic cancer for antiangiogenic therapy.

Authors
Carbone, C; Moccia, T; Zhu, C; Paradiso, G; Budillon, A; Chiao, PJ; Abbruzzese, JL; Melisi, D
MLA Citation
Carbone, C, Moccia, T, Zhu, C, Paradiso, G, Budillon, A, Chiao, PJ, Abbruzzese, JL, and Melisi, D. "Anti-VEGF treatment-resistant pancreatic cancers secrete proinflammatory factors that contribute to malignant progression by inducing an EMT cell phenotype." Clinical cancer research : an official journal of the American Association for Cancer Research 17.17 (September 2011): 5822-5832.
PMID
21737511
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
17
Issue
17
Publish Date
2011
Start Page
5822
End Page
5832
DOI
10.1158/1078-0432.ccr-11-1185

Introducing CCR perspectives in drug approval.

Authors
Abbruzzese, JL
MLA Citation
Abbruzzese, JL. "Introducing CCR perspectives in drug approval." Clinical cancer research : an official journal of the American Association for Cancer Research 17.15 (August 2011): 4929-.
PMID
21791634
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
17
Issue
15
Publish Date
2011
Start Page
4929
DOI
10.1158/1078-0432.ccr-11-1479

Modulation of pancreatic cancer chemoresistance by inhibition of TAK1.

TGF-β-activated kinase-1 (TAK1), a mitogen-activated protein kinase kinase kinase, functions in the activation of nuclear factor κB (NF-κB) and activator protein-1, which can suppress proapoptotic signaling pathways and thus promote resistance to chemotherapeutic drugs. However, it is not known if inhibition of TAK1 is effective in reducing chemoresistance to therapeutic drugs against pancreatic cancer.NF-κB activity was measured by luciferase reporter assay in human pancreatic cancer cell lines AsPc-1, PANC-1, and MDAPanc-28, in which TAK1 expression was silenced by small hairpin RNA. TAK1 kinase activity was targeted in AsPc-1, PANC-1, MDAPanc-28, and Colo357FG cells with exposure to increasing doses of a selective small-molecule inhibitor, LYTAK1, for 24 hours. To test the effect of LYTAK1 in combination with chemotherapeutic agents, AsPc-1, PANC-1, MDAPanc-28 cells, and control cells were treated with increasing doses of oxaliplatin, SN-38, or gemcitabine in combination with LYTAK1. In vivo activity of oral LYTAK1 was evaluated in an orthotopic nude mouse model (n = 40, 5 per group) with luciferase-expressing AsPc-1 pancreatic cancer cells. The results of in vitro proliferation were analyzed for statistical significance of differences by nonlinear regression analysis; differences in mouse survival were determined using a log-rank test. All statistical tests were two-sided.AsPc-1 and MDAPanc-28 TAK1 knockdown cells had a statistically significantly lower NF-κB activity than did their respective control cell lines (relative luciferase activity: AsPc-1, mean = 0.18, 95% confidence interval [CI] = 0.10 to 0.27; control, mean = 3.06, 95% CI = 2.31 to 3.80; MDAPanc-28, mean = 0.30, 95% CI = 0.13 to 0.46; control, mean = 4.53, 95% CI = 3.43 to 5.63; both P < .001). TAK1 inhibitor LYTAK1 had potent in vitro cytotoxic activity in AsPc-1, PANC-1, MDAPanc-28, and Colo357FG cells, with IC(50) between 5 and 40 nM. LYTAK1 also potentiated the cytotoxicity of chemotherapeutic agents oxaliplatin, SN-38, and gemcitabine in AsPc-1, PANC-1, and MDAPanc-28 cells compared with control cells (P < .001). In nude mice, oral administration of LYTAK1 plus gemcitabine statistically significantly reduced tumor burden (gemcitabine vs gemcitabine plus LYTAK1, P = .03) and prolonged survival duration (median survival: gemcitabine, 82 days vs gemcitabine plus LYTAK1, 122 days; hazard ratio = 0.334, 95% CI = 0.027 to 0.826, P = .029).The results of this study suggest that genetic silencing or inhibition of TAK1 kinase activity in vivo is a potential therapeutic approach to reversal of the intrinsic chemoresistance of pancreatic cancer.

Authors
Melisi, D; Xia, Q; Paradiso, G; Ling, J; Moccia, T; Carbone, C; Budillon, A; Abbruzzese, JL; Chiao, PJ
MLA Citation
Melisi, D, Xia, Q, Paradiso, G, Ling, J, Moccia, T, Carbone, C, Budillon, A, Abbruzzese, JL, and Chiao, PJ. "Modulation of pancreatic cancer chemoresistance by inhibition of TAK1." Journal of the National Cancer Institute 103.15 (August 2011): 1190-1204.
PMID
21743023
Source
epmc
Published In
Journal of the National Cancer Institute
Volume
103
Issue
15
Publish Date
2011
Start Page
1190
End Page
1204
DOI
10.1093/jnci/djr243

A phase II study of isoflavones, erlotinib, and gemcitabine in advanced pancreatic cancer.

BACKGROUND: The EGFR/Akt/NF-κB signalling pathway is frequently deregulated in pancreatic cancer and contributes to cell growth, metastasis and chemoresistance. An isoflavone, genistein, inactivates Akt and NF-κB and enhances the anti-tumor activity of erlotinib and gemcitabine in experimental systems of pancreas cancer. This phase II study was undertaken to determine the effects of adding isoflavone to a regimen of gemcitabine and erlotinib on survival in patients with advanced pancreatic cancer. METHODS: Eligibility included previously untreated patients with advanced pancreatic adenocarcinoma. Patients received gemcitabine 1,000 mg/m² on days 1, 8, and 15, and erlotinib 150 mg once daily P.O. on day 1 to day 28. Soy isoflavones (Novasoy®) were administered at a dose of 531 mg twice daily P.O. starting day -7 until the end of study participation. RESULTS: Twenty patients with advanced pancreas cancer were enrolled (median age 57.9 years). Sixteen patients had stage IV disease. The median number of cycles was 2 per patient. The median survival time was 5.2 months (95% CI, 4.6-N/A months). The probability of survival at 6 months was 50% (95% CI, 32-78%). CONCLUSIONS: The addition of soy isoflavones to gemcitabine and erlotinib did not appear to increase the survival of patients with advanced pancreatic cancer.

Authors
El-Rayes, BF; Philip, PA; Sarkar, FH; Shields, AF; Ferris, AM; Hess, K; Kaseb, AO; Javle, MM; Varadhachary, GR; Wolff, RA; Abbruzzese, JL
MLA Citation
El-Rayes, BF, Philip, PA, Sarkar, FH, Shields, AF, Ferris, AM, Hess, K, Kaseb, AO, Javle, MM, Varadhachary, GR, Wolff, RA, and Abbruzzese, JL. "A phase II study of isoflavones, erlotinib, and gemcitabine in advanced pancreatic cancer." Investigational new drugs 29.4 (August 2011): 694-699.
PMID
20107864
Source
epmc
Published In
Investigational New Drugs
Volume
29
Issue
4
Publish Date
2011
Start Page
694
End Page
699
DOI
10.1007/s10637-010-9386-6

Phase II trial of cetuximab, gemcitabine, and oxaliplatin followed by chemoradiation with cetuximab for locally advanced (T4) pancreatic adenocarcinoma: correlation of Smad4(Dpc4) immunostaining with pattern of disease progression.

This phase II trial was designed to assess the efficacy and safety of cetuximab, gemcitabine, and oxaliplatin followed by cetuximab, capecitabine, and radiation therapy in locally advanced pancreatic cancer (LAPC).Treatment-naive eligible patients (n = 69) received intravenous gemcitabine (1,000 mg/m(2)) and oxaliplatin (100 mg/m(2)) every 2 weeks for four doses, followed by radiation (50.4 Gy to the gross tumor only) with concurrent capecitabine (825 mg/m(2) twice daily on radiation treatment days). Cetuximab (500 mg/m(2)) was started on day 1 of chemotherapy and was continued every 2 weeks during chemotherapy and chemoradiotherapy. Diagnostic cytology specimens were immunostained for Smad4(Dpc4) expression.Median overall survival time was 19.2 months (95% CI, 14.2 to 24.2 months), and 1-year, 2-year, and 4-year actuarial overall survival rates were 66.0%, 25.02%, and 11.3%, respectively. Acneiform rash correlated with improved survival (P = .001), but initial CA19-9, borderline resectable initial stage, and surgical resection (n = 7) did not. The 1-year and 2-year radiographic local progression rates were 22.8% and 61.0%, respectively. The worst acute toxic effects were GI toxicity (32% and 10% for grades 2 and 3, respectively); fatigue (26% and 6% for grades 2 and 3, respectively); sensory neuropathy (9% and 1% for grades 2 and 3, respectively); and acneiform rash (54% and 3% for grades 2 and 3, respectively). Smad4(Dpc4) expression correlated with a local rather than a distant dominant pattern of disease progression (P = .016).This regimen appears effective and has acceptable toxicity. The primary end point (1-year overall survival rate > 45%) was met, with encouraging survival duration. Smad4(Dpc4) immunostaining correlated with the pattern of disease progression. Prospective validation of Smad4(Dpc4) expression in cytology specimens as a predictive biomarker is warranted and may lead to personalized treatment strategies for patients with localized pancreatic cancer.

Authors
Crane, CH; Varadhachary, GR; Yordy, JS; Staerkel, GA; Javle, MM; Safran, H; Haque, W; Hobbs, BD; Krishnan, S; Fleming, JB; Das, P; Lee, JE; Abbruzzese, JL; Wolff, RA
MLA Citation
Crane, CH, Varadhachary, GR, Yordy, JS, Staerkel, GA, Javle, MM, Safran, H, Haque, W, Hobbs, BD, Krishnan, S, Fleming, JB, Das, P, Lee, JE, Abbruzzese, JL, and Wolff, RA. "Phase II trial of cetuximab, gemcitabine, and oxaliplatin followed by chemoradiation with cetuximab for locally advanced (T4) pancreatic adenocarcinoma: correlation of Smad4(Dpc4) immunostaining with pattern of disease progression." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 29.22 (August 2011): 3037-3043.
PMID
21709185
Source
epmc
Published In
Journal of Clinical Oncology
Volume
29
Issue
22
Publish Date
2011
Start Page
3037
End Page
3043
DOI
10.1200/jco.2010.33.8038

Association of CHFR promoter methylation with disease recurrence in locally advanced colon cancer.

This study was designed to determine whether DNA methylation biomarkers are associated with recurrence and survival in colon cancer patients.A retrospective analysis of 82 patients who received curative surgical resection for American Joint Committee on Cancer (AJCC) high-risk stage II or III colon cancer (1999-2007) was conducted. DNA methylation status was quantitatively evaluated by the pyrosequencing method. We preselected three tumor suppressor genes and one locus of interest; CHFR, ID4, RECK, and MINT1. Mean methylation levels of multiple CpG sites in the promoter regions were used for analysis; 15% or more was defined as methylation positive. The association of recurrence-free survival (RFS) and overall survival (OS) with methylation status was analyzed by the log-rank test, Kaplan-Meier method, and Cox proportional hazards model.Methylation levels of ID4, MINT1, and RECK did not correlate with RFS or OS. CHFR was methylation positive in 63% patients. When methylation status was dichotomized (negative or low: <30%, high: ≥30%), patients with CHFR methylation-high (44%) had worse RFS (P = 0.006) and reduced OS (P = 0.069). When stratified by stage, CHFR methylation-high was associated with reduced RFS (P = 0.004) and OS (P = 0.010) in stage III patients. CHFR methylation-high was commonly associated with N2 disease (P = 0.04) and proximal tumors (P = 0.002). Multivariate analysis indicated AJCC T4 disease and CHFR methylation-high (P = 0.001 and P = 0.015, respectively) were independent predictors for recurrence.The extent of CHFR promoter methylation correlates with RFS, indicating it is a promising epigenetic marker for recurrence.

Authors
Tanaka, M; Chang, P; Li, Y; Li, D; Overman, M; Maru, DM; Sethi, S; Phillips, J; Bland, GL; Abbruzzese, JL; Eng, C
MLA Citation
Tanaka, M, Chang, P, Li, Y, Li, D, Overman, M, Maru, DM, Sethi, S, Phillips, J, Bland, GL, Abbruzzese, JL, and Eng, C. "Association of CHFR promoter methylation with disease recurrence in locally advanced colon cancer." Clinical cancer research : an official journal of the American Association for Cancer Research 17.13 (July 2011): 4531-4540.
PMID
21551253
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
17
Issue
13
Publish Date
2011
Start Page
4531
End Page
4540
DOI
10.1158/1078-0432.ccr-10-0763

V-CLIP: Integrating plasma vascular endothelial growth factor into a new scoring system to stratify patients with advanced hepatocellular carcinoma for clinical trials.

Several staging systems have been proposed for hepatocellular carcinoma (HCC); however, none has incorporated circulating angiogenic biomarkers. The purpose of this study was to determine whether vascular endothelial growth factor (VEGF) could independently predict overall survival in patients with HCC, and whether adding VEGF level into the Cancer of the Liver Italian Program (CLIP) score could improve patient stratification and prediction of overall survival.Between 2001 and 2008, baseline plasma VEGF levels were available from 288 patients, and multivariate Cox regression models and median survival (95% confidence intervals) were calculated. Recursive partitioning was used to determine the optimal cutpoint for VEGF, using 10 repeated training/validation samples, each using two-thirds of the data to determine the best cutpoint and the remaining one-third to validate it. Prognostic ability of CLIP and V-CLIP was compared using the concordence index.Plasma VEGF was a significant independent predictor of overall survival, with an optimal VEGF cutpoint of 450 pg/mL. After CLIP validation in our patients, we added VEGF to the CLIP score and found that the new V-CLIP score better separates patients into homogenous prognostic groups (P = .005).The assessment of baseline plasma VEGF levels increases the precision of the CLIP scoring system for predicting HCC prognosis, which may assist in equally randomizing patients with HCC in clinical trials. Prospective validation of the V-CLIP scoring system is warranted.

Authors
Kaseb, AO; Hassan, MM; Lin, E; Xiao, L; Kumar, V; Pathak, P; Lozano, R; Rashid, A; Abbruzzese, JL; Morris, JS
MLA Citation
Kaseb, AO, Hassan, MM, Lin, E, Xiao, L, Kumar, V, Pathak, P, Lozano, R, Rashid, A, Abbruzzese, JL, and Morris, JS. "V-CLIP: Integrating plasma vascular endothelial growth factor into a new scoring system to stratify patients with advanced hepatocellular carcinoma for clinical trials." Cancer 117.11 (June 2011): 2478-2488.
PMID
24048796
Source
epmc
Published In
Cancer
Volume
117
Issue
11
Publish Date
2011
Start Page
2478
End Page
2488
DOI
10.1002/cncr.25791

Prospective gene signature study using microRNA to identify the tissue of origin in patients with carcinoma of unknown primary.

PURPOSE: Accurate identification of tissue of origin (ToO) for patients with carcinoma of unknown primary (CUP) may help customize therapy to the putative primary and thereby improve the clinical outcome. We prospectively studied the performance of a microRNA-based assay to identify the ToO in CUP patients. EXPERIMENTAL DESIGN: Formalin-fixed paraffin-embedded (FFPE) metastatic tissue from 104 patients was reviewed and 87 of these contained sufficient tumor for testing. The assay quantitates 48 microRNAs and assigns one of 25 tumor diagnoses by using a biologically motivated binary decision tree and a K-nearest neighbors (KNN). The assay predictions were compared with clinicopathologic features and, where suitable, to therapeutic response. RESULTS: Seventy-four of the 87 cases were processed successfully. The assay result was consistent or compatible with the clinicopathologic features in 84% of cases processed successfully (71% of all samples attempted). In 65 patients, pathology and immunohistochemistry (IHC) suggested a diagnosis or (more often) a differential diagnosis. Out of those, the assay was consistent or compatible with the clinicopathologic presentation in 55 (85%) cases. Of the 9 patients with noncontributory IHC, the assay provided a ToO prediction that was compatible with the clinical presentation in 7 cases. CONCLUSIONS: In this prospective study, the microRNA diagnosis was compatible with the clinicopathologic picture in the majority of cases. Comparative effectiveness research trials evaluating the added benefit of molecular profiling in appropriate CUP subsets are warranted. MicroRNA profiling may be particularly helpful in patients in whom the IHC profile of the metastasis is nondiagnostic or leaves a large differential diagnosis.

Authors
Varadhachary, GR; Spector, Y; Abbruzzese, JL; Rosenwald, S; Wang, H; Aharonov, R; Carlson, HR; Cohen, D; Karanth, S; Macinskas, J; Lenzi, R; Chajut, A; Edmonston, TB; Raber, MN
MLA Citation
Varadhachary, GR, Spector, Y, Abbruzzese, JL, Rosenwald, S, Wang, H, Aharonov, R, Carlson, HR, Cohen, D, Karanth, S, Macinskas, J, Lenzi, R, Chajut, A, Edmonston, TB, and Raber, MN. "Prospective gene signature study using microRNA to identify the tissue of origin in patients with carcinoma of unknown primary." Clinical cancer research : an official journal of the American Association for Cancer Research 17.12 (June 2011): 4063-4070.
PMID
21531815
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
17
Issue
12
Publish Date
2011
Start Page
4063
End Page
4070
DOI
10.1158/1078-0432.ccr-10-2599

Glucose metabolism gene variants modulate the risk of pancreatic cancer.

Long-term type 2 diabetes is a known risk factor for pancreatic cancer (PC). We hypothesized that genetic variants in glucose metabolism modify individual susceptibility to PC, especially those associated with diabetes. We retrospectively genotyped 26 single-nucleotide polymorphisms of 5 glucose metabolism genes: glucokinase (GCK), glutamine-fructose-6-phosphate transaminase 1 (GFPT1), glucose phosphate isomerase (GPI), hexokinase 2 (HK2), and O-linked N-acetylglucosamine transferase (OGT) in a case-control study of PC conducted at MD Anderson during 2004 to 2010. Initial genotyping was conducted in 706 patients with PC and 706 cancer-free controls by using the Sequenom method. A HK2 genotype (R844K) with low frequency of homozygous variant was further examined in additional 948 patients and 476 controls. In the combined set of 1,654 cases and 1,182 controls, we showed a significant association of the HK2 R844K GA/AA genotype with reduced PC risk (OR = 0.78; 95% CI, 0.64-0.94; P = 0.009) and a significant interaction with diabetes (P(interaction) < 0.001). The HK2 R844K GA/AA genotype was associated with a reduced risk of PC among nondiabetic individuals (OR = 0.68; 95% CI, 0.56-0.83) but with increased risk among diabetic patients (OR = 3.69; 95% CI, 2.34-5.82). These risk associations remained statistically significant when the analysis was restricted to whites or after exclusion of recent onset diabetes. No significant main effect of other genes or significant interaction of genotype with other risk factors was observed. The findings show a potential role of HK2 gene, alone or in interaction with diabetes, in modifying the risk of PC.

Authors
Dong, X; Li, Y; Chang, P; Tang, H; Hess, KR; Abbruzzese, JL; Li, D
MLA Citation
Dong, X, Li, Y, Chang, P, Tang, H, Hess, KR, Abbruzzese, JL, and Li, D. "Glucose metabolism gene variants modulate the risk of pancreatic cancer." Cancer prevention research (Philadelphia, Pa.) 4.5 (May 2011): 758-766.
PMID
21411499
Source
epmc
Published In
Cancer Prevention Research
Volume
4
Issue
5
Publish Date
2011
Start Page
758
End Page
766
DOI
10.1158/1940-6207.capr-10-0247

Body mass index and obesity- and diabetes-associated genotypes and risk for pancreatic cancer.

The genetic factors predisposing individuals with obesity or diabetes to pancreatic cancer have not been identified.To investigate the hypothesis that obesity- and diabetes-related genes modify the risk of pancreatic cancer.We genotyped 15 single nucleotide polymorphisms of fat mass and obesity-associated (FTO), peroxisome proliferators-activated receptor gamma (PPARγ), nuclear receptor family 5 member 2 (NR5A2), AMPK, and ADIPOQ genes in 1,070 patients with pancreatic cancer and 1,175 cancer-free controls. Information on risk factors was collected by personal interview. Adjusted ORs (AOR) and 95% CIs were calculated using unconditional logistic regression.The PPARγ P12A GG genotype was inversely associated with risk of pancreatic cancer (AOR, 0.21; 95% CI, 0.07-0.62). Three NR5A2 variants that were previously identified in a genome-wide association study were significantly associated with reduced risk of pancreatic cancer, AORs ranging from 0.57 to 0.79. Two FTO gene variants and one ADIPOQ variant were differentially associated with pancreatic cancer according to levels of body mass index (BMI; P(interaction) = 0.0001, 0.0015, and 0.03). For example, the AOR (95% CI) for FTO IVS1-2777AC/AA genotype was 0.72 (0.55-0.96) and 1.54 (1.14-2.09) in participants with a BMI of less than 25 or 25 kg/m(2) or more, respectively. We observed no significant association between AMPK genotype and pancreatic cancer and no genotype interactions with diabetes or smoking.Our findings suggest the PPARγ P12A GG genotype and NR5A2 variants may reduce the risk for pancreatic cancer. A positive association of FTO and ADIPOQ gene variants with pancreatic cancer may be limited to persons who are overweight.The discovery of genetic factors modifying the risk of pancreatic cancer may help to identify high-risk individuals for prevention efforts.

Authors
Tang, H; Dong, X; Hassan, M; Abbruzzese, JL; Li, D
MLA Citation
Tang, H, Dong, X, Hassan, M, Abbruzzese, JL, and Li, D. "Body mass index and obesity- and diabetes-associated genotypes and risk for pancreatic cancer." Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20.5 (May 2011): 779-792.
PMID
21357378
Source
epmc
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
20
Issue
5
Publish Date
2011
Start Page
779
End Page
792
DOI
10.1158/1055-9965.epi-10-0845

Altered decamer and nonamer from an HLA-A0201-restricted epitope of Survivin differentially stimulate T-cell responses in different individuals.

Survivin is a universal tumor antigen that is being currently targeted in vaccine approaches against cancer. Our study here examined the immunogenicity of a novel variant of an HLA-A0201-binding decamer peptide from region 95 to 104 of Survivin (ELMLGEFLKL) with a T→M modification at position 3 in the peptide. We found that this new modified 10-mer peptide had enhanced HLA-A0201 binding and induced a stronger T-cell response over its wild type counterpart peptide (ELTLGEFLKL) in select HLA-A0201(+) normal donors. In addition, when compared to the previously characterized altered 96-104 peptide (LMLGEFLKL) from the same region of Survivin currently used in vaccine trials, we found that both peptides had similar immunogenicity, but donor T cells preferentially reacted strongly to either one or the other, but not strongly to both. These results suggest that these two closely related Survivin peptides yield distinct T-cell responses and that most individuals dominantly respond to one or the other altered peptide. We also found a novel association between positive reactivity to the new altered decamer Survivin peptide in some individuals and their expression of the HLA-C0701 allele along with HLA-A0201. Thus, vaccinating with both the 10-mer and 9-mer peptides would be required to immunize a maximum number of individuals in the HLA-A0201(+) population and could lead to more consistent T-cell responses against this region of Survivin.

Authors
Bernatchez, C; Zhu, K; Li, Y; Andersson, H; Ionnides, C; Fernandez-Vina, M; Cano, P; Cooper, L; Abbruzzese, J; Hwu, P; Chang, DZ; Radvanyi, LG
MLA Citation
Bernatchez, C, Zhu, K, Li, Y, Andersson, H, Ionnides, C, Fernandez-Vina, M, Cano, P, Cooper, L, Abbruzzese, J, Hwu, P, Chang, DZ, and Radvanyi, LG. "Altered decamer and nonamer from an HLA-A0201-restricted epitope of Survivin differentially stimulate T-cell responses in different individuals." Vaccine 29.16 (April 2011): 3021-3030.
PMID
21320548
Source
epmc
Published In
Vaccine
Volume
29
Issue
16
Publish Date
2011
Start Page
3021
End Page
3030
DOI
10.1016/j.vaccine.2011.01.115

Evidence for the efficacy of Iniparib, a PARP-1 inhibitor, in BRCA2-associated pancreatic cancer.

Pancreatic cancer is an aggressive, frequently fatal malignancy that strikes 37,000 patients annually in the U.S.A. It is poorly responsive to standard chemotherapies such as gemcitabine. Approximately 5-10% of pancreatic cancer occurs in the setting of a BRCA2 mutation. Breast and ovarian carcinomas that harbor BRCA2 mutations are susceptible to the effects of an emerging class of targeted agents, namely, poly(ADP-ribose) polymerase (PARP) inhibitors. This report describes the case of a patient with a germline BRCA2 mutation and an associated pancreatic cancer treated with iniparib (BSI-201), a PARP inhibitor, who demonstrated a complete pathologic response to this agent. This case highlights the potential benefit for PARP inhibition in BRCA2-related pancreatic cancer.

Authors
Fogelman, DR; Wolff, RA; Kopetz, S; Javle, M; Bradley, C; Mok, I; Cabanillas, F; Abbruzzese, JL
MLA Citation
Fogelman, DR, Wolff, RA, Kopetz, S, Javle, M, Bradley, C, Mok, I, Cabanillas, F, and Abbruzzese, JL. "Evidence for the efficacy of Iniparib, a PARP-1 inhibitor, in BRCA2-associated pancreatic cancer." Anticancer research 31.4 (April 2011): 1417-1420.
PMID
21508395
Source
epmc
Published In
Anticancer research
Volume
31
Issue
4
Publish Date
2011
Start Page
1417
End Page
1420

A randomized phase II study of PX-12, an inhibitor of thioredoxin in patients with advanced cancer of the pancreas following progression after a gemcitabine-containing combination.

PURPOSE: This study evaluated PX-12, a novel small molecule inhibitor of the proto-oncogene (Trx-1), in patients with previously treated advanced pancreatic cancer (APC). METHODS: PX-12 (54 or 128 mg/m²) was administered by 3-hour IV infusion daily × 5 days every 21 days (n = 17). Patients were randomized to either 54 or 128 mg/m² and then stratified based on CA 19-9 level (≥ 1,000 vs. < 1,000 U/ml) and SUV values on PET scans (≥ 7.0 vs. <7.0). The primary endpoint was based on a progression-free survival (PFS) at 4 months in ≥ 40% of patients, and required 40 patients in each arm. An amendment required elevated Trx-1 levels (> 18 ng/ml) as an entry criteria after the first 17 patients were accrued. RESULTS: Plasma Trx-1 levels were elevated in 3/28 (11%) patients screened for study. The grade of the expired metabolite odor was higher in the 128 mg/m² arm. Therapy was well tolerated, and Grade ≥ 3 adverse events were uncommon. The best response was stable disease in 2 patients. There was no consistent decrease in SUV, Trx-1 levels or CA 19-9 levels with therapy. No patients had a PFS of >4 months. Median PFS and survival were 0.9 months (95% CI 0.5-1.2) and 3.2 months (95% CI 2.4-4.2), respectively. CONCLUSIONS: Due to the lack of significant antitumor activity and unexpectedly low baseline Trx-1 levels, the study was terminated early. PX-12 does not appear to be active in unselected patients with previously treated APC.

Authors
Ramanathan, RK; Abbruzzese, J; Dragovich, T; Kirkpatrick, L; Guillen, JM; Baker, AF; Pestano, LA; Green, S; Von Hoff, DD
MLA Citation
Ramanathan, RK, Abbruzzese, J, Dragovich, T, Kirkpatrick, L, Guillen, JM, Baker, AF, Pestano, LA, Green, S, and Von Hoff, DD. "A randomized phase II study of PX-12, an inhibitor of thioredoxin in patients with advanced cancer of the pancreas following progression after a gemcitabine-containing combination." Cancer chemotherapy and pharmacology 67.3 (March 2011): 503-509.
PMID
20461382
Source
epmc
Published In
Cancer Chemotherapy and Pharmacology
Volume
67
Issue
3
Publish Date
2011
Start Page
503
End Page
509
DOI
10.1007/s00280-010-1343-8

Glucose metabolism gene polymorphisms and clinical outcome in pancreatic cancer.

Altered glucose metabolism is the most common metabolic hallmark of malignancies. The authors tested the hypothesis that glucose metabolism gene variations affect clinical outcome in pancreatic cancer.The authors retrospectively genotyped 26 single nucleotide polymorphisms from 5 glucose metabolism genes in 154 patients with localized disease and validated the findings in 552 patients with different stages of pancreatic adenocarcinoma. Association between genotypes and overall survival (OS) was evaluated using multivariate Cox proportional hazard regression models with adjustment for clinical predictors.Glucokinase (GCK) IVS1 + 9652C > T and hexokinase 2 (HK2) N692N homozygous variants were significantly associated with reduced OS in the training set of 154 patients (P < .001). These associations were confirmed in the validation set of 552 patients and in the combined dataset of all 706 patients (P ≤ .001). In addition, HK2 R844K variant K allele was associated with a better survival in the validation set and the combined dataset (P ≤ .001). When data were further analyzed by disease stage, glutamine-fructose-6-phosphate transaminase (GFPT1) IVS14-3094T>C, HK2 N692N and R844K in patients with localized disease and GCK IVS1 + 9652C>T in patients with advanced disease were significant independent predictors for OS (P ≤ .001). Haplotype CGG of GPI and GCTATGG of HK2 were associated with better OS, respectively, with P values of .004 and .007.The authors demonstrated that glucose metabolism gene polymorphisms affect clinical outcome in pancreatic cancer. These observations support a role of abnormal glucose metabolism in pancreatic carcinogenesis.

Authors
Dong, X; Tang, H; Hess, KR; Abbruzzese, JL; Li, D
MLA Citation
Dong, X, Tang, H, Hess, KR, Abbruzzese, JL, and Li, D. "Glucose metabolism gene polymorphisms and clinical outcome in pancreatic cancer." Cancer 117.3 (February 2011): 480-491.
PMID
20845477
Source
epmc
Published In
Cancer
Volume
117
Issue
3
Publish Date
2011
Start Page
480
End Page
491
DOI
10.1002/cncr.25612

Overexpression of receptor tyrosine kinase Axl promotes tumor cell invasion and survival in pancreatic ductal adenocarcinoma.

The receptor tyrosine kinase Axl has been reported to be overexpressed in a variety of human cancers. Although previous studies have identified the role of Axl in the transformation, proliferation, survival, and invasion in cancers, the expression and functions of Axl in pancreatic cancer have not been studied in detail.The expression of Axl protein in 12 pancreatic cancer cell lines and 54 patient samples of stage II pancreatic ductal adenocarcinoma (PDA) and their paired non-neoplastic pancreatic tissue samples were examined. Using univariate and multivariate analysis, Axl expression was correlated with survival and other clinicopathologic features. To examine Axl functions in PDA, the effects of Axl knockdown on the invasion ability and radiation-induced apoptosis in PDA cell lines were measured.Axl was overexpressed in 38 of 54 (70%) stage II PDA samples and 9 of 12 (75%) PDA cell lines. Axl overexpression was associated with higher frequencies of distant metastasis and poor overall and recurrence-free survivals (P = .03 and P = .04, respectively) independent of tumor size and stage or lymph node status in patients with stage II PDA. Knockdown of Axl expression in PDA cells abolished Gas6-mediated Akt activation, decreased invasion, and increased radiation-induced PARP cleavage and the percentage of apoptosis.This study showed that Gas6 and Axl are frequently overexpressed in PDA cells and are associated with a poor prognosis in patients with stage II PDA. Axl promotes the invasion and survival of PDA cells. Therefore, targeting the Axl signaling pathway may represent a new approach to the treatment of PDA.

Authors
Song, X; Wang, H; Logsdon, CD; Rashid, A; Fleming, JB; Abbruzzese, JL; Gomez, HF; Evans, DB; Wang, H
MLA Citation
Song, X, Wang, H, Logsdon, CD, Rashid, A, Fleming, JB, Abbruzzese, JL, Gomez, HF, Evans, DB, and Wang, H. "Overexpression of receptor tyrosine kinase Axl promotes tumor cell invasion and survival in pancreatic ductal adenocarcinoma." Cancer 117.4 (February 2011): 734-743.
PMID
20922806
Source
epmc
Published In
Cancer
Volume
117
Issue
4
Publish Date
2011
Start Page
734
End Page
743
DOI
10.1002/cncr.25483

Association of multi-drug resistance gene polymorphisms with pancreatic cancer outcome.

The purpose of this study was to identify single nucleotide polymorphisms (SNPs) of multidrug resistance genes that are associated with clinical outcome in patients with potentially resectable pancreatic adenocarcinoma who were treated with preoperative gemcitabine-based chemoradiotherapy at M. D. Anderson Cancer Center.We selected 8 SNPs of 7 drug resistance genes, including MDR1 (ABCB1), MRP1-5 (ABCC1-5), and BCRP (ABCG2), reported to be important in mediating drug resistance. Genotype was determined by the Taqman method. The associations of genotype with tumor response to therapy and overall survival (OS) were evaluated using log-rank test, Cox regression, and logistic regression models.MRP5 A-2G AA genotype showed significant association with OS (log-rank P = .010). The hazard ratio (95% confidence interval) was 1.65 (1.11-2.45) after adjusting for clinical predictors. The MRP2 G40A GG genotype had a weak association with reduced OS (log-rank P = .097). A combined effect of the two genotypes on OS was observed. Patients with none of the adverse genotypes had a median survival time (MST) of 34.0 months, and those with 1-2 deleterious alleles had a significantly lower MST of 20.7 months (log-rank P = .006). MRP2 G40A GG genotype was also significantly associated with poor histological response to chemoradiotherapy (P = .028).These observations suggest a potential role of polymorphic variants of drug resistance genes in predicting therapeutic efficacy and survival of patients with potentially resectable pancreatic cancer.

Authors
Tanaka, M; Okazaki, T; Suzuki, H; Abbruzzese, JL; Li, D
MLA Citation
Tanaka, M, Okazaki, T, Suzuki, H, Abbruzzese, JL, and Li, D. "Association of multi-drug resistance gene polymorphisms with pancreatic cancer outcome." Cancer 117.4 (February 2011): 744-751.
PMID
20922799
Source
epmc
Published In
Cancer
Volume
117
Issue
4
Publish Date
2011
Start Page
744
End Page
751
DOI
10.1002/cncr.25510

DNA mismatch repair gene polymorphisms affect survival in pancreatic cancer.

DNA mismatch repair (MMR) maintains genomic stability and mediates cellular response to DNA damage. We aim to demonstrate whether MMR genetic variants affect overall survival (OS) in pancreatic cancer.Using the Sequenom method in genomic DNA, we retrospectively genotyped 102 single-nucleotide polymorphisms (SNPs) of 13 MMR genes from 706 patients with pancreatic adenocarcinoma seen at The University of Texas MD Anderson Cancer Center. Association between genotype and OS was evaluated using multivariable Cox proportional hazard regression models.At a false discovery rate of 1% (p ≤ .0015), 15 SNPs of EXO1, MLH1, MSH2, MSH3, MSH6, PMS2, PMS2L3, TP73, and TREX1 in patients with localized disease (n = 333) and 6 SNPs of MSH3, MSH6, and TP73 in patients with locally advanced or metastatic disease (n = 373) were significantly associated with OS. In multivariable Cox proportional hazard regression models, SNPs of EXO1, MSH2, MSH3, PMS2L3, and TP73 in patients with localized disease, MSH2, MSH3, MSH6, and TP73 in patients with locally advanced or metastatic disease, and EXO1, MGMT, MSH2, MSH3, MSH6, PMS2L3, and TP73 in all patients remained significant predictors for OS (p ≤ .0015) after adjusting for all clinical predictors and all SNPs with p ≤ .0015 in single-locus analysis. Sixteen haplotypes of EXO1, MLH1, MSH2, MSH3, MSH6, PMS2, PMS2L3, RECQL, TP73, and TREX1 significantly correlated with OS in all patients (p ≤ .001).MMR gene variants may have potential value as prognostic markers for OS in pancreatic cancer patients.

Authors
Dong, X; Li, Y; Hess, KR; Abbruzzese, JL; Li, D
MLA Citation
Dong, X, Li, Y, Hess, KR, Abbruzzese, JL, and Li, D. "DNA mismatch repair gene polymorphisms affect survival in pancreatic cancer." The oncologist 16.1 (January 6, 2011): 61-70.
PMID
21212431
Source
epmc
Published In
The oncologist
Volume
16
Issue
1
Publish Date
2011
Start Page
61
End Page
70
DOI
10.1634/theoncologist.2010-0127

Therapeutic applications of NSAIDS in cancer: special emphasis on tolfenamic acid.

Non-steroidal anti-inflammatory drugs (NSAIDs) are primarily used for the treatment of acute or chronic conditions with pain and inflammation. Evidence from a wide range of sources suggested that chronic administration of NSAIDs reduced the risk of cancer incidences. Both the epidemiological and animal studies showed an inverse association between the incidence of various cancers and the use of aspirin or other NSAIDs. The chemopreventive and therapeutic interventions of NSAIDs in cancer are obvious; however, the instigation of drug and treatment period depends on the study objective. Typically, prevention involves initiating the medication before the appearance of clinical symptoms and lasts long-term; while treatment could be short-term and contingent to the response of patient to the medication. Recent studies from our laboratories provided substantial evidence on the anti-cancer activity of tolfenamic acid, a NSAID for the potential applications in pancreatic, esophageal and lung cancers. In this review, we provide a summary on the potential benefits of NSAIDs in a variety of human cancers with more emphasis on tolfenamic acid.

Authors
Basha, R; Baker, CH; Sankpal, UT; Ahmad, S; Safe, S; Abbruzzese, JL; Abdelrahim, M
MLA Citation
Basha, R, Baker, CH, Sankpal, UT, Ahmad, S, Safe, S, Abbruzzese, JL, and Abdelrahim, M. "Therapeutic applications of NSAIDS in cancer: special emphasis on tolfenamic acid." Frontiers in bioscience (Scholar edition) 3 (January 2011): 797-805. (Review)
PMID
21196413
Source
epmc
Published In
Frontiers in Bioscience - Scholar
Volume
3
Publish Date
2011
Start Page
797
End Page
805
DOI
10.2741/s188

I-CLIP: improved stratification of advanced hepatocellular carcinoma patients by integrating plasma IGF-1 into CLIP score.

Improving the prognostic stratification of unresectable hepatocellular carcinoma (HCC) patients is critically needed. Since patients' survival is closely linked to the severity of the underlying liver disease, and insulin-like growth factor-1 (IGF-1) is produced predominantly in the liver, we hypothesized that IGF-1 may correlate with patients' survival and hence improve the prognostic ability of the Cancer of the Liver Italian Program (CLIP) score.Baseline plasma IGF-1 and clinicopathologic parameters were available from 288 patients. Multivariate Cox regression models, Kaplan-Meier curves, and the log-rank test were applied. Recursive partitioning was used to determine the optimal cut point for IGF-1 using training/validation samples. Prognostic ability of the I-CLIP (I = IGF) was compared to CLIP using C-index.IGF-1 significantly correlated with the clinicopathologic features. With an optimal IGF-1 cut point of 26 ng/ml, the overall survival of patients with IGF-1 >26 was 17.7 months (95% CI 13.6-22.8), and with IGF-1 ≤26 was 5.8 months (95% CI 4.0-12.5), p < 0.0001. The concordance probabilities for CLIP and I-CLIP were 0.7037 and 0.7096, respectively (p < 0.0001).Our preliminary results indicate that I-CLIP significantly improved prognostic stratification of patients with advanced HCC. However, independent validation of our study is warranted.

Authors
Kaseb, AO; Abbruzzese, JL; Vauthey, J-N; Aloia, TA; Abdalla, EK; Hassan, MM; Lin, E; Xiao, L; El-Deeb, AS; Rashid, A; Morris, JS
MLA Citation
Kaseb, AO, Abbruzzese, JL, Vauthey, J-N, Aloia, TA, Abdalla, EK, Hassan, MM, Lin, E, Xiao, L, El-Deeb, AS, Rashid, A, and Morris, JS. "I-CLIP: improved stratification of advanced hepatocellular carcinoma patients by integrating plasma IGF-1 into CLIP score." Oncology 80.5-6 (January 2011): 373-381.
PMID
21822028
Source
epmc
Published In
Oncology
Volume
80
Issue
5-6
Publish Date
2011
Start Page
373
End Page
381
DOI
10.1159/000329040

ALDH activity selectively defines an enhanced tumor-initiating cell population relative to CD133 expression in human pancreatic adenocarcinoma.

Multiple studies in recent years have identified highly tumorigenic populations of cells that drive tumor formation. These cancer stem cells (CSCs), or tumor-initiating cells (TICs), exhibit properties of normal stem cells and are associated with resistance to current therapies. As pancreatic adenocarcinoma is among the most resistant human cancers to chemo-radiation therapy, we sought to evaluate the presence of cell populations with tumor-initiating capacities in human pancreatic tumors. Understanding which pancreatic cancer cell populations possess tumor-initiating capabilities is critical to characterizing and understanding the biology of pancreatic CSCs towards therapeutic ends.We have isolated populations of cells with high ALDH activity (ALDH(high)) and/or CD133 cell surface expression from human xenograft tumors established from multiple patient tumors with pancreatic adenocarcinoma (direct xenograft tumors) and from the pancreatic cancer cell line L3.6pl. Through fluorescent activated cell sorting (FACs)-mediated enrichment and depletion of selected pancreatic cancer cell populations, we sought to discriminate the relative tumorigenicity of cell populations that express the pancreatic CSC markers CD133 and aldehyde dehydrogenase (ALDH). ALDH(high) and ALDH(low) cell populations were further examined for co-expression of CD44 and/or CD24. We demonstrate that unlike cell populations demonstrating low ALDH activity, as few as 100 cells enriched for high ALDH activity were capable of tumor formation, irrespective of CD133 expression. In direct xenograft tumors, the proportions of total tumor cells expressing ALDH and/or CD133 in xenograft tumors were unchanged through a minimum of two passages. We further demonstrate that ALDH expression among patients with pancreatic adenocarcinoma is heterogeneous, but the expression is constant in serial generations of individual direct xenograft tumors established from bulk human pancreatic tumors in NOD/SCID mice.We conclude that, in contrast to some previous studies, cell populations enriched for high ALDH activity alone are sufficient for efficient tumor-initiation with enhanced tumorigenic potential relative to CD133(+) and ALDH(low) cell populations in some direct xenograft tumors. Although cell populations enriched for CD133 expression may alone possess tumorigenic potential, they are significantly less tumorigenic than ALDH(high) cell populations. ALDH(high)/CD44(+)/CD24(+) or ALDH(low)/CD44(+)/CD24(+) phenotypes do not appear to significantly contribute to tumor formation at low numbers of inoculated tumor cells. ALDH expression broadly varies among patients with pancreatic adenocarcinoma and the apparent expression is recapitulated in serial generations of direct xenograft tumors in NOD/SCID. We have thus identified a distinct population of TICs that should lead to identification of novel targets for pancreatic cancer therapy.

Authors
Kim, MP; Fleming, JB; Wang, H; Abbruzzese, JL; Choi, W; Kopetz, S; McConkey, DJ; Evans, DB; Gallick, GE
MLA Citation
Kim, MP, Fleming, JB, Wang, H, Abbruzzese, JL, Choi, W, Kopetz, S, McConkey, DJ, Evans, DB, and Gallick, GE. "ALDH activity selectively defines an enhanced tumor-initiating cell population relative to CD133 expression in human pancreatic adenocarcinoma." PloS one 6.6 (January 2011): e20636-.
PMID
21695188
Source
epmc
Published In
PloS one
Volume
6
Issue
6
Publish Date
2011
Start Page
e20636
DOI
10.1371/journal.pone.0020636

Therapeutic applications of NSAIDS in cancer: Special emphasis on tolfenamic acid

Non-steroidal anti-inflammatory drugs (NSAIDs) are primarily used for the treatment of acute or chronic conditions with pain and inflammation. Evidence from a wide range of sources suggested that chronic administration of NSAIDs reduced the risk of cancer incidences. Both the epidemiological and animal studies showed an inverse association between the incidence of various cancers and the use of aspirin or other NSAIDs. The chemopreventive and therapeutic interventions of NSAIDs in cancer are obvious; however, the instigation of drug and treatment period depends on the study objective. Typically, prevention involves initiating the medication before the appearance of clinical symptoms and lasts longterm; while treatment could be short-term and contingent to the response of patient to the medication. Recent studies from our laboratories provided substantial evidence on the anti-cancer activity of tolfenamic acid, a NSAID for the potential applications in pancreatic, esophageal and lung cancers. In this review, we provide a summary on the potential benefits of NSAIDs in a variety of human cancers with more emphasis on tolfenamic acid.

Authors
Basha, R; Baker, CT; Sankpal, UT; Ahmad, S; Safe, S; Abbruzzese, JL; Abdelrahim, M
MLA Citation
Basha, R, Baker, CT, Sankpal, UT, Ahmad, S, Safe, S, Abbruzzese, JL, and Abdelrahim, M. "Therapeutic applications of NSAIDS in cancer: Special emphasis on tolfenamic acid." Frontiers in Bioscience - Scholar 3 S.2 (2011): 797-805.
Source
scival
Published In
Frontiers in Bioscience - Scholar
Volume
3 S
Issue
2
Publish Date
2011
Start Page
797
End Page
805

Gemcitabine metabolic and transporter gene polymorphisms are associated with drug toxicity and efficacy in patients with locally advanced pancreatic cancer.

It has not been well established whether genetic variations can be biomarkers for clinical outcome of gemcitabine therapy. The purpose of this study was to identify single nucleotide polymorphisms (SNPs) of gemcitabine metabolic and transporter genes that are associated with toxicity and efficacy of gemcitabine-based therapy in patients with locally advanced pancreatic cancer.The authors evaluated 17 SNPs of the CDA,dCK, DCTD, RRM1, hCNT1-3, and hENT1 genes in 149 patients with locally advanced pancreatic cancer who underwent gemcitabine-based chemoradiotherapy. The association of genotypes with neutropenia, tumor response to therapy, overall survival, and progression-free survival (PFS) was analyzed by logistic regression, log-rank test, Kaplan-Meier plot, and Cox proportional hazards regression.The CDA A-76C, dCK C-1205T, RRM1 A33G, and hENT1 C913T genotypes were significantly associated with grade 3 to 4 neutropenia (P = .020, .015, .003, and .017, respectively).The CDA A-76C and hENT1 A-201G genotypes were significantly associated with tumor response to therapy (P = .017 and P = .019). A combined genotype effect of CDA A-76C, RRM1 A33G, RRM1 C-27A, and hENT1 A-201G on PFS was observed. Patients carrying 0 to 1 (n = 64), 2 (n = 50), or 3 to 4 (n = 17) at-risk genotypes had median PFS times of 8.3, 6.0, and 4.2 months, respectively (P = .002).The results indicated that some polymorphic variations of drug metabolic and transporter genes may be potential biomarkers for clinical outcome of gemcitabine-based therapy in patients with locally advanced pancreatic cancer.

Authors
Tanaka, M; Javle, M; Dong, X; Eng, C; Abbruzzese, JL; Li, D
MLA Citation
Tanaka, M, Javle, M, Dong, X, Eng, C, Abbruzzese, JL, and Li, D. "Gemcitabine metabolic and transporter gene polymorphisms are associated with drug toxicity and efficacy in patients with locally advanced pancreatic cancer." Cancer 116.22 (November 2010): 5325-5335.
PMID
20665488
Source
epmc
Published In
Cancer
Volume
116
Issue
22
Publish Date
2010
Start Page
5325
End Page
5335
DOI
10.1002/cncr.25282

Chemoprevention of pancreatic cancer: ready for the clinic?

Advances in our molecular, clinical, and epidemiologic understanding of the risk and development of pancreatic cancer offer hope for preventing this disease, which is largely intractable once developed. This perspective on provocative, genetically engineered mouse model work reported by Mohammed et al. (beginning on page 1417 in this issue of the journal) examines the prospects for pancreatic cancer chemoprevention with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI). Despite having limited value in advanced pancreatic cancer, EGFR TKIs show promise in the setting of early pancreatic carcinogenesis.

Authors
Logsdon, CD; Abbruzzese, JL
MLA Citation
Logsdon, CD, and Abbruzzese, JL. "Chemoprevention of pancreatic cancer: ready for the clinic?." Cancer prevention research (Philadelphia, Pa.) 3.11 (November 2010): 1375-1378.
PMID
21084259
Source
epmc
Published In
Cancer Prevention Research
Volume
3
Issue
11
Publish Date
2010
Start Page
1375
End Page
1378
DOI
10.1158/1940-6207.capr-10-0216

New strategies in pancreatic cancer: emerging epidemiologic and therapeutic concepts.

Pancreatic cancer (PC) is a highly lethal disease with complex etiology involving both environmental and genetic factors. Although cigarette smoking is known to explain 25% of cases, data from recent studies suggest that obesity and long-term type II diabetes are two major modifiable risk factors for PC. Furthermore, obesity and diabetes seem to affect the clinical outcome of patients with PC. Understanding the mechanistic effects of obesity and diabetes on the pancreas may identify new strategies for prevention or therapy. Experimental and epidemiologic evidence suggests that the antidiabetic drug metformin has protective antitumor activity in PC. In addition to insulin resistance and inflammation as mechanisms of carcinogenesis, obesity and diabetes are linked to impairments in endothelial function and coagulation status, which increase the risks of thrombosis and angiogenesis and, in turn, the risk of PC development and progression. The associations of the ABO blood group gene and NR5A2 gene variants with PC discovered by recent genome-wide association studies may link insulin resistance, inflammation, and thrombosis to pancreatic carcinogenesis. These exciting findings open new avenues for understanding the etiology of PC and provide opportunities for developing novel strategies for prevention and treatment of this disease.

Authors
Li, D; Abbruzzese, JL
MLA Citation
Li, D, and Abbruzzese, JL. "New strategies in pancreatic cancer: emerging epidemiologic and therapeutic concepts." Clinical cancer research : an official journal of the American Association for Cancer Research 16.17 (September 2010): 4313-4318.
PMID
20647474
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
16
Issue
17
Publish Date
2010
Start Page
4313
End Page
4318
DOI
10.1158/1078-0432.ccr-09-1942

Mesenchymal stromal cells alone or expressing interferon-beta suppress pancreatic tumors in vivo, an effect countered by anti-inflammatory treatment.

Because of the inflammatory nature and extensive stromal compartment in pancreatic tumors, we investigated the role of mesenchymal stromal cells (MSC) to engraft selectively in pancreatic carcinomas and serve as anti-tumor drug delivery vehicles to control pancreatic cancer progression.Human pancreatic carcinoma cells, PANC-1, expressing renilla luciferase were orthotopically implanted into SCID mice and allowed to develop for 10 days. Firefly luciferase-transduced MSC or MSC expressing interferon (IFN)-beta were then injected intraperitoneally weekly for 3 weeks. Mice were monitored by bioluminescent imaging for expression of renilla (PANC-1) and firefly (MSC) luciferase.MSC selectively homed to sites of primary and metastatic pancreatic tumors and inhibited tumor growth (P=0.032). The production of IFN-beta within the tumor site by MSC-IFN-beta further suppressed tumor growth (P=0.0000083). Prior studies indicated that MSC home to sites of inflammation; therefore, we sought to alter the tumor microenvironment through treatment with a potent anti-inflammatory agent. After treatment, inflammation-associated mediators were effectively down-regulated, including NFkappaB, vascular endothelial growth factor (VEGF) and interleukin (IL)-6 as well as chemokines involved in MSC migration (CCL3 and CCL25). Treatment with the anti-inflammatory agent CDDO-Me before and after MSC-IFN-beta injections resulted in reduction of MSC in the tumors and reversed the positive effect of tumor inhibition by MSC-IFN-beta alone (P=0.041).These results suggest that MSC exhibit innate anti-tumor effects against PANC-1 cells and can serve as delivery vehicles for IFN-beta for the treatment of pancreatic cancer. However, these beneficial effects may be lost in therapies combining MSC with anti-inflammatory agents.

Authors
Kidd, S; Caldwell, L; Dietrich, M; Samudio, I; Spaeth, EL; Watson, K; Shi, Y; Abbruzzese, J; Konopleva, M; Andreeff, M; Marini, FC
MLA Citation
Kidd, S, Caldwell, L, Dietrich, M, Samudio, I, Spaeth, EL, Watson, K, Shi, Y, Abbruzzese, J, Konopleva, M, Andreeff, M, and Marini, FC. "Mesenchymal stromal cells alone or expressing interferon-beta suppress pancreatic tumors in vivo, an effect countered by anti-inflammatory treatment." Cytotherapy 12.5 (September 2010): 615-625.
PMID
20230221
Source
epmc
Published In
Cytotherapy (Informa)
Volume
12
Issue
5
Publish Date
2010
Start Page
615
End Page
625
DOI
10.3109/14653241003631815

Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205.

Patients with advanced pancreas cancer present with disease that is poorly responsive to conventional therapies. Preclinical and early clinical evidence has supported targeting the epidermal growth factor receptor (EGFR) signaling pathway in patients with pancreas cancer. This trial was conducted to evaluate the contribution of an EGFR-targeted agent to standard gemcitabine therapy. Cetuximab is a monoclonal antibody against the ligand-binding domain of the receptor.Patients with unresectable locally advanced or metastatic pancreatic adenocarcinoma were randomly assigned to receive gemcitabine alone or gemcitabine plus cetuximab. The primary end point was overall survival. Secondary end points included progression-free survival, time to treatment failure, objective response, and toxicity.A total of 745 eligible patients were accrued. No significant difference was seen between the two arms of the study with respect to the median survival time (6.3 months for the gemcitabine plus cetuximab arm v 5.9 months for the gemcitabine alone arm; hazard ratio = 1.06; 95% CI, 0.91 to 1.23; P = .23, one-sided). Objective responses and progression-free survival were similar in both arms of the study. Although time to treatment failure was longer in patients on gemcitabine plus cetuximab (P = .006), the difference in length of treatment was only 2 weeks longer in the combination arm. Among patients who were studied for tumoral EGFR expression, 90% were positive, with no treatment benefit detected in this patient subset.In patients with advanced pancreas cancer, the anti-EGFR monoclonal antibody cetuximab did not improve the outcome compared with patients treated with gemcitabine alone. Alternate targets other than EGFR should be evaluated for new drug development.

Authors
Philip, PA; Benedetti, J; Corless, CL; Wong, R; O'Reilly, EM; Flynn, PJ; Rowland, KM; Atkins, JN; Mirtsching, BC; Rivkin, SE; Khorana, AA; Goldman, B; Fenoglio-Preiser, CM; Abbruzzese, JL; Blanke, CD
MLA Citation
Philip, PA, Benedetti, J, Corless, CL, Wong, R, O'Reilly, EM, Flynn, PJ, Rowland, KM, Atkins, JN, Mirtsching, BC, Rivkin, SE, Khorana, AA, Goldman, B, Fenoglio-Preiser, CM, Abbruzzese, JL, and Blanke, CD. "Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 28.22 (August 2010): 3605-3610.
PMID
20606093
Source
epmc
Published In
Journal of Clinical Oncology
Volume
28
Issue
22
Publish Date
2010
Start Page
3605
End Page
3610
DOI
10.1200/jco.2009.25.7550

Insulin-like growth factor axis gene polymorphisms and clinical outcomes in pancreatic cancer.

Insulin-like growth factor (IGF)-axis mediated signaling pathways play an important role in pancreatic cancer development and progression. We examined whether IGF-axis gene variants are associated with clinical outcomes in pancreatic cancer.We retrospectively genotyped 41 single-nucleotide polymorphisms from 10 IGF-axis genes in 333 patients with localized pancreatic adenocarcinoma and validated the findings in 373 patients with advanced disease. Associations between genotype and overall survival (OS) were evaluated using multivariable Cox proportional hazard regression models.IGF1 *8470T>C, IGF1R IVS2+46329T>C, IGFBP3 A32G, IRS1 G972R in patients with localized disease; IGF1R IVS20-3431A>G, IGF1R T766T, IGFBP3-202A>C, IRS1 IVS1+4315C>G, IRS1 G972R in patients with advanced disease; and IGF1R T766T, IGF2R L252V, IGFBP3 -202A>C, IRS1 IVS1+4315C>G, IRS1 G972R, IRS2 IVS1+5687T>C in all patients were significantly associated with OS (PA, and an IRS2 haplotype predicted worse OS (P

Authors
Dong, X; Javle, M; Hess, KR; Shroff, R; Abbruzzese, JL; Li, D
MLA Citation
Dong, X, Javle, M, Hess, KR, Shroff, R, Abbruzzese, JL, and Li, D. "Insulin-like growth factor axis gene polymorphisms and clinical outcomes in pancreatic cancer." Gastroenterology 139.2 (August 2010): 464-473.e3.
PMID
20416304
Source
epmc
Published In
Gastroenterology
Volume
139
Issue
2
Publish Date
2010
Start Page
464
End Page
473.e3
DOI
10.1053/j.gastro.2010.04.042

Inhibition of the mammalian target of rapamycin (mTOR) in advanced pancreatic cancer: results of two phase II studies.

The phosphoinositide 3-kinase (PI3K)/Akt pathway is constitutively activated in pancreatic cancer and the mammalian target of rapamycin (mTOR) kinase is an important mediator for its signaling. Our recent in vitro studies suggest that prolonged exposure of pancreatic cancer cells to mTOR inhibitors can promote insulin receptor substrate-PI3K interactions and paradoxically increase Akt phosphorylation and cyclin D1 expression in pancreatic cancer cells (negative feedback loop). The addition of erlotinib to rapamycin can down-regulate rapamycin-stimulated Akt and results in synergistic antitumor activity with erlotinib in preclinical tumor models.Two studies prospectively enrolled adult patients with advanced pancreatic cancer, Eastern Cooperative Oncology Group performance status 0-1, adequate hematologic, hepatic and renal parameters and measurable disease. In Study A, temsirolimus was administered intravenously at 25 mg weekly. In Study B, everolimus was administered orally at 30 mg weekly and erlotinib was administered at 150 mg daily. The primary endpoint in both studies was overall survival at 6 months. Secondary endpoints included time to progression, progression-free survival, overall survival, response rate, safety and toxicity. Pretreatment tumor biopsies were analyzed by immunofluorescence and laser scanning cytometry for the expression of pmTOR/mTOR, pAkt/Akt, pErk/Erk, pS6, p4EBP-1 and PTEN.Five patients enrolled in Study A; Two patients died within a month (rapid disease progression and hemorrhagic stroke, respectively). One patient developed dehydration and another developed asthenia. Sixteen patients enrolled in Study B.: 12 males, all ECOG PS = 1. Median cycles = 1 (range 1-2). Grade 4 toxicity: hyponatremia (n = 1), Grade 3: diarrhea (n = 1), cholangitis (n = 3), hyperglycemia (n = 1), fatigue (n = 1). Grade 2: pneumonia (n = 2), dehydration (n = 2), nausea (n = 2), neutropenia (n = 1), mucositis (n = 2) & rash (n = 2). Four patients were hospitalized. Progressive disease occurred in 15 and 1 was non-evaluable. Pretreatment biopsies revealed a higher pAkt/Akt ratio in tumor specimens that in nonmalignant pancreatic tissue. No such trends were noted for the other biomarkers.Neither study with mTOR inhibitors demonstrated objective responses or disease stability. The negative feedback loop resulting from mTOR inhibition may account for the disease progression and toxicity noted in these studies. Future strategies should aim for a broader targeting of the PI3K pathway in pancreatic cancer.NCT 0075647.NCT00640978.

Authors
Javle, MM; Shroff, RT; Xiong, H; Varadhachary, GA; Fogelman, D; Reddy, SA; Davis, D; Zhang, Y; Wolff, RA; Abbruzzese, JL
MLA Citation
Javle, MM, Shroff, RT, Xiong, H, Varadhachary, GA, Fogelman, D, Reddy, SA, Davis, D, Zhang, Y, Wolff, RA, and Abbruzzese, JL. "Inhibition of the mammalian target of rapamycin (mTOR) in advanced pancreatic cancer: results of two phase II studies." BMC cancer 10 (July 14, 2010): 368-.
PMID
20630061
Source
epmc
Published In
BMC Cancer
Volume
10
Publish Date
2010
Start Page
368
DOI
10.1186/1471-2407-10-368

High levels of nucleolar expression of nucleolin are associated with better prognosis in patients with stage II pancreatic ductal adenocarcinoma.

Nucleolin is a major nucleolar protein that has been shown to be overexpressed in rapidly dividing cells and plays an essential role in cell proliferation and survival. However, the expression and significance of nucleolin in pancreatic ductal adenocarcinoma (PDA) have not been studied.We used a tissue microarray consisting of 1.0-mm cores of tumor and paired nonneoplastic pancreatic tissue from 69 pancreaticoduodenectomy specimens with stage II PDA. Nucleolin expression was evaluated by immunohistochemistry and scored quantitatively by image analysis. Nucleolin expression was classified as nucleolin-high or nucleolin-low using the median nucleolin labeling index of 3.5% as cutoff. Staining results were correlated with clinicopathologic features and survival.Both PDAs and PDA cell lines showed nucleolar staining for nucleolin. Nucleolin expression was higher in PDAs and PDA cell lines than in nonneoplastic ductal epithelial cells. Among the 69 stage II PDAs, 34 (49%) were nucleolin-high. The median overall survival was 65.2 +/- 16.3 months for patients who had nucleolin-high PDAs compared with 19.5 +/- 3.3 months for patients whose tumors were nucleolin-low (P = 0.03, log-rank method). No significant correlation between nucleolin expression and other clinicopathologic parameters was found. In multivariate analysis, nucleolin expression was a prognostic factor for overall survival in patients with stage II PDA independent of patient's age, gender, tumor size, differentiation, and lymph node status.Nucleolin was overexpressed in PDAs and PDA cell lines. A high level of nucleolar expression of nucleolin was an independent prognostic marker for better survival for patients with stage II PDAs.

Authors
Peng, L; Liang, J; Wang, H; Song, X; Rashid, A; Gomez, HF; Corley, LJ; Abbruzzese, JL; Fleming, JB; Evans, DB; Wang, H
MLA Citation
Peng, L, Liang, J, Wang, H, Song, X, Rashid, A, Gomez, HF, Corley, LJ, Abbruzzese, JL, Fleming, JB, Evans, DB, and Wang, H. "High levels of nucleolar expression of nucleolin are associated with better prognosis in patients with stage II pancreatic ductal adenocarcinoma." Clinical cancer research : an official journal of the American Association for Cancer Research 16.14 (July 13, 2010): 3734-3742.
PMID
20628027
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
16
Issue
14
Publish Date
2010
Start Page
3734
End Page
3742
DOI
10.1158/1078-0432.ccr-09-3411

Serum CA 19-9 as a marker of resectability and survival in patients with potentially resectable pancreatic cancer treated with neoadjuvant chemoradiation.

The role of carbohydrate antigen (CA) 19-9 in the evaluation of patients with resectable pancreatic cancer treated with neoadjuvant therapy prior to planned surgical resection is unknown. We evaluated CA 19-9 as a marker of therapeutic response, completion of therapy, and survival in patients enrolled on two recently reported clinical trials.We analyzed patients with radiographically resectable adenocarcinoma of the head/uncinate process treated on two phase II trials of neoadjuvant chemoradiation. Patients without evidence of disease progression following chemoradiation underwent pancreaticoduodenectomy (PD). CA 19-9 was evaluated in patients with a normal bilirubin level.We enrolled 174 patients, and 119 (68%) completed all therapy including PD. Pretreatment CA 19-9 <37 U/ml had a positive predictive value (PPV) for completing PD of 86% but a negative predictive value (NPV) of 33%. Among patients without evidence of disease at last follow-up, the highest pretreatment CA 19-9 was 1,125 U/ml. Restaging CA 19-9 <61 U/ml had a PPV of 93% and a NPV of 28% for completing PD among resectable patients. The area under the receiver-operating characteristics curve of pretreatment and restaging CA 19-9 levels for completing PD was 0.59 and 0.74, respectively. We identified no association between change in CA 19-9 and histopathologic response (P = 0.74).Although the PPV of CA 19-9 for completing neoadjuvant therapy and undergoing PD was high, its clinical utility was compromised by a low NPV. Decision-making for patients with resectable PC should remain based on clinical assessment and radiographic staging.

Authors
Katz, MHG; Varadhachary, GR; Fleming, JB; Wolff, RA; Lee, JE; Pisters, PWT; Vauthey, J-N; Abdalla, EK; Sun, CC; Wang, H; Crane, CH; Lee, JH; Tamm, EP; Abbruzzese, JL; Evans, DB
MLA Citation
Katz, MHG, Varadhachary, GR, Fleming, JB, Wolff, RA, Lee, JE, Pisters, PWT, Vauthey, J-N, Abdalla, EK, Sun, CC, Wang, H, Crane, CH, Lee, JH, Tamm, EP, Abbruzzese, JL, and Evans, DB. "Serum CA 19-9 as a marker of resectability and survival in patients with potentially resectable pancreatic cancer treated with neoadjuvant chemoradiation." Annals of surgical oncology 17.7 (July 2010): 1794-1801.
PMID
20162463
Source
epmc
Published In
Annals of Surgical Oncology
Volume
17
Issue
7
Publish Date
2010
Start Page
1794
End Page
1801
DOI
10.1245/s10434-010-0943-1

Is there a role for adjuvant therapy in resected adenocarcinoma of the small intestine.

BACKGROUND: The benefit of adjuvant therapy for resected small bowel adenocarcinoma has not been proven. We undertook a retrospective analysis to evaluate the benefit of adjuvant therapy in a clearly defined patient population with curatively resected small bowel adenocarcinoma. MATERIAL AND METHODS: We identified 54 patients with small bowel adenocarcinoma who underwent margin-negative surgical resection and were evaluated after surgery at the University of Texas, M. D. Anderson Cancer Center between 1990 and 2008. Disease-free survival (DFS) and overall survival (OS) were estimated. RESULTS: Median age was 55 years and primary tumor site was duodenum in 67%, jejunum in 20%, and ileum in 13%. Thirty patients (56%) received adjuvant therapy consisting of systemic chemotherapy with or without radiation in 28 and radiation alone in two. Patients who received adjuvant therapy had significantly higher tumor stage and rate of lymph node involvement. Five-year DFS and OS did not differ between treatment groups. In multivariate analysis, the use of adjuvant therapy was associated with improved DFS (HR 0.27; 95% CI 0.07-0.98, P = 0.05) but not OS (HR 0.47; 95% CI 0.13-1.62, P = 0.23). In patients with a high risk of relapse (defined as a lymph node ratio >or=10%), adjuvant therapy appeared to improve OS, P = 0.04, but not DFS, P = 0.15. DISCUSSION: The use of adjuvant therapy for curatively resected small bowel adenocarcinoma was associated with an improvement in DFS. This finding strongly supports further investigation of adjuvant chemotherapy in this tumor type.

Authors
Overman, MJ; Kopetz, S; Lin, E; Abbruzzese, JL; Wolff, RA
MLA Citation
Overman, MJ, Kopetz, S, Lin, E, Abbruzzese, JL, and Wolff, RA. "Is there a role for adjuvant therapy in resected adenocarcinoma of the small intestine." Acta oncologica (Stockholm, Sweden) 49.4 (May 2010): 474-479.
PMID
20397775
Source
epmc
Published In
Acta Oncologica (Informa)
Volume
49
Issue
4
Publish Date
2010
Start Page
474
End Page
479
DOI
10.3109/02841860903490051

S9511: a Southwest Oncology Group phase II study of trimetrexate, 5-fluorouracil, and leucovorin in unresectable or metastatic adenocarcinoma of the stomach.

The primary objective of this trial was to evaluate the response rate for trimetrexate in conjunction with 5-FU and leucovorin (LV) (= TFL) in the treatment of advanced gastric cancer in a phase II, cooperative group setting.Patients with locally advanced, unresectable, or metastatic adenocarcinoma of the stomach received trimetrexate 110 mg/m IV over 60 minutes day 1, followed by 5-FU 500 mg/m IV bolus and LV 200 mg/m IV over 60 minutes day 2, followed by oral LV 15 mg every 6 hours x 7 doses, all weekly for 6 weeks followed by 2 weeks of rest, continued until progression.Characteristics for 37 eligible patients: median age 63 (range: 23-83); male/female: 69% of 31%; performance status 0/1/2 15/20/1. The confirmed response rate was 19%, and median overall survival was 6 months. Two patients died as a result of therapy, 1 because of infection without significant neutropenia, and 1 due to perforation of a responding gastric lesion. Seventy-two percent experienced grades 3 and 4 toxicity, most commonly diarrhea, fatigue, and lymphopenia.This regimen achieves response rates comparable to other 5-FU-based regimens, when used in treatment of incurable gastric cancer. Toxicity appears manageable.

Authors
Blanke, CD; Chansky, K; Christman, KL; Hundahl, SA; Issell, BF; Van Veldhuizen, PJ; Budd, GT; Abbruzzese, JL; Macdonald, JS
MLA Citation
Blanke, CD, Chansky, K, Christman, KL, Hundahl, SA, Issell, BF, Van Veldhuizen, PJ, Budd, GT, Abbruzzese, JL, and Macdonald, JS. "S9511: a Southwest Oncology Group phase II study of trimetrexate, 5-fluorouracil, and leucovorin in unresectable or metastatic adenocarcinoma of the stomach." American journal of clinical oncology 33.2 (April 2010): 117-120.
PMID
19770625
Source
epmc
Published In
American Journal of Clinical Oncology: Cancer Clinical Trials
Volume
33
Issue
2
Publish Date
2010
Start Page
117
End Page
120
DOI
10.1097/coc.0b013e318199fb84

Association of diabetes duration and diabetes treatment with the risk of hepatocellular carcinoma.

Despite the observed association between diabetes mellitus and hepatocellular carcinoma (HCC), little is known about the effect of diabetes duration before HCC diagnosis and whether some diabetes medications reduced the risk of HCC development. This objective of the current study was to determine the association between HCC risk and diabetes duration and type of diabetes treatment.A total of 420 patients with HCC and 1104 healthy controls were enrolled in an ongoing hospital-based case-control study. Multivariate logistic regression models were used to adjust for HCC risk factors.The prevalence of diabetes mellitus was 33.3% in patients with HCC and 10.4% in the control group, yielding an adjusted odds ratio (AOR) of 4.2 (95% confidence interval [95% CI], 3.0-5.9). In 87% of cases, diabetes was present before the diagnosis of HCC, yielding an AOR of 4.4 (95% CI, 3.0-6.3). Compared with patients with a diabetes duration of 2 to 5 years, the estimated AORs for those with a diabetes duration of 6 to 10 years and those with a diabetes duration >10 years were 1.8 (95% CI, 0.8-4.1) and 2.2 (95% CI, 1.2-4.8), respectively. With respect to diabetes treatment, the AORs were 0.3 (95% CI, 0.2-0.6), 0.3 (95% CI, 0.1-0.7), 7.1 (95% CI, 2.9-16.9), 1.9 (95% CI, 0.8-4.6), and 7.8 (95% CI, 1.5-40.0) for those treated with biguanides, thiazolidinediones, sulfonylureas, insulin, and dietary control, respectively.Diabetes appears to increase the risk of HCC, and such risk is correlated with a long duration of diabetes. Relying on dietary control and treatment with sulfonylureas or insulin were found to confer the highest magnitude of HCC risk, whereas treatment with biguanides or thiazolidinediones was associated with a 70% HCC risk reduction among diabetics.

Authors
Hassan, MM; Curley, SA; Li, D; Kaseb, A; Davila, M; Abdalla, EK; Javle, M; Moghazy, DM; Lozano, RD; Abbruzzese, JL; Vauthey, J-N
MLA Citation
Hassan, MM, Curley, SA, Li, D, Kaseb, A, Davila, M, Abdalla, EK, Javle, M, Moghazy, DM, Lozano, RD, Abbruzzese, JL, and Vauthey, J-N. "Association of diabetes duration and diabetes treatment with the risk of hepatocellular carcinoma." Cancer 116.8 (April 2010): 1938-1946.
PMID
20166205
Source
epmc
Published In
Cancer
Volume
116
Issue
8
Publish Date
2010
Start Page
1938
End Page
1946
DOI
10.1002/cncr.24982

Introducing new strategies in...

Authors
Abbruzzese, JL; Eggermont, AMM; Rubin, EH
MLA Citation
Abbruzzese, JL, Eggermont, AMM, and Rubin, EH. "Introducing new strategies in.." Clinical cancer research : an official journal of the American Association for Cancer Research 16.5 (March 2010): 1347-.
PMID
20179221
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
16
Issue
5
Publish Date
2010
Start Page
1347
DOI
10.1158/1078-0432.ccr-10-0236

Weekly docetaxel, cisplatin, and 5-fluorouracil as initial therapy for patients with advanced gastric and esophageal cancer.

BACKGROUND: Docetaxel, cisplatin, and 5-flurouracil (DCF) administered every 3 weeks produces a high rate of treatment-related adverse events. The objective of the current study was to evaluate the efficacy and tolerability of a weekly formulation of DCF. METHODS: Data from 117 patients treated at The University of Texas M. D. Anderson Cancer Center from 2002 to 2006 with a weekly formulation of DCF were retrospectively collected. A total of 95 patients received front-line therapy with 20 mg/m(2) of cisplatin, 350 mg/m(2) of 5-fluorouracil, and 20 mg/m(2) of docetaxel administered once weekly for 6 consecutive weeks followed by a 2-week break. RESULTS: Ninety-five patients (median age, 62 years [range, 33 to 87 years], with an Eastern Cooperative Oncology Group performance status of 1 or 2 in 67%) received a median of 10 weeks of DCF treatment (range, 3-41 weeks). Grade 3 or 4 hematologic toxicity (assessed according to National Cancer Institute Common Toxicity Criteria [version 3.0]) included granulocytopenia (4 patients) and anemia (9 patients). None of the patients developed a febrile neutropenic infection, but grade 3 or 4 non-neutropenic infections occurred in 8 patients. Eighty patients had measurable disease with an objective response rate determined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria of 34% (95% confidence interval [95% CI], 24-45%). The median follow-up was 9 months, with a median time to disease progression of 4.1 months (95% CI, 3.6-5.7 months) and a median overall survival of 8.9 months (95% CI, 7.7-10.8 months). CONCLUSIONS: In patients with advanced gastric and esophageal cancer who were not candidates for every-3-week DCF, a weekly formulation of DCF demonstrated modest activity with minimal hematologic toxicity, suggesting that weekly DCF is a reasonable treatment option for such patients.

Authors
Overman, MJ; Kazmi, SM; Jhamb, J; Lin, E; Yao, JC; Abbruzzese, JL; Ho, L; Ajani, J; Phan, A
MLA Citation
Overman, MJ, Kazmi, SM, Jhamb, J, Lin, E, Yao, JC, Abbruzzese, JL, Ho, L, Ajani, J, and Phan, A. "Weekly docetaxel, cisplatin, and 5-fluorouracil as initial therapy for patients with advanced gastric and esophageal cancer." Cancer 116.6 (March 2010): 1446-1453.
PMID
20108336
Source
epmc
Published In
Cancer
Volume
116
Issue
6
Publish Date
2010
Start Page
1446
End Page
1453
DOI
10.1002/cncr.24925

Correction: Transforming Growth Factor   Expression Drives Constitutive Epidermal Growth Factor Receptor Pathway Activation and Sensitivity to Gefitinib (Iressa) in Human Pancreatic Cancer Cell Lines

MLA Citation
"Correction: Transforming Growth Factor   Expression Drives Constitutive Epidermal Growth Factor Receptor Pathway Activation and Sensitivity to Gefitinib (Iressa) in Human Pancreatic Cancer Cell Lines." Cancer Research 70.2 (January 15, 2010): 852-853.
Source
crossref
Published In
Cancer Research
Volume
70
Issue
2
Publish Date
2010
Start Page
852
End Page
853
DOI
10.1158/0008-5472.CAN-09-4221

Single nucleotide polymorphisms of gemcitabine metabolic genes and pancreatic cancer survival and drug toxicity.

To show whether single nucleotide polymorphisms (SNP) of drug metabolic genes were associated with toxicity of 2',2'-difluoro 2'-deoxycytidine (gemcitabine)-based chemoradiotherapy and overall survival (OS) of patients with pancreatic cancer.We evaluated 17 SNPs of the CDA, dCK, DCTD, RRM1, hCNT1, hCNT2, hCNT3, and hENT1 genes in 154 patients with potentially resectable pancreatic adenocarcinoma who were enrolled in clinical trials at The University of Texas M.D. Anderson Cancer Center (Houston, TX) from February 1999 to January 2006, with follow-up until April 2009. Patients received neoadjuvant concurrent gemcitabine and radiation therapy with or without gemcitabine-cisplatin induction therapy. The association of genotypes with toxicity or OS was tested, respectively, by logistic regression and Cox regression analysis.None of the 17 SNPs, individually, had a significant association with OS. A combined genotype effect of CDA A-76C, dCK C-1205T, DCTD T-47C, hCNT3 C-69T, hENT1 T-549C, and hENT1 C913T on OS was observed. Patients carrying 0 to 1 (n = 43), 2 to 3 (n = 77), or 4 to 6 (n = 30) variant alleles had median survival time of 31.5, 21.4, and 17.5 months, respectively. The hazard ratio of dying was 1.71 (95% confidence interval, 1.06-2.76) and 3.16 (95% confidence interval, 1.77-5.63) for patients carrying two to three or four to six at-risk genotypes (P = 0.028 and P < 0.001), respectively, after adjusting for clinical predictors. CDA C111T, dCK C-1205T, dCK A9846G, and hCNT3 A25G, individually and jointly, had a significant association with neutropenia toxicity.These observations suggest that polymorphic variations of drug metabolic genes were associated with toxicity of gemcitabine-based therapy and OS of patients with resectable pancreatic cancer.

Authors
Okazaki, T; Javle, M; Tanaka, M; Abbruzzese, JL; Li, D
MLA Citation
Okazaki, T, Javle, M, Tanaka, M, Abbruzzese, JL, and Li, D. "Single nucleotide polymorphisms of gemcitabine metabolic genes and pancreatic cancer survival and drug toxicity." Clinical cancer research : an official journal of the American Association for Cancer Research 16.1 (January 2010): 320-329.
PMID
20028759
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
16
Issue
1
Publish Date
2010
Start Page
320
End Page
329
DOI
10.1158/1078-0432.ccr-09-1555

Immunophenotype and molecular characterisation of adenocarcinoma of the small intestine.

Despite having a dramatically larger surface area than the large intestine, the small intestine is an infrequent site for the development of adenocarcinoma. To better understand the molecular abnormalities in small bowel adenocarcinoma (SBA), we characterised a number of candidate oncogenic pathways and the immunophenotype of this rare cancer.Tissue microarrays were constructed from tumour samples from 54 patients with all stages of the disease. Immunohistochemistry and microsatellite instability (MSI) testing were conducted.The profile of cytokeratin 20 and 7 coexpression was variable, but expression of caudal type homeobox transcription factor 2 (CDX2) was present in 70% of cases. In this young population (median age 54 years), loss of mismatch repair (MMR) proteins occurred in 35% of patients, with confirmed MSI in 100% of tested cases. Expression of vascular endothelial growth factor-A (VEGF-A) and epidermal growth factor receptor (EGFR) was common, occurring in 96 and 71% of patients, respectively. Only one case showed HER2 expression and none showed loss of phosphatase and tensin homologue mutated on chromosome 10 (PTEN).These results suggest that alterations in DNA MMR pathways are common in SBAs, similar to what is observed in large bowel adenocarcinomas. Furthermore, the high percentage of tumours expressing both EGFR and VEGF suggests that patients with this rare cancer may benefit from therapeutic strategies targeting EGFR and VEGF receptor (VEGFR).

Authors
Overman, MJ; Pozadzides, J; Kopetz, S; Wen, S; Abbruzzese, JL; Wolff, RA; Wang, H
MLA Citation
Overman, MJ, Pozadzides, J, Kopetz, S, Wen, S, Abbruzzese, JL, Wolff, RA, and Wang, H. "Immunophenotype and molecular characterisation of adenocarcinoma of the small intestine." British journal of cancer 102.1 (January 2010): 144-150.
PMID
19935793
Source
epmc
Published In
British Journal of Cancer
Volume
102
Issue
1
Publish Date
2010
Start Page
144
End Page
150
DOI
10.1038/sj.bjc.6605449

Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance.

We investigated the efficacy of fluorouracil (FU), leucovorin, irinotecan, and bevacizumab (FOLFIRI + B) in a phase II trial in patients previously untreated for metastatic colorectal cancer (mCRC), and changes during treatment in plasma cytokines and angiogenic factors (CAFs) as potential markers of treatment response and therapeutic resistance.We conducted a phase II, two-institution trial of FOLFIRI + B. Each 14-day cycle consisted of bevacizumab (5 mg/kg), irinotecan (180 mg/m(2)), bolus FU (400 mg/m(2)), and leucovorin (400 mg/m(2)) followed by a 46-hour infusion of FU (2,400 mg/m(2)). Levels of 37 CAFs were assessed using multiplex-bead assays and enzyme-linked immunosorbent assay at baseline, during treatment, and at the time of progressive disease (PD).Forty-three patients were enrolled. Median progression-free survival (PFS), the primary end point of the study, was 12.8 months. Median overall survival was 31.3 months, with a response rate of 65%. Elevated interleukin-8 at baseline was associated with a shorter PFS (11 v 15.1 months, P = .03). Before the radiographic development of PD, several CAFs associated with angiogenesis and myeloid recruitment increased compared to baseline, including basic fibroblast growth factor (P = .046), hepatocyte growth factor (P = .046), placental growth factor (P < .001), stromal-derived factor-1 (P = .04), and macrophage chemoattractant protein-3 (P < .001).Efficacy and tolerability of FOLFIRI + B appeared favorable to historical controls in this single arm study. Before radiographic progression, there was a shift in balance of CAFs, with a rise in alternate pro-angiogenic cytokines and myeloid recruitment factors in subsets of patients that may represent mechanisms of resistance.

Authors
Kopetz, S; Hoff, PM; Morris, JS; Wolff, RA; Eng, C; Glover, KY; Adinin, R; Overman, MJ; Valero, V; Wen, S; Lieu, C; Yan, S; Tran, HT; Ellis, LM; Abbruzzese, JL; Heymach, JV
MLA Citation
Kopetz, S, Hoff, PM, Morris, JS, Wolff, RA, Eng, C, Glover, KY, Adinin, R, Overman, MJ, Valero, V, Wen, S, Lieu, C, Yan, S, Tran, HT, Ellis, LM, Abbruzzese, JL, and Heymach, JV. "Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 28.3 (January 2010): 453-459.
PMID
20008624
Source
epmc
Published In
Journal of Clinical Oncology
Volume
28
Issue
3
Publish Date
2010
Start Page
453
End Page
459
DOI
10.1200/jco.2009.24.8252

Barriers to Integrating Gene Profiling for Stage II Colon Cancer

Authors
Kopetz, S; Abbruzzese, JL
MLA Citation
Kopetz, S, and Abbruzzese, JL. "Barriers to Integrating Gene Profiling for Stage II Colon Cancer." Clinical Cancer Research 15.24 (December 15, 2009): 7451-7452.
Source
crossref
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
15
Issue
24
Publish Date
2009
Start Page
7451
End Page
7452
DOI
10.1158/1078-0432.CCR-09-2523

Genetic and nongenetic covariates of pain severity in patients with adenocarcinoma of the pancreas: assessing the influence of cytokine genes.

We previously demonstrated that select cytokine gene polymorphisms in interleukin (IL)-8 are a significant predictor of pain and analgesia in patients with lung cancer. This study explores the role of 13 potentially functional polymorphisms in cytokine genes, including IL-1beta, IL-6, IL-8, IL-10, IL-18, tumor necrosis factor-alpha, and nuclear factor kappa-B subunit 1, in pain severity in patients with pancreatic cancer. We evaluated a series of patients with histologically confirmed adenocarcinoma of the pancreas (n=484), who had completed a self-administered survey of pain before initiating any cancer treatment. DNA (n=156) available for a subset of white patients was assayed and assessed for association with pain severity. Results showed that 26% (128 of 484) reported experiencing severe pain (score of >7 on a 0-10 scale). Severe pain varied by the stage of disease (odds ratio [OR] Stage II=4.02, 95% confidence interval (CI)=1.07, 15.07; Stage III=5.02, 95% CI=1.28, 19.61; Stage IV=6.90, 95% CI=1.96, 24.29), ethnicity (OR non-Hispanic blacks=3.67; 95% CI=1.44, 9.38), reports of depressed mood (OR=1.94; 95% CI=1.09, 3.43), and female sex (OR=1.78; 95% CI=1.04, 3.05). Controlling for these covariates, IL8-251T/A (OR=2.43, 95% CI=1.3, 4.7, P<0.009) significantly predicted severe pain in a subset of white patients. When we adjusted for reported analgesic use, we found that IL8-251T/A persisted as a predictor for severe pain, with carriers of TT and AT genotypes having more than a threefold risk (OR=3.23, 95% CI=1.4, 4.7) for severe pain relative to the AA genotypes. We provide preliminary evidence of the role of IL-8 in the severity of pain in pancreatic cancer patients. Additional studies are needed in larger cohorts of patients.

Authors
Reyes-Gibby, CC; Shete, S; Yennurajalingam, S; Frazier, M; Bruera, E; Kurzrock, R; Crane, CH; Abbruzzese, J; Evans, D; Spitz, MR
MLA Citation
Reyes-Gibby, CC, Shete, S, Yennurajalingam, S, Frazier, M, Bruera, E, Kurzrock, R, Crane, CH, Abbruzzese, J, Evans, D, and Spitz, MR. "Genetic and nongenetic covariates of pain severity in patients with adenocarcinoma of the pancreas: assessing the influence of cytokine genes." Journal of pain and symptom management 38.6 (December 2009): 894-902.
PMID
19692203
Source
epmc
Published In
Journal of Pain and Symptom Management
Volume
38
Issue
6
Publish Date
2009
Start Page
894
End Page
902
DOI
10.1016/j.jpainsymman.2009.04.019

Oral poly(ADP-ribose) polymerase-1 inhibitor BSI-401 has antitumor activity and synergizes with oxaliplatin against pancreatic cancer, preventing acute neurotoxicity.

Development of novel agents and drug combinations are urgently needed for treatment of pancreatic cancer. Oxaliplatin belongs to an important class of DNA-damaging organoplatinum agents, useful in pancreatic cancer therapy. However, increased ability of cancer cells to recognize and repair DNA damage enables resistance to these agents. Poly (ADP ribose) polymerase-1 is a sensor of DNA damage with key roles in DNA repair. Here, we report the therapeutic activity of the poly (ADP ribose) polymerase-1 inhibitor BSI-401, as a single agent and in combination with oxaliplatin in orthotopic nude mouse models of pancreatic cancer, and its effect on oxaliplatin-induced acute neurotoxicity.We determined in vitro the effect of BSI-401 and its synergism with oxaliplatin on the growth of pancreatic cancer cells. Activity of different dosages of parenteral and oral BSI-401, alone and in combination with oxaliplatin, was evaluated in orthotopic nude mouse models with luciferase-expressing pancreatic cancer cells. The effect of BSI-401 in preventing oxaliplatin-induced acute cold allodynia was measured in rats using a temperature-controlled plate.BSI-401 alone and in synergism with oxaliplatin significantly inhibited the growth of pancreatic cancer cells in vitro. In nude mice, i.p. [200 mg/kg once a week (QW) x 4] and oral [400 mg/kg days 1-5 of each week (QD5 + R2) x 4] administration of BSI-401 significantly reduced tumor burden and prolonged survival (46 versus 144 days, P = 0.0018; 73 versus 194 days, P = 0.0017) compared with no treatment. BSI-401 combined with oxaliplatin had potent synergistic antitumor activity (46 versus 132 days, P = 0.0063), and significantly (P = 0.0148) prevented acute oxaliplatin-induced neurotoxicity.BSI-401, alone or in combination with oxaliplatin, is a promising new therapeutic agent that warrants further evaluation for treatment of pancreatic cancer.

Authors
Melisi, D; Ossovskaya, V; Zhu, C; Rosa, R; Ling, J; Dougherty, PM; Sherman, BM; Abbruzzese, JL; Chiao, PJ
MLA Citation
Melisi, D, Ossovskaya, V, Zhu, C, Rosa, R, Ling, J, Dougherty, PM, Sherman, BM, Abbruzzese, JL, and Chiao, PJ. "Oral poly(ADP-ribose) polymerase-1 inhibitor BSI-401 has antitumor activity and synergizes with oxaliplatin against pancreatic cancer, preventing acute neurotoxicity." Clinical cancer research : an official journal of the American Association for Cancer Research 15.20 (October 6, 2009): 6367-6377.
PMID
19808866
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
15
Issue
20
Publish Date
2009
Start Page
6367
End Page
6377
DOI
10.1158/1078-0432.ccr-09-0910

Phase II trial of romidepsin (NSC-630176) in previously treated colorectal cancer patients with advanced disease: a Southwest Oncology Group study (S0336).

Patients with metastatic colorectal cancer who progress on standard chemotherapy have limited treatment options. New and effective drugs are needed for these patients. Romidepsin is a histone deacetylase inhibitor that can alter chromatin structure and gene transcription leading to multiple changes in cellular protein production. This may result in cell cycle arrest and tumor growth inhibition. Romidepsin has shown anti-proliferative activity in vitro against multiple mouse and human tumor cell lines and in vivo in human tumor xenograft models.Patients were required to have pathologically verified, measurable, metastatic or locally advanced colorectal cancer that was surgically unresectable. They must have failed either one or two prior chemotherapy regimens, had performance status of 0-1, adequate bone marrow, renal and hepatic function, and no significant cardiac disease. Patients were treated with romidepsin at a dose of 13 mg/m(2) as a 4-h iv infusion on days 1, 8, and 15 of a 28-day cycle. The study had a two stage design. The primary objective of the study was to determine the confirmed response probability in this group of patients treated with romidepsin.Twenty-eight patients were registered to the study, two of whom were ineligible. One eligible patient refused all treatment and was not analyzed. For the 25 remaining patients, performance status was 0 in 16 patients and 1 in nine patients. Ten patients had received one prior chemotherapy regimen and fifteen 2 prior regimens. Out of the 25 eligible and analyzable patients accrued in the first stage of the protocol, no objective responses were observed and the study was permanently closed. Four patients had stable disease as the best response. Twenty-five patients were assessed for toxicity. No grade 4 or greater toxicities were seen. Fourteen of the 25 patients experienced grade 3 toxicities the most common of which were fatigue or anorexia.Romidepsin at this dose and schedule is ineffective in the treatment of patients with metastatic colorectal cancer after prior chemotherapy. Future trials might evaluate combinations of romidepsin with chemotherapeutic or other agents.

Authors
Whitehead, RP; Rankin, C; Hoff, PMG; Gold, PJ; Billingsley, KG; Chapman, RA; Wong, L; Ward, JH; Abbruzzese, JL; Blanke, CD
MLA Citation
Whitehead, RP, Rankin, C, Hoff, PMG, Gold, PJ, Billingsley, KG, Chapman, RA, Wong, L, Ward, JH, Abbruzzese, JL, and Blanke, CD. "Phase II trial of romidepsin (NSC-630176) in previously treated colorectal cancer patients with advanced disease: a Southwest Oncology Group study (S0336)." Investigational new drugs 27.5 (October 2009): 469-475.
PMID
18941712
Source
epmc
Published In
Investigational New Drugs
Volume
27
Issue
5
Publish Date
2009
Start Page
469
End Page
475
DOI
10.1007/s10637-008-9190-8

Reply:

Authors
Hassan, MM; Abbruzzese, JL
MLA Citation
Hassan, MM, and Abbruzzese, JL. "Reply:." Hepatology 50.3 (September 2009): 994-994.
Source
crossref
Published In
Hepatology
Volume
50
Issue
3
Publish Date
2009
Start Page
994
End Page
994
DOI
10.1002/hep.23172

Antidiabetic therapies affect risk of pancreatic cancer.

Antidiabetic drugs have been found to have various effects on cancer in experimental systems and in epidemiologic studies, although the association between these therapeutics and the risk of human pancreatic cancer has not been explored. We investigated the effect of antidiabetic therapies on the risk of pancreatic cancer.A hospital-based case-control study was conducted at M. D. Anderson Cancer Center from 2004 to 2008 involving 973 patients with pancreatic adenocarcinoma (including 259 diabetic patients) and 863 controls (including 109 diabetic patients). Information on diabetes history and other risk factors was collected by personal interview. The frequencies of use of insulin, insulin secretagogues, metformin, and other antidiabetic medications among diabetic patients were compared between cases and controls. The risk of pancreatic cancer was estimated using unconditional logistic regression analysis.Diabetic patients who had taken metformin had a significantly lower risk of pancreatic cancer compared with those who had not taken metformin (odds ratio, 0.38; 95% confidence interval, 0.22-0.69; P = .001), with adjustments for potential confounders. This difference remained statistically significant when the analysis was restricted to patients with a duration of diabetes >2 years or those who never used insulin. In contrast, diabetic patients who had taken insulin or insulin secretagogues had a significantly higher risk of pancreatic cancer compared with diabetic patients who had not taken these drugs.Metformin use was associated with reduced risk, and insulin or insulin secretagogue use was associated with increased risk of pancreatic cancer in diabetic patients.

Authors
Li, D; Yeung, S-CJ; Hassan, MM; Konopleva, M; Abbruzzese, JL
MLA Citation
Li, D, Yeung, S-CJ, Hassan, MM, Konopleva, M, and Abbruzzese, JL. "Antidiabetic therapies affect risk of pancreatic cancer." Gastroenterology 137.2 (August 2009): 482-488.
PMID
19375425
Source
epmc
Published In
Gastroenterology
Volume
137
Issue
2
Publish Date
2009
Start Page
482
End Page
488
DOI
10.1053/j.gastro.2009.04.013

Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer.

A better understanding of drug resistance mechanisms is required to improve outcomes in patients with pancreatic cancer. Here, we characterized patterns of sensitivity and resistance to three conventional chemotherapeutic agents with divergent mechanisms of action [gemcitabine, 5-fluorouracil (5-FU), and cisplatin] in pancreatic cancer cells. Four (L3.6pl, BxPC-3, CFPAC-1, and SU86.86) were sensitive and five (PANC-1, Hs766T, AsPC-1, MIAPaCa-2, and MPanc96) were resistant to all three agents based on GI(50) (50% growth inhibition). Gene expression profiling and unsupervised hierarchical clustering revealed that the sensitive and resistant cells formed two distinct groups and differed in expression of specific genes, including several features of "epithelial to mesenchymal transition" (EMT). Interestingly, an inverse correlation between E-cadherin and its transcriptional suppressor, Zeb-1, was observed in the gene expression data and was confirmed by real-time PCR. Independent validation experiment using five new pancreatic cancer cell lines confirmed that an inverse correlation between E-cadherin and Zeb-1 correlated closely with resistance to gemcitabine, 5-FU, and cisplatin. Silencing Zeb-1 in the mesenchymal lines not only increased the expression of E-cadherin but also other epithelial markers, such as EVA1 and MAL2, and restored drug sensitivity. Importantly, immunohistochemical analysis of E-cadherin and Zeb-1 in primary tumors confirmed that expression of the two proteins was mutually exclusive (P = 0.012). Therefore, our results suggest that Zeb-1 and other regulators of EMT may maintain drug resistance in human pancreatic cancer cells, and therapeutic strategies to inhibit Zeb-1 and reverse EMT should be evaluated.

Authors
Arumugam, T; Ramachandran, V; Fournier, KF; Wang, H; Marquis, L; Abbruzzese, JL; Gallick, GE; Logsdon, CD; McConkey, DJ; Choi, W
MLA Citation
Arumugam, T, Ramachandran, V, Fournier, KF, Wang, H, Marquis, L, Abbruzzese, JL, Gallick, GE, Logsdon, CD, McConkey, DJ, and Choi, W. "Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer." Cancer research 69.14 (July 7, 2009): 5820-5828.
PMID
19584296
Source
epmc
Published In
Cancer Research
Volume
69
Issue
14
Publish Date
2009
Start Page
5820
End Page
5828
DOI
10.1158/0008-5472.can-08-2819

Phase II study of capecitabine and oxaliplatin for advanced adenocarcinoma of the small bowel and ampulla of Vater.

PURPOSE: Adenocarcinomas of the small bowel and ampulla of Vater represent rare cancers that have limited data regarding first-line therapy. We conducted a phase II trial to evaluate the benefit of capecitabine in combination with oxaliplatin (CAPOX) in patients with advanced adenocarcinoma of small bowel or ampullary origin. PATIENTS AND METHODS: Eligible patients with metastatic or unresectable tumors and no prior systemic chemotherapy for advanced disease participated in this phase II trial. CAPOX was administered as a 21-day cycle with oxaliplatin 130 mg/m(2) on day 1 and capecitabine 750 mg/m(2) twice a day on days 1 through 14. The primary end point was overall response rate as assessed by Response Evaluation Criteria in Solid Tumors. RESULTS: Thirty-one patients were enrolled onto the study, and 30 patients received study treatment. The confirmed overall response rate was 50%; three patients with metastatic disease achieved complete responses. The median time to progression (TTP) was 11.3 months, and the median overall survival (OS) was 20.4 months. Subset analysis of patients with metastatic disease only (n = 25) revealed a median TTP of 9.4 months and median OS of 15.5 months. The most common grades 3 or 4 toxicities included fatigue (30%), peripheral neuropathy (10%), vomiting (10%), diarrhea (10%), and neutropenia (10%). CONCLUSION: When administered to patients with good performance status, CAPOX is well tolerated and produces a superior response rate and longer OS compared with other regimens in the literature. CAPOX should be considered a new standard regimen for advanced small bowel and ampullary adenocarcinomas.

Authors
Overman, MJ; Varadhachary, GR; Kopetz, S; Adinin, R; Lin, E; Morris, JS; Eng, C; Abbruzzese, JL; Wolff, RA
MLA Citation
Overman, MJ, Varadhachary, GR, Kopetz, S, Adinin, R, Lin, E, Morris, JS, Eng, C, Abbruzzese, JL, and Wolff, RA. "Phase II study of capecitabine and oxaliplatin for advanced adenocarcinoma of the small bowel and ampulla of Vater." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 27.16 (June 2009): 2598-2603.
PMID
19164203
Source
epmc
Published In
Journal of Clinical Oncology
Volume
27
Issue
16
Publish Date
2009
Start Page
2598
End Page
2603
DOI
10.1200/jco.2008.19.7145

Body mass index and risk, age of onset, and survival in patients with pancreatic cancer.

Obesity has been implicated as a risk factor for pancreatic cancer.To demonstrate the association of excess body weight across an age cohort and the risk, age of onset, and overall survival of patients with pancreatic cancer.A case-control study of 841 patients with pancreatic adenocarcinoma and 754 healthy individuals frequency matched by age, race, and sex. The study was conducted at a university cancer center in the United States from 2004 to 2008. Height and body weight histories were collected by personal interview starting at ages 14 to 19 years and over 10-year intervals progressing to the year prior to recruitment in the study.The associations between patients' body mass index (BMI) and risk of pancreatic cancer, age at onset, and overall survival were examined by unconditional logistic regression, linear regression, and Cox proportional hazard regression models, respectively.Individuals who were overweight (a BMI of 25-29.9) from the ages of 14 to 39 years (highest odds ratio [OR], 1.67; 95% confidence interval [CI], 1.20-2.34) or obese (a BMI > or = 30) from the ages of 20 to 49 years (highest OR, 2.58; 95% CI, 1.70-3.90) had an associated increased risk of pancreatic cancer, independent of diabetes status. The association was stronger in men (adjusted OR, 1.80; 95% CI, 1.45-2.23) by mean BMI from the ages of 14 to 59 years than in women (adjusted OR, 1.32; 95% CI, 1.02-1.70) and in ever smokers (adjusted OR, 1.75; 95% CI, 1.37-2.22) than in never smokers (adjusted OR, 1.46; 95% CI, 1.16-1.84). The population-attributable risk percentage of pancreatic cancer based on the mean BMI from the ages of 14 to 59 years was 10.3% for never smokers and 21.3% for ever smokers. Individuals who were overweight or obese from the ages of 20 to 49 years had an earlier onset of pancreatic cancer by 2 to 6 years (median age of onset was 64 years for patients with normal weight, 61 years for overweight patients [P = .02], and 59 years for obese patients [P < .001]). Compared with those with normal body weight and after adjusting for all clinical factors, individuals who were overweight or obese from the ages of 30 to 79 years or in the year prior to recruitment had reduced overall survival of pancreatic cancer regardless of disease stage and tumor resection status (overweight patients: hazard ratio, 1.26 [95% CI, 0.94-1.69], P = .04; obese patients: hazard ratio, 1.86 [95% CI, 1.35-2.56], P < .001).Overweight or obesity during early adulthood was associated with a greater risk of pancreatic cancer and a younger age of disease onset. Obesity at an older age was associated with a lower overall survival in patients with pancreatic cancer.

Authors
Li, D; Morris, JS; Liu, J; Hassan, MM; Day, RS; Bondy, ML; Abbruzzese, JL
MLA Citation
Li, D, Morris, JS, Liu, J, Hassan, MM, Day, RS, Bondy, ML, and Abbruzzese, JL. "Body mass index and risk, age of onset, and survival in patients with pancreatic cancer." JAMA 301.24 (June 2009): 2553-2562.
PMID
19549972
Source
epmc
Published In
JAMA : the journal of the American Medical Association
Volume
301
Issue
24
Publish Date
2009
Start Page
2553
End Page
2562
DOI
10.1001/jama.2009.886

Activator protein-1 has an essential role in pancreatic cancer cells and is regulated by a novel Akt-mediated mechanism.

Activator protein-1 (AP-1) regulates the expression of several genes involved in human tumorigenesis. However, there is little known about this transcription factor in pancreatic ductal adenocarcinoma. We recently found high levels of AP-1-binding activities and multiple AP-1/DNA complexes containing c-Jun, JunD, Fra1, and Fra2 in pancreatic cancer cells. Transient transfection assays indicated that AP-1 was functional and capable of transactivating its gene targets. Furthermore, a c-Jun transactivation mutant inhibited anchorage-dependent and anchorage-independent proliferation, suggesting that AP-1 had an essential role in pancreatic cancer cells. Our study also uncovered a novel mechanism by which protein kinase Akt controls c-Jun activity in pancreatic cancer cells. Indeed, distinct from its known ability to induce c-fos and fra1 and to stabilize c-Jun, Akt appeared to directly regulate the transcriptional activity of c-Jun independently of the phosphorylation sites targeted by c-Jun NH(2)-terminal kinase (Ser(63)/Ser(73)) and glycogen synthase kinase-3 (Thr(239)). Our data also suggest that growth factors might use this Akt-regulated mechanism to potently induce c-Jun targets such as cyclin D1. Collectively, our findings indicate that AP-1 has an important function in pancreatic cancer cells and provide evidence for a previously unknown Akt-mediated mechanism of c-Jun activation.

Authors
Shin, S; Asano, T; Yao, Y; Zhang, R; Claret, F-X; Korc, M; Sabapathy, K; Menter, DG; Abbruzzese, JL; Reddy, SAG
MLA Citation
Shin, S, Asano, T, Yao, Y, Zhang, R, Claret, F-X, Korc, M, Sabapathy, K, Menter, DG, Abbruzzese, JL, and Reddy, SAG. "Activator protein-1 has an essential role in pancreatic cancer cells and is regulated by a novel Akt-mediated mechanism." Molecular cancer research : MCR 7.5 (May 12, 2009): 745-754.
PMID
19435822
Source
epmc
Published In
Molecular cancer research : MCR
Volume
7
Issue
5
Publish Date
2009
Start Page
745
End Page
754
DOI
10.1158/1541-7786.mcr-08-0462

Tumor blood flow measured by perfusion computed tomography and 15O-labeled water positron emission tomography: a comparison study.

OBJECTIVES: To compare blood flow measurements of tumors assessed by perfusion computed tomography (pCT) and the clinical gold standard of 15O-labeled water positron emission tomography (15O-PET). METHODS: Blood flows were estimated by pCT (4-row multidetector, CT Perfusion 3.1) and 15O-PET (Posicam, first-pass model) in 14 patients with solid tumors, totaling 22 index tumors and 57 matched pairs of examinations. Blood flow estimates were compared using t test, Bland-Altman, and linear mixed regression analyses. RESULTS: There was no significant difference between the mean (SD) blood flow values measured by pCT and 15O-PET: 25.9 +/- 15.4 and 27.8 +/- 14.0 mL/min per 100 g, respectively. CONCLUSIONS: The demonstration of a good correlation between pCT and 15O-PET potentially enables the use of pCT, which is more widely available than 15O-PET, when tumor blood flow estimates are required, particularly in the context of clinical studies.

Authors
Ng, CS; Kodama, Y; Mullani, NA; Barron, BJ; Wei, W; Herbst, RS; Abbruzzese, JL; Charnsangavej, C
MLA Citation
Ng, CS, Kodama, Y, Mullani, NA, Barron, BJ, Wei, W, Herbst, RS, Abbruzzese, JL, and Charnsangavej, C. "Tumor blood flow measured by perfusion computed tomography and 15O-labeled water positron emission tomography: a comparison study." Journal of computer assisted tomography 33.3 (May 2009): 460-465.
PMID
19478644
Source
epmc
Published In
Journal of Computer Assisted Tomography
Volume
33
Issue
3
Publish Date
2009
Start Page
460
End Page
465
DOI
10.1097/rct.0b013e318182d2e0

Association between hypothyroidism and hepatocellular carcinoma: a case-control study in the United States.

Thyroid hormones play an essential role in lipid mobilization, lipid degradation, and fatty acid oxidation. Hypothyroidism has been associated with nonalcoholic steatohepatitis; however, the association between thyroid diseases and hepatocellular carcinoma (HCC) in men and women has not been well established. We investigated the association between hypothyroidism and HCC risk in men and women in a case-control study, which included 420 eligible patients with HCC and 1104 healthy controls. We used multivariate unconditional logistic regression models to control for the confounding effects of established HCC risk factors. A long-term history of hypothyroidism (>10 years) was associated with a statistically significant high risk of HCC in women; after adjusting for demographic factors, diabetes, hepatitis, alcohol consumption, cigarette smoking, and family history of cancer, the odds ratio (OR) was 2.9 (95% confidence interval [CI], 1.3-6.3). Restricted analyses among hepatitis virus-negative subjects, nondrinkers, nondiabetics, nonsmokers, and nonobese individuals indicated a significant association between hypothyroidism and HCC, with an approximate two-fold to three-fold increased risk of HCC development. We observed risk modification among women with diabetes mellitus (OR = 9.4; 95% CI = 2.7-32.7) and chronic hepatitis virus infection (OR = 31.2; 95% CI = 6.3-153.2). A history of hyperthyroidism was not significantly related to HCC (OR = 1.7; CI = 0.6-5.1). We noted significant elevated risk association between hypothyroidism and HCC in women that was independent of established HCC risk factors. Experimental investigations are necessary for thorough assessment of the relationship between thyroid disorders and HCC.

Authors
Hassan, MM; Kaseb, A; Li, D; Patt, YZ; Vauthey, J-N; Thomas, MB; Curley, SA; Spitz, MR; Sherman, SI; Abdalla, EK; Davila, M; Lozano, RD; Hassan, DM; Chan, W; Brown, TD; Abbruzzese, JL
MLA Citation
Hassan, MM, Kaseb, A, Li, D, Patt, YZ, Vauthey, J-N, Thomas, MB, Curley, SA, Spitz, MR, Sherman, SI, Abdalla, EK, Davila, M, Lozano, RD, Hassan, DM, Chan, W, Brown, TD, and Abbruzzese, JL. "Association between hypothyroidism and hepatocellular carcinoma: a case-control study in the United States." Hepatology 49.5 (May 2009): 1563-1570.
PMID
19399911
Source
pubmed
Published In
Hepatology
Volume
49
Issue
5
Publish Date
2009
Start Page
1563
End Page
1570
DOI
10.1002/hep.22793

Synergistic activity of the SRC family kinase inhibitor dasatinib and oxaliplatin in colon carcinoma cells is mediated by oxidative stress.

Chemotherapeutic regimens for the treatment of colorectal cancer generally include oxaliplatin, although inherent and acquired resistance is common. One potential mediator of oxaliplatin sensitivity is the nonreceptor protein tyrosine kinase, Src, the activity of which correlates with disease stage and patient survival. Therefore, we investigated the effects of Src inhibition using the tyrosine kinase inhibitor dasatinib on oxaliplatin sensitivity. We show that oxaliplatin acutely activates Src and that combination treatment with dasatinib is synergistic in a cell-line dependent manner, with the level of Src activation correlating with extent of synergy in a panel of six cell lines. Intracellular reactive oxygen species (ROS) are generated after oxaliplatin treatment, and ROS potently activates Src. Pretreatment with antioxidants inhibits oxaliplatin-induced Src activation. In oxaliplatin-resistant cell lines, Src activity is constitutively increased. In a mouse model of colorectal liver metastases, treatment with oxaliplatin also results in chronic Src activation. The combination of dasatinib and oxaliplatin results in significantly smaller tumors compared with single-agent treatment, corresponding with reduced proliferation and angiogenesis. Therefore, we conclude that oxaliplatin activates Src through a ROS-dependent mechanism. Src inhibition increases oxaliplatin activity both in vitro and in vivo. These results suggest that Src inhibitors combined with oxaliplatin may have efficacy in metastatic colon cancer and may provide the first indication of a molecular phenotype that might be susceptible to such combinations.

Authors
Kopetz, S; Lesslie, DP; Dallas, NA; Park, SI; Johnson, M; Parikh, NU; Kim, MP; Abbruzzese, JL; Ellis, LM; Chandra, J; Gallick, GE
MLA Citation
Kopetz, S, Lesslie, DP, Dallas, NA, Park, SI, Johnson, M, Parikh, NU, Kim, MP, Abbruzzese, JL, Ellis, LM, Chandra, J, and Gallick, GE. "Synergistic activity of the SRC family kinase inhibitor dasatinib and oxaliplatin in colon carcinoma cells is mediated by oxidative stress." Cancer research 69.9 (May 2009): 3842-3849.
PMID
19383922
Source
epmc
Published In
Cancer Research
Volume
69
Issue
9
Publish Date
2009
Start Page
3842
End Page
3849
DOI
10.1158/0008-5472.can-08-2246

Long-term survival after multidisciplinary management of resected pancreatic adenocarcinoma.

Actual 5-year survival rates of 10-18% have been reported for patients with resected pancreatic adenocarcinoma (PC), but the use of multimodality therapy was uncommon in these series. We evaluated long-term survival and patterns of recurrence in patients treated for PC with contemporary staging and multimodality therapy.We analyzed 329 consecutive patients with PC evaluated between 1990 and 2002 who underwent resection. Each received a multidisciplinary evaluation and a standard operative approach. Pre- or postoperative chemotherapy and/or chemoradiation were routine. Surgical specimens of 5-year survivors were re-reviewed. A multivariate model of factors associated with long-term survival was constructed.Patients underwent pancreaticoduodenectomy (n = 302; 92%), distal (n = 20; 6%), or total pancreatectomy (n = 7; 2%). A total of 108 patients (33%) underwent vascular reconstruction, 301 patients (91%) received neoadjuvant or adjuvant therapy, 157 specimens (48%) were node positive, and margins were microscopically positive in 52 patients (16%). Median overall survival and disease-specific survival was 23.9 and 26.5 months. Eighty-eight patients (27%) survived a minimum of 5 years and had a median overall survival of 11 years. Of these, 21 (24%) experienced recurrence, 7 (8%) after 5 years. Late recurrences occurred most frequently in the lungs, the latest at 6.7 years. Multivariate analysis identified disease-negative lymph nodes (P = .02) and no prior attempt at resection (P = 0.01) as associated with 5-year survival.Our 27% actual 5-year survival rate for patients with resected PC is superior to that previously reported, and it is influenced by our emphasis on detailed staging and patient selection, a standardized operative approach, and routine use of multimodality therapy.

Authors
Katz, MHG; Wang, H; Fleming, JB; Sun, CC; Hwang, RF; Wolff, RA; Varadhachary, G; Abbruzzese, JL; Crane, CH; Krishnan, S; Vauthey, J-N; Abdalla, EK; Lee, JE; Pisters, PWT; Evans, DB
MLA Citation
Katz, MHG, Wang, H, Fleming, JB, Sun, CC, Hwang, RF, Wolff, RA, Varadhachary, G, Abbruzzese, JL, Crane, CH, Krishnan, S, Vauthey, J-N, Abdalla, EK, Lee, JE, Pisters, PWT, and Evans, DB. "Long-term survival after multidisciplinary management of resected pancreatic adenocarcinoma." April 2009.
PMID
19194760
Source
epmc
Published In
Annals of Surgical Oncology
Volume
16
Issue
4
Publish Date
2009
Start Page
836
End Page
847
DOI
10.1245/s10434-008-0295-2

Significant associations of mismatch repair gene polymorphisms with clinical outcome of pancreatic cancer.

DNA mismatch repair (MMR) is critical in maintaining genomic stability and may modulate the cellular response to gemcitabine. We hypothesized that genetic variations in MMR may affect the clinical outcome of patients with pancreatic cancer.We evaluated 15 single-nucleotide polymorphisms (SNPs) of eight MMR genes in 154 patients with potentially resectable pancreatic adenocarcinoma who were enrolled onto phase II clinical trials for preoperative gemcitabine-based chemoradiotherapy from 1999 to 2006. Associations of genotypes with tumor response to therapy (change of tumor size by radiologic evaluation at restaging), margin-negative tumor resection, and overall survival were evaluated using logistic regression and Cox proportional regression models.Five, six, and 10 genotypes were significantly associated with tumor response to preoperative chemoradiotherapy, tumor resectability, and overall survival, respectively, in univariable analysis. TREX1 EX14-460C>T and TP73 Ex2+4G>A genotypes remained as significant predictors for tumor response, MLH1 IVS12-169C>T and TP73 remained as significant predictors for tumor resectability, and EXO1 R354H, TREX1, and TP73 remained as significant predictors for overall survival in multivariable models that included all clinical factors and genotypes examined. A strong combined genotype effect on each clinical end point was observed. For example, 20 of the 25 patients with zero to one adverse genotypes were alive, those with two, three, four, five, and six to seven adverse genotypes had median survival times of 36.2, 23.9, 16.3, 13.0, and 8.3 months, respectively (P < .001).SNPs of MMR genes have a potential value as predictors for clinical response to chemoradiotherapy and as prognostic markers for tumor resectability and overall survival of patients with resectable pancreatic cancer.

Authors
Dong, X; Jiao, L; Li, Y; Evans, DB; Wang, H; Hess, KR; Abbruzzese, JL; Li, D
MLA Citation
Dong, X, Jiao, L, Li, Y, Evans, DB, Wang, H, Hess, KR, Abbruzzese, JL, and Li, D. "Significant associations of mismatch repair gene polymorphisms with clinical outcome of pancreatic cancer." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 27.10 (April 2009): 1592-1599.
PMID
19237629
Source
epmc
Published In
Journal of Clinical Oncology
Volume
27
Issue
10
Publish Date
2009
Start Page
1592
End Page
1599
DOI
10.1200/jco.2008.20.1111

Hidden biases in an observational study of bevacizumab beyond progression.

Authors
Kopetz, S; Abbruzzese, JL
MLA Citation
Kopetz, S, and Abbruzzese, JL. "Hidden biases in an observational study of bevacizumab beyond progression." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 27.10 (April 2009): 1732-1733. (Letter)
PMID
19255299
Source
epmc
Published In
Journal of Clinical Oncology
Volume
27
Issue
10
Publish Date
2009
Start Page
1732
End Page
1733
DOI
10.1200/jco.2009.21.2084

Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway.

Despite rapid advances in many fronts, pancreatic cancer (PC) remains one of the most difficult human malignancies to treat due, in part, to de novo and acquired chemoresistance and radioresistance. Gemcitabine alone or in combination with other conventional therapeutics is the standard of care for the treatment of advanced PC without any significant improvement in the overall survival of patients diagnosed with this deadly disease. Previous studies have shown that PC cells that are gemcitabine-resistant (GR) acquired epithelial-mesenchymal transition (EMT) phenotype, which is reminiscent of "cancer stem-like cells"; however, the molecular mechanism that led to EMT phenotype has not been fully investigated. The present study shows that Notch-2 and its ligand, Jagged-1, are highly up-regulated in GR cells, which is consistent with the role of the Notch signaling pathway in the acquisition of EMT and cancer stem-like cell phenotype. We also found that the down-regulation of Notch signaling was associated with decreased invasive behavior of GR cells. Moreover, down-regulation of Notch signaling by siRNA approach led to partial reversal of the EMT phenotype, resulting in the mesenchymal-epithelial transition, which was associated with decreased expression of vimentin, ZEB1, Slug, Snail, and nuclear factor-kappaB. These results provide molecular evidence showing that the activation of Notch signaling is mechanistically linked with chemoresistance phenotype (EMT phenotype) of PC cells, suggesting that the inactivation of Notch signaling by novel strategies could be a potential targeted therapeutic approach for overcoming chemoresistance toward the prevention of tumor progression and/or treatment of metastatic PC.

Authors
Wang, Z; Li, Y; Kong, D; Banerjee, S; Ahmad, A; Azmi, AS; Ali, S; Abbruzzese, JL; Gallick, GE; Sarkar, FH
MLA Citation
Wang, Z, Li, Y, Kong, D, Banerjee, S, Ahmad, A, Azmi, AS, Ali, S, Abbruzzese, JL, Gallick, GE, and Sarkar, FH. "Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway." Cancer research 69.6 (March 10, 2009): 2400-2407.
PMID
19276344
Source
epmc
Published In
Cancer Research
Volume
69
Issue
6
Publish Date
2009
Start Page
2400
End Page
2407
DOI
10.1158/0008-5472.can-08-4312

Tolfenamic acid enhances pancreatic cancer cell and tumor response to radiation therapy by inhibiting survivin protein expression.

Survivin is overexpressed in most human cancers, including pancreatic adenocarcinoma. Expression of survivin is regulated by specificity protein (Sp) proteins and related to resistance to radiation therapy. Tolfenamic acid induces Sp protein degradation in several cancer cell lines. The purpose of this study is to investigate whether tolfenamic acid inhibits survivin expression and sensitizes pancreatic cancer cells/tumor to radiotherapy. Panc1 and L3.6pl cells have been used to study the effect of radiation on survivin expression and to investigate the efficacy of tolfenamic acid in enhancing the response to radiation therapy. In addition, an orthotopic model for human pancreatic cancer has been used to confirm the efficacy of tolfenamic acid to enhance tumor response to radiation in vivo. Pancreatic cancer cell lines express variable levels of survivin mRNA/protein, which correlate with their radiosensitivity. Radiation increased survivin promoter activity and protein expression in Panc1 and L3.6pl cells and tolfenamic acid inhibited both constitutive and radiation-induced survivin protein expression and enhanced the response of pancreatic cancer cells to radiation therapy. In vivo studies show that tolfenamic acid enhanced the radiation-induced apoptosis associated with decreased survivin expression in tumors and this correlates with the enhanced response of these tumors to the radiation. Thus, tolfenamic acid significantly enhances pancreatic cancer cells/tumor response to radiation therapy. The underlying mechanism includes tolfenamic acid-induced degradation of Sp proteins, which in tumor decreases expression of the Sp-dependent antiapoptotic protein survivin. These preclinical data suggest that tolfenamic acid has the potential to increase the response of pancreatic adenocarcinoma to radiation therapy.

Authors
Konduri, S; Colon, J; Baker, CH; Safe, S; Abbruzzese, JL; Abudayyeh, A; Basha, MR; Abdelrahim, M
MLA Citation
Konduri, S, Colon, J, Baker, CH, Safe, S, Abbruzzese, JL, Abudayyeh, A, Basha, MR, and Abdelrahim, M. "Tolfenamic acid enhances pancreatic cancer cell and tumor response to radiation therapy by inhibiting survivin protein expression." Molecular cancer therapeutics 8.3 (March 3, 2009): 533-542.
PMID
19258429
Source
epmc
Published In
Molecular cancer therapeutics
Volume
8
Issue
3
Publish Date
2009
Start Page
533
End Page
542
DOI
10.1158/1535-7163.mct-08-0405

Proteasome-mediated degradation and functions of hematopoietic progenitor kinase 1 in pancreatic cancer.

Hematopoietic progenitor kinase 1 (HPK1) regulates stress responses, proliferation, and apoptosis in hematopoietic cells. In this study, we examined the expression, regulation, and functions of HPK1 in pancreatic ductal adenocarcinomas (PDA). We found that loss of HPK1 protein expression correlated significantly with the progression of pancreatic intraepithelial neoplasias (P = 0.001) and development of invasive PDA. Similarly, HPK1 protein was not expressed in any of eight PDA cell lines examined but was expressed in immortalized human pancreatic duct epithelial (HPDE) cells. There was no difference in HPK1 mRNA levels in PDA cell lines or primary PDA compared with those in HPDE cells or ductal epithelium in chronic pancreatitis and normal pancreas, respectively. Treatment of Panc-1 cells with a proteasome inhibitor, MG132, increased the HPK1 protein levels in a dose-dependent manner, suggesting that alteration in proteasome activity contributes to the loss of HPK1 protein expression in pancreatic cancer. Like the endogenous HPK1, both wild-type HPK1 and its kinase-dead mutant, HPK1-M46, overexpressed in Panc-1 cells, were also targeted by proteasome-mediated degradation. After MG132 withdrawal, wild-type HPK1 protein expression was markedly decreased within 24 hours, but kinase-dead HPK1 mutant protein expression was sustained for up to 96 hours. Therefore, HPK1 kinase activities were required for the loss of HPK1 protein in PDAs. Furthermore, restoring wild-type HPK1 protein in PDA cells led to the increase in p21 and p27 protein expression and cell cycle arrest. Thus, HPK1 may function as a novel tumor suppressor and its loss plays a critical role in pancreatic cancer.

Authors
Wang, H; Song, X; Logsdon, C; Zhou, G; Evans, DB; Abbruzzese, JL; Hamilton, SR; Tan, T-H; Wang, H
MLA Citation
Wang, H, Song, X, Logsdon, C, Zhou, G, Evans, DB, Abbruzzese, JL, Hamilton, SR, Tan, T-H, and Wang, H. "Proteasome-mediated degradation and functions of hematopoietic progenitor kinase 1 in pancreatic cancer." Cancer research 69.3 (February 2009): 1063-1070.
PMID
19141650
Source
epmc
Published In
Cancer Research
Volume
69
Issue
3
Publish Date
2009
Start Page
1063
End Page
1070
DOI
10.1158/0008-5472.can-08-1751

Phase II trial of the combination of bevacizumab and erlotinib in patients who have advanced hepatocellular carcinoma.

PURPOSE: The study objective was to determine the proportion of patients with hepatocellular carcinoma (HCC) treated with the combination of bevacizumab (B) and erlotinib (E) who were alive and progression free at 16 weeks (16-week progression-free survival [PFS16]) of continuous therapy. Secondary objectives included response rate, median PFS, survival, and toxicity. PATIENTS AND METHODS: Patients who had advanced HCC that was not amenable to surgical or regional therapies, up to one prior systemic treatment; Childs-Pugh score A or B liver function; Eastern Cooperative Oncology Group performance status 0, 1, or 2 received B 10 mg/kg every 14 days and E 150 mg orally daily, continuously, for 28-day cycles. Tumor response was evaluated every 2 cycles by using Response Evaluation Criteria in Solid Tumors Group criteria. A total of 40 patients were treated. RESULTS: The primary end point of PFS16 was 62.5%. Ten patients achieved a partial response for a confirmed overall response rate (intent-to-treat) of 25%. The median PFSevent was 39 weeks (95% CI, 26 to 45 weeks; 9.0 months), and the median overall survival was 68 weeks (95% CI, 48 to 78 weeks; 15.65 months). Grades 3 to 4 drug-related toxicity included fatigue (n = 8; 20%), hypertension (n = 6; 15%), diarrhea (n = 4; 10%) elevated transaminases (n = 4; 10%), gastrointestinal hemorrhage (n = 5; 12.5%), wound infection (n = 2; 5%) thrombocytopenia (n = 1; 2.5%), and proteinuria, hyperbilirubinemia, back pain, hyperkalemia, and anorexia (n = 1 each). CONCLUSION: The combination of B + E in patients who had advanced HCC showed significant, clinically meaningful antitumor activity. B + E warrant additional evaluation in randomized controlled trials.

Authors
Thomas, MB; Morris, JS; Chadha, R; Iwasaki, M; Kaur, H; Lin, E; Kaseb, A; Glover, K; Davila, M; Abbruzzese, J
MLA Citation
Thomas, MB, Morris, JS, Chadha, R, Iwasaki, M, Kaur, H, Lin, E, Kaseb, A, Glover, K, Davila, M, and Abbruzzese, J. "Phase II trial of the combination of bevacizumab and erlotinib in patients who have advanced hepatocellular carcinoma." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 27.6 (February 2009): 843-850.
PMID
19139433
Source
epmc
Published In
Journal of Clinical Oncology
Volume
27
Issue
6
Publish Date
2009
Start Page
843
End Page
850
DOI
10.1200/jco.2008.18.3301

Polymorphisms of p16, p27, p73, and MDM2 modulate response and survival of pancreatic cancer patients treated with preoperative chemoradiation.

Genetic polymorphisms play an important role in clinical response to cytotoxic therapies. We hypothesized that polymorphisms in cell cycle genes may modulate response to preoperative chemoradiation and survival of pancreatic cancer patients. We evaluated 12 single-nucleotide polymorphisms (SNPs) of ten cell cycle genes in 88 patients with resectable adenocarcinoma of the pancreatic head who were treated with neoadjuvant concurrent gemcitabine and radiotherapy. Response was assessed by computerized tomography obtained before and 4-6 weeks after preoperative treatment. Time to tumor progression and survival after treatment were measured. Patients underwent pancreaticoduodenectomy (PD) if no disease progression was found at restaging after preoperative therapy. MDM2 T309G and p16 C580T genotype distributions were significantly different in the patients who underwent PD and those who did not (P = 0.025 for MDM2; P = 0.016 for p16). The MDM2 and p27 genotypes had a significant effect on survival times after treatment (log-rank test, P = 0.010 and P = 0.050, respectively). A strong joint effect of these two genes was observed (log-rank test, P = 0.010). The p73 and p16 polymorphic genotypes were significantly associated with shorter time to tumor progression (log-rank test, P = 0.021 and P = 0.039, respectively). A gene-dosage effect on time to tumor progression was observed for polymorphisms in the p73, p16, and MDM2 genes. The hazard ratios for patients with one, two, or three adverse genotypes were 2.13 (1.04-4.36), 3.18 (1.37-7.39), and 10.09 (3.17-32.05), respectively. These findings suggest these polymorphisms in the cell cycle genes are promising prognostic markers for patients with pancreatic cancer.

Authors
Chen, J; Li, D; Killary, AM; Sen, S; Amos, CI; Evans, DB; Abbruzzese, JL; Frazier, ML
MLA Citation
Chen, J, Li, D, Killary, AM, Sen, S, Amos, CI, Evans, DB, Abbruzzese, JL, and Frazier, ML. "Polymorphisms of p16, p27, p73, and MDM2 modulate response and survival of pancreatic cancer patients treated with preoperative chemoradiation." Annals of surgical oncology 16.2 (February 2009): 431-439.
PMID
19020940
Source
epmc
Published In
Annals of Surgical Oncology
Volume
16
Issue
2
Publish Date
2009
Start Page
431
End Page
439
DOI
10.1245/s10434-008-0220-8

Hdm2 is regulated by K-Ras and mediates p53-independent functions in pancreatic cancer cells.

There is emerging evidence that the oncogenic potential of hdm2 (human and/or murine double minute-2 protein) stems not only from its ability to counteract tumor suppressor p53 but also from its less understood p53-independent functions. Surprisingly, little is known about the role and regulation of hdm2 in pancreatic tumors, a large proportion (50-75%) of which contain mutant p53. In this study, we determined that hdm2 was expressed in a Ras-signaling-dependent manner in various pancreatic cancer cell lines. As p53 was mutated and inactive in these cells, the expression of hdm2 was seemingly redundant. Indeed, the proliferation and survival of cell lines such as Panc-1 and Panc-28 could be inhibited by PRIMA-1 (mutant p53 activator) but not by Nutlin-3 (inhibitor of the hdm2-p53 interaction). Unexpectedly, however, the proliferation of both cell lines was strongly inhibited by hdm2-specific RNAi. Our data also revealed cyclin D1, c-Jun and c-Myc to be novel targets of hdm2 and suggested that they might mediate hdm2's role in cellular proliferation and/or survival. We conclude from our results that hdm2 is expressed in pancreatic cancer cells as a result of activated Ras signaling, and that it regulates cellular proliferation and the expression of three novel target genes by p53-independent mechanisms.

Authors
Sui, X; Shin, S; Zhang, R; Firozi, PF; Yang, L; Abbruzzese, JL; Reddy, SAG
MLA Citation
Sui, X, Shin, S, Zhang, R, Firozi, PF, Yang, L, Abbruzzese, JL, and Reddy, SAG. "Hdm2 is regulated by K-Ras and mediates p53-independent functions in pancreatic cancer cells." Oncogene 28.5 (February 2009): 709-720.
PMID
19029954
Source
epmc
Published In
Oncogene: Including Oncogene Reviews
Volume
28
Issue
5
Publish Date
2009
Start Page
709
End Page
720
DOI
10.1038/onc.2008.423

The association of family history of liver cancer with hepatocellular carcinoma: a case-control study in the United States.

The study aimed at addressing the connection between positive family history of liver cancer and hepatocellular carcinoma (HCC) development in the USA.At The University of Texas M.D. Anderson Cancer Center, 347 patients with pathologically confirmed HCC and 1075 healthy controls were studied. All subjects were interviewed for their family history of cancer, including the number of relatives with cancer, the type of cancer, the individual's relationship with the relative, and the age at which the relative was diagnosed.Independently of hepatitis B virus (HBV) and hepatitis C virus (HCV), a history of liver cancer in first degree relatives was significantly associated with HCC development (AOR=4.1 [95% CI, 1.3-12.9]). Multiple relatives with liver cancer were only observed among HCC patients with chronic HBV/HCV infection. Affected siblings with liver cancer is significantly associated with HCC development with and without HBV/HCV infection; (AOR=5.7 [95% CI, 1.2-27.3]) and (AOR=4.3 [95% CI, 1.01-20.9]), respectively. Individuals with HBV/HCV and a family history of liver cancer were at higher risk for HCC (AOR=61.9 [95% CI, 6.6-579.7]).First degree family history of liver cancer is associated with HCC development in the USA. Further research exploring the genetic-environment interactions associated with risk of HCC is warranted.

Authors
Hassan, MM; Spitz, MR; Thomas, MB; Curley, SA; Patt, YZ; Vauthey, J-N; Glover, KY; Kaseb, A; Lozano, RD; El-Deeb, AS; Nguyen, NT; Wei, SH; Chan, W; Abbruzzese, JL; Li, D
MLA Citation
Hassan, MM, Spitz, MR, Thomas, MB, Curley, SA, Patt, YZ, Vauthey, J-N, Glover, KY, Kaseb, A, Lozano, RD, El-Deeb, AS, Nguyen, NT, Wei, SH, Chan, W, Abbruzzese, JL, and Li, D. "The association of family history of liver cancer with hepatocellular carcinoma: a case-control study in the United States." Journal of hepatology 50.2 (February 2009): 334-341.
PMID
19070394
Source
epmc
Published In
Journal of Hepatology
Volume
50
Issue
2
Publish Date
2009
Start Page
334
End Page
341
DOI
10.1016/j.jhep.2008.08.016

DNA repair gene polymorphisms and risk of pancreatic cancer.

The current research was undertaken to examine the association between genetic variations in DNA repair and pancreatic cancer risk.We analyzed 9 single nucleotide polymorphisms of 7 DNA repair genes (LIG3, LIG4, OGG1, ATM, POLB, RAD54L, and RECQL) in 734 patients with pancreatic adenocarcinoma and 780 healthy controls using the Taqman method. Information on cigarette smoking, alcohol consumption, medical history, and other risk factors was collected by personal interview.The homozygous mutant genotype of LIG3 G-39A [odds ratio (OR), 0.23; 95% confidence interval (CI), 0.06-0.82; P = 0.027] and ATM D1853N (OR, 2.55; 95% CI, 1.08-6.00; P = 0.032) was significantly associated with altered risk for pancreatic cancer. A statistically significant interaction of ATM D1853N and LIG4 C54T genotype with diabetes on the risk of pancreatic cancer was also detected. Compared with nondiabetics with the ATM D1853N GG genotype, nondiabetics with the GA/AA, diabetics with the GG, and diabetics with the GA/AA genotypes, respectively, had ORs (95% CI) of 0.96 (0.74-1.24), 1.32 (0.89-1.95), and 3.23 (1.47-7.12; P(interaction) = 0.032, likelihood ratio test). The OR (95% CI) was 0.91 (0.71-1.17), 1.11 (0.73-1.69), and 2.44 (1.34-4.46) for nondiabetics carrying the LIG4 CT/TT genotype, diabetics with the CC genotype, and diabetics carrying the CT/TT genotype, respectively, compared with nondiabetics carrying the CC genotype (P(interaction) = 0.02).These observations suggest that genetic variations in DNA repair may act alone or in concert with other risk factors on modifying a patient's risk for pancreatic cancer.

Authors
Li, D; Suzuki, H; Liu, B; Morris, J; Liu, J; Okazaki, T; Li, Y; Chang, P; Abbruzzese, JL
MLA Citation
Li, D, Suzuki, H, Liu, B, Morris, J, Liu, J, Okazaki, T, Li, Y, Chang, P, and Abbruzzese, JL. "DNA repair gene polymorphisms and risk of pancreatic cancer." Clinical cancer research : an official journal of the American Association for Cancer Research 15.2 (January 2009): 740-746.
PMID
19147782
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
15
Issue
2
Publish Date
2009
Start Page
740
End Page
746
DOI
10.1158/1078-0432.ccr-08-1607

Generation of orthotopic and heterotopic human pancreatic cancer xenografts in immunodeficient mice.

For decades, xenografts using well-established human tumor cell lines have been the most commonly used models to study human cancers in mice. More recently, human tumors implanted directly into immunodeficient mice have become increasingly popular as evidence accrues that they more accurately recapitulate features of patient tumors. Here we describe our protocols for the orthotopic and heterotopic implantation of pancreatic cancer cell lines and freshly isolated patient tumors into immunodeficient mice. We also describe procedures for the digestion of tumors into single-cell suspensions for the isolation of subpopulations of tumor cells. Orthotopic or heterotopic implantation of established cell lines requires 1-2 h, with 1-cm tumors arising after 2-5 weeks. Engraftment of patient tumor samples takes approximately 2 h and growth of palpable tumor requires approximately 14 weeks. Once established, direct xenograft tumors require 2 and 5 h for heterotopic and orthotopic implantation, respectively, and 5-6 weeks for palpable tumor growth.

Authors
Kim, MP; Evans, DB; Wang, H; Abbruzzese, JL; Fleming, JB; Gallick, GE
MLA Citation
Kim, MP, Evans, DB, Wang, H, Abbruzzese, JL, Fleming, JB, and Gallick, GE. "Generation of orthotopic and heterotopic human pancreatic cancer xenografts in immunodeficient mice." Nature protocols 4.11 (January 2009): 1670-1680.
PMID
19876027
Source
epmc
Published In
Nature Protocols
Volume
4
Issue
11
Publish Date
2009
Start Page
1670
End Page
1680
DOI
10.1038/nprot.2009.171

Highlights of the 2008 San Antonio Breast Cancer Symposium.

Authors
Abbruzzese, JL
MLA Citation
Abbruzzese, JL. "Highlights of the 2008 San Antonio Breast Cancer Symposium." January 2009.
PMID
19274039
Source
epmc
Published In
Clinical advances in hematology & oncology : H&O
Volume
7
Issue
1
Publish Date
2009
Start Page
39
End Page
41

Consensus report of the national cancer institute clinical trials planning meeting on pancreas cancer treatment

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality, despite significant improvements in diagnostic imaging and operative mortality rates. The 5-year survival rate remains less than 5% because of microscopic or gross metastatic disease at time of diagnosis. The Clinical Trials Planning Meeting in pancreatic cancer was convened by the National Cancer Institute's Gastrointestinal Cancer Steering Committee to discuss the integration of basic and clinical knowledge in the design of clinical trials in PDAC. Major emphasis was placed on the enhancement of research to identify and validate the relevant targets and molecular pathways in PDAC, cancer stem cells, and the microenvironment. Emphasis was also placed on developing rational combinations of targeted agents and the development of predictive biomarkers to assist selection of patient subsets. The development of preclinical tumor models that are better predictive of human PDAC must be supported with wider availability to the research community. Phase III clinical trials should be implemented only if there is a meaningful clinical signal of efficacy and safety in the phase II setting. The emphasis must therefore be on performing well-designed phase II studies with uniform sets of basic entry and evaluation criteria with survival as a primary endpoint. Patients with either metastatic or locally advanced PDAC must be studied separately. © 2009 by American Society of Clinical Oncology.

Authors
Philip, PA; Mooney, M; Jaffe, D; Eckhardt, G; Moore, M; Meropol, N; Emens, L; O'Reilly, E; Korc, M; Ellis, L; Benedetti, J; Rothenberg, M; Willett, C; Tempero, M; Lowy, A; Abbruzzese, J; Simeone, D; Hingorani, S; Berlin, J; Tepper, J
MLA Citation
Philip, PA, Mooney, M, Jaffe, D, Eckhardt, G, Moore, M, Meropol, N, Emens, L, O'Reilly, E, Korc, M, Ellis, L, Benedetti, J, Rothenberg, M, Willett, C, Tempero, M, Lowy, A, Abbruzzese, J, Simeone, D, Hingorani, S, Berlin, J, and Tepper, J. "Consensus report of the national cancer institute clinical trials planning meeting on pancreas cancer treatment." Journal of Clinical Oncology 27.33 (2009): 5660-5669.
PMID
19858397
Source
scival
Published In
Journal of Clinical Oncology
Volume
27
Issue
33
Publish Date
2009
Start Page
5660
End Page
5669
DOI
10.1200/JCO.2009.21.9022

In Reply

Authors
Hassan, MM; Li, D; Abbruzzese, JL
MLA Citation
Hassan, MM, Li, D, and Abbruzzese, JL. "In Reply." Journal of Clinical Oncology 27.4 (December 15, 2008): 648-649.
Source
crossref
Published In
Journal of Clinical Oncology
Volume
27
Issue
4
Publish Date
2008
Start Page
648
End Page
649
DOI
10.1200/JCO.2008.20.8587

Resected pancreatic cancer

Pancreatic cancer is a systemic disease for most patients, and two-thirds of patients have locally advanced or metastatic disease at the time of diagnosis. For the subset of patients (20%) who present with potentially resectable tumors, the 5-year survival rate for those whose tumors are successfully resected is approximately 15-20% and lower for those with positive nodes or margins [1]. Patients usually succumb to metastatic disease or locoregional failure. As with other cancers, the rationale for postoperative therapy is to treat micrometastatic disease and improve survival in patients with resected cancer; unfortunately, despite more than two decades of research, there is no consensus on the best postoperative therapy for pancreatic adenocarcinoma. In a study reported in 1999, trends in disease stage, treatment patterns, and outcomes were analyzed for patients diagnosed with pancreatic adenocarcinoma between 1985 and 1995 [2]. Data were available for 100,313 patients. For the 9,044 patients who underwent pancreatectomy, the overall 5-year survival rate was 23.4%. Adjuvant treatment was used in 40% of cases and consisted of radiation therapy, chemotherapy, or both in 6.5%, 5.1%, and 28.3% of patients, respectively. The approach to adjuvant therapy also differs between high-volume centers in the USA and Europe. Some of the barriers to determining the best postoperative therapy include poor surgical recovery that complicates the use of chemotherapy and chemoradiation therapy, poor patient selection and inadequate staging studies for patients in postoperative trials, lack of standardized criteria for evaluating resection margins, and lack of chemotherapy with significant activity in pancreatic adenocarcinoma. More recently, preoperative or neoadjuvant treatments have been explored as an alternative to adjuvant therapy. In this chapter, we review the data for adjuvant and neoadjuvant strategies for the treatment of pancreatic cancer. © Springer-Verlag Berlin Heidelberg 2008.

Authors
Varadhachary, GR; Abbruzzese, JL
MLA Citation
Varadhachary, GR, and Abbruzzese, JL. "Resected pancreatic cancer." Diseases of the Pancreas: Current Surgical Therapy. December 1, 2008. 675-687.
Source
scopus
Publish Date
2008
Start Page
675
End Page
687
DOI
10.1007/978-3-540-28656-1_65

Molecular Pathogenesis of Pancreatic Adenocarcinoma

Authors
Xiong, HQ; Abbruzzese, JL
MLA Citation
Xiong, HQ, and Abbruzzese, JL. "Molecular Pathogenesis of Pancreatic Adenocarcinoma." The Molecular Basis of Cancer. December 1, 2008. 455-461.
Source
scopus
Publish Date
2008
Start Page
455
End Page
461
DOI
10.1016/B978-141603703-3.10035-4

Polymorphisms of p21 and p27 jointly contribute to an earlier age at diagnosis of pancreatic cancer.

p21 and p27, members of the kinase inhibitor protein (KIP) family, bind to cyclin-CDK complexes to inhibit their catalytic activity and induce cell cycle arrest. The purpose of our study was to identify whether the p21 (C-to-A), and p27 (T-to-G) polymorphisms were associated with age at diagnosis of pancreatic cancer, either independently or jointly. Two hundred and five patients with a diagnosis of pancreatic cancer were genotyped for the p21 and p27 polymorphisms. We found patients with the p21 variant genotype (CA/AA) had an earlier age at diagnosis than those with the wild-type genotype (CC) (log-rank, P=0.001; HR=1.89; 95%CI, 1.28-2.78). The p21 and p27 polymorphisms combined had a joint effect on age-associated risk for early diagnosis of pancreatic cancer (log-rank, P=0.004; HR=2.91; 95%CI, 1.49-5.67). Our findings suggest that the p21 polymorphism independently and p21 and p27 polymorphisms jointly contribute to a significantly earlier age at diagnosis of pancreatic cancer.

Authors
Chen, J; Killary, AM; Sen, S; Amos, CI; Evans, DB; Abbruzzese, JL; Frazier, ML
MLA Citation
Chen, J, Killary, AM, Sen, S, Amos, CI, Evans, DB, Abbruzzese, JL, and Frazier, ML. "Polymorphisms of p21 and p27 jointly contribute to an earlier age at diagnosis of pancreatic cancer." Cancer letters 272.1 (December 2008): 32-39.
PMID
18694622
Source
epmc
Published In
Cancer Letters
Volume
272
Issue
1
Publish Date
2008
Start Page
32
End Page
39
DOI
10.1016/j.canlet.2008.06.022

Effect of insulin-like growth factor gene polymorphisms alone or in interaction with diabetes on the risk of pancreatic cancer.

Insulin-like growth factors (IGF) have been associated with risk of common human cancers, but the association between IGFs and pancreatic cancer risk is unclear. To determine whether genetic variations of IGF modify pancreatic cancer risk, we compared the frequency of six single nucleotide polymorphisms of IGF1 and IGF2 in a large-scale case control study. Single nucleotide polymorphisms were investigated using the TaqMan method in 892 patients with pancreatic ductal adenocarcinoma and 783 healthy controls who were recruited from The University of Texas M. D. Anderson Cancer Center from 2000 to 2007. Cases and controls were frequency matched by age (+/-5 years), race, and sex. Risk factor information was collected using direct interviews. We estimated odds ratios (OR) and 95% confidence intervals (95% CI) using unconditional multivariate logistic regression models. A haplotype of IGF1 gene containing the 3'-UTR Ex4 -177 G>C G allele had a significantly lower frequency in cases (0.027) than in controls (0.041; P = 0.039). A statistically significant joint effect of the IGF1 3'-UTR Ex4 -177 G>C C allele and diabetes on pancreatic cancer risk was observed. The OR (95% CI) were 1.07 (0.81-1.42), 2.12 (1.53-2.93), and 5.69 (2.63-12.3) for individuals who had the CC/CG genotype alone, diabetes alone, or both factors, respectively, compared with subjects without either of the two factors with adjustment for other risk factors. The IGF2 3'-UTR Ex4 -233C>T TT genotype was significantly associated with a reduced risk of pancreatic cancer (OR = 0.07; 95% CI = 0.01-0.57; P = 0.013). The polymorphic variants of the IGF genes may serve as a susceptibility factor for pancreatic cancer.

Authors
Suzuki, H; Li, Y; Dong, X; Hassan, MM; Abbruzzese, JL; Li, D
MLA Citation
Suzuki, H, Li, Y, Dong, X, Hassan, MM, Abbruzzese, JL, and Li, D. "Effect of insulin-like growth factor gene polymorphisms alone or in interaction with diabetes on the risk of pancreatic cancer." Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 17.12 (December 2008): 3467-3473.
PMID
19064563
Source
epmc
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
17
Issue
12
Publish Date
2008
Start Page
3467
End Page
3473
DOI
10.1158/1055-9965.epi-08-0514

A phase I/II trial of TAC-101, an oral synthetic retinoid, in patients with advanced hepatocellular carcinoma.

PURPOSE: Preclinical models showed TAC-101 (4-[3,5-bis(trimethylsilyl) benzamide] benzoic acid), an oral synthetic retinoid, has anti-tumor activity in hepatocellular carcinoma (HCC). A phase I/II study was performed in advanced HCC patients (pts). PATIENTS AND METHODS: Thirty-three patients were enrolled. During Phase I, pts received 40 mg daily for 14 days q3 weeks; 2 of 5 patients developed DLT so dose was reduced to 20 mg/day. Twenty-eight patients received 20 mg/day. RESULTS: No pt had a CR or PR, but 12 of 21 (57%) had SD. Two pts (9.5%) had late PR after discontinuing TAC-101. Median survival (MS) for all 28 pts treated with 20 mg/day was 12.7 months (95% CI 8.8-22.7); MS for 21 evaluable pts was 19.2 months (95% CI 10.4-27.6). CONCLUSIONS: 20 mg of TAC- was well tolerated. Significant disease stabilization (12/21 pts, 57%), 2 late PRs, and prolonged MS (19.2 months) suggest that TAC-101 provides meaningful patient benefit.

Authors
Higginbotham, KB; Lozano, R; Brown, T; Patt, YZ; Arima, T; Abbruzzese, JL; Thomas, MB
MLA Citation
Higginbotham, KB, Lozano, R, Brown, T, Patt, YZ, Arima, T, Abbruzzese, JL, and Thomas, MB. "A phase I/II trial of TAC-101, an oral synthetic retinoid, in patients with advanced hepatocellular carcinoma." Journal of cancer research and clinical oncology 134.12 (December 2008): 1325-1335.
PMID
18504614
Source
epmc
Published In
Journal of Cancer Research and Clinical Oncology
Volume
134
Issue
12
Publish Date
2008
Start Page
1325
End Page
1335
DOI
10.1007/s00432-008-0406-2

Novel approaches to 'borderline resectable' pancreatic tumors.

Authors
Varadhachary, GR; Abbruzzese, JL
MLA Citation
Varadhachary, GR, and Abbruzzese, JL. "Novel approaches to 'borderline resectable' pancreatic tumors." Oncology (Williston Park, N.Y.) 22.13 (November 2008): 1529-1530.
PMID
19227575
Source
epmc
Published In
Oncology
Volume
22
Issue
13
Publish Date
2008
Start Page
1529
End Page
1530

Expression of MAP4K4 is associated with worse prognosis in patients with stage II pancreatic ductal adenocarcinoma.

PURPOSE: Mitogen-activated protein 4 kinase 4 (MAP4K4) is a serine/threonine kinase and belongs to the mammalian STE20/MAP4K family. Recent studies have shown that MAP4K4 is overexpressed in many types of human cancer and cancer cell lines. MAP4K4 plays an important role in transformation, invasiveness, adhesion, and cell migration. However, the expression of MAP4K4 and its significance in pancreatic ductal adenocarcinoma (PDA) has not been studied. EXPERIMENTAL DESIGN: We examined the expression of MAP4K4 by immunohistochemistry using tissue microarrays consisting of 66 stage II PDA and their paired benign pancreatic tissue. The staining results were categorized as MAP4K4-H or MAP4K4-L. The results were correlated with clinicopathologic features and patient survival. RESULTS: MAP4K4 was overexpressed (MAP4K4-H) in 30 of 66 (46%) PDAs and was higher than the paired benign pancreatic tissue samples (19%; P=0.002). The median overall and recurrence-free survival for patients with MAP4K4-H PDAs were 19.5 and 9.3 months, respectively, compared with 65.2 and 28.8 months for patients with MAP4K4-L tumor (P=0.02 and 0.0005, log-rank test). MAP4K4 expression was associated with poor overall and recurrence-free survival in univariate analysis (P=0.02 and 0.001). In multivariate analysis, MAP4K4 expression significantly correlated with overall and recurrence-free survival (P=0.025 and 0.004) independent of age, tumor size, differentiation, and stage. MAP4K4 expression was also associated with higher frequency of recurrence/metastasis, larger tumor size, and increased number of positive lymph nodes (P<0.05). CONCLUSION: MAP4K4 was overexpressed in about half of PDAs. Overexpression of MAP4K4 was associated with worse prognosis and is a prognostic marker for stage II PDAs.

Authors
Liang, JJ; Wang, H; Rashid, A; Tan, T-H; Hwang, RF; Hamilton, SR; Abbruzzese, JL; Evans, DB; Wang, H
MLA Citation
Liang, JJ, Wang, H, Rashid, A, Tan, T-H, Hwang, RF, Hamilton, SR, Abbruzzese, JL, Evans, DB, and Wang, H. "Expression of MAP4K4 is associated with worse prognosis in patients with stage II pancreatic ductal adenocarcinoma." Clinical cancer research : an official journal of the American Association for Cancer Research 14.21 (November 2008): 7043-7049.
PMID
18981001
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
14
Issue
21
Publish Date
2008
Start Page
7043
End Page
7049
DOI
10.1158/1078-0432.ccr-08-0381

Chemotherapy with 5-fluorouracil and a platinum compound improves outcomes in metastatic small bowel adenocarcinoma.

Metastatic small bowel adenocarcinoma (SBA) has a poor prognosis. Because of the rarity of SBA, only a few studies have evaluated the role of chemotherapy in the treatment of metastatic SBA; thus, the benefit, if any, of adding a platinum compound to fluorouracil (5-FU) is unknown. The objective of this retrospective study was to determine whether the addition of a platinum compound to 5-FU provided any benefit in the treatment of patients with metastatic SBA.The authors identified 80 patients with metastatic SBA who were treated with chemotherapy at the University of Texas M. D. Anderson Cancer Center between 1978 and 2005. Response rates, progression-free survival (PFS), and overall survival (OS) were compared between patients who received 5-FU and a platinum compound and patients who received other chemotherapy combinations.The median patient age was 53 years. The primary tumor site was the jejunum in 35 patients (43%), duodenum in 30 patients (38%), ileum in 6 patients (8%), and nonspecified small bowel in 9 patients (11%). Of all 80 patients, 29 patients (36%) received 5-FU and a platinum compound, 41 patients (51%) received 5-FU without a platinum compound, and 10 patients (13%) received non-5-FU-based treatment. Compared with other chemotherapy regimens, treatment with 5-FU and a platinum agent resulted in a higher response rate (46% vs 16% with other regimens; P = .01) and longer median PFS (8.7 months vs 3.9 months; P < or = .01) but not better OS (14.8 months vs 12 months; P = .1). In multivariate analysis, treatment with 5-FU and a platinum compound was a significant predictor of response (odds ratio, 4.5; 95% confidence interval [CI], 1.3-15.8; P = .02) and PFS (hazard ratio. 0.49; 95% CI, 0.29-0.84; P = .01) but only reached borderline significance for OS (hazard ratio, 0.63; 95% CI, 0.37-1.07; P = .08).To the authors' knowledge, the current analysis represents the largest number of patients with metastatic SBA treated with chemotherapy in the literature, and the results suggested that the combination of 5-FU and a platinum compound leads to a higher response rate and PFS compared with other chemotherapy regimes. The authors concluded that prospective investigation of platinum analogues in the treatment of SBA is warranted.

Authors
Overman, MJ; Kopetz, S; Wen, S; Hoff, PM; Fogelman, D; Morris, J; Abbruzzese, JL; Ajani, JA; Wolff, RA
MLA Citation
Overman, MJ, Kopetz, S, Wen, S, Hoff, PM, Fogelman, D, Morris, J, Abbruzzese, JL, Ajani, JA, and Wolff, RA. "Chemotherapy with 5-fluorouracil and a platinum compound improves outcomes in metastatic small bowel adenocarcinoma." Cancer 113.8 (October 2008): 2038-2045.
PMID
18759326
Source
epmc
Published In
Cancer
Volume
113
Issue
8
Publish Date
2008
Start Page
2038
End Page
2045
DOI
10.1002/cncr.23822

Association between hepatitis B virus and pancreatic cancer.

Hepatitis B virus (HBV) and hepatitis C virus (HCV) are considered to be hepatotropic and are a major cause of hepatocellular carcinoma. However, little is known about the role of HBV and HCV infection in other malignancies. This study aimed to determine whether HBV and HCV infections increase the risk for pancreatic cancer development.At The University of Texas M. D. Anderson Cancer Center, Houston, TX, we recruited 476 patients with pathologically confirmed adenocarcinoma of the pancreas and 879 age-, sex-, and race-matched healthy controls. Blood samples were tested for the presence of HCV antibodies (anti-HCV), HBV surface antigen (HBsAg), antibodies against HBV core antigen (anti-HBc), and antibodies against HBsAg (anti-HBs). The positive samples were retested by two confirmatory tests. An unconditional multivariable logistic regression analysis was used to estimate adjusted odds ratios (AORs).Anti-HCV was positive in seven cases (1.5%) and nine controls (1%). Anti-HBc was positive in 36 cases (7.6%) and 28 controls (3.2%). The estimated AORs and 95% CIs were as follows: anti-HCV-positive, 0.9 (95% CI, 0.3 to 2.8), anti-HBc-positive, 2.5 (95% CI, 1.5 to 4.2), anti-HBc-positive/anti-HBs-positive, 2.3 (95% CI, 1.2 to 4.2), and anti-HBc-positive/anti-HBs-negative, 4 (95% CI, 1.4 to 11.1). Risk modification by past exposure to HBV was observed among diabetics (AOR, 7.1; 95% CI, 1.7 to 28.7).Past exposure to HBV may be associated with pancreatic cancer development. Should such findings be confirmed by other studies, it may offer important insights into the etiology of pancreatic cancer and may suggest the need to consider prevention of HBV reactivation among patients with HBV-related pancreatic cancer during chemotherapy.

Authors
Hassan, MM; Li, D; El-Deeb, AS; Wolff, RA; Bondy, ML; Davila, M; Abbruzzese, JL
MLA Citation
Hassan, MM, Li, D, El-Deeb, AS, Wolff, RA, Bondy, ML, Davila, M, and Abbruzzese, JL. "Association between hepatitis B virus and pancreatic cancer." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 26.28 (October 2008): 4557-4562.
PMID
18824707
Source
epmc
Published In
Journal of Clinical Oncology
Volume
26
Issue
28
Publish Date
2008
Start Page
4557
End Page
4562
DOI
10.1200/jco.2008.17.3526

Phase I clinical study of three times a day oral administration of TAS-102 in patients with solid tumors.

TAS-102 is a novel formulation of the fluorinated pyrimidine analogue trifluorothymidine (FTD) with an inhibitor of thymidine phosphorylase. The purpose of this study was to determine the MTD and DLT for TAS-102 administered three times a day on days 1-5 and 8-12 every 4 weeks. Fifteen patients were enrolled with two patients experiencing dose-limiting fatigue and granulocytopenia at the first dose level (80 mg/m2/day). Granulocytopenia was the primary toxicity: 7 patients experienced grade 3 or 4 granulocytopenia with the first course. No responses were noted, but nine patients demonstrated prolonged stable disease in this heavily pretreated 5-FU refractory population.

Authors
Overman, MJ; Kopetz, S; Varadhachary, G; Fukushima, M; Kuwata, K; Mita, A; Wolff, RA; Hoff, P; Xiong, H; Abbruzzese, JL
MLA Citation
Overman, MJ, Kopetz, S, Varadhachary, G, Fukushima, M, Kuwata, K, Mita, A, Wolff, RA, Hoff, P, Xiong, H, and Abbruzzese, JL. "Phase I clinical study of three times a day oral administration of TAS-102 in patients with solid tumors." Cancer investigation 26.8 (October 2008): 794-799.
PMID
18798063
Source
epmc
Published In
Cancer Investigation (Informa)
Volume
26
Issue
8
Publish Date
2008
Start Page
794
End Page
799
DOI
10.1080/07357900802087242

Phase 1 study of TAS-102 administered once daily on a 5-day-per-week schedule in patients with solid tumors.

This study was designed to determine the safety and optimal dosing of TAS-102, a novel oral combination of alphaalphaalpha-trifluorothymidine (FTD) and an inhibitor of thymidine phoshorylase, in patients with solid tumors. Patients who met the eligibility criteria were treated with one of two different TAS-102 regimens: once per day on either days 1-5 and 8-12 every 4 weeks (schedule A) or days 1-5 every 3 weeks (schedule B). The primary objectives were the determination of the maximum tolerated dose, dose-limiting toxicities (DLTs), and recommended phase II dose. Pharmacokinetic analysis was conducted during courses 1 and 2. Sixty-three patients received a total of 172 courses of therapy with the median number of courses delivered on both schedules being 2. DLTs were observed in three patients on schedule A, 70 mg/m(2)/day (1) and 110 mg/m(2)/day (2); and in five patients on schedule B, 120 mg/m(2)/day (1), 170 mg/m(2)/day (2), 180 mg/m(2)/day (2). Granulocytopenia was the DLT in seven of the eight cases. The most frequent toxicities were nausea, fatigue, granulocytopenia, anemia, diarrhea, and abdominal pain. Twelve patients, 6 on schedule A and 6 on schedule B, were treated at the recommended phase II dose, with good tolerance. No objective responses were seen in this heavily pretreated, 5-FU-refractory population. The pharmacokinetic parameters of FTD are a T (max) of 0.53 to 3.15 h, t (1/2) of 1.46 to 4.20 h, volume of distribution of 0.0526 to 0.483 l/kg, and clearance of 0.0194 to 0.197 1/h/kg. The recommended phase II doses for TAS-102 are 100 mg/m(2)/day on schedule A and 160 mg/m(2)/day on schedule B. Future development of TAS-102 should focus upon multiple daily dosing schedules.

Authors
Overman, MJ; Varadhachary, G; Kopetz, S; Thomas, MB; Fukushima, M; Kuwata, K; Mita, A; Wolff, RA; Hoff, PM; Xiong, H; Abbruzzese, JL
MLA Citation
Overman, MJ, Varadhachary, G, Kopetz, S, Thomas, MB, Fukushima, M, Kuwata, K, Mita, A, Wolff, RA, Hoff, PM, Xiong, H, and Abbruzzese, JL. "Phase 1 study of TAS-102 administered once daily on a 5-day-per-week schedule in patients with solid tumors." Investigational new drugs 26.5 (October 2008): 445-454.
PMID
18528634
Source
epmc
Published In
Investigational New Drugs
Volume
26
Issue
5
Publish Date
2008
Start Page
445
End Page
454
DOI
10.1007/s10637-008-9142-3

Phase 2 trial of oxaliplatin plus capecitabine (XELOX) as second-line therapy for patients with advanced pancreatic cancer.

BACKGROUND: To the authors' knowledge, there is no established second-line chemotherapy for patients with pancreatic cancer who have received gemcitabine-based therapy. A phase 2 trial was conducted to explore the efficacy of capecitabine and oxaliplatin (XELOX) in patients with advanced pancreatic cancer previously who were treated with gemcitabine. METHODS: Patients aged < or = 65 years who had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 1 received oxaliplatin at a dose of 130 mg/m(2) given on Day 1 and capecitabine at a dose of 1000 mg/m(2) twice daily for 14 days. For patients aged >65 years or with an ECOG PS of 2, the oxaliplatin dose was 110 mg/m(2) on Day 1 and the capecitabine dose was 750 mg/m(2) twice daily for 14 days. The treatment was repeated every 3 weeks. Tumor measurements were performed every 9 weeks and the primary study objective was 6-month overall survival. RESULTS: The study enrolled 41 patients. Of the 39 evaluable patients, 1 patient had a partial response and 10 patients demonstrated stable disease. The Kaplan-Meier estimate of the overall median survival was 23 weeks (95% confidence interval [95% CI], 17.0-31.0 weeks). Progression-free survival was 9.9 weeks (95% CI, 9.6-14.5 weeks). The 6-month and 1-year survival rates were 44% (95% CI, 31%-62%) and 21% (95% CI, 11%-38%), respectively. The most common grade 3-4 nonhematologic toxicity was fatigue (toxicity was graded using the National Cancer Institute Common Toxicity Criteria [version 2.0]). CONCLUSIONS: The combination of capecitabine and oxaliplatin is active in gemcitabine-pretreated patients with advanced pancreatic cancer, especially in patients with a good PS and those who have responded to first-line chemotherapy.

Authors
Xiong, HQ; Varadhachary, GR; Blais, JC; Hess, KR; Abbruzzese, JL; Wolff, RA
MLA Citation
Xiong, HQ, Varadhachary, GR, Blais, JC, Hess, KR, Abbruzzese, JL, and Wolff, RA. "Phase 2 trial of oxaliplatin plus capecitabine (XELOX) as second-line therapy for patients with advanced pancreatic cancer." Cancer 113.8 (October 2008): 2046-2052.
PMID
18756532
Source
epmc
Published In
Cancer
Volume
113
Issue
8
Publish Date
2008
Start Page
2046
End Page
2052
DOI
10.1002/cncr.23810

Effect of different types of smoking and synergism with hepatitis C virus on risk of hepatocellular carcinoma in American men and women: case-control study.

The International Agency for Research on Cancer has declared smoking to be a risk factor for hepatocellular carcinoma (HCC). However, passive exposure to cigarette smoke and use of noncigarette tobacco products on the risk of HCC has not been examined. Therefore, we evaluated the independent effects of different types of smoking exposure along with multiple risk factors for HCC and determined whether the magnitude of smoking was modified by other risk factors in men and women. We conducted a case-control study at The University of Texas M. D. Anderson Cancer Center where 319 HCC patients and 1,061 healthy control subjects were personally interviewed for several HCC risk factors. Multivariate logistic regression analysis was performed to estimate the adjusted odds ratio (AOR) and 95% confidence interval (CI) for each potential risk factor. Use of smokeless tobacco (chewing tobacco and snuff), cigars, pipes and passive smoking exposure were not related to HCC among noncigarette smokers. However, regular cigarette smoking was associated with HCC in men: AOR, 1.9 (95% CI, 1.1-3.1). Heavy alcohol consumption was associated with HCC in women: AOR, 7.7 (95% CI, 2.3-25.1). Cigarette smoking interacted synergistically with chronic infection of hepatitis C virus in men: AOR, 136.3 (95% CI, 43.2-429.6) and with heavy alcohol consumption in women: AOR, 13.7 (95% CI, 3.2-57.9). We conclude that sex differences were observed in HCC relationship with cigarette smoking and alcohol consumption. Controlling for smoking exposure might be a prudent approach to the prevention of HCC, especially in patients with chronic viral hepatitis infections.

Authors
Hassan, MM; Spitz, MR; Thomas, MB; El-Deeb, AS; Glover, KY; Nguyen, NT; Chan, W; Kaseb, A; Curley, SA; Vauthey, J-N; Ellis, LM; Abdalla, E; Lozano, RD; Patt, YZ; Brown, TD; Abbruzzese, JL; Li, D
MLA Citation
Hassan, MM, Spitz, MR, Thomas, MB, El-Deeb, AS, Glover, KY, Nguyen, NT, Chan, W, Kaseb, A, Curley, SA, Vauthey, J-N, Ellis, LM, Abdalla, E, Lozano, RD, Patt, YZ, Brown, TD, Abbruzzese, JL, and Li, D. "Effect of different types of smoking and synergism with hepatitis C virus on risk of hepatocellular carcinoma in American men and women: case-control study." International journal of cancer 123.8 (October 2008): 1883-1891.
PMID
18688864
Source
epmc
Published In
International Journal of Cancer
Volume
123
Issue
8
Publish Date
2008
Start Page
1883
End Page
1891
DOI
10.1002/ijc.23730

A phase II study of UFT with leucovorin administered as a twice daily schedule in the treatment of patients with metastatic colorectal cancer.

Prolonged infusions have been shown to be safer and potentially more effective than bolus regimens of 5-fluorouracil (5-FU) as treatment for metastatic colorectal cancer (mCRC). However, infusional 5-FU requires central venous access and costly infusion pumps. Oral fluoropyrimidines enable longer exposures to 5-FU with increased convenience. Tegafur-uracil (UFT) with leucovorin (LV) given thrice daily has improved safety plus comparable survival and response rates to bolus 5-FU/LV. We conducted a phase II clinical study in 98 patients with mCRC to evaluate if UFT with LV given twice daily provided comparable time to progression (TTP), efficacy and tolerability to that reported for thrice daily in two phase III clinical studies. Secondary objectives included overall response rate (ORR) and overall survival (OS). Median TTP was 3.8 months, when compared with 3.5 months for thrice daily. The ORR (11%) and median OS (12.8 months) with twice daily administration were similar to that of thrice daily administration (12% and 12.4 months). The incidence of grade 3/4 treatment-related diarrhoea was 30% on the twice daily and 21% on the thrice daily schedule. These results suggest that twice daily administration has similar efficacy and tolerability to thrice daily administration and is an acceptable alternative for patients who would benefit from UFT with LV therapy.

Authors
Hoff, PM; Kopetz, S; Thomas, MB; Langleben, A; Rinaldi, D; Anthony, L; Wolff, RA; Lassere, Y; Abbruzzese, JL
MLA Citation
Hoff, PM, Kopetz, S, Thomas, MB, Langleben, A, Rinaldi, D, Anthony, L, Wolff, RA, Lassere, Y, and Abbruzzese, JL. "A phase II study of UFT with leucovorin administered as a twice daily schedule in the treatment of patients with metastatic colorectal cancer." British journal of cancer 99.5 (September 2008): 722-726.
PMID
18728662
Source
epmc
Published In
British Journal of Cancer
Volume
99
Issue
5
Publish Date
2008
Start Page
722
End Page
726
DOI
10.1038/sj.bjc.6604541

Knowledge of indications and utilization of EUS: a survey of oncologists in the United States.

BACKGROUND: Since its advent, endoscopic ultrasonography (EUS) has emerged as an invaluable tool in the diagnosis and management of gastrointestinal and adjacent cancers. Yet, it remains unclear how non-gastroenterologists who manage these malignancies use EUS in their practices. METHODS: A link to a self-administered questionnaire, hosted on our university website, was emailed to 650 practicing medical, radiation, and surgical oncologists in the United States. RESULTS: Data were analyzed from 100 responses. When available, the overall utilization of EUS for staging nonsmall cell lung cancer (NSCLC) was significantly low (19.0%), although available. When EUS was unavailable, majority of the patients with pancreatobiliary cancer (79%; P<0.01) were not referred for staging, unlike those with esophageal (57.9%) and rectal cancer (73.7%) were. EUS availability did not impact its use in staging gastric cancer. Majority of the respondents thought EUS made an impact in managing patients with rectal (89.5%), esophageal (84.5%), and pancreatobiliary cancers (58.5%) but not gastric (54.7%) or NSCLC (61.5%). In staging NSCLC, endoscopic ultrasound-guided fine-needle aspirate (35.7%) and mediastinoscopy (34.7%) were noted as the most accurate for tissue sampling of lymph nodes in levels 5, 7, and 8. EUS was deemed better than computerized tomography or magnetic resonance imaging by 42% in detecting small pancreatic tumors. Majority have not referred patients for EUS-guided celiac plexus neurolysis for palliation of pain in unresectable pancreatic cancer. CONCLUSIONS: These data highlight the utilization of EUS that did not necessarily follow established guidelines. Further research is essential to evaluate obstacles to utilization of endoscopic ultrasound-guided fine-needle aspirate.

Authors
Reddy, NK; Markowitz, AB; Abbruzzese, JL; Bhutani, MS
MLA Citation
Reddy, NK, Markowitz, AB, Abbruzzese, JL, and Bhutani, MS. "Knowledge of indications and utilization of EUS: a survey of oncologists in the United States." Journal of clinical gastroenterology 42.8 (September 2008): 892-896.
PMID
18645535
Source
epmc
Published In
Journal of Clinical Gastroenterology
Volume
42
Issue
8
Publish Date
2008
Start Page
892
End Page
896
DOI
10.1097/mcg.0b013e3180cab11a

Molecular profiling of carcinoma of unknown primary and correlation with clinical evaluation.

To evaluate the feasibility of a 10-gene reverse transcriptase polymerase chain reaction assay to identify the tissue of origin in patients with carcinoma of unknown primary (CUP) site.Diagnostic biopsy formalin-fixed, paraffin-embedded (FFPE) specimens from 120 patients with CUP were collected retrospectively from Sarah Cannon Research Institute, Nashville, TN, and prospectively from The University of Texas M. D. Anderson Cancer Center, Houston, TX. Tissue of origin assignments by the assay were correlated with clinical and pathologic features and with response to therapy.The assay was successfully performed in 104 patients (87%), and a tissue of origin was assigned in 63 patients (61%). In the remaining 41 patients (39%), the molecular profiles were not specific for the six tumor types detectable by this assay. The tissues of origin most commonly identified were lung, pancreas, and colon; most of these patients had clinical and pathologic features consistent with these diagnoses. Patients with lung and pancreas profiles had poor response to treatment. Patients with colon cancer profiles had better response to colon cancer-specific therapies than they did to empiric CUP therapy with taxane/platinum regimens. Patients with ovarian cancer profiles were atypical, with widespread visceral metastases and a paucity of overt peritoneal involvement.This gene expression profiling assay was feasible using FFPE biopsy specimens and identified a putative tissue of origin in 61% of patients with CUP. In most patients, the assigned tissue of origin was compatible with clinicopathologic features and response to treatment. Prospective studies in which assay results are used to direct therapy are indicated.

Authors
Varadhachary, GR; Talantov, D; Raber, MN; Meng, C; Hess, KR; Jatkoe, T; Lenzi, R; Spigel, DR; Wang, Y; Greco, FA; Abbruzzese, JL; Hainsworth, JD
MLA Citation
Varadhachary, GR, Talantov, D, Raber, MN, Meng, C, Hess, KR, Jatkoe, T, Lenzi, R, Spigel, DR, Wang, Y, Greco, FA, Abbruzzese, JL, and Hainsworth, JD. "Molecular profiling of carcinoma of unknown primary and correlation with clinical evaluation." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 26.27 (September 2008): 4442-4448.
PMID
18802157
Source
epmc
Published In
Journal of Clinical Oncology
Volume
26
Issue
27
Publish Date
2008
Start Page
4442
End Page
4448
DOI
10.1200/jco.2007.14.4378

Loss of trimethylation at lysine 27 of histone H3 is a predictor of poor outcome in breast, ovarian, and pancreatic cancers.

Methylation of lysine 27 on histone H3 (H3K27) by the EZH2 complex is an epigenetic mark that mediates gene silencing. EZH2 is overexpressed in many cancers and correlates with poor prognosis in both breast and prostate cancers. However, the status of H3K27 methylation and its clinical implication in cancer patients have not been reported. We thus examined trimethylation of H3K27 (H3K27me3) by immunohistochemistry and its association with clinical variables and prognosis in breast, ovarian, and pancreatic cancers. We found that H3K27me3 expression was significantly lower in breast, ovarian and pancreatic cancers than in normal tissues (62% in breast cancer vs. 88% in normal breast tissue, P = 0.001; 38.4% in ovarian cancer vs. 83.3% in normal ovarian tissue, P < 0.05; and 26% in pancreatic cancer vs. 89% in normal pancreatic tissue, P < 0.001). H3K27me3 expression showed significant prognostic impact in breast, ovarian and pancreatic cancers in univariate survival analyses. In all three cancer types, patients with low expression of H3K27me3 had significantly shorter overall survival time when compared with those with high H3K27me3 expression. In a multivariate model, H3K27me3 expression was an independent prognostic value for overall survival in all three cancer types. These results suggest that H3K27me3 expression is a prognostic indicator for clinical outcome in patients with breast, ovarian, and pancreatic cancers.

Authors
Wei, Y; Xia, W; Zhang, Z; Liu, J; Wang, H; Adsay, NV; Albarracin, C; Yu, D; Abbruzzese, JL; Mills, GB; Bast, RC; Hortobagyi, GN; Hung, M-C
MLA Citation
Wei, Y, Xia, W, Zhang, Z, Liu, J, Wang, H, Adsay, NV, Albarracin, C, Yu, D, Abbruzzese, JL, Mills, GB, Bast, RC, Hortobagyi, GN, and Hung, M-C. "Loss of trimethylation at lysine 27 of histone H3 is a predictor of poor outcome in breast, ovarian, and pancreatic cancers." Molecular carcinogenesis 47.9 (September 2008): 701-706.
PMID
18176935
Source
epmc
Published In
Molecular Carcinogenesis
Volume
47
Issue
9
Publish Date
2008
Start Page
701
End Page
706
DOI
10.1002/mc.20413

Synergistic effects of multiple natural products in pancreatic cancer cells.

Pancreatic cancer (PC) remains the fourth most common cause of cancer related death in the United States. Therefore, novel strategies for the prevention and treatment are urgently needed. Numerous dietary and pharmacological agents have been proposed as alternative strategies for the prevention and/or treatment of PC. Isoflavone is a prominent flavonoid found in soy products and has been proposed to be responsible for lowering the incidence of PC in Asians. Similarly, curcumin, an active ingredient of turmeric, that inhibits growth of malignant neoplasms, has a promising role in the prevention and/or treatment of PC. Here we examined whether isoflavone together with curcumin could elicit a greater inhibition of growth of PC cells than either agent alone, and also sought to determine the molecular mechanism of action. We found that the inhibition of cell growth and induction of apoptosis was significantly greater in the combination group than that could be achieved by either agent alone. These changes were associated with decreased Notch-1 expression and DNA binding activity of NF-kappaB and its target genes such as Cyclin D1, Bcl-2, and Bcl-xL. Moreover, we found that the combination of four natural agents at lower concentration was much more effective. Collectively, our results suggest that diet containing multiple natural products should be preferable over single agents for the prevention and/or treatment of PC. The superior effects of the combinatorial treatment could partly be attributed to the inhibition of constitutive activation of Notch-1 and NF-kappaB signaling pathways.

Authors
Wang, Z; Desmoulin, S; Banerjee, S; Kong, D; Li, Y; Deraniyagala, RL; Abbruzzese, J; Sarkar, FH
MLA Citation
Wang, Z, Desmoulin, S, Banerjee, S, Kong, D, Li, Y, Deraniyagala, RL, Abbruzzese, J, and Sarkar, FH. "Synergistic effects of multiple natural products in pancreatic cancer cells." Life sciences 83.7-8 (August 2008): 293-300.
PMID
18640131
Source
epmc
Published In
Life Sciences
Volume
83
Issue
7-8
Publish Date
2008
Start Page
293
End Page
300
DOI
10.1016/j.lfs.2008.06.017

Phase II trial of curcumin in patients with advanced pancreatic cancer.

PURPOSE: Pancreatic cancer is almost always lethal, and the only U.S. Food and Drug Administration-approved therapies for it, gemcitabine and erlotinib, produce objective responses in <10% of patients. We evaluated the clinical biological effects of curcumin (diferuloylmethane), a plant-derived dietary ingredient with potent nuclear factor-kappaB (NF-kappaB) and tumor inhibitory properties, against advanced pancreatic cancer. EXPERIMENTAL DESIGN: Patients received 8 g curcumin by mouth daily until disease progression, with restaging every 2 months. Serum cytokine levels for interleukin (IL)-6, IL-8, IL-10, and IL-1 receptor antagonists and peripheral blood mononuclear cell expression of NF-kappaB and cyclooxygenase-2 were monitored. RESULTS: Twenty-five patients were enrolled, with 21 evaluable for response. Circulating curcumin was detectable as drug in glucuronide and sulfate conjugate forms, albeit at low steady-state levels, suggesting poor oral bioavailability. Two patients showed clinical biological activity. One had ongoing stable disease for >18 months; interestingly, one additional patient had a brief, but marked, tumor regression (73%) accompanied by significant increases (4- to 35-fold) in serum cytokine levels (IL-6, IL-8, IL-10, and IL-1 receptor antagonists). No toxicities were observed. Curcumin down-regulated expression of NF-kappaB, cyclooxygenase-2, and phosphorylated signal transducer and activator of transcription 3 in peripheral blood mononuclear cells from patients (most of whom had baseline levels considerably higher than those found in healthy volunteers). Whereas there was considerable interpatient variation in plasma curcumin levels, drug levels peaked at 22 to 41 ng/mL and remained relatively constant over the first 4 weeks. CONCLUSIONS: Oral curcumin is well tolerated and, despite its limited absorption, has biological activity in some patients with pancreatic cancer.

Authors
Dhillon, N; Aggarwal, BB; Newman, RA; Wolff, RA; Kunnumakkara, AB; Abbruzzese, JL; Ng, CS; Badmaev, V; Kurzrock, R
MLA Citation
Dhillon, N, Aggarwal, BB, Newman, RA, Wolff, RA, Kunnumakkara, AB, Abbruzzese, JL, Ng, CS, Badmaev, V, and Kurzrock, R. "Phase II trial of curcumin in patients with advanced pancreatic cancer." Clinical cancer research : an official journal of the American Association for Cancer Research 14.14 (July 2008): 4491-4499.
PMID
18628464
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
14
Issue
14
Publish Date
2008
Start Page
4491
End Page
4499
DOI
10.1158/1078-0432.ccr-08-0024

Preoperative gemcitabine and cisplatin followed by gemcitabine-based chemoradiation for resectable adenocarcinoma of the pancreatic head.

We conducted a phase II trial of preoperative gemcitabine and cisplatin chemotherapy in addition to chemoradiation (Gem-Cis-XRT) and pancreaticoduodenectomy (PD) for patients with stage I/II pancreatic adenocarcinoma.Chemotherapy consisted of gemcitabine (750 mg/m(2)) and cisplatin (30 mg/m(2)) given every 2 weeks for four doses. Chemoradiation consisted of four weekly infusions of gemcitabine (400 mg/m(2)) combined with radiation therapy (30 Gy in 10 fractions administered over 2 weeks) delivered 5 days per week. Patients underwent restaging 4 to 6 weeks after completion of chemoradiation and, in the absence of disease progression, were taken to surgery.The study enrolled 90 patients; 79 patients (88%) completed chemo-chemoradiation. Sixty-two (78%) of 79 patients were taken to surgery and 52 (66%) of 79 underwent PD. The median overall survival of all 90 patients was 17.4 months. Median survival for the 79 patients who completed chemo-chemoradiation was 18.7 months, with a median survival of 31 months for the 52 patients who underwent PD and 10.5 months for the 27 patients who did not undergo surgical resection of their primary tumor (P < .001).Preoperative Gem-Cis-XRT did not improve survival beyond that achieved with preoperative gemcitabine-based chemoradiation (Gem-XRT) alone. The longer preoperative interval required more durable biliary decompression (metal stents) but was not associated with local tumor progression. The gemcitabine-based chemoradiation platform is a reasonable foundation on which to build future phase II multimodality trials for stage I/II pancreatic cancer incorporating emerging systemic therapies.

Authors
Varadhachary, GR; Wolff, RA; Crane, CH; Sun, CC; Lee, JE; Pisters, PWT; Vauthey, J-N; Abdalla, E; Wang, H; Staerkel, GA; Lee, JH; Ross, WA; Tamm, EP; Bhosale, PR; Krishnan, S; Das, P; Ho, L; Xiong, H; Abbruzzese, JL; Evans, DB
MLA Citation
Varadhachary, GR, Wolff, RA, Crane, CH, Sun, CC, Lee, JE, Pisters, PWT, Vauthey, J-N, Abdalla, E, Wang, H, Staerkel, GA, Lee, JH, Ross, WA, Tamm, EP, Bhosale, PR, Krishnan, S, Das, P, Ho, L, Xiong, H, Abbruzzese, JL, and Evans, DB. "Preoperative gemcitabine and cisplatin followed by gemcitabine-based chemoradiation for resectable adenocarcinoma of the pancreatic head." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 26.21 (July 2008): 3487-3495.
PMID
18640929
Source
epmc
Published In
Journal of Clinical Oncology
Volume
26
Issue
21
Publish Date
2008
Start Page
3487
End Page
3495
DOI
10.1200/jco.2007.15.8642

Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head.

We conducted a phase II trial to assess the outcomes of patients who received preoperative gemcitabine-based chemoradiation and pancreaticoduodenectomy (PD) for stage I/II pancreatic adenocarcinoma.Eligible patients with pancreatic head/uncinate process adenocarcinoma and radiographically defined potentially resectable disease received chemoradiation with 7 weekly intravenous (IV) infusions of gemcitabine (400 mg/m(2) IV over 30 minutes) plus radiation therapy (30 Gy in 10 fractions over 2 weeks). Patients underwent restaging 4 to 6 weeks after completion of chemoradiation and, in the absence of disease progression, were taken to surgery.The study enrolled 86 patients. At the time of restaging, disease progression or a decline in performance status precluded 13 patients from surgery. Seventy-three (85%) of 86 patients were taken to surgery, extrapancreatic disease was found in nine, and 64 (74%) of 86 underwent a successful PD. Median overall survival (86 patients) was 22.7 months with a 27% 5-year survival. Median survival was 34 months for the 64 patients who underwent PD and 7 months for the 22 unresected patients (P < .001). The 5-year survival for those who did and did not undergo PD was 36% and 0%, respectively.Preoperative gemcitabine-based chemoradiation followed by restaging and evaluation for surgery separated the study population into two different subsets: patients likely to benefit from PD (n = 64) and those in whom surgery would be unlikely to provide clinical benefit (n = 22). Furthermore, the encouraging overall survival observed in this large trial supports the continued investigation of gemcitabine-based preoperative therapy in resectable pancreatic cancer.

Authors
Evans, DB; Varadhachary, GR; Crane, CH; Sun, CC; Lee, JE; Pisters, PWT; Vauthey, J-N; Wang, H; Cleary, KR; Staerkel, GA; Charnsangavej, C; Lano, EA; Ho, L; Lenzi, R; Abbruzzese, JL; Wolff, RA
MLA Citation
Evans, DB, Varadhachary, GR, Crane, CH, Sun, CC, Lee, JE, Pisters, PWT, Vauthey, J-N, Wang, H, Cleary, KR, Staerkel, GA, Charnsangavej, C, Lano, EA, Ho, L, Lenzi, R, Abbruzzese, JL, and Wolff, RA. "Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 26.21 (July 2008): 3496-3502.
PMID
18640930
Source
epmc
Published In
Journal of Clinical Oncology
Volume
26
Issue
21
Publish Date
2008
Start Page
3496
End Page
3502
DOI
10.1200/jco.2007.15.8634

Carcinoma of unknown primary with a colon-cancer profile-changing paradigm and emerging definitions.

Carcinoma of unknown primary (CUP), which accounts for about 3-5% of all new cancers, is a challenging heterogeneous entity with an unmet research need. Traditionally, CUP has been managed with broad-spectrum chemotherapy, but with the increasing availability of sophisticated diagnostic techniques and the emergence of new treatments that have been shown to be effective in specific cancers the one-treatment-fits-all approach to CUP might eventually no longer be valid. CUP in association with a colon-cancer profile (CCP-CUP) is an example of an emerging, specific CUP subset that seems to benefit from a tailored approach. CCP-CUP is identified by CK20 and CDX2-positive and CK7-negative immunohistochemistry and a clinical course consistent with that of patients known to have metastatic colon cancer. Our findings suggest that patients with CCP-CUP derive substantial benefit from the use of specific treatments developed for colon cancer and larger clinical trials are warranted to more definitely test this finding. In the era of molecular profiling, we expect that additional work with CCP-CUP and other CUP subsets will provide attractive tailored treatment alternatives, with efficacies that exceed the current one-treatment-fits-all approach.

Authors
Varadhachary, GR; Raber, MN; Matamoros, A; Abbruzzese, JL
MLA Citation
Varadhachary, GR, Raber, MN, Matamoros, A, and Abbruzzese, JL. "Carcinoma of unknown primary with a colon-cancer profile-changing paradigm and emerging definitions." The Lancet. Oncology 9.6 (June 2008): 596-599.
PMID
18510991
Source
epmc
Published In
The Lancet Oncology
Volume
9
Issue
6
Publish Date
2008
Start Page
596
End Page
599
DOI
10.1016/s1470-2045(08)70151-7

Interaction of the cytochrome P4501A2, SULT1A1 and NAT gene polymorphisms with smoking and dietary mutagen intake in modification of the risk of pancreatic cancer.

Aromatic amines, N-nitroso compounds and heterocyclic amines are suspected human pancreatic carcinogens. Cytochrome P450 (CYP) 1A2, N-acetyltransferase (NAT) 1, NAT2 and sulfotransferase (SULT) are enzymes involved in the metabolism of these carcinogens. To test the hypothesis that genetic variations in carcinogen metabolism modify the risk of pancreatic cancer (PC), we investigated the effect of single-nucleotide polymorphisms (SNPs) of the CYP1A2, NAT1, NAT2 and SULT1A1 gene on modification of the risk of PC in a hospital-based study of 755 patients with pancreatic adenocarcinoma and 636 healthy frequency-matched controls. Smoking and dietary mutagen exposure information was collected by personal interviews. Genotypes were determined using the polymerase chain reaction-restriction fragment length polymorphism and Taqman methods. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional multivariate logistic regression analysis. We observed no significant main effects of any of these genes on the risk of PC. The CYP1A2 and NAT1 but not SULT1A1 and NAT2 genotypes showed significant interactions with heavy smoking in women not men. In contrast, a significant interaction between NAT1 genotype and dietary mutagen intake on modifying the risk of PC were observed among men but not women. The OR (95% CI) of PC was 2.23 (1.33-3.72) and 2.54 (1.51-4.25) for men having the NAT1*10 and a higher intake of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and benzo[a]pyrene, respectively, compared with individuals having no NAT1*10 or a lower intake of these dietary mutagens. These data suggest the existence of gender-specific susceptibility to tobacco carcinogen and dietary mutagen exposure in PC.

Authors
Suzuki, H; Morris, JS; Li, Y; Doll, MA; Hein, DW; Liu, J; Jiao, L; Hassan, MM; Day, RS; Bondy, ML; Abbruzzese, JL; Li, D
MLA Citation
Suzuki, H, Morris, JS, Li, Y, Doll, MA, Hein, DW, Liu, J, Jiao, L, Hassan, MM, Day, RS, Bondy, ML, Abbruzzese, JL, and Li, D. "Interaction of the cytochrome P4501A2, SULT1A1 and NAT gene polymorphisms with smoking and dietary mutagen intake in modification of the risk of pancreatic cancer." Carcinogenesis 29.6 (June 2008): 1184-1191.
PMID
18499698
Source
epmc
Published In
Carcinogenesis
Volume
29
Issue
6
Publish Date
2008
Start Page
1184
End Page
1191
DOI
10.1093/carcin/bgn085

Development of an integrated biospecimen bank and multidisciplinary clinical database for pancreatic cancer.

The integration of biospecimens with reliable clinical data is critical to advance molecular findings from the laboratory to the clinic. We describe the development of an integrated pancreatic tissue bank (PTB) and clinical database for patients with pancreatic cancer and other pancreatic disorders.A clinical database and PTB were created in 1990 and 2000, respectively, to collect clinical information and biospecimens from patients with suspected or confirmed pancreatic cancer, other pancreatic diseases, and tumors of the duodenum, ampulla of Vater, and distal bile duct. Standard procedures for biospecimen collection and data entry were developed.From 2000 through 2006, the PTB collected 8,061 pancreatic tissue specimens from 620 patients. The most common histologies of pancreatic tumors were pancreatic ductal adenocarcinoma (55.3%) and neuroendocrine carcinoma (16.3%). The biospecimen collection also includes 431 plasma samples, 40 fine-needle aspiration samples, and a tissue microarray containing 85 pancreatic adenocarcinomas and matched normal tissue specimens. The clinical database contains information for 7,647 patients with pancreatic cancer, other pancreatic disorders, and duodenal, ampullary, or bile duct neoplasms. The data are arranged into nine modules: patient, presentation, risk factors, diagnostic imaging, treatment plan, surgery, pathology, postoperative complications, and follow-up.We have established a pancreatic cancer tissue bank with standardized procedures for collection of biospecimens along with a comprehensive multidisciplinary clinical database. The integrated biospecimen bank and clinical database for pancreatic cancer described here can serve as a model from which other groups may develop similar systems.

Authors
Hwang, RF; Wang, H; Lara, A; Gomez, H; Chang, T; Sieffert, N; Moon, Y; Ram, S; Zimmerman, S; Lee, JH; Pisters, PWT; Tamm, EP; Fleming, JB; Abbruzzese, JL; Evans, DB
MLA Citation
Hwang, RF, Wang, H, Lara, A, Gomez, H, Chang, T, Sieffert, N, Moon, Y, Ram, S, Zimmerman, S, Lee, JH, Pisters, PWT, Tamm, EP, Fleming, JB, Abbruzzese, JL, and Evans, DB. "Development of an integrated biospecimen bank and multidisciplinary clinical database for pancreatic cancer." Annals of surgical oncology 15.5 (May 2008): 1356-1366.
PMID
18256882
Source
epmc
Published In
Annals of Surgical Oncology
Volume
15
Issue
5
Publish Date
2008
Start Page
1356
End Page
1366
DOI
10.1245/s10434-008-9833-1

Systematic survey of therapeutic trials for metastatic colorectal cancer: room for improvement in the critical pathway.

PURPOSE: The current strategy of drug development has been criticized as being highly inefficient. In 2004, the US Food and Drug Administration (FDA) released recommendations to improve this process, including a push for increased use of enrichment trials. It is unclear to what extent aspects of this "Critical Path Initiative" have been adopted in trial designs in metastatic colorectal cancer. METHODS: A systematic review was conducted of actively enrolling treatment trials in metastatic colorectal cancer. Trials were identified from the National Cancer Institute's clinicaltrials.gov and Investigative Drug Branch databases. Trials were categorized based on the number of prior treatments allowed, phase of the trial, agent mechanism of action, and FDA approval status of agents under investigation. RESULTS: One hundred two trials are enrolling, with a combined enrollment goal of more than 20,000 patients. Thirteen percent of trials investigated an agent not yet FDA-approved for any oncology indication. The most common study design was a phase II study limited to previously untreated patients; compared with the remaining trials, these phase II trials were more than 10 times more likely to only use agents FDA-approved for colorectal cancer. Three percent of patients were enrolled onto trials enriched for tumor characteristics that were hypothesized to improve clinical benefit. CONCLUSION: Current clinical trials for metastatic colorectal cancer are deficient in the investigation of agents directed at a novel therapeutic target, overuse phase II studies of FDA-approved agents, and fail to incorporate enrichment trial designs as encouraged by the FDA initiative.

Authors
Kopetz, S; Overman, M; Chang, DZ; Glover, KY; Shureiqi, I; Wolff, RA; Abbruzzese, JL; Eng, C
MLA Citation
Kopetz, S, Overman, M, Chang, DZ, Glover, KY, Shureiqi, I, Wolff, RA, Abbruzzese, JL, and Eng, C. "Systematic survey of therapeutic trials for metastatic colorectal cancer: room for improvement in the critical pathway." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 26.12 (April 2008): 2000-2005.
PMID
18421052
Source
epmc
Published In
Journal of Clinical Oncology
Volume
26
Issue
12
Publish Date
2008
Start Page
2000
End Page
2005
DOI
10.1200/jco.2007.13.2407

Tissue transglutaminase regulates focal adhesion kinase/AKT activation by modulating PTEN expression in pancreatic cancer cells.

Pancreatic ductal adenocarcinoma (PDAC) progresses rapidly and exhibits profound resistance to treatment. We recently reported that a great majority of PDAC tumors and tumor cell lines express elevated levels of tissue transglutaminase (TG2). Here, we provide first evidence that TG2 expression in PDAC cells results in constitutive activation of focal adhesion kinase/AKT by modulating the expression of the tumor suppressor phosphatase PTEN.Using PDAC cell lines, we determined the effect of TG2 overexpression on PTEN stability and functions. We confirmed the correlation between TG2 expression and PTEN levels in a few (n=51) PDAC tumor samples.We observed that expression of TG2 is inversely correlated with PTEN expression in PDAC cells. Ectopic expression of TG2 inhibited PTEN phosphorylation and promoted its degradation by ubiquitin-proteasomal pathway. Conversely, down-regulation of TG2 by small interfering RNA up-regulated PTEN expression. Clinical relevance of these results was evident in an athymic nude mouse model where down-regulation of endogenous TG2 caused a significant retardation in PDAC xenograft growth. Importantly, the analysis of 51 tumor samples from patients with stage II PDAC revealed that overexpression of TG2 was associated with loss of PTEN expression (P=0.023; odds ratio, 4.1). In multivariate analysis, TG2-mediated loss of PTEN was a prognostic factor for overall survival in patients with stage II pancreatic ductal carcinoma independent of tumor stage/lymph node status and tumor differentiation (P=0.01).TG2 expression in PDAC promotes degradation of PTEN by ubiquitin-proteasomal pathway and results in constitutive activation of focal adhesion kinase/AKT cell survival signaling.

Authors
Verma, A; Guha, S; Wang, H; Fok, JY; Koul, D; Abbruzzese, J; Mehta, K
MLA Citation
Verma, A, Guha, S, Wang, H, Fok, JY, Koul, D, Abbruzzese, J, and Mehta, K. "Tissue transglutaminase regulates focal adhesion kinase/AKT activation by modulating PTEN expression in pancreatic cancer cells." Clinical cancer research : an official journal of the American Association for Cancer Research 14.7 (April 2008): 1997-2005.
PMID
18381937
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
14
Issue
7
Publish Date
2008
Start Page
1997
End Page
2005
DOI
10.1158/1078-0432.ccr-07-1533

Tumor blood flow measured by PET dynamic imaging of first-pass 18F-FDG uptake: a comparison with 15O-labeled water-measured blood flow.

UNLABELLED: PET molecular imaging of 15O-labeled water is the gold standard for measuring blood flow in humans. However, this requires an on-site cyclotron to produce the short-lived 15O tracer, which is cost-prohibitive for most clinical PET centers. The purpose of this study was to determine if the early uptake of 18F-FDG could be used to measure regional blood flow in tumors in the absence of 15O-water. METHODS: PET scans were obtained in patients being evaluated for tumor perfusion and glucose metabolism in a phase I dose-escalating protocol for endostatin, a novel antiangiogenic agent. A 2-min perfusion scan was performed with a bolus injection of 2,220 MBq (60 mCi) of 15O-water, which was followed by a 370-MBq (10 mCi) dose of 18F-FDG. Four sequential scans of 18F-FDG uptake were acquired, consisting of an early 2-min uptake scan-or first-pass scan-and 3 sequential 15-min late 18F-FDG uptake scans. Regions of interest (ROIs) were drawn on 2 or more tumor sites and on back muscle, as a control ROI, for each patient. Arterial blood concentration was derived from the PET scans by drawing an ROI over a large artery in the field of view. Blood flow was computed with a simple 1-compartment blood flow model using the first 2 min of data after injection. RESULTS: Blood flow estimated from the early uptake of 18F-FDG was linearly correlated with 15O-measured blood flow, with an intercept of 0.01, a slope of 0.86, and an R2 regression coefficient of 0.74 (r = 0.86). The 18F-FDG tumor extraction fraction relative to 15O-water averaged 0.86. A preliminary case study of a patient with prostate cancer confirms the utility of the first-pass 18F-FDG blood flow analysis in tumor diagnosis. CONCLUSION: These results suggest that the first-pass uptake of 18F-FDG may provide an estimate of perfusion in a tumor within the limitations of incomplete extraction of 18F-FDG compared with 15O-water.

Authors
Mullani, NA; Herbst, RS; O'Neil, RG; Gould, KL; Barron, BJ; Abbruzzese, JL
MLA Citation
Mullani, NA, Herbst, RS, O'Neil, RG, Gould, KL, Barron, BJ, and Abbruzzese, JL. "Tumor blood flow measured by PET dynamic imaging of first-pass 18F-FDG uptake: a comparison with 15O-labeled water-measured blood flow." Journal of nuclear medicine : official publication, Society of Nuclear Medicine 49.4 (April 2008): 517-523.
PMID
18344436
Source
epmc
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
49
Issue
4
Publish Date
2008
Start Page
517
End Page
523
DOI
10.2967/jnumed.107.048504

Single-nucleotide polymorphisms of DNA damage response genes are associated with overall survival in patients with pancreatic cancer.

The goals of this study were to determine if single-nucleotide polymorphisms in DNA damage repair genes and cell cycle regulating genes affect clinical response to combined gemcitabine radiation therapy and the overall survival (OS) of patients with pancreatic cancer.We evaluated six single-nucleotide polymorphisms of the ATM, ATM and Rad3-related (ATR), CHEK1, and CHEK2 genes in 119 patients with potentially resectable pancreatic cancer who were enrolled in clinical trials at The University of Texas M. D. Anderson Cancer Center from February 1999 to January 2006, with follow-up until February 2007. Patients received neoadjuvant concurrent gemcitabine and radiation therapy with or without gemcitabine-cisplatin induction therapy. Genotypes were determined and tested for associations with OS by Kaplan-Meier estimation, the log-rank test, and Cox regression analysis. P values of

Authors
Okazaki, T; Jiao, L; Chang, P; Evans, DB; Abbruzzese, JL; Li, D
MLA Citation
Okazaki, T, Jiao, L, Chang, P, Evans, DB, Abbruzzese, JL, and Li, D. "Single-nucleotide polymorphisms of DNA damage response genes are associated with overall survival in patients with pancreatic cancer." Clinical cancer research : an official journal of the American Association for Cancer Research 14.7 (April 2008): 2042-2048.
PMID
18381943
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
14
Issue
7
Publish Date
2008
Start Page
2042
End Page
2048
DOI
10.1158/1078-0432.ccr-07-1520

LY2109761, a novel transforming growth factor beta receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis.

Most pancreatic cancer patients present with inoperable disease or develop metastases after surgery. Conventional therapies are usually ineffective in treating metastatic disease. It is evident that novel therapies remain to be developed. Transforming growth factor beta (TGF-beta) plays a key role in cancer metastasis, signaling through the TGF-beta type I/II receptors (TbetaRI/II). We hypothesized that targeting TbetaRI/II kinase activity with the novel inhibitor LY2109761 would suppress pancreatic cancer metastatic processes. The effect of LY2109761 has been evaluated on soft agar growth, migration, invasion using a fibroblast coculture model, and detachment-induced apoptosis (anoikis) by Annexin V flow cytometric analysis. The efficacy of LY2109761 on tumor growth, survival, and reduction of spontaneous metastasis have been evaluated in an orthotopic murine model of metastatic pancreatic cancer expressing both luciferase and green fluorescence proteins (L3.6pl/GLT). To determine whether pancreatic cancer cells or the cells in the liver microenvironment were involved in LY2109761-mediated reduction of liver metastasis, we used a model of experimental liver metastasis. LY2109761 significantly inhibited the L3.6pl/GLT soft agar growth, suppressed both basal and TGF-beta1-induced cell migration and invasion, and induced anoikis. In vivo, LY2109761, in combination with gemcitabine, significantly reduced the tumor burden, prolonged survival, and reduced spontaneous abdominal metastases. Results from the experimental liver metastasis models indicate an important role for targeting TbetaRI/II kinase activity on tumor and liver microenvironment cells in suppressing liver metastasis. Targeting TbetaRI/II kinase activity on pancreatic cancer cells or the cells of the liver microenvironment represents a novel therapeutic approach to prevent pancreatic cancer metastasis.

Authors
Melisi, D; Ishiyama, S; Sclabas, GM; Fleming, JB; Xia, Q; Tortora, G; Abbruzzese, JL; Chiao, PJ
MLA Citation
Melisi, D, Ishiyama, S, Sclabas, GM, Fleming, JB, Xia, Q, Tortora, G, Abbruzzese, JL, and Chiao, PJ. "LY2109761, a novel transforming growth factor beta receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis." Molecular cancer therapeutics 7.4 (April 2008): 829-840.
PMID
18413796
Source
epmc
Published In
Molecular cancer therapeutics
Volume
7
Issue
4
Publish Date
2008
Start Page
829
End Page
840
DOI
10.1158/1535-7163.mct-07-0337

Targeting vascular endothelial growth factor in advanced carcinoid tumor: a random assignment phase II study of depot octreotide with bevacizumab and pegylated interferon alpha-2b.

Effective systemic therapy for advanced carcinoid is lacking. The combination of bevacizumab (BEV) and pegylated (PEG) interferon alpha-2b was evaluated among patients with metastatic or unresectable carcinoid tumors.Forty-four patients on stable doses of octreotide were randomly assigned to 18 weeks of treatment with bevacizumab or PEG interferon alpha-2b. At disease progression (PD) or at the end of 18 weeks (whichever occurred earlier), patients received bevacizumab plus PEG interferon until progression. Functional computer tomography (CT) scans were performed to measure effect on tumor blood flow.In the bevacizumab arm, four patients (18%) achieved confirmed partial response (PR), 17 patients (77%) had stable disease (SD), and one patient (5%) had PD. In the PEG interferon arm, 15 patients (68%) had SD and six patients (27%) had PD. Progression-free survival (PFS) rates after 18 weeks of monotherapy were 95% in bevacizumab versus 68% on the PEG interferon arm. The overall median PFS for all 44 patients is 63 weeks. Compared with paired baseline measurements on functional CT scans, we observed a 49% (P < .01) and 28% (P < .01) decrease in tumor blood flow at day 2 and week 18 among patients treated with bevacizumab. No significant changes in tumor blood flow were observed following PEG interferon. PEG interferon alpha-2b treatment was associated with decrease in plasma basic fibroblast growth factor (bFGF; P = .04) and increase in plasma interleukin-18 (IL-18; P < .01). No significant changes in bFGF or IL-18 following treatment with bevacizumab were observed.Bevacizumab therapy resulted in objective responses, reduction of tumor blood flow, and longer PFS in patients with carcinoid than PEG interferon treatment.

Authors
Yao, JC; Phan, A; Hoff, PM; Chen, HX; Charnsangavej, C; Yeung, S-CJ; Hess, K; Ng, C; Abbruzzese, JL; Ajani, JA
MLA Citation
Yao, JC, Phan, A, Hoff, PM, Chen, HX, Charnsangavej, C, Yeung, S-CJ, Hess, K, Ng, C, Abbruzzese, JL, and Ajani, JA. "Targeting vascular endothelial growth factor in advanced carcinoid tumor: a random assignment phase II study of depot octreotide with bevacizumab and pegylated interferon alpha-2b." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 26.8 (March 2008): 1316-1323.
PMID
18323556
Source
epmc
Published In
Journal of Clinical Oncology
Volume
26
Issue
8
Publish Date
2008
Start Page
1316
End Page
1323
DOI
10.1200/jco.2007.13.6374

Adjuvant therapy for surgically resected pancreatic adenocarcinoma.

Authors
Abbruzzese, JL
MLA Citation
Abbruzzese, JL. "Adjuvant therapy for surgically resected pancreatic adenocarcinoma." JAMA 299.9 (March 2008): 1066-1067.
PMID
18319419
Source
epmc
Published In
JAMA : the journal of the American Medical Association
Volume
299
Issue
9
Publish Date
2008
Start Page
1066
End Page
1067
DOI
10.1001/jama.299.9.1066

XRCC2 and XRCC3 gene polymorphism and risk of pancreatic cancer.

XRCC2 and XRCC3 are key components of the homologous recombination (HR) machinery that repairs DNA double-strand breaks. We hypothesized that the altered HR repair capacity conferred by single nucleotide polymorphisms (SNPs) would modify individual susceptibility to sporadic pancreatic cancer.In a hospital-based case-control study, genomic DNA and exposure information was obtained from 468 patients with pathologically confirmed pancreatic adenocarcinoma and 498 frequency-matched healthy controls at M.D. Anderson Cancer Center during January 2000 to September 2006. Genotypes of XRCC2 31479 G>A (Arg188His) and XRCC3 17893 A>G and 18067 C>T (Thr241Met) were determined using the Masscode technology. Unconditional logistic regression models were used to estimate the odds ratio (OR) and its 95% confidence interval (CI) in non-Hispanic whites (408 cases and 449 controls).The distribution of genotype frequencies was not different between cases and controls. We observed a significant effect modification between XRCC2 polymorphism and smoking status and pack-year of smoking in modifying pancreatic cancer risk (P value for interaction 0.02 and 0.05, respectively). Compared with never-smokers carrying the XRCC2 Arg188Arg genotype, the OR (95% CI) for individuals carrying the (188)His allele was 2.32 (1.25-4.31) among ever-smokers, 1.43 (0.59-3.48) among light smokers (< or = 22 pack-years), and 3.42 (1.47-7.96) among heavy smokers (> or =22 pack-years). The two XRCC3 SNPs are in strong linkage disequilibrium, but there was no suggestive association between XRCC3 genotype and the risk of pancreatic cancer.XRCC2 Arg188His polymorphism may be one of the genetic modifiers for smoking-related pancreatic cancer.

Authors
Jiao, L; Hassan, MM; Bondy, ML; Wolff, RA; Evans, DB; Abbruzzese, JL; Li, D
MLA Citation
Jiao, L, Hassan, MM, Bondy, ML, Wolff, RA, Evans, DB, Abbruzzese, JL, and Li, D. "XRCC2 and XRCC3 gene polymorphism and risk of pancreatic cancer." The American journal of gastroenterology 103.2 (February 2008): 360-367.
PMID
17986315
Source
epmc
Published In
The American Journal of Gastroenterology (Elsevier)
Volume
103
Issue
2
Publish Date
2008
Start Page
360
End Page
367
DOI
10.1111/j.1572-0241.2007.01615.x

Stemming the tide of hepatitis B virus related hepatocellular carcinoma?

Authors
Thomas, MB; Davila, M; Abbruzzese, JL
MLA Citation
Thomas, MB, Davila, M, and Abbruzzese, JL. "Stemming the tide of hepatitis B virus related hepatocellular carcinoma?." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 26.2 (January 2008): 172-174.
PMID
18182657
Source
epmc
Published In
Journal of Clinical Oncology
Volume
26
Issue
2
Publish Date
2008
Start Page
172
End Page
174
DOI
10.1200/jco.2007.14.4337

Second-Line Chemotherapy Use in Metastatic Colon Cancer Varies by Disease Responsiveness

Authors
Politano, S; Overman, M; Pathak, P; Chadha, R; Glover, K; Chang, DZ; Wolff, RA; Hoff, PM; Abbruzzese, J; Eng, C; Kopetz, S
MLA Citation
Politano, S, Overman, M, Pathak, P, Chadha, R, Glover, K, Chang, DZ, Wolff, RA, Hoff, PM, Abbruzzese, J, Eng, C, and Kopetz, S. "Second-Line Chemotherapy Use in Metastatic Colon Cancer Varies by Disease Responsiveness." Clinical Colorectal Cancer 7.1 (January 2008): 55-59.
Source
crossref
Published In
Clinical colorectal cancer
Volume
7
Issue
1
Publish Date
2008
Start Page
55
End Page
59
DOI
10.3816/CCC.2008.n.008

Down-regulation of platelet-derived growth factor-D inhibits cell growth and angiogenesis through inactivation of Notch-1 and nuclear factor-kappaB signaling.

Platelet-derived growth factor-D (PDGF-D) signaling plays critical roles in the pathogenesis and progression of human malignancies; however, the precise mechanism by which PDGF-D causes tumor cell invasion and angiogenesis remain unclear. Because Notch-1, nuclear factor-kappaB (NF-kappaB), vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMP) are critically involved in the processes of tumor cell invasion and metastasis, we investigated whether PDGF-D down-regulation could be mechanistically associated with the down-regulation of Notch-1, NF-kappaB, VEGF, and MMP-9, resulting in the inhibition of tumor cell invasion and angiogenesis. Our data showed that down-regulation of PDGF-D leads to the inactivation of Notch-1 and NF-kappaB DNA-binding activity and, in turn, down regulates the expression of its target genes, such as VEGF and MMP-9. We also found that the down-regulation of PDGF-D by small interfering RNA (siRNA) decreased tumor cell invasion, whereas PDGF-D overexpression by cDNA transfection led to increased cell invasion. Consistent with these results, we also found that the down-regulation of PDGF-D not only decreased MMP-9 mRNA and its protein expression but also inhibited the processing of pro-MMP-9 protein to its active form. Moreover, conditioned medium from PDGF-D siRNA-transfected cells showed reduced levels of VEGF and, in turn, inhibited the tube formation of human umbilical vascular endothelial cells, suggesting that down-regulation of PDGF-D leads to the inhibition of angiogenesis. Taken together, we conclude that the down-regulation of PDGF-D by novel approaches could lead to the down-regulation of Notch-1 and, in turn, inactivate NF-kappaB and its target genes (i.e., MMP-9 and VEGF), resulting in the inhibition of invasion and angiogenesis.

Authors
Wang, Z; Kong, D; Banerjee, S; Li, Y; Adsay, NV; Abbruzzese, J; Sarkar, FH
MLA Citation
Wang, Z, Kong, D, Banerjee, S, Li, Y, Adsay, NV, Abbruzzese, J, and Sarkar, FH. "Down-regulation of platelet-derived growth factor-D inhibits cell growth and angiogenesis through inactivation of Notch-1 and nuclear factor-kappaB signaling." Cancer research 67.23 (December 2007): 11377-11385.
PMID
18056465
Source
epmc
Published In
Cancer Research
Volume
67
Issue
23
Publish Date
2007
Start Page
11377
End Page
11385
DOI
10.1158/0008-5472.can-07-2803

Risk factors for pancreatic cancer: case-control study.

Although cigarette smoking is the most well-established environmental risk factor for pancreatic cancer, the interaction between smoking and other risk factors has not been assessed. We evaluated the independent effects of multiple risk factors for pancreatic cancer and determined whether the magnitude of cigarette smoking was modified by other risk factors in men and women.We conducted a hospital-based case-control study involving 808 patients with pathologically diagnosed pancreatic cancer and 808 healthy frequency-matched controls. Information on risk factors was collected by personal interview, and unconditional logistic regression was used to determine adjusted odds ratios (AORs) by the maximum-likelihood method.Cigarette smoking, family history of pancreatic cancer, heavy alcohol consumption (>60 mL ethanol/day), diabetes mellitus, and history of pancreatitis were significant risk factors for pancreatic cancer. We found synergistic interactions between cigarette smoking and family history of pancreatic cancer (AOR 12.8, 95% confidence interval [CI] 1.6-108.9) and diabetes mellitus (AOR 9.3, 95% CI 2.0-44.1) in women, according to an additive model. Approximately 23%, 9%, 3%, and 5% of pancreatic cancer cases in this study were related to cigarette smoking, diabetes mellitus, heavy alcohol consumption, and family history of pancreatic cancer, respectively.The significant synergy between these risk factors suggests a common pathway for carcinogenesis of the pancreas. Determining the underlying mechanisms for such synergies may lead to the development of pancreatic cancer prevention strategies for high-risk individuals.

Authors
Hassan, MM; Bondy, ML; Wolff, RA; Abbruzzese, JL; Vauthey, J-N; Pisters, PW; Evans, DB; Khan, R; Chou, T-H; Lenzi, R; Jiao, L; Li, D
MLA Citation
Hassan, MM, Bondy, ML, Wolff, RA, Abbruzzese, JL, Vauthey, J-N, Pisters, PW, Evans, DB, Khan, R, Chou, T-H, Lenzi, R, Jiao, L, and Li, D. "Risk factors for pancreatic cancer: case-control study." The American journal of gastroenterology 102.12 (December 2007): 2696-2707.
PMID
17764494
Source
epmc
Published In
The American Journal of Gastroenterology (Elsevier)
Volume
102
Issue
12
Publish Date
2007
Start Page
2696
End Page
2707
DOI
10.1111/j.1572-0241.2007.01510.x

Pancreatic cancer targeted C-VISA-BikDD: DNA-liposome complex results in minimal toxicity in vivo

Authors
Javle, MM; Xie, X; Xia, W; Li, Z; Kuo, H; Liu, Y; Ding, Q; Zhang, S; Spohn, B; Yang, Y; Wei, Y; Lang, Y; Abbruzzese, JL; Hung, MC
MLA Citation
Javle, MM, Xie, X, Xia, W, Li, Z, Kuo, H, Liu, Y, Ding, Q, Zhang, S, Spohn, B, Yang, Y, Wei, Y, Lang, Y, Abbruzzese, JL, and Hung, MC. "Pancreatic cancer targeted C-VISA-BikDD: DNA-liposome complex results in minimal toxicity in vivo." December 2007.
Source
wos-lite
Published In
Molecular cancer therapeutics
Volume
6
Issue
12
Publish Date
2007
Start Page
3482S
End Page
3482S

'Unresectable' pancreatic cancer: Conceptual challenges

Authors
Fogelman, DR; Abbruzzese, JL
MLA Citation
Fogelman, DR, and Abbruzzese, JL. "'Unresectable' pancreatic cancer: Conceptual challenges." ONCOLOGY 21.13 (November 1, 2007): 1571-1572. (Review)
Source
scopus
Published In
Oncology
Volume
21
Issue
13
Publish Date
2007
Start Page
1571
End Page
1572

Survivin DNA vaccine generated specific antitumor effects in pancreatic carcinoma and lymphoma mouse models.

We investigated the antitumor effect of survivin DNA vaccine in murine pancreatic and lymphoma models, and if xenogenic survivin can generate stronger immune response. We found that mice vaccinated with either human or mouse survivin DNA have significantly slower tumor growth and longer survival than those vaccinated with vector DNA. There was no significant difference between groups that received human and mouse survivin DNA. Lymphocyte infiltration was greater in tumors of mice immunized with survivin DNA than in tumors of control mice. We conclude that survivin DNA vaccine generated specific antitumor effects with increased lymphocyte infiltration at the tumor sites.

Authors
Zhu, K; Qin, H; Cha, S-C; Neelapu, SS; Overwijk, W; Lizee, GA; Abbruzzese, JL; Hwu, P; Radvanyi, L; Kwak, LW; Chang, DZ
MLA Citation
Zhu, K, Qin, H, Cha, S-C, Neelapu, SS, Overwijk, W, Lizee, GA, Abbruzzese, JL, Hwu, P, Radvanyi, L, Kwak, LW, and Chang, DZ. "Survivin DNA vaccine generated specific antitumor effects in pancreatic carcinoma and lymphoma mouse models." Vaccine 25.46 (November 2007): 7955-7961.
PMID
17933439
Source
epmc
Published In
Vaccine
Volume
25
Issue
46
Publish Date
2007
Start Page
7955
End Page
7961
DOI
10.1016/j.vaccine.2007.08.050

Haplotype of N-acetyltransferase 1 and 2 and risk of pancreatic cancer.

We examined the association between N-acetyltransferase 1 and 2 (NAT1 and NAT2) haplotype and risk of pancreatic cancer by genotyping eight NAT1 and seven NAT2 single nucleotide polymorphisms in 532 patients and in 581 healthy controls (all non-Hispanic white) who were recruited at M. D. Anderson Cancer Center from January 2000 to December 2006. Haplotypes were reconstructed by using an expectation-maximization algorithm. Odds ratios and 95% confidence intervals were estimated by using unconditional logistic regression models. Covariates included age (continuous variable), sex, pack-year of smoking (categorical), and history of diabetes when appropriate. NAT1 and NAT2 genotype was mutually adjusted. The prevalence of haplotype NAT1*10-NAT2*6A was 4.3% versus 2.7% (P=0.06) and NAT1*11-NAT2*6A was 1.2% versus 0.4% (P=0.05) in patients and controls, respectively. The diplotype NAT1*10/*10 or NAT1*10/*11 and NAT2*6A/any slow allele was associated with a higher risk of pancreatic cancer compared with other diplotypes (multivariate odds ratio, 4.15; 95% confidence interval, 1.15-15.00; P=0.03). NAT2 slow genotype were associated with increased risk of pancreatic cancer among heavy smokers and among individuals with a history of diabetes. We for the first time found that rare NAT1*10 or NAT1*11-NAT2*6A diplotype may be an "at-risk" genetic variant for pancreatic cancer. The NAT2*6A/any slow acetylation genotype may be a predisposing factor for pancreatic cancer among diabetics with smoking exposure. Our observations must be confirmed in larger independent studies.

Authors
Jiao, L; Doll, MA; Hein, DW; Bondy, ML; Hassan, MM; Hixson, JE; Abbruzzese, JL; Li, D
MLA Citation
Jiao, L, Doll, MA, Hein, DW, Bondy, ML, Hassan, MM, Hixson, JE, Abbruzzese, JL, and Li, D. "Haplotype of N-acetyltransferase 1 and 2 and risk of pancreatic cancer." Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 16.11 (November 2007): 2379-2386.
PMID
18006927
Source
epmc
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
16
Issue
11
Publish Date
2007
Start Page
2379
End Page
2386
DOI
10.1158/1055-9965.epi-06-0992

Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial-mesenchymal transition in cancer cells via up-regulation of TWIST gene expression.

Aberrant epidermal growth factor receptor (EGFR) signaling is a major cause of tumor progression and metastasis; the underlying mechanisms, however, are not well understood. In particular, it remains elusive whether deregulated EGFR pathway is involved in epithelial-mesenchymal transition (EMT), an early event that occurs during metastasis of cancers of an epithelial origin. Here, we show that EGF induces EGFR-expressing cancer cells to undergo a transition from the epithelial to the spindle-like mesenchymal morphology. EGF reduced E-cadherin expression and increased that of mesenchymal proteins. In search of a downstream mediator that may account for EGF-induced EMT, we focused on transcription repressors of E-cadherin, TWIST, SLUG, and Snail and found that cancer cells express high levels of TWIST and that EGF enhances its expression. EGF significantly increases TWIST transcripts and protein in EGFR-expressing lines. Forced expression of EGFR reactivates TWIST expression in EGFR-null cells. TWIST expression is suppressed by EGFR and Janus-activated kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) inhibitors, but not significantly by those targeting phosphoinositide-3 kinase and MEK/ERK. Furthermore, constitutively active STAT3 significantly activates the TWIST promoter, whereas the JAK/STAT3 inhibitor and dominant-negative STAT3 suppressed TWIST promoter. Deletion/mutation studies further show that a 26-bp promoter region contains putative STAT3 elements required for the EGF-responsiveness of the TWIST promoter. Chromatin immunoprecipitation assays further show that EGF induces binding of nuclear STAT3 to the TWIST promoter. Immunohistochemical analysis of 130 primary breast carcinomas indicates positive correlations between non-nuclear EGFR and TWIST and between phosphorylated STAT3 and TWIST. Together, we report here that EGF/EGFR signaling pathways induce cancer cell EMT via STAT3-mediated TWIST gene expression.

Authors
Lo, H-W; Hsu, S-C; Xia, W; Cao, X; Shih, J-Y; Wei, Y; Abbruzzese, JL; Hortobagyi, GN; Hung, M-C
MLA Citation
Lo, H-W, Hsu, S-C, Xia, W, Cao, X, Shih, J-Y, Wei, Y, Abbruzzese, JL, Hortobagyi, GN, and Hung, M-C. "Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial-mesenchymal transition in cancer cells via up-regulation of TWIST gene expression." Cancer research 67.19 (October 2007): 9066-9076.
PMID
17909010
Source
epmc
Published In
Cancer Research
Volume
67
Issue
19
Publish Date
2007
Start Page
9066
End Page
9076
DOI
10.1158/0008-5472.can-07-0575

Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma.

BACKGROUND: Growth factor overexpression, including epidermal growth factor receptor (EGFR) expression, is common in hepatocellular cancers. Erlotinib is a receptor tyrosine kinase inhibitor with specificity for EGFR. The primary objective of this study was to determine the proportion of hepatocellular carcinoma (HCC) patients treated with erlotinib who were alive and progression-free (PFS) at 16 weeks of continuous treatment. METHODS: Patients with unresectable HCC, no prior systemic therapy, performance status (PS) of 0, 1, or 2, and Childs-Pugh (CP) cirrhosis A or B received oral erlotinib 150 mg daily for 28-day cycles. Tumor response was assessed every 2 cycles by using Response Evaluation Criteria in Solid Tumors (RECIST; National Cancer Institute Cancer Therapy Evaluation Program, Bethesda, Md) criteria. Patients accrued to either "low" or "high" EGFR expression cohorts; each cohort had stopping rules applied when there was a lack of efficacy. RESULTS: Forty HCC patients were enrolled. Median age was 64 years (range, 33-83 years), sex distribution was 32 males and 8 females, performance scores were 40% PS 0, 55% PS 1, Childs-Pugh distribution was 75% A and 20% B. There were no complete or partial responses; however, 17 of 40 patients achieved stable disease at 16 weeks of continuous therapy. The PFS at 16 weeks was 43%, and the median overall survival (OS) was 43 weeks (10.75 months). No patients required dose reductions of erlotinib. No correlation between EGFR expression and outcome was found. CONCLUSIONS: Results of this study indicated that single-agent erlotinib is well tolerated and has modest disease-control benefit in HCC, manifested as modestly prolonged PFS and OS when compared with historical controls.

Authors
Thomas, MB; Chadha, R; Glover, K; Wang, X; Morris, J; Brown, T; Rashid, A; Dancey, J; Abbruzzese, JL
MLA Citation
Thomas, MB, Chadha, R, Glover, K, Wang, X, Morris, J, Brown, T, Rashid, A, Dancey, J, and Abbruzzese, JL. "Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma." Cancer 110.5 (September 2007): 1059-1067.
PMID
17623837
Source
epmc
Published In
Cancer
Volume
110
Issue
5
Publish Date
2007
Start Page
1059
End Page
1067
DOI
10.1002/cncr.22886

Patterns of self-reported symptoms in pancreatic cancer patients receiving chemoradiation.

Pancreatic cancer is a lethal disease characterized by multiple disease-related symptoms. Chemoradiation therapy is a standard of treatment for locally advanced pancreatic cancer. Although shown to prolong survival, there is little information about treatment-related symptoms or the palliative benefits of chemoradiation. We assessed symptoms of patients with locally advanced pancreatic cancer receiving chemoradiation to determine the prevalence, and co-occurrence, of symptoms and to identify the extent to which symptoms interfered with function. Forty-eight patients were treated with chemoradiation on a Phase I protocol. Patients received radiotherapy (50.4 Gy in 28 fractions), capecitabine (median dose 825 mg/m(2) twice daily), and bevacizumab (2.5-10 mg/kg). Symptom severity and its interference with function were prospectively assessed (at presentation, during, and after chemoradiation) in 43 consenting patients using the M.D. Anderson Symptom Inventory. Results showed that 95% of patients reported at least one of the 13 symptoms assessed at presentation. The most commonly reported symptoms of moderate to severe (>or=5 on a 0-10 scale) intensity at presentation were lack of appetite (24%), pain (19%), fatigue (19%), and sleep disturbance (10%). We observed an increase in patients reporting moderate to severe fatigue, nausea, and sleep disturbance during chemoradiation. McNemar tests for paired binary observations showed the proportion of patients reporting moderate to severe symptoms significantly (P<0.001) decreased after chemoradiation at 94 days follow-up (lack of appetite=7%, pain=7%, fatigue=13%, sleep disturbance=7%). This study demonstrates the feasibility and usefulness of symptom assessment in chemoradiation protocols. Future studies with larger cohorts are needed to further characterize multiple symptoms associated with chemoradiation.

Authors
Reyes-Gibby, CC; Chan, W; Abbruzzese, JL; Xiong, HQ; Ho, L; Evans, DB; Varadhachary, G; Bhat, S; Wolff, RA; Crane, C
MLA Citation
Reyes-Gibby, CC, Chan, W, Abbruzzese, JL, Xiong, HQ, Ho, L, Evans, DB, Varadhachary, G, Bhat, S, Wolff, RA, and Crane, C. "Patterns of self-reported symptoms in pancreatic cancer patients receiving chemoradiation." Journal of pain and symptom management 34.3 (September 2007): 244-252.
PMID
17513082
Source
epmc
Published In
Journal of Pain and Symptom Management
Volume
34
Issue
3
Publish Date
2007
Start Page
244
End Page
252
DOI
10.1016/j.jpainsymman.2006.11.007

Differences in K-ras and p53 gene mutations among pancreatic adenocarcinomas associated with regional environmental pollution.

BACKGROUND: Variations in genetic mutations in pancreatic carcinoma between different geographical regions have not been studied extensively, especially in developing countries where pancreatic cancer is relatively rare. METHODS: We studied the molecular pathology of 54 pancreatic adenocarcinomas from Egyptian patients residing in a heavily polluted region of the eastern Nile River delta and compared the findings with 45 tumors from patients residing in low-pollution regions. RESULTS: Rates of K-ras mutation in codon 12 and of p53 mutation in exons 5-8 were higher in tumors of patients from the high-pollution region as compared with the low-pollution regions (61.5 versus 34.2%, respectively, for K-ras, P = 0.01; 25.9 versus 11.6%, respectively, for p53, P = 0.08). There were also distinct differences in the specific types of K-ras and p53 mutations between the two regions. The ratio of G-to-T k-ras transversion mutation (codon 12) relative to wild-type was significantly higher in tumors from the high-pollution region (0.90) than tumors from the non-pollution site (0.28) (P = 0.03). Relative to tumors with wild-type, the ratio of p53 mutations in exons 5, 7 or 8 to wild-type in tumors from the high-pollution region was significantly higher than the ratio from the non-pollution site (0.28 versus 0.03, P = 0.01). Logistic regression showed that G-to-T transversion mutation in K-ras was predicted by the region of residence of the patients. CONCLUSIONS: Our study reveals that there are differences in the frequencies and types of K-ras and p53 mutations found in pancreatic adenocarcinomas of patients in high-pollution and low-pollution regions in Egypt and suggests that environmental factors may explain these differences. We speculate that gene-environment interactions in pancreatic carcinogenesis also occur in other populations.

Authors
Soliman, AS; Lo, A-C; Banerjee, M; El-Ghawalby, N; Khaled, HM; Bayoumi, S; Seifeldin, IA; Abdel-Aziz, A; Abbruzzese, JL; Greenson, JK; Hamilton, SR
MLA Citation
Soliman, AS, Lo, A-C, Banerjee, M, El-Ghawalby, N, Khaled, HM, Bayoumi, S, Seifeldin, IA, Abdel-Aziz, A, Abbruzzese, JL, Greenson, JK, and Hamilton, SR. "Differences in K-ras and p53 gene mutations among pancreatic adenocarcinomas associated with regional environmental pollution." Carcinogenesis 28.8 (August 2007): 1794-1799.
PMID
17575320
Source
epmc
Published In
Carcinogenesis
Volume
28
Issue
8
Publish Date
2007
Start Page
1794
End Page
1799
DOI
10.1093/carcin/bgm138

Lifestyle, occupational, and reproductive factors in relation to pancreatic cancer risk.

OBJECTIVES: This study examined the epidemiology of pancreatic cancer in Egypt. METHODS: We obtained detailed information on smoking, occupational, medical, and reproductive histories from 194 pancreatic cancer cases and 194 controls. RESULTS: Compared with not smoking, smoking cigarettes alone or in conjunction with other smoking methods (eg, water pipe, cigar) was associated with an increased risk (odds ratio [OR], 4.5 and 7.8; 95% confidence interval [95% CI], 1.9-10.7 and 3.0-20.6, respectively). Passive smoking was also a significant risk factor (OR, 6.0; 95% CI, 2.4-14.8). The risk of pancreatic cancer was elevated among subjects exposed to pesticides (OR, 2.6; 95% CI, 0.97-7.2). A prior diagnosis of diabetes mellitus for a period of 10 years was associated with higher risk (OR, 5.4; 95% CI, 1.5-19.9). For women, having 7 or more live births and lactating for 144 months or longer were associated with a reduced risk (OR, 0.5 and 0.2; 95% CI, 0.2-1.3 and 0.1-0.9, respectively). No association was found between family history, allergy, or obesity and pancreatic cancer in Egypt. CONCLUSIONS: Multiple tobacco consumption methods, passive smoking, pesticide exposures, and diabetes are associated with an increased risk for pancreatic cancer. Prolonged lactation and increased parity are associated with a reduced risk for pancreatic cancer.

Authors
Lo, A-C; Soliman, AS; El-Ghawalby, N; Abdel-Wahab, M; Fathy, O; Khaled, HM; Omar, S; Hamilton, SR; Greenson, JK; Abbruzzese, JL
MLA Citation
Lo, A-C, Soliman, AS, El-Ghawalby, N, Abdel-Wahab, M, Fathy, O, Khaled, HM, Omar, S, Hamilton, SR, Greenson, JK, and Abbruzzese, JL. "Lifestyle, occupational, and reproductive factors in relation to pancreatic cancer risk." Pancreas 35.2 (August 2007): 120-129.
PMID
17632317
Source
epmc
Published In
Pancreas
Volume
35
Issue
2
Publish Date
2007
Start Page
120
End Page
129
DOI
10.1097/mpa.0b013e318053e7d3

Who should go first in trials with scarce agents? The views of potential participants.

Authors
Pentz, RD; Flamm, AL; Sugarman, J; Cohen, MZ; Xu, Z; Herbst, RS; Abbruzzese, JL
MLA Citation
Pentz, RD, Flamm, AL, Sugarman, J, Cohen, MZ, Xu, Z, Herbst, RS, and Abbruzzese, JL. "Who should go first in trials with scarce agents? The views of potential participants." IRB 29.4 (July 2007): 1-6.
PMID
17847620
Source
epmc
Published In
IRB
Volume
29
Issue
4
Publish Date
2007
Start Page
1
End Page
6

Induction chemotherapy selects patients with locally advanced, unresectable pancreatic cancer for optimal benefit from consolidative chemoradiation therapy.

BACKGROUND: The current study was conducted to determine whether there were differences in outcome for patients with unresectable locally advanced pancreatic cancer (LAPC) who received treatment with chemoradiation therapy (CR) versus induction chemotherapy followed by CR (CCR). METHODS: Between December 1993 and July 2005, 323 consecutive patients with LAPC were treated at the authors' institution with radiotherapy and concurrent gemcitabine or fluoropyrimidine chemotherapy. Two hundred forty-seven patients received CR as initial treatment, and 76 patients received a median of 2.5 months of gemcitabine-based induction chemotherapy prior to CR. Most patients received a radiation dose of 30 grays in 10 fractions (85%) concurrently with infusional 5-fluorouracil (41%), gemcitabine (39%), or capecitabine (20%). RESULTS: The median follow-up was 5.5 months (range, 1-63 months). For all patients, the median overall survival (OS) and progression-free survival (PFS) were 9 months and 5 months, respectively, and the 2-year estimated OS and PFS rates were 9% and 5%, respectively. The median OS and PFS were 8.5 months and 4.2 months, respectively, in the CR group and 11.9 months and 6.4 months, respectively, in the CCR group (both P < .001). The median times to local and distant progression were 6.0 months and 5.6 months, respectively, in the CR group and 8.9 and 9.5 months, respectively, in the CCR group (P = .003 and P = .007, respectively). There was no significant difference in the patterns of failure with the use of induction chemotherapy. CONCLUSIONS: The results from this analysis indicated that, by excluding patients with rapid distant progression, induction chemotherapy may select patients with LAPC for optimal benefit from consolidative CR. The authors believe that this strategy of enriching the population of patients who receive a locoregional treatment modality merits prospective randomized evaluation.

Authors
Krishnan, S; Rana, V; Janjan, NA; Varadhachary, GR; Abbruzzese, JL; Das, P; Delclos, ME; Gould, MS; Evans, DB; Wolff, RA; Crane, CH
MLA Citation
Krishnan, S, Rana, V, Janjan, NA, Varadhachary, GR, Abbruzzese, JL, Das, P, Delclos, ME, Gould, MS, Evans, DB, Wolff, RA, and Crane, CH. "Induction chemotherapy selects patients with locally advanced, unresectable pancreatic cancer for optimal benefit from consolidative chemoradiation therapy." Cancer 110.1 (July 2007): 47-55.
PMID
17538975
Source
epmc
Published In
Cancer
Volume
110
Issue
1
Publish Date
2007
Start Page
47
End Page
55
DOI
10.1002/cncr.22735

Phase I participants' views of quality of life and trial participation burdens.

PURPOSE: Participants' perception of quality of life (QOL) and respondent burden have significant implications for investigators' ethical responsibilities to their subjects in phase I cancer trials. To address these responsibilities, analysis was conducted on participants' views of their experiences of a phase I trial, including the associated burdens and what constitutes QOL. PATIENTS AND METHODS: One hundred potential participants of the endostatin trial were surveyed. Sixteen of the 18 trial participants were interviewed extensively about their experiences on the trial. RESULTS: Participants described 'normality' as a baseline ability to function, be productive, and be free from symptoms of disease and side effects of treatment. Reflecting the relative nontoxicity of the study drug, participants contrasted their current QOL with their negative experience of previous cancer treatments and viewed their QOL as fairly good. However, participants emphasized that indirect and procedural burdens of trial participation had a significant impact on their current QOL. CONCLUSIONS: Candid descriptions of a trial's practical demands, in addition to potential physical complications in a trial, could improve the quality of informed consent.

Authors
Cohen, MZ; Slomka, J; Pentz, RD; Flamm, AL; Gold, D; Herbst, RS; Abbruzzese, JL
MLA Citation
Cohen, MZ, Slomka, J, Pentz, RD, Flamm, AL, Gold, D, Herbst, RS, and Abbruzzese, JL. "Phase I participants' views of quality of life and trial participation burdens." Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer 15.7 (July 2007): 885-890.
PMID
17252219
Source
epmc
Published In
Supportive Care in Cancer
Volume
15
Issue
7
Publish Date
2007
Start Page
885
End Page
890
DOI
10.1007/s00520-007-0216-0

Establishment of three-dimensional cultures of human pancreatic duct epithelial cells.

Three-dimensional (3D) cultures of epithelial cells offer singular advantages for studies of morphogenesis or the role of cancer genes in oncogenesis. In this study, as part of establishing a 3D culture system of pancreatic duct epithelial cells, we compared human pancreatic duct epithelial cells (HPDE-E6E7) with pancreatic cancer cell lines. Our results show, that in contrast to cancer cells, HPDE-E6E7 organized into spheroids with what appeared to be apical and basal membranes and a luminal space. Immunostaining experiments indicated that protein kinase Akt was phosphorylated (Ser473) and CTMP, a negative Akt regulator, was expressed in both HPDE-E6E7 and cancer cells. However, a nuclear pool of CTMP was detectable in HPDE-E6E7 cells that showed a dynamic concentrated expression pattern, a feature that further distinguished HPDE-E637 cells from cancer cells. Collectively, these data suggest that 3D cultures of HPDE-E6E7 cells are useful for investigating signaling and morphological abnormalities in pancreatic cancer cells.

Authors
Gutierrez-Barrera, AM; Menter, DG; Abbruzzese, JL; Reddy, SAG
MLA Citation
Gutierrez-Barrera, AM, Menter, DG, Abbruzzese, JL, and Reddy, SAG. "Establishment of three-dimensional cultures of human pancreatic duct epithelial cells." Biochemical and biophysical research communications 358.3 (July 2007): 698-703.
PMID
17512909
Source
epmc
Published In
Biochemical and Biophysical Research Communications
Volume
358
Issue
3
Publish Date
2007
Start Page
698
End Page
703
DOI
10.1016/j.bbrc.2007.04.166

Targeted expression of BikDD eradicates pancreatic tumors in noninvasive imaging models.

Pancreatic cancer is an aggressive malignancy with morbidity rates almost equal to mortality rates because of the current lack of effective treatment options. Here, we describe a targeted approach to treating pancreatic cancer with effective therapeutic efficacy and safety in noninvasive imaging models. We developed a versatile expression vector "VISA" (VP16-GAL4-WPRE integrated systemic amplifier) and a CCKAR (cholecystokinin type A receptor) gene-based, pancreatic-cancer-specific promoter VISA (CCKAR-VISA) composite to target transgene expression in pancreatic tumors in vivo. Targeted expression of BikDD, a potent proapoptotic gene driven by CCKAR-VISA, exhibited significant antitumor effects on pancreatic cancer and prolonged survival in multiple xenograft and syngeneic orthotopic mouse models of pancreatic tumors with virtually no toxicity.

Authors
Xie, X; Xia, W; Li, Z; Kuo, H-P; Liu, Y; Li, Z; Ding, Q; Zhang, S; Spohn, B; Yang, Y; Wei, Y; Lang, J-Y; Evans, DB; Chiao, PJ; Abbruzzese, JL; Hung, M-C
MLA Citation
Xie, X, Xia, W, Li, Z, Kuo, H-P, Liu, Y, Li, Z, Ding, Q, Zhang, S, Spohn, B, Yang, Y, Wei, Y, Lang, J-Y, Evans, DB, Chiao, PJ, Abbruzzese, JL, and Hung, M-C. "Targeted expression of BikDD eradicates pancreatic tumors in noninvasive imaging models." Cancer cell 12.1 (July 2007): 52-65.
PMID
17613436
Source
epmc
Published In
Cancer Cell
Volume
12
Issue
1
Publish Date
2007
Start Page
52
End Page
65
DOI
10.1016/j.ccr.2007.05.009

Passive smoking and the use of noncigarette tobacco products in association with risk for pancreatic cancer: a case-control study.

The associations between passive smoking and the use of noncigarette tobacco products with pancreatic cancer are not clear.In this case-control study, the authors collected information on passive smoking and the use of noncigarette tobacco products in 808 patients with pancreatic adenocarcinoma and 808 healthy controls by personal interview. Multivariable logistic regression was performed to estimate the adjusted odds ratio (AOR) and 95% confidence interval (95% CI).The results confirmed the previously reported association between active smoking and increased risk for pancreatic cancer. The AOR was 1.7 (95% CI, 1.4-2.2) for regular smokers, 1.8 (95% CI, 1.4-2.4) for long-term smokers, and 3.1 (95% CI, 2.2-4.3) for former smokers. Although passive smoking showed a nonsignificantly elevated risk for pancreatic cancer in the entire study population (AOR, 1.3; 95% CI, 0.9-1.7), the association was present among ever smokers (AOR, 1.7; 95% CI, 1.03-2.6) but was absent among never smokers (AOR, 1.1; 95% CI, 0.8-1.6). Neither intensity nor duration of passive smoking modified the risk of pancreatic cancer among never smokers. The use of chewing tobacco, snuff, and pipes showed no significant risk elevation for pancreatic cancer after controlling for the confounding effects of demographics and other known risk factors. The use of cigars in never smokers showed a borderline significant increase of risk for pancreatic cancer (AOR, 2.2; 95% CI, 1.0-4.7; P = .05).The current observations did not support a role for passive smoking or the use of noncigarette tobacco products in the etiology of pancreatic cancer. The association between cigar use and the risk of pancreatic cancer needs to be confirmed in other study populations.

Authors
Hassan, MM; Abbruzzese, JL; Bondy, ML; Wolff, RA; Vauthey, J-N; Pisters, PW; Evans, DB; Khan, R; Lenzi, R; Jiao, L; Li, D
MLA Citation
Hassan, MM, Abbruzzese, JL, Bondy, ML, Wolff, RA, Vauthey, J-N, Pisters, PW, Evans, DB, Khan, R, Lenzi, R, Jiao, L, and Li, D. "Passive smoking and the use of noncigarette tobacco products in association with risk for pancreatic cancer: a case-control study." Cancer 109.12 (June 2007): 2547-2556.
PMID
17492688
Source
epmc
Published In
Cancer
Volume
109
Issue
12
Publish Date
2007
Start Page
2547
End Page
2556
DOI
10.1002/cncr.22724

Mechanisms of synthetic serine protease inhibitor (FUT-175)-mediated cell death.

BACKGROUND: Constitutive activation of nuclear factor-kappaB (NF-kappaB) is a frequent molecular alteration in pancreatic cancer and a number of studies have suggested that constitutive NF-kappaB activity plays a key role in the aggressive behavior of this disease. In an attempt to identify an effective therapeutic agent for pancreatic cancer, the authors studied the role of FUT-175, a synthetic serine protease inhibitor, in the inhibition of NF-kappaB activation and the induction of apoptotic responses. METHODS: To examine the effect of FUT-175 on the inhibition of NF-kappaB and the induction of apoptosis in pancreatic cancer cell lines, Western and Northern blot analyses, electromobility shift (EMSA), luciferase reporter gene, DNA fragmentation, immunoprecipitation, in vitro kinase, small interfering RNA (siRNA), and chromatin immunoprecipitation (ChIP) assays were performed. RESULTS: In a time-dependent and dose-dependent manner, FUT-175 inhibited IkappaBalpha phosphorylation and NF-kappaB activation, thereby inhibiting the antiapoptotic activity of NF-kappaB. Simultaneously, FUT-175 up-regulated the expression of tumor necrosis factor receptor-1 (TNFR1), which in turn activated the proapoptotic caspase-8 and Bid pathways and induced apoptosis in pancreatic cancer cells. FUT-175-induced activation of Fas-associated death domain (FADD) and caspase-8 was suppressed by RNA interference-mediated inhibition of TNFR1 expression. Furthermore, expression of the transcription factor PEA3 was up-regulated by FUT-175 and was involved in FUT-175-mediated TNFR1 expression. CONCLUSIONS: These results suggested a possible mechanism by which FUT-175 may disrupt interconnected signaling pathways by both suppressing the NF-kappaB antiapoptotic activity and inducing TNFR-mediated apoptosis. Supported by this unique function as a NF-kappaB inhibitor and apoptosis inducer, this well-established synthetic serine protease inhibitor with as-of-yet poorly understood mechanisms of actions appears to be a potentially therapeutic agent for pancreatic cancer.

Authors
Uwagawa, T; Li, Z; Chang, Z; Xia, Q; Peng, B; Sclabas, GM; Ishiyama, S; Hung, M-C; Evans, DB; Abbruzzese, JL; Chiao, PJ
MLA Citation
Uwagawa, T, Li, Z, Chang, Z, Xia, Q, Peng, B, Sclabas, GM, Ishiyama, S, Hung, M-C, Evans, DB, Abbruzzese, JL, and Chiao, PJ. "Mechanisms of synthetic serine protease inhibitor (FUT-175)-mediated cell death." Cancer 109.10 (May 2007): 2142-2153.
PMID
17410536
Source
epmc
Published In
Cancer
Volume
109
Issue
10
Publish Date
2007
Start Page
2142
End Page
2153
DOI
10.1002/cncr.22658

Prognostic significance of maspin in pancreatic ductal adenocarcinoma: tissue microarray analysis of 223 surgically resected cases.

Maspin (SERPINB5), a serine proteinase inhibitor, was first identified as a potential tumor suppressor on the basis of its differential expression between normal mammary epithelial cells and human breast carcinoma cell lines. Recent studies have shown that maspin might be a prognostic tumor marker. Pancreatic ductal adenocarcinoma acquires maspin expression through hypomethylation of the maspin promoter. However, no study has investigated the prognostic significance of maspin expression in pancreatic ductal adenocarcinomas. In this study, we investigated maspin protein expression in a large series of 223 surgically resected pancreatic ductal adenocarcinomas using immunohistochemical staining and high throughput tissue microarrays. Maspin expression was correlated with postoperative survival and other clinicopathologic factors. Maspin was detected in 209 of these 223 (94% cases) pancreatic ductal adenocarcinomas including 39 (18% cases) focal (5-50% tumor cells) and 170 (76% cases) diffuse (>50% tumor cells). Fourteen (or 6% cases) pancreatic ductal adenocarcinomas did not show maspin expression by immunohistochemical staining (<5% tumor cells). Normal ductal epithelium is not labeled with maspin. Overexpression of maspin in pancreatic ductal adenocarcinoma is associated with worse postoperative survival especially in patients whose tumors exhibit diffuse expression of maspin. After adjusting other clinicopathologic factors, maspin expression remains to be an independent adverse prognosticator for postoperative survival. Maspin expression is not associated with patient age, gender, tumor size, tumor pathologic stage, lymph node status, and vascular invasion or perineural invasion. Nuclear labeling of maspin is associated with better tumor differentiation although this staining pattern is not associated with a better prognosis. In addition, maspin overexpression is also observed in 48% low-grade (grades 1a and 1b) pancreatic intraepithelial neoplasias (PanINs) and 78% high-grade (grades 2 and 3) PanINs, suggesting that maspin upregulation occurs early during the multi-step progression model of pancreatic ductal adenocarcinoma.

Authors
Cao, D; Zhang, Q; Wu, LS-F; Salaria, SN; Winter, JW; Hruban, RH; Goggins, MS; Abbruzzese, JL; Maitra, A; Ho, L
MLA Citation
Cao, D, Zhang, Q, Wu, LS-F, Salaria, SN, Winter, JW, Hruban, RH, Goggins, MS, Abbruzzese, JL, Maitra, A, and Ho, L. "Prognostic significance of maspin in pancreatic ductal adenocarcinoma: tissue microarray analysis of 223 surgically resected cases." Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 20.5 (May 2007): 570-578.
PMID
17396143
Source
epmc
Published In
Modern Pathology
Volume
20
Issue
5
Publish Date
2007
Start Page
570
End Page
578
DOI
10.1038/modpathol.3800772

HLA-A0201 positive pancreatic cell lines: new findings and discrepancies.

Pancreatic cancer is being pursued as an immunotherapy target using antigen-specific vaccine approaches activating CD8(+) CTL and CD4(+) T-helper cells. CD8(+) CTL exert their anti-tumor effects in an HLA-restricted manner and only tumor cells carrying a matched HLA class I sub-type are targets for antigen-specific CTL. In the process of characterizing CD8(+) T cell responses against pancreatic cancer, we screened a number of human pancreatic tumor cell lines for HLA-A0201 positive (HLA-A2(+)) cell lines to be used in the evaluation of CTL function. This analysis revealed some new findings and discrepancies in the literature on the HLA sub-type of some commonly used pancreatic cell lines. We found that Capan-1 cells, originally reported to be HLA-A0201(+), actually only express HLA-A010101 and HLA-A300101 and were targets for HLA-A0201-restricted CTL only after transduction with an HLA-A0201-expressing lentivirus. Panc-1 cells were found to be HLA-A0201 positive, in agreement with published reports, while CF-Pac-1 cells were found to express both HLA-A020101 and HLA-A030101. We also found a normal human pancreatic ductal epithelial cell line, HPDE, to be HLA-A0201 positive. Our findings were verified with two different sequence-based typing methods, antibody staining followed by flow cytometry analysis, and functional analysis using an HLA-A0201-restricted peptide-specific T cell response.

Authors
Zhu, K; Lizee, G; Cano, P; Fernando-Vina, M; Ji, B; Abbruzzese, JL; Hwu, P; Radvanyi, L; Chang, DZ
MLA Citation
Zhu, K, Lizee, G, Cano, P, Fernando-Vina, M, Ji, B, Abbruzzese, JL, Hwu, P, Radvanyi, L, and Chang, DZ. "HLA-A0201 positive pancreatic cell lines: new findings and discrepancies." Cancer immunology, immunotherapy : CII 56.5 (May 2007): 719-724.
PMID
16947023
Source
epmc
Published In
Cancer Immunology, Immunotherapy
Volume
56
Issue
5
Publish Date
2007
Start Page
719
End Page
724
DOI
10.1007/s00262-006-0217-8

Aurora-A and p16 polymorphisms contribute to an earlier age at diagnosis of pancreatic cancer in Caucasians.

Aurora-A and p16 play a major role in cell cycle checkpoint regulation. Both of them are important in the maintenance of centrosome duplication. Therefore, we hypothesized that polymorphisms in the two genes may interact or work together to influence the finely tuned mechanisms of cell cycle regulation that these proteins regulate. The purpose of this study was to investigate the association of the Aurora-A (T91A), and p16 (C540G and C580T) polymorphisms with age at diagnosis of pancreatic cancer.We genotyped 148 Caucasian patients with a diagnosis of pancreatic cancer for the Aurora-A and p16 polymorphisms using pyrosequencing. We tested the association between age at diagnosis and the Aurora-A and p16 genotypes by comparing Kaplan-Meier curves, evaluating the homogeneity of the curves using the log-rank test. We used Cox proportional hazard regression analysis to estimate the association between time to diagnosis and genotype, adjusting for gender.Patients with the Aurora-A polymorphic genotypes had a median age at diagnosis with pancreatic cancer that was 2.8 years earlier than those with the wild-type genotype [log-rank, P=0.015; hazard ratio (HR), 1.55; 95% confidence intervals (95% CI), 1.09-2.20]. There was no significant association between the p16 genotypes and age at diagnosis. However, the Aurora-A and p16 C580T polymorphisms combined had a synergistic effect on age-associated risk for early diagnosis of pancreatic cancer. Compared with patients with wild-type genotypes for both genes, the median age at diagnosis for patients with one or two polymorphic alleles for both genes was 12.6 years earlier (log-rank, P=0.0002; HR, 3.88; 95% CI, 1.94-7.76). No significant associations between the polymorphisms and the cancer metastatic status or survival after diagnosis were found.Our findings suggest that the Aurora-A polymorphism contributes to a significantly earlier age at diagnosis of pancreatic cancer, and that Aurora-A and p16 C580T polymorphisms synergistically contribute to an earlier age at diagnosis of pancreatic cancer.

Authors
Chen, J; Li, D; Wei, C; Sen, S; Killary, AM; Amos, CI; Evans, DB; Abbruzzese, JL; Frazier, ML
MLA Citation
Chen, J, Li, D, Wei, C, Sen, S, Killary, AM, Amos, CI, Evans, DB, Abbruzzese, JL, and Frazier, ML. "Aurora-A and p16 polymorphisms contribute to an earlier age at diagnosis of pancreatic cancer in Caucasians." Clinical cancer research : an official journal of the American Association for Cancer Research 13.10 (May 2007): 3100-3104.
PMID
17505013
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
13
Issue
10
Publish Date
2007
Start Page
3100
End Page
3104
DOI
10.1158/1078-0432.ccr-06-2319

Regulation of vascular endothelial growth factor receptor-1 expression by specificity proteins 1, 3, and 4 in pancreatic cancer cells.

Vascular endothelial growth factor receptor-1 (VEGFR1) is expressed in cancer cell lines and tumors and, in pancreatic and colon cancer cells, activation of VEGFR1 is linked to increased tumor migration and invasiveness. Tolfenamic acid, a nonsteroidal anti-inflammatory drug, decreases Sp protein expression in Panc-1 and L3.6pl pancreatic cancer cells, and this was accompanied by decreased VEGFR1 protein and mRNA and decreased luciferase activity on cells transfected with constructs (pVEGFR1) containing VEGFR1 promoter inserts. Comparable results were obtained in pancreatic cancer cells transfected with small inhibitory RNAs for Sp1, Sp3, and Sp4 and all three proteins bound to GC-rich elements in the VEGFR1 promoter. These results show that VEGFR1 is regulated by Sp proteins and that treatment with tolfenamic acid decreases expression of this critical angiogenic factor. Moreover, in vitro studies in Panc-1 cells show that activation of VEGFR1 by VEGFB to increase mitogen-activated protein kinase 1/2 phosphorylation and cell migration on collagen-coated plates is also inhibited by tolfenamic acid. Thus, targeted degradation of Sp proteins is highly effective for inhibiting VEGFR1 and associated angiogenic responses in pancreatic cancer.

Authors
Abdelrahim, M; Baker, CH; Abbruzzese, JL; Sheikh-Hamad, D; Liu, S; Cho, SD; Yoon, K; Safe, S
MLA Citation
Abdelrahim, M, Baker, CH, Abbruzzese, JL, Sheikh-Hamad, D, Liu, S, Cho, SD, Yoon, K, and Safe, S. "Regulation of vascular endothelial growth factor receptor-1 expression by specificity proteins 1, 3, and 4 in pancreatic cancer cells." Cancer research 67.7 (April 2007): 3286-3294.
PMID
17409437
Source
epmc
Published In
Cancer Research
Volume
67
Issue
7
Publish Date
2007
Start Page
3286
End Page
3294
DOI
10.1158/0008-5472.can-06-3831

Effects of base excision repair gene polymorphisms on pancreatic cancer survival.

To explore the association between single nucleotide polymorphisms of DNA repair genes and overall survival of patients with pancreatic cancer, we conducted a study in 378 cases of pancreatic adenocarcinoma who were treated at The University of Texas M. D. Anderson Cancer Center between February 1999 and October 2004 and were followed up to April 2006. Genotypes were determined using genomic DNA and the MassCode method. Overall survival was analyzed using the Kaplan-Meier plot, log-rank test and Cox regression. We observed a strong effect of the POLB A165G and T2133C genotypes on overall survival. The median survival time (MST) was 35.7 months for patients carrying at least 1 of the 2 homozygous variant POLB GG or CC genotypes, compared with 14.8 months for those carrying the AA/AG or TT/TC genotypes (p = 0.02, log rank test). The homozygous variants of hOGG1 G2657A, APEX1 D148E and XRCC1 R194W polymorphisms all showed a weak but significant effect on overall survival as demonstrated by either log rank test or multivariate COX regression after adjusting for other potential confounders. In combined genotype analysis, a predominant effect of the POLB homozygous variants on survival was observed. When POLB was not included in the model, a slightly better survival was observed among those carrying none of the adverse genotypes than those carrying at least one of the adverse genotypes. These observations suggest that polymorphisms of base excision repair genes significantly affect the clinical outcome of patients with pancreatic cancer. These observations need to be confirmed in a larger study of homogenous patient population.

Authors
Li, D; Li, Y; Jiao, L; Chang, DZ; Beinart, G; Wolff, RA; Evans, DB; Hassan, MM; Abbruzzese, JL
MLA Citation
Li, D, Li, Y, Jiao, L, Chang, DZ, Beinart, G, Wolff, RA, Evans, DB, Hassan, MM, and Abbruzzese, JL. "Effects of base excision repair gene polymorphisms on pancreatic cancer survival." International journal of cancer 120.8 (April 2007): 1748-1754.
PMID
17230526
Source
epmc
Published In
International Journal of Cancer
Volume
120
Issue
8
Publish Date
2007
Start Page
1748
End Page
1754
DOI
10.1002/ijc.22301

Dietary mutagen exposure and risk of pancreatic cancer.

To investigate the association between dietary exposure to food mutagens and risk of pancreatic cancer, we conducted a hospital-based case-control study at the University of Texas M. D. Anderson Cancer Center during June 2002 to May 2006. A total of 626 cases and 530 noncancer controls were frequency matched for race, sex and age (+/-5 years). Dietary exposure information was collected via personal interview using a meat preparation questionnaire. A significantly greater portion of the cases than controls showed a preference to well-done pork, bacon, grilled chicken, and pan-fried chicken, but not to hamburger and steak. Cases had a higher daily intake of food mutagens and mutagenicity activity (revertants per gram of daily meat intake) than controls did. The daily intakes of 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx) and benzo(a)pyrene (BaP), as well as the mutagenic activity, were significant predictors for pancreatic cancer (P = 0.008, 0.031, and 0.029, respectively) with adjustment of other confounders. A significant trend of elevated cancer risk with increasing DiMeIQx intake was observed in quintile analysis (P(trend) = 0.024). A higher intake of dietary mutagens (those in the two top quintiles) was associated with a 2-fold increased risk of pancreatic cancer among those without a family history of cancer but not among those with a family history of cancer. A possible synergistic effect of dietary mutagen exposure and smoking was observed among individuals with the highest level of exposure (top 10%) to PhIP and BaP, P(interaction) = 0.09 and 0.099, respectively. These data support the hypothesis that dietary mutagen exposure alone and in interaction with other factors contribute to the development of pancreatic cancer.

Authors
Li, D; Day, RS; Bondy, ML; Sinha, R; Nguyen, NT; Evans, DB; Abbruzzese, JL; Hassan, MM
MLA Citation
Li, D, Day, RS, Bondy, ML, Sinha, R, Nguyen, NT, Evans, DB, Abbruzzese, JL, and Hassan, MM. "Dietary mutagen exposure and risk of pancreatic cancer." Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 16.4 (April 2007): 655-661.
PMID
17416754
Source
epmc
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
16
Issue
4
Publish Date
2007
Start Page
655
End Page
661
DOI
10.1158/1055-9965.epi-06-0993

Polymorphisms of phase II xenobiotic-metabolizing and DNA repair genes and in vitro N-ethyl-N-nitrosourea-induced O6-ethylguanine levels in human lymphocytes.

This study tested the hypothesis that genetic variants of phase II detoxification enzymes and DNA repair proteins affect individual response to DNA damage from alkylating agents. In 171 healthy individuals, an immunoslot blot assay was used to measure O6-ethylguanosine (O6-EtGua) adduct levels in peripheral blood lymphocytes treated with N-ethyl-N-nitrosourea (ENU) in vitro. The genotypes of GSTM1, GSTT1, GSTP1 I(105)V and A(114)V, MGMT L(84)F and I(143)V, XPD D(312)N and K(751)Q, and XRCC3 T(241)M were determined. Demographic and exposure information was collected by in-person interview. Student's t-test, analysis of (co)variance, and multiple linear regression models were used in statistical analyses. The mean and median (range) O6-EtGua levels were 94.6 and 84.8 (3.2-508.1)fmol/g DNA, respectively. The adduct level was significantly lower in people who smoked >or=25 years than that in never-smokers (square-root transformed mean values 8.20 versus 9.37, P=0.03). Multiple linear regression models revealed that GSTT1 (beta=-2.36, P=0.009) polymorphism was a significant predictor of the level of adducts in 82 never-smokers, whereas the number of years smoked (beta=-0.08, P=0.005) and XRCC3 T(241)M (beta=2.22, P=0.007) in 89 ever-smokers. The association between GSTP1 I(105)V, MGMT I(143)V, and XPD D(312)N with the level of adducts was not conclusive. Each polymorphism could explain 2-10% of the variation of the adduct level. These observations suggest that GSTT1 null and XRCC3 T(241)M polymorphism may have some functional significance in modulating the level of ENU-induced DNA damage and these effects are smoking-dependent. Results from this exploratory study need to be confirmed in other experimental systems.

Authors
Jiao, L; Chang, P; Firozi, PF; Lai, D; Abbruzzese, JL; Li, D
MLA Citation
Jiao, L, Chang, P, Firozi, PF, Lai, D, Abbruzzese, JL, and Li, D. "Polymorphisms of phase II xenobiotic-metabolizing and DNA repair genes and in vitro N-ethyl-N-nitrosourea-induced O6-ethylguanine levels in human lymphocytes." Mutation research 627.2 (March 2007): 146-157.
PMID
17158087
Source
epmc
Published In
Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
Volume
627
Issue
2
Publish Date
2007
Start Page
146
End Page
157
DOI
10.1016/j.mrgentox.2006.11.001

Delayed recovery after pancreaticoduodenectomy: a major factor impairing the delivery of adjuvant therapy?

BACKGROUND: Delayed recovery after pancreaticoduodenectomy (PD) is believed to preclude adjuvant therapy for approximately 30% of patients who undergo elective PD as initial treatment for pancreatic adenocarcinoma. This study reexamined the frequency of delayed recovery and assessed other factors associated with adjuvant therapy administration after PD at a high-volume center. STUDY DESIGN: Preoperative and perioperative variables were reviewed in a consecutive series of 85 patients with pancreatic adenocarcinoma undergoing PD without preoperative chemotherapy or radiotherapy from 1990 to 2004. RESULTS: Study groups included patients undergoing emergency PD (group 1, n=13); elective PD with good preoperative Eastern Cooperative Oncology Group (ECOG) performance status (PS) (group 2, ECOG PS: 0 to 1, n=63); and elective PD with marginal preoperative PS (group 3, ECOG PS: 2 to 3, n=9). Delayed recovery of PS precluded adjuvant therapy in 23% of patients in group 1, 6% of patients in group 2, and 44% of patients in group 3 (p=0.0001). CONCLUSIONS: The impact of delayed recovery after PD on the delivery of adjuvant therapy depends on the urgency of surgery and the preoperative PS. For patients with good preoperative PS who undergo elective PD at a high-volume center, it is uncommon for delayed recovery to preclude delivery of adjuvant therapy.

Authors
Aloia, TA; Lee, JE; Vauthey, J-N; Abdalla, EK; Wolff, RA; Varadhachary, GR; Abbruzzese, JL; Crane, CH; Evans, DB; Pisters, PWT
MLA Citation
Aloia, TA, Lee, JE, Vauthey, J-N, Abdalla, EK, Wolff, RA, Varadhachary, GR, Abbruzzese, JL, Crane, CH, Evans, DB, and Pisters, PWT. "Delayed recovery after pancreaticoduodenectomy: a major factor impairing the delivery of adjuvant therapy?." Journal of the American College of Surgeons 204.3 (March 2007): 347-355.
PMID
17324767
Source
epmc
Published In
Journal of The American College of Surgeons
Volume
204
Issue
3
Publish Date
2007
Start Page
347
End Page
355
DOI
10.1016/j.jamcollsurg.2006.12.011

Glutathione S-transferase gene polymorphisms and risk and survival of pancreatic cancer.

Pancreatic cancer is a multifactorial disease with metastasis-prone and therapy-resistant nature. The authors hypothesized that genetic variants of glutathione S-transferase (GST) affect detoxification of carcinogens and anticancer agents in the human pancreas and, thus, the risk and survival of pancreatic cancer.Genotypes of GSTM1, GSTT1, and GSTP1 were determined in 352 patients with pancreatic ductal adenocarcinoma and in a control group of 315 healthy, non-Hispanic whites (frequency-matched by age and sex). Survival analysis was performed in a subset of 290 patients. Epidemiological and clinical information was obtained. A multiple unconditional logistic regression model, a Cox proportional hazards model, and log-rank tests were used for statistical analysis.No significant main effects of any of 3 GST genes on the risk of pancreatic cancer were observed. Subgroup analysis showed that older individuals (aged >or=62 years) who carried the GSTP1*C ((105)Val-(114)Val) containing genotype tended to have a reduced risk compared with younger individuals who carried the non-*C genotype (for sex and pack-years of smoking, the adjusted odd ratio was 0.54; 95% confidence interval [95% CI], 0.29-1.02). In a survival analysis of 138 patients who received 5-flurorouracil, patients who carried the GSTP1*C containing genotype had a significantly longer survival than patients who carried the non-*C genotype (multivariate hazard ratio, 0.45; 95% CI, 0.22-0.94).The GSTP1*C variant conferred a possible protective effect against pancreatic cancer in older individuals and a significant survival advantage in patients who received 5-florouracil. The current findings must be confirmed before further inferences can be made.

Authors
Jiao, L; Bondy, ML; Hassan, MM; Chang, DZ; Abbruzzese, JL; Evans, DB; Smolensky, MH; Li, D
MLA Citation
Jiao, L, Bondy, ML, Hassan, MM, Chang, DZ, Abbruzzese, JL, Evans, DB, Smolensky, MH, and Li, D. "Glutathione S-transferase gene polymorphisms and risk and survival of pancreatic cancer." Cancer 109.5 (March 2007): 840-848.
PMID
17265526
Source
epmc
Published In
Cancer
Volume
109
Issue
5
Publish Date
2007
Start Page
840
End Page
848
DOI
10.1002/cncr.22468

In vitro and in vivo molecular evidence of genistein action in augmenting the efficacy of cisplatin in pancreatic cancer.

We recently reported the potential of genistein in augmenting gemcitabine-induced killing of pancreatic cancer (Banerjee, S. et al., Cancer Research 2005;65:9064-72). Since cis-diaminedichloroplatinum (II) (cisplatin) is widely used against solid tumors, we further investigated whether genistein pretreatment could be used as a novel strategy for cisplatin-induced killing of pancreatic cancer cells in vitro and enhanced antitumor activity in vivo. Our in vitro results showed that pretreatment of cells with genistein followed by cisplatin resulted in significant loss of cell viability and potentiated apoptosis irrespective of the metastatic ability of cells. Mechanistically, genistein augmented cisplatin induced killing by down regulating transcription factor-NF-kappaB and anti-apoptotic Akt expression. NF-kappaB was found upregulated when pancreatic cancer cells were exposed to cisplatin, suggesting the potential mechanism of acquired chemo-resistance. In addition, we also showed, for the first time, that genistein in combination with cisplatin is more effective antitumor agent in our orthotopic tumor model. But most importantly, our data also showed that a specific target, such as NF-kappaB, was inactivated in animal tumors treated with genistein and cisplatin. Immunohistochemical data showed reduced staining for phospho-p65, Bcl-xL and MMP-9 in treated tumors compared to control tumors, but the lowest activity was seen in the combination group. These results provide strong molecular in vivo evidence in support of our hypothesis that inactivation of the NF-kappaB signaling pathway by genistein results in the chemo-sensitization of pancreatic tumors to cisplatin, which is likely to be an important and novel strategy for the treatment of pancreatic cancer.

Authors
Banerjee, S; Zhang, Y; Wang, Z; Che, M; Chiao, PJ; Abbruzzese, JL; Sarkar, FH
MLA Citation
Banerjee, S, Zhang, Y, Wang, Z, Che, M, Chiao, PJ, Abbruzzese, JL, and Sarkar, FH. "In vitro and in vivo molecular evidence of genistein action in augmenting the efficacy of cisplatin in pancreatic cancer." International journal of cancer 120.4 (February 2007): 906-917.
PMID
17131310
Source
epmc
Published In
International Journal of Cancer
Volume
120
Issue
4
Publish Date
2007
Start Page
906
End Page
917
DOI
10.1002/ijc.22332

Clinical and in vitro studies of imatinib in advanced carcinoid tumors.

PURPOSE: Effective systemic therapy options for carcinoid tumors are lacking. We conducted in vitro studies and a phase II clinical trial to explore the activity of imatinib in carcinoid tumors. EXPERIMENTAL DESIGN: Cells of the human bronchial carcinoid cell line NCI-H727 and the human pancreatic carcinoid cell line BON-1 were treated with increasing concentrations of imatinib using standard procedures to assess in vitro growth-inhibitory activity. A clinical trial using a two-stage phase II design to assess the response rate and safety profile of imatinib at a dose of 400 mg given twice daily in patients with advanced carcinoid tumors was completed. RESULTS: In both cell lines, there was a dose- and time-dependent cytotoxic effect. The clinical trial enrolled 27 evaluable patients. Median duration on trial was 16 weeks. One patient had a partial response, 17 had stable disease, and 9 had progressive disease by the Response Evaluation Criteria in Solid Tumors criteria. Median progression-free survival time was 24 weeks. Median overall survival is 36 months. Seven patients who achieved a biochemical response had a superior progression-free survival time compared with patients without biochemical response (115 weeks compared with 24 weeks; P = 0.003). An increase in plasma basic fibroblast growth factor was associated with a shorter progression-free survival duration (P = 0.02). CONCLUSIONS: Our data suggest that imatinib is active in vitro and has a modest clinical activity in carcinoid patients. Changes in tumor markers may help select patients who are likely to benefit from therapy.

Authors
Yao, JC; Zhang, JX; Rashid, A; Yeung, S-CJ; Szklaruk, J; Hess, K; Xie, K; Ellis, L; Abbruzzese, JL; Ajani, JA
MLA Citation
Yao, JC, Zhang, JX, Rashid, A, Yeung, S-CJ, Szklaruk, J, Hess, K, Xie, K, Ellis, L, Abbruzzese, JL, and Ajani, JA. "Clinical and in vitro studies of imatinib in advanced carcinoid tumors." Clinical cancer research : an official journal of the American Association for Cancer Research 13.1 (January 2007): 234-240.
PMID
17200360
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
13
Issue
1
Publish Date
2007
Start Page
234
End Page
240
DOI
10.1158/1078-0432.ccr-06-1618

K-ras mutation and p16 and preproenkephalin promoter hypermethylation in plasma DNA of pancreatic cancer patients: in relation to cigarette smoking.

To examine the profiles of K-ras mutations and p16 and preproenkephalin (ppENK) promoter hypermethylation and their associations with cigarette smoking in pancreatic cancer patients.In plasma DNA of 83 patients with untreated primary pancreatic ductal adenocarcinoma, DNA hypermethylation was determined by methylation-specific polymerase chain reaction and K-ras codon 12 mutations by enriched-nested polymerase chain reaction followed by direct sequencing. Information on smoking exposure was collected by in-person interview. Pearson chi test and Fisher exact test were used in statistical analysis.K-ras mutations, ppENK, and p16 promoter hypermethylation were detected in 32.5%, 29.3%, and 24.6% of the patients, respectively. Sixty-three percent (52/83) of patients exhibited at least one of the alterations. Smoking was associated with the presence of K-ras mutations (P = 0.003). A codon 12 G-to-A mutation was predominantly observed in regular smokers and in heavy smokers (pack-year of smoking > or =36). Smoking was not associated with p16 or ppENK hypermethylation.These preliminary observations suggest that plasma DNA might be a useful surrogate in detecting genetic and epigenetic alterations of pancreatic cancer. The findings on the association between K-ras mutation and smoking were in consistency with previous studies. Further studies on environmental modulators of epigenetic changes in pancreatic cancer are warranted.

Authors
Jiao, L; Zhu, J; Hassan, MM; Evans, DB; Abbruzzese, JL; Li, D
MLA Citation
Jiao, L, Zhu, J, Hassan, MM, Evans, DB, Abbruzzese, JL, and Li, D. "K-ras mutation and p16 and preproenkephalin promoter hypermethylation in plasma DNA of pancreatic cancer patients: in relation to cigarette smoking." Pancreas 34.1 (January 2007): 55-62.
PMID
17198183
Source
epmc
Published In
Pancreas
Volume
34
Issue
1
Publish Date
2007
Start Page
55
End Page
62
DOI
10.1097/01.mpa.0000246665.68869.d4

The XPD Asp312Asn and Lys751Gln polymorphisms, corresponding haplotype, and pancreatic cancer risk.

We evaluated the association between the XPD exon 10 Asp(312)Asn and exon 23 Lys(751)Gln polymorphisms and the risk of pancreatic cancer in a hospital-based study of 344 patients and 386 controls frequency matched by age, gender, and race. Stratified analyses showed ever smokers carrying the Asn(312)Asn genotype had a significantly reduced risk when compared with those carrying the (312)Asp allele (OR=0.46, 95% confidence interval 0.24-0.88) (P for interaction=0.03). The (312)Asp-(751)Gln was identified as the putative at risk haplotype. Our study shows that the XPD gene polymorphism could be a genetic risk modifier for smoking-related pancreatic cancer.

Authors
Jiao, L; Hassan, MM; Bondy, ML; Abbruzzese, JL; Evans, DB; Li, D
MLA Citation
Jiao, L, Hassan, MM, Bondy, ML, Abbruzzese, JL, Evans, DB, and Li, D. "The XPD Asp312Asn and Lys751Gln polymorphisms, corresponding haplotype, and pancreatic cancer risk." Cancer letters 245.1-2 (January 2007): 61-68.
PMID
16458430
Source
epmc
Published In
Cancer Letters
Volume
245
Issue
1-2
Publish Date
2007
Start Page
61
End Page
68
DOI
10.1016/j.canlet.2005.12.026

Prognostic factors in patients with unresectable locally advanced pancreatic adenocarcinoma treated with chemoradiation.

BACKGROUND: Although patients with locally advanced pancreatic cancer (LAPC) have an extremely poor prognosis, they are a heterogeneous group. Prognostic factors are inadequately defined for disease-free survival and overall survival in patients with LAPC who are receiving chemoradiation, so more definitive prognostic factors would be very useful for designing clinical trials. METHODS: Between December 1993 and July 2005, 247 patients with nonmetastatic LAPC were treated at M. D. Anderson Cancer Center (Houston, Tex) with concurrent chemoradiation (CRT). Median radiation dose was 30 Gy (range, 15-52.2 Gy). Radiosensitizers included 5-fluorouracil (54%), gemcitabine (33%), and capecitabine (13%). Actuarial univariate and multivariate statistical methods were used to determine significant prognostic factors for disease-free survival and overall survival. RESULTS: Median follow-up was 4.3 months (range, 1-63 months). Median disease-free survival and overall survival were 4.2 months and 8.5 months, respectively. On univariate analysis, prognostic factors for improved disease-free survival were a Karnofsky performance scale (KPS) status of >80 (P < .01) and a hemoglobin (Hgb)level at presentation of >/=12 (P = .03). On multivariate analysis, KPS was the only independent prognostic factor for disease-free survival. Median disease-free survival was 4.9 months among patients with a KPS score of >80 and was 3.9 months among those with a KPS score of /=12 (P = .02), KPS>80 (P < .001), and <5% weight loss (P = .03). On multivariate analysis, Hgb and KPS were independent prognostic factors for overall survival. CONCLUSIONS: In the current study, KPS score was an independent prognostic factor for disease-free and overall survival among patients treated with chemoradiation for LAPC. The pretreatment Hgb level was an additional independent prognostic factor for overall survival.

Authors
Krishnan, S; Rana, V; Janjan, NA; Abbruzzese, JL; Gould, MS; Das, P; Delclos, ME; Palla, S; Guha, S; Varadhachary, G; Evans, DB; Wolff, RA; Crane, CH
MLA Citation
Krishnan, S, Rana, V, Janjan, NA, Abbruzzese, JL, Gould, MS, Das, P, Delclos, ME, Palla, S, Guha, S, Varadhachary, G, Evans, DB, Wolff, RA, and Crane, CH. "Prognostic factors in patients with unresectable locally advanced pancreatic adenocarcinoma treated with chemoradiation." Cancer 107.11 (December 2006): 2589-2596.
PMID
17083124
Source
epmc
Published In
Cancer
Volume
107
Issue
11
Publish Date
2006
Start Page
2589
End Page
2596
DOI
10.1002/cncr.22328

Phase II trial of PN401, 5-FU, and leucovorin in unresectable or metastatic adenocarcinoma of the stomach: a Southwest Oncology Group study.

From February, 2001 to September, 2002, the Southwest Oncology Group (SWOG) accrued 65 patients with advanced gastric adenocarcinoma to a phase II trial of weekly 5-FU, leucovorin, and the orally-administered uridine analog PN401. Of these 65 patients, 57 were assessable for survival and toxicity, which were the endpoints for the study. Treatment consisted of the administration of 1200 mg/m(2) of 5-FU, 500 mg/m(2) of leucovorin, and 6 grams of PN401 every 8 h, beginning 8 h after the completion of the 5-FU infusion, and continuing for a total of 8 doses (48 grams) during each weekly chemotherapy session. Therapy was delivered for six weeks out of every 8-week treatment cycle. The gastrointestinal toxicity of this regimen was mild with 2 patients experiencing grade 3 stomatitis, and 6 patients having grade 3 diarrhea; and the hematologic toxicity was acceptable with 6 of 57 patients found to have had grade 3 or 4 leukopenia, and 14 of 57 patients experiencing grade 3 or 4 neutropenia. There were two deaths judged possibly related to treatment; one in a patient who experienced a variety of Grade 2 gastrointestinal toxicities and died at home with an unknown cause of death; and a second patient who also died at home, and for whom treatment-related sepsis could not be ruled out. The overall median survival was 7.2 months. The ability to safely deliver twice the usual dose of 5-FU with leucovorin on a weekly schedule suggests that oral uridine analog supplementation with PN401 may enhance the therapeutic index of the fluoropyrimidines.

Authors
Doroshow, JH; McCoy, S; Macdonald, JS; Issell, BF; Patel, T; Cobb, PW; Yost, KJ; Abbruzzese, JL
MLA Citation
Doroshow, JH, McCoy, S, Macdonald, JS, Issell, BF, Patel, T, Cobb, PW, Yost, KJ, and Abbruzzese, JL. "Phase II trial of PN401, 5-FU, and leucovorin in unresectable or metastatic adenocarcinoma of the stomach: a Southwest Oncology Group study." Investigational new drugs 24.6 (November 2006): 537-542.
PMID
16832602
Source
epmc
Published In
Investigational New Drugs
Volume
24
Issue
6
Publish Date
2006
Start Page
537
End Page
542
DOI
10.1007/s10637-006-9244-8

Synthetic microRNA designed to target glioma-associated antigen 1 transcription factor inhibits division and induces late apoptosis in pancreatic tumor cells.

To determine whether the synthetic microRNAs (miRNA) could effectively target tumor cells we designed several miRNA complementary to glioma-associated antigen-1 (Gli-1) mRNA and investigated their ability to inhibit tumor cell proliferation. The sonic hedgehog pathway is an early and late mediator of tumorigenesis in epithelial cancers. Activation of sonic hedgehog signaling seems to precede transformation of tissue stem cells to cancerous stem cells, with the Gli-1 transcription factor functioning as a mediator of environmental signals. Inhibiting cancer cell proliferation by targeting the Gli-1 effector pathway is difficult to achieve by chemotherapeutic agents or short interfering RNA.We hypothesized that targeting the 3'-untranslated region of Gli-1 mRNA would effectively inhibit tumor cell proliferation. To test this hypothesis, we used synthetic miRNAs of our own design and corresponding duplex/small temporal RNAs by introducing three-nucleotide loops in the 3'-untranslated region Gli-1 sequence of high GU content.We found that miRNA (Gli-1-miRNA-3548) and its corresponding duplex (Duplex-3548) significantly inhibited proliferation of Gli-1+ ovarian (SK-OV-3) and pancreatic (MiaPaCa-2) tumor cells. The miRNAs mediated delayed cell division and activation of late apoptosis in MiaPaCa-2 cells. This is the first demonstration of inhibition of pancreatic tumor cell division by designed miRNA.Gli-1 miRNAs should significantly add to the general understanding of the mechanisms of metastasis and contribute toward the design of better treatments for epithelial cancers.

Authors
Tsuda, N; Ishiyama, S; Li, Y; Ioannides, CG; Abbruzzese, JL; Chang, DZ
MLA Citation
Tsuda, N, Ishiyama, S, Li, Y, Ioannides, CG, Abbruzzese, JL, and Chang, DZ. "Synthetic microRNA designed to target glioma-associated antigen 1 transcription factor inhibits division and induces late apoptosis in pancreatic tumor cells." Clinical cancer research : an official journal of the American Association for Cancer Research 12.21 (November 2006): 6557-6564.
PMID
17085671
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
12
Issue
21
Publish Date
2006
Start Page
6557
End Page
6564
DOI
10.1158/1078-0432.ccr-06-0588

Potentiation of the effect of erlotinib by genistein in pancreatic cancer: the role of Akt and nuclear factor-kappaB.

The epidermal growth factor receptor (EGFR) is a target of new therapies in most nonhematologic cancers. EGFR blockade alone may not be sufficient for the control of growth and invasion of human pancreas cancer because of the independent activation of Akt and nuclear factor-kappaB (NF-kappaB). The expression of EGFR, Akt, and NF-kappaB was determined in six human pancreatic cancer cell lines. Selected cells for specific expression were treated with erlotinib, genistein, gemcitabine, or the combination. Growth inhibition was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and apoptosis was assayed by ELISA. EGFR, phosphorylated EGFR, phosphorylated Akt, and survivin expressions were determined by immunoblotting. Electrophoretic mobility shift assay was used to evaluate the DNA binding activity of NF-kappaB. Genistein significantly increased (P < 0.05) erlotinib-induced growth inhibition and apoptosis in BxPC-3, CAPAN-2, and AsPC-1 cells. In the BxPC-3 cell line, significant down-regulation of EGFR, phosphorylated Akt, NF-kappaB activation, and survivin was observed in the cells treated with the combination compared with the erlotinib-treated cells. In the HPAC and MIAPaCa cell line, no potentiation of the effects of erlotinib by genistein on cell growth or inhibition of the EGFR/Akt/NF-kappaB was observed. Genistein potentiated growth inhibition and apoptosis of the gemcitabine and erlotinib combination in COLO-357 cell line. Genistein potentiates the growth inhibition and apoptosis induced by erlotinib and gemcitabine in certain pancreatic cancer cells. Akt and NF-kappaB inhibition represents one of the mechanisms for the potentiation of erlotinib- and gemcitabine-induced cell death by genistein.

Authors
El-Rayes, BF; Ali, S; Ali, IF; Philip, PA; Abbruzzese, J; Sarkar, FH
MLA Citation
El-Rayes, BF, Ali, S, Ali, IF, Philip, PA, Abbruzzese, J, and Sarkar, FH. "Potentiation of the effect of erlotinib by genistein in pancreatic cancer: the role of Akt and nuclear factor-kappaB." Cancer research 66.21 (November 2006): 10553-10559.
PMID
17079479
Source
epmc
Published In
Cancer Research
Volume
66
Issue
21
Publish Date
2006
Start Page
10553
End Page
10559
DOI
10.1158/0008-5472.can-06-2333

A Phase II trial of epothilone B analogue BMS-247550 (NSC #710428) ixabepilone, in patients with advanced pancreas cancer: a Southwest Oncology Group study.

PURPOSE: The purpose of this Phase II multi-institutional study was to define the efficacy and toxicity of ixabepilone in patients with advance pancreatic adenocarcinoma. PATIENTS AND METHODS: Patients were required to have pancreatic adenocarcinoma and metastatic or recurrent disease that was not amenable to curative resection. Performance status was 0-1, and patients could not have had prior chemotherapy, or chemoradiation therapy for their advanced disease although prior local palliative radiation was allowed. Ixabepilone was administered iv as a 3 hour infusion every 21 days. Initially, the dose was 50 mg/m(2) but this was lowered to 40 mg/m(2) shortly after the trial opened because of concerns about neurotoxicity. RESULTS: Sixty-two patients were registered however 2 were ineligible because they did not have recurrent or metastatic disease. For the 60 eligible patients, 22 had performance status of 0 and 38 performance status of 1. The estimated 6-month survival was 60% (95% CI 48%-72%) with a median survival of 7.2 months and an estimated time to treatment failure of 2.3 months. Out of 56 patients with measurable disease there were 5 confirmed partial responses for a confirmed response probability of 9% (95% CI 3%-20%) and 7 unconfirmed partial responses for an overall response probability of 21% (95% CI 12%-34%). Common toxicities were neutropenia/granulocytopenia, nausea and vomiting and neuropathy. There was one death, cause not determined but judged "possibly" related to treatment. CONCLUSION: Ixabepilone shows encouraging activity in patients with advanced pancreatic cancer and should be investigated further in this disease.

Authors
Whitehead, RP; McCoy, S; Rivkin, SE; Gross, HM; Conrad, ME; Doolittle, GC; Wolff, RA; Goodwin, JW; Dakhil, SR; Abbruzzese, JL
MLA Citation
Whitehead, RP, McCoy, S, Rivkin, SE, Gross, HM, Conrad, ME, Doolittle, GC, Wolff, RA, Goodwin, JW, Dakhil, SR, and Abbruzzese, JL. "A Phase II trial of epothilone B analogue BMS-247550 (NSC #710428) ixabepilone, in patients with advanced pancreas cancer: a Southwest Oncology Group study." Investigational new drugs 24.6 (November 2006): 515-520.
PMID
16699973
Source
epmc
Published In
Investigational New Drugs
Volume
24
Issue
6
Publish Date
2006
Start Page
515
End Page
520
DOI
10.1007/s10637-006-8440-x

Early effects of imatinib mesylate on the expression of insulin-like growth factor binding protein-3 and positron emission tomography in patients with gastrointestinal stromal tumor.

BACKGROUND: Imatinib has demonstrated marked clinical efficacy against gastrointestinal stromal tumor (GIST). Microarray technology, real-time polymerase chain reaction (PCR) validation, and fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging were used to study the early molecular effects of imatinib antitumor activity in GIST. METHODS: After exposure of sensitive and resistant sarcoma cell lines to imatinib for 24 to 48 hours, the changes in gene expression were evaluated using a 1146 unique pathway array with Western blot validation. Real-time PCR was used to confirm changes in gene expression in human GIST samples (preimatinib biopsy and postimatinib surgical specimen after 3-7 days of therapy). FDG-PET was performed to correlate radiographic findings with the effects of imatinib on gene expression in GIST. RESULTS: In all, 55 genes demonstrated a > or = 2-fold change after imatinib treatment of the GIST882 cells. Among these genes there was up-regulation of insulin-like growth factor binding protein-3 (IGFBP-3), a protein that modulates proliferation and apoptosis. Western blot analysis confirmed the increase of IGFBP-3 only in imatinib-sensitive GIST882 cells. Up to a 7-fold induction (49% mean increase; P = .08) of IGFBP-3 mRNA was found in tumor samples from patients with low residual FDG uptake, whereas there was an up to 12-fold reduction (-102% mean decrease; P = .03) in IGFBP-3 in those patients with high residual FDG uptake after imatinib therapy. CONCLUSIONS: In the current study, imatinib appears to regulate numerous genes and specifically induces IGFBP-3 in GIST cells and tumor samples. IGFBP-3 levels also were found to be inversely correlated with residual FDG uptake in GIST patients early in imatinib therapy. These initial observations suggest that IGFBP-3 is an important early marker of antitumor activity of imatinib in GIST.

Authors
Trent, JC; Ramdas, L; Dupart, J; Hunt, K; Macapinlac, H; Taylor, E; Hu, L; Salvado, A; Abbruzzese, JL; Pollock, R; Benjamin, RS; Zhang, W
MLA Citation
Trent, JC, Ramdas, L, Dupart, J, Hunt, K, Macapinlac, H, Taylor, E, Hu, L, Salvado, A, Abbruzzese, JL, Pollock, R, Benjamin, RS, and Zhang, W. "Early effects of imatinib mesylate on the expression of insulin-like growth factor binding protein-3 and positron emission tomography in patients with gastrointestinal stromal tumor." Cancer 107.8 (October 2006): 1898-1908.
PMID
16986125
Source
epmc
Published In
Cancer
Volume
107
Issue
8
Publish Date
2006
Start Page
1898
End Page
1908
DOI
10.1002/cncr.22214

Phase II trial of erlotinib in gastroesophageal junction and gastric adenocarcinomas: SWOG 0127.

PURPOSE: A phase II trial of the oral epidermal growth factor receptor (EGFR) inhibitor erlotinib in patients with gastroesophageal adenocarcinomas stratified according to primary tumor location into two groups: gastroesophageal junction (GEJ)/cardia and distal gastric adenocarcinomas. PATIENTS AND METHODS: Patients with a histologically proven diagnosis of adenocarcinoma of the GEJ or stomach (ST) that was unresectable or metastatic; presence of measurable disease; no prior chemotherapy for advanced or metastatic cancer; Zubrod performance status (PS) of 0 to 1; and adequate renal, hepatic, and hematologic function were treated with erlotinib 150 mg/d orally. Patient characteristics were median age, GEJ-63 years, ST-64 years; sex, GEJ-84% male and 16% female, ST-60 male and 40 female; Zubrod PS, GEJ-25 had a PS of 0 and 18 had a PS 1, ST-13 had a PS of 0 and 12 had a PS of 1. RESULTS: Percentage of common toxicities were skin rash, 86% and 72%; fatigue, 51% and 44%; and AST/ALT elevation, 28% and 28%, respectively for GEJ and ST. There has been one confirmed complete response, three confirmed partial responses (PRs) and one unconfirmed PR for an overall response probability of 9% confirmed (95% CI, 3% to 22%), all occurring in GEJ stratum. No responses were observed in ST stratum. The median survival was 6.7 months in GEJ and 3.5 months in ST stratum. Neither intratumoral EGFR, transforming growth factor-alpha or phosphorylated Akt kinase expression nor plasma proteomic analyses were predictive of clinical outcome. No somatic mutations of the EGFR exons 18, 19, or 21 were detected and there was no gross amplification of EGFR by fluorescence in situ hybridization. CONCLUSION: Erlotinib is active in patients with GEJ adenocarcinomas, but appears inactive in gastric cancers. The molecular correlates examined were not predictive of the patient therapeutic response.

Authors
Dragovich, T; McCoy, S; Fenoglio-Preiser, CM; Wang, J; Benedetti, JK; Baker, AF; Hackett, CB; Urba, SG; Zaner, KS; Blanke, CD; Abbruzzese, JL
MLA Citation
Dragovich, T, McCoy, S, Fenoglio-Preiser, CM, Wang, J, Benedetti, JK, Baker, AF, Hackett, CB, Urba, SG, Zaner, KS, Blanke, CD, and Abbruzzese, JL. "Phase II trial of erlotinib in gastroesophageal junction and gastric adenocarcinomas: SWOG 0127." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 24.30 (October 2006): 4922-4927.
PMID
17050876
Source
epmc
Published In
Journal of Clinical Oncology
Volume
24
Issue
30
Publish Date
2006
Start Page
4922
End Page
4927
DOI
10.1200/jco.2006.07.1316

Nuclear factor-kappaB maintains TRAIL resistance in human pancreatic cancer cells.

Although it displays promising activity in other tumor models, the effects of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on human pancreatic cancer cells have not been comprehensively explored. We report that a majority of human pancreatic cancer cell lines (seven of nine) underwent apoptosis when they were exposed to recombinant human TRAIL in vitro. Characterization of surface TRAIL receptors by fluorescence-activated cell sorting showed that TRAIL-resistant cells (Panc-1 and HS766T) expressed lower levels of DR4 and DR5 than did TRAIL-sensitive cells. The proteasome inhibitor bortezomib (PS-341, Velcade) further increased TRAIL responsiveness in the TRAIL-sensitive cells and synergized with TRAIL to reverse resistance in Panc-1 and HS776T cells. The effects of bortezomib were mimicked by transfection with a small interfering RNA construct specific for the p65 subunit of nuclear factor-kappaB (NF-kappaB) or exposure to a selective chemical inhibitor of IKK (PS-1145). Silencing IkappaBalpha prevented TRAIL sensitization by PS-1145, confirming that IkappaBalpha mediated the effects of PS-1145. NF-kappaB inhibition resulted in down-regulation of BCL-XL and XIAP, and silencing either restored TRAIL sensitivity in TRAIL-resistant cells. Finally, therapy with TRAIL plus PS-1145 reversed TRAIL resistance in vivo to produce synergistic growth inhibition in orthotopic Panc-1 tumors. Together, our results show that NF-kappaB inhibits TRAIL-induced apoptosis in human pancreatic cancer cells and suggest that combination therapy with TRAIL and NF-kappaB inhibitors, such as bortezomib, PS-1145, or curcumin, should be considered as a possible treatment strategy in patients with pancreatic cancer.

Authors
Khanbolooki, S; Nawrocki, ST; Arumugam, T; Andtbacka, R; Pino, MS; Kurzrock, R; Logsdon, CD; Abbruzzese, JL; McConkey, DJ
MLA Citation
Khanbolooki, S, Nawrocki, ST, Arumugam, T, Andtbacka, R, Pino, MS, Kurzrock, R, Logsdon, CD, Abbruzzese, JL, and McConkey, DJ. "Nuclear factor-kappaB maintains TRAIL resistance in human pancreatic cancer cells." Molecular cancer therapeutics 5.9 (September 2006): 2251-2260.
PMID
16985059
Source
epmc
Published In
Molecular cancer therapeutics
Volume
5
Issue
9
Publish Date
2006
Start Page
2251
End Page
2260
DOI
10.1158/1535-7163.mct-06-0075

Phase I study to determine the safety and pharmacokinetics of oral administration of TAS-102 in patients with solid tumors.

BACKGROUND: The purpose of the current study was to determine the maximum tolerated dose, dose-limiting toxicities, pharmacokinetic profile, and recommended Phase II dose of oral administration of TAS-102, a novel nucleoside formed by the combination of alpha,alpha,alpha-trifluorothymidine (FTD) and a thymidine phosphorylase inhibitor (TPI: 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidinedione). METHODS: Eligible patients had advanced solid tumors, adequate organ function, and had not received anticancer therapy in the preceding 4 weeks. TAS-102 was administered orally once daily for 14 days, followed by a 1-week rest, repeated every 3 weeks. The initial dose of TAS-102 administered was 100 mg/m2/day. The first 2 patients treated at that dose experienced substantial toxicity and, therefore, lower dose levels of TAS-102 were subsequently explored. RESULTS: Fourteen patients were enrolled; all patients were evaluable for toxicity assessment and 12 were evaluable for response. The initial dose explored was 100 mg/m2/day, based on a preclinical monkey model. However, the first 2 patients experienced bone marrow suppression of Grade 3 or 4 in course 1. The protocol was amended to study the next cohort of patients at 50 mg/m2/day. At this dose level no Grade 3 or 4 toxicities were observed in course 1. In the subsequent dose level (60 mg/m2/day), 3 of 6 patients experienced Grade 3 or 4 granulocytopenia as dose-limiting toxicity. Three additional patients for a total of 6 were enrolled at 50 mg/m2/day without occurrence of dose-limiting toxicity. Thus, 50 mg/m2/day was declared the maximum tolerated dose for this schedule. CONCLUSIONS: The authors' study showed that 50 mg/m2/day was a tolerable dose of the novel antimetabolite FTD in combination with an inhibitor of its inactivating enzyme TP, and this is the recommended Phase II dose. Evaluation of this daily dose in malignancies for which fluoropyrimidines have failed is needed.

Authors
Hong, DS; Abbruzzese, JL; Bogaard, K; Lassere, Y; Fukushima, M; Mita, A; Kuwata, K; Hoff, PM
MLA Citation
Hong, DS, Abbruzzese, JL, Bogaard, K, Lassere, Y, Fukushima, M, Mita, A, Kuwata, K, and Hoff, PM. "Phase I study to determine the safety and pharmacokinetics of oral administration of TAS-102 in patients with solid tumors." Cancer 107.6 (September 2006): 1383-1390.
PMID
16902987
Source
epmc
Published In
Cancer
Volume
107
Issue
6
Publish Date
2006
Start Page
1383
End Page
1390
DOI
10.1002/cncr.22125

Differing molecular pathology of pancreatic adenocarcinoma in Egyptian and United States patients.

Variations in genetic mutations in pancreatic carcinoma between different populations have not been studied extensively, especially in developing countries where pancreatic cancer is rare. We studied the molecular pathology of 44 pancreatic carcinomas from patients residing in a heavily polluted region in the Nile River delta and compared the findings with tumors from 44 United States (US) patients. We evaluated K-ras mutations in codon 12, p53 mutations in exons 5-8, and Gadd45a mutations in exons 1 and 4. Overall, rates of K-ras, p53 and Gadd45 mutations were not statistically different in tumors of patients from Egypt and the US (67.4 vs. 63.4%; 27.3 vs. 36.4% and 9.1 vs. 4.5%, respectively). However, there were distinct differences in the specific types of K-ras and p53 mutations between the 2 groups. In K-ras, G --> T transversion mutation was more frequent in the tumors from Egypt than from the US (58.6 vs. 26.9%), whereas G --> C transversion was detected in 26.9% of US tumors but none from Egypt (p = 0.003). We also found a trend toward differences in the p53 exons in which mutations occurred, with higher frequency of exon 5 mutation and lower frequency of exon 6 mutation in Egyptian tumors. Logistic regression showed that K-ras G --> T transversion mutations and p53 exon 6 mutations were predicted by the country of residence of the patients. Our study identifies that there are differences in the types of mutations found in tumors from pancreatic carcinoma patients in Egypt and the US, and suggests that environmental factors may explain these differences.

Authors
Soliman, AS; Bondy, M; Webb, CR; Schottenfeld, D; Bonner, J; El-Ghawalby, N; Soultan, A; Abdel-Wahab, M; Fathy, O; Ebidi, G; Zhang, Q; Greenson, JK; Abbruzzese, JL; Hamilton, SR
MLA Citation
Soliman, AS, Bondy, M, Webb, CR, Schottenfeld, D, Bonner, J, El-Ghawalby, N, Soultan, A, Abdel-Wahab, M, Fathy, O, Ebidi, G, Zhang, Q, Greenson, JK, Abbruzzese, JL, and Hamilton, SR. "Differing molecular pathology of pancreatic adenocarcinoma in Egyptian and United States patients." International journal of cancer 119.6 (September 2006): 1455-1461.
PMID
16619252
Source
epmc
Published In
International Journal of Cancer
Volume
119
Issue
6
Publish Date
2006
Start Page
1455
End Page
1461
DOI
10.1002/ijc.21986

Epidermal growth factor receptor-related protein inhibits cell growth and invasion in pancreatic cancer.

The epidermal growth factor receptor (EGFR) signaling network plays critical roles in human cancers, including pancreatic cancer, suggesting that the discovery of specific agents targeting EGFR would be extremely valuable for pancreatic cancer therapy. EGFR-related protein (ERRP), a recently identified pan-erbB inhibitor, has been shown to inhibit growth and induce apoptosis of pancreatic cancer cells in vitro and tumor growth in a xenograft model. However, the precise molecular mechanism(s) by which ERRP exerts its antitumor activity remains unclear. The current investigation was undertaken to delineate the tumor growth inhibitory mechanism(s) of ERRP in pancreatic cancer cells. Using multiple molecular assays, such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, apoptosis, gene transfection, real-time reverse transcription-PCR, Western blotting, invasion, and electrophoretic mobility shift assay for measuring DNA-binding activity of nuclear factor-kappaB (NF-kappaB), we found that ERRP caused marked inhibition of pancreatic cancer cell growth. This was accompanied by increased apoptosis and concomitant attenuation of Notch-1 and NF-kappaB and down-regulation of NF-kappaB downstream genes, such as matrix metalloproteinase-9 and vascular endothelial growth factor, resulting in the inhibition of pancreatic cancer cell invasion through the Matrigel. We also found that down-regulation of Notch-1 by small interfering RNA before ERRP treatment resulted in enhanced cell growth inhibition and apoptosis. Our data suggest that the ERRP-mediated inactivation of EGFR, Notch-1, NF-kappaB, and its downstream target genes contributed to the inhibition of cell growth and invasion. We conclude that ERRP could be an effective agent for inhibiting tumor growth and invasion for the treatment of pancreatic cancer.

Authors
Wang, Z; Sengupta, R; Banerjee, S; Li, Y; Zhang, Y; Rahman, KMW; Aboukameel, A; Mohammad, R; Majumdar, APN; Abbruzzese, JL; Sarkar, FH
MLA Citation
Wang, Z, Sengupta, R, Banerjee, S, Li, Y, Zhang, Y, Rahman, KMW, Aboukameel, A, Mohammad, R, Majumdar, APN, Abbruzzese, JL, and Sarkar, FH. "Epidermal growth factor receptor-related protein inhibits cell growth and invasion in pancreatic cancer." Cancer research 66.15 (August 2006): 7653-7660.
PMID
16885366
Source
epmc
Published In
Cancer Research
Volume
66
Issue
15
Publish Date
2006
Start Page
7653
End Page
7660
DOI
10.1158/0008-5472.can-06-1019

Borderline resectable pancreatic cancer: definitions, management, and role of preoperative therapy.

With recent advances in pancreatic imaging and surgical techniques, a distinct subset of pancreatic tumors is emerging that blurs the distinction between resectable and locally advanced disease: tumors of "borderline resectability." In our practice, patients with borderline-resectable pancreatic cancer include those whose tumors exhibit encasement of a short segment of the hepatic artery, without evidence of tumor extension to the celiac axis, that is amenable to resection and reconstruction; tumor abutment of the superior mesenteric artery involving <180 degrees of the circumference of the artery; or short-segment occlusion of the superior mesenteric vein, portal vein, or their confluence with a suitable option available for vascular reconstruction because the veins are normal above and below the area of tumor involvement. With currently available surgical techniques, patients with borderline-resectable pancreatic head cancer are at high risk for a margin-positive resection. Therefore, our approach to these patients is to use preoperative systemic therapy and local-regional chemoradiation to maximize the potential for an R0 resection and to avoid R2 resections. In our experience, patients with favorable responses to preoperative therapy (radiographical evidence of tumor regression and improvement in serum tumor marker levels) are the subset of patients who have the best chance for an R0 resection and a favorable long-term outcome.

Authors
Varadhachary, GR; Tamm, EP; Abbruzzese, JL; Xiong, HQ; Crane, CH; Wang, H; Lee, JE; Pisters, PWT; Evans, DB; Wolff, RA
MLA Citation
Varadhachary, GR, Tamm, EP, Abbruzzese, JL, Xiong, HQ, Crane, CH, Wang, H, Lee, JE, Pisters, PWT, Evans, DB, and Wolff, RA. "Borderline resectable pancreatic cancer: definitions, management, and role of preoperative therapy." Annals of surgical oncology 13.8 (August 2006): 1035-1046. (Review)
PMID
16865597
Source
epmc
Published In
Annals of Surgical Oncology
Volume
13
Issue
8
Publish Date
2006
Start Page
1035
End Page
1046
DOI
10.1245/aso.2006.08.011

Phase II trial of R115777 (NSC #70818) in patients with advanced colorectal cancer: a Southwest Oncology Group study.

The purpose of this Phase II multi-institutional trial was to determine the efficacy and toxicity of R115777 in previously untreated patients with metastatic colorectal carcinoma.Patients were required to have histologically confirmed colorectal cancer with distant metastatic disease that was not surgically curable. They could not have received prior chemotherapy for metastatic disease. R115777 was given at a dose of 300 mg p.o. twice a day for 21 days every 28 days until tumor progression or toxicity or other reason for discontinuation occurred. The primary endpoint was to determine the confirmed response probability with this treatment.There were 55 eligible patients accrued to the study. There were no complete responses, but one confirmed partial response for a confirmed response probability of 2% (95%CI 0-10%). Three additional patients had an unconfirmed partial response for an overall response probability of 7%. The time to treatment failure was 1.7 months and the estimated median survival was 8.1 months. One patient died of treatment related infection and there were 7 other patients with grade 4 toxicities consisting of neutropenia, leukopenia, febrile neutropenia and thrombocytopenia, depression, increased bilirubin, anemia, and pneumonitis/infiltrates.R115777 given as a single agent by this dose and schedule is ineffective in patients with metastatic colorectal cancer.

Authors
Whitehead, RP; McCoy, S; Macdonald, JS; Rivkin, SE; Neubauer, MA; Dakhil, SR; Lenz, H-J; Tanaka, MS; Abbruzzese, JL
MLA Citation
Whitehead, RP, McCoy, S, Macdonald, JS, Rivkin, SE, Neubauer, MA, Dakhil, SR, Lenz, H-J, Tanaka, MS, and Abbruzzese, JL. "Phase II trial of R115777 (NSC #70818) in patients with advanced colorectal cancer: a Southwest Oncology Group study." Investigational new drugs 24.4 (July 2006): 335-341.
PMID
16683076
Source
epmc
Published In
Investigational New Drugs
Volume
24
Issue
4
Publish Date
2006
Start Page
335
End Page
341
DOI
10.1007/s10637-005-4345-3

Geographical clustering of pancreatic cancers in the Northeast Nile Delta region of Egypt.

The northeast Nile Delta, Egypt's most polluted region, appears to have a high incidence of pancreatic cancer. We sought to determine whether there is any geographic clustering of pancreatic cancers there and, if so, whether such clustering might be associated with environmental pollution. Using data from the medical records of the Gastrointestinal Surgical Center of Mansoura University in the Dakahleia Province of Egypt and detailed geographical maps of the northeast Nile Delta region, we plotted the residences of all 373 patients who had pancreatic cancer diagnosed between 1995 and 2000. The study region has 15 administrative districts, whose centroid coordinates, population, and number of pancreatic cancer patients were determined for this study. Monte Carlo simulation identified statistically significant clustering of pancreatic cancer in five subdivisions located near the Nile River and Delta plains. This clustering was independent of population size and formed two larger clusters. When data were analyzed by sex, clustering of pancreatic cancer was observed in the same five subdivisions for men but only two subdivisions showed clustering for women. Together, our data suggest that there is clustering of pancreatic cancer cases in the northeast Nile delta region and that this clustering may be related to water pollution. Our data also warrant future studies of the association between water pollution and pancreatic cancer in the region.

Authors
Soliman, AS; Wang, X; Stanley, J-D; El-Ghawalby, N; Bondy, ML; Ezzat, F; Soultan, A; Abdel-Wahab, M; Fathy, O; Ebidi, G; Abdel-Karim, N; Do, K-A; Levin, B; Hamilton, SR; Abbruzzese, JL
MLA Citation
Soliman, AS, Wang, X, Stanley, J-D, El-Ghawalby, N, Bondy, ML, Ezzat, F, Soultan, A, Abdel-Wahab, M, Fathy, O, Ebidi, G, Abdel-Karim, N, Do, K-A, Levin, B, Hamilton, SR, and Abbruzzese, JL. "Geographical clustering of pancreatic cancers in the Northeast Nile Delta region of Egypt." Archives of environmental contamination and toxicology 51.1 (July 2006): 142-148.
PMID
16453066
Source
epmc
Published In
Archives of Environmental Contamination and Toxicology
Volume
51
Issue
1
Publish Date
2006
Start Page
142
End Page
148
DOI
10.1007/s00244-005-0154-0

Detection of 2-amino-1-methyl-6-phenylimidazo [4,5-b]-pyridine (PhIP)-DNA adducts in human pancreatic tissues.

Recent epidemiological investigations have observed an association between the consumption of grilled or barbecued meat and an increased risk of pancreatic cancer, suggesting that dietary exposure to heterocyclic aromatic amines (HCA) may contribute to the development of this disease. 2-Amino-1-methyl-6-phenylimidazo [4,5-b]-pyridine (PhIP) is the most abundant HCA found in well-done and grilled meats. To determine whether HCA-induced DNA damage is present in the human pancreas, immunohistochemistry and computer-assisted image analysis were used to measure PhIP-DNA adducts in 54 normal pancreatic tissues (N) from persons without pancreatic cancer and in 38 normal adjacent pancreatic tissues (A) and in 39 cancer tissues (T) from 68 patients with pancreatic adenocarcinoma. PhIP-DNA adducts were detected in 53 N, 34 A and 39 T samples. Mean values (+/-SD) of the absorbency for PhIP staining were 0.22+/-0.04, 0.24+/-0.04, and 0.24+/-0.03 for N, A, and T samples, respectively (p=0.004). Using the median absorbency (0.21) of the samples from normal controls as the cut-off, 71% of A and 77% of T tissues, compared with 48% of N tissues, were distributed in the higher range (p=0.009). The odds ratio of pancreatic cancer was 3.4 (95% confidence interval 1.5-7.5, p=0.002) for individuals with a higher level of PhIP-DNA adducts. This is the first report of the detection of PhIP-DNA adducts in human pancreatic tissue samples obtained from patients with unknown exposure to HCA. Although limited by the small sample size, these preliminary results suggest that PhIP exposure may contribute to human pancreatic cancer development.

Authors
Zhu, J; Rashid, A; Cleary, K; Abbruzzese, JL; Friess, H; Takahashi, S; Shirai, T; Li, D
MLA Citation
Zhu, J, Rashid, A, Cleary, K, Abbruzzese, JL, Friess, H, Takahashi, S, Shirai, T, and Li, D. "Detection of 2-amino-1-methyl-6-phenylimidazo [4,5-b]-pyridine (PhIP)-DNA adducts in human pancreatic tissues." Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals 11.4 (July 2006): 319-328.
PMID
16908439
Source
epmc
Published In
Biomarkers (Informa)
Volume
11
Issue
4
Publish Date
2006
Start Page
319
End Page
328
DOI
10.1080/13547500600667911

Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma.

PURPOSE: This phase II randomized discontinuation trial evaluated the effects of sorafenib (BAY 43-9006), an oral multikinase inhibitor targeting the tumor and vasculature, on tumor growth in patients with metastatic renal cell carcinoma. PATIENTS AND METHODS: Patients initially received oral sorafenib 400 mg twice daily during the initial run-in period. After 12 weeks, patients with changes in bidimensional tumor measurements that were less than 25% from baseline were randomly assigned to sorafenib or placebo for an additional 12 weeks; patients with > or = 25% tumor shrinkage continued open-label sorafenib; patients with > or = 25% tumor growth discontinued treatment. The primary end point was the percentage of randomly assigned patients remaining progression free at 24 weeks after the initiation of sorafenib. RESULTS: Of 202 patients treated during the run-in period, 73 patients had tumor shrinkage of > or = 25%. Sixty-five patients with stable disease at 12 weeks were randomly assigned to sorafenib (n = 32) or placebo (n = 33). At 24 weeks, 50% of the sorafenib-treated patients were progression free versus 18% of the placebo-treated patients (P = .0077). Median progression-free survival (PFS) from randomization was significantly longer with sorafenib (24 weeks) than placebo (6 weeks; P = .0087). Median overall PFS was 29 weeks for the entire renal cell carcinoma population (n = 202). Sorafenib was readministered in 28 patients whose disease progressed on placebo; these patients continued on sorafenib until further progression, for a median of 24 weeks. Common adverse events were skin rash/desquamation, hand-foot skin reaction, and fatigue; 9% of patients discontinued therapy, and no patients died from toxicity. CONCLUSION: Sorafenib has significant disease-stabilizing activity in metastatic renal cell carcinoma and is tolerable with chronic daily therapy.

Authors
Ratain, MJ; Eisen, T; Stadler, WM; Flaherty, KT; Kaye, SB; Rosner, GL; Gore, M; Desai, AA; Patnaik, A; Xiong, HQ; Rowinsky, E; Abbruzzese, JL; Xia, C; Simantov, R; Schwartz, B; O'Dwyer, PJ
MLA Citation
Ratain, MJ, Eisen, T, Stadler, WM, Flaherty, KT, Kaye, SB, Rosner, GL, Gore, M, Desai, AA, Patnaik, A, Xiong, HQ, Rowinsky, E, Abbruzzese, JL, Xia, C, Simantov, R, Schwartz, B, and O'Dwyer, PJ. "Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 24.16 (June 2006): 2505-2512.
PMID
16636341
Source
epmc
Published In
Journal of Clinical Oncology
Volume
24
Issue
16
Publish Date
2006
Start Page
2505
End Page
2512
DOI
10.1200/jco.2005.03.6723

Tolfenamic acid and pancreatic cancer growth, angiogenesis, and Sp protein degradation.

BACKGROUND: Sp1, Sp3, and Sp4 are transcription factors that regulate cell proliferation and vascular endothelial growth factor (VEGF) expression and are overexpressed in many cancer cell lines. For some cancers, Sp1 overexpression is associated with poor survival. Cyclooxygenase inhibitors decrease Sp1 expression in cancer cells, and therefore different structural classes of nonsteroidal anti-inflammatory drugs (NSAIDs) were screened for their ability to decrease levels of Sp1, Sp3, and Sp4 and to decrease pancreatic tumor growth and metastasis in an in vivo model. METHODS: Levels of Sp1, Sp3, Sp4, and VEGF proteins in pancreatic cancer cell lines were assessed by immunoblot analysis. mRNA was assessed by reverse transcription-polymerase chain reaction. Panc-1 pancreatic cancer cells transfected with VEGF promoter constructs were used to assess VEGF promoter activation. Pancreatic tumor weight and size and liver metastasis were assessed in an orthotopic mouse model of pancreatic cancer (groups of 10 mice). Protein expression in tumors was assessed immunohistochemically. RESULTS: Tolfenamic acid and structurally related biaryl derivatives induced degradation of Sp1, Sp3, and Sp4 in pancreatic cancer cells. Tolfenamic acid also inhibited VEGF mRNA and protein expression in pancreatic cancer cells; this inhibition was associated with the decreased Sp-dependent activation of the VEGF promoter. In the mouse model for pancreatic cancer, treatment with tolfenamic acid (50 mg/kg of body weight), compared with control treatment, statistically significantly decreased tumor growth and weight (P = .005), liver metastasis (P = .027), and levels of Sp3 and VEGF (P = .009) and Sp1 and Sp4 (P = .006) proteins in tumors. For example, tumors from mice treated with tolfenamic acid (50 mg/kg) had statistically significantly lower VEGF levels (45%, 95% confidence interval = 39% to 51%; P = .009) than tumors from control mice. CONCLUSIONS: Tolfenamic acid is a new antipancreatic cancer NSAID that activates degradation of transcription factors Sp1, Sp3, and Sp4; reduces VEGF expression; and decreases tumor growth and metastasis.

Authors
Abdelrahim, M; Baker, CH; Abbruzzese, JL; Safe, S
MLA Citation
Abdelrahim, M, Baker, CH, Abbruzzese, JL, and Safe, S. "Tolfenamic acid and pancreatic cancer growth, angiogenesis, and Sp protein degradation." Journal of the National Cancer Institute 98.12 (June 2006): 855-868.
PMID
16788159
Source
epmc
Published In
Journal of the National Cancer Institute
Volume
98
Issue
12
Publish Date
2006
Start Page
855
End Page
868
DOI
10.1093/jnci/djj232

Suppression of pancreatic tumor progression by systemic delivery of a pancreatic-cancer-specific promoter driven Bik mutant.

Pancreatic cancer is highly aggressive with extremely poor prognosis. Developing a pancreatic cancer specific promoter (PCSP) is one approach for pancreatic cancer gene therapy. We have modified the promoter of cholecystokinin type A receptor (CCKAR), named CCK/Mpd, which possesses a relatively high activity in pancreatic cancer cells as compared with normal cells. The CCK/Mpd promoter-driven luciferase exhibits a better tumor specific tissue distribution than the CMV promoter-driven luciferase when systemically administered in vivo. Notably, we demonstrate a treatment efficacy by using CCK/Mpd-Bik-DD/liposome in a nude mice xenograft model, suggesting the feasibility of PCSP-based gene therapy in pancreatic cancer treatment.

Authors
Li, Z; Ding, Q; Li, Y; Miller, SA; Abbruzzese, JL; Hung, M-C
MLA Citation
Li, Z, Ding, Q, Li, Y, Miller, SA, Abbruzzese, JL, and Hung, M-C. "Suppression of pancreatic tumor progression by systemic delivery of a pancreatic-cancer-specific promoter driven Bik mutant." Cancer letters 236.1 (May 2006): 58-63.
PMID
15953675
Source
epmc
Published In
Cancer Letters
Volume
236
Issue
1
Publish Date
2006
Start Page
58
End Page
63
DOI
10.1016/j.canlet.2005.05.001

Metastatic patterns in adenocarcinoma.

BACKGROUND: Unique metastatic patterns cited in the literature often arise from anecdotal clinical observations and autopsy reports. The authors analyzed clinical data from a large number of patients with histologically confirmed, distant-stage adenocarcinoma to evaluate metastatic patterns. METHODS: Tumor registry data were collected between 1994-1996 on 11 primary tumor sites and 15 metastatic sites from 4399 patients. The primary and metastatic sites were cross-tabulated in various ways to identify patterns, and the authors developed algorithms by using multinomial logistic regression analysis to predict the locations of primary tumors based on metastatic patterns. RESULTS: Three primary tumors had single, dominant metastatic sites: ovary to abdominal cavity (91%), prostate to bone (90%), and pancreas to liver (85%). The liver was the dominant metastatic site for gastrointestinal (GI) primary tumors (71% of patients), whereas bone and lung metastases were noted most frequently in non-GI primary tumors (43% and 29%, respectively). In a study of combinations of liver, abdominal cavity, and bone metastases, 86% of prostate primary tumors had only bone metastases, 80% of ovarian primary tumors had only abdominal cavity metastases, and 74% of pancreas primary tumors had only liver metastases. A single organ was the dominant source of metastases in 7 sites: axillary lymph node from the breast (97%), intestinal lymph node from the colon (84%), thoracic lymph node from the lung (66%), brain from the lung (64%), mediastinal lymph node from the lung (62%), supraclavicular lymph node from the breast (51%), and adrenal gland from the lung (51%). CONCLUSIONS: The algorithms that the authors developed achieved a cross-validated accuracy of 64% and an accuracy of 64% on an 1851-patient independent test set, compared with 9% accuracy when a random classifier was used.

Authors
Hess, KR; Varadhachary, GR; Taylor, SH; Wei, W; Raber, MN; Lenzi, R; Abbruzzese, JL
MLA Citation
Hess, KR, Varadhachary, GR, Taylor, SH, Wei, W, Raber, MN, Lenzi, R, and Abbruzzese, JL. "Metastatic patterns in adenocarcinoma." Cancer 106.7 (April 2006): 1624-1633.
PMID
16518827
Source
epmc
Published In
Cancer
Volume
106
Issue
7
Publish Date
2006
Start Page
1624
End Page
1633
DOI
10.1002/cncr.21778

Phase II trial of gemcitabine plus irinotecan in patients with esophageal cancer: a Southwest Oncology Group (SWOG) trial.

Metastatic esophageal carcinoma is an incurable disease with median survival duration of 6 to 8 months. Based on preclinical data suggesting a dose-dependent synergy between gemcitabine and irinotecan we have conducted a phase II trial in patients with advanced or metastatic esophageal carcinoma.Patient eligibility included a diagnosis of squamous cell or adenocarcinoma of the esophagus/gastroesophageal (GE) junction, metastatic or recurrent disease, no CNS metastasis, no prior chemotherapy, prior adjuvant/neoadjuvant chemotherapy was allowed, no prior gemcitabine or irinotecan, performance status of 0 to 2 and adequate organ function. Patients received gemcitabine 1000 mg/m2 and irinotecan 100 mg/m2 given day 1 and day 8, every 3 weeks. The primary end point was the 6-month survival rate. The secondary end point was to assess qualitative and quantitative toxicities.Fifty-seven eligible patients were accrued. There were 4 treatment-related deaths. The primary grade 3 to 4 toxic events were diarrhea, dehydration, neutropenia, thrombocytopenia, anemia, and anorexia; and 4 episodes of grade 3 to 5 febrile neutropenia, 1 fatal. The study was designed to detect a difference between the null hypothesis of 30% 6-month survival and the alternative hypothesis of 50% 6-month survival. The Kaplan-Meier estimate of 6-month survival is 56% (95% CI: 43-69%), with a median of 6.3 months. The median time to progression was 3.7 months. The 6-month progression-free survival estimate is 25% (95% CI: 13-36%).The length of survival suggests that this combination has benefit similar to platinum containing regimens, however, the toxicity is substantial and is unlikely to prove superior to platinum containing regimens.

Authors
Williamson, SK; McCoy, SA; Gandara, DR; Dakhil, SR; Yost, KJ; Paradelo, JC; Atkins, JN; Blanke, CD; Abbruzzese, JL
MLA Citation
Williamson, SK, McCoy, SA, Gandara, DR, Dakhil, SR, Yost, KJ, Paradelo, JC, Atkins, JN, Blanke, CD, and Abbruzzese, JL. "Phase II trial of gemcitabine plus irinotecan in patients with esophageal cancer: a Southwest Oncology Group (SWOG) trial." American journal of clinical oncology 29.2 (April 2006): 116-122.
PMID
16601427
Source
epmc
Published In
American Journal of Clinical Oncology: Cancer Clinical Trials
Volume
29
Issue
2
Publish Date
2006
Start Page
116
End Page
122
DOI
10.1097/01.coc.0000199883.10685.2b

Transforming growth factor alpha expression drives constitutive epidermal growth factor receptor pathway activation and sensitivity to gefitinib (Iressa) in human pancreatic cancer cell lines.

The epidermal growth factor receptor (EGFR) is considered an important therapeutic target in pancreatic cancer, but it is currently impossible to identify those patients who are most likely to benefit from EGFR-directed therapy. We examined the biological effects of the EGFR tyrosine kinase inhibitor gefitinib (ZD1839, Iressa) in a panel of nine human pancreatic cancer cell lines. The drug strongly inhibited DNA synthesis and induced low levels of apoptosis at clinically relevant concentrations in a subset of three of the lines (L3.6pl, BxPC3, and Cfpac1). Sensitivity to gefitinib correlated directly with ligand [transforming growth factor-alpha (TGF-alpha)] expression (r(2) = 0.71, P = 0.004) but not with surface EGFR expression. The gefitinib-sensitive cells displayed constitutive baseline EGFR phosphorylation, whereas the gefitinib-resistant cells did not. Exposure to gefitinib or a small interfering RNA construct specific for TGF-alpha reversed the constitutive EGFR phosphorylation and downstream target [extracellular signal-regulated kinases (ERK), AKT] phosphorylation in the gefitinib-sensitive cells but had no effects on ERK or AKT phosphorylation in gefitinib-resistant cells. Baseline EGFR phosphorylation was lower in a subclone of L3.6pl selected for low TGF-alpha expression, and these cells were also resistant to gefitinib-mediated growth inhibition. Gefitinib blocked the growth of tumor xenografts derived from L3.6pl cells but had no effect on the growth of tumors derived from EGFR-independent MiaPaCa-2 cells. Together, our data show that TGF-alpha expression identifies a subset of human pancreatic cancer cells that is dependent on EGFR signaling in vitro and in vivo. Quantification of TGF-alpha expression may therefore represent an effective means of identifying EGFR-responsive primary tumors.

Authors
Pino, MS; Shrader, M; Baker, CH; Cognetti, F; Xiong, HQ; Abbruzzese, JL; McConkey, DJ
MLA Citation
Pino, MS, Shrader, M, Baker, CH, Cognetti, F, Xiong, HQ, Abbruzzese, JL, and McConkey, DJ. "Transforming growth factor alpha expression drives constitutive epidermal growth factor receptor pathway activation and sensitivity to gefitinib (Iressa) in human pancreatic cancer cell lines." Cancer research 66.7 (April 2006): 3802-3812.
PMID
16585207
Source
epmc
Published In
Cancer Research
Volume
66
Issue
7
Publish Date
2006
Start Page
3802
End Page
3812
DOI
10.1158/0008-5472.can-05-3753

Intraductal papillary mucinous neoplasms of the pancreas: effect of invasion and pancreatic margin status on recurrence and survival.

BACKGROUND: The natural history and prognosis for patients with intraductal papillary mucinous neoplasms (IPMN) with and without invasion remain poorly defined. This study evaluated the outcome after pancreatectomy for IPMN according to the pancreatic transection margin status and the presence or absence of invasive carcinoma. METHODS: Data from a prospective pancreatic tumor database and medical records were reviewed for all patients who underwent pancreatic resection for IPMN at our institution between July 1990 and July 2003. Surgical specimens were re-reviewed by a single pathologist. RESULTS: IPMN was diagnosed in 35 (26%) of 137 patients who underwent pancreatic resection for cystic neoplasms. Invasive IPMN was confirmed in 13 (37%) of 35 patients. Noninvasive IPMN was found in 22 (63%) of 35 patients; pathology re-review changed the original diagnosis from invasive to noninvasive IPMN in 6 patients. Noninvasive IPMN was found at the final pancreatic margin in eight patients; none developed recurrent disease at a median follow-up of 34 months. Recurrent disease was identified in 7 (58%) of 13 patients with invasive IPMN and in none with noninvasive IPMN. The median overall survival was 22.9 and 84.9 months in patients with invasive and noninvasive IPMN, respectively (P=.0009). CONCLUSIONS: Distinction between invasive and noninvasive IPMN is essential in estimating prognosis and determining the need for adjuvant therapy and the frequency of follow-up surveillance. Noninvasive IPMN, even if present at the pancreatic margin, was not associated with recurrent disease. In contrast, invasive IPMN was associated with early recurrence and short survival.

Authors
Raut, CP; Cleary, KR; Staerkel, GA; Abbruzzese, JL; Wolff, RA; Lee, JH; Vauthey, J-N; Lee, JE; Pisters, PWT; Evans, DB
MLA Citation
Raut, CP, Cleary, KR, Staerkel, GA, Abbruzzese, JL, Wolff, RA, Lee, JH, Vauthey, J-N, Lee, JE, Pisters, PWT, and Evans, DB. "Intraductal papillary mucinous neoplasms of the pancreas: effect of invasion and pancreatic margin status on recurrence and survival." Annals of surgical oncology 13.4 (April 2006): 582-594.
PMID
16523362
Source
epmc
Published In
Annals of Surgical Oncology
Volume
13
Issue
4
Publish Date
2006
Start Page
582
End Page
594
DOI
10.1245/aso.2006.05.002

Aggresome disruption: a novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells.

The proteasome inhibitor bortezomib (formerly known as PS-341) recently received Food and Drug Administration approval for the treatment of multiple myeloma, and its activity is currently being evaluated in solid tumors. Bortezomib triggers apoptosis in pancreatic cancer cells, but the mechanisms involved have not been fully elucidated. Here, we show that pancreatic cancer cells exposed to bortezomib formed aggregates of ubiquitin-conjugated proteins ("aggresomes") in vitro and in vivo. Bortezomib-induced aggresome formation was determined to be cytoprotective and could be disrupted using histone deacetylase (HDAC) 6 small interfering RNA or chemical HDAC inhibitors, which resulted in endoplasmic reticulum stress and synergistic levels of apoptosis in vitro and in an orthotopic pancreatic cancer xenograft model in vivo. Interestingly, bortezomib did not induce aggresome formation in immortalized normal human pancreatic epithelial cells in vitro or in murine pancreatic epithelial cells in vivo. In addition, these cells did not undergo apoptosis following treatment with bortezomib, suberoylanilide hydroxamic acid, or the combination, showing tumor selectivity. Taken together, our study shows that inhibition of aggresome formation can strongly potentiate the efficacy of bortezomib and provides the foundation for clinical trials of bortezomib in combination with HDAC inhibitors for the treatment of pancreatic cancer.

Authors
Nawrocki, ST; Carew, JS; Pino, MS; Highshaw, RA; Andtbacka, RHI; Dunner, K; Pal, A; Bornmann, WG; Chiao, PJ; Huang, P; Xiong, H; Abbruzzese, JL; McConkey, DJ
MLA Citation
Nawrocki, ST, Carew, JS, Pino, MS, Highshaw, RA, Andtbacka, RHI, Dunner, K, Pal, A, Bornmann, WG, Chiao, PJ, Huang, P, Xiong, H, Abbruzzese, JL, and McConkey, DJ. "Aggresome disruption: a novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells." Cancer research 66.7 (April 2006): 3773-3781.
PMID
16585204
Source
epmc
Published In
Cancer Research
Volume
66
Issue
7
Publish Date
2006
Start Page
3773
End Page
3781
DOI
10.1158/0008-5472.can-05-2961

Protein fragment domains identified using 2D gel electrophoresis/MALDI-TOF.

We previously reported a protein expression profiling experiment conducted on human pancreatic tissues using 2D gel electrophoresis and mass spectrometry. Here, 18 spots that were identified in the gel at molecular weights more than 10 kDa lower than database values are characterized. The matrix-assisted laser desorption/ionization mass spectrometry coverage is sufficient to identify the protein region present in each spot. Most of the fragments correspond to processed chains and known structural or functional domains, which may result from limited proteolysis.

Authors
Person, MD; Shen, J; Traner, A; Hensley, SC; Lo, H-H; Abbruzzese, JL; Li, D
MLA Citation
Person, MD, Shen, J, Traner, A, Hensley, SC, Lo, H-H, Abbruzzese, JL, and Li, D. "Protein fragment domains identified using 2D gel electrophoresis/MALDI-TOF." Journal of biomolecular techniques : JBT 17.2 (April 2006): 145-156.
PMID
16741242
Source
epmc
Published In
Journal of Biomolecular Techniques
Volume
17
Issue
2
Publish Date
2006
Start Page
145
End Page
156

Single nucleotide polymorphisms of RecQ1, RAD54L, and ATM genes are associated with reduced survival of pancreatic cancer.

Our goal was to determine whether single nucleotide polymorphisms (SNPs) in DNA repair genes influence the clinical outcome of pancreatic cancer.We evaluated 13 SNPs of eight DNA damage response and repair genes in 92 patients with potentially resectable pancreatic adenocarcinoma. All patients were treated with neoadjuvant concurrent gemcitabine and radiotherapy with or without a component of induction gemcitabine/cisplatin at The University of Texas M.D. Anderson Cancer Center (Houston, TX) from February 1999 to August 2004 and observed through August 2005. Response to the pretreatment was assessed by evaluating time to tumor progression and overall survival. Kaplan-Meier plot, log-rank test, and Cox regression were used to compare survival of patients according to genotype.The RecQ1 A159C, RAD54L C157T, XRCC1 R194W, and ATM T77C genotypes had a significant effect on the overall survival with log-rank P values of .001, .004, .001, and .02, respectively. A strong combined effect of the four genotypes was observed. Patients with none of the adverse genotypes had a mean survival time of 62.1 months, and those with one, two, or three or more at-risk alleles had median survival times of 27.5, 14.4, and 9.9 months, respectively (log-rank P < .001). There is a significant interaction between the RecQ1 gene and other genotypes. All four genes except XRCC1 remained as independent predictors of survival in multivariate Cox regression models adjusted for other clinical predictors.These observations support the hypothesis that polymorphic variants of DNA repair genes affect clinical prognosis of patients with pancreatic cancer.

Authors
Li, D; Frazier, M; Evans, DB; Hess, KR; Crane, CH; Jiao, L; Abbruzzese, JL
MLA Citation
Li, D, Frazier, M, Evans, DB, Hess, KR, Crane, CH, Jiao, L, and Abbruzzese, JL. "Single nucleotide polymorphisms of RecQ1, RAD54L, and ATM genes are associated with reduced survival of pancreatic cancer." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 24.11 (April 2006): 1720-1728.
PMID
16520463
Source
epmc
Published In
Journal of Clinical Oncology
Volume
24
Issue
11
Publish Date
2006
Start Page
1720
End Page
1728
DOI
10.1200/jco.2005.04.4206

Introducing CCR Practice of Translational Oncology

Authors
Abbruzzese, JL
MLA Citation
Abbruzzese, JL. "Introducing CCR Practice of Translational Oncology." Clinical Cancer Research 12.6 (March 15, 2006): 1657-1657.
Source
crossref
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
12
Issue
6
Publish Date
2006
Start Page
1657
End Page
1657
DOI
10.1158/1078-0432.CCR-06-0403

Significant effect of homologous recombination DNA repair gene polymorphisms on pancreatic cancer survival.

Genetic variation in DNA repair may affect the clinical response to cytotoxic therapies. We investigated the effect of six single nucleotide polymorphisms of the RecQ1, RAD54L, XRCC2, and XRCC3 genes on overall survival of 378 patients with pancreatic adenocarcinoma who were treated at University of Texas M.D. Anderson Cancer Center during February 1999 to October 2004 and were followed up to October 2005. Genotypes were determined using the MassCode method. Survival was determined from pathologic diagnosis to death. Patients who were alive at the last follow-up evaluation were censored at that time. Kaplan-Meier plot, log-rank test, and Cox regression were used to compare overall survival by genotypes. A significant effect on survival of all patients was observed for RecQ1 and RAD54L genes. The median survival time was 19.2, 14.7, and 13.2 months for the RecQ1 159 AA, AC, and CC genotypes, and 16.4, 13.3, and 10.3 months for RAD54L 157 CC, CT, and TT genotypes, respectively. A significantly reduced survival was associated with the variant alleles of XRCC2 R188H and XRCC3 A17893G in subgroup analysis. When the four genes were analyzed in combination, an increasing number of adverse alleles were associated with a significantly decreased survival. Subgroup analyses have shown that the genotype effect on survival was present among patients without metastatic disease or among patients who receive radiotherapy. These observations suggest that polymorphisms of genes involved in the repair of DNA double-strand breaks significantly affect the clinical outcome of patients with pancreatic cancer.

Authors
Li, D; Liu, H; Jiao, L; Chang, DZ; Beinart, G; Wolff, RA; Evans, DB; Hassan, MM; Abbruzzese, JL
MLA Citation
Li, D, Liu, H, Jiao, L, Chang, DZ, Beinart, G, Wolff, RA, Evans, DB, Hassan, MM, and Abbruzzese, JL. "Significant effect of homologous recombination DNA repair gene polymorphisms on pancreatic cancer survival." Cancer research 66.6 (March 2006): 3323-3330.
PMID
16540687
Source
epmc
Published In
Cancer Research
Volume
66
Issue
6
Publish Date
2006
Start Page
3323
End Page
3330
DOI
10.1158/0008-5472.can-05-3032

Inhibition of SRC expression and activity inhibits tumor progression and metastasis of human pancreatic adenocarcinoma cells in an orthotopic nude mouse model.

The nonreceptor protein tyrosine kinase Src is overexpressed in 70% of pancreatic adenocarcinomas. Here, we describe the effect of molecular and pharmacological down-regulation of Src on incidence, growth, and metastasis of pancreatic tumor cells in an orthotopic model. Src expression in L3.6pl human pancreatic tumor cells was reduced by stable expression of a plasmid encoding small interfering RNA (siRNA) to c-src. In stable siRNA clones, Src expression was reduced >80%, with no change in expression of the related kinases c-Yes and c-Lyn, and proliferation rates were similar in all clones. Phosphorylation of Akt and p44/42 Erk mitogen-activated protein kinase and production of VEGF and IL-8 in culture supernatants were also reduced (P < 0.005). On orthotopic implantation of varying cell numbers into nude mice, tumor incidence was unchanged; however, in the siRNA clones, large tumors failed to develop, and incidence of metastasis was significantly reduced, suggesting that c-Src activity is critical to tumor progression. To examine this possibility further, animals bearing established wild-type tumors were treated with the Src/Abl-selective inhibitor BMS-354825 (dasatinib). Tumor size was decreased, and incidence of metastases was significantly reduced in treated mice compared with controls. These results demonstrate that Src activation contributes to pancreatic tumor progression in this model, offering Src as a candidate for targeted therapy.

Authors
Trevino, JG; Summy, JM; Lesslie, DP; Parikh, NU; Hong, DS; Lee, FY; Donato, NJ; Abbruzzese, JL; Baker, CH; Gallick, GE
MLA Citation
Trevino, JG, Summy, JM, Lesslie, DP, Parikh, NU, Hong, DS, Lee, FY, Donato, NJ, Abbruzzese, JL, Baker, CH, and Gallick, GE. "Inhibition of SRC expression and activity inhibits tumor progression and metastasis of human pancreatic adenocarcinoma cells in an orthotopic nude mouse model." The American journal of pathology 168.3 (March 2006): 962-972.
PMID
16507911
Source
epmc
Published In
The American journal of pathology
Volume
168
Issue
3
Publish Date
2006
Start Page
962
End Page
972
DOI
10.2353/ajpath.2006.050570

Phase I trial evaluating the safety of bevacizumab with concurrent radiotherapy and capecitabine in locally advanced pancreatic cancer.

PURPOSE: To study the safety of bevacizumab with capecitabine-based chemoradiotherapy. PATIENTS AND METHODS: Patients with inoperable pancreatic adenocarcinoma received bevacizumab 2 weeks before radiotherapy (50.4 Gy treating the primary tumor and gross adenopathy), every 2 weeks during radiotherapy (12 patients each at 2.5, 5.0, 7.5, and 10 mg/kg), and after radiotherapy until disease progression. Capecitabine was administered on days 14 through 52 (650 mg/m2 orally twice daily for the first six patients; 825 mg/m2 for the remaining patients). RESULTS: Significant acute gastrointestinal (43% grade 2; 4% grade 3), hand and foot syndrome (21% grade 2), and transient hematologic (8% grade 3 or greater) events were uncommon with protocol mandated dose reductions of capecitabine grade 2 toxicity (43% of patients). Among the first 30 patients treated, three patients had tumor-associated bleeding duodenal ulcers, and one had a contained duodenal perforation. No additional bleeding events occurred among the final 18 patients after patients with duodenal involvement by tumor were excluded. Nine (20%) of 46 assessable patients had confirmed partial responses until distant progression for a median of 6.2 months. Four patients have undergone pancreaticoduodenectomy without perioperative complication. The median survival was 11.6 months (95% CI, 9.6 to 13.6), from the start of protocol therapy. CONCLUSION: Concurrent bevacizumab did not significantly increase the acute toxicity of a relatively well-tolerated chemoradiotherapy regimen. However, ulceration and bleeding in the radiation field possibly related to bevacizumab occurred when tumor involved the duodenal mucosa. The encouraging efficacy end points suggest that the further study of bevacizumab with chemoradiotherapy is warranted.

Authors
Crane, CH; Ellis, LM; Abbruzzese, JL; Amos, C; Xiong, HQ; Ho, L; Evans, DB; Tamm, EP; Ng, C; Pisters, PWT; Charnsangavej, C; Delclos, ME; O'Reilly, M; Lee, JE; Wolff, RA
MLA Citation
Crane, CH, Ellis, LM, Abbruzzese, JL, Amos, C, Xiong, HQ, Ho, L, Evans, DB, Tamm, EP, Ng, C, Pisters, PWT, Charnsangavej, C, Delclos, ME, O'Reilly, M, Lee, JE, and Wolff, RA. "Phase I trial evaluating the safety of bevacizumab with concurrent radiotherapy and capecitabine in locally advanced pancreatic cancer." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 24.7 (March 2006): 1145-1151.
PMID
16505434
Source
epmc
Published In
Journal of Clinical Oncology
Volume
24
Issue
7
Publish Date
2006
Start Page
1145
End Page
1151
DOI
10.1200/jco.2005.03.6780

A Phase I study of escalating doses of the tyrosine kinase inhibitor semaxanib (SU5416) in combination with irinotecan in patients with advanced colorectal carcinoma.

One of the most studied pro-angiogenic factors involved in the development of colorectal cancer is the vascular endothelial growth factor (VEGF). The small molecule tyrosine kinase inhibitor semaxanib (SU5416) is one of the several agents targeting the VEGF signaling pathway, and its development centered mostly in the treatment of colorectal cancer.We designed and conducted an NCI-sponsored trial to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of semaxanib given twice weekly in combination with weekly irinotecan in patients with advanced colorectal cancer who had failed at least one prior treatment. The irinotecan dose was fixed at 125 mg/m(2) given weekly for 4 weeks followed by 2 weeks of rest. Patients with prior pelvic irradiation received a reduced dose of 100 mg/m(2). The semaxanib dose was escalated, going from 85 to 110 mg/m(2) and finally to 145 mg/m(2).Ten patients were treated in our study and all were evaluable for toxicity. There were no drug-related Grade 4 toxicities. There was one episode of Grade 3 headache and one episode of Grade 3 vomiting. The most common Grades 1 and 2 toxicities included diarrhea, abdominal cramping, anemia and nausea. Nine patients completed at least one 6 week cycle of treatment and were considered evaluable for response. Among those nine, two had a partial response, three had stable disease and four had progressive disease after the first cycle.Both irinotecan and semaxanib could be given at their full single-agent recommended doses without significant toxicity, and the combination showed signs of clinical activity. However, owing to discouraging results from Phase III trials, it is unlikely that this combination will be further explored.

Authors
Hoff, PM; Wolff, RA; Bogaard, K; Waldrum, S; Abbruzzese, JL
MLA Citation
Hoff, PM, Wolff, RA, Bogaard, K, Waldrum, S, and Abbruzzese, JL. "A Phase I study of escalating doses of the tyrosine kinase inhibitor semaxanib (SU5416) in combination with irinotecan in patients with advanced colorectal carcinoma." Japanese journal of clinical oncology 36.2 (February 2006): 100-103.
PMID
16449240
Source
epmc
Published In
Japanese Journal of Clinical Oncology
Volume
36
Issue
2
Publish Date
2006
Start Page
100
End Page
103
DOI
10.1093/jjco/hyi229

Selected polymorphisms of DNA repair genes and risk of pancreatic cancer.

Genetic variants of DNA repair genes may contribute to pancreatic carcinogenesis. O(6)-methylguanine-DNA methyltransferase (MGMT) is the major protein that removes alkylating DNA adducts, and apurinic/apyrimidinic endonuclease 1 (APE1) and X-ray repair cross-complementing group 1 (XRCC1) play important roles in the base excision repair pathway.We investigated the association between polymorphisms of MGMT (Leu(84)Phe and Ile(143)Val), APE1 (Asp(148)Glu), and XRCC1 (Arg(194)Trp and Arg(399)Gln) and risk of pancreatic cancer in a case-control study. Exposure information from 384 patients with primary pancreatic ductal adenocarcinoma and 357 cancer-free healthy controls were collected and genomic DNAs were genotyped for five markers. Controls were frequency matched to patients by age at enrollment (+/-5 years), gender, and race. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) by using unconditional logistic regression models.There was no significant main effect or interaction with smoking of these genetic variants on the risk of pancreatic cancer. However, the XRCC1(194) polymorphism had a significant interaction with the APE1(148) (p=0.005) or MGMT(84) polymorphism (p=0.02) in modifying the risk of pancreatic cancer.This study suggests that polymorphisms of genes involved in the repair of alkylating DNA adduct and DNA base damage may play a role in modulating the risk of pancreatic cancer. Larger studies are required to validate these preliminary findings. The mechanism of the combined genotype effects remains to be elucidated.

Authors
Jiao, L; Bondy, ML; Hassan, MM; Wolff, RA; Evans, DB; Abbruzzese, JL; Li, D
MLA Citation
Jiao, L, Bondy, ML, Hassan, MM, Wolff, RA, Evans, DB, Abbruzzese, JL, and Li, D. "Selected polymorphisms of DNA repair genes and risk of pancreatic cancer." Cancer detection and prevention 30.3 (January 2006): 284-291.
PMID
16844323
Source
epmc
Published In
Cancer Detection and Prevention
Volume
30
Issue
3
Publish Date
2006
Start Page
284
End Page
291
DOI
10.1016/j.cdp.2006.05.002

Antitumor activity of epidermal growth factor receptor-related protein is mediated by inactivation of ErbB receptors and nuclear factor-kappaB in pancreatic cancer.

The erbB family of receptor tyrosine kinases plays critical roles in human cancers, including pancreatic cancer. Discovering a specific agent, which targets multiple members of the erbB family, would be important in pancreatic cancer therapy. Recently, we isolated a novel negative regulator of epidermal growth factor receptor (EGFR), termed EGFR-related protein (ERRP), whose expression attenuates EGFR activation. In the current study, we examined the effects of recombinant ERRP on the growth and ligand-induced activation of multiple members of erbB family in three pancreatic cancer cell lines that express varying levels of EGFR and other member(s) of its family, specifically HER-2. Additionally, we compared the growth inhibitory effect of ERRP with that of Erbitux or Herceptin. Our results showed that ERRP is most effective in inhibiting proliferation of BxPC-3, HPAC, and PANC-1 pancreatic cancer cells. ERRP also inhibited ligand-induced activation of EGFR, HER-2, and HER-3 (ErbB3). In contrast, Erbitux and Herceptin only partially or modestly inhibited activation of EGFR, HER-2, and HER-3. Most importantly, ERRP was found to inhibit pancreatic tumor growth in a severe combined immunodeficient mouse xenograft model. The antitumor activity of ERRP correlates well with tumor differentiation and down-regulation of nuclear factor-kappaB activity. In summary, our results suggest that ERRP is an effective pan-erbB inhibitor, which could be a potential therapeutic agent for pancreatic cancers expressing different levels and subclasses of erbB family of proteins.

Authors
Zhang, Y; Banerjee, S; Wang, Z; Xu, H; Zhang, L; Mohammad, R; Aboukameel, A; Adsay, NV; Che, M; Abbruzzese, JL; Majumdar, APN; Sarkar, FH
MLA Citation
Zhang, Y, Banerjee, S, Wang, Z, Xu, H, Zhang, L, Mohammad, R, Aboukameel, A, Adsay, NV, Che, M, Abbruzzese, JL, Majumdar, APN, and Sarkar, FH. "Antitumor activity of epidermal growth factor receptor-related protein is mediated by inactivation of ErbB receptors and nuclear factor-kappaB in pancreatic cancer." Cancer research 66.2 (January 2006): 1025-1032.
PMID
16424038
Source
epmc
Published In
Cancer Research
Volume
66
Issue
2
Publish Date
2006
Start Page
1025
End Page
1032
DOI
10.1158/0008-5472.can-05-2968

Concurrent capecitabine and upper abdominal radiation therapy is well tolerated.

We retrospectively evaluated acute toxicity in 88 patients that were treated with capecitabine and concurrent radiotherapy to the upper abdomen. These patients included 28 (32%) with pancreatic adenocarcinoma, 18 (20%) with cholangiocarcinoma, 11 (13%) with ampullary carcinoma, 11 (13%) with other primary tumors, 14 (16%) with liver metastases, and 6 (7%) with metastases at other sites. The median dose of radiotherapy was 45 Gy (range 30-72 Gy). The median dose of capecitabine was 850 mg/m(2) twice daily, with 77% receiving 800-900 mg/m(2) twice daily. The highest grade of acute toxicity was Common Terminology Criteria (CTC) grade 0 in 5 (6%), grade 1 in 60 (68%), grade 2 in 18 (20%), and grade 3 in 5 (6%) patients. No patient had CTC grade 4 toxicity. The most common grade 2 toxicities were nausea, hand-foot syndrome, fatigue, anorexia and diarrhea. The grade 3 toxicities included nausea, vomiting and fatigue. Three patients (3%) required hospitalization due to grade 3 acute toxicity. Capecitabine was interrupted, discontinued or given at an adjusted dose in 13 (15%) patients because of acute toxicity. Therefore, capecitabine and concurrent radiotherapy to the upper abdomen appears to be well tolerated. Capecitabine may serve as an alternative to bolus or infusional 5-FU during chemoradiation for upper gastrointestinal malignancies.

Authors
Das, P; Wolff, RA; Abbruzzese, JL; Varadhachary, GR; Evans, DB; Vauthey, JN; Baschnagel, A; Delclos, ME; Krishnan, S; Janjan, NA; Crane, CH
MLA Citation
Das, P, Wolff, RA, Abbruzzese, JL, Varadhachary, GR, Evans, DB, Vauthey, JN, Baschnagel, A, Delclos, ME, Krishnan, S, Janjan, NA, and Crane, CH. "Concurrent capecitabine and upper abdominal radiation therapy is well tolerated." Radiation oncology (London, England) 1 (January 2006): 41-.
PMID
17062148
Source
epmc
Published In
Radiation Oncology
Volume
1
Publish Date
2006
Start Page
41
DOI
10.1186/1748-717x-1-41

Serum cadmium levels in pancreatic cancer patients from the East Nile Delta region of Egypt.

The northeast Nile Delta region exhibits a high incidence of early-onset pancreatic cancer. It is well documented that this region has one of the highest levels of pollution in Egypt. Epidemiologic studies have suggested that cadmium, a prevalent pollutant in the northeast Nile Delta region, plays a role in the development of pancreatic cancer.We aimed to assess serum cadmium levels as markers of exposure in pancreatic cancer patients and noncancer comparison subjects from the same region in Egypt.We assessed serum cadmium levels of 31 newly diagnosed pancreatic cancer patients and 52 hospital comparison subjects from Mansoura, Egypt. EVALUATION/MEASUREMENTS: Serum cadmium levels were measured using a novel immunoassay procedure.We found a significant difference between the mean serum cadmium levels in patients versus comparison subjects (mean+/-SD, 11.1+/-7.7 ng/mL vs. 7.1+/-5.0 ng/mL, respectively; p=0.012) but not in age, sex, residence, occupation, or smoking status. The odds ratio (OR) for pancreatic cancer risk was significant for serum cadmium level [OR=1.12; 95% confidence interval (CI), 1.04-1.23; p=0.0089] and farming (OR=3.25; 95% CI, 1.03-11.64; p=0.0475) but not for age, sex, residence, or smoking status.The results from this pilot study suggest that pancreatic cancer in the East Nile Delta region is significantly associated with high levels of serum cadmium and farming. RELEVANCE TO CLINICAL PRACTICE/PUBLIC HEALTH: Future studies should further investigate the etiologic relationship between cadmium exposure and pancreatic carcinogenesis in cadmium-exposed populations.

Authors
Kriegel, AM; Soliman, AS; Zhang, Q; El-Ghawalby, N; Ezzat, F; Soultan, A; Abdel-Wahab, M; Fathy, O; Ebidi, G; Bassiouni, N; Hamilton, SR; Abbruzzese, JL; Lacey, MR; Blake, DA
MLA Citation
Kriegel, AM, Soliman, AS, Zhang, Q, El-Ghawalby, N, Ezzat, F, Soultan, A, Abdel-Wahab, M, Fathy, O, Ebidi, G, Bassiouni, N, Hamilton, SR, Abbruzzese, JL, Lacey, MR, and Blake, DA. "Serum cadmium levels in pancreatic cancer patients from the East Nile Delta region of Egypt." Environmental health perspectives 114.1 (January 2006): 113-119.
PMID
16393667
Source
epmc
Published In
Environmental health perspectives
Volume
114
Issue
1
Publish Date
2006
Start Page
113
End Page
119

Pancreatic cancer mortality in Egypt: comparison to the United States pancreatic cancer mortality rates.

OBJECTIVES: Little is known about the descriptive epidemiology of pancreatic cancer in many developing countries, such as Egypt. It is believed to be rare in developing countries, but this may reflect lack of systematic cancer registration. Mortality may serve as a surrogate for incidence, since the disease is lethal. Because of availability of reliable mortality registration in Egypt, we used the national mortality data to estimate pancreatic cancer mortality in 2765 deaths from 2000 to 2004, and to gain insights into the disease incidence. METHODS: Mortality data in Egypt was obtained from the electronic national mortality records of the Ministry of Health. We calculated population-based age-specific and age-standardized pancreatic cancer mortality rates for Egypt, and compared them with the Surveillance, Epidemiology, and End Results (SEER) mortality data of the United States. RESULTS: Comparisons of age-specific mortality demonstrated higher rates in Egypt compared to the United States for subjects under age 20 years (relative risks (RR) of 7.7 and 4.2, for the age groups 0-15 and 15-20, respectively), and significantly higher rates in the United States compared to Egypt for subjects 40 years and older (RR 1.8-80.5 for the age groups of 40-45 to 75+). For the majority of age groups in Egypt and the United States, mortality in males was higher than in females. Analysis of regional distribution of pancreatic cancer mortality in Egypt showed significant variations in rates among provinces (p<0.0001) with Northern provinces having average rate that is 2.85 times the rate of Southern provinces. The highest mortality rates were observed in the Nile Delta compared to southern Egypt and the oasis. CONCLUSIONS: The findings of this study demonstrate both international and regional variation in pancreatic cancer mortality, and highlight the importance of further investigation to explore the possible factors that may contribute to the observed epidemiological patterns.

Authors
Soliman, AS; Zhang, Q; Saleh, T; Zarzour, A; Selim, M; Abdel-Fattah, M; Abbruzzese, JL
MLA Citation
Soliman, AS, Zhang, Q, Saleh, T, Zarzour, A, Selim, M, Abdel-Fattah, M, and Abbruzzese, JL. "Pancreatic cancer mortality in Egypt: comparison to the United States pancreatic cancer mortality rates." Cancer detection and prevention 30.5 (January 2006): 473-479.
PMID
17067749
Source
epmc
Published In
Cancer Detection and Prevention
Volume
30
Issue
5
Publish Date
2006
Start Page
473
End Page
479
DOI
10.1016/j.cdp.2006.06.006

Cytotoxic chemotherapy for pancreatic cancer: Advances to date and future directions.

Chemotherapy remains the mainstay of treatment for pancreatic cancer as most patients present with advanced disease, which precludes locoregional treatment. However, the efficacy of chemotherapy is limited. Gemcitabine is the only agent that improves symptoms and confers a modest survival advantage. Many combination therapy regimens have been studied in phase II settings. Eleven randomised phase III trials have been conducted to compare gemcitabine-containing regimens with gemcitabine monotherapy since gemcitabine became available clinically. The combination of gemcitabine plus capecitabine has demonstrated a survival advantage over gemcitabine, whereas gemcitabine plus oxaliplatin and gemcitabine plus cisplatin have shown improved progression-free survival or time to tumour progression but failed to demonstrate a survival advantage over gemcitabine. The search for effective therapy for advanced pancreatic cancer continues. Gemcitabine in combination with cytotoxic agents or molecular targeted agents hold promise.

Authors
Xiong, HQ; Carr, K; Abbruzzese, JL
MLA Citation
Xiong, HQ, Carr, K, and Abbruzzese, JL. "Cytotoxic chemotherapy for pancreatic cancer: Advances to date and future directions." Drugs 66.8 (January 2006): 1059-1072. (Review)
PMID
16789792
Source
epmc
Published In
Drugs
Volume
66
Issue
8
Publish Date
2006
Start Page
1059
End Page
1072
DOI
10.2165/00003495-200666080-00003

Polymorphisms of cytochrome P4501A2 and N-acetyltransferase genes, smoking, and risk of pancreatic cancer.

To test the hypothesis that genetic variation in the metabolism of tobacco carcinogens, such as aromatic amines (AA) and heterocyclic amines (HCA), contributes to pancreatic cancer, we have examined genetic polymorphisms of three key enzymes, i.e. cytochrome P450 1A2 (CYP1A2) and N-acetyltransferase 1 and 2 (NAT1 and NAT2), in a hospital-based case-control study of 365 patients with pancreatic adenocarcinoma and 379 frequency-matched healthy controls. Genotypes were determined using PCR-restriction fragment length polymorphism (RFLP) and Taqman methods. Smoking information was collected by personal interview. Adjusted odds ratio (AOR) and 95% confidence interval (CI) was estimated by unconditional multivariate logistic regression analysis. We found that the NAT1 'rapid' alleles were associated with a 1.5-fold increased risk of pancreatic cancer (95% CI: 1.0-2.1) with adjustment of potential confounders. This effect was more prominent among never smokers (AOR: 2.4, 95% CI: 1.4-4.3) and females (AOR: 1.8, 95% CI: 1.0-3.1). Some genotypes were significantly associated with increased risk for pancreatic cancer among smokers, especially heavy smokers (<20 pack years). For example, heavy smokers with the CYP1A2*1D (T-2467delT) delT, CYP1A2*1F(A-163C) C allele, NAT1 'rapid' or NAT2 'slow' alleles had an AOR (95% CI) of 1.4 (0.7-2.3), 1.9 (1.1-3.4), 3.0 (1.6-5.4) and 1.5 (0.8-2.6), respectively, compared with never smokers carrying the non-at-risk alleles. These effects were more prominent in females than in males. The corresponding AOR (95% CI) was 3.1 (1.0-8.0), 3.8 (1.5-10.1), 4.5 (1.6-12.7) and 2.0 (0.8-5.1) for females versus 1.0 (0.4-1.9), 1.1 (0.5-2.4), 2.1 (1.0-4.6) and 1.1 (0.5-2.6) for males. A significant synergistic effect of CYP1A2*1F C allele and NAT1"rapid" alleles on the risk for pancreatic cancer was also detected among never smokers (AOR: 2.9, 95% CI: 1.2-6.9) and among females (AOR: 2.5, 95% CI: 1.1-5.7). These data suggest that polymorphisms of the CYP1A2 and NAT1 genes modify the risk of pancreatic cancer.

Authors
Li, D; Jiao, L; Li, Y; Doll, MA; Hein, DW; Bondy, ML; Evans, DB; Wolff, RA; Lenzi, R; Pisters, PW; Abbruzzese, JL; Hassan, MM
MLA Citation
Li, D, Jiao, L, Li, Y, Doll, MA, Hein, DW, Bondy, ML, Evans, DB, Wolff, RA, Lenzi, R, Pisters, PW, Abbruzzese, JL, and Hassan, MM. "Polymorphisms of cytochrome P4501A2 and N-acetyltransferase genes, smoking, and risk of pancreatic cancer." Carcinogenesis 27.1 (January 2006): 103-111.
PMID
15987714
Source
epmc
Published In
Carcinogenesis
Volume
27
Issue
1
Publish Date
2006
Start Page
103
End Page
111
DOI
10.1093/carcin/bgi171

Bortezomib inhibits PKR-like endoplasmic reticulum (ER) kinase and induces apoptosis via ER stress in human pancreatic cancer cells.

Bortezomib (Velcade, formerly known as PS-341) is a boronic acid dipeptide derivative that is a selective and potent inhibitor of the proteasome. We hypothesized that proteasome inhibition would lead to an accumulation of misfolded proteins in the cell resulting in endoplasmic reticulum (ER) stress. The ability of bortezomib to induce ER stress and the unfolded protein response was investigated in a human pancreatic cancer cell line, L3.6pl. Bortezomib increased expression of ER stress markers, CHOP and BiP, but inhibited PKR-like ER kinase and subsequent phosphorylation of eukaryotic initiation factor 2alpha (eif2alpha), both of which are key events in translational suppression. These effects resulted in an accumulation of ubiquitylated proteins leading to protein aggregation and proteotoxicity. Peptide inhibitor or small interfering RNA targeting ER-resident caspase-4 blocked DNA fragmentation, establishing a central role for caspase-4 in bortezomib-induced cell death. The translation inhibitor cycloheximide abrogated bortezomib-induced protein aggregation, caspase-4 processing, and all other characteristics of apoptosis. Because malignant cells have higher protein synthesis rates than normal cells, they may be more prone to protein aggregation and proteotoxicity and possess increased sensitivity to bortezomib-induced apoptosis. Taken together, the results show that bortezomib induces a unique type of ER stress compared with other ER stress agents characterized by an absence of eif2alpha phosphorylation, ubiquitylated protein accumulation, and proteotoxicity.

Authors
Nawrocki, ST; Carew, JS; Dunner, K; Boise, LH; Chiao, PJ; Huang, P; Abbruzzese, JL; McConkey, DJ
MLA Citation
Nawrocki, ST, Carew, JS, Dunner, K, Boise, LH, Chiao, PJ, Huang, P, Abbruzzese, JL, and McConkey, DJ. "Bortezomib inhibits PKR-like endoplasmic reticulum (ER) kinase and induces apoptosis via ER stress in human pancreatic cancer cells." Cancer research 65.24 (December 2005): 11510-11519.
PMID
16357160
Source
epmc
Published In
Cancer Research
Volume
65
Issue
24
Publish Date
2005
Start Page
11510
End Page
11519
DOI
10.1158/0008-5472.can-05-2394

Bortezomib sensitizes pancreatic cancer cells to endoplasmic reticulum stress-mediated apoptosis.

Bortezomib (PS-341, Velcade) is a potent and selective inhibitor of the proteasome that is currently under investigation for the treatment of solid malignancies. We have shown previously that bortezomib has activity in pancreatic cancer models and that the drug induces endoplasmic reticulum (ER) stress but also suppresses the unfolded protein response (UPR). Because the UPR is an important cytoprotective mechanism, we hypothesized that bortezomib would sensitize pancreatic cancer cells to ER stress-mediated apoptosis. Here, we show that bortezomib promotes apoptosis triggered by classic ER stress inducers (tunicamycin and thapsigargin) via a c-Jun NH(2)-terminal kinase (JNK)-dependent mechanism. We also show that cisplatin stimulates ER stress and interacts with bortezomib to increase ER dilation, intracellular Ca(2+) levels, and cell death. Importantly, combined therapy with bortezomib plus cisplatin induced JNK activation and apoptosis in orthotopic pancreatic tumors resulting in a reduction in tumor burden. Taken together, our data establish that bortezomib sensitizes pancreatic cancer cells to ER stress-induced apoptosis and show that bortezomib strongly enhances the anticancer activity of cisplatin.

Authors
Nawrocki, ST; Carew, JS; Pino, MS; Highshaw, RA; Dunner, K; Huang, P; Abbruzzese, JL; McConkey, DJ
MLA Citation
Nawrocki, ST, Carew, JS, Pino, MS, Highshaw, RA, Dunner, K, Huang, P, Abbruzzese, JL, and McConkey, DJ. "Bortezomib sensitizes pancreatic cancer cells to endoplasmic reticulum stress-mediated apoptosis." Cancer research 65.24 (December 2005): 11658-11666.
PMID
16357177
Source
epmc
Published In
Cancer Research
Volume
65
Issue
24
Publish Date
2005
Start Page
11658
End Page
11666
DOI
10.1158/0008-5472.can-05-2370

Opportunities for targeted therapies in hepatocellular carcinoma.

Hepatocellular cancer (HCC) is the fifth most common solid tumor worldwide, accounting for 500,000 new cases annually. Although less common in the United States, HCC is expected to increase in incidence over the next two decades largely because of the prevalence of hepatitis C virus infection. A majority of patients present with advanced disease and are not candidates for liver transplantation, surgical resection, or regional therapy. In 60% to 80% of patients with HCC, treatment is complicated by underlying liver cirrhosis and hepatic dysfunction. Systemic treatments are minimally effective, can have significant toxicity, and have not been shown to improve patient survival. New approaches targeting molecular abnormalities specific to HCC are needed to improve patient outcome. This review summarizes the state of knowledge of those key aspects of the molecular pathogenesis of HCC that may represent rational therapeutic targets in this disease. Relevant preclinical and clinical information on novel compounds directed toward abnormalities in HCC is reviewed.

Authors
Thomas, MB; Abbruzzese, JL
MLA Citation
Thomas, MB, and Abbruzzese, JL. "Opportunities for targeted therapies in hepatocellular carcinoma." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 23.31 (November 2005): 8093-8108. (Review)
PMID
16258107
Source
epmc
Published In
Journal of Clinical Oncology
Volume
23
Issue
31
Publish Date
2005
Start Page
8093
End Page
8108
DOI
10.1200/jco.2004.00.1537

Serum amyloid A as a tumor marker in sera of nude mice with orthotopic human pancreatic cancer and in plasma of patients with pancreatic cancer.

We screened an orthotopic nude mouse model of human pancreatic cancer for candidate serum biomarkers and examined their presence in the plasma of pancreatic cancer patients. Nude mice were injected in the pancreas with L3.9pl human pancreatic cancer cells. One week later, the mice were randomized into 4 treatment groups: i) control, saline; ii) oral STI 571; iii) intraperitoneal gemcitabine; and iv) STI 571 and gemcitabine. After 1, 2, and 3 weeks of treatment, sera and tumors were collected from mice in each group as well as uninjected mice. All sera were analyzed by surface enhanced laser desorption ionization mass spectrometry using ProteinChip technology. Protein profiles were analyzed with the Biomarker Wizard software package. The concentration of candidate proteins was evaluated in mouse sera and plasma from 135 pancreatic cancer patients, 7 pancreatitis patients, and 113 healthy volunteers. The combination therapy inhibited tumor growth. A 11.7-kDa protein peak correlating with tumor weight was purified by gel filtration, separated by SDS-PAGE, and identified as mouse serum amyloid A (SAA) by amino acid sequencing and public database searches. The expression of SAA in mouse sera was confirmed by Western blotting and correlated with tumor weight. The level of SAA in plasma of pancreatic cancer patients correlated with clinical stage and was significantly higher than in normal volunteers (mean value: 180.1 microg/ml vs 27.9 microg/ml: P<0.01) or pancreatitis patients. For SAA used as a single tumor marker with a cut-off of 75 microg/ml, the sensitivity for pancreatic cancer was 96.5% and specificity was 31.9%. Our search for specific marker proteins to identify pancreatic cancer was unsuccessful. Although SAA is not specific for pancreatic cancer and not sensitive enough to detect stage I patients, it may be a candidate biomarker for detecting and monitoring the progressive growth of pancreatic cancer.

Authors
Yokoi, K; Shih, L-CN; Kobayashi, R; Koomen, J; Hawke, D; Li, D; Hamilton, SR; Abbruzzese, JL; Coombes, KR; Fidler, IJ
MLA Citation
Yokoi, K, Shih, L-CN, Kobayashi, R, Koomen, J, Hawke, D, Li, D, Hamilton, SR, Abbruzzese, JL, Coombes, KR, and Fidler, IJ. "Serum amyloid A as a tumor marker in sera of nude mice with orthotopic human pancreatic cancer and in plasma of patients with pancreatic cancer." International journal of oncology 27.5 (November 2005): 1361-1369.
PMID
16211233
Source
epmc
Published In
International journal of oncology
Volume
27
Issue
5
Publish Date
2005
Start Page
1361
End Page
1369

Simultaneous inhibition of EGFR, VEGFR, and platelet-derived growth factor receptor signaling combined with gemcitabine produces therapy of human pancreatic carcinoma and prolongs survival in an orthotopic nude mouse model.

Although gemcitabine has been approved as the first-line chemotherapeutic reagent for pancreatic cancer, its response rate is low and average survival duration is still only marginal. Because epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR) modulate tumor progression, we hypothesized that inhibition of phosphorylation of all three on tumor cells, tumor-associated endothelial cells, and stroma cells would improve the treatment efficacy of gemcitabine in an orthotopic pancreatic tumor model in nude mice and prolong survival. We implanted L3.6pl, a human pancreatic cancer cell, in the pancreas of nude mice. We found that tumor-associated endothelial cells in this model highly expressed phosphorylated EGFR, VEGFR, and PDGFR. Oral administration of AEE788, a dual tyrosine kinase inhibitor against EGFR and VEGFR, decreased phosphorylation of EGFR and VEGFR. PDGFR phosphorylation was inhibited by STI571. Although i.p. injection of gemcitabine did not inhibit tumor growth, its combination with AEE788 and STI571 produced >80% inhibition of tumor growth and prolonged survival in parallel with increases in number of tumor cells and tumor-associated endothelial cell apoptosis, decreased microvascular density, decreased proliferation rate, and prolonged survival. STI571 treatment also decreased pericyte coverage on tumor-associated endothelial cells. Thus, inhibiting phosphorylation of EGFR, VEGFR, and PDGFR in combination with gemcitabine enhanced the efficacy of gemcitabine, resulting in inhibition of experimental human pancreatic cancer growth and significant prolongation of survival.

Authors
Yokoi, K; Sasaki, T; Bucana, CD; Fan, D; Baker, CH; Kitadai, Y; Kuwai, T; Abbruzzese, JL; Fidler, IJ
MLA Citation
Yokoi, K, Sasaki, T, Bucana, CD, Fan, D, Baker, CH, Kitadai, Y, Kuwai, T, Abbruzzese, JL, and Fidler, IJ. "Simultaneous inhibition of EGFR, VEGFR, and platelet-derived growth factor receptor signaling combined with gemcitabine produces therapy of human pancreatic carcinoma and prolongs survival in an orthotopic nude mouse model." Cancer research 65.22 (November 2005): 10371-10380.
PMID
16288027
Source
epmc
Published In
Cancer Research
Volume
65
Issue
22
Publish Date
2005
Start Page
10371
End Page
10380
DOI
10.1158/0008-5472.can-05-1698

The subcellular localization of syntaxin 17 varies among different cell types and is altered in some malignant cells.

Syntaxin 17 (STX17) is a divergent member of the syntaxin family of proteins first discovered by Scheller and colleagues in a yeast two-hybrid screen designed to identify novel mammalian SNAREs (soluble N-ethylmaleimide-sensitive factor-attachment protein receptors). We recently independently identified STX17 as a novel Ras-interacting protein, but immunohistochemical studies suggested that STX17 is localized to the nucleus in normal pancreatic ductal epithelial, acinar, and islet cells in contrast to previous reports of cytoplasmic localization, albeit in other cell types. Therefore, we have conducted a more thorough survey of various human and mouse tissues to better establish the expression pattern of STX17 in different tissues and cell types. Although RT-PCR experiments demonstrate ubiquitous expression of STX17, closer examination by immunohistochemistry reveal that STX17 expression is limited to certain cell types. Furthermore, in contrast to the cytoplasmic localization previously reported in a limited number of cell types, we find that in many other cell types, syntaxin 17 can be found in the nucleus. Finally, we demonstrate that in human hepatocellular carcinoma cell lines, STX17 localization is altered relative to normal hepatocytes, although the localization of STX17 differs even between these established human cancer cell lines and fresh human hepatocellular carcinoma cells, emphasizing the caution that must be exercised in drawing conclusions from data gathered in cell lines. The sequence divergence of STX17, the unexpected nuclear localization of STX17 in many cell types, and the altered localization of STX17 in malignant cells argue for a novel function of syntaxin 17 distinct from its hypothesized role in mediating membrane fusion events.

Authors
Zhang, Q; Li, J; Deavers, M; Abbruzzese, JL; Ho, L
MLA Citation
Zhang, Q, Li, J, Deavers, M, Abbruzzese, JL, and Ho, L. "The subcellular localization of syntaxin 17 varies among different cell types and is altered in some malignant cells." The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 53.11 (November 2005): 1371-1382.
PMID
15956034
Source
epmc
Published In
Journal of Histochemistry and Cytochemistry
Volume
53
Issue
11
Publish Date
2005
Start Page
1371
End Page
1382
DOI
10.1369/jhc.4a6508.2005

Prostate size and risk of high-grade, advanced prostate cancer and biochemical progression after radical prostatectomy: a search database study.

PURPOSE: Prostate growth and differentiation are under androgenic control, and prior studies suggested that tumors that develop in hypogonadal men are more aggressive. We examined whether prostate weight was associated with tumor grade, advanced disease, or risk of biochemical progression after radical prostatectomy (RP). PATIENTS AND METHODS: We evaluated the association of prostate weight with pathologic tumor grade, positive surgical margins, extracapsular disease, and seminal vesicle invasion using logistic regression and with biochemical progression using Cox proportional hazards regression among 1,602 men treated with RP between 1988 and 2003 at five equal-access medical centers, which composed the Shared Equal Access Regional Cancer Hospital (SEARCH) Database. RESULTS: In outcome prediction models including multiple predictor variables, it was found that the predictor variable of prostate weight was significantly inversely associated with the outcomes of high-grade disease, positive surgical margins, extracapsular extension (all P < or = .004), and biochemical progression (comparing prostate weight < 20 v > or = 100 g: relative risk = 8.43; 95% CI, 2.9 to 24.0; P < .001). Similar associations were seen between preoperative transrectal ultrasound-measured prostate volume and high-grade disease, positive surgical margins, extracapsular extension (all P < or = .005), seminal vesicle invasion (P = .07), and biochemical progression (P = .06). CONCLUSION: Men with smaller prostates had more high-grade cancers and more advanced disease and were at greater risk of progression after RP. These results suggest that prostate size may be an important prognostic variable that should be evaluated for use pre- and postoperatively to predict biochemical progression.

Authors
Freedland, SJ; Isaacs, WB; Platz, EA; Terris, MK; Aronson, WJ; Amling, CL; Presti, JC; Kane, CJ
MLA Citation
Freedland, SJ, Isaacs, WB, Platz, EA, Terris, MK, Aronson, WJ, Amling, CL, Presti, JC, and Kane, CJ. "Prostate size and risk of high-grade, advanced prostate cancer and biochemical progression after radical prostatectomy: a search database study." J Clin Oncol 23.30 (October 20, 2005): 7546-7554.
PMID
16234520
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
23
Issue
30
Publish Date
2005
Start Page
7546
End Page
7554
DOI
10.1200/JCO.2005.05.525

Insulin receptor substrate is a mediator of phosphoinositide 3-kinase activation in quiescent pancreatic cancer cells.

Phosphoinositide 3-kinase (PI3K) is activated in pancreatic cancer cells and plays a central role in their proliferation, survival, and drug resistance. Although the mechanism is unclear, PI3K activation in these cells could be due to physical interaction between its regulatory subunit (p85) and specific tyrosine kinases or their mediators. Consistent with this possibility, PI3K was precipitated with anti-phosphotyrosine antibodies and Akt phosphorylation was blocked by the tyrosine kinase inhibitors SU6656 and PD158780 in quiescent pancreatic cancer cells. Pull-down assays with a fusion protein (GST-p85NC-SH2), and coimmunoprecipitation studies, indicated that the insulin receptor substrate (IRS), and not the epidermal growth factor and insulin-like growth factor receptors or the Src tyrosine kinase, was physically associated with PI3K in these cells. Our data also indicated that SU6656 and PD158780 inhibited Akt activation in pancreatic cancer cells by interfering with the ability of IRS-1 to recruit PI3K. Furthermore, IRS-1 was phosphorylated on a p85-binding site (Y(612)), and IRS-specific small interfering RNA potently inhibited activation of PI3K and Akt in transfected cells. Taken together, these observations indicate that IRS is a mediator of PI3K activation in quiescent pancreatic cancer cells.

Authors
Asano, T; Yao, Y; Shin, S; McCubrey, J; Abbruzzese, JL; Reddy, SAG
MLA Citation
Asano, T, Yao, Y, Shin, S, McCubrey, J, Abbruzzese, JL, and Reddy, SAG. "Insulin receptor substrate is a mediator of phosphoinositide 3-kinase activation in quiescent pancreatic cancer cells." Cancer research 65.20 (October 2005): 9164-9168.
PMID
16230374
Source
epmc
Published In
Cancer Research
Volume
65
Issue
20
Publish Date
2005
Start Page
9164
End Page
9168
DOI
10.1158/0008-5472.can-05-0779

A phase II study of farnesyl transferase inhibitor R115777 in pancreatic cancer: a Southwest oncology group (SWOG 9924) study.

Ninety per cent of pancreatic adenocarcinomas (PC) contain mutations of the K-Ras proto-oncogene resulting in constitutively activated Ras protein. A critical step in Ras activation is farnesylation of Ras protein. Farnesyl transferase inhibitors are compounds that inhibit farnesylation. We report the results of a phase II trial of R115777, an oral farnesyl transferase inhibitor, in patients with surgically incurable locally advanced or metastatic PC. Between 6/1/2000 and 11/20/2001, 58 cases were accrued, 53 of whom were eligible and analyzable. Patients were required to have a performance status (PS) 0 to 1, be able to take oral medications, and to have adequate renal, hepatic, and hematologic functions. Fifty-five percent were male. Median age was 64.7 years (38.9 to 80.6), and patients had no previous systemic therapy for advanced PC. Treatment consisted of R115777 300 mg po bid given for 3 out of every 4 weeks. Toxicities were as follows: Grade 3 in 19/53 (36%), grade 4 in 53 (173%), and grade 5 in 53 (8%). Most frequent toxicities were: anemia 35/53 (66%), fatigue and malaise 33/53 (62%), nausea 31/53 (58%). Grade 5 toxicities included: thromboembolism 1, infection 2, other 1. Median survival was 2.6 months (mo) (95% CI 2.1-3.6), 6-mo survival is 19% (95% CI, 8-29%), median time to treatment failure was 1.4 mo (95% GI 1.1-1.6). R115777 is ineffective as monotherapy in advanced pancreatic cancer.

Authors
Macdonald, JS; McCoy, S; Whitehead, RP; Iqbal, S; Wade, JL; Giguere, JK; Abbruzzese, JL
MLA Citation
Macdonald, JS, McCoy, S, Whitehead, RP, Iqbal, S, Wade, JL, Giguere, JK, and Abbruzzese, JL. "A phase II study of farnesyl transferase inhibitor R115777 in pancreatic cancer: a Southwest oncology group (SWOG 9924) study." Investigational new drugs 23.5 (October 2005): 485-487.
PMID
16133800
Source
epmc
Published In
Investigational New Drugs
Volume
23
Issue
5
Publish Date
2005
Start Page
485
End Page
487
DOI
10.1007/s10637-005-2908-y

Molecular evidence for increased antitumor activity of gemcitabine by genistein in vitro and in vivo using an orthotopic model of pancreatic cancer.

Soy isoflavone genistein exhibits growth inhibitory activity against human pancreatic cancer cell lines. We previously reported the potential of genistein to augment chemotherapeutic response of pancreatic cancer cells in vitro. In the present study, we investigated whether genistein pretreatment could be used as a novel strategy for gemcitabine-induced killing in vitro and enhanced antitumor activity in vivo using an orthotopic tumor model. We conducted our studies using paired isogenic human pancreatic cancer cell line with differences in metastatic behavior (COLO 357 and L3.6pl). In vitro studies were done to measure growth inhibition and degree of apoptotic cell death induced by either genistein alone, gemcitabine alone, or genistein followed by gemcitabine. Our results show that pretreatment of cells with genistein for 24 hours followed by gemcitabine resulted in 60% to 80% growth inhibition compared with 25% to 30% when gemcitabine was used alone. The overall growth inhibition was directly correlated with apoptotic cell death irrespective of the metastatic potential of cells. Several genes that are known to inhibit apoptosis and contribute to chemoresistance such as nuclear factor-kappaB (NF-kappaB) and Akt were assessed to investigate the basis for the observed chemosensitizing effects of genistein. Genistein potentiated the gemcitabine-induced killing by down-regulation of NF-kappaB and Akt. In contrast, Akt and NF-kappaB were found to be up-regulated when pancreatic cancer cells were exposed to gemcitabine alone, suggesting the potential mechanism of acquired chemoresistance. In addition to in vitro results, we show here for the first time, that genistein in combination with gemcitabine is much more effective as an antitumor agent compared with either agent alone in our orthotopic tumor model. But most importantly, our data also showed that a specific target, such as NF-kappaB, was inactivated in genistein-treated animal tumors and that gemcitabine-induced activation of NF-kappaB was completely inhibited in animal tumors treated with genistein and gemcitabine. These results provide strong molecular in vivo evidence in support of our hypothesis that inactivation of NF-kappaB signaling pathway by genistein could also abrogate gemcitabine-induced activation of NF-kappaB resulting in the chemosensitization of pancreatic tumors to gemcitabine, which is likely to be an important and novel strategy for the treatment of pancreatic cancer.

Authors
Banerjee, S; Zhang, Y; Ali, S; Bhuiyan, M; Wang, Z; Chiao, PJ; Philip, PA; Abbruzzese, J; Sarkar, FH
MLA Citation
Banerjee, S, Zhang, Y, Ali, S, Bhuiyan, M, Wang, Z, Chiao, PJ, Philip, PA, Abbruzzese, J, and Sarkar, FH. "Molecular evidence for increased antitumor activity of gemcitabine by genistein in vitro and in vivo using an orthotopic model of pancreatic cancer." Cancer research 65.19 (October 2005): 9064-9072.
PMID
16204081
Source
epmc
Published In
Cancer Research
Volume
65
Issue
19
Publish Date
2005
Start Page
9064
End Page
9072
DOI
10.1158/0008-5472.can-05-1330

Phase II trials of dolastatin-10 in advanced pancreaticobiliary cancers.

BACKGROUND: Pancreaticobiliary malignancies respond poorly to conventional chemotherapy, and novel agents are needed. Dolatstatin-10 is a potent antimitotic pentapeptide isolated from the marine mollusk Dolabella auricularia that inhibits microtubule assembly. We conducted 2 parallel phase II trials of dolastatin-10 in patients with advanced hepatobiliary cancers and pancreatic adenocarcinoma. PATIENTS AND METHODS: Eligible patients had histologically-confirmed metastatic pancreatic adenocarcinoma or metastatic, locally advanced or recurrent cancer of the liver, bile duct or gallbladder, and had received no prior chemotherapy for advanced disease. Dolastatin-10 400 microg/m(2) was administered intravenously by bolus every 21 days. Restaging CT scans were obtained every 2 cycles. RESULTS: Twenty-eight patients (16 hepatobiliary, including 7 hepatomas, 6 cholangiocarcinomas, 2 gallbladder carcinomas, and 12 pancreatic carcinomas) enrolled; 27 were evaluable for response. There were no objective responses. Grade 3/4 neutropenia occurred in 59% of patients and neutropenic fever in 18%. Median and 1-year survival were 5.0 months and 17% for the pancreatic cancer patients, and 3.0 months and 29% for the hepatobiliary patients. Median time to progression was 1.3 months for the pancreatic cancer patients and 1.6 months for the hepatobiliary patients. CONCLUSIONS: Dolastatin-10 is inactive against hepatobiliary and pancreatic carcinomas.

Authors
Kindler, HL; Tothy, PK; Wolff, R; McCormack, RA; Abbruzzese, JL; Mani, S; Wade-Oliver, KT; Vokes, EE
MLA Citation
Kindler, HL, Tothy, PK, Wolff, R, McCormack, RA, Abbruzzese, JL, Mani, S, Wade-Oliver, KT, and Vokes, EE. "Phase II trials of dolastatin-10 in advanced pancreaticobiliary cancers." Investigational new drugs 23.5 (October 2005): 489-493.
PMID
16133801
Source
epmc
Published In
Investigational New Drugs
Volume
23
Issue
5
Publish Date
2005
Start Page
489
End Page
493
DOI
10.1007/s10637-005-2909-x

Induction of apoptosis in tumor-associated endothelial cells and therapy of orthotopic human pancreatic carcinoma in nude mice.

Although gemcitabine has been accepted as the first-line chemotherapeutic reagent for advanced pancreatic cancer, improvement of response rate and survival is not sufficient and patients often develop resistance. We hypothesized that the inhibition of phosphorylation of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) on tumor cells and tumor-associated endothelial cells, combined with gemcitabine, would overcome the resistance to gemcitabine in orthotopic pancreatic tumor animal model. L3.6pl, human pancreatic cancer cells growing in the pancreas, and tumor-associated endothelial cells in microorgan environment highly expressed phosphorylated EGFR, VEGFR, and Akt, which regulates antiapoptotic mechanism. Oral administration of AEE788 (dual tyrosine kinase inhibitor against EGFR and VEGFR) inhibited the phosphorylation of EGFR, VEGFR, and Akt on tumor-associated endothelial cells as well as tumor cells. Although intraperitoneal (i.p.) injection of gemcitabine showed limited inhibitory effect on tumor growth, combination with AEE788 and gemcitabine produced nearly 95% inhibition of tumor growth in parallel with a high level of apoptosis on tumor cells and tumor-associated endothelial cells, and decreased microvascular density and proliferation rate. Collectively, these data indicate that dual inhibition of phosphorylation of EGFR and VEGFR, in combination with gemcitabine, produces apoptosis of tumor-associated endothelial cells and significantly suppresses human pancreatic cancer in nude mice.

Authors
Yokoi, K; Kim, S-J; Thaker, P; Yazici, S; Nam, D-H; He, J; Sasaki, T; Chiao, PJ; Sclabas, GM; Abbruzzese, JL; Hamilton, SR; Fidler, IJ
MLA Citation
Yokoi, K, Kim, S-J, Thaker, P, Yazici, S, Nam, D-H, He, J, Sasaki, T, Chiao, PJ, Sclabas, GM, Abbruzzese, JL, Hamilton, SR, and Fidler, IJ. "Induction of apoptosis in tumor-associated endothelial cells and therapy of orthotopic human pancreatic carcinoma in nude mice." Neoplasia (New York, N.Y.) 7.7 (July 2005): 696-704.
PMID
16026649
Source
epmc
Published In
Neoplasia (New York, N.Y.)
Volume
7
Issue
7
Publish Date
2005
Start Page
696
End Page
704
DOI
10.1593/neo.05193

Serum CA19-9 response as a surrogate for clinical outcome in patients receiving fixed-dose rate gemcitabine for advanced pancreatic cancer.

The use of serial serum measurements of the carbohydrate antigen 19-9 (CA19-9) to guide treatment decisions and serve as a surrogate end point in clinical trial design requires further validation. We investigated whether CA19-9 decline represents an accurate surrogate for survival and time to treatment failure (TTF) in a cohort of 76 patients with advanced pancreatic cancer receiving fixed-dose rate gemcitabine in three separate studies. Statistically significant correlations between percentage CA19-9 decline and both overall survival and TTF were found, with median survival ranging from 12.0 months for patients with the greatest degree of biomarker decline (> 75%) compared with 4.3 months in those whose CA19-9 did not decline during therapy (P < 0.001). Using specific thresholds, patients with > or = 25% decline in CA19-9 during treatment had significantly better outcomes than those who did not (median survival and TTF of 9.6 and 4.6 months vs 4.4 and 1.5 months; P < 0.001). Similar results were seen using both 50 and 75% as cutoff points. We conclude that serial CA19-9 measurements correlate well with clinical outcomes in this patient population, and that decline in this biomarker should be entertained for possible use as a surrogate end point in clinical trials for the selection of new treatments in this disease.

Authors
Ko, AH; Hwang, J; Venook, AP; Abbruzzese, JL; Bergsland, EK; Tempero, MA
MLA Citation
Ko, AH, Hwang, J, Venook, AP, Abbruzzese, JL, Bergsland, EK, and Tempero, MA. "Serum CA19-9 response as a surrogate for clinical outcome in patients receiving fixed-dose rate gemcitabine for advanced pancreatic cancer." British journal of cancer 93.2 (July 2005): 195-199.
PMID
15999098
Source
epmc
Published In
British Journal of Cancer
Volume
93
Issue
2
Publish Date
2005
Start Page
195
End Page
199
DOI
10.1038/sj.bjc.6602687

The PI 3-kinase/Akt signaling pathway is activated due to aberrant Pten expression and targets transcription factors NF-κB and c-Myc in pancreatic cancer cells

Authors
Asano, T; Yao, Y; Zhu, J; Li, D; Abbruzzese, JL; Reddy, SAG
MLA Citation
Asano, T, Yao, Y, Zhu, J, Li, D, Abbruzzese, JL, and Reddy, SAG. "The PI 3-kinase/Akt signaling pathway is activated due to aberrant Pten expression and targets transcription factors NF-κB and c-Myc in pancreatic cancer cells." Oncogene 24.26 (June 16, 2005): 4320-4320.
Source
crossref
Published In
Oncogene: Including Oncogene Reviews
Volume
24
Issue
26
Publish Date
2005
Start Page
4320
End Page
4320
DOI
10.1038/sj.onc.1208766

A pharmacological study of celecoxib and gemcitabine in patients with advanced pancreatic cancer.

PURPOSE: To evaluate whether celecoxib alters the conversion of gemcitabine into its active metabolite, difluorodeoxycytidine triphosphate (dFdCTP), in peripheral blood mononuclear cells (PBMCs). METHODS: Patients with advanced pancreatic cancer who had not received chemotherapy and had acceptable organ function were eligible for the study. The initial dose of gemcitabine was 750 mg/m(2) administered intravenously at a rate of 10 mg/m(2)/min on days 1, 8, and 15 every 4 weeks. Celecoxib was administered orally at 400 mg twice a day starting 2 days after the first dose of gemcitabine. Serial blood samples were taken during the first and second gemcitabine infusions and the cellular dFdCTP levels from PBMCs were analyzed. RESULTS: Five patients received gemcitabine at 750 mg/m(2) and six patients received it at 650 mg/m(2). Severe adverse events included neutropenia, thrombocytopenia, enteritis, and gastric perforation. Two patient died early during treatment. Cellular pharmacology studies showed that the conversion of gemcitabine into dFdCTP was not affected by celecoxib. CONCLUSION: Despite the increased clinical toxicities encountered with the combination, celecoxib did not alter the conversion of gemcitabine into its active metabolites in PBMCs. Gemcitabine 650 mg/m(2) infusion over 65 min on days 1, 8, and 15 every 4 weeks in combination with celecoxib at 400 mg twice a day was the dose recommended for further study.

Authors
Xiong, HQ; Plunkett, W; Wolff, R; Du, M; Lenzi, R; Abbruzzese, JL
MLA Citation
Xiong, HQ, Plunkett, W, Wolff, R, Du, M, Lenzi, R, and Abbruzzese, JL. "A pharmacological study of celecoxib and gemcitabine in patients with advanced pancreatic cancer." Cancer chemotherapy and pharmacology 55.6 (June 2005): 559-564.
PMID
15726370
Source
epmc
Published In
Cancer Chemotherapy and Pharmacology
Volume
55
Issue
6
Publish Date
2005
Start Page
559
End Page
564
DOI
10.1007/s00280-004-0916-9

Radiation dose considerations in the palliative treatment of locally advanced adenocarcinoma of the pancreas.

Treatment of locally advanced pancreatic cancer with high-dose radiotherapy has not been curative, and can be difficult to tolerate. We decided to compare retrospectively the outcomes of patients treated concurrently with 5-fluorouracil and either 30 Gy or more than 30 Gy of radiation. From December 1993 through May 2001, 107 patients with locally advanced adenocarcinoma of the pancreas had been treated with palliative chemoradiation. Eighty-six patients had received a prescribed dose of 30 Gy and 50.4 Gy had been prescribed in 18 patients. Two of these patients were unable to complete the full dose of radiotherapy due to toxicity, and 3 received intraoperative radiotherapy boost (20 Gy). Three additional patients received a prescribed dose of 33 Gy, 36 Gy, and 52.2 Gy, respectively. These patients were grouped together (n = 21, median 50.4 Gy). All patients had received concurrent protracted venous infusions of 5-fluorouracil (300 mg/m Monday through Friday). The median survival time was not affected significantly by a higher radiotherapy dose (8 months for the 30 Gy group versus 9 months for the group receiving higher doses; P = 0.64). The 6-month actuarial progression rates were 45% versus 50% (P = 0.90) for local disease progression, and 54% versus 50% (P = 0.94) for distant metastasis for the 30 Gy and the higher dose groups, respectively. Ten of the 86 patients (12%) who had received 30 Gy were hospitalized for treatment-related gastrointestinal toxicity (grade 3) versus 6 of the 21 (29%) patients given higher doses (P = 0.05). Compared with higher doses given over 5 to 6 weeks, chemoradiation (30 Gy in 10 fractions in 2 weeks with concurrent infusional 5-FU) results in a similar median survival, and local disease progression rates in patients with locally advanced pancreatic cancer apparently do not substantially improve local disease control or median survival time. Because higher doses of radiotherapy can lead to increased acute treatment-related morbidity, we recommend using 30 Gy in 10 fractions unless the patient is part of a prospective study evaluating novel biologic or cytotoxic radiosensitizers.

Authors
Wong, AA; Delclos, ME; Wolff, RA; Evans, DB; Abbruzzese, JL; Tamm, EP; Xiong, HQ; Ho, L; Crane, CH
MLA Citation
Wong, AA, Delclos, ME, Wolff, RA, Evans, DB, Abbruzzese, JL, Tamm, EP, Xiong, HQ, Ho, L, and Crane, CH. "Radiation dose considerations in the palliative treatment of locally advanced adenocarcinoma of the pancreas." American journal of clinical oncology 28.3 (June 2005): 227-233.
PMID
15923793
Source
epmc
Published In
American Journal of Clinical Oncology: Cancer Clinical Trials
Volume
28
Issue
3
Publish Date
2005
Start Page
227
End Page
233
DOI
10.1097/01.coc.0000145290.06582.c3

5,10-Methylenetetrahydrofolate reductase polymorphisms and the risk of pancreatic cancer.

To test the hypothesis that 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms modify the risk of pancreatic cancer, we conducted a hospital-based, case-control study involving 347 patients with newly diagnosed pancreatic adenocarcinoma and 348 healthy controls, frequency matched by age, sex, and race. MTHFR polymorphisms were determined using the PCR-RFLP method. Association of these polymorphisms with the risk of pancreatic cancer was estimated by unconditional logistic regression analysis. We found that the C667T (but not the A1298C) polymorphism had a significant main effect on the risk of pancreatic cancer. The frequencies of the MTHFR 667CC, 667CT, and 667TT genotypes were 49.5%, 38.6%, and 11.9%, respectively, among cases compared with 48.5%, 45.0%, and 6.5%, respectively, among controls. Individuals with the 667TT genotype displayed a 2-fold increased risk for pancreatic cancer compared with those with the CC/CT genotypes [adjusted odds ratio (OR), 2.14; 95% confidence interval (95% CI), 1.14-4.01]. Multivariate analyses found that the effect of the 677TT genotype on the risk of pancreatic cancer was present among ever smokers (OR, 5.53; 95% CI, 2.0-15.3) and ever alcohol drinkers (OR, 3.16; 95% CI, 1.30-7.69) but not in never smokers (OR, 0.82; 95% CI, 0.33-2.06) and never drinkers (OR, 1.42; 95% CI, 0.56-3.62). Furthermore, a positive interaction between the MTHFR TT genotype and heavy smoking or heavy alcohol consumption was detected. The OR (95% CI) of pancreatic cancer was 6.83 (1.91-24.38) for heavy smokers among the TT carriers compared with never smokers with the CC/CT genotypes and 4.23 (0.88-20.3) for heavy drinkers with the TT genotype compared with nondrinkers with the CC/CT genotypes. These observations support a role for folate metabolism in pancreatic cancer, especially among smokers and heavy drinkers.

Authors
Li, D; Ahmed, M; Li, Y; Jiao, L; Chou, T-H; Wolff, RA; Lenzi, R; Evans, DB; Bondy, ML; Pisters, PW; Abbruzzese, JL; Hassan, MM
MLA Citation
Li, D, Ahmed, M, Li, Y, Jiao, L, Chou, T-H, Wolff, RA, Lenzi, R, Evans, DB, Bondy, ML, Pisters, PW, Abbruzzese, JL, and Hassan, MM. "5,10-Methylenetetrahydrofolate reductase polymorphisms and the risk of pancreatic cancer." Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 14.6 (June 2005): 1470-1476.
PMID
15941958
Source
epmc
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
14
Issue
6
Publish Date
2005
Start Page
1470
End Page
1476
DOI
10.1158/1055-9965.epi-04-0894

Nuclear factor kappa B activation is a potential target for preventing pancreatic carcinoma by aspirin.

BACKGROUND: Pancreatic carcinoma exhibits a unique genetic profile of mutations that may play key roles in its progression to malignant phenotypes. Constitutive activation of transcription factor nuclear factor kappa B (NF-kappaB) is a frequent molecular alteration in pancreatic carcinoma, suggesting a possible link between inflammation and cancer. The aims of the current study were to determine the effects of aspirin on pancreatic carcinoma prevention and to reveal a possible mechanism of aspirin-mediated cancer chemoprevention. METHODS: An orthotopic mouse model with human pancreatic carcinoma cell lines PANC-1, PANC-1/Puro, and PANC-1/IkappaBalphaM was used to study the inhibitory effects of aspirin on pancreatic tumor formation. RESULTS: Aspirin inhibited constitutive NF-kappaB activity in culture and, in turn, decreased the expression of the NF-kappaB downstream target gene, Cox-2, in PANC-1 or PANC-1/Puro cells, without significantly inhibiting the in vitro growth of PANC-1/Puro cells. All animals inoculated with either PANC-1 or PANC-1/Puro cells, and not given aspirin, developed pancreatic tumors, whereas none of the mice injected with PANC-1/IkappaBalphaM cells showed any evidence of pancreatic tumor formation. Animals given aspirin for 6 days before, or at the time of, orthotopic tumor cell injection showed a significantly lower incidence of tumor formation compared with those receiving aspirin 2 weeks after inoculation and controls receiving no aspirin. CONCLUSIONS: Aspirin repressed tumor formation by PANC-1 cells in vivo in a prophylactic setting, suggesting a possible mechanism for aspirin's preventive effect in pancreatic carcinoma through inhibition of NF-kappaB activation and a mechanistic link between inflammation and tumorigenesis. Aspirin-mediated antiinflammatory approaches might be an effective strategy to prevent pancreatic carcinoma.

Authors
Sclabas, GM; Uwagawa, T; Schmidt, C; Hess, KR; Evans, DB; Abbruzzese, JL; Chiao, PJ
MLA Citation
Sclabas, GM, Uwagawa, T, Schmidt, C, Hess, KR, Evans, DB, Abbruzzese, JL, and Chiao, PJ. "Nuclear factor kappa B activation is a potential target for preventing pancreatic carcinoma by aspirin." Cancer 103.12 (June 2005): 2485-2490.
PMID
15861417
Source
epmc
Published In
Cancer
Volume
103
Issue
12
Publish Date
2005
Start Page
2485
End Page
2490
DOI
10.1002/cncr.21075

Capecitabine plus oxaliplatin vs infusional 5-fluorouracil plus oxaliplatin in the treatment of colorectal cancer. Pro: The CapeOx regimen is preferred over FOLFOX.

Authors
Chang, DZ; Abbruzzese, JL
MLA Citation
Chang, DZ, and Abbruzzese, JL. "Capecitabine plus oxaliplatin vs infusional 5-fluorouracil plus oxaliplatin in the treatment of colorectal cancer. Pro: The CapeOx regimen is preferred over FOLFOX." Clinical advances in hematology & oncology : H&O 3.5 (May 2005): 400-404. (Review)
PMID
16167013
Source
epmc
Published In
Clinical advances in hematology & oncology : H&O
Volume
3
Issue
5
Publish Date
2005
Start Page
400
End Page
404

Dual inhibition of epidermal growth factor receptor and vascular endothelial growth factor receptor phosphorylation by AEE788 reduces growth and metastasis of human colon carcinoma in an orthotopic nude mouse model.

We studied growth factors and their receptors in tumor cells and tumor-associated endothelial cells as the therapeutic targets in colon cancer. Immunohistochemical analysis of 13 surgical specimens of human colon adenocarcinoma revealed that both tumor cells and tumor-associated endothelial cells in 11 of the 13 specimens expressed the epidermal growth factor (EGF), transforming growth factor alpha (TGF-alpha), EGF receptor (EGFR), phosphorylated EGFR (pEGFR), vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR), and phosphorylated VEGFR (pVEGFR). HT29 human colon cancer cells growing orthotopically in the cecum of nude mice expressed a high level of EGF, EGFR, pEGFR, VEGF, VEGFR, and pVEGFR. Double-immunofluorescence staining found that tumor-associated mouse endothelial cells also expressed pEGFR and pVEGFR. Tumors in mice treated for 5 weeks with oral AEE788 (an inhibitor of EGFR and VEGFR tyrosine kinase) as a single agent or with CPT-11 alone were smaller (>50%) than those in control mice. Mice treated with the combination of AEE788 and CPT-11 had significantly smaller tumors (P < 0.01) and complete inhibition of lymph node metastasis. AEE788 alone or in combination with CPT-11 inhibited pEGFR, pVEGFR, and phosphorylated Akt expression on tumor-associated endothelial cells as well as on tumor cells. The combination therapy also significantly decreased microvessel density and tumor cell proliferation and increased the level of apoptosis in both tumor cells and tumor-associated endothelial cells. Collectively, these data suggest that the dual inhibition of EGFR and VEGFR signaling pathways in tumor cells and tumor-associated endothelial cells in combination with chemotherapy can provide a new approach to the treatment of colon cancer.

Authors
Yokoi, K; Thaker, PH; Yazici, S; Rebhun, RR; Nam, D-H; He, J; Kim, S-J; Abbruzzese, JL; Hamilton, SR; Fidler, IJ
MLA Citation
Yokoi, K, Thaker, PH, Yazici, S, Rebhun, RR, Nam, D-H, He, J, Kim, S-J, Abbruzzese, JL, Hamilton, SR, and Fidler, IJ. "Dual inhibition of epidermal growth factor receptor and vascular endothelial growth factor receptor phosphorylation by AEE788 reduces growth and metastasis of human colon carcinoma in an orthotopic nude mouse model." Cancer research 65.9 (May 2005): 3716-3725.
PMID
15867367
Source
epmc
Published In
Cancer Research
Volume
65
Issue
9
Publish Date
2005
Start Page
3716
End Page
3725
DOI
10.1158/0008-5472.can-04-3700

The rapamycin analog CCI-779 is a potent inhibitor of pancreatic cancer cell proliferation.

We present immunohistochemical evidence that the mTOR/p70s6k pathway is activated in pancreatic tumors and show that the mTOR inhibitor and rapamycin analog CCI-779 potently suppresses the proliferation of pancreatic cancer cells. Consistent with a recent study, CCI-779 increased c-Jun phosphorylation (Ser63) in a dose- and time-dependent manner, and induced apoptosis in p53-defective BxPC-3 cells. In contrast to the study, however, we observed that CCI-779 concomitantly increased c-Jun protein levels and that its ability to induce apoptosis might not require the activated c-Jun. Furthermore, CCI-779 neither induced c-Jun phosphorylation in other p53-defective pancreatic cancer cells (MiaPaCa-2) nor inhibited their proliferation. c-Jun, in fact, appeared to be partly responsible for the resistance of MiaPaCa-2 cells to CCI-779. Together, these results indicate a complex role for c-Jun in cellular responses to CCI-779 and provide an important basis for investigating CCI-779 further as a potential therapeutic agent for pancreatic tumors.

Authors
Asano, T; Yao, Y; Zhu, J; Li, D; Abbruzzese, JL; Reddy, SA
MLA Citation
Asano, T, Yao, Y, Zhu, J, Li, D, Abbruzzese, JL, and Reddy, SA. "The rapamycin analog CCI-779 is a potent inhibitor of pancreatic cancer cell proliferation." Biochemical and biophysical research communications 331.1 (May 2005): 295-302.
PMID
15845392
Source
epmc
Published In
Biochemical and Biophysical Research Communications
Volume
331
Issue
1
Publish Date
2005
Start Page
295
End Page
302
DOI
10.1016/j.bbrc.2005.03.166

Direct tandem mass spectrometry reveals limitations in protein profiling experiments for plasma biomarker discovery.

The low molecular weight plasma proteome and its biological relevance are not well defined; therefore, experiments were conducted to directly sequence and identify peptides observed in plasma and serum protein profiles. Protein fractionation, matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS) profiling, and liquid-chromatography coupled to MALDI tandem mass spectrometry (MS/MS) sequencing were used to analyze the low molecular weight proteome of heparinized plasma. Four fractionation techniques using functionally derivatized 96-well plates were used to extract peptides from plasma. Tandem TOF was successful for identifying peptides up to m/z 5500 with no prior knowledge of the sequence and was also used to verify the sequence assignments for larger ion signals. The peptides (n>250) sequenced in these profiles came from a surprisingly small number of proteins (n approximately 20), which were all common to plasma, including fibrinogen, complement components, antiproteases, and carrier proteins. The cleavage patterns were consistent with those of known plasma proteases, including initial cleavages by thrombin, plasmin and complement proteins, followed by aminopeptidase and carboxypeptidase activity. On the basis of these data, we discuss limitations in biomarker discovery in the low molecular weight plasma or serum proteome using crude fractionation coupled to MALDI-MS profiling.

Authors
Koomen, JM; Li, D; Xiao, L-C; Liu, TC; Coombes, KR; Abbruzzese, J; Kobayashi, R
MLA Citation
Koomen, JM, Li, D, Xiao, L-C, Liu, TC, Coombes, KR, Abbruzzese, J, and Kobayashi, R. "Direct tandem mass spectrometry reveals limitations in protein profiling experiments for plasma biomarker discovery." Journal of proteome research 4.3 (May 2005): 972-981.
PMID
15952745
Source
epmc
Published In
Journal of Proteome Research
Volume
4
Issue
3
Publish Date
2005
Start Page
972
End Page
981
DOI
10.1021/pr050046x

AURKA amplification, chromosome instability, and centrosome abnormality in human pancreatic carcinoma cells.

To test the hypothesis that AURKA amplification contributes to pancreatic tumorigenesis by increasing centrosome abnormality and chromosome instability, the current study explored the associations between AURKA amplification, chromosome instability, centrosome abnormality, and the expression of several important proteins that are involved in cell proliferation (Ki-67), cell cycle regulation (p53, p16), and apoptosis (survivin) in 12 human pancreatic carcinoma cell lines. Using fluorescence in situ hybridization (FISH), we observed that 5 of the 12 cell lines had an AURKA amplification index (AI) (percentage of cells with more than three signals) >60%. Both the AURKA AI and the average number of signals per cell (ANSPC) were significantly associated with the copy number of chromosome 9 but not chromosome 17. The AURKA ANSPC was positively associated with the percentage of cells with the centrosome abnormality. Furthermore, centrosome abnormality was significantly associated with the frequency of cells with abnormal nuclei and abnormal mitotic figures, but no direct association was detected between the frequency of centrosome abnormalities and chromosome instabilities. The AURKA AI was also associated with a lower expression of Ki-67, a higher expression of survivin, and the lack of expression of p16. These associations support our hypothesis that AURKA amplification contributes to pancreatic carcinogenesis by increasing chromosome instability and centrosome abnormality.

Authors
Zhu, J; Abbruzzese, JL; Izzo, J; Hittelman, WN; Li, D
MLA Citation
Zhu, J, Abbruzzese, JL, Izzo, J, Hittelman, WN, and Li, D. "AURKA amplification, chromosome instability, and centrosome abnormality in human pancreatic carcinoma cells." Cancer genetics and cytogenetics 159.1 (May 2005): 10-17.
PMID
15860351
Source
epmc
Published In
Cancer Genetics and Cytogenetics
Volume
159
Issue
1
Publish Date
2005
Start Page
10
End Page
17
DOI
10.1016/j.cancergencyto.2004.09.008

Plasma protein profiling for diagnosis of pancreatic cancer reveals the presence of host response proteins.

Plasma protein profiling using separations coupled to matrix-assisted laser desorption ionization mass spectrometry (MALDI MS) has great potential in translational research; it can be used for biomarker discovery and contribute to disease diagnosis and therapy. Previously reported biomarker searches have been done solely by MS protein profiling followed by bioinformatics analysis of the data. To add to current methods, we tested an alternative strategy for plasma protein profiling using pancreatic cancer as the model. First, offline solid-phase extraction is done with 96-well plates to fractionate and partially purify the proteins. Then, multiple profiling and identification experiments can be conducted on the same protein fractions because only 5% of the fractions are used for MALDI MS profiling. After MALDI MS analysis, the mass spectra are normalized and subjected to a peak detection algorithm. Over three sets of mass spectra acquired using different instrument variables, approximately 400 unique ion signals were detected. Classification schemes employing as many as eight individual peaks were developed using a training set with 123 members (82 cancer patients) and a blinded validation set with 125 members (57 cancer patients). The sensitivity of the study was 88%, but the specificity was significantly lower, 75%. The reason for the low specificity becomes apparent upon protein identification of the ion signals used for the classification. The identifications reveal only common serum proteins and components of the acute phase response, including serum amyloid A, alpha-1-antitrypsin, alpha-1-antichymotrypsin, and inter-alpha-trypsin inhibitor.

Authors
Koomen, JM; Shih, LN; Coombes, KR; Li, D; Xiao, L-C; Fidler, IJ; Abbruzzese, JL; Kobayashi, R
MLA Citation
Koomen, JM, Shih, LN, Coombes, KR, Li, D, Xiao, L-C, Fidler, IJ, Abbruzzese, JL, and Kobayashi, R. "Plasma protein profiling for diagnosis of pancreatic cancer reveals the presence of host response proteins." Clinical cancer research : an official journal of the American Association for Cancer Research 11.3 (February 2005): 1110-1118.
PMID
15709178
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
11
Issue
3
Publish Date
2005
Start Page
1110
End Page
1118

Thalidomide in the treatment of patients with hepatocellular carcinoma: a phase II trial.

BACKGROUND: The treatment of patients with hepatocellular carcinoma (HCC) presents a major challenge, because associated cirrhosis limits the choice of chemotherapeutic agents. However, the abundant vascularity of HCC presents an attractive target for antiangiogenic therapy that potentially may be tolerated by cirrhotic patients. The current study was conducted to assess the antitumor activity, treatment tolerance, treatment-related toxicity, and patient survival after the administration of thalidomide in a Phase II trial. METHODS: Thirty-seven HCC patients were accrued between March, 1999, and March, 2000. Initially, the dose of oral thalidomide was escalated from 400 mg per day during the first week to 1000 mg per day by the fifth week, delivering one-third of the dose in the morning and the remaining two-thirds of the dose in the evening prior to bedtime. Changes in the daily drug administration schedule were allowed based on tolerance. Response was assessed at 8-week intervals. RESULTS: Thirty-two of 37 registered patients were evaluable for response. One patient had a partial response (PR), 1 patient had a minor response (MR), 10 patients had stable disease (SD) (31%; 95% confidence interval [95%CI], 16-51%), and 20 patients) (61%; 95%CI, 42-78%) had disease progression. The most commonly encountered toxicity was somnolence, with Grade 3-4 somnolence (>or= 4 hours of sleep during normal waking hours) in 9 patients (35%) and Grade 2 somnolence (800 mg if it was delivered at bedtime. Grade 3-4 skin reactions were observed in 20% of patients, and exfoliative dermatitis was observed in 1 responding patient. The overall median survival was 6.8 months. CONCLUSIONS: With a 5% PR rate, a 5% MR rate, and a 31% SD rate, the results indicate that thalidomide mostly may offer HCC patients disease stabilization. It is possible that, at a different dosage, or combined with other chemotherapy agents, or with the use of a different thalidomide analogue, longer patient survival may be achieved. However, in view of the significant neurologic toxicity encountered among these commonly cirrhotic HCC patients, thalidomide monotherapy at the high doses studied cannot be recommended for the treatment of HCC.

Authors
Patt, YZ; Hassan, MM; Lozano, RD; Nooka, AK; Schnirer, II; Zeldis, JB; Abbruzzese, JL; Brown, TD
MLA Citation
Patt, YZ, Hassan, MM, Lozano, RD, Nooka, AK, Schnirer, II, Zeldis, JB, Abbruzzese, JL, and Brown, TD. "Thalidomide in the treatment of patients with hepatocellular carcinoma: a phase II trial." Cancer 103.4 (February 2005): 749-755.
PMID
15660400
Source
epmc
Published In
Cancer
Volume
103
Issue
4
Publish Date
2005
Start Page
749
End Page
755
DOI
10.1002/cncr.20821

Overexpression of tropomysin-related kinase B in metastatic human pancreatic cancer cells.

PURPOSE: Pancreatic adenocarcinoma is currently the fourth leading cause of cancer death in the United States, and most pancreatic cancers develop locally advanced disease or metastasis at the time of diagnosis. The mechanisms by which it invades and metastasizes are not known. EXPERIMENTAL DESIGN: To identify the genes involved in pancreatic cancer metastasis, we analyzed the gene expression profiles between highly metastatic Colo357L3.6pl and parental Colo357FG pancreatic cancer cell lines using cDNA microarrays and confirmed differential gene expression by reverse transcription-PCR, Western blotting, and immunologic analysis of 54 samples from pancreatic cancer patients. The correlation with clinical outcome was also examined. The possible signaling pathways involved with tropomyosin-related kinase B (TrkB) were analyzed. RESULTS: Our findings showed that TrkB was overexpressed in the highly metastatic Colo357L3.6pl cells, which correlated with perineural invasion (P = 0.026), positive retroperitoneal margin (P = 0.0005), and shorter latency to development of liver metastasis (Cox proportional hazard ratio, 0.3; 95% confidence interval, 0.1-0.8; P = 0.01) in patient samples. Extracellular signal-regulated kinases 1 and 2 were activated and Elk-1 and AP-1 DNA binding activity was induced in Colo357L3.6pl cells. Furthermore, interleukin 8 and vascular endothelial growth factor were more strongly expressed in Colo357L3.6pl than Colo357FG cells, and these findings were confirmed in Colo357L3.6pl and Colo357FG orthotopic tumors. CONCLUSION: These results suggest that overexpression of TrkB and activation of mitogen-activated protein kinase and AP-1, which may in turn induce the expression of vascular endothelial growth factor and interleukin 8, may mediate the cardinal clinical features of locally aggressive growth and metastasis of pancreatic cancer. Our results also imply that TrkB receptor may be a novel therapeutic target for pancreatic cancer.

Authors
Sclabas, GM; Fujioka, S; Schmidt, C; Li, Z; Frederick, WAI; Yang, W; Yokoi, K; Evans, DB; Abbruzzese, JL; Hess, KR; Zhang, W; Fidler, IJ; Chiao, PJ
MLA Citation
Sclabas, GM, Fujioka, S, Schmidt, C, Li, Z, Frederick, WAI, Yang, W, Yokoi, K, Evans, DB, Abbruzzese, JL, Hess, KR, Zhang, W, Fidler, IJ, and Chiao, PJ. "Overexpression of tropomysin-related kinase B in metastatic human pancreatic cancer cells." Clinical cancer research : an official journal of the American Association for Cancer Research 11.2 Pt 1 (January 2005): 440-449.
PMID
15701826
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
11
Issue
2 Pt 1
Publish Date
2005
Start Page
440
End Page
449

Diagnostic protein discovery using liquid chromatography/mass spectrometry for proteolytic peptide targeting.

A peptide targeting method has been developed for diagnostic protein discovery, which combines proteolytic digestion of fractionated plasma proteins and liquid chromatography coupled to electrospray time-of-flight mass spectrometry (LC/ESI-TOFMS) profiling. Proteolysis prior to profiling overcomes molecular weight limitations and compensates for the poor sensitivity of matrix-assisted laser desorption/ionization (MALDI) protein profiling. LC/MS increases the peak capacity compared to crude fractionation techniques or single sample MALDI analysis. Differentially expressed peptides are targeted in the mass chromatograms using bioinformatic techniques and subsequently sequenced with MALDI tandem MS. In a model study comparing pancreatic cancer patients to controls, 74% of the peptide targets were successfully sequenced. This profiling method was superior to previous experiments using single sample MALDI analysis for protein profiling or proteolytic peptide profiling, because more potential protein markers were identified.

Authors
Koomen, JM; Zhao, H; Li, D; Nasser, W; Hawke, DH; Abbruzzese, JL; Baggerly, KA; Kobayashi, R
MLA Citation
Koomen, JM, Zhao, H, Li, D, Nasser, W, Hawke, DH, Abbruzzese, JL, Baggerly, KA, and Kobayashi, R. "Diagnostic protein discovery using liquid chromatography/mass spectrometry for proteolytic peptide targeting." Rapid communications in mass spectrometry : RCM 19.12 (January 2005): 1624-1636.
PMID
15915451
Source
epmc
Published In
Rapid Communications in Mass Spectrometry
Volume
19
Issue
12
Publish Date
2005
Start Page
1624
End Page
1636
DOI
10.1002/rcm.1963

Pharmacodynamic analysis of target inhibition and endothelial cell death in tumors treated with the vascular endothelial growth factor receptor antagonists SU5416 or SU6668.

PURPOSE: To determine the effects of small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR)-2 (SU5416 and SU6668) on receptor phosphorylation in tumor xenografts and in paired tumor biopsies obtained in three clinical trials in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: The dose-dependent effects of SU6668 on angiogenesis and tumor growth were investigated in orthotopic L3.6pl pancreatic tumors. Excisional or 18G core biopsies were obtained from patients before and after therapy with SU5416 or SU6668. Laser scanning cytometry-mediated analysis was used to quantify levels of phosphorylated and total VEGFRs and platelet-derived growth factor receptors (PDGFR), tumor microvessel densities, vessel sizes, and endothelial and tumor cell apoptosis. RESULTS: Significant inhibition of tumor microvessel density and growth and increased apoptosis were observed at SU6668 maximum tolerated dose (100 mg/kg) in L3.6pl xenografts. At 6 hours post therapy, SU6668 reduced VEGFR and PDGFR phosphorylation in the tumors by 50% and 92%, respectively, but levels rebounded beyond the baselines by 24 hours. Levels of phosphorylated VEGFR-2 and PDGFR also decreased significantly ( approximately 50%) 6 hours after therapy in 1 of 6 primary human tumors treated with SU6668, but these effects were not associated with increased apoptosis. A significant increase in endothelial cell apoptosis was observed in one tumor exposed to SU5416 and was associated with an increase in vessel size, but these changes occurred without an increase in tumor cell death. CONCLUSIONS: SU5416 and SU6668 displayed biological activity in xenografts. However, neither drug produced marked biological activity in primary patient tumors.

Authors
Davis, DW; Takamori, R; Raut, CP; Xiong, HQ; Herbst, RS; Stadler, WM; Heymach, JV; Demetri, GD; Rashid, A; Shen, Y; Wen, S; Abbruzzese, JL; McConkey, DJ
MLA Citation
Davis, DW, Takamori, R, Raut, CP, Xiong, HQ, Herbst, RS, Stadler, WM, Heymach, JV, Demetri, GD, Rashid, A, Shen, Y, Wen, S, Abbruzzese, JL, and McConkey, DJ. "Pharmacodynamic analysis of target inhibition and endothelial cell death in tumors treated with the vascular endothelial growth factor receptor antagonists SU5416 or SU6668." Clinical cancer research : an official journal of the American Association for Cancer Research 11.2 Pt 1 (January 2005): 678-689.
PMID
15701856
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
11
Issue
2 Pt 1
Publish Date
2005
Start Page
678
End Page
689

Aberrant expression of maspin in idiopathic inflammatory bowel disease is associated with disease activity and neoplastic transformation.

BACKGROUND: Maspin is both overexpressed in tumors and inflammation, implicating a possible role in bridging inflammation and neoplasia. Idiopathic inflammatory bowel disease (IBD) and IBD-associated dysplasias and carcinomas represent a prototype for studying the relationship between chronic inflammatory states and neoplasia. AIM OF STUDY: To investigate expression of maspin in IBD and IBD-associated dysplasia and colorectal carcinoma. METHODS: Immunohistochemical labeling of maspin was examined using tissue microarrays constructed from archival biopsy and resection tissue from 90 patients with 125 histologically defined lesions including 30 with inactive chronic IBD, 51 with active chronic IBD, 4 IBD-associated foci with epithelial changes indefinite for dysplasia (IFD), 7 with IBD-associated low-grade epithelial dysplasia (LGD), 8 with IBD-associated high grade epithelial dysplasia (HGD), and 25 with IBD-associated invasive colorectal adenocarcinomas. RESULTS: Maspin was expressed in 47/51 (92%) active chronic IBD lesions, which was significantly higher than both inactive chronic IBD (13/30, 43%) and normal mucosa (1 of 9, 11%) (p < 0.01); in particular, the diffuse pattern of maspin expression was significantly higher in active IBD (41/51, 80%), compared with inactive IBD (5/30, 17%) and normal mucosa (0%) (p < 0.01). In the multistage progression model of colitis-associated neoplasia, aberrant labeling was observed at the earliest stages, with 3/4 (75%) IFD foci, 6/7 (86%) LGD, and 8/8 (100%) HGD specimens expressing maspin, virtually always in a diffuse pattern. Expectedly, 22/25 (88%) of invasive IBD-associated cancers overexpressed maspin, including 21 with diffuse labeling. CONCLUSIONS: Maspin is significantly overexpressed in both active IBD and colitis-associated dysplasia compared to either inactive IBD or normal colonic mucosa, suggesting a potential role in disease "flare" as well as neoplastic progression. Targeting maspin for control of disease activity and cancer prophylaxis may be a promising novel therapeutic strategy for IBD.

Authors
Cao, D; Wilentz, RE; Abbruzzese, JL; Ho, L; Maitra, A
MLA Citation
Cao, D, Wilentz, RE, Abbruzzese, JL, Ho, L, and Maitra, A. "Aberrant expression of maspin in idiopathic inflammatory bowel disease is associated with disease activity and neoplastic transformation." International journal of gastrointestinal cancer 36.1 (January 2005): 39-46.
PMID
16227634
Source
epmc
Published In
International Journal of Gastrointestinal Cancer
Volume
36
Issue
1
Publish Date
2005
Start Page
39
End Page
46
DOI
10.1385/ijgc:36:1:039

Aberrant expression of maspin in idiopathic inflammatory bowel disease is associated with disease activity and neoplastic transformation

Background. Maspin is both overexpressed in tumors and inflammation, implicating a possible role in bridging inflammation and neoplasia. Idiopathic inflammatory bowel disease (IBD) and IBD-associated dysplasias and carcinomas represent a prototype for studying the relationship between chronic inflammatory states and neoplasia. Aim of Study. To investigate expression of maspin in IBD and IBD-associated dysplasia and colorectal carcinoma. Methods. Immunohistochemical labeling of maspin was examined using tissue microarrays constructed from archival biopsy and resection tissue from 90 patients with 125 histologically defined lesions including 30 with inactive chronic IBD, 51 with active chronic IBD, 4 IBD-associated foci with epithelial changes indefinite for dysplasia (IFD), 7 with IBD-associated low-grade epithelial dysplasia (LGD), 8 with IBD-associated high grade epithelial dysplasia (HGD), and 25 with IBD-associated invasive colorectal adenocarcinomas. Results. Maspin was expressed in 47/51 (92%) active chronic IBD lesions, which was significantly higher than both inactive chronic IBD (13/30, 43%) and normal mucosa (1 of 9, 11%) (p < 0.01); in particular, the diffuse pattern of maspin expression was significantly higher in active IBD (41/51, 80%), compared with inactive IBD (5/30, 17%) and normal mucosa (0%) (p < 0.01). In the multistage progression model of colitis-associated neoplasia, aberrant labeling was observed at the earliest stages, with 3/4 (75%) IFD foci, 6/7 (86%) LGD, and 8/8 (100%) HGD specimens expressing maspin, virtually always in a diffuse pattern. Expectedly, 22/25 (88%) of invasive IBD-associated cancers overexpressed maspin, including 21 with diffuse labeling. Conclusions. Maspin is significantly overexpressed in both active IBD and colitis-associated dysplasia compared to either inactive IBD or normal colonie mucosa, suggesting a potential role in disease "flare" as well as neoplastic progression. Targeting maspin for control of disease activity and cancer prophylaxis may be a promising novel therapeutic strategy for IBD. © Copyright 2005 by Humana Press Inc. All rights of any nature whatsoever reserved.

Authors
Cao, D; Wilentz, RE; Abbruzzese, JL; Ho, L; Maitra, A
MLA Citation
Cao, D, Wilentz, RE, Abbruzzese, JL, Ho, L, and Maitra, A. "Aberrant expression of maspin in idiopathic inflammatory bowel disease is associated with disease activity and neoplastic transformation." International Journal of Gastrointestinal Cancer 36.1 (2005): 39-46.
Source
scival
Published In
International Journal of Pancreatology
Volume
36
Issue
1
Publish Date
2005
Start Page
39
End Page
46

Hepatic resection: The last surgical frontier for colorectal cancer

Authors
Petrelli, NJ; Abbruzzese, J; Mansfield, P; Minsky, B
MLA Citation
Petrelli, NJ, Abbruzzese, J, Mansfield, P, and Minsky, B. "Hepatic resection: The last surgical frontier for colorectal cancer." Journal of Clinical Oncology 23.20 (2005): 4475-4477.
Source
scival
Published In
Journal of Clinical Oncology
Volume
23
Issue
20
Publish Date
2005
Start Page
4475
End Page
4477
DOI
10.1200/JCO.2005.05.025

Overexpression of tropomysin-related kinase B in metastatic human pancreatic cancer cells

Purpose: Pancreatic adenocarcinoma is currently the fourth leading cause of cancer death in the United States, and most pancreatic cancers develop locally advanced disease or metastasis at the time of diagnosis. The mechanisms by which it invades and metastasizes are not known. Experimental Design: To identify the genes involved in pancreatic cancer metastasis, we analyzed the gene expression profiles between highly metastatic Colo357L3.6pl and parental Colo357FG pancreatic cancer cell lines using cDNA microarrays and confirmed differential gene expression by reverse transcription-PCR, Western blotting, and immunologic analysis of 54 samples from pancreatic cancer patients. The correlation with clinical outcome was also examined. The possible signaling pathways involved with tropomyosin-related kinase B (TrkB) were analyzed. Results: Our findings showed that TrkB was overexpressed in the highly metastatic Colo357L3.6pl cells, which correlated with perineural invasion (P = 0.026), positive retroperitoneal margin (P = 0.0005), and shorter latency to development of liver metastasis (Cox proportional hazard ratio, 0.3; 95% confidence interval, 0.1-0.8; P = 0.01) in patient samples. Extracellular signal-regulated kinases 1 and 2 were activated and Elk-1 and AP-1 DNA binding activity was induced in Colo357L3.6pl cells. Furthermore, interleukin 8 and vascular endothelial growth factor were more strongly expressed in Colo357L3.6pl than Colo357FG cells, and these findings were confirmed in Colo357L3.6pl and Colo357FG orthotopic tumors. Conclusion: These results suggest that overexpression of TrkB and activation of mitogen-activated protein kinase and AP-1, which may in turn induce the expression of vascular endothelial growth factor and interleukin 8, may mediate the cardinal clinical features of locally aggressive growth and metastasis of pancreatic cancer. Our results also imply that TrkB receptor may be a novel therapeutic target for pancreatic cancer.

Authors
Sclabas, GM; Fujioka, S; Schmidt, C; Li, Z; Frederick, WAI; Yang, W; Yokoi, K; Evans, DB; Abbruzzese, JL; Hess, KR; Zhang, W; Fidler, IJ; Chiao, PJ
MLA Citation
Sclabas, GM, Fujioka, S, Schmidt, C, Li, Z, Frederick, WAI, Yang, W, Yokoi, K, Evans, DB, Abbruzzese, JL, Hess, KR, Zhang, W, Fidler, IJ, and Chiao, PJ. "Overexpression of tropomysin-related kinase B in metastatic human pancreatic cancer cells." Clinical Cancer Research 11.2 I (2005): 440-449.
Source
scival
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
11
Issue
2 I
Publish Date
2005
Start Page
440
End Page
449

Pharmacodynamic analysis of target inhibition and endothelial cell death in tumors treated with the vascular endothelial growth factor receptor antagonists SU5416 or SU6668

Purpose: To determine the effects of small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR)-2 (SU5416 and SU6668) on receptor phosphorylation in tumor xenografts and in paired tumor biopsies obtained in three clinical trials in patients with advanced solid malignancies. Experimental Design: The dose-dependent effects of SU6668 on angiogenesis and tumor growth were investigated in orthotopic L3.6pl pancreatic tumors. Excisional or 18G core biopsies were obtained from patients before and after therapy with SU5416 or SU6668. Laser scanning cytometry-mediated analysis was used to quantify levels of phosphorylated and total VEGFRs and platelet-derived growth factor receptors (PDGFR), tumor microvessel densities, vessel sizes, and endothelial and tumor cell apoptosis. Results: Significant inhibition of tumor microvessel density and growth and increased apoptosis were observed at SU6668 maximum tolerated dose (100 mg/kg) in L3.6pl xenografts. At 6 hours post therapy, SU6668 reduced VEGFR and PDGFR phosphorylation in the tumors by 50% and 92%, respectively, but levels rebounded beyond the baselines by 24 hours. Levels of phosphorylated VEGFR-2 and PDGFR also decreased significantly (≈50%) 6 hours after therapy in 1 of 6 primary human tumors treated with SU6668, but these effects were not associated with increased apoptosis. A significant increase in endothelial cell apoptosis was observed in one tumor exposed to SU5416 and was associated with an increase in vessel size, but these changes occurred without an increase in tumor cell death. Conclusions: SU5416 and SU6668 displayed biological activity in xenografts. However, neither drug produced marked biological activity in primary patient tumors.

Authors
Davis, DW; Takamori, R; Raut, CP; Xiong, HQ; Herbst, RS; Stadler, WM; Heymach, JV; Demetri, GD; Rashid, A; Shen, Y; Wen, S; Abbruzzese, JL; McConkey, DJ
MLA Citation
Davis, DW, Takamori, R, Raut, CP, Xiong, HQ, Herbst, RS, Stadler, WM, Heymach, JV, Demetri, GD, Rashid, A, Shen, Y, Wen, S, Abbruzzese, JL, and McConkey, DJ. "Pharmacodynamic analysis of target inhibition and endothelial cell death in tumors treated with the vascular endothelial growth factor receptor antagonists SU5416 or SU6668." Clinical Cancer Research 11.2 I (2005): 678-689.
Source
scival
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
11
Issue
2 I
Publish Date
2005
Start Page
678
End Page
689

Protein expression profiles in pancreatic adenocarcinoma compared with normal pancreatic tissue and tissue affected by pancreatitis as detected by two-dimensional gel electrophoresis and mass spectrometry.

Pancreatic cancer is a rapidly fatal disease, and there is an urgent need for early detection markers and novel therapeutic targets. The current study has used a proteomic approach of two-dimensional (2D) gel electrophoresis and mass spectrometry (MS) to identify differentially expressed proteins in six cases of pancreatic adenocarcinoma, two normal adjacent tissues, seven cases of pancreatitis, and six normal pancreatic tissues. Protein extracts of individual sample and pooled samples of each type of tissues were separated on 2D gels using two different pH ranges. Differentially expressed protein spots were in-gel digested and identified by MS. Forty proteins were identified, of which five [i.e., alpha-amylase; copper zinc superoxide dismutase; protein disulfide isomerase, pancreatic; tropomyosin 2 (TM2); and galectin-1] had been associated previously with pancreatic disease in gene expression studies. The identified proteins include antioxidant enzymes, chaperones and/or chaperone-like proteins, calcium-binding proteins, proteases, signal transduction proteins, and extracellular matrix proteins. Among these proteins, annexin A4, cyclophilin A, cathepsin D, galectin-1, 14-3-3zeta, alpha-enolase, peroxiredoxin I, TM2, and S100A8 were specifically overexpressed in tumors compared with normal and pancreatitis tissues. Differential expression of some of the identified proteins was further confirmed by Western blot analyses and/or immunohistochemical analysis. These results show the value of a proteomic approach in identifying potential markers for early diagnosis and therapeutic manipulation. The newly identified proteins in pancreatic tumors may eventually serve as diagnostic markers or therapeutic targets.

Authors
Shen, J; Person, MD; Zhu, J; Abbruzzese, JL; Li, D
MLA Citation
Shen, J, Person, MD, Zhu, J, Abbruzzese, JL, and Li, D. "Protein expression profiles in pancreatic adenocarcinoma compared with normal pancreatic tissue and tissue affected by pancreatitis as detected by two-dimensional gel electrophoresis and mass spectrometry." Cancer research 64.24 (December 2004): 9018-9026.
PMID
15604267
Source
epmc
Published In
Cancer Research
Volume
64
Issue
24
Publish Date
2004
Start Page
9018
End Page
9026
DOI
10.1158/0008-5472.can-04-3262

Cytokines in pancreatic carcinoma: correlation with phenotypic characteristics and prognosis.

BACKGROUND: Cytokines have been implicated in diverse processes that are relevant to pancreatic carcinoma, including cachexia, asthenia, and tumor growth. The objective of this study was to examine the association between serum levels of proinflammatory and antiinflammatory or angiogenic cytokines and the outcomes of patients with pancreatic carcinoma. METHODS: Serum cytokine levels were measured by enzyme-linked immunosorbent assay from 51 patients with pancreatic carcinoma and from 48-62 healthy volunteers. Cytokine levels were compared with disease manifestations and overall survival. RESULTS: Circulating levels of vascular endothelial growth factor, tumor necrosis factor alpha, interleukin-1alpha (IL-1alpha), and IL-1beta were not elevated significantly in patients with pancreatic carcinoma, but levels of IL-6, IL-8, IL-10, and IL-1 receptor antagonist (IL-1RA) were elevated significantly (P <0.05). Cytokine levels were dichotomized based on an analysis of null Martingale residuals. Patients who had IL-6 levels > 5.2 pg/mL or IL-10 levels >9.8 pg/mL had significantly worse survival compared with patients who had lower IL-6 or IL-10 levels (P <0.05). IL-8 levels were not associated with survival differences. Patients who had IL-1RA levels <159 pg/mL had significantly worse survival compared with patients who had higher IL-1RA levels (P <0.05). Higher IL-6, IL-10, and IL-8 levels were associated with poor performance status and/or weight loss. In multivariate analysis, only T4 tumors and high IL-6 levels were selected as independent prognostic factors for poor survival. CONCLUSIONS: Circulating levels of several cytokines were high in patients with pancreatic carcinoma, and their association with weight loss and poor performance status suggested that they may be involved in these disease manifestations. Furthermore, serum cytokine levels, in particular IL-6, may be a useful prognostic marker.

Authors
Ebrahimi, B; Tucker, SL; Li, D; Abbruzzese, JL; Kurzrock, R
MLA Citation
Ebrahimi, B, Tucker, SL, Li, D, Abbruzzese, JL, and Kurzrock, R. "Cytokines in pancreatic carcinoma: correlation with phenotypic characteristics and prognosis." Cancer 101.12 (December 2004): 2727-2736.
PMID
15526319
Source
epmc
Published In
Cancer
Volume
101
Issue
12
Publish Date
2004
Start Page
2727
End Page
2736
DOI
10.1002/cncr.20672

The PI 3-kinase/Akt signaling pathway is activated due to aberrant Pten expression and targets transcription factors NF-kappaB and c-Myc in pancreatic cancer cells.

The persistent activation of signaling cascades results in dramatic consequences that include loss of cellular growth control and neoplastic transformation. We show here that phosphoinositide 3-kinase (PI 3-kinase) and its mediator Akt were constitutively activated in pancreatic cancer and that this might be due to the aberrant expression of their natural antagonist MMAC/PTEN. Indeed, our results show that MMAC/PTEN expression was either lost or significantly reduced in five of eight cell lines and in twelve of seventeen tumor specimens examined. That the poor expression of MMAC/PTEN in pancreatic cancer cells could be due to promoter methylation was indicated by methylation-specific PCR analysis. Our studies also indicated that PI 3-kinase targeted two important transcription factors in pancreatic cancer cells. The ability of constitutively activated NF-kappaB to induce gene expression and the stabilization of c-MYC protein by decreased phosphorylation of Thr58 were both dependent on PI 3-kinase activity. When pancreatic cancer cells were treated with a peptide antagonist of NF-kappaB nuclear translocation, or stably transfected with a dominant-negative mutant of MYC, their proliferation was markedly inhibited. Taken together, these data indicate that the aberrant expression of MMAC/PTEN contributes to the activation of the PI 3-kinase/Akt pathway and its transcription factor mediators in pancreatic cancer.

Authors
Asano, T; Yao, Y; Zhu, J; Li, D; Abbruzzese, JL; Reddy, SAG
MLA Citation
Asano, T, Yao, Y, Zhu, J, Li, D, Abbruzzese, JL, and Reddy, SAG. "The PI 3-kinase/Akt signaling pathway is activated due to aberrant Pten expression and targets transcription factors NF-kappaB and c-Myc in pancreatic cancer cells." Oncogene 23.53 (November 2004): 8571-8580.
PMID
15467756
Source
epmc
Published In
Oncogene: Including Oncogene Reviews
Volume
23
Issue
53
Publish Date
2004
Start Page
8571
End Page
8580
DOI
10.1038/sj.onc.1207902

Nuclear factor-kappaB and IkappaB kinase are constitutively active in human pancreatic cells, and their down-regulation by curcumin (diferuloylmethane) is associated with the suppression of proliferation and the induction of apoptosis.

Pancreatic carcinoma is a lethal malignancy, with the best available therapeutic option-gemcitabine-yielding response rates of < 10%. Because nuclear factor-kappaB (NF-kappaB) has been determined to play a role in cell survival/proliferation in human pancreatic carcinoma, this transcription factor is a potential therapeutic target.The authors investigated the ability of curcumin (diferuloylmethane), an agent that is pharmacologically safe in humans, to modulate NF-kappaB activity.NF-kappaB and IkappaB kinase (IKK) were constitutively active in all human pancreatic carcinoma cell lines examined, and curcumin consistently suppressed NF-kappaB binding (as assessed using an electrophoretic mobility gel-shift assay) and IKK activity. Curcumin decreased the expression of NF-kappaB-regulated gene products, including cyclooxygenase-2 (as assessed using immunoblot analysis), prostaglandin E2, and interleukin-8 (as assessed using an enzyme-linked immunoassay), all of which have been implicated in the growth and invasiveness of pancreatic carcinoma. These changes were associated with concentration- and time-dependent antiproliferative activity (as assessed using a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide [MTT] assay) and proapoptotic effects (as assessed via annexin V/propidium iodide staining [fluorescence-activated cell sorting, as well as with the induction of polyadenosine-5'-diphosphate-ribose polymerase cleavage).Curcumin down-regulated NF-kappaB and growth control molecules induced by NF-kappaB in human pancreatic cells. These effects were accompanied by marked growth inhibition and apoptosis. Through these findings, the authors provided a biologic rationale for the treatment of patients with pancreatic carcinoma using this nontoxic phytochemical.

Authors
Li, L; Aggarwal, BB; Shishodia, S; Abbruzzese, J; Kurzrock, R
MLA Citation
Li, L, Aggarwal, BB, Shishodia, S, Abbruzzese, J, and Kurzrock, R. "Nuclear factor-kappaB and IkappaB kinase are constitutively active in human pancreatic cells, and their down-regulation by curcumin (diferuloylmethane) is associated with the suppression of proliferation and the induction of apoptosis." Cancer 101.10 (November 2004): 2351-2362.
PMID
15476283
Source
epmc
Published In
Cancer
Volume
101
Issue
10
Publish Date
2004
Start Page
2351
End Page
2362
DOI
10.1002/cncr.20605

A phase II pilot study of high-dose 24-hour continuous infusion of 5-FU and leucovorin and low-dose PALA for patients with colorectal cancer: a Southwest Oncology Group study.

The purpose of this phase II multi-institutional study was to define the efficacy and toxicity of infusional 5-FU in combination with PALA and leucovorin in patients with advanced colorectal cancer.Patients were required to have histologically confirmed colorectal cancer with distant metastases. The treatment regimen consisted of 5-FU 2600 mg/m(2) as a 24-hours continuous infusion given once a week, concurrently with leucovorin (LV) at 500 mg/m(2) as a 24-hour continuous infusion. PALA was administered 24 hours prior to 5-FU/LV at a dose of 250 mg/m(2) iv over 15 minutes weekly. Patients were continued on the assigned treatment regimen until progression of disease, unacceptable toxicity, or the patient declined further therapy.This study accrued 28 patients and all were eligible and evaluable for toxicity. Four patients had inadequate assessment of response and are considered non-responders. There was one complete response and five partial responses for an overall response rate of 6/28 or 21% (95% confidence interval 8-41%). Estimated median survival was 17.4 months (95% confidence interval 13.3-20.5 months). One patient died of a treatment related infection. This patient also had grade 4 diarrhea and vomiting.The combination of 5-FU, leucovorin, and PALA in the doses and schedule used here, produces a response rate similar to other modulated schedules of 5-FU with similar survival and toxicity profiles.

Authors
Whitehead, RP; Benedetti, JK; Abbruzzese, JL; Ardalan, B; Williamson, S; Gaynor, ER; Balcerzak, SP; Macdonald, JS
MLA Citation
Whitehead, RP, Benedetti, JK, Abbruzzese, JL, Ardalan, B, Williamson, S, Gaynor, ER, Balcerzak, SP, and Macdonald, JS. "A phase II pilot study of high-dose 24-hour continuous infusion of 5-FU and leucovorin and low-dose PALA for patients with colorectal cancer: a Southwest Oncology Group study." Investigational new drugs 22.4 (November 2004): 467-473.
PMID
15292717
Source
epmc
Published In
Investigational New Drugs
Volume
22
Issue
4
Publish Date
2004
Start Page
467
End Page
473
DOI
10.1023/b:drug.0000036689.28596.c6

A phase I surrogate endpoint study of SU6668 in patients with solid tumors.

PURPOSE: To evaluate the biologic effects of SU6668 in patients with solid tumors using comprehensive measures of pharmacokinetics (PK), functional imaging, and tissue correlative studies. EXPERIMENTAL DESIGN: Eligible patients with tumors accessible for core needle biopsy were treated with SU6668 at doses of 200 or 400 mg/m(2)/day. Functional computed tomography (CT) scan and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were performed at baseline and repeated 4 weeks and 12 weeks after treatment for analysis of tumor angiogenesis. The PK was analyzed using a high-performance liquid chromatography assay. Tumor specimens obtained via core needle biopsy at baseline and 4 weeks later were analyzed for the biologic effects of SU6668. RESULTS: Six of a total of seven patients received treatment for at least 3 months and underwent comprehensive correlative studies, including PK, imaging, and tissue biopsy. Functional CT showed that five of six patients had decreased blood flow in tumors in response to treatment, and DCE-MRI results indicated significant change of area under the signal intensity vs. time curve (AUC) and/or maximum slope (maximum rate of signal intensity change) in two of four patients evaluated with this technique. PK studies showed that the mean apparent oral clearance (Cl(oral)) measured on day 1 was 6.3 +/- 2.7 L/hr/m(2), yielding a mean AUC of 16.6 +/- 4.3 mg/L.hr. By day 22, the Cl(oral) was 40% more than that observed on day 1. CONCLUSION: It is feasible to evaluate the biologic effects of antiangiogenic agents using comprehensive surrogate measures.

Authors
Xiong, HQ; Herbst, R; Faria, SC; Scholz, C; Davis, D; Jackson, EF; Madden, T; McConkey, D; Hicks, M; Hess, K; Charnsangavej, CA; Abbruzzese, JL
MLA Citation
Xiong, HQ, Herbst, R, Faria, SC, Scholz, C, Davis, D, Jackson, EF, Madden, T, McConkey, D, Hicks, M, Hess, K, Charnsangavej, CA, and Abbruzzese, JL. "A phase I surrogate endpoint study of SU6668 in patients with solid tumors." Investigational new drugs 22.4 (November 2004): 459-466.
PMID
15292716
Source
epmc
Published In
Investigational New Drugs
Volume
22
Issue
4
Publish Date
2004
Start Page
459
End Page
466
DOI
10.1023/b:drug.0000036688.96453.8d

Pancreatic cancer: future outlook, promising trials, newer systemic agents, and strategies from the Gastrointestinal Intergroup Pancreatic Cancer Task Force.

This article summarizes the results of recent studies using newer agents, including farnesyl transferase inhibitors, matrix metalloproteinase inhibitors, inhibitors of the epidermal growth factor pathway, antiangiogenic therapeutics by inhibition of vascular endothelial growth factor, and some forms of immunotherapy. Although some results have been disappointing, others seem to be promising, serving as a basis for planned larger trials.

Authors
Jafari, M; Abbruzzese, JL
MLA Citation
Jafari, M, and Abbruzzese, JL. "Pancreatic cancer: future outlook, promising trials, newer systemic agents, and strategies from the Gastrointestinal Intergroup Pancreatic Cancer Task Force." Surgical oncology clinics of North America 13.4 (October 2004): 751-xi. (Review)
PMID
15350946
Source
epmc
Published In
Surgical Oncology Clinics of North America
Volume
13
Issue
4
Publish Date
2004
Start Page
751
End Page
xi
DOI
10.1016/j.soc.2004.06.009

Near-infrared optical imaging of integrin alphavbeta3 in human tumor xenografts.

In vivo optical imaging is potentially useful for evaluating the presence of tumor markers that are targets of molecular medicine. Here we report the synthesis and characterization of integrin alphavbeta3-targeted peptide cyclo(Lys-Arg-Gly-Asp-Phe) [c(KRGDf )] labeled with fluorescence dyes with wavelength spanning from the visible/near infrared (Cy5.5) to the true near infrared (IRDye800) for optical imaging. In vitro, the peptide-dye conjugates bound specifically to tumor cells expressing alphavbeta3. When administered intravenously into mice at a dose of 6 nmol /mouse, the conjugates accumulated in tumors expressing alphavbeta3. The tumor-to-background ratios for human KS1767 Kaposi's sarcoma in mice injected with Cy5.5-c(KRGDf ) and Cy5.5 were 5.5 and 1.5, respectively. Preinjection of c(KRGDf ) blocked the uptake of Cy5.5-c(KRGDf ) in tumors by 89%. In alphavbeta3-positive M21 and alphavbeta3-negative M21-L human melanoma, fluorescence intensity in the tumor of mice injected with IRDye800 - c(KRGDf ) was 2.3 and 1.3 times that in normal tissue, respectively. Dynamic imaging revealed that Cy5.5- c(KRGDf ) was rapidly taken up by KS1767 tumor immediately after bolus injection. The rate of its uptake in the tumor was reduced by preinjection of c(KRGDf ) in an interval time-dependent manner. Our data suggest that near-infrared fluorescence imaging may be applied to the detection of tumors expressing integrin alphavbeta3 and to the assessment of the optimal biological dose and schedule of targeted therapies.

Authors
Wang, W; Ke, S; Wu, Q; Charnsangavej, C; Gurfinkel, M; Gelovani, JG; Abbruzzese, JL; Sevick-Muraca, EM; Li, C
MLA Citation
Wang, W, Ke, S, Wu, Q, Charnsangavej, C, Gurfinkel, M, Gelovani, JG, Abbruzzese, JL, Sevick-Muraca, EM, and Li, C. "Near-infrared optical imaging of integrin alphavbeta3 in human tumor xenografts." Molecular imaging 3.4 (October 2004): 343-351.
PMID
15802051
Source
epmc
Published In
Molecular imaging : official journal of the Society for Molecular Imaging
Volume
3
Issue
4
Publish Date
2004
Start Page
343
End Page
351
DOI
10.1162/1535350042973481

Adjuvant therapy for pancreatic cancer: current status and future directions.

This article summarizes the important past and ongoing adjuvant therapy trials for pancreatic cancer. The recent developments in the fields of radiosensitization, chemotherapy, and molecular-targeted therapy are outlined. Finally, the future study strategies for adjuvant therapy trials are discussed.

Authors
Xiong, HQ; Abbruzzese, JL
MLA Citation
Xiong, HQ, and Abbruzzese, JL. "Adjuvant therapy for pancreatic cancer: current status and future directions." Surgical oncology clinics of North America 13.4 (October 2004): 737-xi. (Review)
PMID
15350945
Source
epmc
Published In
Surgical Oncology Clinics of North America
Volume
13
Issue
4
Publish Date
2004
Start Page
737
End Page
xi
DOI
10.1016/j.soc.2004.06.010

The convergence of cancer prevention and therapy in early-phase clinical drug development.

After decades of separate but not equal drug development, prevention and therapy are beginning to converge at the level of early-phase clinical testing. This highly beneficial convergence is due to spectacular molecular advances in our understanding of neoplasia (both cancer and precancer), cancer risk and prognosis, and the mechanisms by which novel drugs with less toxicity and more cytostatic activity profiles target specific molecular events to suppress malignant and premalignant cells. The future full convergence of prevention-therapy drug development (aided by technological advances, such as in molecular imaging) promises to hasten the progress of oncology in reducing the public health impact of the major cancers.

Authors
Abbruzzese, JL; Lippman, SM
MLA Citation
Abbruzzese, JL, and Lippman, SM. "The convergence of cancer prevention and therapy in early-phase clinical drug development." Cancer cell 6.4 (October 2004): 321-326. (Review)
PMID
15488755
Source
epmc
Published In
Cancer Cell
Volume
6
Issue
4
Publish Date
2004
Start Page
321
End Page
326
DOI
10.1016/j.ccr.2004.09.021

The treatment of colorectal carcinoma: standard chemotherapy and beyond.

Significant advances in the management of colorectal cancer patients have occurred within the past 5 years. New cytotoxic agents as well as novel targeted therapies have notably prolonged the survival of colorectal cancer patients with advanced disease. Some of these regimens have also been successfully applied to the adjuvant setting. Our improved scientific understanding of colorectal cancer will form the basis for further development of new methods to treat this common malignancy. The introduction of targeted therapeutics into the management of colorectal cancer is likely to extend the overall survival of patients further.

Authors
Eng, C; Abbruzzese, JL
MLA Citation
Eng, C, and Abbruzzese, JL. "The treatment of colorectal carcinoma: standard chemotherapy and beyond." Clinical advances in hematology & oncology : H&O 2.9 (September 2004): 592-598. (Review)
PMID
16163242
Source
epmc
Published In
Clinical advances in hematology & oncology : H&O
Volume
2
Issue
9
Publish Date
2004
Start Page
592
End Page
598

Comparison of the efficacy, toxicity, and pharmacokinetics of a uracil/tegafur (UFT) plus oral leucovorin (LV) regimen between Japanese and American patients with advanced colorectal cancer: joint United States and Japan study of UFT/LV.

PURPOSE: To compare the efficacy, toxicities, and pharmacokinetics of an oral regimen consisting of uracil/tegafur (UFT) and leucovorin (LV) between Japanese patients and patients in the United States with previously untreated metastatic colorectal cancer. PATIENTS AND METHODS: Forty-four Japanese patients and 45 patients in the United States were enrolled in concurrent nonrandomized phase II trials. UFT 300 mg/m2/d and leucovorin 75 mg/d were administered orally for 28 days followed by a 7-day rest period. The total daily dose of each drug was divided into three equal doses. Treatment was repeated every 5 weeks until disease progression. Blood samples for the pharmacokinetic study were obtained after the initial dose on day 1 of the first course. RESULTS: The response rate for the Japanese patients and the patients in the United States was 36.4% (95% CI, 22.4% to 52.2%) and 34.1% (95% CI, 20.5% to 49.9%), respectively. The only major toxicity was diarrhea, and other toxicities were mild in both populations. The incidence of grade 3 or higher diarrhea in the Japanese and Americans was 9% and 22%, respectively. Although the area under the curve and maximum concentration of fluorouracil were found to be slightly higher in the Japanese patients than the patients in the United States, and area under the curve-adjusted body surface area appeared to be comparable between the two groups. CONCLUSION: The efficacy and pharmacokinetic parameters of UFT and LV are comparable in Japanese and American patients; however, a difference in toxicity profile, specifically diarrhea, was noted. This oral regimen of UFT and LV is considered to have similar activity against metastatic colorectal cancer and to have acceptable toxicity in patients in both countries.

Authors
Shirao, K; Hoff, PM; Ohtsu, A; Loehrer, PJ; Hyodo, I; Wadler, S; Wadleigh, RG; O'Dwyer, PJ; Muro, K; Yamada, Y; Boku, N; Nagashima, F; Abbruzzese, JL
MLA Citation
Shirao, K, Hoff, PM, Ohtsu, A, Loehrer, PJ, Hyodo, I, Wadler, S, Wadleigh, RG, O'Dwyer, PJ, Muro, K, Yamada, Y, Boku, N, Nagashima, F, and Abbruzzese, JL. "Comparison of the efficacy, toxicity, and pharmacokinetics of a uracil/tegafur (UFT) plus oral leucovorin (LV) regimen between Japanese and American patients with advanced colorectal cancer: joint United States and Japan study of UFT/LV." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 22.17 (September 2004): 3466-3474.
PMID
15277535
Source
epmc
Published In
Journal of Clinical Oncology
Volume
22
Issue
17
Publish Date
2004
Start Page
3466
End Page
3474
DOI
10.1200/jco.2004.05.017

NF-kappaB and AP-1 connection: mechanism of NF-kappaB-dependent regulation of AP-1 activity.

Nuclear factor kappaB (NF-kappaB) and activator protein 1 (AP-1) transcription factors regulate many important biological and pathological processes. Activation of NF-kappaB is regulated by the inducible phosphorylation of NF-kappaB inhibitor IkappaB by IkappaB kinase. In contrast, Fos, a key component of AP-1, is primarily transcriptionally regulated by serum responsive factors (SRFs) and ternary complex factors (TCFs). Despite these different regulatory mechanisms, there is an intriguing possibility that NF-kappaB and AP-1 may modulate each other, thus expanding the scope of these two rapidly inducible transcription factors. To determine whether NF-kappaB activity is involved in the regulation of fos expression in response to various stimuli, we analyzed activity of AP-1 and expression of fos, fosB, fra-1, fra-2, jun, junB, and junD, as well as AP-1 downstream target gene VEGF, using MDAPanc-28 and MDAPanc-28/IkappaBalphaM pancreatic tumor cells and wild-type, IKK1-/-, and IKK2-/- murine embryonic fibroblast cells. Our results show that elk-1, a member of TCFs, is one of the NF-kappaB downstream target genes. Inhibition of NF-kappaB activity greatly decreased expression of elk-1. Consequently, the reduced level of activated Elk-1 protein by extracellular signal-regulated kinase impeded constitutive, serum-, and superoxide-inducible c-fos expression. Thus, our study revealed a distinct and essential role of NF-kappaB in participating in the regulation of elk-1, c-fos, and VEGF expression.

Authors
Fujioka, S; Niu, J; Schmidt, C; Sclabas, GM; Peng, B; Uwagawa, T; Li, Z; Evans, DB; Abbruzzese, JL; Chiao, PJ
MLA Citation
Fujioka, S, Niu, J, Schmidt, C, Sclabas, GM, Peng, B, Uwagawa, T, Li, Z, Evans, DB, Abbruzzese, JL, and Chiao, PJ. "NF-kappaB and AP-1 connection: mechanism of NF-kappaB-dependent regulation of AP-1 activity." Molecular and cellular biology 24.17 (September 2004): 7806-7819.
PMID
15314185
Source
epmc
Published In
Molecular and Cellular Biology
Volume
24
Issue
17
Publish Date
2004
Start Page
7806
End Page
7819
DOI
10.1128/mcb.24.17.7806-7819.2004

Phase I trial of combined irinotecan and oxaliplatin given every three weeks to patients with metastatic colorectal cancer.

Both irinotecan and oxaliplatin are active agents in the treatment of patients with metastatic colorectal cancer (MCC). There is a strong preclinical rationale for combining these two agents. We sought to determine the dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD) of combined irinotecan and oxaliplatin given every three weeks.Cohorts of patients with MCC previously treated with 5-fluorouracil received escalating doses of irinotecan (150, 175, and 200 mg/m(2)) and a fixed dose of oxaliplatin (130 mg/m(2)), both given intravenously every 3 weeks. DLT was evaluated within the first course of treatment. Objective responses were evaluated every two courses and were confirmed at least four weeks later.Fourteen patients were treated and evaluated for toxicity. The DLT was neutropenia, with or without fever, and delayed recovery of neutrophil counts was frequent (13 courses in six patients). Other toxic effects (peripheral neuropathy, nausea, vomiting, diarrhea, and fatigue) were mild to moderate. Among 13 patients evaluable for activity, four achieved partial responses and nine had stable disease.The combination of irinotecan and oxaliplatin is safe and apparently active in the treatment of MCC patients. The recommended dose for phase II studies is 175 mg/m(2) irinotecan plus 130 mg/m(2) oxaliplatin, given every 3 weeks. Neutropenia and delayed recovery of neutrophil counts are the predominant early toxicities with this schedule.

Authors
Hoff, PM; Saad, ED; Pazdur, R; Wolff, R; Lassere, Y; Bogaard, KR; Abbruzzese, JL
MLA Citation
Hoff, PM, Saad, ED, Pazdur, R, Wolff, R, Lassere, Y, Bogaard, KR, and Abbruzzese, JL. "Phase I trial of combined irinotecan and oxaliplatin given every three weeks to patients with metastatic colorectal cancer." Investigational new drugs 22.3 (August 2004): 307-313.
PMID
15122078
Source
epmc
Published In
Investigational New Drugs
Volume
22
Issue
3
Publish Date
2004
Start Page
307
End Page
313
DOI
10.1023/b:drug.0000026257.31142.41

A phase II study of high-dose 24 hour continuous infusion 5-FU and leucovorin and low-dose PALA for patients with advanced pancreatic adenocarcinoma: a Southwest Oncology Group Study.

The purpose of this phase II multi-institutional study was to define the efficacy and toxicity of infusional 5-FU in combination with PALA and leucovorin in patients with advanced pancreatic cancer.Patients were required to have histologically confirmed pancreatic cancer that was locally advanced, unresectable or disseminated. The treatment regimen consisted of weekly 5-FU 2600 mg/m(2) given concurrently with leucovorin at 500 mg/m(2). Both drugs were administered by 24-hour continuous infusion. PALA was administered 24 hours prior to the administration of 5-FU/LV at a dose of 250 mg/m(2) IV over 15 minutes weekly. Patients were continued on the assigned treatment regimen until progression of disease, unacceptable toxicity, or the patient declined further therapy.This study accrued 30 patients. Four of these patients were ineligible. All 26 eligible patients were evaluated for toxicity. One patient had inadequate assessment of response and was considered a non-responder. Three of the twenty-six eligible patients had partial responses, for a response rate of 12% (95% confidence interval 2% to 30%). All 26 eligible patients have died and the median overall survival was 7 months (95% confidence interval: 5.2 to 9 months). Four patients experienced grade 4 toxicities, including bilirubin increase (2 patients), vomiting (1 patient) and non-local skin ulceration (1). Two patients discontinued therapy due to toxicity.The dual modulation of 5-FU with PALA and leucovorin in the dose and schedule used here, has a response rate similar to other single agents in pancreatic cancer and can result in some long term survival while having relatively mild toxicity.

Authors
Whitehead, RP; Benedetti, JK; Abbruzzese, JL; Ardalan, B; Goodwin, JW; Balcerzak, SP; Samlowski, WE; Lenz, H-J; Macdonald, JS
MLA Citation
Whitehead, RP, Benedetti, JK, Abbruzzese, JL, Ardalan, B, Goodwin, JW, Balcerzak, SP, Samlowski, WE, Lenz, H-J, and Macdonald, JS. "A phase II study of high-dose 24 hour continuous infusion 5-FU and leucovorin and low-dose PALA for patients with advanced pancreatic adenocarcinoma: a Southwest Oncology Group Study." Investigational new drugs 22.3 (August 2004): 335-341.
PMID
15122082
Source
epmc
Published In
Investigational New Drugs
Volume
22
Issue
3
Publish Date
2004
Start Page
335
End Page
341
DOI
10.1023/b:drug.0000026261.76197.54

Overexpression of synuclein-gamma in pancreatic adenocarcinoma.

BACKGROUND: Currently, pancreatic adenocarcinoma is the fourth leading cause of cancer-related death in the United States. Despite the advances in pancreatic carcinoma research, patients with this devastating disease have a very poor prognosis. To identify the gene expression profile of pancreatic carcinoma, an important step in the process of developing new diagnostic and therapeutic strategies, the authors investigated the alteration of gene expression in this disease. METHODS: The authors analyzed a public serial analysis of gene expression (SAGE) database and examined in greater detail the expression of synuclein-gamma mRNA in several pancreatic carcinoma cell lines and tumor tissue samples by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis and Northern blot analysis. The expression of synuclein-gamma protein was investigated further by immunohistochemical and Western blot analyses using tumor cell lines, tumor tissue, and serum samples. RESULTS: Synuclein-gamma mRNA was overexpressed in 11 of 12 pancreatic carcinoma cell lines, including AsPc-1, MDAPanc28, Capan-1, Capan-2, PANC-1, HS766T, MDAPanc3, MDAPanc48, Colo357FG, MiaPaCa2, CFPac1, and BxPc3. The expression of synuclein-gamma protein was detectable in 8 of 12 pancreatic carcinoma cell lines (67%) and in 22 of 32 pancreatic tumor tissue samples (69%) by Western blot analysis. On immunohistochemical staining, synuclein-gamma protein was present in 61% of the tumor tissue samples examined from patients with Stage I and II pancreatic carcinoma. The overexpression of synuclein-gamma is correlated with perineural and lymph node invasion. Synuclein-gamma protein also was detectable by Western blot in serum samples from 21 of 56 patients (38%) with pancreatic carcinoma. CONCLUSIONS: Synuclein-gamma, which initially was described as a breast carcinoma-specific gene involved in invasion, metastasis, and chemotherapy resistance, was frequently overexpressed in pancreatic carcinoma. Overexpression of synuclein-gamma may play a role in pancreatic carcinoma invasion. Further studies will be necessary to determine the role of synuclein-gamma in pancreatic carcinoma.

Authors
Li, Z; Sclabas, GM; Peng, B; Hess, KR; Abbruzzese, JL; Evans, DB; Chiao, PJ
MLA Citation
Li, Z, Sclabas, GM, Peng, B, Hess, KR, Abbruzzese, JL, Evans, DB, and Chiao, PJ. "Overexpression of synuclein-gamma in pancreatic adenocarcinoma." Cancer 101.1 (July 2004): 58-65.
PMID
15221989
Source
epmc
Published In
Cancer
Volume
101
Issue
1
Publish Date
2004
Start Page
58
End Page
65
DOI
10.1002/cncr.20321

Regional effects of an antivascular endothelial growth factor receptor monoclonal antibody on receptor phosphorylation and apoptosis in human 253J B-V bladder cancer xenografts.

Vascular endothelial growth factor (VEGF) is a key angiogenic factor in a variety of solid tumors, making it one of the most attractive therapeutic targets. VEGF promotes the proliferation, survival, and differentiation of vascular endothelial cells by stimulating autophosphorylation and activation of VEGF receptor-2 (VEGFR-2, fetal liver kinase-1, and kinase insert domain-containing receptor). We developed fluorescence-based, quantitative methods to measure total VEGFR-2, VEGFR-2 phosphorylation, apoptosis, and microvessel density and size within whole tumor cross-sections using a laser scanning cytometer. Using these methods, we characterized the effects of DC101, a blocking antibody specific for murine VEGFR-2, on orthotopic human 253J-BV bladder tumors growing in nude mice. Basal levels of receptor phosphorylation were heterogeneous, with approximately 50% of endothelial cells positive for phosphorylated VEGFR-2 at baseline. DC101 therapy resulted in a 50% decrease in overall VEGFR-2 phosphorylation and a 15-fold and 8-fold increase in endothelial cell (CD31-positive) and tumor cell apoptosis, respectively. DC101 also decreased overall tumor microvessel density, but it mostly affected smaller CD105-negative microvessels located in the periphery of the tumor. Intriguingly, anti-VEGFR-2 therapy resulted in increased mean vessel size and an increase in overall VEGFR-2 levels. Increases in total VEGFR-2 levels were localized to the tumor core and were associated with increased expression of the oxygen-sensitive transcription factor, hypoxia inducible factor-1alpha. These data suggest that VEGFR inhibitors preferentially target discrete populations of tumor endothelial cells associated with the smaller peripheral blood vessels. Thus, agents that target a single receptor (e.g., VEGFR-2) may not be sufficient to completely inhibit tumor angiogenesis.

Authors
Davis, DW; Inoue, K; Dinney, CPN; Hicklin, DJ; Abbruzzese, JL; McConkey, DJ
MLA Citation
Davis, DW, Inoue, K, Dinney, CPN, Hicklin, DJ, Abbruzzese, JL, and McConkey, DJ. "Regional effects of an antivascular endothelial growth factor receptor monoclonal antibody on receptor phosphorylation and apoptosis in human 253J B-V bladder cancer xenografts." Cancer research 64.13 (July 2004): 4601-4610.
PMID
15231672
Source
epmc
Published In
Cancer Research
Volume
64
Issue
13
Publish Date
2004
Start Page
4601
End Page
4610
DOI
10.1158/0008-5472.can-2879-2

Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: a multicenter phase II Trial.

PURPOSE: To determine the response rate, time to disease progression, survival duration and rate, and toxicity with the combination of cetuximab and gemcitabine in patients with epidermal growth factor receptor (EGFR)-expressing advanced pancreatic cancer. PATIENTS AND METHODS: Patients with measurable locally advanced or metastatic pancreatic cancer who had never received chemotherapy for their advanced disease and had immunohistochemical evidence of EGFR expression were eligible for the multicenter phase II trial. Patients were treated with cetuximab at an initial dose of 400 mg/m(2), followed by 250 mg/m(2) weekly for 7 weeks. Gemcitabine was administered at 1,000 mg/m(2) for 7 weeks, followed by 1 week of rest. In subsequent cycles, cetuximab was administered weekly, and gemcitabine was administered weekly for 3 weeks every 4 weeks. RESULTS: Sixty-one patients were screened for EGFR expression, 58 patients (95%) had at least 1+ staining, and 41 were enrolled onto the trial. Five patients (12.2%) achieved a partial response, and 26 (63.4%) had stable disease. The median time to disease progression was 3.8 months, and the median overall survival duration was 7.1 months. One-year progression-free survival and overall survival rates were 12% and 31.7%, respectively. The most frequently reported grade 3 or 4 adverse events were neutropenia (39.0%), asthenia (22.0%), abdominal pain (22.0%), and thrombocytopenia (17.1%). CONCLUSION: Cetuximab in combination with gemcitabine showed promising activity against advanced pancreatic cancer. Further clinical investigation is warranted.

Authors
Xiong, HQ; Rosenberg, A; LoBuglio, A; Schmidt, W; Wolff, RA; Deutsch, J; Needle, M; Abbruzzese, JL
MLA Citation
Xiong, HQ, Rosenberg, A, LoBuglio, A, Schmidt, W, Wolff, RA, Deutsch, J, Needle, M, and Abbruzzese, JL. "Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: a multicenter phase II Trial." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 22.13 (July 2004): 2610-2616.
PMID
15226328
Source
epmc
Published In
Journal of Clinical Oncology
Volume
22
Issue
13
Publish Date
2004
Start Page
2610
End Page
2616
DOI
10.1200/jco.2004.12.040

Stabilization of p53 is a novel mechanism for proapoptotic function of NF-kappaB.

Both pro- and antiapoptotic activities of NF-kappaB transcription factor have been observed; however, less is known about the mechanism by which NF-kappaB induces apoptosis. To elucidate how NF-kappaB regulates proapoptotic signaling, we performed functional analyses using wild-type, ikk1(-/-), ikk2(-/-), rela(-/-) murine fibroblasts, MDAPanc-28/Puro, MDAPanc-28/IkappaBalphaM, and HCT116/p53(+/+) and HCT116/p53(-/-) cells with investigational anticancer agent doxycycline as a superoxide inducer for generating apoptotic stimulus. In this report, we show that doxycycline increased superoxide generation and subsequently activated NF-kappaB, which in turn up-regulated p53 expression and increased the stability and DNA binding activity of p53. Consequently, NF-kappaB-dependent p53 activity induced the expression of p53-regulated genes PUMA and p21(waf1) as well as apoptosis. Importantly, lack of RelA, IKK, and p53 as well as expression of a dominant negative IkappaBalpha (IkappaBalphaM) inhibited NF-kappaB-dependent p53 activation and apoptosis. The doxycycline-induced NF-kappaB activation was not inhibited in HCT116/p53(-/-) cells. Our results demonstrate that NF-kappaB plays an essential role in activation of wild-type p53 tumor suppressor to initiate proapoptotic signaling in response to overgeneration of superoxide. Thus, these findings reveal a mechanism of NF-kappaB-regulated proapoptotic signaling.

Authors
Fujioka, S; Schmidt, C; Sclabas, GM; Li, Z; Pelicano, H; Peng, B; Yao, A; Niu, J; Zhang, W; Evans, DB; Abbruzzese, JL; Huang, P; Chiao, PJ
MLA Citation
Fujioka, S, Schmidt, C, Sclabas, GM, Li, Z, Pelicano, H, Peng, B, Yao, A, Niu, J, Zhang, W, Evans, DB, Abbruzzese, JL, Huang, P, and Chiao, PJ. "Stabilization of p53 is a novel mechanism for proapoptotic function of NF-kappaB." The Journal of biological chemistry 279.26 (June 2004): 27549-27559.
PMID
15102862
Source
epmc
Published In
The Journal of biological chemistry
Volume
279
Issue
26
Publish Date
2004
Start Page
27549
End Page
27559
DOI
10.1074/jbc.m313435200

Phase II study of capecitabine in patients with fluorouracil-resistant metastatic colorectal carcinoma.

PURPOSE: Capecitabine is an oral fluoropyrimidine converted to fluourouracil (FU) preferentially in tumor tissue. It has proven clinical activity against colorectal cancer when used as first-line therapy. The objectives of this study were to assess the safety and efficacy of capecitabine in patients with metastatic colorectal carcinoma who progressed despite previous FU therapy. PATIENTS AND METHODS: According to the group sequential analysis design of this study, accrual would stop if no responses were observed in the first 20 patients treated. If one or more objective responses were confirmed, the trial would be expanded. Patients received capecitabine 1,250 mg/m(2) twice a day for 14 days, every 3 weeks. Tumor lesions were assessed every 6 weeks, and patients were followed for survival every 3 months after completing treatment. RESULTS: Twenty-three patients were enrolled onto the study; 22 fulfilled all the eligibility criteria. No objective responses were observed among the 22 eligible patients; 11 patients (50%) had stable disease for a median duration of 141 days (range, 88-289 days). The Kaplan-Meier estimate of median time to disease progression was 64 days (95% CI, 41 to 134 days). The median survival time estimate was 389 days (95% CI, 267 to 637 days). The most frequent treatment-related adverse events were hand-foot syndrome, diarrhea, and nausea or vomiting. There were no grade 4 toxicities and no treatment-related deaths. CONCLUSION: Single-agent capecitabine in patients with metastatic colorectal carcinoma refractory to FU showed no objective responses and clinical benefit that was, at best, modest. The use of capecitabine in combination with other treatments in this patient population is under investigation.

Authors
Hoff, PM; Pazdur, R; Lassere, Y; Carter, S; Samid, D; Polito, D; Abbruzzese, JL
MLA Citation
Hoff, PM, Pazdur, R, Lassere, Y, Carter, S, Samid, D, Polito, D, and Abbruzzese, JL. "Phase II study of capecitabine in patients with fluorouracil-resistant metastatic colorectal carcinoma." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 22.11 (June 2004): 2078-2083.
PMID
15169794
Source
epmc
Published In
Journal of Clinical Oncology
Volume
22
Issue
11
Publish Date
2004
Start Page
2078
End Page
2083
DOI
10.1200/jco.2004.05.072

Monoclonal antibodies: the foundation of therapy for colorectal cancer in the 21st century?

The treatment of colorectal cancer has undergone enormous changes in the past decade. From a disease with a single treatment option (ie, fluorouracil, a modestly effective drug), the treatment options have evolved to include at least five new classes of antineoplastic agents. Among the considerable number of recently approved drugs, two are monoclonal antibodies and are the testing ground for our rapidly emerging knowledge about cancer cell biology. Cetuximab (Erbitux) targets the epidermal growth factor receptor, an important molecule involved with cell cycling, survival, invasion, and metastasis. Bevacizumab (Avastin) neutralizes the vascular endothelial growth factor, blocking its ability to activate its receptor on the endothelial cells. The development of both antibodies resulted from decades of research in molecular and cell biology, as well as preclinical and clinical studies, and signals a new paradigm where the tumor cells' own unique features are exploited in a rational way.

Authors
Hoff, PM; Ellis, LM; Abbruzzese, JL
MLA Citation
Hoff, PM, Ellis, LM, and Abbruzzese, JL. "Monoclonal antibodies: the foundation of therapy for colorectal cancer in the 21st century?." Oncology (Williston Park, N.Y.) 18.6 (May 2004): 736-746. (Review)
PMID
15214593
Source
epmc
Published In
Oncology
Volume
18
Issue
6
Publish Date
2004
Start Page
736
End Page
746

Novel therapies for pancreatic adenocarcinoma.

Despite advances in our understanding of the molecular and genetic basis of pancreatic cancer, the disease remains a clinical challenge. Gemcitabine, the standard chemotherapy for pancreatic cancer, offers modest improvement of tumor-related symptoms and marginal advantage of survival. New approaches, alone and in combination with gemcitabine, are being developed to combat this cancer. In this article we review the current status of investigations into several classes of agents: matrix metalloproteinase inhibitors; farnesyl transferase inhibitors; epidermal growth factor receptor inhibitors, including monoclonal antibodies and tyrosine kinase inhibitors; cyclooxygenase-2 inhibitors, and others. The scientific rationale, mechanism of action, and clinical trial data for these novel agents are discussed.

Authors
Pino, SM; Xiong, HQ; McConkey, D; Abbruzzese, JL
MLA Citation
Pino, SM, Xiong, HQ, McConkey, D, and Abbruzzese, JL. "Novel therapies for pancreatic adenocarcinoma." Current oncology reports 6.3 (May 2004): 199-206. (Review)
PMID
15066231
Source
epmc
Published In
Current Oncology Reports
Volume
6
Issue
3
Publish Date
2004
Start Page
199
End Page
206
DOI
10.1007/s11912-004-0050-1

Diagnostic strategies for unknown primary cancer.

Unknown primary cancer (UPC) is defined by the presence of metastatic disease for which a primary site is undetectable on presentation. Computed tomography scan of the body was performed routinely in search of the primary cancer and invasive procedures were pursued in selective cases. Magnetic resonance imaging of the breast enables identification of an occult breast primary tumor in < or = 75% of women who present with adenocarcinoma in the axillary lymph nodes and can influence surgical management. Positron emission tomography scan also can be used in the diagnosis of UPCs, but its value is controversial. Cytokeratins 7 and 20 and thyroid transcription factor are some of the histochemical markers used in most patients who present with metastatic adenocarcinoma. Some of the newly discovered immunohistochemical markers further assist in narrowing the differential diagnosis. The role of molecular profiling to make the diagnosis, establish the prognosis, and assess the response to treatment in UPCs is evolving. The authors discuss the role of histochemical markers in the diagnosis of UPC and the most recent data regarding the use of imaging and invasive diagnostic modalities and gene expression profiles.

Authors
Varadhachary, GR; Abbruzzese, JL; Lenzi, R
MLA Citation
Varadhachary, GR, Abbruzzese, JL, and Lenzi, R. "Diagnostic strategies for unknown primary cancer." Cancer 100.9 (May 2004): 1776-1785. (Review)
PMID
15112256
Source
epmc
Published In
Cancer
Volume
100
Issue
9
Publish Date
2004
Start Page
1776
End Page
1785
DOI
10.1002/cncr.20202

Novel therapies for pancreatic adenocarcinoma.

Despite advances in our understanding of the molecular and genetic basis of pancreatic cancer, the disease remains a clinical challenge. Gemcitabine, the standard chemotherapy for pancreatic cancer, offers modest improvement of tumor-related symptoms and marginal advantage of survival. New approaches, alone and in combination with gemcitabine, are being developed to combat this cancer. In this article we review the current status of investigations into several classes of agents: matrix metalloproteinase inhibitors; farnesyl transferase inhibitors; epidermal growth factor receptor inhibitors, including monoclonal antibodies and tyrosine kinase inhibitors; cyclooxygenase-2 inhibitors, and others. The scientific rationale, mechanism of action, and clinical trial data for these novel agents are discussed.

Authors
Pino, SM; Xiong, HQ; McConkey, D; Abbruzzese, JL
MLA Citation
Pino, SM, Xiong, HQ, McConkey, D, and Abbruzzese, JL. "Novel therapies for pancreatic adenocarcinoma." Current gastroenterology reports 6.2 (April 2004): 119-125. (Review)
PMID
15191689
Source
epmc
Published In
Current Gastroenterology Reports
Volume
6
Issue
2
Publish Date
2004
Start Page
119
End Page
125
DOI
10.1007/s11894-004-0038-x

Chemotherapy and radiation of anal canal cancer: the first approach.

Since the late 1970's, increasing evidence from single-arm phase II studies has indicated that combined modality therapy yields a complete response rate of approximately 80-90% in most patients with squamous cell cancers of the anal canal. Surgery, most commonly an abdominoperineal resection, is reserved for salvage therapy. Although patients with large primary tumors (>5 cm) have a lower complete response rate of 50-75%, the majority of patients may be spared a colostomy and have an excellent overall survival. This chapter reviews the recent literature of patients treated for squamous cell, basaloid, and cloacogenic carcinoma (collectively defined as squamous cell cancer) of the anal canal.

Authors
Eng, C; Abbruzzese, J; Minsky, BD
MLA Citation
Eng, C, Abbruzzese, J, and Minsky, BD. "Chemotherapy and radiation of anal canal cancer: the first approach." Surgical oncology clinics of North America 13.2 (April 2004): 309-viii. (Review)
PMID
15137959
Source
epmc
Published In
Surgical Oncology Clinics of North America
Volume
13
Issue
2
Publish Date
2004
Start Page
309
End Page
viii
DOI
10.1016/j.soc.2003.12.004

Celecoxib inhibits vascular endothelial growth factor expression in and reduces angiogenesis and metastasis of human pancreatic cancer via suppression of Sp1 transcription factor activity.

The aggressive biology of human pancreatic adenocarcinoma has been linked with overexpression of vascular endothelial growth factor (VEGF). Constitutive activation of the transcription factor Sp1 plays a critical role in VEGF overexpression. Recent studies indicated that celecoxib, a selective cyclooxygenase-2 inhibitor, exhibits potent antitumor activity. However, the underlying molecular mechanisms of this activity remain unclear. In the present study, we used a pancreatic cancer model to determine the role of Sp1 in the antitumor activity of celecoxib. Treatment of various pancreatic cancer cells with celecoxib suppressed VEGF expression at both the mRNA and protein level in a dose-dependent manner. VEGF promoter deletion and point mutation analyses indicated that a region between nucleotide -109 and -61 and its intact Sp1-binding sites were required for the inhibition of VEGF promoter activity by celecoxib. Also, celecoxib treatment reduced both Sp1 DNA binding activity and transactivating activity. This decreased activity correlated with reduced Sp1 protein and its phosphorylation as determined using Western blot analysis. Furthermore, in an orthotopic pancreatic cancer animal model, celecoxib treatment inhibited tumor growth and metastasis. The antitumor activity was consistent with inhibition of angiogenesis as determined by evaluating tumor microvessel formation, which correlated with decreased Sp1 activity and VEGF expression. Collectively, our data provide a novel molecular mechanism for the antitumor activity of celecoxib and may help further improve its effectiveness in controlling pancreatic cancer growth and metastasis.

Authors
Wei, D; Wang, L; He, Y; Xiong, HQ; Abbruzzese, JL; Xie, K
MLA Citation
Wei, D, Wang, L, He, Y, Xiong, HQ, Abbruzzese, JL, and Xie, K. "Celecoxib inhibits vascular endothelial growth factor expression in and reduces angiogenesis and metastasis of human pancreatic cancer via suppression of Sp1 transcription factor activity." Cancer research 64.6 (March 2004): 2030-2038.
PMID
15026340
Source
epmc
Published In
Cancer Research
Volume
64
Issue
6
Publish Date
2004
Start Page
2030
End Page
2038
DOI
10.1158/0008-5472.can-03-1945

Pancreatic cancer.

Pancreatic cancer remains a major unsolved health problem, with conventional cancer treatments having little impact on disease course. Almost all patients who have pancreatic cancer develop metastases and die. The main risk factors are smoking, age, and some genetic disorders, although the primary causes are poorly understood. Advances in molecular biology have, however, greatly improved understanding of the pathogenesis of pancreatic cancer. Many patients have mutations of the K-ras oncogene, and various tumour-suppressor genes are also inactivated. Growth factors also play an important part. However, disease prognosis is extremely poor. Around 15-20% of patients have resectable disease, but only around 20% of these survive to 5 years. For locally advanced, unresectable, and metastatic disease, treatment is palliative, although fluorouracil chemoradiation for locally advanced and gemcitabine chemotherapy for metastatic disease can provide palliative benefits. Despite pancreatic cancer's resistance to currently available treatments, new methods are being investigated. Preoperative chemoradiation is being advocated, with seemingly sound reasoning, and a wider role for gemcitabine is being explored. However, new therapeutic strategies based on the molecular biology of pancreatic cancer seem to hold the greatest promise.

Authors
Li, D; Xie, K; Wolff, R; Abbruzzese, JL
MLA Citation
Li, D, Xie, K, Wolff, R, and Abbruzzese, JL. "Pancreatic cancer." March 2004.
PMID
15051286
Source
epmc
Published In
The Lancet
Volume
363
Issue
9414
Publish Date
2004
Start Page
1049
End Page
1057
DOI
10.1016/s0140-6736(04)15841-8

NF-?B activity blockade impairs the angiogenic potential of human pancreatic cancer cells

Authors
Xiong, HQ; Abbruzzese, JL; Lin, E; Wang, L; Zheng, L; Xie, K
MLA Citation
Xiong, HQ, Abbruzzese, JL, Lin, E, Wang, L, Zheng, L, and Xie, K. "NF-?B activity blockade impairs the angiogenic potential of human pancreatic cancer cells." International Journal of Cancer 108.2 (January 10, 2004): 181-188.
Source
crossref
Published In
International Journal of Cancer
Volume
108
Issue
2
Publish Date
2004
Start Page
181
End Page
188
DOI
10.1002/ijc.11562

Imaging taxane-induced tumor apoptosis using PEGylated, 111In-labeled annexin V.

UNLABELLED: 99mTc-Labeled annexin V has been used for the imaging of tumor apoptosis induced by chemotherapy. However, owing to the short half-life of annexin V, multiple injections of the radiotracer are necessary to capture the peak apoptotic activity. In this study, we evaluated the imaging properties of an (111)In-labeled, long-circulating annexin V. METHODS: Both polyethylene glycol (PEG) and the metal chelator diethylenetriaminepentaacetic acid (DTPA) were simultaneously introduced to annexin V or ovalbumin through the use of a heterofunctional PEG precursor. Imaging studies were performed in mice bearing subcutaneously inoculated human mammary MDA-MB-468 tumors. The mice were treated with poly(L-glutamic acid)-paclitaxel, monoclonal antibody C225, or a combination of poly(L-glutamic acid)-paclitaxel and C225, followed by intravenous injection of (111)In-DTPA-PEG-annexin V. Images were acquired 48 h after the injection of the radiotracer. Autoradiography and TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling) staining were performed on adjacent tumor slices for the localization of apoptotic cells. The imaging properties of unPEGylated annexin V and PEGylated ovalbumin were also determined to permit assessment of the specificity of (111)In-DTPA-PEG-annexin V. RESULTS: Tumor apoptotic index increased from 1.67% +/- 0.31% at baseline to 7.60% +/- 0.72% and 11.07% +/- 1.81%, respectively, 4 d after treatment with poly(L-glutamic acid)-paclitaxel or combined poly(L-glutamic acid)-paclitaxel and C225. Tumor uptake (percentage of injected dose per gram of tumor [%ID/g]) of PEGylated (111)In-DTPA-PEG-annexin 4 d after treatment was significantly higher in tumors treated with poly(L-glutamic acid)-paclitaxel (10.76 +/- 1.38 %ID/g; P = 0.001) and with combined poly(L-glutamic acid)-paclitaxel and C225 (9.84 +/- 2.51 %ID/g; P = 0.029) than in nontreated tumors (6.14 +/- 0.67 %ID/g), resulting in enhanced visualization of treated tumors. (111)In-DTPA-PEG-annexin V distributed into the central zone of tumors, whereas (111)In-DTPA-annexin V was largely confined to the tumor periphery. Furthermore, uptake of (111)In-DTPA-PEG-annexin V by tumors correlated with apoptotic index (r = 0.87, P = 0.02). Increase in tumor uptake of the nonspecific PEGylated protein (111)In-DTPA-PEG-ovalbumin was also observed after poly(L-glutamic acid)-paclitaxel treatment (55.6%), although this increase was less than that observed for (111)In-DTPA-PEG-annexin V (96.7%). CONCLUSION: Increased uptake of and improved visualization with (111)In-DTPA-PEG-annexin V in solid tumors after chemotherapy are mediated through both specific binding to apoptotic cells and nonspecific retention of macromolecular contrast agents in the tumors. (111)In-Labeled, PEGylated annexin V may be used to assess tumor response to chemotherapy.

Authors
Ke, S; Wen, X; Wu, Q-P; Wallace, S; Charnsangavej, C; Stachowiak, AM; Stephens, CL; Abbruzzese, JL; Podoloff, DA; Li, C
MLA Citation
Ke, S, Wen, X, Wu, Q-P, Wallace, S, Charnsangavej, C, Stachowiak, AM, Stephens, CL, Abbruzzese, JL, Podoloff, DA, and Li, C. "Imaging taxane-induced tumor apoptosis using PEGylated, 111In-labeled annexin V." Journal of nuclear medicine : official publication, Society of Nuclear Medicine 45.1 (January 2004): 108-115.
PMID
14734682
Source
epmc
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
45
Issue
1
Publish Date
2004
Start Page
108
End Page
115

Gemcitabine and cisplatin for patients with metastatic or recurrent esophageal carcinoma: a Southwest Oncology Group Study.

PURPOSE: Experimental data, both in vivo and in vitro, suggest that the combination of gemcitabine and cisplatin acts synergistically. Within the Southwest Oncology Group, we designed a Phase II trial to test this chemotherapy combination for patients with esophageal cancer. EXPERIMENTAL DESIGN: Patients with metastatic or recurrent esophageal cancer were treated with gemcitabine 1000 mg/m(2) on days 1, 8, and 15, and cisplatin 100 mg/m(2) on day 15. Cycles were repeated every 28 days. The statistical endpoint was overall survival. RESULTS: Sixty-four eligible patients were accrued from 37 institutions. Twenty-six percent of patients had prior chemotherapy. The treatment was generally well-tolerated, with the most common toxicity being neutropenia in 31% of patients. All 64 patients have died. Survival at 3 months was 81%, and at 1 year was 20%. Median survival was 7.3 months. CONCLUSIONS: This regimen is tolerable palliative option for patients with metastatic esophageal cancer.

Authors
Urba, SG; Chansky, K; VanVeldhuizen, PJ; Pluenneke, RE; Benedetti, JK; Macdonald, JS; Abbruzzese, JL
MLA Citation
Urba, SG, Chansky, K, VanVeldhuizen, PJ, Pluenneke, RE, Benedetti, JK, Macdonald, JS, and Abbruzzese, JL. "Gemcitabine and cisplatin for patients with metastatic or recurrent esophageal carcinoma: a Southwest Oncology Group Study." Investigational new drugs 22.1 (January 2004): 91-97.
PMID
14707499
Source
epmc
Published In
Investigational New Drugs
Volume
22
Issue
1
Publish Date
2004
Start Page
91
End Page
97
DOI
10.1023/b:drug.0000006179.20974.af

Diagnostic protein discovery using proteolytic peptide targeting and identification.

Plasma protein profiling with mass spectrometry is currently being evaluated as a diagnostic tool for cancer and other diseases. These experiments consist of three steps: plasma protein fractionation, analysis with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS), and comparisons of the MALDI profiles to develop diagnostic fingerprints using bioinformatic techniques. While preliminary results appear promising in small sample groups, the method is limited by the sensitivity of MALDI-MS for intact proteins, the limited mass range of MALDI-MS, and difficulties associated with isolating individual proteins for identification to validate the diagnostic fingerprint. Here we present an alternative and improved method directed toward diagnostic protein discovery, which incorporates proteolytic peptide profiling, bioinformatic targeting of ion signals, and MALDI tandem mass spectrometry (MS/MS) peptide sequencing, rather than fingerprinting. Pancreatic cancer patients, pancreatitis patients, and controls are used as the model system. Profiling peptides after enzymatic digestion improves sensitivity and extends the accessible protein molecular weight range when compared to intact protein profiling. The first step is to extract and fractionate the proteins from plasma. Each fraction is digested with trypsin and subsequently analyzed by MALDI-MS. Rather than using bioinformatic analysis as a pattern-matching technique, peptides are targeted based on the disease to control peak intensity ratios measured in the averages of all mass spectra in each group and t-tests of the intensity of each individual peak. The targeted peptide ion signals are subsequently identified using MALDI-MS/MS in quadrupole-TOF and tandem-TOF instruments. This study found not only the proteins targeted and identified by a previous protein profiling experiment, but also detected additional proteins. These initial results are consistent with the known biology of pancreatic cancer or pancreatitis, but are not specific to those diseases.

Authors
Koomen, JM; Zhao, H; Li, D; Abbruzzese, J; Baggerly, K; Kobayashi, R
MLA Citation
Koomen, JM, Zhao, H, Li, D, Abbruzzese, J, Baggerly, K, and Kobayashi, R. "Diagnostic protein discovery using proteolytic peptide targeting and identification." Rapid communications in mass spectrometry : RCM 18.21 (January 2004): 2537-2548.
PMID
15468157
Source
epmc
Published In
Rapid Communications in Mass Spectrometry
Volume
18
Issue
21
Publish Date
2004
Start Page
2537
End Page
2548
DOI
10.1002/rcm.1657

Quantitative analysis of biomarkers defines an optimal biological dose for recombinant human endostatin in primary human tumors.

PURPOSE: In a recent study, we presented preliminary evidence for biological activity in a Phase I dose-finding study (15-600 mg/m(2)) of recombinant human endostatin in patients with refractory solid tumors. Here, we conducted additional biomarker analyses to correlate changes in tumor biology with dose. EXPERIMENTAL DESIGN: Excisional tumor biopsies were obtained at baseline and after 56 days of endostatin therapy. Laser scanning cytometry (LSC) was used to quantify biomarker levels in whole tissue sections. Apoptosis in tumor cells (TCs) and tumor-associated endothelial cells (ECs) was quantified by fluorescent three-color anti-CD31/terminal deoxynucleotidyl transferase-mediated nick end labeling staining. Microvessel densities were measured by LSC-guided vessel contouring. Levels of tumor-associated EC BCL-2 and hypoxia-inducible factor 1alpha were determined by immunofluorescence and LSC quantification. The results, including tumor blood flow measured by positron emission tomography, were analyzed using a quadratic polynomial model. RESULTS: Significant increases in EC death and decreases in tumor microvessel density were observed, with maximal effects of endostatin at a dose of 249 mg/m(2) (95% confidence interval, 159-338) and 257 mg/m(2) (95% confidence interval, 183-331), respectively. In contrast, levels of TC death were uniformly low and did not correlate with endostatin dose. Maximal nuclear hypoxia-inducible factor 1alpha and minimal EC Bcl-2 levels were observed at approximately 250 mg/m(2), although the changes did not reach statistical significance. CONCLUSIONS: The data suggest that endostatin had optimal biological activity at doses approximately 250 mg/m(2) in our cohort of patients. Endostatin's failure to induce high levels of TC death may explain its lack of significant clinical activity in this Phase I trial.

Authors
Davis, DW; Shen, Y; Mullani, NA; Wen, S; Herbst, RS; O'Reilly, M; Abbruzzese, JL; McConkey, DJ
MLA Citation
Davis, DW, Shen, Y, Mullani, NA, Wen, S, Herbst, RS, O'Reilly, M, Abbruzzese, JL, and McConkey, DJ. "Quantitative analysis of biomarkers defines an optimal biological dose for recombinant human endostatin in primary human tumors." Clinical cancer research : an official journal of the American Association for Cancer Research 10.1 Pt 1 (January 2004): 33-42.
PMID
14734449
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
10
Issue
1 Pt 1
Publish Date
2004
Start Page
33
End Page
42
DOI
10.1158/1078-0432.ccr-0736-3

A high expression level of insulin-like growth factor I receptor is associated with increased expression of transcription factor Sp1 and regional lymph node metastasis of human gastric cancer.

Insulin-like growth factor I receptor (IGF-IR) is critical to cell survival and growth and altered IGF-IR expression is found in many human cancers. However, its expression and potential role in gastric cancer development and progression has not been explored. The IGF-IR expression level was determined via immunohistochemistry in primary tumor and lymph node metastasis of 86 cases of resected gastric cancer. Relationships of IGF-IR expression with transcription factor Spl expression and clinicopathological features were analyzed. The impact of altered Sp1 expression on IGF-IR expression and gastric cancer biology was further determined using small inhibitory RNA for Sp1 mRNA. We found that IGF-IR was overexpressed in 62% of the tumor samples when compared with adjacent tumor-free gastric mucosa. Patients with lymph node metastases had strong expression of IGF-IR in both primary and metastatic tumor cells. IGF-IR overexpression in the primary tumor correlated with increased lymph node metastasis. Furthermore, the level of IGF-IR expression directly correlated with that of Spl, an important transcription factor for IGF-IR regulation. Knocking-down of Spl expression by small inhibitory RNA led to decreased IGF-IR expression and attenuated growth and metastasis of gastric cancer cells. Therefore, dysregulated expression of IGF-IR and/or Sp1 may contribute to the growth and metastasis of gastric cancer and potentially can be a target of therapeutic intervention.

Authors
Jiang, Y; Wang, L; Gong, W; Wei, D; Le, X; Yao, J; Ajani, J; Abbruzzese, JL; Huang, S; Xie, K
MLA Citation
Jiang, Y, Wang, L, Gong, W, Wei, D, Le, X, Yao, J, Ajani, J, Abbruzzese, JL, Huang, S, and Xie, K. "A high expression level of insulin-like growth factor I receptor is associated with increased expression of transcription factor Sp1 and regional lymph node metastasis of human gastric cancer." Clinical & experimental metastasis 21.8 (January 2004): 755-764.
PMID
16035620
Source
epmc
Published In
Clinical & Experimental Metastasis
Volume
21
Issue
8
Publish Date
2004
Start Page
755
End Page
764
DOI
10.1007/s10585-005-1198-2

Mechanisms of proinflammatory cytokine-induced biphasic NF-kappaB activation.

The transcription factor NF-kappaB regulates genes involved in innate and adaptive immune response, inflammation, apoptosis, and oncogenesis. Proinflammatory cytokines induce the activation of NF-kappaB in both transient and persistent phases. We investigated the mechanism for this biphasic NF-kappaB activation. Our results show that MEKK3 is essential in the regulation of rapid activation of NF-kappaB, whereas MEKK2 is important in controlling the delayed activation of NF-kappaB in response to stimulation with the cytokines TNF-alpha and IL-1alpha. MEKK3 is involved in the formation of the IkappaBalpha:NF-kappaB/IKK complex, whereas MEKK2 participates in assembling the IkappaBbeta:NF-kappaB/IKK complex; these two distinct complexes regulate the proinflammatory cytokine-induced biphasic NF-kappaB activation. Thus, our study reveals a novel mechanism in which different MAP3K and IkappaB isoforms are involved in specific complex formation with IKK and NF-kappaB for regulating the biphasic NF-kappaB activation. These findings provide further insight into the regulation of cytokine-induced specific and temporal gene expression.

Authors
Schmidt, C; Peng, B; Li, Z; Sclabas, GM; Fujioka, S; Niu, J; Schmidt-Supprian, M; Evans, DB; Abbruzzese, JL; Chiao, PJ
MLA Citation
Schmidt, C, Peng, B, Li, Z, Sclabas, GM, Fujioka, S, Niu, J, Schmidt-Supprian, M, Evans, DB, Abbruzzese, JL, and Chiao, PJ. "Mechanisms of proinflammatory cytokine-induced biphasic NF-kappaB activation." Molecular cell 12.5 (November 2003): 1287-1300.
PMID
14636585
Source
epmc
Published In
Molecular Cell
Volume
12
Issue
5
Publish Date
2003
Start Page
1287
End Page
1300
DOI
10.1016/s1097-2765(03)00390-3

Developmental biology informs cancer: the emerging role of the hedgehog signaling pathway in upper gastrointestinal cancers.

The hedgehog (Hh) signaling pathway plays many roles in invertebrate and vertebrate development. For example, specific inhibition of sonic Hh expression is critical during early stages of pancreas organogenesis, but an active Hh pathway appears to be required for maintenance of adult endocrine functions. Mutational inactivation of the Hh pathway has been demonstrated in human malignancies of the skin, cerebellum, and skeletal muscle. Now, two papers implicate aberrant Hh signaling in human upper gastrointestinal cancers including those developing from the esophagus, stomach, biliary tract, and pancreas.

Authors
Xie, K; Abbruzzese, JL
MLA Citation
Xie, K, and Abbruzzese, JL. "Developmental biology informs cancer: the emerging role of the hedgehog signaling pathway in upper gastrointestinal cancers." Cancer cell 4.4 (October 2003): 245-247. (Review)
PMID
14585350
Source
epmc
Published In
Cancer Cell
Volume
4
Issue
4
Publish Date
2003
Start Page
245
End Page
247
DOI
10.1016/s1535-6108(03)00246-0

Adenoma recurrences after resection of colorectal carcinoma: results from the Southwest Oncology Group 9041 calcium chemoprevention pilot study.

BACKGROUND: Colorectal adenomas are the usual precursors to carcinoma in sporadic and hereditary colorectal cancers (CRC). METHODS: A total of 220 CRC patients (stages 0, I, and II) were randomized prospectively in a double-blind pilot study of calcium chemoprevention by using recurrent colorectal adenomas as a surrogate end point. This trial is still in progress, and we report the preliminary findings on adenoma recurrence rates. RESULTS: Synchronous adenomas were present in 60% of patients, and cancer confined in a polyp was present in 23% of patients. The overall cumulative adenoma recurrence rate was 31% (19% in the first year, 29% for 2 years, and 35% for 3 years). The recurrence rates were greater for patients with synchronous adenomas: 38% at 3 years (P =.01). Lower stage was associated with higher adenoma recurrence rates (P =.04). Factors including age, sex, site of primary cancer, and whether the cancer was confined to a polyp were not significantly associated with differences in adenoma recurrence rates. CONCLUSIONS: The substantial adenoma recurrence rate in patients resected of CRC justifies colonoscopic surveillance on a periodic basis. Patients with higher rates of adenoma recurrences, such as CRC with synchronous adenomas, are ideal subjects for chemoprevention trials.

Authors
Chu, DZJ; Chansky, K; Alberts, DS; Meyskens, FL; Fenoglio-Preiser, CM; Rivkin, SE; Mills, GM; Giguere, JK; Goodman, GE; Abbruzzese, JL; Lippman, SM
MLA Citation
Chu, DZJ, Chansky, K, Alberts, DS, Meyskens, FL, Fenoglio-Preiser, CM, Rivkin, SE, Mills, GM, Giguere, JK, Goodman, GE, Abbruzzese, JL, and Lippman, SM. "Adenoma recurrences after resection of colorectal carcinoma: results from the Southwest Oncology Group 9041 calcium chemoprevention pilot study." Annals of surgical oncology 10.8 (October 2003): 870-875.
PMID
14527904
Source
epmc
Published In
Annals of Surgical Oncology
Volume
10
Issue
8
Publish Date
2003
Start Page
870
End Page
875
DOI
10.1245/aso.2003.03.037

Randomized phase II comparison of dose-intense gemcitabine: thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma.

PURPOSE: To conduct a randomized phase II trial of dose-intense gemcitabine using a standard 30-minute infusion or the fixed dose rate (FDR) infusion (10 mg/m2/min) in patients with pancreatic adenocarcinoma. PATIENTS AND METHODS: In this prospective trial, patients with locally advanced and metastatic pancreatic adenocarcinoma were treated with 2,200 mg/m2 gemcitabine over 30 minutes (standard arm) or 1,500 mg/m2 gemcitabine over 150 minutes (FDR arm) on days 1, 8, and 15 of every 4-week cycle. The primary end point of this trial was time to treatment failure. Secondary end points included time to progression, median survival, safety, and pharmacokinetic studies of gemcitabine. RESULTS: Ninety-two patients were enrolled onto this study; 91% of the patients had metastatic disease. Time to treatment failure was comparable in both treatment groups; however, the median survival for all patients was 5.0 months in the standard arm and 8.0 months in the FDR arm (P =.013). For patients with metastases, the median survival was 4.9 months in the standard arm and 7.3 months in FDR arm (P =.094). The 1- and 2-year survival rates for all patients were 9% (standard arm) versus 28.8% (FDR; P =.014) and 2.2% (standard arm) versus 18.3% (FDR; P =.007), respectively. Patients in the FDR infusion arm experienced consistently more hematologic toxicity. Pharmacokinetic analyses demonstrated a two-fold increase in intracellular gemcitabine triphosphate concentration in the FDR arm (P =.046). CONCLUSION: Pharmacokinetic and clinical data in this trial supports the continued evaluation of the FDR infusion strategy with gemcitabine.

Authors
Tempero, M; Plunkett, W; Ruiz Van Haperen, V; Hainsworth, J; Hochster, H; Lenzi, R; Abbruzzese, J
MLA Citation
Tempero, M, Plunkett, W, Ruiz Van Haperen, V, Hainsworth, J, Hochster, H, Lenzi, R, and Abbruzzese, J. "Randomized phase II comparison of dose-intense gemcitabine: thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 21.18 (September 2003): 3402-3408.
PMID
12885837
Source
epmc
Published In
Journal of Clinical Oncology
Volume
21
Issue
18
Publish Date
2003
Start Page
3402
End Page
3408
DOI
10.1200/jco.2003.09.140

Surrogate markers in antiangiogenesis clinical trials.

Novel antiangiogenic agents currently being developed may ultimately be more effective against solid tumours and less toxic than cytotoxic chemotherapy. As a result of the early clinical trials of angiogenesis inhibitors, investigators are beginning to appreciate the complexity of targeting angiogenesis and the realisation that developing clinically useful antiangiogenic therapy will be more challenging than originally thought. It is now apparent that new methods and surrogate markers to assess these agents' biological activity are crucial for their successful development. This review summarises the currently available clinical data on the development of surrogate markers of angiogenesis inhibitors.

Authors
Davis, DW; McConkey, DJ; Abbruzzese, JL; Herbst, RS
MLA Citation
Davis, DW, McConkey, DJ, Abbruzzese, JL, and Herbst, RS. "Surrogate markers in antiangiogenesis clinical trials." British journal of cancer 89.1 (July 2003): 8-14. (Review)
PMID
12838293
Source
epmc
Published In
British Journal of Cancer
Volume
89
Issue
1
Publish Date
2003
Start Page
8
End Page
14
DOI
10.1038/sj.bjc.6601035

Phase I and pharmacological study of oral 9-aminocamptothecin colloidal dispersion (NSC 603071) in patients with advanced solid tumors.

PURPOSE: 9-Aminocamptothecin colloidal dispersion (9-ACCD; NSC 603071) is a specific inhibitor of topoisomerase I that can be given p.o. This Phase I trial was conducted to determine the toxicity profile, maximal tolerated dose, and pharmacokinetics profile, including bioavailability, of p.o. 9-ACCD in patients with advanced solid tumors. EXPERIMENTAL DESIGN: After receiving one i.v. dose of 9-ACCD, patients were treated with 9-ACCD p.o., starting with a 2-week schedule, to establish the safety. Once safety was established, patients were treated continuously for 4 weeks followed by a rest period of 2 weeks at dosages of 0.2, 0.3, 0.45, 0.56, 0.7, and 0.63 mg/m(2)/day. Serial blood samples were collected for the pharmacokinetics study on day 1 after the i.v. dose and day 2 after p.o. administration. Lactone and total 9-aminocamptothecin were analyzed by high-pressure liquid chromatographic assay. RESULTS: Thirty-two patients were treated on the study. The dose-limiting toxicity was myelosuppression at the dosage of 0.7 mg/m(2)/day. Other toxic effects included nausea, vomiting, fatigue, and transient elevation of the total bilirubin level. The maximal tolerated dose was 0.63 mg/m(2)/day. There was no objective response. The mean terminal half-life of p.o. total 9-ACCD was 1.2 +/- 1.2 h, and the volume of distribution was 17.7 +/- 20.6 l/m(2). The mean bioavailability of total 9-ACCD was 68.1 +/- 36.4%. CONCLUSIONS: Despite good tolerance of p.o. administration, the lack of clinical activity and variable absorption of 9-ACCD suggested that further development might not be warranted.

Authors
Xiong, HQ; Tran, HT; Madden, TL; Newman, RA; Abbruzzese, JL
MLA Citation
Xiong, HQ, Tran, HT, Madden, TL, Newman, RA, and Abbruzzese, JL. "Phase I and pharmacological study of oral 9-aminocamptothecin colloidal dispersion (NSC 603071) in patients with advanced solid tumors." Clinical cancer research : an official journal of the American Association for Cancer Research 9.6 (June 2003): 2066-2071.
PMID
12796369
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
9
Issue
6
Publish Date
2003
Start Page
2066
End Page
2071

Report of the 16th International Symposium of the Foundation for Promotion of Cancer Research: Recent advances in pancreatic cancer.

Authors
Xiong, HQ; Abbruzzese, JL; Esumi, H; Kosuge, T; Kakizoe, T; Sugimura, T
MLA Citation
Xiong, HQ, Abbruzzese, JL, Esumi, H, Kosuge, T, Kakizoe, T, and Sugimura, T. "Report of the 16th International Symposium of the Foundation for Promotion of Cancer Research: Recent advances in pancreatic cancer." May 2003.
PMID
12865470
Source
epmc
Published In
Japanese Journal of Clinical Oncology
Volume
33
Issue
5
Publish Date
2003
Start Page
246
End Page
253
DOI
10.1093/jjco/hyg047

Intraperitoneal fluid neopterin, nitrate, and tryptophan after regional administration of interleukin-12.

Activated monocytes-macrophages may be associated with antitumor activity, and activation of these cells by certain cytokines, primarily interferon gamma (IFN-gamma), can be indicated by alterations in the concentrations of neopterin, nitrate, or tryptophan. Specimens of peritoneal fluid were obtained from patients with intra-abdominal neoplasia who were undergoing treatment in a phase I trial of weekly intraperitoneal recombinant interleukin-12 (rhIL-12), an inducer of IFN-gamma. Concentrations of neopterin, nitrate, tryptophan, IFN-gamma, and tumor necrosis factor alpha (TNF-alpha) were determined at various times during the first 48 hours in 11 patients who received intraperitoneal rhIL-12 in doses ranging from 100 to 1,500 ng/kg. An increase in peritoneal fluid nitrate concentrations was observed in nine of these patients. Increased concentrations of TNF-alpha and IFN-gamma were detected in 3 of 9 and 8 of 11 patients, respectively. Increased peritoneal fluid neopterin concentrations were detected by 24 hours after the injection in all patients studied. A significant increase in the ascitic fluid neopterin level could still be detected after 1 or 2 weeks of treatment (mean +/- standard error, 7.8 +/- 1.5 nM vs. 4.6 +/- 0.3 nM; Wilcoxon test, p = 0.0019), which is consistent with monocyte-macrophage activation. In contrast, the tryptophan concentration was lower (4.7 +/- 1.1 microM vs. 6.1 +/- 1.2 microM; p = 0.0428) after 1 or 2 weeks of treatment. There was a significant correlation between the dose of rhIL-12 and posttreatment neopterin concentrations (r(s) = 0.559, p = 0.0102). The intraperitoneal delivery of rhIL-12 appears to be associated with an immediate, sustained, and dose-dependent increase in peritoneal fluid neopterin, associated in most patients by an increase in IFN-gamma and in certain patients by an increase in nitrate and a decrease in tryptophan concentrations.

Authors
Melichar, B; Lenzi, R; Rosenblum, M; Kudelka, AP; Kavanagh, JJ; Melicharova, K; Templin, S; Garcia, ME; Abbruzzese, JL; Freedman, RS
MLA Citation
Melichar, B, Lenzi, R, Rosenblum, M, Kudelka, AP, Kavanagh, JJ, Melicharova, K, Templin, S, Garcia, ME, Abbruzzese, JL, and Freedman, RS. "Intraperitoneal fluid neopterin, nitrate, and tryptophan after regional administration of interleukin-12." Journal of immunotherapy (Hagerstown, Md. : 1997) 26.3 (May 2003): 270-276.
PMID
12806280
Source
epmc
Published In
Journal of Immunotherapy
Volume
26
Issue
3
Publish Date
2003
Start Page
270
End Page
276
DOI
10.1097/00002371-200305000-00010

Phase II study of MGI-114 administered intravenously for 5 days every 28 days to patients with metastatic colorectal cancer.

We examined the use of MGI-114 (6-hydroxymethyacylfulvene) for the treatment of patients with advanced colorectal carcinoma. Twenty-six patients were enrolled, with a median age of 60 years (range 41-75); 64% were male and all patients had a performance status of 0 or 1. We administered a dose of 11 mg/m2/d x 5 days every 4 weeks. With a median of two cycles (range 0-6) administered, no complete responses or partial responses were observed. Four patients had no change in disease (16%); 15 patients (57%) had progressive disease; seven patients were inevaluable (27%). Toxicity was evaluated in 25 of 26 patients. The main toxicities were hematologic, including granulocytopenia and thrombocytopenia. Neuropsychiatric adverse events included hallucination (7.7%), depression/anxiety (15.4%), and/or insomnia (19.2%). Given the lack of antitumor activity, further study of MGI-114 in colorectal cancer does not appear warranted.

Authors
Nasta, SD; Hoff, PM; George, CS; Neubauer, M; Cohen, SC; Abbruzzese, J; Winn, R; Pazdur, RM
MLA Citation
Nasta, SD, Hoff, PM, George, CS, Neubauer, M, Cohen, SC, Abbruzzese, J, Winn, R, and Pazdur, RM. "Phase II study of MGI-114 administered intravenously for 5 days every 28 days to patients with metastatic colorectal cancer." American journal of clinical oncology 26.2 (April 2003): 132-134.
PMID
12714882
Source
epmc
Published In
American Journal of Clinical Oncology: Cancer Clinical Trials
Volume
26
Issue
2
Publish Date
2003
Start Page
132
End Page
134
DOI
10.1097/00000421-200304000-00006

Phase II and pharmacodynamic study of the farnesyltransferase inhibitor R115777 as initial therapy in patients with metastatic pancreatic adenocarcinoma.

R115777 is a selective nonpeptidomimetic inhibitor of farnesyltransferase (FTase), one of several enzymes responsible for posttranslational modification that is required for the function of p21(ras) and other proteins. Given that RAS mutations are nearly universal in pancreatic cancer and R115777 demonstrated preclinical activity against pancreatic cell lines and xenografts, this phase II study was undertaken to determine its clinical activity and effect on target proteins in patients with measurable metastatic pancreatic adenocarcinoma.Twenty patients who had not received prior therapy for metastatic disease were treated with 300 mg of R115777 orally every 12 hours for 21 of 28 days. Inhibition of FTase activity in peripheral-blood mononuclear cells was measured using a lamin B C-terminus peptide as substrate. Western blot analysis was performed to monitor farnesylation status of the chaperone protein HDJ-2.No objective responses were seen. Median time to progression was 4.9 weeks, and median survival time was 19.7 weeks. The estimated 6-month survival rate was 25%, with no patients progression-free at 6 months. Grade 3/4 toxicities were liver enzyme elevation, anemia, neutropenia, thrombocytopenia, fatigue, nausea/vomiting, rash, and anorexia. FTase activity (mean +/- SD) decreased by 49.8% +/- 9.8% 4 hours after treatment on day 1 and 36.1% +/- 24.8% before treatment on day 15. HDJ-2 farnesylation (mean +/- SD) decreased by 33.4% +/- 19.8% on day 15.Although treatment with R115777 resulted in partial inhibition of FTase activity in mononuclear cells, it did not exhibit single-agent antitumor activity in patients with previously untreated metastatic pancreatic cancer.

Authors
Cohen, SJ; Ho, L; Ranganathan, S; Abbruzzese, JL; Alpaugh, RK; Beard, M; Lewis, NL; McLaughlin, S; Rogatko, A; Perez-Ruixo, JJ; Thistle, AM; Verhaeghe, T; Wang, H; Weiner, LM; Wright, JJ; Hudes, GR; Meropol, NJ
MLA Citation
Cohen, SJ, Ho, L, Ranganathan, S, Abbruzzese, JL, Alpaugh, RK, Beard, M, Lewis, NL, McLaughlin, S, Rogatko, A, Perez-Ruixo, JJ, Thistle, AM, Verhaeghe, T, Wang, H, Weiner, LM, Wright, JJ, Hudes, GR, and Meropol, NJ. "Phase II and pharmacodynamic study of the farnesyltransferase inhibitor R115777 as initial therapy in patients with metastatic pancreatic adenocarcinoma." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 21.7 (April 2003): 1301-1306.
PMID
12663718
Source
epmc
Published In
Journal of Clinical Oncology
Volume
21
Issue
7
Publish Date
2003
Start Page
1301
End Page
1306
DOI
10.1200/jco.2003.08.040

Overexpression of oncogenic STK15/BTAK/Aurora A kinase in human pancreatic cancer.

PURPOSE: Multiple chromosome abnormalities, including gain of chromosome20q, have been detected frequently in human pancreatic cancers. Overexpression of the STK15/BTAK/Aurora A gene located on chromosome 20q13, which encodes a centrosome-associated serine/threonine kinase, has been shown to induce chromosomal instability, leading to aneuploidy and cell transformation in multiple in vitro experimental systems. The purpose of this study was to investigate the expression and copy number alteration of STK15 in pancreatic cancer. EXPERIMENTAL DESIGN: STK15 expression at both the mRNA and protein levels together with the copy number of STK15 gene was measured in nine pancreatic carcinoma cell lines: (a) HPAF-II; (b) Aspc-1; (c) Panc-1; (d) Panc-3; (e) Panc-28; (f) Panc-48; (g) HS766T; (h) MIAPaCa-2; and (i) BxPc3. STK15 protein expression was also examined in normal pancreatic tissues and tumors by Western blotting and immunohistochemistry. RESULTS: STK15 was overexpressed in all of the nine cell lines examined, but gene amplification was infrequent. Western Blot analysis of primary tumor tissues revealed 2-10 times overexpression of STK15 protein compared with normal adjacent tissues from pancreatic cancer patients. Concurrent overexpression of cdc20, an STK15-associated protein, and reduced expression of cdc25, a mitosis-activating protein phosphatase, were detected in the same tumor samples. Elevated STK15 protein expression was detected in 22 of 38 tumor sections (58%) from pancreatic cancer patients. The extent of STK15 expression was not significantly correlated with the size, degree of differentiation, and metastasis status of the tumors. CONCLUSIONS: These results show that STK15 is overexpressed in pancreatic tumors and carcinoma cell lines and suggest that overexpression of STK15 may play a role in pancreatic carcinogenesis.

Authors
Li, D; Zhu, J; Firozi, PF; Abbruzzese, JL; Evans, DB; Cleary, K; Friess, H; Sen, S
MLA Citation
Li, D, Zhu, J, Firozi, PF, Abbruzzese, JL, Evans, DB, Cleary, K, Friess, H, and Sen, S. "Overexpression of oncogenic STK15/BTAK/Aurora A kinase in human pancreatic cancer." Clinical cancer research : an official journal of the American Association for Cancer Research 9.3 (March 2003): 991-997.
PMID
12631597
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
9
Issue
3
Publish Date
2003
Start Page
991
End Page
997

A novel model system for studying the double-edged roles of nitric oxide production in pancreatic cancer growth and metastasis.

In the present study, a model system for studying the role of nitric oxide (NO) in tumor growth and metastasis was reported. Incubation of Panc02 murine pancreatic adenocarcinoma cells in vitro with cytokines and interferon led to heterogeneous expression of NO synthase II (NOS II) protein. Clonal sublines expressing different levels of NOS II were then established using a limited dilution technique. After orthotopical implantation into the pancreas of syngeneic C57BL/6 mice, clones with a low level of NOS II expression produced tumors in pancreas, metastasized to the liver, and formed ascites, whereas those having a high level of NOS II expression did not. Liver-metastasis variants having low to high metastatic ability were also established using in vivo/in vitro passage. Compared with parental Panc02 cells exhibiting a high level of NOS II expression, these variants had a decreased level of NOS II expression. Furthermore, the heterogeneous Panc02 cells were injected intravenously into a large number of syngeneic mice. Variants that metastasized to the liver, lung, skin, peritoneum, ovary, and lymph nodes were established. All of the metastatic variants exhibited a lower level of NOS II expression than the parental Panc02 cell line did. However, the phenotypes of NOS II induction and metastatic ability were unstable. Multiple in vitro/in vivo selection led to stable low NOS II expression and high metastatic potential. Finally, to further confirm the role of NOS II expression derived from tumor cells in metastasis, poorly metastatic Panc02-H0 and highly metastatic Panc02-H7 cells were injected into the pancreas of syngeneic NOS II(-/-) mice, and groups of mice received i.p. injections of either phosphate-buffered saline or L-N(6)-(1-iminoethyl) lysine. Inhibition of NOS II activity in vivo significantly promoted distant liver metastasis. Collectively, these data show that NOS II expression is highly heterogeneous and dynamically regulated, which can directly influence tumor growth and metastasis.

Authors
Wang, B; Wei, D; Crum, VE; Richardson, EL; Xiong, HH; Luo, Y; Huang, S; Abbruzzese, JL; Xie, K
MLA Citation
Wang, B, Wei, D, Crum, VE, Richardson, EL, Xiong, HH, Luo, Y, Huang, S, Abbruzzese, JL, and Xie, K. "A novel model system for studying the double-edged roles of nitric oxide production in pancreatic cancer growth and metastasis." Oncogene 22.12 (March 2003): 1771-1782.
PMID
12660813
Source
epmc
Published In
Oncogene: Including Oncogene Reviews
Volume
22
Issue
12
Publish Date
2003
Start Page
1771
End Page
1782
DOI
10.1038/sj.onc.1206386

Inhibition of constitutive NF-kappa B activity by I kappa B alpha M suppresses tumorigenesis.

We have demonstrated that nuclear factor-kappa B (NF-kappa B) is constitutively activated in human pancreatic adenocarcinoma and human pancreatic cancer cell lines but not in normal pancreatic tissues or in immortalized, nontumorigenic pancreatic epithelial cells, suggesting that NF-kappa B plays a critical role in the development of pancreatic adenocarcinoma. To elucidate the role of constitutive NF-kappa B activity in human pancreatic cancer cells, we generated pancreatic tumor cell lines that express a phosphorylation defective I kappa B alpha (S32, 36A) (I kappa B alpha M) that blocks NF-kappa B activity. In this study, we showed that inhibiting constitutive NF-kappa B activity by expressing I kappa B alpha M suppressed the tumorigenicity of a nonmetastatic human pancreatic cancer cell line, PANC-1, in an orthotopic nude mouse model. Immunohistochemical analysis showed that PANC-1-derived tumors expressed vascular endothelial growth factor (VEGF) and induced angiogenesis. Inhibiting NF-kappa B signaling by expressing I kappa B alpha M significantly reduced expression of Bcl-x(L) and Bcl-2. The cytokine-induced expression of VEGF and Interleukin-8 in PANC-1 cells is also decreased. Taken together, these results suggest that the inhibition of NF-kappa B signaling can suppress tumorigenesis of pancreatic cancer cells and that the NF-kappa B signaling pathway is a potential target for anticancer agents.

Authors
Fujioka, S; Sclabas, GM; Schmidt, C; Niu, J; Frederick, WA; Dong, QG; Abbruzzese, JL; Evans, DB; Baker, C; Chiao, PJ
MLA Citation
Fujioka, S, Sclabas, GM, Schmidt, C, Niu, J, Frederick, WA, Dong, QG, Abbruzzese, JL, Evans, DB, Baker, C, and Chiao, PJ. "Inhibition of constitutive NF-kappa B activity by I kappa B alpha M suppresses tumorigenesis." Oncogene 22.9 (March 2003): 1365-1370.
PMID
12618762
Source
epmc
Published In
Oncogene: Including Oncogene Reviews
Volume
22
Issue
9
Publish Date
2003
Start Page
1365
End Page
1370
DOI
10.1038/sj.onc.1206323

A phase I/II trial of intratumoral endoscopic ultrasound injection of ONYX-015 with intravenous gemcitabine in unresectable pancreatic carcinoma.

PURPOSE: Localized pancreatic carcinoma is rarely resectable and is resistant to conventional therapies. ONYX-015 (dl1520) is an E1B-55kD gene-deleted replication-selective adenovirus that preferentially replicates in and kills malignant cells. Endoscopic ultrasound (EUS) has the potential to conveniently and accurately deliver local therapy to the pancreas. Therefore, we undertook a trial of the feasibility, tolerability, and efficacy of EUS injection of ONYX-015 into unresectable pancreatic carcinomas. EXPERIMENTAL DESIGN: Twenty-one patients with locally advanced adenocarcinoma of the pancreas or with metastatic disease, but minimal or absent liver metastases, underwent eight sessions of ONYX-015 delivered by EUS injection into the primary pancreatic tumor over 8 weeks. The final four treatments were given in combination with gemcitabine (i.v., 1,000 mg/m(2)). Patients received 2 x 10(10) (n = 3) or 2 x 10(11) (n = 18) virus particles/treatment. RESULTS: After combination therapy, 2 patients had partial regressions of the injected tumor, 2 had minor responses, 6 had stable disease, and 11 had progressive disease or had to go off study because of treatment toxicity. No clinical pancreatitis occurred despite mild, transient elevations in lipase in a minority of patients. Two patients had sepsis before the institution of prophylactic oral antibiotics. Two patients had duodenal perforations from the rigid endoscope tip. No perforations occurred after the protocol was changed to transgastic injections only. CONCLUSIONS: This study indicates that ONYX-015 injection via EUS into pancreatic carcinomas by the transgastic route with prophylactic antibiotics is feasible and generally well tolerated either alone or in combination with gemcitabine. Transgastric EUS-guided injection is a new and practical method of delivering biological agents to pancreatic tumors.

Authors
Hecht, JR; Bedford, R; Abbruzzese, JL; Lahoti, S; Reid, TR; Soetikno, RM; Kirn, DH; Freeman, SM
MLA Citation
Hecht, JR, Bedford, R, Abbruzzese, JL, Lahoti, S, Reid, TR, Soetikno, RM, Kirn, DH, and Freeman, SM. "A phase I/II trial of intratumoral endoscopic ultrasound injection of ONYX-015 with intravenous gemcitabine in unresectable pancreatic carcinoma." Clinical cancer research : an official journal of the American Association for Cancer Research 9.2 (February 2003): 555-561.
PMID
12576418
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
9
Issue
2
Publish Date
2003
Start Page
555
End Page
561

Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis.

Expression of vascular endothelial growth factor (VEGF), a key angiogenic protein, has been linked with pancreatic cancer progression. However, the molecular basis for VEGF overexpression remains unclear. Immunohistochemical studies have indicated that VEGF overexpression coincides with elevated Stat3 activation in human pancreatic cancer specimens. In our study, more than 80% of the human pancreatic cancer cell lines used exhibited constitutively activated Stat3, with Stat3 activation correlated with the VEGF expression level. Blockade of activated Stat3 via ectopic expression of dominant-negative Stat3 significantly suppressed VEGF expression, angiogenesis, tumor growth, and metastasis in vivo. Furthermore, constitutively activated Stat3 directly activated the VEGF promoter, whereas dominant-negative Stat3 inhibited the VEGF promoter. A putative Stat3-responsive element on the VEGF promoter was identified using a protein-DNA binding assay and confirmed using a promoter mutagenesis assay. These results indicate that Stat3 directly regulates VEGF expression and hence angiogenesis, growth, and metastasis of human pancreatic cancer, suggesting that Stat3 signaling may be targeted for treatment of pancreatic cancer.

Authors
Wei, D; Le, X; Zheng, L; Wang, L; Frey, JA; Gao, AC; Peng, Z; Huang, S; Xiong, HQ; Abbruzzese, JL; Xie, K
MLA Citation
Wei, D, Le, X, Zheng, L, Wang, L, Frey, JA, Gao, AC, Peng, Z, Huang, S, Xiong, HQ, Abbruzzese, JL, and Xie, K. "Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis." Oncogene 22.3 (January 2003): 319-329.
PMID
12545153
Source
epmc
Published In
Oncogene: Including Oncogene Reviews
Volume
22
Issue
3
Publish Date
2003
Start Page
319
End Page
329
DOI
10.1038/sj.onc.1206122

Function of nuclear factor kappaB in pancreatic cancer metastasis.

PURPOSE: We seek to elucidate the role of constitutive nuclear factor kappaB (NFkappaB) activity in human pancreatic cancer cells. We have demonstrated that the transcription factor NFkappaB is activated constitutively in human pancreatic adenocarcinoma and human pancreatic cancer cell lines but not in normal pancreatic tissues or in immortalized/nontumorigenic pancreatic epithelial cells, suggesting that NFkappaB plays a critical role in development of pancreatic adenocarcinoma. EXPERIMENTAL DESIGN: By pooling all of the puromycin resistant clones after inhibitor of nuclear factor-kappaB phosphorylation mutant (IkappaBalphaM) retroviral infection, we generated pancreatic tumor cell lines that express a IkappaBalphaM (S32, 36A) that blocks NFkappaB activity. Inhibition of metastatic phenotype was assayed in an orthotopic nude mouse model. NFkappaB activity was determined by electrophoretic mobility shift assay, and the expression of NFkappaB downstream target genes was analyzed by Northern, Western, and immunohistochemical analyses. RESULTS: We showed that inhibiting constitutive NFkappaB activity by expressing IkappaBalphaM suppresses liver metastasis, but not tumorigenesis, from the metastatic human pancreatic tumor cell line AsPc-1 in an orthotopic nude mouse model. Furthermore, inhibiting NFkappaB activation by expressing IkappaBalphaM significantly reduced in vivo expression of a major proangiogenic molecule, vascular endothelial growth factor, and, hence, decreased neoplastic angiogenesis. Inhibiting NFkappaB activation by expressing IkappaBalphaM and using pharmacologic NFkappaB inhibitor PS-341 also significantly reduced cytokine-induced vascular endothelial growth factor and interleukin-8 expression in AsPc-1 pancreatic cancer cells. CONCLUSION: These results demonstrated that the inhibition of NFkappaB signaling can suppress the angiogenic potential and metastasis of pancreatic cancer, and suggest that the NFkappaB signaling pathway is a potential target for anticancer agents.

Authors
Fujioka, S; Sclabas, GM; Schmidt, C; Frederick, WA; Dong, QG; Abbruzzese, JL; Evans, DB; Baker, C; Chiao, PJ
MLA Citation
Fujioka, S, Sclabas, GM, Schmidt, C, Frederick, WA, Dong, QG, Abbruzzese, JL, Evans, DB, Baker, C, and Chiao, PJ. "Function of nuclear factor kappaB in pancreatic cancer metastasis." Clinical cancer research : an official journal of the American Association for Cancer Research 9.1 (January 2003): 346-354.
PMID
12538487
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
9
Issue
1
Publish Date
2003
Start Page
346
End Page
354

Experimental animal models of pancreatic carcinogenesis and metastasis.

Pancreatic cancer is a lethal disease characterized by early metastasis, local invasion, and resistance to conventional therapies. To understand its etiology and eventually make prevention of it possible and effective, appropriate carcinogenesis models will certainly help us understand the effects of environmental and genetic elements on pancreatic carcinogenesis. The development of new treatment strategies to control cancer metastasis is of immediate urgency. Fulfillment of this task relies on our knowledge of the cellular and molecular biology of pancreatic cancer metastasis and the availability of biologically and clinically relevant model systems. Many of the existing pancreatic cancer carcinogenesis and metastasis animal models are described in this review. The advantages and disadvantages of each model and their clinical implications are discussed, and special attention is focused on experimental therapeutic strategies targeting pancreatic cancer metastasis.

Authors
Wei, D; Xiong, HQ; Abbruzzese, JL; Xie, K
MLA Citation
Wei, D, Xiong, HQ, Abbruzzese, JL, and Xie, K. "Experimental animal models of pancreatic carcinogenesis and metastasis." International journal of gastrointestinal cancer 33.1 (January 2003): 43-60. (Review)
PMID
12909737
Source
epmc
Published In
International Journal of Gastrointestinal Cancer
Volume
33
Issue
1
Publish Date
2003
Start Page
43
End Page
60
DOI
10.1385/ijgc:33:1:43

The challenge of pancreatic cancer.

Authors
Abbruzzese, JL
MLA Citation
Abbruzzese, JL. "The challenge of pancreatic cancer." International journal of gastrointestinal cancer 33.1 (January 2003): 1-2.
PMID
12909733
Source
epmc
Published In
International Journal of Gastrointestinal Cancer
Volume
33
Issue
1
Publish Date
2003
Start Page
1
End Page
2
DOI
10.1385/ijgc:33:1:1

Function of nuclear factor κB in pancreatic cancer metastasis

Purpose: We seek to elucidate the role of constitutive nuclear factor κB (NFκB) activity in human pancreatic cancer cells. We have demonstrated that the transcription factor NFκB is activated constitutively in human pancreatic adenocarcinoma and human pancreatic cancer cell lines but not in normal pancreatic tissues or in immortalized/nontumorigenic pancreatic epithelial cells, suggesting that NFκB plays a critical role in development of pancreatic adenocarcinoma. Experimental Design: By pooling all of the puromycin resistant clones after inhibitor of nuclear factor-κB phosphorylation mutant (IκBαM) retroviral infection, we generated pancreatic tumor cell lines that express a IκBαM (S32, 36A) that blocks NFκB activity. Inhibition of metastatic phenotype was assayed in an orthotopic nude mouse model. NFκB activity was determined by electrophoretic mobility shift assay, and the expression of NFKB downstream target genes was analyzed by Northern, Western, and immunohistochemical analyses. Results: We showed that inhibiting constitutive NFκB activity by expressing IκBαM suppresses liver metastasis, but not tumorigenesis, from the metastatic human pancreatic tumor cell line AsPc-1 in an orthotopic nude mouse model. Furthermore, inhibiting NFκB activation by expressing IκBαM significantly reduced in vivo expression of a major proangiogenic molecule, vascular endothelial growth factor, and, hence, decreased neoplastic angiogenesis. Inhibiting NFκB activation by expressing IκBαM and using pharmacologic NFκB inhibitor PS-341 also significantly reduced cytokine-induced vascular endothelial growth factor and interleukin-8 expression in AsPc-1 pancreatic cancer cells. Conclusion: These results demonstrated that the inhibition of NFκB signaling can suppress the angiogenic potential and metastasis of pancreatic cancer, and suggest that the NFκB signaling pathway is a potential target for anticancer agents.

Authors
Fujioka, S; Sclabas, GM; Schmidt, C; Frederick, WA; Dong, QG; Abbruzzese, JL; Evans, DB; Baker, C; Chiao, PJ
MLA Citation
Fujioka, S, Sclabas, GM, Schmidt, C, Frederick, WA, Dong, QG, Abbruzzese, JL, Evans, DB, Baker, C, and Chiao, PJ. "Function of nuclear factor κB in pancreatic cancer metastasis." Clinical Cancer Research 9.1 I (2003): 346-354.
Source
scival
Published In
Clinical Cancer Research
Volume
9
Issue
1 I
Publish Date
2003
Start Page
346
End Page
354

Evolving concepts in chemotherapy and surgery for bilio-pancreatic cancer: Introduction

Authors
Abbruzzese, JL; Yamauchi, H
MLA Citation
Abbruzzese, JL, and Yamauchi, H. "Evolving concepts in chemotherapy and surgery for bilio-pancreatic cancer: Introduction." December 1, 2002.
Source
scopus
Published In
Seminars in Oncology
Volume
29
Issue
6 SUPPL. 20
Publish Date
2002
Start Page
1

Phase I study of intraperitoneal recombinant human interleukin 12 in patients with Müllerian carcinoma, gastrointestinal primary malignancies, and mesothelioma.

PURPOSE: The purpose is to determine dose-limiting toxicity, pharmacokinetics,pharmacodynamics, and immunobiology after i.p. injections of recombinant human IL-12 (rhIL-12). EXPERIMENTAL DESIGN: rhIL-12 was administered to 29 previously treated patients with peritoneal carcinomatosis from Müllerian carcinomas, gastrointestinal tract carcinomas and peritoneal mesothelioma in a Phase I trial. rhIL-12 doses were increased from 3 to 600 ng/kg. Three or more patients at each level received weekly i.p. injections of rhIL-12. RESULTS: Dose-limiting toxicity (elevated transaminase) occurred in 2 of 4 patients at the 600 ng/kg dose. More frequent toxicities included fever, fatigue, abdominal pain, nausea, and catheter-related infections. Ten patients received 300 ng/kg with acceptable frequency and severity of side effects. Two patients (one with ovarian cancer and one with mesothelioma) had no remaining disease at laparoscopy. Eight patients had stable disease and 19 progressive disease. At 300 ng/kg i.p., IL-12 was cleared from peritoneal fluid in a biphasic manner with a terminal-phase half-life of 18.7 h; peritoneal fluid levels of IL-12 5 min after i.p. injection were 100-200 pg/ml, and serum levels reached approximately 10 pg/ml between 24 and 36 h. IL-1-alpha, IL-2, IL-10, tumor necrosis factor alpha, and IFN-gamma were determined in serum and peritoneal fluid. IFN-gamma, IL-10, and tumor necrosis factor alpha were detected most frequently. Immunobiological effects included peritoneal tumor cell apoptosis, decreased tumor cell expression of basic fibroblast growth factor and vascular endothelial growth factor, elevated IFN-gamma and IFN-inducible protein 10 transcripts in peritoneal exudate cells, and increased proportions of peritoneal CD3(+) relative to CD14(+) cells. CONCLUSIONS: rhIL-12 at 300 ng/kg by weekly i.p. injection is biologically active and adequately tolerated for Phase II studies.

Authors
Lenzi, R; Rosenblum, M; Verschraegen, C; Kudelka, AP; Kavanagh, JJ; Hicks, ME; Lang, EA; Nash, MA; Levy, LB; Garcia, ME; Platsoucas, CD; Abbruzzese, JL; Freedman, RS
MLA Citation
Lenzi, R, Rosenblum, M, Verschraegen, C, Kudelka, AP, Kavanagh, JJ, Hicks, ME, Lang, EA, Nash, MA, Levy, LB, Garcia, ME, Platsoucas, CD, Abbruzzese, JL, and Freedman, RS. "Phase I study of intraperitoneal recombinant human interleukin 12 in patients with Müllerian carcinoma, gastrointestinal primary malignancies, and mesothelioma." Clinical cancer research : an official journal of the American Association for Cancer Research 8.12 (December 2002): 3686-3695.
PMID
12473577
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
8
Issue
12
Publish Date
2002
Start Page
3686
End Page
3695

Effects of the proteasome inhibitor PS-341 on apoptosis and angiogenesis in orthotopic human pancreatic tumor xenografts.

Recent studies have shown that the transcription factor, nuclear factor kappaB (NF-kappaB), regulates critical survival pathways in a variety of different cell types, including human pancreatic cancer cells. The activation of NF-kappaB is controlled by proteasome-mediated degradation of its endogenous polypeptide inhibitor, inhibitor of nuclear factor kappaBalpha. We investigated the effects of PS-341, a peptide boronate inhibitor of the proteasome in human pancreatic cancer cells in vitro and in vivo. Comparison of PS-341's effects on the growth of eight different human pancreatic cancer cell lines revealed marked heterogeneity in drug responsiveness, ranging from highly resistant (IC50 > 10 microM; Panc-48, HS766T, and Mia-PaCa-2) to extremely sensitive (IC50 < 40 nM; L3.6pl, Hpaf2, and BxPC3). However, these effects did not correlate with differential inhibition of NF-kappaB activation. Direct quantification of apoptosis revealed that PS-341's effects on cell growth largely correlated with sensitivity to programmed cell death. Evaluation of PS-341's effects on established orthotopic tumor xenografts demonstrated that biweekly intravenous administration of the maximum-tolerated dose of the drug (1 mg/kg) led to significant reductions in the volumes of L3.6pl tumors but not Mia-PaCa-2 tumors. Laser scanning cytometer-mediated quantification of drug-induced apoptosis in the xenografts confirmed that PS-341 induced DNA fragmentation and activation of caspase-3 in L3.6pl tumors but not in Mia-PaCa-2 tumors. However, histological examination of drug-treated tumors revealed extensive central necrosis and reductions in microvessel density and VEGF expression in both tumor types. Taken together, our results demonstrate that PS-341 inhibits the growth of human pancreatic tumors via direct effects on tumor cells and indirect effects on the tumor vasculature.

Authors
Nawrocki, ST; Bruns, CJ; Harbison, MT; Bold, RJ; Gotsch, BS; Abbruzzese, JL; Elliott, P; Adams, J; McConkey, DJ
MLA Citation
Nawrocki, ST, Bruns, CJ, Harbison, MT, Bold, RJ, Gotsch, BS, Abbruzzese, JL, Elliott, P, Adams, J, and McConkey, DJ. "Effects of the proteasome inhibitor PS-341 on apoptosis and angiogenesis in orthotopic human pancreatic tumor xenografts." Molecular cancer therapeutics 1.14 (December 2002): 1243-1253.
PMID
12516957
Source
epmc
Published In
Molecular cancer therapeutics
Volume
1
Issue
14
Publish Date
2002
Start Page
1243
End Page
1253

Past and present treatment of pancreatic adenocarcinoma: chemotherapy as a standard treatment modality.

Pancreatic cancer continues to be a challenging therapeutic problem, with approximately 28,000 deaths annually in the United States. Most studies of single-agent or combination chemotherapy in the treatment of patients with advanced adenocarcinoma of the pancreas have documented low response rates and little reproducible impact on patient survival or quality of life. However, the recent success of gemcitabine in patients with locally advanced and metastatic pancreatic cancer suggests that systemic therapy can have a beneficial effect on the natural history of this disease. Also, the rapidly evolving understanding of the molecular biology of pancreatic cancer may contribute to the development and use of targeted therapies with novel agents for even more effective treatments in the near future.

Authors
Abbruzzese, JL
MLA Citation
Abbruzzese, JL. "Past and present treatment of pancreatic adenocarcinoma: chemotherapy as a standard treatment modality." December 2002.
PMID
12577227
Source
epmc
Published In
Seminars in Oncology
Volume
29
Issue
6 Suppl 20
Publish Date
2002
Start Page
2
End Page
8

Risk factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and diabetes mellitus.

Risk factors associated with hepatocellular carcinoma (HCC) are well documented, but the synergisms between these risk factors are not well examined. We conducted a hospital-based, case-control study among 115 HCC patients and 230 non-liver cancer controls. Cases and controls were pathologically diagnosed at The University of Texas M. D. Anderson Cancer Center and were matched by 5-year age groups, sex, and year of diagnosis. Information on risk factors was collected by personal interview and medical records review. Blood samples were tested for the presence of antibodies to hepatitis C virus antigen (anti-HCV), hepatitis B surface antigen (HBsAg), and antibodies to hepatitis B core antigen (anti-HBc). Conditional logistic regression was used to determine odds ratios (ORs) by the maximum likelihood method. Multivariate ORs and 95% confidence intervals (CIs) were 15.3 (4.3-54.4), 12.6 (2.5-63.1), 4.5 (1.4-14.8), and 4.3 (1.9-9.9) for anti-HCV, HBsAg, heavy alcohol consumption (>/=80 mL ethanol/d), and diabetes mellitus, respectively. Synergistic interactions on the additive model were observed between heavy alcohol consumption and chronic hepatitis virus infection (OR, 53.9; 95% CI, 7.0-415.7) and diabetes mellitus (OR, 9.9; 95% CI, 2.5-39.3). Independent of the effect of HCV, HBV, and diabetes mellitus, heavy alcohol consumption contributes to the majority of HCC cases (32%), whereas 22%, 16%, and 20% were explained by HCV, HBV, and diabetes mellitus, respectively. In conclusion, the significant synergy between heavy alcohol consumption, hepatitis virus infection, and diabetes mellitus may suggest a common pathway for hepatocarcinogenesis. Exploring the underlying mechanisms for such synergisms may indicate new HCC prevention strategies in high-risk individuals.

Authors
Hassan, MM; Hwang, L-Y; Hatten, CJ; Swaim, M; Li, D; Abbruzzese, JL; Beasley, P; Patt, YZ
MLA Citation
Hassan, MM, Hwang, L-Y, Hatten, CJ, Swaim, M, Li, D, Abbruzzese, JL, Beasley, P, and Patt, YZ. "Risk factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and diabetes mellitus." Hepatology (Baltimore, Md.) 36.5 (November 2002): 1206-1213.
PMID
12395331
Source
epmc
Published In
Hepatology
Volume
36
Issue
5
Publish Date
2002
Start Page
1206
End Page
1213
DOI
10.1053/jhep.2002.36780

Biochemical modulation of 5-fluorouacil through dihydropyrimidine dehydrogenase inhibition: a Southwest Oncology Group phase II trial of eniluracil and 5-fluorouracil in advanced resistant colorectal cancer.

PURPOSE: To investigate the hypothesis that a systemic agent designed to inhibit dihydropyrimidine dehydrogenase (DPD), the first enzyme in the fluoropyrimidine degradative pathway, could improve the effective amount of 5-fluorouracil (5-FU) delivered to a tumor resulting in enhanced response. PATIENTS AND METHODS: Eligibility included cytologically or pathologically verified diagnosis of colorectal cancer that recurred during or within 12 months of completion of adjuvant therapy, representing patients generally considered resistant to fluorinated pyrimidine therapy. Stratification was into two cohorts: recurrence while receiving adjuvant therapy, and relapse within 12 months of completing adjuvant therapy. Treatment consisted of 28 days of oral therapy every five weeks with eniluracil and 5-FU administered in a 10:1 ratio. The daily dose of eniluracil was 10 mg/m2 with 5-FU 1 mg/m2, divided into two doses. RESULTS: Twenty-five patients are evaluable for response: 9 relapsed during therapy and 16 relapsed within one year of adjuvant therapy. In the first group, there was one partial response (9%; 95% CI 0-41%); in the second cohort there was one confirmed complete response (5%; 95% CI 0-23%) and one unconfirmed partial response, for an overall response rate of 10%. CONCLUSIONS: This regimen lacks significant activity in this target population. Pre-treatment intratumoral DPD expression was not assessed, therefore the mechanism of fluorinated pyrimidine resistance cannot be specifically attributed to elevated DPD levels. Attempting restoration of chemotherapy sensitivity through blockade of enzymes or signal transduction molecules responsible for resistance is rational, provided that tumor target expression is the basis for trial entry.

Authors
Leichman, CG; Chansky, K; Macdonald, JS; Doukas, MA; Budd, GT; Giguere, JK; Abbruzzese, JL
MLA Citation
Leichman, CG, Chansky, K, Macdonald, JS, Doukas, MA, Budd, GT, Giguere, JK, and Abbruzzese, JL. "Biochemical modulation of 5-fluorouacil through dihydropyrimidine dehydrogenase inhibition: a Southwest Oncology Group phase II trial of eniluracil and 5-fluorouracil in advanced resistant colorectal cancer." Investigational new drugs 20.4 (November 2002): 419-424.
PMID
12448660
Source
epmc
Published In
Investigational New Drugs
Volume
20
Issue
4
Publish Date
2002
Start Page
419
End Page
424
DOI
10.1023/a:1020662113061

Hepatic arterial infusion of a replication-selective oncolytic adenovirus (dl1520): phase II viral, immunologic, and clinical endpoints.

Replication-selective oncolytic adenoviruses are being developed for the treatment of cancer, but the safety and feasibility of repeated adenovirus delivery to tumors via the bloodstream was unknown, particularly in light of a patient death after hepatic artery infusion of a replication-defective adenovirus vector. We performed a Phase II trial of an oncolytic replication-selective adenovirus (dl1520, also known as Onyx-015) administered by hepatic artery infusion in patients with gastrointestinal carcinoma metastatic to the liver (n = 27). dl1520 was infused into the hepatic artery (2 x 10(12) particles) on days 1 and 8 as a single agent, and thereafter starting on day 22 in combination with i.v. 5-fluorouracil and leucovorin every 28 days. Repeated viral infusions were feasible, and no deaths occurred on study; reversible grade 3/4 hyperbilirubinemia occurred in 2 patients. Systemic inflammatory cytokine responses varied greatly between patients and even between cycles within a given patient. Proinflammatory cytokines [e.g., tumor necrosis factor, IFN-gamma, and interleukin (IL) 6] typically rose within 3 h and were followed at 18 h by a rise in IL-10. However, in the single patient who suffered a severe but reversible systemic inflammatory response, a unique cytokine profile was detected: marked acute increases of IL-6 (20-fold higher than average for all of the patients) and inhibition of IL-10 production. Delayed secondary peaks of viremia were reproducibly detected 3-6 days after treatment, even in the presence of high level neutralizing antibody titers and antiviral cytokines. Mathematical modeling was used to calculate the number of virus particles produced and shed into the blood with each replication cycle. The combination of virotherapy and chemotherapy had antitumoral activity in some chemotherapy-resistant colorectal tumors. The intra-arterial infusion of oncolytic adenoviruses warrants additional study.

Authors
Reid, T; Galanis, E; Abbruzzese, J; Sze, D; Wein, LM; Andrews, J; Randlev, B; Heise, C; Uprichard, M; Hatfield, M; Rome, L; Rubin, J; Kirn, D
MLA Citation
Reid, T, Galanis, E, Abbruzzese, J, Sze, D, Wein, LM, Andrews, J, Randlev, B, Heise, C, Uprichard, M, Hatfield, M, Rome, L, Rubin, J, and Kirn, D. "Hepatic arterial infusion of a replication-selective oncolytic adenovirus (dl1520): phase II viral, immunologic, and clinical endpoints." Cancer research 62.21 (November 2002): 6070-6079.
PMID
12414631
Source
epmc
Published In
Cancer Research
Volume
62
Issue
21
Publish Date
2002
Start Page
6070
End Page
6079

Suppression of tumorigenesis and induction of p15(ink4b) by Smad4/DPC4 in human pancreatic cancer cells.

PURPOSE: The tumor suppressor gene Smad4/DPC4, a key transcription factorin transforming growth factor beta (TGF-beta) signaling cascades,is inactivated in 50% of pancreatic adenocarcinomas. We seek to determine the role of Smad4/DPC4 in the suppression of tumor cell growth and in the regulation of TGF-beta-mediated expression of cell-cycle regulatory genes p15(ink4b) and p21(waf1). EXPERIMENTAL DESIGN: Smad4/DPC4 is overexpressed by adenoviral infection in CFPac-1 pancreatic cancer cells, in which the Smad4/DPC4 is homozygously deleted, and in Capan-1 pancreatic cancer cells, in which Smad4/DPC4 is not expressed. Expression of the TGF-beta downstream target gene p21(waf1), regulation of the p15(ink4b) promoter, anchorage-independent growth, and tumorigenesis were examined. RESULTS: We demonstrate that expression of Smad4/DPC4 in Capan-1 cells reduced anchorage-independent growth by more than 50%, and inhibited xenograft tumor growth. However, overexpression of Smad4/DPC4 did not inhibit CFPac-1 cell growth. Interestingly, Smad4/DPC4 induced expression of p15(ink4b), p21(waf1), and TGF-beta-responsive reporter gene in Capan-1 but not in CFPac-1 cells. Furthermore, we found a previously unidentified Smad4 binding element (SBE) located in the region between -356 and -329 bp of the p15(ink4b) promoter. The p15(ink4b) promoter reporter gene assays revealed that Smad4-dependent transcriptional activation is mediated by this SBE, which indicates that p15(ink4b) is one of the downstream target genes regulated by Smad/DPC4. CONCLUSION: These results explain the role of Smad4/DPC4 in TGF-beta-mediated inhibition of cell proliferation in vitro and in vivo. Moreover, these results suggest that Smad4/DPC4-mediated tumor suppression and induction of TGF-beta-regulated cell-cycle-inhibitory genes may depend on additional factors that are absent in CFPac-1 cells.

Authors
Peng, B; Fleming, JB; Breslin, T; Grau, AM; Fojioka, S; Abbruzzese, JL; Evans, DB; Ayers, D; Wathen, K; Wu, T; Robertson, KD; Chiao, PJ
MLA Citation
Peng, B, Fleming, JB, Breslin, T, Grau, AM, Fojioka, S, Abbruzzese, JL, Evans, DB, Ayers, D, Wathen, K, Wu, T, Robertson, KD, and Chiao, PJ. "Suppression of tumorigenesis and induction of p15(ink4b) by Smad4/DPC4 in human pancreatic cancer cells." Clinical cancer research : an official journal of the American Association for Cancer Research 8.11 (November 2002): 3628-3638.
PMID
12429655
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
8
Issue
11
Publish Date
2002
Start Page
3628
End Page
3638

Phase II trial of 5-fluorouracil plus eniluracil in patients with advanced pancreatic cancer: a Southwest Oncology Group study.

Eniluracil is a potent, irreversible inactivator of dihydropyrimidine dehydrogenase, the major catabolic enzyme for 5-fluorouracil (5-FU). Pretreatment with eniluracil significantly increases plasma half-life, plasma concentration and oral bioavailability of 5-FU. This multicenter phase II trial was designed to estimate the 6-month survival rate in patients with metastatic adenocarcinoma of the pancreas treated with 5-FU and eniluracil.One hundred and sixteen patients (61 with no prior chemotherapy and 55 with prior chemotherapy) were registered for treatment with eniluracil 50 mg (total dose) p.o. on days 1-7 and 5-FU 20 mg/m(2)/day p.o. on days 2-6 of a 28-day treatment cycle.In 106 patients evaluable for survival, the 6-month survival rate was 34% [95% confidence interval (CI) 22% to 47%, median survival 3.6 months] for patients who had not been treated previously with chemotherapy and 29% (95% CI 16% to 42%, median survival 3.4 months) for those who had received prior chemotherapy. For those patients with measurable disease, the confirmed response rates were 8% and 2%, respectively. The most common grade 3-4 toxicities were neutropenia (29% of patients) and diarrhea (12% of patients). Overall, 69% of patients experienced a grade 3 or worse adverse event during treatment.These results suggest that the combination of a 7-day course of eniluracil and a 5-day course of oral 5-FU has limited activity in patients with advanced pancreatic cancer, and is associated with a high frequency of clinically significant adverse events.

Authors
Rothenberg, ML; Benedetti, JK; Macdonald, JS; Seay, TE; Neubauer, MA; George, CS; Tanaka, MS; Giguere, JK; Pruitt, BT; Abbruzzese, JL
MLA Citation
Rothenberg, ML, Benedetti, JK, Macdonald, JS, Seay, TE, Neubauer, MA, George, CS, Tanaka, MS, Giguere, JK, Pruitt, BT, and Abbruzzese, JL. "Phase II trial of 5-fluorouracil plus eniluracil in patients with advanced pancreatic cancer: a Southwest Oncology Group study." Annals of oncology : official journal of the European Society for Medical Oncology 13.10 (October 2002): 1576-1582.
PMID
12377645
Source
epmc
Published In
Annals of Oncology
Volume
13
Issue
10
Publish Date
2002
Start Page
1576
End Page
1582
DOI
10.1093/annonc/mdf274

Phase II study of dolastatin-10 as first-line treatment for advanced colorectal cancer.

Dolastatin-10 is a potent inhibitor of microtubule assembly derived from the sea hare, which displayed significant antitumor activity in preclinical models. We conducted a phase II study of dolastatin-10 in patients with advanced colorectal cancer and no prior chemotherapy for metastatic disease. Fourteen patients received doses ranging from 300 microg/m(2) to 450 microg/m(2) as an intravenous push every 21 days. There were no major objective responses. Toxicity was mainly hematologic, with grade III or IV granulocytopenia occurring in 9 of 42 treatment courses. Other toxic effects were generally mild. Dolastatin-10 lacks clinically significant activity in advanced colorectal cancer when used in this dose and schedule.

Authors
Saad, ED; Kraut, EH; Hoff, PM; Moore, DF; Jones, D; Pazdur, R; Abbruzzese, JL
MLA Citation
Saad, ED, Kraut, EH, Hoff, PM, Moore, DF, Jones, D, Pazdur, R, and Abbruzzese, JL. "Phase II study of dolastatin-10 as first-line treatment for advanced colorectal cancer." American journal of clinical oncology 25.5 (October 2002): 451-453.
PMID
12393982
Source
epmc
Published In
American Journal of Clinical Oncology: Cancer Clinical Trials
Volume
25
Issue
5
Publish Date
2002
Start Page
451
End Page
453
DOI
10.1097/00000421-200210000-00005

Epidermal growth factor receptor-targeted therapy for pancreatic cancer.

Epidermal growth factor receptor (EGFR) plays an important role in tumor development and maintenance. It is a cell surface molecule that mediates signal transduction from the cell surface to cytoplasm. Elevated expression of EGFR or its ligand correlates with worse prognosis in a variety of human cancers. Therefore, blockade of EGFR activity would provide a novel strategy for the treatment of cancer. Two classes of EGFR inhibitors, monoclonal antibodies and tyrosine kinase inhibitors, have been described. The preclinical activity of these EGFR inhibitors and phase I clinical data are summarized in this article. A phase II trial of the EGFR inhibitor IMC-C225 in combination with gemcitabine for patients with advanced pancreatic cancer is discussed.

Authors
Xiong, HQ; Abbruzzese, JL
MLA Citation
Xiong, HQ, and Abbruzzese, JL. "Epidermal growth factor receptor-targeted therapy for pancreatic cancer." October 2002.
PMID
12422311
Source
epmc
Published In
Seminars in Oncology
Volume
29
Issue
5 Suppl 14
Publish Date
2002
Start Page
31
End Page
37
DOI
10.1053/sonc.2002.35645

Study of the media's potential influence on prospective research participants' understanding of and motivations for participation in a high-profile phase I trial.

To describe prospective participants' initial source of information about, understanding of, and motivation to participate in a phase I clinical trial of the antiangiogenesis agent human recombinant endostatin.We surveyed 100 of 130 persons referred to the endostatin trial between October 1999 and November 2000 and analyzed media coverage of the agent from 1997 to 2000.Forty-seven percent of survey respondents first heard about the trial from media reports. Fifty-one percent of these subsequently contacted their physicians. Thirty-three percent of respondents correctly understood the purpose of the trial. Seventy-nine respondents were interviewed before they met trial investigators to discuss the trial. Of these, those who first heard about endostatin from the media were five times more likely to understand correctly the trial's purpose than those who first heard from other sources. Seventy-four percent (70 of 95) of respondents cited hope for personal benefit as the main reason for their willingness to enroll. Those who first heard about endostatin from the media were no more motivated by hope of personal benefit (77%) than those who first heard from other sources (71%) (P =.46). Ninety-nine percent of all respondents cited "joining the study gives me hope" as a contributing factor in their decision making about the trial.Media coverage prompted prospective participants to contact their physicians but did not seem to hinder understanding nor could it be shown to heighten their hope for personal benefit.

Authors
Pentz, RD; Flamm, AL; Sugarman, J; Cohen, MZ; Daniel Ayers, G; Herbst, RS; Abbruzzese, JL
MLA Citation
Pentz, RD, Flamm, AL, Sugarman, J, Cohen, MZ, Daniel Ayers, G, Herbst, RS, and Abbruzzese, JL. "Study of the media's potential influence on prospective research participants' understanding of and motivations for participation in a high-profile phase I trial." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20.18 (September 2002): 3785-3791.
PMID
12228198
Source
epmc
Published In
Journal of Clinical Oncology
Volume
20
Issue
18
Publish Date
2002
Start Page
3785
End Page
3791
DOI
10.1200/jco.2002.04.084

Development of biologic markers of response and assessment of antiangiogenic activity in a clinical trial of human recombinant endostatin.

Angiogenesis is a target for the treatment of cancer and other diseases, and its complex biology suggests that establishing the appropriate dose and schedule for antiangiogenic treatment will require extensive study. We present the initial results of a dose-finding clinical trial of recombinant human endostatin (rh-Endo) that examined potential surrogates for response to antiangiogenic therapy.Twenty-five patients were treated with escalating doses of rh-Endo. Positron emission tomography (PET) was used to assess tumor blood flow (with [15O]H2O) and metabolism (with [18F]fluorodeoxyglucose) before the start of therapy and then every 4 weeks. To directly assess the effects of rh-Endo on endothelial cells within the tumors, biopsy specimens of tumor tissue were obtained before therapy and again at 8 weeks and evaluated for endothelial cell and tumor cell apoptosis.Tumor blood flow and metabolism as measured by PET scans generally decreased with increasing doses of rh-Endo; however, the effects were complex and in some analyses nonlinear. Tumor biopsy analysis revealed a significant increase in tumor cell apoptosis (P =.027) and endothelial cell apoptosis (P =.027) after 8 weeks of therapy. However, there was no statistically significant relationship between rh-Endo dose and induction of tumor cell or endothelial cell apoptosis.These initial data suggest that rh-Endo has measurable effects on tumor blood flow and metabolism and induces endothelial and tumor cell apoptosis even in the absence of demonstrable anticancer effects. Further study and validation of these biomarkers in the context of antiangiogenic therapy will be required.

Authors
Herbst, RS; Mullani, NA; Davis, DW; Hess, KR; McConkey, DJ; Charnsangavej, C; O'Reilly, MS; Kim, H-W; Baker, C; Roach, J; Ellis, LM; Rashid, A; Pluda, J; Bucana, C; Madden, TL; Tran, HT; Abbruzzese, JL
MLA Citation
Herbst, RS, Mullani, NA, Davis, DW, Hess, KR, McConkey, DJ, Charnsangavej, C, O'Reilly, MS, Kim, H-W, Baker, C, Roach, J, Ellis, LM, Rashid, A, Pluda, J, Bucana, C, Madden, TL, Tran, HT, and Abbruzzese, JL. "Development of biologic markers of response and assessment of antiangiogenic activity in a clinical trial of human recombinant endostatin." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20.18 (September 2002): 3804-3814.
PMID
12228200
Source
epmc
Published In
Journal of Clinical Oncology
Volume
20
Issue
18
Publish Date
2002
Start Page
3804
End Page
3814
DOI
10.1200/jco.2002.05.102

Phase I study of recombinant human endostatin in patients with advanced solid tumors.

Endostatin, a 20-kd fragment of collagen XVIII, is a potent inhibitor of angiogenesis. We evaluated recombinant human endostatin (rh-Endo) in a phase I trial designed to assess safety, pharmacokinetics, and serum markers of angiogenesis in patients with solid tumors.Twenty-six patients were enrolled onto a dose-finding trial of rh-Endo administered as an intravenous bolus over a 20-minute period once daily. Three patients each were treated at dose levels of 15, 30, 60, 120, 180, and 600 mg/m(2)/d, and seven patients were treated at 300 mg/m(2)/d. Treatment consisted of a minimum of two 28-day cycles. Evaluations included noninvasive imaging, pharmacokinetics, and serum biomarkers.Twenty-five patients were treated with rh-Endo. Treatment was well tolerated; there were no dose-limiting toxic effects. Bacteremia from frequent central line access was the most common problem. The pharmacokinetic disposition of rh-Endo was linear and best described using a two-compartmental open model. The overall mean half-life was 10.7 +/- 4.1 hours. A dose of 300 mg/m(2) achieved an area under the concentration-time curve associated with activity in preclinical models. In two patients, there was evidence of antitumor activity, but no responses were seen. Serum markers of angiogenic activity did not provide insight into rh-Endo's activity. Serum antibodies were observed against both rh-Endo and the Pichia pastoris vector, but no allergic reactions were observed.rh-Endo was safe and well tolerated. rh-Endo pharmacokinetic profiles achieved area under the concentration-time curves associated with activity in preclinical models. Evidence of minor antitumor activity was observed and further studies are indicated.

Authors
Herbst, RS; Hess, KR; Tran, HT; Tseng, JE; Mullani, NA; Charnsangavej, C; Madden, T; Davis, DW; McConkey, DJ; O'Reilly, MS; Ellis, LM; Pluda, J; Hong, WK; Abbruzzese, JL
MLA Citation
Herbst, RS, Hess, KR, Tran, HT, Tseng, JE, Mullani, NA, Charnsangavej, C, Madden, T, Davis, DW, McConkey, DJ, O'Reilly, MS, Ellis, LM, Pluda, J, Hong, WK, and Abbruzzese, JL. "Phase I study of recombinant human endostatin in patients with advanced solid tumors." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20.18 (September 2002): 3792-3803.
PMID
12228199
Source
epmc
Published In
Journal of Clinical Oncology
Volume
20<