You are here

Niedzwiecki, Donna

Overview:

Primary interests include clinical trials design and the design and analysis of biomarker and imaging studies especially in the areas of GI cancer, lymphoma, melanoma, transplant and cancer immunotherapy.

Positions:

Associate Professor of Biostatistics and Bioinformatics

Biostatistics & Bioinformatics
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1984

Ph.D. — Yale University

Grants:

Alliance for Clinical Trials in Oncology

Administered By
Duke Cancer Institute
AwardedBy
Brigham and Women's Hospital
Role
Principal Investigator
Start Date
April 17, 2014
End Date
February 28, 2018

National Clinical Trials Network - Network Group Statistics and DMCs

Administered By
Duke Cancer Institute
AwardedBy
Mayo Clinic
Role
Principal Investigator
Start Date
April 17, 2014
End Date
August 31, 2017

Impact of Celecoxib and Inflammation on Surival in Stage III Colon Cancer

Administered By
Duke Cancer Institute
AwardedBy
Dana Farber Cancer Institute
Role
Principal Investigator
Start Date
September 01, 2016
End Date
January 31, 2017

Dietary & Lifestyle Determinants of Colon Cancer Recurrence & Survival

Administered By
Duke Cancer Institute
AwardedBy
Dana Farber Cancer Institute
Role
Principal Investigator
Start Date
May 07, 2007
End Date
January 31, 2017

The Influence of Diet and Lifestyle on Patients with Advanced Colorectal Cancer

Administered By
Duke Cancer Institute
AwardedBy
Dana Farber Cancer Institute
Role
Principal Investigator
Start Date
June 01, 2015
End Date
May 31, 2016

Mayo Alliance Foundation Funds

Administered By
Duke Cancer Institute
AwardedBy
Mayo Foundation
Role
Principal Investigator
Start Date
January 01, 2012
End Date
February 28, 2014

Graft Engineering and Immunotherapy After Unrelated Cord Blood Transplantation

Administered By
Pediatrics, Blood and Marrow Transplantation
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
August 13, 2007
End Date
June 30, 2011

Cancer and Leukemia Group B Statistical Center

Administered By
Duke Cancer Institute
AwardedBy
National Institutes of Health
Role
Associate Director
Start Date
December 01, 1982
End Date
September 30, 2010

Targeting hCG-beta for Breast Cancer Immunotherapy

Administered By
Duke Cancer Institute
AwardedBy
National Institutes of Health
Role
Biostatistician
Start Date
January 01, 2004
End Date
December 31, 2009

Vaccination with Regulatory T Cell Depletion

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Biostatistician
Start Date
September 01, 2006
End Date
June 30, 2008

Immunotherapy using peptide MHC tetramer isolated Tcells

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Biostatistician
Start Date
September 16, 2002
End Date
July 31, 2007

Planning a Duke Academic Public Private Partnership Program (AP4) Center

Administered By
Duke Cancer Institute
AwardedBy
National Cancer Institute
Role
Biostatistician
Start Date
July 20, 2004
End Date
June 30, 2006

Elimination of Regulatory T Cells

Administered By
Surgery, Urology
AwardedBy
National Institutes of Health
Role
Biostatistician
Start Date
August 06, 2003
End Date
July 31, 2005

Prospective comparison of colonic imaging tests

Administered By
Duke Clinical Research Institute
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
August 24, 2000
End Date
May 31, 2005

Immunotherapy with Renal Tumor RNA Transfected Dendritic Cells

Administered By
Surgery, Urology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
February 14, 2001
End Date
January 31, 2005

Dexasome Based Immunotherapy of Lung Cancer

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Statistician
Start Date
March 01, 2001
End Date
February 28, 2004

Immunotherapy with TRICOM Modified Dendritic Cells

AwardedBy
National Institutes of Health
Role
Statistician
Start Date
September 19, 2001
End Date
August 31, 2003
Show More

Publications:

Predictors of overall and recurrence-free survival after neoadjuvant chemotherapy for gastroesophageal adenocarcinoma: Pooled analysis of individual patient data (IPD) from randomized controlled trials (RCTs).

Neoadjuvant chemotherapy improves prognosis of patients with locally advanced gastroesophageal adenocarcinoma. The aim of this study was to identify predictors for postoperative survival following neoadjuvant therapy. These could be useful in deciding about postoperative continuation of chemotherapy.This meta-analysis used IPD from RCTs comparing neoadjuvant chemotherapy with surgery alone for gastroesophageal adenocarcinoma. Trials providing IPD on age, sex, performance status, pT/N stage, resection status, overall and recurrence-free survival were included. Survival was calculated in the entire study population and subgroups stratified by supposed predictors and compared using the log-rank test. Multivariable Cox models were used to identify independent survival predictors.Four RCTs providing IPD from 553 patients fulfilled the inclusion criteria. (y)pT and (y)pN stage and resection status strongly predicted postoperative survival both after neoadjuvant therapy and surgery alone. Patients with R1 resection after neoadjuvant therapy survived longer than those with R1 resection after surgery alone. Patients with stage pN0 after surgery alone had better prognosis than those with ypN0 after neoadjuvant therapy. Patients with stage ypT3/4 after neoadjuvant therapy survived longer than those with stage pT3/4 after surgery alone. Multivariable regression identified resection status and (y)pN stage as predictors of survival in both groups. (y)pT stage predicted survival only after surgery alone.After neoadjuvant therapy for gastroesophageal adenocarcinoma, survival is determined by the same factors as after surgery alone. However, ypT stage is not an independent predictor. These results can facilitate the decision about postoperative continuation of chemotherapy in pretreated patients.

Authors
Ronellenfitsch, U; Schwarzbach, M; Hofheinz, R; Kienle, P; Nowak, K; Kieser, M; Slanger, TE; Burmeister, B; Kelsen, D; Niedzwiecki, D; Schuhmacher, C; Urba, S; van de Velde, C; Walsh, TN; Ychou, M; Jensen, K
MLA Citation
Ronellenfitsch, U, Schwarzbach, M, Hofheinz, R, Kienle, P, Nowak, K, Kieser, M, Slanger, TE, Burmeister, B, Kelsen, D, Niedzwiecki, D, Schuhmacher, C, Urba, S, van de Velde, C, Walsh, TN, Ychou, M, and Jensen, K. "Predictors of overall and recurrence-free survival after neoadjuvant chemotherapy for gastroesophageal adenocarcinoma: Pooled analysis of individual patient data (IPD) from randomized controlled trials (RCTs)." European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 43.8 (August 2017): 1550-1558.
PMID
28551325
Source
epmc
Published In
EJSO - European Journal of Surgical Oncology
Volume
43
Issue
8
Publish Date
2017
Start Page
1550
End Page
1558
DOI
10.1016/j.ejso.2017.05.005

Socioeconomic Status, Not Race, Is Associated With Reduced Survival in Esophagectomy Patients.

Black patients with esophageal cancer have worse survival than white patients. This study examines this racial disparity in conjunction with socioeconomic status (SES) and explores whether race-based outcome differences exist using a national database.The associations between race and SES with overall survival of patients treated with esophagectomy for stages I to III esophageal cancer between 2003 and 2011 in the National Cancer Data Base were investigated using the Kaplan-Meier method and proportional hazards analyses. Median income by zip code and proportion of the zip code residents without a high school diploma were grouped into income and education quartiles, respectively and used as surrogates for SES. The association between race and overall survival stratified by SES is explored.Of 11,599 esophagectomy patients who met study criteria, 3,503 (30.2%) were in the highest income quartile, 2,847 (24.5%) were in the highest education quartile, and 610 patients (5%) were black. Before adjustment for SES, black patients had worse overall survival than white patients (median survival 23.0 versus 34.7 months, log rank p < 0.001), and overall, survival times improved with increasing income and education (p < 0.001 for both). After adjustment for putative prognostic factors, SES was associated with overall survival, whereas race was not.Prior studies have suggested that survival of esophageal cancer patients after esophagectomy is associated with race. Our study suggests that race is not significantly related to overall survival when adjusted for other prognostic variables. Socioeconomic status, however, remains significantly related to overall survival in our model.

Authors
Erhunmwunsee, L; Gulack, BC; Rushing, C; Niedzwiecki, D; Berry, MF; Hartwig, MG
MLA Citation
Erhunmwunsee, L, Gulack, BC, Rushing, C, Niedzwiecki, D, Berry, MF, and Hartwig, MG. "Socioeconomic Status, Not Race, Is Associated With Reduced Survival in Esophagectomy Patients." The Annals of thoracic surgery 104.1 (July 2017): 234-244.
PMID
28410639
Source
epmc
Published In
The Annals of Thoracic Surgery
Volume
104
Issue
1
Publish Date
2017
Start Page
234
End Page
244
DOI
10.1016/j.athoracsur.2017.01.049

Predicted vitamin D status and colon cancer recurrence and mortality in CALGB 89803 (Alliance).

Observational studies suggest that higher levels of 25-hydroxyvitamin D3 (25(OH)D) are associated with a reduced risk of colorectal cancer and improved survival of colorectal cancer patients. However, the influence of vitamin D status on cancer recurrence and survival of patients with stage III colon cancer is unknown.We prospectively examined the influence of post-diagnosis predicted plasma 25(OH)D on outcome among 1016 patients with stage III colon cancer who were enrolled in a National Cancer Institute-sponsored adjuvant therapy trial (CALGB 89803). Predicted 25(OH)D scores were computed using validated regression models. We examined the influence of predicted 25(OH)D scores on cancer recurrence and mortality (disease-free survival; DFS) using Cox proportional hazards.Patients in the highest quintile of predicted 25(OH)D score had an adjusted hazard ratio (HR) for colon cancer recurrence or mortality (DFS) of 0.62 (95% confidence interval [CI], 0.44-0.86), compared with those in the lowest quintile (Ptrend = 0.005). Higher predicted 25(OH)D score was also associated with a significant improvement in recurrence-free survival and overall survival (Ptrend = 0.01 and 0.0004, respectively). The benefit associated with higher predicted 25(OH)D score appeared consistent across predictors of cancer outcome and strata of molecular tumor characteristics, including microsatellite instability and KRAS, BRAF, PIK3CA, and TP53 mutation status.Higher predicted 25(OH)D levels after a diagnosis of stage III colon cancer may be associated with decreased recurrence and improved survival. Clinical trials assessing the benefit of vitamin D supplementation in the adjuvant setting are warranted.NCT00003835.

Authors
Fuchs, MA; Yuan, C; Sato, K; Niedzwiecki, D; Ye, X; Saltz, LB; Mayer, RJ; Mowat, RB; Whittom, R; Hantel, A; Benson, A; Atienza, D; Messino, M; Kindler, H; Venook, A; Innocenti, F; Warren, RS; Bertagnolli, MM; Ogino, S; Giovannucci, EL; Horvath, E; Meyerhardt, JA; Ng, K
MLA Citation
Fuchs, MA, Yuan, C, Sato, K, Niedzwiecki, D, Ye, X, Saltz, LB, Mayer, RJ, Mowat, RB, Whittom, R, Hantel, A, Benson, A, Atienza, D, Messino, M, Kindler, H, Venook, A, Innocenti, F, Warren, RS, Bertagnolli, MM, Ogino, S, Giovannucci, EL, Horvath, E, Meyerhardt, JA, and Ng, K. "Predicted vitamin D status and colon cancer recurrence and mortality in CALGB 89803 (Alliance)." Annals of oncology : official journal of the European Society for Medical Oncology 28.6 (June 2017): 1359-1367.
PMID
28327908
Source
epmc
Published In
Annals of Oncology
Volume
28
Issue
6
Publish Date
2017
Start Page
1359
End Page
1367
DOI
10.1093/annonc/mdx109

Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type Advanced or Metastatic Colorectal Cancer: A Randomized Clinical Trial.

Combining biologic monoclonal antibodies with chemotherapeutic cytotoxic drugs provides clinical benefit to patients with advanced or metastatic colorectal cancer, but the optimal choice of the initial biologic therapy in previously untreated patients is unknown.To determine if the addition of cetuximab vs bevacizumab to the combination of leucovorin, fluorouracil, and oxaliplatin (mFOLFOX6) regimen or the combination of leucovorin, fluorouracil, and irinotecan (FOLFIRI) regimen is superior as first-line therapy in advanced or metastatic KRAS wild-type (wt) colorectal cancer.Patients (≥18 years) enrolled at community and academic centers throughout the National Clinical Trials Network in the United States and Canada (November 2005-March 2012) with previously untreated advanced or metastatic colorectal cancer whose tumors were KRAS wt chose to take either the mFOLFOX6 regimen or the FOLFIRI regimen as chemotherapy and were randomized to receive either cetuximab (n = 578) or bevacizumab (n = 559). The last date of follow-up was December 15, 2015.Cetuximab vs bevacizumab combined with either mFOLFOX6 or FOLFIRI chemotherapy regimen chosen by the treating physician and patient.The primary end point was overall survival. Secondary objectives included progression-free survival and overall response rate, site-reported confirmed or unconfirmed complete or partial response.Among 1137 patients (median age, 59 years; 440 [39%] women), 1074 (94%) of patients met eligibility criteria. As of December 15, 2015, median follow-up for 263 surviving patients was 47.4 months (range, 0-110.7 months), and 82% of patients (938 of 1137) experienced disease progression. The median overall survival was 30.0 months in the cetuximab-chemotherapy group and 29.0 months in the bevacizumab-chemotherapy group with a stratified hazard ratio (HR) of 0.88 (95% CI, 0.77-1.01; P = .08). The median progression-free survival was 10.5 months in the cetuximab-chemotherapy group and 10.6 months in the bevacizumab-chemotherapy group with a stratified HR of 0.95 (95% CI, 0.84-1.08; P = .45). Response rates were not significantly different, 59.6% vs 55.2% for cetuximab and bevacizumab, respectively (difference, 4.4%, 95% CI, 1.0%-9.0%, P = .13).Among patients with KRAS wt untreated advanced or metastatic colorectal cancer, there was no significant difference in overall survival between the addition of cetuximab vs bevacizumab to chemotherapy as initial biologic treatment.clinicaltrials.gov identifier: NCT00265850.

Authors
Venook, AP; Niedzwiecki, D; Lenz, H-J; Innocenti, F; Fruth, B; Meyerhardt, JA; Schrag, D; Greene, C; O'Neil, BH; Atkins, JN; Berry, S; Polite, BN; O'Reilly, EM; Goldberg, RM; Hochster, HS; Schilsky, RL; Bertagnolli, MM; El-Khoueiry, AB; Watson, P; Benson, AB; Mulkerin, DL; Mayer, RJ; Blanke, C
MLA Citation
Venook, AP, Niedzwiecki, D, Lenz, H-J, Innocenti, F, Fruth, B, Meyerhardt, JA, Schrag, D, Greene, C, O'Neil, BH, Atkins, JN, Berry, S, Polite, BN, O'Reilly, EM, Goldberg, RM, Hochster, HS, Schilsky, RL, Bertagnolli, MM, El-Khoueiry, AB, Watson, P, Benson, AB, Mulkerin, DL, Mayer, RJ, and Blanke, C. "Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type Advanced or Metastatic Colorectal Cancer: A Randomized Clinical Trial." JAMA 317.23 (June 2017): 2392-2401.
PMID
28632865
Source
epmc
Published In
JAMA : the journal of the American Medical Association
Volume
317
Issue
23
Publish Date
2017
Start Page
2392
End Page
2401
DOI
10.1001/jama.2017.7105

Reply to L. Casadaban et al.

Authors
Niedzwiecki, D; Frankel, WL; Venook, AP; Ye, X; Friedman, PN; Goldberg, RM; Mayer, RJ; Colacchio, TA; Mulligan, JM; Davison, TS; O'Brien, E; Kerr, P; Johnston, PG; Kennedy, RD; Harkin, DP; Schilsky, RL; Bertagnolli, MM; Warren, RS; Innocenti, F
MLA Citation
Niedzwiecki, D, Frankel, WL, Venook, AP, Ye, X, Friedman, PN, Goldberg, RM, Mayer, RJ, Colacchio, TA, Mulligan, JM, Davison, TS, O'Brien, E, Kerr, P, Johnston, PG, Kennedy, RD, Harkin, DP, Schilsky, RL, Bertagnolli, MM, Warren, RS, and Innocenti, F. "Reply to L. Casadaban et al." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 35.12 (April 2017): 1373-1374.
PMID
28113023
Source
epmc
Published In
Journal of Clinical Oncology
Volume
35
Issue
12
Publish Date
2017
Start Page
1373
End Page
1374
DOI
10.1200/jco.2016.71.2646

Phase I study of pazopanib plus TH-302 in advanced solid tumors.

To define the maximum tolerated dose (MTD), recommended phase II dose (RPTD), and assess safety and tolerability for the combination of pazopanib plus TH-302, an investigational hypoxia-activated prodrug (HAP), in adult patients with advanced solid tumors.This was an open-label, non-randomized, single-center, phase I trial consisting 2 stages. Stage 1 was a standard "3 + 3" dose escalation design to determine safety and the RPTD for TH-302 plus pazopanib combination. Stage 2 was an expanded cohort to better describe the tolerability and toxicity profile at the MTD. Pazopanib was orally dosed at 800 mg daily on days 1-28 for all cohorts. TH-302 was administered intravenously on days 1, 8 and 15 of a 28-day cycle at doses of 340 mg/m2 (cohort 1) or 480 mg/m2 (cohort 2). Dose limiting toxicity (DLT) was assessed in the first 28-day cycle. Efficacy was assessed every 2 cycles.Thirty patients were enrolled between December 2011 and September 2013. In the dose escalation stage, 7 patients were enrolled in the 340 mg/m2 TH-302 cohort and 6 patients in the 480 mg/m2 TH-302 cohort. Ten patients were evaluable for DLT. DLTs included grade 2 intolerable esophagitis (n = 1) in the 340 mg/m2 TH-302 cohort, and grade 3 vaginal inflammation (n = 1) and grade 3 neutropenia with grade 3 thrombocytopenia (n = 1, same patient) in the 480 mg/m2 TH-302 cohort. The 340 mg/m2 TH-302 cohort was determined to be MTD and RPTD. The most common treatment-related adverse events were hematologic (anemia, neutropenia, and thrombocytopenia), nausea/vomiting, palmar-plantar erythrodysesthesia syndrome, constipation, fatigue, mucositis, anorexia, pain, and hypertension. Partial response (PR) was observed in 10% (n = 3) of patients, stable disease (SD) in 57% (n = 17), and progressive disease (PD) in 23% (n = 7). Due to toxicity, 3 patients were discontinued from study drug prior to first radiographic assessment but were included in these calculations. Disease control ≥6 months was observed in 37% of patients (n = 11).The RPTD for this novel combination is pazopanib 800 mg daily on days 1-28 plus TH-302 340 mg/m2 on days 1, 8 and 15 of each 28-day cycle. Preliminary activity was seen in treatment-refractory cancers and supports potential value of co-targeting tumor angiogenesis and tumor hypoxia.

Authors
Riedel, RF; Meadows, KL; Lee, PH; Morse, MA; Uronis, HE; Blobe, GC; George, DJ; Crawford, J; Niedzwiecki, D; Rushing, CN; Arrowood, CC; Hurwitz, HI
MLA Citation
Riedel, RF, Meadows, KL, Lee, PH, Morse, MA, Uronis, HE, Blobe, GC, George, DJ, Crawford, J, Niedzwiecki, D, Rushing, CN, Arrowood, CC, and Hurwitz, HI. "Phase I study of pazopanib plus TH-302 in advanced solid tumors." Cancer chemotherapy and pharmacology 79.3 (March 2017): 611-619.
PMID
28238078
Source
epmc
Published In
Cancer Chemotherapy and Pharmacology
Volume
79
Issue
3
Publish Date
2017
Start Page
611
End Page
619
DOI
10.1007/s00280-017-3256-2

A Study of Thymidylate Synthase Expression as a Biomarker for Resectable Colon Cancer: Alliance (Cancer and Leukemia Group B) 9581 and 89803.

Tumor levels of thymidylate synthase (TS), a target of 5-fluorouracil (5-FU)-based chemotherapy for colorectal cancer, have been studied as a predictive or prognostic biomarker with mixed results.Tumor TS levels were prospectively evaluated in two adjuvant therapy trials for patients with resected stage II or III colon cancer. TS expression was determined by standard immunohistochemistry and by automated quantitative analysis. Tumor mismatch repair deficiency (MMR-D) and BRAF c.1799T > A (p.V600E) mutation status were also examined. Relationships between tumor TS, MMR-D, and BRAF mutation status, overall survival (OS), and disease-free survival (DFS) were investigated in the subset of stage III patients.Patients whose tumors demonstrated high TS expression experienced better treatment outcomes, with DFS hazard ratio (HR) = 0.67, 95% confidence interval (CI) = 0.53, 0.84; and OS HR = 0.68, 95% CI = 0.53, 0.88, for high versus low TS expression, respectively. No significant interaction between TS expression and stage was observed (DFS: interaction HR = 0.94; OS: interaction HR = 0.94). Tumors with high TS expression were more likely to demonstrate MMR-D (22.2% vs. 12.8%; p =  .0003). Patients whose tumors demonstrated both high TS and MMR-D had a 7-year DFS of 77%, compared with 58% for those whose tumors had low TS and were non-MMR-D (log-rank p =  .0006). Tumor TS expression did not predict benefit of a particular therapeutic regimen.This large prospective analysis showed that high tumor TS levels were associated with improved DFS and OS following adjuvant therapy for colon cancer, although tumor TS expression did not predict benefit of 5-FU-based chemotherapy. The Oncologist 2017;22:107-114Implications for Practice: This study finds that measurement of tumor levels of thymidylate synthase is not helpful in assigning specific adjuvant treatment for colorectal cancer. It also highlights the importance of using prospective analyses within treatment clinical trials as the optimal method of determining biomarker utility.

Authors
Niedzwiecki, D; Hasson, RM; Lenz, H-J; Ye, C; Redston, M; Ogino, S; Fuchs, CS; Compton, CC; Mayer, RJ; Goldberg, RM; Colacchio, TA; Saltz, LB; Warren, RS; Bertagnolli, MM
MLA Citation
Niedzwiecki, D, Hasson, RM, Lenz, H-J, Ye, C, Redston, M, Ogino, S, Fuchs, CS, Compton, CC, Mayer, RJ, Goldberg, RM, Colacchio, TA, Saltz, LB, Warren, RS, and Bertagnolli, MM. "A Study of Thymidylate Synthase Expression as a Biomarker for Resectable Colon Cancer: Alliance (Cancer and Leukemia Group B) 9581 and 89803." The oncologist 22.1 (January 2017): 107-114.
PMID
27821793
Source
epmc
Published In
The oncologist
Volume
22
Issue
1
Publish Date
2017
Start Page
107
End Page
114
DOI
10.1634/theoncologist.2016-0215

Association Between Results of a Gene Expression Signature Assay and Recurrence-Free Interval in Patients With Stage II Colon Cancer in Cancer and Leukemia Group B 9581 (Alliance).

Conventional staging methods are inadequate to identify patients with stage II colon cancer (CC) who are at high risk of recurrence after surgery with curative intent. ColDx is a gene expression, microarray-based assay shown to be independently prognostic for recurrence-free interval (RFI) and overall survival in CC. The objective of this study was to further validate ColDx using formalin-fixed, paraffin-embedded specimens collected as part of the Alliance phase III trial, C9581.C9581 evaluated edrecolomab versus observation in patients with stage II CC and reported no survival benefit. Under an initial case-cohort sampling design, a randomly selected subcohort (RS) comprised 514 patients from 901 eligible patients with available tissue. Forty-nine additional patients with recurrence events were included in the analysis. Final analysis comprised 393 patients: 360 RS (58 events) and 33 non-RS events. Risk status was determined for each patient by ColDx. The Self-Prentice method was used to test the association between the resulting ColDx risk score and RFI adjusting for standard prognostic variables.Fifty-five percent of patients (216 of 393) were classified as high risk. After adjustment for prognostic variables that included mismatch repair (MMR) deficiency, ColDx high-risk patients exhibited significantly worse RFI (multivariable hazard ratio, 2.13; 95% CI, 1.3 to 3.5; P < .01). Age and MMR status were marginally significant. RFI at 5 years for patients classified as high risk was 82% (95% CI, 79% to 85%), compared with 91% (95% CI, 89% to 93%) for patients classified as low risk.ColDx is associated with RFI in the C9581 subsample in the presence of other prognostic factors, including MMR deficiency. ColDx could be incorporated with the traditional clinical markers of risk to refine patient prognosis.

Authors
Niedzwiecki, D; Frankel, WL; Venook, AP; Ye, X; Friedman, PN; Goldberg, RM; Mayer, RJ; Colacchio, TA; Mulligan, JM; Davison, TS; O'Brien, E; Kerr, P; Johnston, PG; Kennedy, RD; Harkin, DP; Schilsky, RL; Bertagnolli, MM; Warren, RS; Innocenti, F
MLA Citation
Niedzwiecki, D, Frankel, WL, Venook, AP, Ye, X, Friedman, PN, Goldberg, RM, Mayer, RJ, Colacchio, TA, Mulligan, JM, Davison, TS, O'Brien, E, Kerr, P, Johnston, PG, Kennedy, RD, Harkin, DP, Schilsky, RL, Bertagnolli, MM, Warren, RS, and Innocenti, F. "Association Between Results of a Gene Expression Signature Assay and Recurrence-Free Interval in Patients With Stage II Colon Cancer in Cancer and Leukemia Group B 9581 (Alliance)." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 34.25 (September 2016): 3047-3053.
PMID
27432924
Source
epmc
Published In
Journal of Clinical Oncology
Volume
34
Issue
25
Publish Date
2016
Start Page
3047
End Page
3053
DOI
10.1200/jco.2015.65.4699

Blood-based markers of efficacy and resistance to cetuximab treatment in metastatic colorectal cancer: results from CALGB 80203 (Alliance).

Circulating protein markers were assessed in patients with colorectal cancer (CRC) treated with cetuximab in CALGB 80203 to identify prognostic and predictive biomarkers. Patients with locally advanced or metastatic CRC received FOLFOX or FOLFIRI chemotherapy (chemo) or chemo in combination with cetuximab. Baseline plasma samples from 152 patients were analyzed for six candidate markers [epidermal growth factor (EGF), heparin-binding EGF (HBEGF), epidermal growth factor receptor (EGFR), HER2, HER3, and CD73]. Analyte levels were associated with survival endpoints using univariate Cox proportional hazards models. Predictive markers were identified using a treatment-by-marker interaction term in the Cox model. Plasma levels of EGF, HBEGF, HER3, and CD73 were prognostic for overall survival (OS) across all patients (KRAS mutant and wild-type). High levels of EGF predicted for lack of OS benefit from cetuximab in KRAS wild-type (WT) patients (chemo HR = 0.98, 95% CI = 0.74-1.29; chemo+cetuximab HR = 1.54, 95% CI = 1.05-2.25; interaction P = 0.045) and benefit from cetuximab in KRAS mutant patients (chemo HR = 1.72, 95% CI = 1.02-2.92; chemo+cetuximab HR = 0.90, 95% CI = 0.67-1.21; interaction P = 0.026). Across all patients, higher HER3 levels were associated with significant OS benefit from cetuximab treatment (chemo HR = 4.82, 95% CI = 1.68-13.84; chemo+cetuximab HR = 0.95, 95% CI = 0.31-2.95; interaction P = 0.046). CD73 was also identified as predictive of OS benefit in KRAS WT patients (chemo HR = 1.28, 95% CI = 0.88-1.84; chemo+cetuximab HR = 0.60, 95% CI = 0.32-1.13; interaction P = 0.049). Although these results are preliminary, and confirmatory studies are necessary before clinical application, the data suggest that HER3 and CD73 may play important roles in the biological response to cetuximab.

Authors
Hatch, AJ; Sibley, AB; Starr, MD; Brady, JC; Jiang, C; Jia, J; Bowers, DL; Pang, H; Owzar, K; Niedzwiecki, D; Innocenti, F; Venook, AP; Hurwitz, HI; Nixon, AB; Alliance for Clinical Trials in Oncology,
MLA Citation
Hatch, AJ, Sibley, AB, Starr, MD, Brady, JC, Jiang, C, Jia, J, Bowers, DL, Pang, H, Owzar, K, Niedzwiecki, D, Innocenti, F, Venook, AP, Hurwitz, HI, Nixon, AB, and Alliance for Clinical Trials in Oncology, . "Blood-based markers of efficacy and resistance to cetuximab treatment in metastatic colorectal cancer: results from CALGB 80203 (Alliance)." Cancer medicine 5.9 (September 2016): 2249-2260.
PMID
27465221
Source
epmc
Published In
Cancer Medicine
Volume
5
Issue
9
Publish Date
2016
Start Page
2249
End Page
2260
DOI
10.1002/cam4.806

CALGB 80403 (Alliance)/E1206: A Randomized Phase II Study of Three Chemotherapy Regimens Plus Cetuximab in Metastatic Esophageal and Gastroesophageal Junction Cancers.

To determine the optimal chemotherapy backbone for testing in future US cooperative group studies for metastatic esophageal and gastroesophageal junction cancers. Cetuximab was added to each treatment arm based on promising preclinical data.Patients with previously untreated metastatic esophageal or gastroesophageal junction cancer were randomly assigned at a one-to-one-to-one ratio to epirubicin, cisplatin, and continuous-infusion fluorouracil (ECF), irinotecan plus cisplatin (IC), or FOLFOX (oxaliplatin, leucovorin, and bolus and infusional fluorouracil). All treatment programs included cetuximab once per week. The primary end point was response rate. Secondary outcomes included overall survival, progression-free survival, time to treatment failure, and safety. As prespecified, primary and secondary analyses were conducted only among patients with adenocarcinoma.This study randomly assigned 245 patients, including 222 with adenocarcinoma. Among patients with adenocarcinoma, response rate was 60.9% (95% CI, 47.9 to 72.8) for ECF plus cetuximab, 45.0% (95% CI, 33.0 to 57.0) for IC plus cetuximab, and 54.3% (95% CI, 42.0 to 66.2) for FOLFOX plus cetuximab. Median overall survival was 11.6, 8.6, and 11.8 months; median progression-free survival was 7.1, 4.9, and 6.8 months; and median time to treatment failure was 5.6, 4.3, and 6.7 months for each of these arms, respectively. FOLFOX plus cetuximab required fewer treatment modifications compared with ECF plus cetuximab and IC plus cetuximab (P = .013), and fewer patients were removed from treatment because of an adverse event or experienced treatment-related death.In combination with cetuximab, ECF and FOLFOX had similar efficacy, but FOLFOX was better tolerated. Although differences were nonsignificant, IC plus cetuximab seemed to be the least effective and most toxic of the three regimens tested.

Authors
Enzinger, PC; Burtness, BA; Niedzwiecki, D; Ye, X; Douglas, K; Ilson, DH; Villaflor, VM; Cohen, SJ; Mayer, RJ; Venook, A; Benson, AB; Goldberg, RM
MLA Citation
Enzinger, PC, Burtness, BA, Niedzwiecki, D, Ye, X, Douglas, K, Ilson, DH, Villaflor, VM, Cohen, SJ, Mayer, RJ, Venook, A, Benson, AB, and Goldberg, RM. "CALGB 80403 (Alliance)/E1206: A Randomized Phase II Study of Three Chemotherapy Regimens Plus Cetuximab in Metastatic Esophageal and Gastroesophageal Junction Cancers." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 34.23 (August 2016): 2736-2742.
PMID
27382098
Source
epmc
Published In
Journal of Clinical Oncology
Volume
34
Issue
23
Publish Date
2016
Start Page
2736
End Page
2742
DOI
10.1200/jco.2015.65.5092

Big Data, Small Effects.

Authors
Hochster, HS; Niedzwiecki, D
MLA Citation
Hochster, HS, and Niedzwiecki, D. "Big Data, Small Effects." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 34.11 (April 2016): 1170-1171.
PMID
26884573
Source
epmc
Published In
Journal of Clinical Oncology
Volume
34
Issue
11
Publish Date
2016
Start Page
1170
End Page
1171
DOI
10.1200/jco.2015.65.8161

Randomized Phase II Study of Everolimus (E) Versus Everolimus plus Bevacizumab (E plus B) in Patients (Pts) With Locally Advanced or Metastatic Pancreatic Neuroendocrine Tumors (pNET), CALGB 80701 (Alliance)

Authors
Kulke, MH; Niedzwiecki, D; Foster, NR; Fruth, B; Kunz, PL; Kennecke, H; Wolin, EM; Venook, AP
MLA Citation
Kulke, MH, Niedzwiecki, D, Foster, NR, Fruth, B, Kunz, PL, Kennecke, H, Wolin, EM, and Venook, AP. "Randomized Phase II Study of Everolimus (E) Versus Everolimus plus Bevacizumab (E plus B) in Patients (Pts) With Locally Advanced or Metastatic Pancreatic Neuroendocrine Tumors (pNET), CALGB 80701 (Alliance)." PANCREAS 45.3 (March 2016): 477-477.
Source
wos-lite
Published In
Pancreas
Volume
45
Issue
3
Publish Date
2016
Start Page
477
End Page
477

X-TRAP: Phase I/II study of capecitabine (X) plus ziv-aflibercept (TRAP) in metastatic colorectal cancer (mCRC).

Authors
Strickler, JH; Rangwala, FA; Rushing, C; Niedzwiecki, D; Altomare, I; Uronis, HE; Hsu, SD; Zafar, Y; Morse, M; Chang, DZ; Wells, JL; Blackwell, KL; Marcom, PK; Webb, AR; Dropkin, E; Arrowood, C; Hurwitz, H
MLA Citation
Strickler, JH, Rangwala, FA, Rushing, C, Niedzwiecki, D, Altomare, I, Uronis, HE, Hsu, SD, Zafar, Y, Morse, M, Chang, DZ, Wells, JL, Blackwell, KL, Marcom, PK, Webb, AR, Dropkin, E, Arrowood, C, and Hurwitz, H. "X-TRAP: Phase I/II study of capecitabine (X) plus ziv-aflibercept (TRAP) in metastatic colorectal cancer (mCRC)." February 1, 2016.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
34
Issue
4
Publish Date
2016

Coffee Intake, Recurrence, and Mortality in Stage III Colon Cancer: Results From CALGB 89803 (Alliance).

Observational studies have demonstrated increased colon cancer recurrence in states of relative hyperinsulinemia, including sedentary lifestyle, obesity, and increased dietary glycemic load. Greater coffee consumption has been associated with decreased risk of type 2 diabetes and increased insulin sensitivity. The effect of coffee on colon cancer recurrence and survival is unknown.During and 6 months after adjuvant chemotherapy, 953 patients with stage III colon cancer prospectively reported dietary intake of caffeinated coffee, decaffeinated coffee, and nonherbal tea, as well as 128 other items. We examined the influence of coffee, nonherbal tea, and caffeine on cancer recurrence and mortality using Cox proportional hazards regression.Patients consuming 4 cups/d or more of total coffee experienced an adjusted hazard ratio (HR) for colon cancer recurrence or mortality of 0.58 (95% CI, 0.34 to 0.99), compared with never drinkers (Ptrend = .002). Patients consuming 4 cups/d or more of caffeinated coffee experienced significantly reduced cancer recurrence or mortality risk compared with abstainers (HR, 0.48; 95% CI, 0.25 to 0.91; Ptrend = .002), and increasing caffeine intake also conferred a significant reduction in cancer recurrence or mortality (HR, 0.66 across extreme quintiles; 95% CI, 0.47 to 0.93; Ptrend = .006). Nonherbal tea and decaffeinated coffee were not associated with patient outcome. The association of total coffee intake with improved outcomes seemed consistent across other predictors of cancer recurrence and mortality.Higher coffee intake may be associated with significantly reduced cancer recurrence and death in patients with stage III colon cancer.

Authors
Guercio, BJ; Sato, K; Niedzwiecki, D; Ye, X; Saltz, LB; Mayer, RJ; Mowat, RB; Whittom, R; Hantel, A; Benson, A; Atienza, D; Messino, M; Kindler, H; Venook, A; Hu, FB; Ogino, S; Wu, K; Willett, WC; Giovannucci, EL; Meyerhardt, JA; Fuchs, CS
MLA Citation
Guercio, BJ, Sato, K, Niedzwiecki, D, Ye, X, Saltz, LB, Mayer, RJ, Mowat, RB, Whittom, R, Hantel, A, Benson, A, Atienza, D, Messino, M, Kindler, H, Venook, A, Hu, FB, Ogino, S, Wu, K, Willett, WC, Giovannucci, EL, Meyerhardt, JA, and Fuchs, CS. "Coffee Intake, Recurrence, and Mortality in Stage III Colon Cancer: Results From CALGB 89803 (Alliance)." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 33.31 (November 2015): 3598-3607.
PMID
26282659
Source
epmc
Published In
Journal of Clinical Oncology
Volume
33
Issue
31
Publish Date
2015
Start Page
3598
End Page
3607
DOI
10.1200/jco.2015.61.5062

A genome-wide association study (GWAS) of overall survival (OS) in 609 metastatic colorectal cancer (mCRC) patients treated with chemotherapy and biologics in CALGB 80405

Authors
Innocenti, F; Owzar, K; Chen, J; Sibley, A; Niedzwiecki, D; Bertagnolli, M; Friedman, P; Furukawa, Y; Kubo, M; Ratain, M; Blanke, C; Heinz-Josef, L; Venook, A; McLeod, H
MLA Citation
Innocenti, F, Owzar, K, Chen, J, Sibley, A, Niedzwiecki, D, Bertagnolli, M, Friedman, P, Furukawa, Y, Kubo, M, Ratain, M, Blanke, C, Heinz-Josef, L, Venook, A, and McLeod, H. "A genome-wide association study (GWAS) of overall survival (OS) in 609 metastatic colorectal cancer (mCRC) patients treated with chemotherapy and biologics in CALGB 80405." September 2015.
Source
wos-lite
Published In
European Journal of Cancer
Volume
51
Publish Date
2015
Start Page
S329
End Page
S330

Outcomes for FOLFIRI plus bevacizumab (BEV) or cetuximab (CET) in patients previously treated with oxaliplatin-based adjuvant therapy: A combined analysis of data from FIRE-3 and CALGB 80405

Authors
Heinemann, V; Niedzwiecki, D; Pearline, RV; Grothey, A; Hochster, HS; Goldberg, RM; Innocenti, F; Mayer, RJ; Schilsky, RL; Blanke, CD; Bertagnolli, MM; Venook, AP; Stinzing, S; O'Neil, BH
MLA Citation
Heinemann, V, Niedzwiecki, D, Pearline, RV, Grothey, A, Hochster, HS, Goldberg, RM, Innocenti, F, Mayer, RJ, Schilsky, RL, Blanke, CD, Bertagnolli, MM, Venook, AP, Stinzing, S, and O'Neil, BH. "Outcomes for FOLFIRI plus bevacizumab (BEV) or cetuximab (CET) in patients previously treated with oxaliplatin-based adjuvant therapy: A combined analysis of data from FIRE-3 and CALGB 80405." May 20, 2015.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
33
Issue
15
Publish Date
2015

Cost of chemotherapy for metastatic colorectal cancer with either bevacizumab or cetuximab: Economic analysis of CALGB/SWOG 80405

Authors
Schrag, D; Dueck, AC; Naughton, MJ; Niedzwiecki, D; Earle, C; Shaw, JE; Grothey, A; Hochster, HS; Blanke, CD; Venook, AP
MLA Citation
Schrag, D, Dueck, AC, Naughton, MJ, Niedzwiecki, D, Earle, C, Shaw, JE, Grothey, A, Hochster, HS, Blanke, CD, and Venook, AP. "Cost of chemotherapy for metastatic colorectal cancer with either bevacizumab or cetuximab: Economic analysis of CALGB/SWOG 80405." May 20, 2015.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
33
Issue
15
Publish Date
2015

A genome-wide association study (GWAS) of overall survival (OS) in 609 metastatic colorectal cancer (mCRC) patients treated with chemotherapy and biologics in CALGB 80405

Authors
Innocenti, F; Owzar, K; Jiang, C; Sibley, A; Niedzwiecki, D; Lenz, H-J; Bertagnolli, MM; Friedman, PN; Furukawa, Y; Kubo, M; Ratain, MJ; Blanke, CD; Venook, AP; McLeod, HL
MLA Citation
Innocenti, F, Owzar, K, Jiang, C, Sibley, A, Niedzwiecki, D, Lenz, H-J, Bertagnolli, MM, Friedman, PN, Furukawa, Y, Kubo, M, Ratain, MJ, Blanke, CD, Venook, AP, and McLeod, HL. "A genome-wide association study (GWAS) of overall survival (OS) in 609 metastatic colorectal cancer (mCRC) patients treated with chemotherapy and biologics in CALGB 80405." May 20, 2015.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
33
Issue
15
Publish Date
2015

Vitamin D status and survival of metastatic colorectal cancer patients: Results from CALGB/SWOG 80405 (Alliance).

Authors
Ng, K; Venook, AP; Sato, K; Yuan, C; Hollis, BW; Niedzwiecki, D; Ye, C; Chang, I-W; O'Neil, BH; Innocenti, F; Lenz, H-J; Blanke, CD; Mayer, RJ; Fuchs, CS; Meyerhardt, JA
MLA Citation
Ng, K, Venook, AP, Sato, K, Yuan, C, Hollis, BW, Niedzwiecki, D, Ye, C, Chang, I-W, O'Neil, BH, Innocenti, F, Lenz, H-J, Blanke, CD, Mayer, RJ, Fuchs, CS, and Meyerhardt, JA. "Vitamin D status and survival of metastatic colorectal cancer patients: Results from CALGB/SWOG 80405 (Alliance)." May 20, 2015.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
33
Issue
15
Publish Date
2015

Randomized phase II study of everolimus (E) versus everolimus plus bevacizumab (E plus B) in patients (Pts) with locally advanced or metastatic pancreatic neuroendocrine tumors (pNET), CALGB 80701 (Alliance)

Authors
Kulke, MH; Niedzwiecki, D; Foster, NR; Fruth, B; Kunz, PL; Kennecke, HF; Wolin, EM; Venook, AP
MLA Citation
Kulke, MH, Niedzwiecki, D, Foster, NR, Fruth, B, Kunz, PL, Kennecke, HF, Wolin, EM, and Venook, AP. "Randomized phase II study of everolimus (E) versus everolimus plus bevacizumab (E plus B) in patients (Pts) with locally advanced or metastatic pancreatic neuroendocrine tumors (pNET), CALGB 80701 (Alliance)." May 20, 2015.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
33
Issue
15
Publish Date
2015

Treatment of palmar-plantar erythrodysesthesia (PPE) with topical sildenafil: a pilot study.

Palmar-plantar erythrodysesthesia (PPE) is a common chemotherapy and anti-VEGF multi-kinase inhibitor class-related toxicity that often results in debilitating skin changes and often limits the use of active anti-cancer regimens. Mechanistic and anecdotal clinical evidence suggested that topical application of sildenafil cream may help reduce the severity of PPE. Therefore, we conducted a randomized, double-blind, placebo-controlled pilot study to evaluate the feasibility, safety and efficacy of topical sildenafil cream for the treatment of PPE.Eligible subjects were required to have grade 1-3 PPE associated with either capecitabine or sunitinib. Subjects were randomized to receive 1 % topical sildenafil cream to the left extremities or right extremities and placebo cream on the opposite extremity. Two times per day, 0.5 mL of cream was applied to each affected hand/foot. The primary endpoint was improvement in PPE grading at any point on study. Clinical assessments were evaluated by NCI-CTC 4.0 grading and patient self-reported pain.Ten subjects were enrolled, nine were evaluable for safety and efficacy. Five of nine subjects reported some improvement in foot pain and three of eight subjects for hand pain improvement. One of these subjects noted specific improvement in tactile function. No treatment-related toxicities were observed.In this limited, single-center study, topical cream containing 1 % sildenafil is feasible to administer, is well-tolerated, and may mitigate PPE-related symptoms due to anti-cancer therapeutic agents. Further validation is necessary.

Authors
Meadows, KL; Rushing, C; Honeycutt, W; Latta, K; Howard, L; Arrowood, CA; Niedzwiecki, D; Hurwitz, HI
MLA Citation
Meadows, KL, Rushing, C, Honeycutt, W, Latta, K, Howard, L, Arrowood, CA, Niedzwiecki, D, and Hurwitz, HI. "Treatment of palmar-plantar erythrodysesthesia (PPE) with topical sildenafil: a pilot study." Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer 23.5 (May 2015): 1311-1319.
PMID
25341548
Source
epmc
Published In
Supportive Care in Cancer
Volume
23
Issue
5
Publish Date
2015
Start Page
1311
End Page
1319
DOI
10.1007/s00520-014-2465-z

Gene expression markers of efficacy and resistance to cetuximab treatment in metastatic colorectal cancer: results from CALGB 80203 (Alliance).

Formalin-fixed, paraffin-embedded tumor samples from CALGB 80203 were analyzed for expression of EGFR axis-related genes to identify prognostic or predictive biomarkers for cetuximab treatment.Patients (238 total) with first-line metastatic colorectal cancer (mCRC) were randomized to FOLFOX or FOLFIRI chemotherapy ± cetuximab. qRT-PCR analyses were conducted on tissues from 103 patients at baseline to measure gene expression levels of HER-related genes, including amphiregulin (AREG), betacellulin (BTC), NT5E (CD73), DUSP4, EGF, EGFR, epigen (EPGN), epiregulin (EREG), HBEGF, ERBB2 (HER2), ERBB3 (HER3), ERBB4 (HER4), PHLDA1, and TGFA. The interactions between expression levels and treatment with respect to progression-free survival (PFS) and overall survival (OS) were modeled using multiplicative Cox proportional hazards models.High tumor mRNA levels of HER2 [hazard ratio (HR), 0.64; P = 0.002] and EREG (HR, 0.89; P = 0.016) were prognostic markers associated with longer PFS across all patients. HER3 and CD73 expression levels were identified as potential predictive markers of benefit from cetuximab. In KRAS wild-type (WT) tumors, low HER3 expression was associated with longer OS from cetuximab treatment, whereas high HER3 expression was associated with shorter OS from cetuximab treatment (chemo + cetuximab: HR, 1.15; chemo-only: HR, 0.48; Pinteraction = 0.029). High CD73 expression was associated with longer PFS from cetuximab treatment in patients with KRAS-WT (chemo + cetuximab: HR, 0.91; chemo-only: HR, 1.57; Pinteraction = 0.026) and KRAS-mutant (Mut) tumors (chemo + cetuximab: HR, 0.80; chemo-only: HR, 1.29; P = 0.025).Gene expression of HER3 and CD73 was identified as a potential predictive marker for cetuximab. These data implicate HER axis signaling and immune modulation as potential mechanisms of cetuximab action and sensitivity.

Authors
Cushman, SM; Jiang, C; Hatch, AJ; Shterev, I; Sibley, AB; Niedzwiecki, D; Venook, AP; Owzar, K; Hurwitz, HI; Nixon, AB
MLA Citation
Cushman, SM, Jiang, C, Hatch, AJ, Shterev, I, Sibley, AB, Niedzwiecki, D, Venook, AP, Owzar, K, Hurwitz, HI, and Nixon, AB. "Gene expression markers of efficacy and resistance to cetuximab treatment in metastatic colorectal cancer: results from CALGB 80203 (Alliance)." Clinical cancer research : an official journal of the American Association for Cancer Research 21.5 (March 2015): 1078-1086.
PMID
25520391
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
21
Issue
5
Publish Date
2015
Start Page
1078
End Page
1086
DOI
10.1158/1078-0432.ccr-14-2313

Vitamin D status and survival of metastatic colorectal cancer patients: Results from CALGB/SWOG 80405 (Alliance)

Authors
Ng, K; Venook, AP; Sato, K; Hollis, BW; Niedzwiecki, D; Ye, C; Chang, I-W; O'Neil, BH; Innocenti, F; Lenz, H-J; Blanke, CD; Mayer, RJ; Fuchs, CS; Meyerhardt, JA
MLA Citation
Ng, K, Venook, AP, Sato, K, Hollis, BW, Niedzwiecki, D, Ye, C, Chang, I-W, O'Neil, BH, Innocenti, F, Lenz, H-J, Blanke, CD, Mayer, RJ, Fuchs, CS, and Meyerhardt, JA. "Vitamin D status and survival of metastatic colorectal cancer patients: Results from CALGB/SWOG 80405 (Alliance)." January 20, 2015.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
33
Issue
3
Publish Date
2015

Aspirin and COX-2 inhibitor use in patients with stage III colon cancer.

We conducted a prospective, observational study of aspirin and COX-2 inhibitor use and survival in stage III colon cancer patients enrolled in an adjuvant chemotherapy trial. Among 799 eligible patients, aspirin use was associated with improved recurrence-free survival (RFS) (multivariable hazard ratio [HR] = 0.51, 95% confidence interval [CI] = 0.28 to 0.95), disease-free survival (DFS) (HR = 0.68, 95% CI = 0.42 to 1.11), and overall survival (OS) (HR = 0.63, 95% CI = 0.35 to 1.12). Adjusted HRs for DFS and OS censored at five years (in an attempt to minimize misclassification from noncancer death) were 0.61 (95% CI = 0.36 to 1.04) and 0.48 (95% CI = 0.23 to 0.99). Among 843 eligible patients, those who used COX-2 inhibitors had multivariable HRs for RFS, DFS, and OS of 0.53 (95% CI = 0.27 to 1.04), 0.60 (95% CI = 0.33 to 1.08), and 0.50 (95% CI = 0.23 to 1.07), and HRs of 0.47 (95% CI = 0.24 to 0.91) and 0.26 (95% CI = 0.08 to 0.81) for DFS and OS censored at five years. Aspirin and COX-2 inhibitor use may be associated with improved outcomes in stage III colon cancer patients.

Authors
Ng, K; Meyerhardt, JA; Chan, AT; Sato, K; Chan, JA; Niedzwiecki, D; Saltz, LB; Mayer, RJ; Benson, AB; Schaefer, PL; Whittom, R; Hantel, A; Goldberg, RM; Venook, AP; Ogino, S; Giovannucci, EL; Fuchs, CS
MLA Citation
Ng, K, Meyerhardt, JA, Chan, AT, Sato, K, Chan, JA, Niedzwiecki, D, Saltz, LB, Mayer, RJ, Benson, AB, Schaefer, PL, Whittom, R, Hantel, A, Goldberg, RM, Venook, AP, Ogino, S, Giovannucci, EL, and Fuchs, CS. "Aspirin and COX-2 inhibitor use in patients with stage III colon cancer." Journal of the National Cancer Institute 107.1 (January 2015): 345-.
PMID
25432409
Source
epmc
Published In
Journal of the National Cancer Institute
Volume
107
Issue
1
Publish Date
2015
Start Page
345
DOI
10.1093/jnci/dju345

Treatment of palmar-plantar erythrodysesthesia (PPE) with topical sildenafil: a pilot study

© 2014, Springer-Verlag Berlin Heidelberg.Purpose: Palmar-plantar erythrodysesthesia (PPE) is a common chemotherapy and anti-VEGF multi-kinase inhibitor class-related toxicity that often results in debilitating skin changes and often limits the use of active anti-cancer regimens. Mechanistic and anecdotal clinical evidence suggested that topical application of sildenafil cream may help reduce the severity of PPE. Therefore, we conducted a randomized, double-blind, placebo-controlled pilot study to evaluate the feasibility, safety and efficacy of topical sildenafil cream for the treatment of PPE. Methods: Eligible subjects were required to have grade 1–3 PPE associated with either capecitabine or sunitinib. Subjects were randomized to receive 1 % topical sildenafil cream to the left extremities or right extremities and placebo cream on the opposite extremity. Two times per day, 0.5 mL of cream was applied to each affected hand/foot. The primary endpoint was improvement in PPE grading at any point on study. Clinical assessments were evaluated by NCI-CTC 4.0 grading and patient self-reported pain. Results: Ten subjects were enrolled, nine were evaluable for safety and efficacy. Five of nine subjects reported some improvement in foot pain and three of eight subjects for hand pain improvement. One of these subjects noted specific improvement in tactile function. No treatment-related toxicities were observed. Conclusions: In this limited, single-center study, topical cream containing 1 % sildenafil is feasible to administer, is well-tolerated, and may mitigate PPE-related symptoms due to anti-cancer therapeutic agents. Further validation is necessary.

Authors
Meadows, KL; Rushing, C; Honeycutt, W; Latta, K; Howard, L; Arrowood, CA; Niedzwiecki, D; Hurwitz, HI
MLA Citation
Meadows, KL, Rushing, C, Honeycutt, W, Latta, K, Howard, L, Arrowood, CA, Niedzwiecki, D, and Hurwitz, HI. "Treatment of palmar-plantar erythrodysesthesia (PPE) with topical sildenafil: a pilot study." Supportive Care in Cancer 23.5 (2015): 1311-1319.
Source
scival
Published In
Supportive Care in Cancer
Volume
23
Issue
5
Publish Date
2015
Start Page
1311
End Page
1319
DOI
10.1007/s00520-014-2465-z

Projecting Event-Based Analysis Dates in Clinical Trials: An Illustration Based on the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) Collaboration. Projecting analysis dates for the IDEA collaboration.

Clinical trials are expensive and lengthy, where success of a given trial depends on observing a prospectively defined number of patient events required to answer the clinical question. The point at which this analysis time occurs depends on both patient accrual and primary event rates, which typically vary throughout the trial's duration. We demonstrate real-time analysis date projections using data from a collection of six clinical trials that are part of the IDEA collaboration, an international preplanned pooling of data from six trials testing the duration of adjuvant chemotherapy in stage III colon cancer, and we additionally consider the hypothetical impact of one trial's early termination of follow-up.In the absence of outcome data from IDEA, monthly accrual rates for each of the six IDEA trials were used to project subsequent trial-specific accrual, while historical data from similar Adjuvant Colon Cancer Endpoints (ACCENT) Group trials were used to construct a parametric model for IDEA's primary endpoint, disease-free survival, under the same treatment regimen. With this information and using the planned total accrual from each IDEA trial protocol, individual patient accrual and event dates were simulated and the overall IDEA interim and final analysis times projected. Projections were then compared with actual (previously undisclosed) trial-specific event totals at a recent census time for validation. The change in projected final analysis date assuming early termination of follow-up for one IDEA trial was also calculated.Trial-specific predicted event totals were close to the actual number of events per trial for the recent census date at which the number of events per trial was known, with the overall IDEA projected number of events only off by eight patients. Potential early termination of follow-up by one IDEA trial was estimated to postpone the overall IDEA final analysis date by 9 months.Real-time projection of the final analysis time during a trial, or the overall analysis time during a trial collaborative such as IDEA, has practical implications for trial feasibility when these projections are translated into additional time and resources required.

Authors
Renfro, LA; Grothey, AM; Paul, J; Floriani, I; Bonnetain, F; Niedzwiecki, D; Yamanaka, T; Souglakos, I; Yothers, G; Sargent, DJ
MLA Citation
Renfro, LA, Grothey, AM, Paul, J, Floriani, I, Bonnetain, F, Niedzwiecki, D, Yamanaka, T, Souglakos, I, Yothers, G, and Sargent, DJ. "Projecting Event-Based Analysis Dates in Clinical Trials: An Illustration Based on the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) Collaboration. Projecting analysis dates for the IDEA collaboration." Forum of clinical oncology 5.2 (December 10, 2014): 1-7.
PMID
26989447
Source
epmc
Published In
Forum of Clinical Oncology
Volume
5
Issue
2
Publish Date
2014
Start Page
1
End Page
7

CpG island methylator phenotype is associated with response to adjuvant irinotecan-based therapy for stage III colon cancer.

The CpG island methylator phenotype (CIMP), defined by a high frequency of aberrantly methylated genes, is a characteristic of a subclass of colon tumors with distinct clinical and molecular features. Cohort studies have produced conflicting results on responses of CIMP-positive tumors to chemotherapy. We assessed the association between tumor CIMP status and survival of patients receiving adjuvant fluorouracil and leucovorin alone or with irinotecan (IFL).We analyzed data from patients with stage III colon adenocarcinoma randomly assigned to groups given fluorouracil and leucovorin or IFL after surgery, from April 1999 through April 2001. The primary end point of the trial was overall survival and the secondary end point was disease-free survival. DNA isolated from available tumor samples (n = 615) was used to determine CIMP status based on methylation patterns at the CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1 loci. The effects of CIMP on survival were modeled using Kaplan-Meier and Cox proportional hazards; interactions with treatment and BRAF, KRAS, and mismatch repair (MMR) status were also investigated.Of the tumor samples characterized for CIMP status, 145 were CIMP positive (23%). Patients with CIMP-positive tumors had shorter overall survival times than patients with CIMP-negative tumors (hazard ratio = 1.36; 95% confidence interval: 1.01-1.84). Treatment with IFL showed a trend toward increased overall survival for patients with CIMP-positive tumors, compared with treatment with fluorouracil and leucovorin (hazard ratio = 0.62; 95% CI: 0.37-1.05; P = .07), but not for patients with CIMP-negative tumors (hazard ratio = 1.38; 95% CI: 1.00-1.89; P = .049). In a 3-way interaction analysis, patients with CIMP-positive, MMR-intact tumors benefited most from the addition of irinotecan to fluorouracil and leucovorin therapy (for the interaction, P = .01). CIMP was more strongly associated with response to IFL than MMR status. Results for disease-free survival times were comparable among all analyses.Patients with stage III, CIMP-positive, MMR-intact colon tumors have longer survival times when irinotecan is added to combination therapy with fluorouracil and leucovorin.

Authors
Shiovitz, S; Bertagnolli, MM; Renfro, LA; Nam, E; Foster, NR; Dzieciatkowski, S; Luo, Y; Lao, VV; Monnat, RJ; Emond, MJ; Maizels, N; Niedzwiecki, D; Goldberg, RM; Saltz, LB; Venook, A; Warren, RS; Grady, WM; Alliance for Clinical Trials in Oncology,
MLA Citation
Shiovitz, S, Bertagnolli, MM, Renfro, LA, Nam, E, Foster, NR, Dzieciatkowski, S, Luo, Y, Lao, VV, Monnat, RJ, Emond, MJ, Maizels, N, Niedzwiecki, D, Goldberg, RM, Saltz, LB, Venook, A, Warren, RS, Grady, WM, and Alliance for Clinical Trials in Oncology, . "CpG island methylator phenotype is associated with response to adjuvant irinotecan-based therapy for stage III colon cancer." Gastroenterology 147.3 (September 2014): 637-645.
PMID
24859205
Source
epmc
Published In
Gastroenterology
Volume
147
Issue
3
Publish Date
2014
Start Page
637
End Page
645
DOI
10.1053/j.gastro.2014.05.009

CpG Island Methylator Phenotype Is Associated With Response to Adjuvant Irinotecan-Based Therapy for Stage III Colon Cancer

Authors
Shiovitz, S; Bertagnolli, MM; Renfro, LA; Nam, E; Foster, NR; Dzieciatkowski, S; Luo, Y; Lao, VV; Monnat, RJ; Emond, MJ; Maizels, N; Niedzwiecki, D; Goldberg, RM; Saltz, LB; Venook, A; Warren, RS; Grady, WM
MLA Citation
Shiovitz, S, Bertagnolli, MM, Renfro, LA, Nam, E, Foster, NR, Dzieciatkowski, S, Luo, Y, Lao, VV, Monnat, RJ, Emond, MJ, Maizels, N, Niedzwiecki, D, Goldberg, RM, Saltz, LB, Venook, A, Warren, RS, and Grady, WM. "CpG Island Methylator Phenotype Is Associated With Response to Adjuvant Irinotecan-Based Therapy for Stage III Colon Cancer." Gastroenterology 147.3 (September 2014): 637-645.
Source
crossref
Published In
Gastroenterology
Volume
147
Issue
3
Publish Date
2014
Start Page
637
End Page
645
DOI
10.1053/j.gastro.2014.05.009

25-Hydroxyvitamin D levels and survival in advanced pancreatic cancer: findings from CALGB 80303 (Alliance).

Data from animal and cell-line models suggest that vitamin D metabolism plays an important role in pancreatic tumor behavior. Although vitamin D deficiency has been implicated in numerous cancers, the vitamin D status of patients with advanced pancreatic cancer and the effect of baseline vitamin D levels on survival are unknown.Participants in this correlative study (CALGB 151006) were enrolled in CALGB 80303, which was a randomized trial of patients with advanced pancreatic cancer that demonstrated no difference in overall survival (OS) among patients treated with gemcitabine plus placebo vs gemcitabine plus bevacizumab. We measured baseline serum 25-hydroxyvitamin D (25[OH]D) levels and examined associations between baseline 25(OH)D levels and progression-free survival and OS using the Cox rank score test. All statistical tests were two-sided.Of 256 patients with available serum, the median 25(OH)D level was 21.7ng/mL (range 4 to 77). 44.5% of patients were vitamin D deficient (25[OH]D <20ng/mL), and 32.4% were insufficient (25[OH]D ≥20 and <30ng/mL). 25(OH)D levels were lower in black patients compared with white patients, and patients of other/undisclosed race (10.7 vs 22.4 vs 20.9ng/mL, P < .001). Baseline 25(OH)D levels were not associated with PFS (HR = 1.00, 95% CI = 0.99 to 1.01, P = .60) or OS (HR = 1.00, 95% CI = 0.99 to 1.01, P = .95).Vitamin D deficiency was highly prevalent among patients with a new diagnosis of advanced pancreatic cancer. Black patients had statistically significantly lower 25(OH)D levels than white patients. In this cohort of patients with advanced pancreatic cancer receiving gemcitabine-based chemotherapy, baseline 25(OH)D levels were not associated with PFS or OS.

Authors
Van Loon, K; Owzar, K; Jiang, C; Kindler, HL; Mulcahy, MF; Niedzwiecki, D; O'Reilly, EM; Fuchs, C; Innocenti, F; Venook, AP; Alliance for Clinical Trials in Oncology,
MLA Citation
Van Loon, K, Owzar, K, Jiang, C, Kindler, HL, Mulcahy, MF, Niedzwiecki, D, O'Reilly, EM, Fuchs, C, Innocenti, F, Venook, AP, and Alliance for Clinical Trials in Oncology, . "25-Hydroxyvitamin D levels and survival in advanced pancreatic cancer: findings from CALGB 80303 (Alliance)." Journal of the National Cancer Institute 106.8 (August 6, 2014).
PMID
25099612
Source
epmc
Published In
Journal of the National Cancer Institute
Volume
106
Issue
8
Publish Date
2014
DOI
10.1093/jnci/dju185

CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC).

Authors
Venook, AP; Niedzwiecki, D; Lenz, H-J; Innocenti, F; Mahoney, MR; O'Neil, BH; Shaw, JE; Polite, BN; Hochster, HS; Atkins, JN; Goldberg, RM; Mayer, RJ; Schilsky, RL; Bertagnolli, MM; David, C; Blanke, CD; Alliance, CLGB; SWOG, ; ECOG,
MLA Citation
Venook, AP, Niedzwiecki, D, Lenz, H-J, Innocenti, F, Mahoney, MR, O'Neil, BH, Shaw, JE, Polite, BN, Hochster, HS, Atkins, JN, Goldberg, RM, Mayer, RJ, Schilsky, RL, Bertagnolli, MM, David, C, Blanke, CD, Alliance, CLGB, SWOG, , and ECOG, . "CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC)." JOURNAL OF CLINICAL ONCOLOGY 32.18 (June 20, 2014).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
32
Issue
18
Publish Date
2014

Prognostic and predictive blood-based biomarkers of overall survival (OS) in patients (pts) with advanced colorectal cancer (CRC) treated with cetuximab (C): Results from CALGB 80203 (Alliance).

Authors
Hatch, AJ; Pang, H; Starr, MD; Brady, JC; Jia, J; Jiang, C; Sibley, A; Owzar, K; Niedzwiecki, D; Venook, AP; Cushman, SM; Hurwitz, H; Nixon, AB
MLA Citation
Hatch, AJ, Pang, H, Starr, MD, Brady, JC, Jia, J, Jiang, C, Sibley, A, Owzar, K, Niedzwiecki, D, Venook, AP, Cushman, SM, Hurwitz, H, and Nixon, AB. "Prognostic and predictive blood-based biomarkers of overall survival (OS) in patients (pts) with advanced colorectal cancer (CRC) treated with cetuximab (C): Results from CALGB 80203 (Alliance)." May 20, 2014.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
32
Issue
15
Publish Date
2014

CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (RV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC).

Authors
Venook, AP; Niedzwiecki, D; Lenz, H-J; Innocenti, F; Mahoney, MR; O'Neil, BH; Shaw, JE; Polite, BN; Hochster, HS; Atkins, JN; Goldberg, RM; Mayer, RJ; Schilsky, RL; Bertagnolli, MM; Blanke, CD; Alliance, CLGB; SWOG, ; ECOG,
MLA Citation
Venook, AP, Niedzwiecki, D, Lenz, H-J, Innocenti, F, Mahoney, MR, O'Neil, BH, Shaw, JE, Polite, BN, Hochster, HS, Atkins, JN, Goldberg, RM, Mayer, RJ, Schilsky, RL, Bertagnolli, MM, Blanke, CD, Alliance, CLGB, SWOG, , and ECOG, . "CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (RV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC)." May 20, 2014.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
32
Issue
15
Publish Date
2014

A novel reduced-intensity conditioning regimen for unrelated umbilical cord blood transplantation in children with nonmalignant diseases

Reduced-intensity conditioning (RIC) regimens have the potential to decrease transplantation-related morbidity and mortality. However, engraftment failure has been prohibitively high after RIC unrelated umbilical cord blood transplantation (UCBT) in chemotherapy-naïve children with nonmalignant diseases (NMD). Twenty-two children with a median age of 2.8years, many with severe comorbidities and prior viral infections, were enrolled in a novel RIC protocol consisting of hydroxyurea, alemtuzumab, fludarabine, melphalan, and thiotepa followed by single UCBT. Patients underwent transplantation for inherited metabolic disorders (n=8), primary immunodeficiencies (n=9), hemoglobinopathies (n=4) and Diamond Blackfan anemia (n=1). Most umbilical cord blood (UCB) units were HLA-mismatched with median infused total nucleated cell dose of 7.9× 10 7 /kg. No serious organ toxicities were attributable to the regimen. The cumulative incidence of neutrophil engraftment was 86.4% (95% confidence interval [CI], 65% to 100%) in a median of 20days, with the majority sustaining > 95% donor chimerism at 1year. Cumulative incidence of acute graft-versus-host disease (GVHD) grades II to IV and III to IV by day 180 was 27.3% (95% CI, 8.7% to 45.9%) and 13.6% (95 CI, 0% to 27.6%), respectively. Cumulative incidence of extensive chronic GVHD was 9.1% (95% CI, 0% to 20.8%). The primary causes of death were viral infections (n=3), acute GVHD (n=1) and transfusion reaction (n=1). One-year overall and event-free survivals were 77.3% (95% CI, 53.7% to 89.8%) and 68.2% (95% CI, 44.6% to 83.4%) with 31months median follow-up. This is the first RIC protocol demonstrating durable UCB engraftment in children with NMD. Future risk-based modifications of this regimen could decrease the incidence of viral infections. (www.clinicaltrials.gov/NCT00744692). © 2014 American Society for Blood and Marrow Transplantation.

Authors
Parikh, SH; Mendizabal, A; Benjamin, CL; Komanduri, KV; Antony, J; Petrovic, A; Hale, G; Driscoll, TA; Martin, PL; Page, KM; Flickinger, K; Moffet, J; Niedzwiecki, D; Kurtzberg, J; Szabolcs, P
MLA Citation
Parikh, SH, Mendizabal, A, Benjamin, CL, Komanduri, KV, Antony, J, Petrovic, A, Hale, G, Driscoll, TA, Martin, PL, Page, KM, Flickinger, K, Moffet, J, Niedzwiecki, D, Kurtzberg, J, and Szabolcs, P. "A novel reduced-intensity conditioning regimen for unrelated umbilical cord blood transplantation in children with nonmalignant diseases." Biology of Blood and Marrow Transplantation 20.3 (March 1, 2014): 326-336.
Source
scopus
Published In
Biology of Blood and Marrow Transplantation
Volume
20
Issue
3
Publish Date
2014
Start Page
326
End Page
336
DOI
10.1016/j.bbmt.2013.11.021

A novel reduced-intensity conditioning regimen for unrelated umbilical cord blood transplantation in children with nonmalignant diseases.

Reduced-intensity conditioning (RIC) regimens have the potential to decrease transplantation-related morbidity and mortality. However, engraftment failure has been prohibitively high after RIC unrelated umbilical cord blood transplantation (UCBT) in chemotherapy-naïve children with nonmalignant diseases (NMD). Twenty-two children with a median age of 2.8 years, many with severe comorbidities and prior viral infections, were enrolled in a novel RIC protocol consisting of hydroxyurea, alemtuzumab, fludarabine, melphalan, and thiotepa followed by single UCBT. Patients underwent transplantation for inherited metabolic disorders (n = 8), primary immunodeficiencies (n = 9), hemoglobinopathies (n = 4) and Diamond Blackfan anemia (n = 1). Most umbilical cord blood (UCB) units were HLA-mismatched with median infused total nucleated cell dose of 7.9 × 10(7)/kg. No serious organ toxicities were attributable to the regimen. The cumulative incidence of neutrophil engraftment was 86.4% (95% confidence interval [CI], 65% to 100%) in a median of 20 days, with the majority sustaining > 95% donor chimerism at 1 year. Cumulative incidence of acute graft-versus-host disease (GVHD) grades II to IV and III to IV by day 180 was 27.3% (95% CI, 8.7% to 45.9%) and 13.6% (95 CI, 0% to 27.6%), respectively. Cumulative incidence of extensive chronic GVHD was 9.1% (95% CI, 0% to 20.8%). The primary causes of death were viral infections (n = 3), acute GVHD (n = 1) and transfusion reaction (n = 1). One-year overall and event-free survivals were 77.3% (95% CI, 53.7% to 89.8%) and 68.2% (95% CI, 44.6% to 83.4%) with 31 months median follow-up. This is the first RIC protocol demonstrating durable UCB engraftment in children with NMD. Future risk-based modifications of this regimen could decrease the incidence of viral infections. (www.clinicaltrials.gov/NCT00744692).

Authors
Parikh, SH; Mendizabal, A; Benjamin, CL; Komanduri, KV; Antony, J; Petrovic, A; Hale, G; Driscoll, TA; Martin, PL; Page, KM; Flickinger, K; Moffet, J; Niedzwiecki, D; Kurtzberg, J; Szabolcs, P
MLA Citation
Parikh, SH, Mendizabal, A, Benjamin, CL, Komanduri, KV, Antony, J, Petrovic, A, Hale, G, Driscoll, TA, Martin, PL, Page, KM, Flickinger, K, Moffet, J, Niedzwiecki, D, Kurtzberg, J, and Szabolcs, P. "A novel reduced-intensity conditioning regimen for unrelated umbilical cord blood transplantation in children with nonmalignant diseases." Biol Blood Marrow Transplant 20.3 (March 2014): 326-336.
PMID
24296492
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
20
Issue
3
Publish Date
2014
Start Page
326
End Page
336
DOI
10.1016/j.bbmt.2013.11.021

Prognostic and predictive blood-based biomarkers of overall survival (OS) in patients (pts) with advanced colorectal cancer (CRC) treated with cetuximab (C): Results from CALGB 80203 (Alliance)

Authors
Hatch, AJ; Pang, H; Starr, MD; Brady, JC; Jia, J; Niedzwiecki, D; Venook, AP; Cushman, SM; Hurwitz, H; Nixon, AB
MLA Citation
Hatch, AJ, Pang, H, Starr, MD, Brady, JC, Jia, J, Niedzwiecki, D, Venook, AP, Cushman, SM, Hurwitz, H, and Nixon, AB. "Prognostic and predictive blood-based biomarkers of overall survival (OS) in patients (pts) with advanced colorectal cancer (CRC) treated with cetuximab (C): Results from CALGB 80203 (Alliance)." January 20, 2014.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
32
Issue
3
Publish Date
2014

Association between ColDx assay result and recurrence-free interval in stage II colon cancer patients on CALGB (Alliance) 9581

Authors
Niedzwiecki, D; Frankel, W; Venook, AP; Ye, X; Friedman, PN; Goldberg, RM; Mayer, RJ; Colacchio, TA; Kennedy, RD; Davison, T; O'Brien, EJ; Mulligan, J; Johnston, PG; Harkin, DP; Schilsky, RL; Bertagnolli, MM; Innocenti, F
MLA Citation
Niedzwiecki, D, Frankel, W, Venook, AP, Ye, X, Friedman, PN, Goldberg, RM, Mayer, RJ, Colacchio, TA, Kennedy, RD, Davison, T, O'Brien, EJ, Mulligan, J, Johnston, PG, Harkin, DP, Schilsky, RL, Bertagnolli, MM, and Innocenti, F. "Association between ColDx assay result and recurrence-free interval in stage II colon cancer patients on CALGB (Alliance) 9581." January 20, 2014.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
32
Issue
3
Publish Date
2014

Sugar-sweetened beverage intake and cancer recurrence and survival in CALGB 89803 (Alliance).

In colon cancer patients, obesity, sedentary lifestyle, and high dietary glycemic load have been associated with increased risk of cancer recurrence. High sugar-sweetened beverage intake has been associated with obesity, diabetes, and cardio-metabolic diseases, but the influence on colon cancer survival is unknown.We assessed the association between sugar-sweetened beverage consumption on cancer recurrence and mortality in 1,011 stage III colon cancer patients who completed food frequency questionnaires as part of a U.S. National Cancer Institute-sponsored adjuvant chemotherapy trial. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated with Cox proportional hazard models.Patients consuming ≥ 2 servings of sugar-sweetened beverages per day experienced an adjusted HR for disease recurrence or mortality of 1.67 (95% CI, 1.04-2.68), compared with those consuming <2 servings per month (P(trend) = 0.02). The association of sugar-sweetened beverages on cancer recurrence or mortality appeared greater among patients who were both overweight (body mass index ≥ 2 5 kg/m(2)) and less physically active (metabolic equivalent task-hours per week <18) (HR = 2.22; 95% CI, 1.29-3.81, P(trend) = 0.0025).Higher sugar-sweetened beverage intake was associated with a significantly increased risk of cancer recurrence and mortality in stage III colon cancer patients.

Authors
Fuchs, MA; Sato, K; Niedzwiecki, D; Ye, X; Saltz, LB; Mayer, RJ; Mowat, RB; Whittom, R; Hantel, A; Benson, A; Atienza, D; Messino, M; Kindler, H; Venook, A; Ogino, S; Wu, K; Willett, WC; Giovannucci, EL; Meyerhardt, JA
MLA Citation
Fuchs, MA, Sato, K, Niedzwiecki, D, Ye, X, Saltz, LB, Mayer, RJ, Mowat, RB, Whittom, R, Hantel, A, Benson, A, Atienza, D, Messino, M, Kindler, H, Venook, A, Ogino, S, Wu, K, Willett, WC, Giovannucci, EL, and Meyerhardt, JA. "Sugar-sweetened beverage intake and cancer recurrence and survival in CALGB 89803 (Alliance)." PloS one 9.6 (January 2014): e99816-.
PMID
24937507
Source
epmc
Published In
PloS one
Volume
9
Issue
6
Publish Date
2014
Start Page
e99816
DOI
10.1371/journal.pone.0099816

MRE11-deficiency associated with improved long-term disease free survival and overall survival in a subset of stage III colon cancer patients in randomized CALGB 89803 trial.

Colon cancers deficient in mismatch repair (MMR) may exhibit diminished expression of the DNA repair gene, MRE11, as a consequence of contraction of a T11 mononucleotide tract. This study investigated MRE11 status and its association with prognosis, survival and drug response in patients with stage III colon cancer.Cancer and Leukemia Group B 89803 (Alliance) randomly assigned 1,264 patients with stage III colon cancer to postoperative weekly adjuvant bolus 5-fluorouracil/leucovorin (FU/LV) or irinotecan+FU/LV (IFL), with 8 year follow-up. Tumors from these patients were analyzed to determine stability of a T11 tract in the MRE11 gene. The primary endpoint was overall survival (OS), and a secondary endpoint was disease-free survival (DFS). Non-proportional hazards were addressed using time-dependent covariates in Cox analyses.Of 625 tumor cases examined, 70 (11.2%) exhibited contraction at the T11 tract in one or both MRE11 alleles and were thus predicted to be deficient in MRE11 (dMRE11). In pooled treatment analyses, dMRE11 patients showed initially reduced DFS and OS but improved long-term DFS and OS compared with patients with an intact MRE11 T11 tract. In the subgroup of dMRE11 patients treated with IFL, an unexplained early increase in mortality but better long-term DFS than IFL-treated pMRE11 patients was observed.Analysis of this relatively small number of patients and events showed that the dMRE11 marker predicts better prognosis independent of treatment in the long-term. In subgroup analyses, dMRE11 patients treated with irinotecan exhibited unexplained short-term mortality. MRE11 status is readily assayed and may therefore prove to be a useful prognostic marker, provided that the results reported here for a relatively small number of patients can be generalized in independent analyses of larger numbers of samples.ClinicalTrials.gov NCT00003835.

Authors
Pavelitz, T; Renfro, L; Foster, NR; Caracol, A; Welsch, P; Lao, VV; Grady, WB; Niedzwiecki, D; Saltz, LB; Bertagnolli, MM; Goldberg, RM; Rabinovitch, PS; Emond, M; Monnat, RJ; Maizels, N
MLA Citation
Pavelitz, T, Renfro, L, Foster, NR, Caracol, A, Welsch, P, Lao, VV, Grady, WB, Niedzwiecki, D, Saltz, LB, Bertagnolli, MM, Goldberg, RM, Rabinovitch, PS, Emond, M, Monnat, RJ, and Maizels, N. "MRE11-deficiency associated with improved long-term disease free survival and overall survival in a subset of stage III colon cancer patients in randomized CALGB 89803 trial." PloS one 9.10 (January 2014): e108483-.
PMID
25310185
Source
epmc
Published In
PloS one
Volume
9
Issue
10
Publish Date
2014
Start Page
e108483
DOI
10.1371/journal.pone.0108483

A novel reduced-intensity conditioning regimen for unrelated umbilical cord blood transplantation in children with nonmalignant diseases

Authors
Parikh, SH; Mendizabal, A; Benjamin, CL; Komanduri, KV; Antony, J; Petrovic, A; Hale, G; Driscoll, TA; Martin, PL; Page, KM; Flickinger, K; Moffet, J; Niedzwiecki, D; Kurtzberg, J; Szabolcs, P
MLA Citation
Parikh, SH, Mendizabal, A, Benjamin, CL, Komanduri, KV, Antony, J, Petrovic, A, Hale, G, Driscoll, TA, Martin, PL, Page, KM, Flickinger, K, Moffet, J, Niedzwiecki, D, Kurtzberg, J, and Szabolcs, P. "A novel reduced-intensity conditioning regimen for unrelated umbilical cord blood transplantation in children with nonmalignant diseases." Biology of Blood and Marrow Transplantation 20.3 (2014): 326-336.
Source
scopus
Published In
Biology of Blood and Marrow Transplantation
Volume
20
Issue
3
Publish Date
2014
Start Page
326
End Page
336

Predictive and prognostic analysis of PIK3CA mutation in stage III colon cancer intergroup trial.

BACKGROUND: Somatic mutations in PIK3CA (phosphatidylinositol-4,5-bisphosphonate 3-kinase [PI3K], catalytic subunit alpha gene) activate the PI3K-AKT signaling pathway and contribute to pathogenesis of various malignancies, including colorectal cancer. METHODS: We examined associations of PIK3CA oncogene mutation with relapse, survival, and treatment efficacy in 627 stage III colon carcinoma case subjects within a randomized adjuvant chemotherapy trial (5-fluorouracil and leucovorin [FU/LV] vs irinotecan [CPT11], fluorouracil and leucovorin [IFL]; Cancer and Leukemia Group B 89803 [Alliance]). We detected PIK3CA mutation in exons 9 and 20 by polymerase chain reaction and pyrosequencing. Cox proportional hazards model was used to assess prognostic and predictive role of PIK3CA mutation, adjusting for clinical features and status of routine standard molecular pathology features, including KRAS and BRAF mutations and microsatellite instability (mismatch repair deficiency). All statistical tests were two-sided. RESULTS: Compared with PIK3CA wild-type cases, overall status of PIK3CA mutation positivity or the presence of PIK3CA mutation in either exon 9 or 20 alone was not statistically significantly associated with recurrence-free, disease-free, or overall survival (log-rank P > .70; P > .40 in multivariable regression models). There was no statistically significant interaction between PIK3CA and KRAS (or BRAF) mutation status in survival analysis (P(interaction) > .18). PIK3CA mutation status did not appear to predict better or worse response to IFL therapy compared with FU/LV therapy (P(interaction) > .16). CONCLUSIONS: Overall tumor PIK3CA mutation status is not associated with stage III colon cancer prognosis. PIK3CA mutation does not appear to serve as a predictive tumor molecular biomarker for response to irinotecan-based adjuvant chemotherapy.

Authors
Ogino, S; Liao, X; Imamura, Y; Yamauchi, M; McCleary, NJ; Ng, K; Niedzwiecki, D; Saltz, LB; Mayer, RJ; Whittom, R; Hantel, A; Benson, AB; Mowat, RB; Spiegelman, D; Goldberg, RM; Bertagnolli, MM; Meyerhardt, JA; Fuchs, CS; Alliance for Clinical Trials in Oncology,
MLA Citation
Ogino, S, Liao, X, Imamura, Y, Yamauchi, M, McCleary, NJ, Ng, K, Niedzwiecki, D, Saltz, LB, Mayer, RJ, Whittom, R, Hantel, A, Benson, AB, Mowat, RB, Spiegelman, D, Goldberg, RM, Bertagnolli, MM, Meyerhardt, JA, Fuchs, CS, and Alliance for Clinical Trials in Oncology, . "Predictive and prognostic analysis of PIK3CA mutation in stage III colon cancer intergroup trial." J Natl Cancer Inst 105.23 (December 4, 2013): 1789-1798.
PMID
24231454
Source
pubmed
Published In
Journal of the National Cancer Institute
Volume
105
Issue
23
Publish Date
2013
Start Page
1789
End Page
1798
DOI
10.1093/jnci/djt298

A randomized phase II study of immunization with dendritic cells modified with poxvectors encoding CEA and MUC1 compared with the same poxvectors plus GM-CSF for resected metastatic colorectal cancer

OBJECTIVE:: To determine whether 1 of 2 vaccines based on dendritic cells (DCs) and poxvectors encoding CEA (carcinoembryonic antigen) and MUC1 (PANVAC) would lengthen survival in patients with resected metastases of colorectal cancer (CRC). BACKGROUND:: Recurrences after complete resections of metastatic CRC remain frequent. Immune responses to CRC are associated with fewer recurrences, suggesting a role for cancer vaccines as adjuvant therapy. Both DCs and poxvectors are potent stimulators of immune responses against cancer antigens. METHODS:: Patients, disease-free after CRC metastasectomy and perioperative chemotherapy (n = 74), were randomized to injections of autologous DCs modified with PANVAC (DC/PANVAC) or PANVAC with per injection GM-CSF (granulocyte-macrophage colony-stimulating factor). Endpoints were recurrence-free survival overall survival, and rate of CEA-specific immune responses. Clinical outcome was compared with that of an unvaccinated, contemporary group of patients who had undergone CRC metastasectomy, received similar perioperative therapy, and would have otherwise been eligible for the study. RESULTS:: Recurrence-free survival at 2 years was similar (47% and 55% for DC/PANVAC and PANVAC/GM-CSF, respectively) (χ P = 0.48). At a median follow-up of 35.7 months, there were 2 of 37 deaths in the DC/PANVAC arm and 5 of 37 deaths in the PANVAC/GM-CSF arm. The rate and magnitude of T-cell responses against CEA was statistically similar between study arms. As a group, vaccinated patients had superior survival compared with the contemporary unvaccinated group. CONCLUSIONS:: Both DC and poxvector vaccines have similar activity. Survival was longer for vaccinated patients than for a contemporary unvaccinated group, suggesting that a randomized trial of poxvector vaccinations compared with standard follow-up after metastasectomy is warranted. © 2013 Lippincott Williams and Wilkins.

Authors
Morse, MA; Niedzwiecki, D; Marshall, JL; Garrett, C; Chang, DZ; Aklilu, M; Crocenzi, TS; Cole, DJ; Dessureault, S; Hobeika, AC; Osada, T; Onaitis, M; Clary, BM; Hsu, D; Devi, GR; Bulusu, A; Annechiarico, RP; Chadaram, V; Clay, TM; Lyerly, HK
MLA Citation
Morse, MA, Niedzwiecki, D, Marshall, JL, Garrett, C, Chang, DZ, Aklilu, M, Crocenzi, TS, Cole, DJ, Dessureault, S, Hobeika, AC, Osada, T, Onaitis, M, Clary, BM, Hsu, D, Devi, GR, Bulusu, A, Annechiarico, RP, Chadaram, V, Clay, TM, and Lyerly, HK. "A randomized phase II study of immunization with dendritic cells modified with poxvectors encoding CEA and MUC1 compared with the same poxvectors plus GM-CSF for resected metastatic colorectal cancer." Annals of Surgery 258.6 (December 1, 2013): 879-886.
Source
scopus
Published In
Annals of Surgery
Volume
258
Issue
6
Publish Date
2013
Start Page
879
End Page
886
DOI
10.1097/SLA.0b013e318292919e

Impact of physical activity after cancer diagnosis on survival in patients with recurrent colon cancer: Findings from CALGB 89803/alliance

Background The impact of physical activity on survival outcomes in patients with recurrent colon cancer has not been studied. We tested the association between the level of postdiagnosis physical activity and survival outcomes of patients with recurrent colon cancer. Patients and Methods We conducted a prospective observational study of 237 patients with stage III colon cancer who had recurrence of disease. Physical activity was measured approximately 6 months after the completion of therapy (14 months after surgical resection) but before detection of recurrent disease. The primary end point of the study was survival time after recurrence. Results The hazard ratio comparing patients who reported at least 18 metabolic equivalent task (MET) hours per week of physical activity with those engaging in < 3 MET hours per week was 0.71 (95% confidence interval, 0.46-1.11). Increasing total MET hours of physical activity per week was associated with a borderline statistical significance trend for improved survival after recurrence (P =.052). The benefit of physical activity on survival was not significantly modified by sex, body mass index (BMI), number of positive lymph nodes, age, baseline performance status, adjuvant chemotherapy regimen, or recurrence-free survival period. Conclusion To our knowledge, this is the first study investigating the association of physical activity with survival outcome of patients with recurrent colon cancer. Although the association exceeded our predefined P trend < .05 for statistical significance, these findings warrant further studies of physical activity in patients with recurrent colorectal cancer. © 2013 Elsevier Inc. All rights reserved.

Authors
Jeon, J; Sato, K; Niedzwiecki, D; Ye, X; Saltz, LB; Mayer, RJ; Mowat, RB; Whittom, R; Hantel, A; Benson, A; Wigler, DS; Atienza, D; Messino, M; Kindler, H; Venook, A; Fuchs, CS; Meyerhardt, JA
MLA Citation
Jeon, J, Sato, K, Niedzwiecki, D, Ye, X, Saltz, LB, Mayer, RJ, Mowat, RB, Whittom, R, Hantel, A, Benson, A, Wigler, DS, Atienza, D, Messino, M, Kindler, H, Venook, A, Fuchs, CS, and Meyerhardt, JA. "Impact of physical activity after cancer diagnosis on survival in patients with recurrent colon cancer: Findings from CALGB 89803/alliance." Clinical Colorectal Cancer 12.4 (December 1, 2013): 233-238.
Source
scopus
Published In
Clinical colorectal cancer
Volume
12
Issue
4
Publish Date
2013
Start Page
233
End Page
238
DOI
10.1016/j.clcc.2013.06.005

A randomized phase II study of immunization with dendritic cells modified with poxvectors encoding CEA and MUC1 compared with the same poxvectors plus GM-CSF for resected metastatic colorectal cancer.

OBJECTIVE: To determine whether 1 of 2 vaccines based on dendritic cells (DCs) and poxvectors encoding CEA (carcinoembryonic antigen) and MUC1 (PANVAC) would lengthen survival in patients with resected metastases of colorectal cancer (CRC). BACKGROUND: Recurrences after complete resections of metastatic CRC remain frequent. Immune responses to CRC are associated with fewer recurrences, suggesting a role for cancer vaccines as adjuvant therapy. Both DCs and poxvectors are potent stimulators of immune responses against cancer antigens. METHODS: Patients, disease-free after CRC metastasectomy and perioperative chemotherapy (n = 74), were randomized to injections of autologous DCs modified with PANVAC (DC/PANVAC) or PANVAC with per injection GM-CSF (granulocyte-macrophage colony-stimulating factor). Endpoints were recurrence-free survival overall survival, and rate of CEA-specific immune responses. Clinical outcome was compared with that of an unvaccinated, contemporary group of patients who had undergone CRC metastasectomy, received similar perioperative therapy, and would have otherwise been eligible for the study. RESULTS: Recurrence-free survival at 2 years was similar (47% and 55% for DC/PANVAC and PANVAC/GM-CSF, respectively) (χ P = 0.48). At a median follow-up of 35.7 months, there were 2 of 37 deaths in the DC/PANVAC arm and 5 of 37 deaths in the PANVAC/GM-CSF arm. The rate and magnitude of T-cell responses against CEA was statistically similar between study arms. As a group, vaccinated patients had superior survival compared with the contemporary unvaccinated group. CONCLUSIONS: Both DC and poxvector vaccines have similar activity. Survival was longer for vaccinated patients than for a contemporary unvaccinated group, suggesting that a randomized trial of poxvector vaccinations compared with standard follow-up after metastasectomy is warranted. (NCT00103142).

Authors
Morse, MA; Niedzwiecki, D; Marshall, JL; Garrett, C; Chang, DZ; Aklilu, M; Crocenzi, TS; Cole, DJ; Dessureault, S; Hobeika, AC; Osada, T; Onaitis, M; Clary, BM; Hsu, D; Devi, GR; Bulusu, A; Annechiarico, RP; Chadaram, V; Clay, TM; Lyerly, HK
MLA Citation
Morse, MA, Niedzwiecki, D, Marshall, JL, Garrett, C, Chang, DZ, Aklilu, M, Crocenzi, TS, Cole, DJ, Dessureault, S, Hobeika, AC, Osada, T, Onaitis, M, Clary, BM, Hsu, D, Devi, GR, Bulusu, A, Annechiarico, RP, Chadaram, V, Clay, TM, and Lyerly, HK. "A randomized phase II study of immunization with dendritic cells modified with poxvectors encoding CEA and MUC1 compared with the same poxvectors plus GM-CSF for resected metastatic colorectal cancer." Ann Surg 258.6 (December 2013): 879-886.
PMID
23657083
Source
pubmed
Published In
Annals of Surgery
Volume
258
Issue
6
Publish Date
2013
Start Page
879
End Page
886
DOI
10.1097/SLA.0b013e318292919e

Association of TP53 mutational status and gender with survival after adjuvant treatment for stage III colon cancer: results of CALGB 89803.

PURPOSE: The TP53 tumor suppressor is frequently mutated in colon cancer, but the influence of such mutations on survival remains controversial. We investigated whether mutations in the DNA-binding domain of TP53 are associated with survival in stage III colon cancer. EXPERIMENTAL DESIGN: The impact of TP53 genotype was prospectively evaluated in Cancer and Leukemia Group B 89803, a trial that randomized stage III colon cancer patients to receive adjuvant 5-fluorouracil/leucovorin (5FU/LV) or 5FU/LV with irinotecan (IFL). RESULTS: TP53 mutations were identified in 274 of 607 cases. The presence of any TP53 mutation did not predict disease-free survival (DFS) or overall survival with either adjuvant regimen when men and women were considered together or as separate groups. However, outcome differences among women became apparent when tumor TP53 genotype was stratified as wild-type versus zinc- or non-zinc-binding mutations in the TP53 DNA-binding domain. DFS at 5 years was 0.59, 0.52, and 0.78 for women with TP53 wild-type tumors, and tumors with zinc- or non-zinc-binding mutations, respectively. Survival at 5 years for these same women was 0.72, 0.59, and 0.90, respectively. No differences in survival by TP53 genotype were observed in men. CONCLUSIONS: The presence of any TP53 mutation within the DNA-binding domain did not predict survival in stage III colon cancer. However, TP53 genotype was predictive of survival in women following adjuvant therapy. Future colon cancer therapeutic trials, with inclusion of correlative molecular markers, should be designed to permit evaluation of survival and/or response to treatment in women separately from men.

Authors
Warren, RS; Atreya, CE; Niedzwiecki, D; Weinberg, VK; Donner, DB; Mayer, RJ; Goldberg, RM; Compton, CC; Zuraek, MB; Ye, C; Saltz, LB; Bertagnolli, MM
MLA Citation
Warren, RS, Atreya, CE, Niedzwiecki, D, Weinberg, VK, Donner, DB, Mayer, RJ, Goldberg, RM, Compton, CC, Zuraek, MB, Ye, C, Saltz, LB, and Bertagnolli, MM. "Association of TP53 mutational status and gender with survival after adjuvant treatment for stage III colon cancer: results of CALGB 89803." Clin Cancer Res 19.20 (October 15, 2013): 5777-5787.
PMID
23983256
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
19
Issue
20
Publish Date
2013
Start Page
5777
End Page
5787
DOI
10.1158/1078-0432.CCR-13-0351

Comparison of Dietary. and Lifestyle Habits Among Stage III and Metastatic Colorectal Cancer Patients: Findings from CALGB 89803 and CALGB 80405

Authors
Van Loon, K; Wigler, D; Niedzwiecki, D; Venook, AP; Fuchs, C; Blanke, C; Saltz, L; Goldberg, RM; Meyerhardt, JA
MLA Citation
Van Loon, K, Wigler, D, Niedzwiecki, D, Venook, AP, Fuchs, C, Blanke, C, Saltz, L, Goldberg, RM, and Meyerhardt, JA. "Comparison of Dietary. and Lifestyle Habits Among Stage III and Metastatic Colorectal Cancer Patients: Findings from CALGB 89803 and CALGB 80405." CLINICAL COLORECTAL CANCER 12.2 (June 2013): 95-102.
PMID
23317558
Source
wos-lite
Published In
Clinical colorectal cancer
Volume
12
Issue
2
Publish Date
2013
Start Page
95
End Page
102
DOI
10.1016/j.clcc.2012.11.002

Tumor markers of efficacy and resistance to cetuximab (C) treatment in metastatic colorectal cancer (mCRC): Results from CALGB 80203 (Alliance)

Authors
Hurwitz, H; Cushman, S; Jiang, C; Shterev, I; Mahoney, MR; Niedzwiecki, D; Mayer, RJ; Venook, AP; Owzar, K; Nixon, AB; Oncology, ACT
MLA Citation
Hurwitz, H, Cushman, S, Jiang, C, Shterev, I, Mahoney, MR, Niedzwiecki, D, Mayer, RJ, Venook, AP, Owzar, K, Nixon, AB, and Oncology, ACT. "Tumor markers of efficacy and resistance to cetuximab (C) treatment in metastatic colorectal cancer (mCRC): Results from CALGB 80203 (Alliance)." May 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

25-hydroxyvitamin D levels and survival in patients with advanced pancreatic cancer (APC): Findings from CALGB 80303

Authors
Van Loon, K; Owzar, K; Jiang, C; Kindler, HL; Mulcahy, MF; Niedzwiecki, D; O'Reilly, EM; Fuchs, CS; Innocenti, F; Venook, AP
MLA Citation
Van Loon, K, Owzar, K, Jiang, C, Kindler, HL, Mulcahy, MF, Niedzwiecki, D, O'Reilly, EM, Fuchs, CS, Innocenti, F, and Venook, AP. "25-hydroxyvitamin D levels and survival in patients with advanced pancreatic cancer (APC): Findings from CALGB 80303." May 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

Quality of life (QOL) and toxicity among patients in CALGB 80405

Authors
Naughton, MJ; Schrag, D; Venook, AP; Niedzwiecki, D; Anderson, RT; Lenz, H-J; Grubbs, SS
MLA Citation
Naughton, MJ, Schrag, D, Venook, AP, Niedzwiecki, D, Anderson, RT, Lenz, H-J, and Grubbs, SS. "Quality of life (QOL) and toxicity among patients in CALGB 80405." May 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

Biologic determinants of tumor recurrence in stage II colon cancer: validation study of the 12-gene recurrence score in cancer and leukemia group B (CALGB) 9581.

PURPOSE: A greater understanding of the biology of tumor recurrence should improve adjuvant treatment decision making. We conducted a validation study of the 12-gene recurrence score (RS), a quantitative assay integrating stromal response and cell cycle gene expression, in tumor specimens from patients enrolled onto Cancer and Leukemia Group B (CALGB) 9581. PATIENTS AND METHODS: CALGB 9581 randomly assigned 1,713 patients with stage II colon cancer to treatment with edrecolomab or observation and found no survival difference. The analysis reported here included all patients with available tissue and recurrence (n = 162) and a random (approximately 1:3) selection of nonrecurring patients. RS was assessed in 690 formalin-fixed paraffin-embedded tumor samples with quantitative reverse transcriptase polymerase chain reaction by using prespecified genes and a previously validated algorithm. Association of RS and recurrence was analyzed by weighted Cox proportional hazards regression. RESULTS: Continuous RS was significantly associated with risk of recurrence (P = .013) as was mismatch repair (MMR) gene deficiency (P = .044). In multivariate analyses, RS was the strongest predictor of recurrence (P = .004), independent of T stage, MMR, number of nodes examined, grade, and lymphovascular invasion. In T3 MMR-intact (MMR-I) patients, prespecified low and high RS groups had average 5-year recurrence risks of 13% (95% CI, 10% to 16%) and 21% (95% CI, 16% to 26%), respectively. CONCLUSION: The 12-gene RS predicts recurrence in stage II colon cancer in CALGB 9581. This is consistent with the importance of stromal response and cell cycle gene expression in colon tumor recurrence. RS appears to be most discerning for patients with T3 MMR-I tumors, although markers such as grade and lymphovascular invasion did not add value in this subset of patients.

Authors
Venook, AP; Niedzwiecki, D; Lopatin, M; Ye, X; Lee, M; Friedman, PN; Frankel, W; Clark-Langone, K; Millward, C; Shak, S; Goldberg, RM; Mahmoud, NN; Warren, RS; Schilsky, RL; Bertagnolli, MM
MLA Citation
Venook, AP, Niedzwiecki, D, Lopatin, M, Ye, X, Lee, M, Friedman, PN, Frankel, W, Clark-Langone, K, Millward, C, Shak, S, Goldberg, RM, Mahmoud, NN, Warren, RS, Schilsky, RL, and Bertagnolli, MM. "Biologic determinants of tumor recurrence in stage II colon cancer: validation study of the 12-gene recurrence score in cancer and leukemia group B (CALGB) 9581." J Clin Oncol 31.14 (May 10, 2013): 1775-1781.
PMID
23530100
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
31
Issue
14
Publish Date
2013
Start Page
1775
End Page
1781
DOI
10.1200/JCO.2012.45.1096

Preoperative chemo(radio)therapy versus primary surgery for gastroesophageal adenocarcinoma: Systematic review with meta-analysis combining individual patient and aggregate data

Background: The prognosis of patients with gastroesophageal adenocarcinoma is poor. There is conflicting evidence regarding effects of preoperative chemotherapy on survival and other outcomes. Methods: We conducted a meta-analysis with aggregate and individual patient data (IPD) to assess the effect of preoperative chemotherapy for gastroesophageal adenocarcinoma on survival and other outcomes. Two independent reviewers identified eligible randomised controlled trials (RCTs) comparing chemotherapy+/-radiotherapy followed by surgery with surgery alone for gastroesophageal adenocarcinoma. IPD was solicited from all trials. Meta-analyses were performed using the two stage method. Results: We identified 14 RCTs (2422 patients). For eight RCTs (1049 patients; 43.3%) we obtained IPD. Preoperative chemotherapy was associated with longer overall survival (hazard ratio [HR] 0.81; 95% confidence interval [CI] 0.73-0.89; p < 0.0001). There were larger treatment effects in tumours of the gastroesophageal junction and for chemoradiotherapy compared to chemotherapy, but the tests for subgroup differences were not statistically significant. Preoperative chemotherapy was associated with longer disease-free survival, higher likelihood of R0 resection and more favourable post-treatment tumour stage, but not perioperative complications. Conclusion: Preoperative chemotherapy for locoregional gastroesophageal adenocarcinoma increases survival compared to surgery alone. It should be offered to all eligible patients. There appear to be larger survival advantages in tumours of the gastroesophageal junction and for chemoradiotherapy, but these findings require prospective confirmation. © 2013 Elsevier Ltd. All rights reserved.

Authors
Ronellenfitsch, U; Schwarzbach, M; Hofheinz, R; Kienle, P; Kieser, M; Slanger, TE; Burmeister, B; Kelsen, D; Niedzwiecki, D; Schuhmacher, C; al, E
MLA Citation
Ronellenfitsch, U, Schwarzbach, M, Hofheinz, R, Kienle, P, Kieser, M, Slanger, TE, Burmeister, B, Kelsen, D, Niedzwiecki, D, Schuhmacher, C, and al, E. "Preoperative chemo(radio)therapy versus primary surgery for gastroesophageal adenocarcinoma: Systematic review with meta-analysis combining individual patient and aggregate data." European Journal of Cancer (2013).
PMID
23800671
Source
scival
Published In
European Journal of Cancer
Publish Date
2013
DOI
10.1016/j.ejca.2013.05.029

Preoperative chemo(radio)therapy versus primary surgery for gastroesophageal adenocarcinoma: Systematic review with meta-analysis combining individual patient and aggregate data

Background The prognosis of patients with gastroesophageal adenocarcinoma is poor. There is conflicting evidence regarding effects of preoperative chemotherapy on survival and other outcomes. Methods We conducted a meta-analysis with aggregate and individual patient data (IPD) to assess the effect of preoperative chemotherapy for gastroesophageal adenocarcinoma on survival and other outcomes. Two independent reviewers identified eligible randomised controlled trials (RCTs) comparing chemotherapy+/-radiotherapy followed by surgery with surgery alone for gastroesophageal adenocarcinoma. IPD was solicited from all trials. Meta-analyses were performed using the two stage method. Results We identified 14 RCTs (2422 patients). For eight RCTs (1049 patients; 43.3%) we obtained IPD. Preoperative chemotherapy was associated with longer overall survival (hazard ratio [HR] 0.81; 95% confidence interval [CI] 0.73-0.89; p < 0.0001). There were larger treatment effects in tumours of the gastroesophageal junction and for chemoradiotherapy compared to chemotherapy, but the tests for subgroup differences were not statistically significant. Preoperative chemotherapy was associated with longer disease-free survival, higher likelihood of R0 resection and more favourable post-treatment tumour stage, but not perioperative complications. Conclusion Preoperative chemotherapy for locoregional gastroesophageal adenocarcinoma increases survival compared to surgery alone. It should be offered to all eligible patients. There appear to be larger survival advantages in tumours of the gastroesophageal junction and for chemoradiotherapy, but these findings require prospective confirmation. © 2013 Elsevier Ltd. All rights reserved.

Authors
Ronellenfitsch, U; Schwarzbach, M; Hofheinz, R; Kienle, P; Kieser, M; Slanger, TE; Burmeister, B; Kelsen, D; Niedzwiecki, D; Schuhmacher, C; Urba, S; Velde, CVD; Walsh, TN; Ychou, M; Jensen, K
MLA Citation
Ronellenfitsch, U, Schwarzbach, M, Hofheinz, R, Kienle, P, Kieser, M, Slanger, TE, Burmeister, B, Kelsen, D, Niedzwiecki, D, Schuhmacher, C, Urba, S, Velde, CVD, Walsh, TN, Ychou, M, and Jensen, K. "Preoperative chemo(radio)therapy versus primary surgery for gastroesophageal adenocarcinoma: Systematic review with meta-analysis combining individual patient and aggregate data." European Journal of Cancer 49.15 (2013): 3149-3158.
Source
scival
Published In
European Journal of Cancer
Volume
49
Issue
15
Publish Date
2013
Start Page
3149
End Page
3158
DOI
10.1016/j.ejca.2013.05.029

Impact of Physical Activity After Cancer Diagnosis on Survival in Patients With Recurrent Colon Cancer: Findings From CALGB 89803/Alliance

Authors
Jeon, J; Sato, K; Niedzwiecki, D; Ye, X; Saltz, LB; Mayer, RJ; Mowat, RB; Whittom, R; Hantel, A; Benson, A; Wigler, DS; Atienza, D; Messino, M; Kindler, H; Venook, A; Fuchs, CS; Meyerhardt, JA
MLA Citation
Jeon, J, Sato, K, Niedzwiecki, D, Ye, X, Saltz, LB, Mayer, RJ, Mowat, RB, Whittom, R, Hantel, A, Benson, A, Wigler, DS, Atienza, D, Messino, M, Kindler, H, Venook, A, Fuchs, CS, and Meyerhardt, JA. "Impact of Physical Activity After Cancer Diagnosis on Survival in Patients With Recurrent Colon Cancer: Findings From CALGB 89803/Alliance." Clinical Colorectal Cancer (2013).
PMID
24035029
Source
scopus
Published In
Clinical colorectal cancer
Publish Date
2013

Phase II study of the farnesyltransferase inhibitor R115777 in advanced melanoma (CALGB 500104)

Authors
Gajewski, TF; Salama, AKS; Niedzwiecki, D; Johnson, J; Linette, G; Bucher, C; Blaskovich, MA; Sebti, SM; Haluska, F; Canc, LGB
MLA Citation
Gajewski, TF, Salama, AKS, Niedzwiecki, D, Johnson, J, Linette, G, Bucher, C, Blaskovich, MA, Sebti, SM, Haluska, F, and Canc, LGB. "Phase II study of the farnesyltransferase inhibitor R115777 in advanced melanoma (CALGB 500104)." JOURNAL OF TRANSLATIONAL MEDICINE 10 (December 10, 2012).
PMID
23228035
Source
wos-lite
Published In
Journal of Translational Medicine
Volume
10
Publish Date
2012
DOI
10.1186/1479-5876-10-246

Immune recovery in adult patients after myeloablative dual umbilical cord blood, matched sibling, and matched unrelated donor hematopoietic cell transplantation.

Immunologic reconstitution after allogeneic hematopoietic cell transplantation is a critical component of successful outcome. Umbilical cord blood (UCB) transplantation in adult recipients is associated with slow and often inadequate immune recovery. We characterized the kinetics and extent of immune recovery in 95 adult recipients after a dual UCB (n = 29) and matched sibling donor (n = 33) or matched unrelated donor (n = 33) transplantation. All patients were treated with myeloablative conditioning. There were no differences in the immune recovery profile of matched sibling donor and matched unrelated donor recipients. Significantly lower levels of CD3+, CD4+, and CD8+ T cells were observed in UCB recipients until 6 months after transplantation. Lower levels of regulatory T cells persisted until 1 year after transplantation. Thymopoiesis as measured by TCR rearrangement excision circle was comparable among all recipients by 6 months after transplantation. In a subset of patients 1 year after transplantation with similar levels of circulating T cells and TCR rearrangement excision circle, there was no difference in TCR diversity. Compared to HLA-identical matched sibling donor and matched unrelated donor adult hematopoietic cell transplantation recipients, quantitative lymphoid recovery in UCB transplantation recipients is slower in the first 3 months, but these differences disappeared by 6 to 12 months after transplantation.

Authors
Kanda, J; Chiou, L-W; Szabolcs, P; Sempowski, GD; Rizzieri, DA; Long, GD; Sullivan, KM; Gasparetto, C; Chute, JP; Morris, A; McPherson, J; Hale, J; Livingston, JA; Broadwater, G; Niedzwiecki, D; Chao, NJ; Horwitz, ME
MLA Citation
Kanda, J, Chiou, L-W, Szabolcs, P, Sempowski, GD, Rizzieri, DA, Long, GD, Sullivan, KM, Gasparetto, C, Chute, JP, Morris, A, McPherson, J, Hale, J, Livingston, JA, Broadwater, G, Niedzwiecki, D, Chao, NJ, and Horwitz, ME. "Immune recovery in adult patients after myeloablative dual umbilical cord blood, matched sibling, and matched unrelated donor hematopoietic cell transplantation." Biol Blood Marrow Transplant 18.11 (November 2012): 1664-1676.e1.
PMID
22698485
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
18
Issue
11
Publish Date
2012
Start Page
1664
End Page
1676.e1
DOI
10.1016/j.bbmt.2012.06.005

Co-delivery of antigen and IL-12 by Venezuelan equine encephalitis virus replicon particles enhances antigen-specific immune responses and antitumor effects.

We recently demonstrated that Venezuelan equine encephalitis virus-based replicon particle (VRPs) encoding tumor antigens could break tolerance in the immunomodulatory environment of advanced cancer. We hypothesized that local injection of VRP-expressing interleukin-12 (IL-12) at the site of injections of VRP-based cancer vaccines would enhance the tumor-antigen-specific T cell and antibody responses and antitumor efficacy. Mice were immunized with VRP encoding the human tumor-associated antigen, carcinoembryonic antigen (CEA) (VRP-CEA(6D)), and VRP-IL-12 was also administered at the same site or at a distant location. CEA-specific T cell and antibody responses were measured. To determine antitumor activity, mice were implanted with MC38-CEA-2 cells and immunized with VRP-CEA with and without VRP-IL-12, and tumor growth and mouse survival were measured. VRP-IL-12 greatly enhanced CEA-specific T cell and antibody responses when combined with VRP-CEA(6D) vaccination. VRP-IL-12 was superior to IL-12 protein at enhancing immune responses. Vaccination with VRP-CEA(6D) plus VRP-IL-12 was superior to VRP-CEA(6D) or VRP-IL-12 alone in inducing antitumor activity and prolonging survival in tumor-bearing mice. Importantly, local injection of VRP-IL-12 at the VRP-CEA(6D) injection site provided more potent activation of CEA-specific immune responses than that of VRP-IL-12 injected at a distant site from the VRP-CEA injections. Together, this study shows that VRP-IL-12 enhances vaccination with VRP-CEA(6D) and was more effective at activating CEA-specific T cell responses when locally expressed at the vaccine site. Clinical trials evaluating the adjuvant effect of VRP-IL-12 at enhancing the immunogenicity of cancer vaccines are warranted.

Authors
Osada, T; Berglund, P; Morse, MA; Hubby, B; Lewis, W; Niedzwiecki, D; Yang, XY; Hobeika, A; Burnett, B; Devi, GR; Clay, TM; Smith, J; Kim Lyerly, H
MLA Citation
Osada, T, Berglund, P, Morse, MA, Hubby, B, Lewis, W, Niedzwiecki, D, Yang, XY, Hobeika, A, Burnett, B, Devi, GR, Clay, TM, Smith, J, and Kim Lyerly, H. "Co-delivery of antigen and IL-12 by Venezuelan equine encephalitis virus replicon particles enhances antigen-specific immune responses and antitumor effects." Cancer Immunol Immunother 61.11 (November 2012): 1941-1951.
PMID
22488274
Source
pubmed
Published In
Cancer Immunology, Immunotherapy
Volume
61
Issue
11
Publish Date
2012
Start Page
1941
End Page
1951
DOI
10.1007/s00262-012-1248-y

Effect of the vaccine Ad5 [E1-, E2b-]-CEA(6D) on CEA-directed CMI responses in patients with advanced CEA-expressing malignancies in a phase I/II clinical trial

Authors
Morse, M; Hobeika, A; Chaudhry, A; Amalfitano, A; Niedzwiecki, D; Clay, TM; Osada, T; Devi, G; Burnett, BK; Weinhold, K; Hsu, SD; Blobe, GC; Xu, Y; Nguyen, S; Dua, R; Balcaitis, S; Gabitzsch, E; Balint, J; Jones, F; Lyerly, HK
MLA Citation
Morse, M, Hobeika, A, Chaudhry, A, Amalfitano, A, Niedzwiecki, D, Clay, TM, Osada, T, Devi, G, Burnett, BK, Weinhold, K, Hsu, SD, Blobe, GC, Xu, Y, Nguyen, S, Dua, R, Balcaitis, S, Gabitzsch, E, Balint, J, Jones, F, and Lyerly, HK. "Effect of the vaccine Ad5 [E1-, E2b-]-CEA(6D) on CEA-directed CMI responses in patients with advanced CEA-expressing malignancies in a phase I/II clinical trial." May 20, 2012.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
30
Issue
15
Publish Date
2012

Abstract 4514: A comparison of two methodologies to quantify Thymidylate synthase for predicting survival in patients with colorectal cancer treated on CALGB 89803

Authors
Hasson, RM; Niedzwiecki, D; Bertagnolli, MM
MLA Citation
Hasson, RM, Niedzwiecki, D, and Bertagnolli, MM. "Abstract 4514: A comparison of two methodologies to quantify Thymidylate synthase for predicting survival in patients with colorectal cancer treated on CALGB 89803." Cancer Research 72.8 Supplement (April 15, 2012): 4514-4514.
Source
crossref
Published In
Cancer Research
Volume
72
Issue
8 Supplement
Publish Date
2012
Start Page
4514
End Page
4514
DOI
10.1158/1538-7445.AM2012-4514

A novel interaction of genotype, gender, and adjuvant treatment in survival after resection of stage III colon cancer: Results of CALGB 89803.

452 Background: The p53 tumor suppressor gene is frequently mutated in colorectal cancer, but reports on the effect of p53 mutations on response to adjuvant chemotherapy and survival are inconclusive. This study investigates whether p53 mutational status (wild-type, zinc or non-zinc binding mutations) impacts survival following adjuvant therapy containing fluorouracil/leucovorin with or without irinotecan (5FU/LV or IFL) in women and men with stage III colon cancer.As part of a retrospective analysis of prospectively accrued data, p53 mutational status was determined for 609 patients with stage III colon cancer who were randomized on CALGB 89803, a phase III adjuvant chemotherapy trial. p53 exons 5-8 were analyzed by direct sequencing or sequencing by hybridization. p53 mutations were identified in 276 tumors (45%), of which 134 were in the zinc binding and 142 were in the non-zinc binding regions of the core domain. Cox regression was used to study the impact of p53 mutational status, sex, and adjuvant chemotherapy on disease-free (DFS) and overall survival (OS).p53 mutational status did not predict differential survival or response to adjuvant therapy among the 609 patients assessed. However, a significant sex by treatment interaction was observed for both DFS (Pinteraction=0.008) and OS (Pinteraction=0.002). Significant differences in DFS by p53 mutational status were observed among women (logrank P = 0.009). No such differences were observed among men (logrank P = 0.33). Similar results were observed for OS. There was marginal evidence of a treatment-related impact on the interaction between sex and p53 mutational status for both DFS and OS (DFS Pinteraction = 0.07; OS Pinteraction = 0.11). There was a trend toward improved OS when women with zinc binding mutations received IFL versus 5FU/LV (P = 0.08) and toward worse DFS when women with non-zinc binding mutations were treated with IFL versus 5FU/LV (P =0.08).This exploratory subset analysis suggests that p53 mutational status may be used to predict prognosis in a sex- and potentially chemotherapeutic regimen-specific manner.

Authors
Atreya, CE; Warren, RS; Niedzwiecki, D; Mayer, RJ; Goldberg, RM; Compton, CC; Zuraek, M; Bergsland, EK; Ye, C; Weinberg, VK; Bertagnolli, MM
MLA Citation
Atreya, CE, Warren, RS, Niedzwiecki, D, Mayer, RJ, Goldberg, RM, Compton, CC, Zuraek, M, Bergsland, EK, Ye, C, Weinberg, VK, and Bertagnolli, MM. "A novel interaction of genotype, gender, and adjuvant treatment in survival after resection of stage III colon cancer: Results of CALGB 89803." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 30.4_suppl (February 2012): 452-.
PMID
27983199
Source
epmc
Published In
Journal of Clinical Oncology
Volume
30
Issue
4_suppl
Publish Date
2012
Start Page
452

Dietary glycemic load and cancer recurrence and survival in patients with stage III colon cancer: Findings from CALGB 89803

Background The influence of glycemic load and related measures on survival among colon cancer patients remains largely unknown.MethodsWe conducted a prospective, observational study of 1011 stage III colon cancer patients reporting dietary intake during and 6 months after participation in an adjuvant chemotherapy trial. We examined the influence of glycemic load, glycemic index, fructose, and carbohydrate intakes on cancer recurrence and mortality using Cox proportional hazards regression; all tests of statistical significance were two-sided.ResultsStage III colon cancer patients in the highest quintile of dietary glycemic load experienced an adjusted hazard ratio (HR) for disease-free survival of 1.79 (95% confidence interval [CI] 1.29 to 2.48), compared with those in the lowest quintile (Ptrend across quintiles <.001). Increased glycemic load was associated with similar detriments in recurrence-free (Ptrend across quintiles <.001) and overall survival (Ptrend across quintiles <.001). These associations differed statistically significant by body mass index (BMI) (P interaction .01). Whereas glycemic load was not associated with disease-free survival in patients with BMI < 25kg/m2, higher glycemic load was statistically significant associated with worse disease-free survival among overweight or obese participants (BMI < 25kg/m2; HR 2.26; 95% CI 1.53 to 3.32; Ptrend across quintiles <.001). Increasing total carbohydrate intake was similarly associated with inferior disease-free, recurrence-free, and overall survival (Ptrend across quintiles <.001).ConclusionHigher dietary glycemic load and total carbohydrate intake were statistically significant associated with an increased risk of recurrence and mortality in stage III colon cancer patients. These findings support the role of energy balance factors in colon cancer progression and may offer potential opportunities to improve patient survival. © 2012 The Author.

Authors
Meyerhardt, JA; Sato, K; Niedzwiecki, D; Ye, C; Saltz, LB; Mayer, RJ; Mowat, RB; Whittom, R; Hantel, A; Benson, A; Wigler, DS; Venook, A; Fuchs, CS
MLA Citation
Meyerhardt, JA, Sato, K, Niedzwiecki, D, Ye, C, Saltz, LB, Mayer, RJ, Mowat, RB, Whittom, R, Hantel, A, Benson, A, Wigler, DS, Venook, A, and Fuchs, CS. "Dietary glycemic load and cancer recurrence and survival in patients with stage III colon cancer: Findings from CALGB 89803." Journal of the National Cancer Institute 104.22 (2012): 1702-1711.
PMID
23136358
Source
scival
Published In
Journal of the National Cancer Institute
Volume
104
Issue
22
Publish Date
2012
Start Page
1702
End Page
1711
DOI
10.1093/jnci/djs399

Does health-related quality of life improve for advanced pancreatic cancer patients who respond to gemcitabine? Analysis of a randomized phase III trial of the cancer and leukemia group B (CALGB 80303)

Context: Gemcitabine for advanced pancreatic cancer (APC) is palliative and the prognosis is poor, making health-related quality of life (HRQOL) particularly important. Objectives: We evaluated HRQOL with the EuroQol (EQ-5D™) in patients with APC participating in Cancer and Leukemia Group B 80303, a multicenter, double-blind, randomized trial comparing overall survival (OS) between two treatment arms: gemcitabine with bevacizumab or gemcitabine with placebo. Methods: A consecutive subsample of patients was invited to complete the EQ-5D surveys. Because neither clinical nor HRQOL outcomes differed based on the study arm, analyses were pooled. Changes in mean scores from baseline to eight weeks and the prognostic value of the EQ-5D were evaluated. Results: Mean index scores remained stable (0.78 at baseline [n = 267], 0.79 at eight weeks [n = 186], P = 0.34, Wilcoxon signed rank test), attributable to a modest deterioration of physical function domain scores coincident with small improvements in pain and anxiety/depression scores. A small decline in visual analogue scale scores was observed (70.7 vs. 68.2, P = 0.026). HRQOL changes within chemotherapy response strata revealed stable index scores but a trend of worsened physical function among patients with disease progression compared with those with stable or improved disease. Visual analogue scale scores trended downward over time irrespective of chemotherapy response status, with a statistically meaningful deterioration in patients who progressed (68.9 vs. 64.4, P = 0.029). Baseline scores from both EQ-5D scales were significant predictors of OS in Cox proportional hazard models. Conclusion: Response to gemcitabine treatment in APC is not associated with appreciable improvement of global HRQOL. Small improvements in pain and mood are observed despite progressive functional decline. Those who respond to gemcitabine may experience a slight slowing of functional deterioration. © 2012 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

Authors
Romanus, D; Kindler, HL; Archer, L; Basch, E; Niedzwiecki, D; Weeks, J; Schrag, D
MLA Citation
Romanus, D, Kindler, HL, Archer, L, Basch, E, Niedzwiecki, D, Weeks, J, and Schrag, D. "Does health-related quality of life improve for advanced pancreatic cancer patients who respond to gemcitabine? Analysis of a randomized phase III trial of the cancer and leukemia group B (CALGB 80303)." Journal of Pain and Symptom Management 43.2 (2012): 205-217.
PMID
22104618
Source
scival
Published In
Journal of Pain and Symptom Management
Volume
43
Issue
2
Publish Date
2012
Start Page
205
End Page
217
DOI
10.1016/j.jpainsymman.2011.09.001

The Impact of Lymphocyte Subset Recovery At 3 Months on Progression-Free Survival After Myeloablative Allogeneic Stem Cell Transplantation

Authors
Kanda, J; Rizzieri, DA; Long, GD; Gasparetto, C; Chute, JP; Sullivan, KM; Morris, A; McPherson, J; Livingston, JA; Broadwater, G; Niedzwiecki, D; Chao, NJ; Horwitz, ME
MLA Citation
Kanda, J, Rizzieri, DA, Long, GD, Gasparetto, C, Chute, JP, Sullivan, KM, Morris, A, McPherson, J, Livingston, JA, Broadwater, G, Niedzwiecki, D, Chao, NJ, and Horwitz, ME. "The Impact of Lymphocyte Subset Recovery At 3 Months on Progression-Free Survival After Myeloablative Allogeneic Stem Cell Transplantation." November 18, 2011.
Source
wos-lite
Published In
Blood
Volume
118
Issue
21
Publish Date
2011
Start Page
1736
End Page
1736

Endpoints for Validation of Tumour Markers for Recurrence Risk - Recurrence-free Interval (RFI), Disease-free Survival (DFS), Overall Survival (OS), and Colon-cancer Specific Survival (CCSS) in CALGB 9581

Authors
Mahmoud, NN; Lopatin, M; Clark-Langone, K; Lee, M; Niedzwiecki, D; Venook, AP
MLA Citation
Mahmoud, NN, Lopatin, M, Clark-Langone, K, Lee, M, Niedzwiecki, D, and Venook, AP. "Endpoints for Validation of Tumour Markers for Recurrence Risk - Recurrence-free Interval (RFI), Disease-free Survival (DFS), Overall Survival (OS), and Colon-cancer Specific Survival (CCSS) in CALGB 9581." September 2011.
Source
wos-lite
Published In
European Journal of Cancer
Volume
47
Publish Date
2011
Start Page
S172
End Page
S172

Documenting the natural history of patients with resected stage II adenocarcinoma of the colon after random assignment to adjuvant treatment with edrecolomab or observation: results from CALGB 9581.

PURPOSE: We conducted a randomized trial comparing adjuvant treatment with edrecolomab versus observation in patients with resected, low-risk, stage II colon cancer. This study also prospectively studied patient- and tumor-specific markers of treatment outcome. PATIENTS AND METHODS: After surgical resection, patients with stage II colon cancer were randomly assigned to either five infusions of edrecolomab at 28-day intervals or observation without adjuvant therapy. RESULTS: Final accrual included 1,738 patients; 865 patients received edrecolomab, and 873 patients were observed without adjuvant treatment. Median follow-up time was 7.9 years. There were no significant outcome differences between study arms (overall survival [OS], P = .71; disease-free survival, P = .64). The combined 5-year all-cause OS was 0.86 (95% CI, 0.84 to 0.88), and the combined 5-year disease-specific OS was 0.93 (95% CI, 0.91 to 0.94). The relationships between demographic and histopathologic factors and survival differed for all-cause and disease-specific survival outcomes, but no combined prognostic factor model was found to adequately classify patients at higher risk of recurrence or death as a result of colon cancer. CONCLUSION: Edrecolomab did not prolong survival. Consequently, this large study with a long duration of follow-up provided unique data concerning the natural history of resected stage II colon cancer. Prognostic factors identified in previous retrospective and pooled analyses were associated with survival outcomes in this stage II patient cohort. Results from ongoing molecular marker studies may enhance our ability to determine the risk profile of these patients.

Authors
Niedzwiecki, D; Bertagnolli, MM; Warren, RS; Compton, CC; Kemeny, NE; Benson, AB; Eckhardt, SG; Alberts, S; Porjosh, GN; Kerr, DJ; Fields, A; Rougier, P; Pipas, JM; Schwartz, JH; Atkins, J; O'Rourke, M; Perry, MC; Goldberg, RM; Mayer, RJ; Colacchio, TA
MLA Citation
Niedzwiecki, D, Bertagnolli, MM, Warren, RS, Compton, CC, Kemeny, NE, Benson, AB, Eckhardt, SG, Alberts, S, Porjosh, GN, Kerr, DJ, Fields, A, Rougier, P, Pipas, JM, Schwartz, JH, Atkins, J, O'Rourke, M, Perry, MC, Goldberg, RM, Mayer, RJ, and Colacchio, TA. "Documenting the natural history of patients with resected stage II adenocarcinoma of the colon after random assignment to adjuvant treatment with edrecolomab or observation: results from CALGB 9581." J Clin Oncol 29.23 (August 10, 2011): 3146-3152.
PMID
21747085
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
29
Issue
23
Publish Date
2011
Start Page
3146
End Page
3152
DOI
10.1200/JCO.2010.32.5357

Adult dual umbilical cord blood transplantation using myeloablative total body irradiation (1350 cGy) and fludarabine conditioning.

High treatment-related mortality (TRM) and high graft failure rate are serious concerns in HLA-mismatched umbilical cord blood (UCB) transplantation with myeloablative conditioning. We conducted a prospective trial of dual UCB transplantation using modified myeloablation consisting of total-body irradiation (TBI; 1350 cGy) and fludarabine (Flu) (160 mg/m(2)). Twenty-seven patients (median age, 33 years; range: 20-58 years) with hematologic malignancies were enrolled. The median combined cryopreserved total nucleated cell (TNC) dose was 4.3 × 10(7)/kg (range: 3.2-7.7 × 10(7)/kg). The cumulative incidences of neutrophil (≥500/μL) and platelet (≥50,000/μL) engraftment were 80% (95% confidence interval [CI], 58%-91%) and 68% (95% CI, 46%-83%), respectively. Among engrafted patients, a single cord blood unit was predominant by 100 days posttransplantation. A higher cryopreserved and infused TNC dose and infused CD3(+) cell dose were significant factors associated with the predominant UCB unit (P = .032, .020, and .042, respectively). TRM and relapse rates at 2 years were 28% (95% CI, 12%-47%) and 20% (95% CI, 7%-37%), respectively. Cumulative incidences of grades II-IV and grades III-IV acute graft-versus-host disease (aGVHD) were 37% (95% CI, 20%-55%) and 11% (95% CI, 3%-26%), respectively, and that of chronic GVHD was 31% (95% CI, 15%-49%). With a median follow-up of 23 months, overall survival and disease-free survival rates at 2 years were 58% (95% CI, 34%-75%) and 52% (95% CI, 29%-70%), respectively. This study supports the use of TBI 1350 cGy/Flu as an alternative to conventional myeloablative conditioning for dual UCB transplantation.

Authors
Kanda, J; Rizzieri, DA; Gasparetto, C; Long, GD; Chute, JP; Sullivan, KM; Morris, A; Smith, CA; Hogge, DE; Nitta, J; Song, K; Niedzwiecki, D; Chao, NJ; Horwitz, ME
MLA Citation
Kanda, J, Rizzieri, DA, Gasparetto, C, Long, GD, Chute, JP, Sullivan, KM, Morris, A, Smith, CA, Hogge, DE, Nitta, J, Song, K, Niedzwiecki, D, Chao, NJ, and Horwitz, ME. "Adult dual umbilical cord blood transplantation using myeloablative total body irradiation (1350 cGy) and fludarabine conditioning." Biol Blood Marrow Transplant 17.6 (June 2011): 867-874.
PMID
20868761
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
17
Issue
6
Publish Date
2011
Start Page
867
End Page
874
DOI
10.1016/j.bbmt.2010.09.009

Survival rates among patients vaccinated following resection of colorectal cancer metastases in a phase II randomized study compared with contemporary controls

Authors
Morse, M; Niedzwiecki, D; Marshall, J; Garrett, CR; Chang, DZ; Aklilu, M; Crocenzi, TS; Cole, DJ; Dessureault, S; Hobeika, A; Osada, T; Clary, BM; Hsu, SD; Devi, G; Bulusu, A; Annechiarico, R; Chadaram, V; Clay, TM; Lyerly, HK
MLA Citation
Morse, M, Niedzwiecki, D, Marshall, J, Garrett, CR, Chang, DZ, Aklilu, M, Crocenzi, TS, Cole, DJ, Dessureault, S, Hobeika, A, Osada, T, Clary, BM, Hsu, SD, Devi, G, Bulusu, A, Annechiarico, R, Chadaram, V, Clay, TM, and Lyerly, HK. "Survival rates among patients vaccinated following resection of colorectal cancer metastases in a phase II randomized study compared with contemporary controls." May 20, 2011.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
29
Issue
15
Publish Date
2011

A dendritic cell-based vaccine effects on T-cell responses compared with a viral vector vaccine when administered to patients following resection of colorectal metastases in a randomized phase II study.

Authors
Lyerly, HK; Hobeika, A; Niedzwiecki, D; Osada, T; Marshall, J; Garrett, CR; Chang, DZ; Aklilu, M; Crocenzi, TS; Cole, DJ; Dessureault, S; Hsu, SD; Bulusu, A; Clary, BM; Annechiarico, R; Devi, G; Chadaram, V; Clay, TM; Morse, M
MLA Citation
Lyerly, HK, Hobeika, A, Niedzwiecki, D, Osada, T, Marshall, J, Garrett, CR, Chang, DZ, Aklilu, M, Crocenzi, TS, Cole, DJ, Dessureault, S, Hsu, SD, Bulusu, A, Clary, BM, Annechiarico, R, Devi, G, Chadaram, V, Clay, TM, and Morse, M. "A dendritic cell-based vaccine effects on T-cell responses compared with a viral vector vaccine when administered to patients following resection of colorectal metastases in a randomized phase II study." May 20, 2011.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
29
Issue
15
Publish Date
2011

Validation of a 12-gene colon cancer recurrence score (RS) in patients (pts) with stage II colon cancer (CC) from CALGB 9581

Authors
Venook, AP; Niedzwiecki, D; Lopatin, M; Lee, M; Friedman, PN; Frankel, W; Clark-Langone, K; Yoshizawa, C; Millward, C; Shak, S; Goldberg, RM; Mahmoud, NN; Schilsky, RL; Bertagnolli, MM; Canc, LGB
MLA Citation
Venook, AP, Niedzwiecki, D, Lopatin, M, Lee, M, Friedman, PN, Frankel, W, Clark-Langone, K, Yoshizawa, C, Millward, C, Shak, S, Goldberg, RM, Mahmoud, NN, Schilsky, RL, Bertagnolli, MM, and Canc, LGB. "Validation of a 12-gene colon cancer recurrence score (RS) in patients (pts) with stage II colon cancer (CC) from CALGB 9581." JOURNAL OF CLINICAL ONCOLOGY 29.15 (May 20, 2011).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
29
Issue
15
Publish Date
2011

Postoperative adjuvant chemoradiation for gastric or gastroesophageal junction (GEJ) adenocarcinoma using epirubicin, cisplatin, and infusional (CI) 5-FU (ECF) before and after CI 5-FU and radiotherapy (CRT) compared with bolus 5-FU/LV before and after CRT: Intergroup trial CALGB 80101.

Authors
Fuchs, CS; Tepper, JE; Niedzwiecki, D; Hollis, D; Mamon, HJ; Swanson, R; Haller, DG; Dragovich, T; Alberts, SR; Bjarnason, GA; Willett, CG; Enzinger, PC; Goldberg, RM; Venook, AP; Mayer, RJ
MLA Citation
Fuchs, CS, Tepper, JE, Niedzwiecki, D, Hollis, D, Mamon, HJ, Swanson, R, Haller, DG, Dragovich, T, Alberts, SR, Bjarnason, GA, Willett, CG, Enzinger, PC, Goldberg, RM, Venook, AP, and Mayer, RJ. "Postoperative adjuvant chemoradiation for gastric or gastroesophageal junction (GEJ) adenocarcinoma using epirubicin, cisplatin, and infusional (CI) 5-FU (ECF) before and after CI 5-FU and radiotherapy (CRT) compared with bolus 5-FU/LV before and after CRT: Intergroup trial CALGB 80101." JOURNAL OF CLINICAL ONCOLOGY 29.15 (May 20, 2011).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
29
Issue
15
Publish Date
2011

A comparison of dietary and lifestyle habits among stage III and metastatic colorectal cancer patients.

Authors
Van Loon, K; Wigler, D; Niedzwiecki, D; Hollis, D; Venook, AP; Blanke, CD; Saltz, L; Goldberg, RM; Fuchs, CS; Meyerhardt, JA
MLA Citation
Van Loon, K, Wigler, D, Niedzwiecki, D, Hollis, D, Venook, AP, Blanke, CD, Saltz, L, Goldberg, RM, Fuchs, CS, and Meyerhardt, JA. "A comparison of dietary and lifestyle habits among stage III and metastatic colorectal cancer patients." JOURNAL OF CLINICAL ONCOLOGY 29.15 (May 20, 2011).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
29
Issue
15
Publish Date
2011

A dendritic cell-based vaccine effects on T-cell responses compared with a viral vector vaccine when administered to patients following resection of colorectal metastases in a randomized phase II study.

2533 Background: CD8+ T cell responses to colorectal cancer are associated with longer survival. This has led to the hypothesis that cancer vaccines, capable of activating T cell responses, may improve clinical outcome. Vaccines based on antigen-presenting cells/dendritic cells (DC) and viral vectors, potent stimulators of adaptive immunity, have been associated with enhanced survival in prostate cancer patients. We compared rates of tumor antigen-specific T cell and antibody responses between a DC and a poxvector vaccine. The clinical outcome data is reported elsewhere.74 patients with no evidence of disease after colorectal cancer metastasectomy and completion of peri-operative chemotherapy were randomized 1:1 to receive injections of one of either: DC mixed with PANVAC-VF (poxvectors encoding CEA, MUC1, CD54, CD58, CD80) or PANVAC-VF along with local injections of GM-CSF. Peripheral blood was drawn before and after completing the immunizations for analysis of CEA and MUC-1 immune (T cell and antibody) responses by ELISPOT and ELISA.T cell responses against CEA were significantly more frequent in the DC arm (69 versus 41%, p=0.02) although the magnitude of the T cell response among responders was similar. There was a trend for improved relapse-free survival among patients with CEA-specific T cell responses (log rank p = 0.10). The antibody response to CEA was more frequent with the PANVAC alone (100% versus 67%, (p= 0.018)) and the antibodies in serum from vaccinated patients could bind to CEA-expressing tumor cells and mediated ADCC. No antibody response was induced against MUC-1. The antibody response against CEA did not correlate with clinical benefit. Few deaths were observed limiting comparison of survival by immune response.A dendritic cell vaccine leads to a greater frequency of CEA-specific T cell responses which is associated with enhanced RFS. Ongoing studies are evaluating the role of additional immunostimulatory cytokines and modulation of regulatory cell populations and molecules in enhancing the adaptive immune response to the DC-based vaccine.

Authors
Lyerly, HK; Hobeika, A; Niedzwiecki, D; Osada, T; Marshall, J; Garrett, CR; Chang, DZ; Aklilu, M; Crocenzi, TS; Cole, DJ; Dessureault, S; Hsu, SD; Bulusu, A; Clary, BM; Annechiarico, R; Devi, G; Chadaram, V; Clay, TM; Morse, M
MLA Citation
Lyerly, HK, Hobeika, A, Niedzwiecki, D, Osada, T, Marshall, J, Garrett, CR, Chang, DZ, Aklilu, M, Crocenzi, TS, Cole, DJ, Dessureault, S, Hsu, SD, Bulusu, A, Clary, BM, Annechiarico, R, Devi, G, Chadaram, V, Clay, TM, and Morse, M. "A dendritic cell-based vaccine effects on T-cell responses compared with a viral vector vaccine when administered to patients following resection of colorectal metastases in a randomized phase II study." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 29.15_suppl (May 2011): 2533-.
PMID
28022328
Source
epmc
Published In
Journal of Clinical Oncology
Volume
29
Issue
15_suppl
Publish Date
2011
Start Page
2533

Survival rates among patients vaccinated following resection of colorectal cancer metastases in a phase II randomized study compared with contemporary controls.

3557 Background: Patients with completely resected metastases from colorectal cancer (CRC) remain at high risk of recurrence and death despite adjuvant chemotherapy. Recently, survival of prostate cancer patients was enhanced by antigen-presenting cell therapy. We investigated whether administration of an antigen-presenting cell vaccine based on dendritic cells (DC) after metastasectomy would reduce the risk of recurrence and increase survival.Patients (n=74) with no evidence of disease after resection of CRC metastases and completion of their physician-determined peri-operative chemotherapy were randomized 1:1 to four immunizations with: DC modified with the PANVAC-VF poxvectors encoding CEA, MUC1, CD54, CD58, and CD80 or the PANVAC-VF poxvectors along with GM-CSF at the injection site. We report recurrence-free survival (RFS) at 2 years and overall survival (OS). CEA specific T cell responses were measured by ELISPOT. Data from a prospectively registered, comparable, contemporary control group of patients who had undergone metastasectomy for CRC were also available.The arms of the study and contemporary controls were well balanced. The majority of the toxicities for the DC and PANVAC arms respectively were grade 1, 2 injection site reactions (63% versus 64%), low grade fevers (17% vs 31%), myalgia (11% vs 11%), and fatigue (26% vs 34%). The two year RFS was similar in all groups (50, 56 and 55% for the DC arm, the PANVAC arm and the contemporary control group, respectively). However, there was a trend for improved RFS among patients with CEA-specific T cell responses (log rank p = 0.10). At a median follow-up of 40 months, 2 of 37 patients treated with DC and 5 of 37 treated with PANVAC alone have died, with a combined survival rate exceeding that of the unvaccinated control patients.Patients vaccinated after metastasectomy experienced a longer survival relative to contemporary controls. A phase III study of OS comparing patients vaccinated after resection with the DC vaccine and observation is warranted.

Authors
Morse, M; Niedzwiecki, D; Marshall, J; Garrett, CR; Chang, DZ; Aklilu, M; Crocenzi, TS; Cole, DJ; Dessureault, S; Hobeika, A; Osada, T; Clary, BM; Hsu, SD; Devi, G; Bulusu, A; Annechiarico, R; Chadaram, V; Clay, TM; Lyerly, HK
MLA Citation
Morse, M, Niedzwiecki, D, Marshall, J, Garrett, CR, Chang, DZ, Aklilu, M, Crocenzi, TS, Cole, DJ, Dessureault, S, Hobeika, A, Osada, T, Clary, BM, Hsu, SD, Devi, G, Bulusu, A, Annechiarico, R, Chadaram, V, Clay, TM, and Lyerly, HK. "Survival rates among patients vaccinated following resection of colorectal cancer metastases in a phase II randomized study compared with contemporary controls." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 29.15_suppl (May 2011): 3557-.
PMID
28020295
Source
epmc
Published In
Journal of Clinical Oncology
Volume
29
Issue
15_suppl
Publish Date
2011
Start Page
3557

A comparison of dietary and lifestyle habits among stage III and metastatic colorectal cancer patients.

e14026 Background: Patients with colorectal cancer are often highly motivated to seek information about lifestyle and dietary changes which may optimize outcomes. Using data from two large National Cancer Institute-sponsored clinical trials, we compared the dietary and lifestyle practices of patients receiving chemotherapy for stage III colon cancer and metastatic colorectal cancer.Self-administered questionnaires were completed by patients with stage III colon cancer enrolled in CALGB 89803 (n=1095) and by patients with metastatic colorectal cancer enrolled in CALGB 80405 (n=875), while they were undergoing chemotherapy. Descriptive statistical analyses were performed to evaluate body mass index (BMI), dietary patterns, physical activity, alcohol consumption, cigarette smoking, vitamin and supplement use, and aspirin use in each cohort.Median BMI was comparable for patients with stage III disease and patients with metastatic disease (27.3 vs. 26.5 kg/m2). Stage III patients reported a slightly higher total median MET-hours per week than patients with metastatic disease (4.6 vs. 3.4). 10% of patients with stage III disease and 9% of patients with metastatic disease reported ongoing cigarette use. 47% of patients with stage III disease and 43% of patients with metastatic disease reported abstinence from alcohol. Dietary patterns for both groups were comparable; however, patients with metastatic disease consumed fewer servings per week of many food groups. The vast majority of stage III and metastatic patients failed to meet recommended daily intake of vegetables, fruits, and dairy products. Stage III patients took an average of 1.5 vitamins daily, and patients with metastatic disese took an average of 1.1 vitamins daily.We observed remarkable similarities in dietary patterns and lifestyle behaviors between two large cohorts of stage III colon cancer patients and metastatic colorectal cancer patients actively receiving chemotherapy in the context of a clinical trial. Future research should aim to elucidate the effect of these behavioral factors on patient outcomes.

Authors
Van Loon, K; Wigler, D; Niedzwiecki, D; Hollis, D; Venook, AP; Blanke, CD; Saltz, L; Goldberg, RM; Fuchs, CS; Meyerhardt, JA
MLA Citation
Van Loon, K, Wigler, D, Niedzwiecki, D, Hollis, D, Venook, AP, Blanke, CD, Saltz, L, Goldberg, RM, Fuchs, CS, and Meyerhardt, JA. "A comparison of dietary and lifestyle habits among stage III and metastatic colorectal cancer patients." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 29.15_suppl (May 2011): e14026-.
PMID
28022586
Source
epmc
Published In
Journal of Clinical Oncology
Volume
29
Issue
15_suppl
Publish Date
2011
Start Page
e14026

Postoperative adjuvant chemoradiation for gastric or gastroesophageal junction (GEJ) adenocarcinoma using epirubicin, cisplatin, and infusional (CI) 5-FU (ECF) before and after CI 5-FU and radiotherapy (CRT) compared with bolus 5-FU/LV before and after CRT: Intergroup trial CALGB 80101.

4003 Background: Following curative resection of gastric or GEJ adenocarcinoma, INT-0116 demonstrated superior survival for pts who received postoperative bolus 5-FU and leucovorin (LV) before and after concomitant 5-FU and RT compared to surgery alone. We assessed whether a postoperative chemoRT regimen that replaces 5-FU/LV with a potentially more active systemic therapy (ECF) improves overall survival (OS).Patients with resected gastric or GEJ adenocarcinoma were randomly assigned to either: Arm A: 1 cycle of 5-FU 425 mg/m2/day plus LV20 mg/m2/day for 5 days/month, followed by 45 Gy (1.8 Gy/day) and concurrent 5-FU (200 mg/m2/day CI throughout RT), followed by 2 cyclesof 5-FU/LV; or Arm B: 1 cycle of ECF (E 50 mg/m2 day 1, C 60 mg/m2 day 1, and 5-FU 200 mg/m2/day CI days 1-21) followed by 45 Gy (1.8 Gy/day) and concurrent 5-FU (200 mg/m2/day CI throughout RT), followed by 2 cycles of reduced dose of ECF (E 40 mg/m2 day 1, C 50 mg/m2 day 1, and 5-FU 200 mg/m2/day CI days 1-21).Between 4/03 and 5/09, 546 pts were enrolled. There were no significant differences between arms with regard to age, sex, race, performance status, T or N stage or extent of lymphadenectomy. Treatment related deaths occurred in 8 (3%) pts on Arm A (5-FU/LV) and 1 (<1%) pt on Arm B (ECF). Grade 4 toxicity: 40%, Arm A v 26%, Arm B (p<0.001). Major toxicities (≥ gr. 3) included: neutropenia (53 v 48%), diarrhea (15 v 7%), and mucositis (15 v 7%) for Arms A and B, respectively. With 242 deaths reported, median OS was 37 months in Arm A and 38 months in Arm B (HR, 1.03; 95% CI, 0.80-1.34; p=0.80). 3yr-OS was 50% in Arm A and 52% in Arm B. Median disease-free survival (DFS) was 30 months in Arm A and 28 months in Arm B (HR, 1.00; 95% CI, 0.79-1.27; p=0.99). 3yr-DFS was 46% in Arm A and 47% in Arm B.Following curative resection of gastric or GEJ adenocarcinoma, postoperative chemoRT using ECF before and after 5-FU/RT does not improve survival when compared to bolus 5-FU/LV before and after 5-FU/RT.

Authors
Fuchs, CS; Tepper, JE; Niedzwiecki, D; Hollis, D; Mamon, HJ; Swanson, R; Haller, DG; Dragovich, T; Alberts, SR; Bjarnason, GA; Willett, CG; Enzinger, PC; Goldberg, RM; Venook, AP; Mayer, RJ
MLA Citation
Fuchs, CS, Tepper, JE, Niedzwiecki, D, Hollis, D, Mamon, HJ, Swanson, R, Haller, DG, Dragovich, T, Alberts, SR, Bjarnason, GA, Willett, CG, Enzinger, PC, Goldberg, RM, Venook, AP, and Mayer, RJ. "Postoperative adjuvant chemoradiation for gastric or gastroesophageal junction (GEJ) adenocarcinoma using epirubicin, cisplatin, and infusional (CI) 5-FU (ECF) before and after CI 5-FU and radiotherapy (CRT) compared with bolus 5-FU/LV before and after CRT: Intergroup trial CALGB 80101." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 29.15_suppl (May 2011): 4003-.
PMID
28020574
Source
epmc
Published In
Journal of Clinical Oncology
Volume
29
Issue
15_suppl
Publish Date
2011
Start Page
4003

Validation of a 12-gene colon cancer recurrence score (RS) in patients (pts) with stage II colon cancer (CC) from CALGB 9581.

3518 Background: The 12-gene RS (Genomic Health, Inc.) has been shown to predict risk of recurrence in stage II colon cancer (CC) pts in QUASAR. We conducted a validation study in tumor specimens from pts enrolled in CALGB 9581, which found no difference for edrecolomab (MoAb 17-1A) v. observation in 1672 pts with, on average, low risk stage II CC (14% 5-yr recurrence.) Methods: Cohort sampling included all pts with available tissue and recurrence and random pts w/o recurrence (3:1 ratio). Gene expression was analyzed by RT-PCR using FFPE from primary tumor. Mismatch repair (MMR) protein status (D= Deficient; I= Intact) was assessed by IHC for MLH1 and MSH2. Primary aim: prognostic value of continuous RS alone and in presence of MMR and traditional clinical/pathologic prognostic variables. A weighted Cox proportional hazards model was used to test the association between RS and recurrence-free interval (RFI) based on a Wald-type test statistic constructed using a weighted partial likelihood estimate and robust variance estimate.Tumor was available for 1361/1672 (81%) pts. RT-PCR was successful in 690 (162 recurrences) of 736 pts (21% MMR-D, 35% > 70 yrs old, 47% < 12 nodes.) The continuous RS was significantly associated with RFI in univariate analysis (hazard ratio (HR)/ 25 units, 1.52; 95% CI, 1.09-2.12; p=0.01). MMR-D was also associated with RFI (HR, 0.62; 95%CI, 0.39-0.99; p=0.04); # nodes examined and lymphovascular invasion (LVI) were borderline significant (both p=0.06). In a pre-specified multivariate analysis w/ MMR, T-stage, nodes examined, grade, and LVI, RS was the only significant predictor of recurrence (HR/25 units=1.68, 95%CI 1.18-2.38; p=0.004). Recurrence risk at 5 yrs increased as RS increased and among subgroups defined by T-stage and MMR. In pts with T3, MMR-I tumors (n=488) pre-specified low (44% of pts RS < 29), intermediate (33%), and high (22% w/ RS > 39) RS groups had average 5-yr recurrence risks of 13%, 16%, and 21%, respectively.In 9581, RS improves the ability to discriminate higher from lower recurrence risk stage II CC pts beyond known prognostic factors, particularly in T3, MMR-I pts where traditional factors like grade and LVI were not prognostic.

Authors
Venook, AP; Niedzwiecki, D; Lopatin, M; Lee, M; Friedman, PN; Frankel, W; Clark-Langone, K; Yoshizawa, C; Millward, C; Shak, S; Goldberg, RM; Mahmoud, NN; Schilsky, RL; Bertagnolli, MM
MLA Citation
Venook, AP, Niedzwiecki, D, Lopatin, M, Lee, M, Friedman, PN, Frankel, W, Clark-Langone, K, Yoshizawa, C, Millward, C, Shak, S, Goldberg, RM, Mahmoud, NN, Schilsky, RL, and Bertagnolli, MM. "Validation of a 12-gene colon cancer recurrence score (RS) in patients (pts) with stage II colon cancer (CC) from CALGB 9581." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 29.15_suppl (May 2011): 3518-.
PMID
28020339
Source
epmc
Published In
Journal of Clinical Oncology
Volume
29
Issue
15_suppl
Publish Date
2011
Start Page
3518

Relationship between statin use and colon cancer recurrence and survival: Results from CALGB 89803

Background Although preclinical and epidemiological data suggest that statins may have antineoplastic properties, the impact of statin use on patient survival after a curative resection of stage III colon cancer is unknown. Methods We conducted a prospective observational study of 842 patients with stage III colon cancer enrolled in a randomized adjuvant chemotherapy trial from April 1999 to May 2001 to investigate the relationship between statin use and survival. Disease-free survival (DFS), recurrence-free survival (RFS), and overall survival (OS) were investigated by Kaplan-Meier curves and log-rank tests in the overall study population and in a subset of patients stratified by KRAS mutation status (n = 394), and Cox proportional hazards regression was used to assess the simultaneous impact of confounding variables. All statistical tests were two-sided. Results Among 842 patients, 134 (15.9%) reported statin use after completing adjuvant chemotherapy. DFS among statin users and nonusers was similar (hazard ratio [HR] of cancer recurrence or death = 1.04, 95% confidence interval [CI] = 0.73 to 1.49). RFS and OS were also similar between statin users and nonusers (adjusted HR of cancer recurrence = 1.14, 95% CI = 0.77 to 1.69; adjusted HR of death = 1.15, 95% CI = 0.77 to 1.71). Survival outcomes were similar regardless of increasing duration of statin use before cancer diagnosis (Ptrend =. 63,. 63, and. 59 for DFS, RFS, and OS, respectively). The impact of statin use did not differ by tumor KRAS mutation status, with similar DFS, RFS, and OS for statin use among mutant and wild-type subgroups (Pinteraction =. 84,. 67, and. 98 for DFS, RFS, and OS, respectively). Conclusion Statin use during and after adjuvant chemotherapy was not associated with improved DFS, RFS, or OS in patients with stage III colon cancer, regardless of KRAS mutation status. © The Author 2011. Published by Oxford University Press.

Authors
Ng, K; Ogino, S; Meyerhardt, JA; Chan, JA; Chan, AT; Niedzwiecki, D; Hollis, D; Saltz, LB; Mayer, RJ; Benson, AB; Schaefer, PL; Whittom, R; Hantel, A; Goldberg, RM; Bertagnolli, MM; Venook, AP; Fuchs, CS
MLA Citation
Ng, K, Ogino, S, Meyerhardt, JA, Chan, JA, Chan, AT, Niedzwiecki, D, Hollis, D, Saltz, LB, Mayer, RJ, Benson, AB, Schaefer, PL, Whittom, R, Hantel, A, Goldberg, RM, Bertagnolli, MM, Venook, AP, and Fuchs, CS. "Relationship between statin use and colon cancer recurrence and survival: Results from CALGB 89803." Journal of the National Cancer Institute 103.20 (2011): 1540-1551.
PMID
21849660
Source
scival
Published In
Journal of the National Cancer Institute
Volume
103
Issue
20
Publish Date
2011
Start Page
1540
End Page
1551
DOI
10.1093/jnci/djr307

Microsatellite instability and loss of heterozygosity at chromosomal location 18q: Pospective evaluation of biomarkers for stages II and III colon cancer - A study of CALGB 9581 and 89803

Purpose: Colorectal cancer (CRC) develops as a result of a series of accumulated genomic changes that produce oncogene activation and tumor suppressor gene loss. These characteristics may classify CRC into subsets of distinct clinical behaviors. Patients and Methods: We studied two of these genomic defects - mismatch repair deficiency (MMR-D) and loss of heterozygosity at chromosomal location 18q (18qLOH) - in patients enrolled onto two phase III cooperative group trials for treatment of potentially curable colon cancer. These trials included prospective secondary analyses to determine the relationship between these markers and treatment outcome. A total of 1,852 patients were tested for MMR status and 955 (excluding patients with MMR-D tumors) for 18qLOH. Results: Compared with stage III, more stage II tumors were MMR-D (21.3% v 14.4%; P < .001) and were intact at 18q (24.2% v 15.1%; P = .001). For the combined cohort, patients with MMR-D tumors had better 5-year disease-free survival (DFS; 0.76 v 0.67; P < .001) and overall survival (OS; 0.81 v 0.78; P = .029) than those with MMR intact (MMR-I) tumors. Among patients with MMR-I tumors, the status of 18q did not affect outcome, with 5-year values for patients with 18q intact versus 18qLOH tumors of 0.74 versus 0.65 (P = .18) for DFS and 0.81 versus 0.77 (P = .18) for OS. Conclusion: We conclude that MMR-D tumor status, but not the presence of 18qLOH, has prognostic value for stages II and III colon cancer. © 2011 by American Society of Clinical Oncology.

Authors
Bertagnolli, MM; Redston, M; Compton, CC; Niedzwiecki, D; Mayer, RJ; Goldberg, RM; Colacchio, TA; Saltz, LB; Warren, RS
MLA Citation
Bertagnolli, MM, Redston, M, Compton, CC, Niedzwiecki, D, Mayer, RJ, Goldberg, RM, Colacchio, TA, Saltz, LB, and Warren, RS. "Microsatellite instability and loss of heterozygosity at chromosomal location 18q: Pospective evaluation of biomarkers for stages II and III colon cancer - A study of CALGB 9581 and 89803." Journal of Clinical Oncology 29.23 (2011): 3153-3162.
PMID
21747089
Source
scival
Published In
Journal of Clinical Oncology
Volume
29
Issue
23
Publish Date
2011
Start Page
3153
End Page
3162
DOI
10.1200/JCO.2010.33.0092

A phase 2 trial of gemcitabine, 5-fluorouracil, and radiation therapy in locally advanced nonmetastatic pancreatic adenocarcinoma

BACKGROUND: The purpose of this study was to assess the efficacy and safety of 5-fluorouracil (5FU) and gemcitabine administered concurrently with radiation in patients with locally advanced, nonmetastatic pancreatic cancer. METHODS: Eligible patients had histologically confirmed pancreatic adenocarcinoma deemed locally unresectable without evidence of metastatic disease. In addition, all patients underwent laparoscopy or laparotomy before study entry to rule out peritoneal carcinomatosis. Patients received radiation therapy (50.4 Gy) with concurrent infusional 5FU (200 mg/m2 5 days/week) and weekly gemcitabine (200 mg/m2). After a 3-week break, patients received weekly gemcitabine at 1000 mg/m2 for 3 of 4 weeks, for 4 cycles. The primary endpoint of the trial was the proportion of patients surviving 9 months from study entry. Secondary endpoints included objective tumor response, CA19-9 response, overall survival (OS) time to progression (TTP), and toxicity. RESULTS: Between November 2001 and October 2004, 81 patients were enrolled, 78 of whom were eligible for analysis. With a median follow-up of 55.2 months, the median OS was 12.2 months (95% confidence interval [CI], 10.9-14.9) and the median TTP was 10 months (95% CI, 6.4-12.0). An objective tumor response was seen in 19 patients (25%), and among 56 patients with an elevated CA19-9 at baseline, 29 (52%) had a sustained CA19-9 response. Overall, 41% of patients had grade 3 or greater treatment-related gastrointestinal adverse events. CONCLUSIONS: The combination of 5FU, gemcitabine, and radiation is well tolerated. Survival is comparable with the best results of other recent studies of 5FU and radiation or gemcitabine and radiation. Copyright © 2010 American Cancer Society.

Authors
Mamon, HJ; Niedzwiecki, D; Hollis, D; Tan, BR; Mayer, RJ; Tepper, JE; Goldberg, RM; Blackstock, AW; Fuchs, CS
MLA Citation
Mamon, HJ, Niedzwiecki, D, Hollis, D, Tan, BR, Mayer, RJ, Tepper, JE, Goldberg, RM, Blackstock, AW, and Fuchs, CS. "A phase 2 trial of gemcitabine, 5-fluorouracil, and radiation therapy in locally advanced nonmetastatic pancreatic adenocarcinoma." Cancer 117.12 (2011): 2620-2628.
PMID
21656739
Source
scival
Published In
Cancer
Volume
117
Issue
12
Publish Date
2011
Start Page
2620
End Page
2628
DOI
10.1002/cncr.25742

Adult Dual Umbilical Cord Blood Transplantation Using Myeloablative Total Body Irradiation (1350cGy) and Fludarabine Conditioning

Authors
Kanda, J; Rizzieri, DA; Gasparetto, C; Long, GD; Chute, JP; Sullivan, KM; Morris, A; Smith, CA; Hogge, DE; Nitta, J; Song, K; Niedzwiecki, D; Chao, NJ; Horwitz, ME
MLA Citation
Kanda, J, Rizzieri, DA, Gasparetto, C, Long, GD, Chute, JP, Sullivan, KM, Morris, A, Smith, CA, Hogge, DE, Nitta, J, Song, K, Niedzwiecki, D, Chao, NJ, and Horwitz, ME. "Adult Dual Umbilical Cord Blood Transplantation Using Myeloablative Total Body Irradiation (1350cGy) and Fludarabine Conditioning." November 19, 2010.
PMID
28729147
Source
wos-lite
Published In
Blood
Volume
116
Issue
21
Publish Date
2010
Start Page
1448
End Page
1448

A Comprehensive Comparison Immune Recovery In Adult Patients Following Allogeneic Umbilical Cord Blood, Matched Sibling and Matched Unrelated Donor Stem Cell Transplantation

Authors
Chiou, L-W; Kanda, J; Szabolcs, P; Sempowski, GE; Hale, J; Niedzwiecki, D; Broadwater, G; Chao, NJ; Horwitz, ME
MLA Citation
Chiou, L-W, Kanda, J, Szabolcs, P, Sempowski, GE, Hale, J, Niedzwiecki, D, Broadwater, G, Chao, NJ, and Horwitz, ME. "A Comprehensive Comparison Immune Recovery In Adult Patients Following Allogeneic Umbilical Cord Blood, Matched Sibling and Matched Unrelated Donor Stem Cell Transplantation." November 19, 2010.
Source
wos-lite
Published In
Blood
Volume
116
Issue
21
Publish Date
2010
Start Page
954
End Page
955

Lung Transplantation Alters Esophageal Motility and is Associated with Abnormal pH Testing

Authors
Castor, J; Wood, R; Niedzwiecki, D; Muir, A; Palmer, S; Shimpi, R
MLA Citation
Castor, J, Wood, R, Niedzwiecki, D, Muir, A, Palmer, S, and Shimpi, R. "Lung Transplantation Alters Esophageal Motility and is Associated with Abnormal pH Testing." October 2010.
Source
wos-lite
Published In
The American Journal of Gastroenterology (Elsevier)
Volume
105
Publish Date
2010
Start Page
S13
End Page
S14

An alphavirus vector overcomes the presence of neutralizing antibodies and elevated numbers of Tregs to induce immune responses in humans with advanced cancer.

Therapeutic anticancer vaccines are designed to boost patients' immune responses to tumors. One approach is to use a viral vector to deliver antigen to in situ DCs, which then activate tumor-specific T cell and antibody responses. However, vector-specific neutralizing antibodies and suppressive cell populations such as Tregs remain great challenges to the efficacy of this approach. We report here that an alphavirus vector, packaged in virus-like replicon particles (VRP) and capable of efficiently infecting DCs, could be repeatedly administered to patients with metastatic cancer expressing the tumor antigen carcinoembryonic antigen (CEA) and that it overcame high titers of neutralizing antibodies and elevated Treg levels to induce clinically relevant CEA-specific T cell and antibody responses. The CEA-specific antibodies mediated antibody-dependent cellular cytotoxicity against tumor cells from human colorectal cancer metastases. In addition, patients with CEA-specific T cell responses exhibited longer overall survival. These data suggest that VRP-based vectors can overcome the presence of neutralizing antibodies to break tolerance to self antigen and may be clinically useful for immunotherapy in the setting of tumor-induced immunosuppression.

Authors
Morse, MA; Hobeika, AC; Osada, T; Berglund, P; Hubby, B; Negri, S; Niedzwiecki, D; Devi, GR; Burnett, BK; Clay, TM; Smith, J; Lyerly, HK
MLA Citation
Morse, MA, Hobeika, AC, Osada, T, Berglund, P, Hubby, B, Negri, S, Niedzwiecki, D, Devi, GR, Burnett, BK, Clay, TM, Smith, J, and Lyerly, HK. "An alphavirus vector overcomes the presence of neutralizing antibodies and elevated numbers of Tregs to induce immune responses in humans with advanced cancer." J Clin Invest 120.9 (September 2010): 3234-3241.
Website
http://hdl.handle.net/10161/4330
PMID
20679728
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
120
Issue
9
Publish Date
2010
Start Page
3234
End Page
3241
DOI
10.1172/JCI42672

Overcoming drug resistance in mantle cell lymphoma using a combination of dose-dense and intense therapy.

We present a study of the prevalence of genetic polymorphisms and expression of genes encoding the drug-resistance proteins glutathione S-transferases (GSTs) in order to gain insights into the pattern of failure evident in mantle cell lymphoma. We note a high preponderance of genetic alterations conferring resistance to standard chemotherapy in this illness. Concurrent with this investigation, we present a series of patients who were provided dose-dense and intense chemotherapy to circumvent these drug-resistance mechanisms. High responses were noted, though durable remissions were few, indicating non-traditional chemotherapy options are important to investigate in this illness.

Authors
Crout, CA; Koh, L-P; Gockerman, JP; Moore, JO; Decastro, C; Long, GD; Diehl, L; Gasparetto, C; Niedzwiecki, D; Edwards, J; Prosnitz, L; Horwitz, M; Chute, J; Morris, A; Davis, P; Beaven, A; Chao, NJ; Ali-Osman, F; Rizzieri, DA
MLA Citation
Crout, CA, Koh, L-P, Gockerman, JP, Moore, JO, Decastro, C, Long, GD, Diehl, L, Gasparetto, C, Niedzwiecki, D, Edwards, J, Prosnitz, L, Horwitz, M, Chute, J, Morris, A, Davis, P, Beaven, A, Chao, NJ, Ali-Osman, F, and Rizzieri, DA. "Overcoming drug resistance in mantle cell lymphoma using a combination of dose-dense and intense therapy." Cancer Invest 28.6 (July 2010): 654-660.
PMID
20521909
Source
pubmed
Published In
Cancer Investigation (Informa)
Volume
28
Issue
6
Publish Date
2010
Start Page
654
End Page
660
DOI
10.3109/07357901003631015

Effect of a novel recombinant alphaviral vector on tolerance to self-antigen in the setting of elevated regulatory T cells.

Authors
Morse, M; Hobeika, A; Osada, T; Berglund, P; Negri, S; Niedzwiecki, D; Hubby, B; Burnett, B; Clay, TM; Lyerly, HK
MLA Citation
Morse, M, Hobeika, A, Osada, T, Berglund, P, Negri, S, Niedzwiecki, D, Hubby, B, Burnett, B, Clay, TM, and Lyerly, HK. "Effect of a novel recombinant alphaviral vector on tolerance to self-antigen in the setting of elevated regulatory T cells." May 20, 2010.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
28
Issue
15
Publish Date
2010

A randomized phase II study of three standard chemotherapy regimens (ECF, IC, FOLFOX) plus cetuximab in metastatic esophageal and GE junction cancer

Authors
Enzinger, PC; Burtness, B; Hollis, D; Niedzwiecki, D; Ilson, D; Benson, AB; Mayer, RJ; Goldberg, RM
MLA Citation
Enzinger, PC, Burtness, B, Hollis, D, Niedzwiecki, D, Ilson, D, Benson, AB, Mayer, RJ, and Goldberg, RM. "A randomized phase II study of three standard chemotherapy regimens (ECF, IC, FOLFOX) plus cetuximab in metastatic esophageal and GE junction cancer." JOURNAL OF CLINICAL ONCOLOGY 28.15 (May 20, 2010).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
28
Issue
15
Publish Date
2010

Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: Phase III trial of the Cancer and Leukemia Group B (CALGB 80303)

Purpose: The combination of gemcitabine plus bevacizumab produced a 21% response rate and a median survival of 8.8 months in a multicenter phase II trial in patients with metastatic pancreatic cancer. These encouraging data led Cancer and Leukemia Group B (CALGB) to conduct a double-blind, placebo-controlled, randomized phase III trial of gemcitabine/bevacizumab versus gemcitabine/ placebo in advanced pancreatic cancer patients. Patients and Methods: Eligible patients had no prior therapy for advanced disease, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2, no tumor invasion of adjacent organs, and no increased bleeding risk. The primary end point was overall survival. Patients were stratified by performance status, extent of disease, and prior radiotherapy. Patients received gemcitabine at 1,000 mg/m2 over 30 minutes on days 1, 8, and 15 every 28 days and bevacizumab at 10 mg/kg or placebo on days 1 and 15 every 28 days. Results: Between June 2004 and April 2006, 602 patients were enrolled onto the study and 535 were treated. Median overall survival was 5.8 months for gemcitabine/bevacizumab and 5.9 months for gemcitabine/placebo (P = .95). Median progression-free survival was 3.8 and 2.9 months, respectively (P = .07). Overall response rates were 13% and 10%, respectively. Patients with a performance status of 0, 1, and 2 survived a median of 7.9, 4.8, and 2.4 months, respectively. The only statistically significant differences in grades 3 and 4 toxicity occurred for hypertension (10% v 3%; P <.001) and proteinuria (5% v 1%; P =.002); venous thrombosis grade ≥ 3 was equivalent in both arms (14% and 15%, respectively). Conclusion: The addition of bevacizumab to gemcitabine does not improve survival in advanced pancreatic cancer patients. © 2010 by American Society of Clinical Oncology.

Authors
Kindler, HL; Niedzwiecki, D; Hollis, D; Sutherland, S; Schrag, D; Hurwitz, H; Innocenti, F; Mulcahy, MF; O'Reilly, E; Wozniak, TF; Picus, J; Bhargava, P; Mayer, RJ; Schilsky, RL; Goldberg, RM
MLA Citation
Kindler, HL, Niedzwiecki, D, Hollis, D, Sutherland, S, Schrag, D, Hurwitz, H, Innocenti, F, Mulcahy, MF, O'Reilly, E, Wozniak, TF, Picus, J, Bhargava, P, Mayer, RJ, Schilsky, RL, and Goldberg, RM. "Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: Phase III trial of the Cancer and Leukemia Group B (CALGB 80303)." Journal of Clinical Oncology 28.22 (2010): 3617-3622.
PMID
20606091
Source
scival
Published In
Journal of Clinical Oncology
Volume
28
Issue
22
Publish Date
2010
Start Page
3617
End Page
3622
DOI
10.1200/JCO.2010.28.1386

Optimizing collection of adverse event data in cancer clinical trials supporting supplemental indications

Purpose: Although much is known about the safety of an anticancer agent at the time of initial marketing approval, sponsors customarily collect comprehensive safety data for studies that support supplemental indications. This adds significant cost and complexity to the study but may not provide useful new information. The main purpose of this analysis was to assess the amount of safety and concomitant medication data collected to determine a more optimal approach in the collection of these data when used in support of supplemental applications. Methods: Following a prospectively developed statistical analysis plan, we reanalyzed safety data from eight previously completed prospective randomized trials. Results: A total of 107,884 adverse events and 136,608 concomitant medication records were reviewed for the analysis. Of these, four grade 1 to 2 and nine grade 3 and higher events were identified as drug effects that were not included in the previously established safety profiles and could potentially have been missed using subsampling. These events were frequently detected in subsamples of 400 patients or larger. Furthermore, none of the concomitant medication records contributed to labeling changes for the supplemental indications. Conclusion: Our study found that applying the optimized methodologic approach, described herein, has a high probability of detecting new drug safety signals. Focusing data collection on signals that cause physicians to modify or discontinue treatment ensures that safety issues of the highest concern for patients and regulators are captured and has significant potential to relieve strain on the clinical trials system. © 2010 by American Society of Clinical Oncology.

Authors
Kaiser, LD; Melemed, AS; Preston, AJ; Ross, HAC; Niedzwiecki, D; Fyfe, GA; Gough, JM; Bushnell, WD; Stephens, CL; Mace, MK; Abrams, JS; Schilsky, RL
MLA Citation
Kaiser, LD, Melemed, AS, Preston, AJ, Ross, HAC, Niedzwiecki, D, Fyfe, GA, Gough, JM, Bushnell, WD, Stephens, CL, Mace, MK, Abrams, JS, and Schilsky, RL. "Optimizing collection of adverse event data in cancer clinical trials supporting supplemental indications." Journal of Clinical Oncology 28.34 (2010): 5046-5053.
PMID
20921453
Source
scival
Published In
Journal of Clinical Oncology
Volume
28
Issue
34
Publish Date
2010
Start Page
5046
End Page
5053
DOI
10.1200/JCO.2010.29.6608

A Cancer and Leukemia group B phase II study of sunitinib malate in patients with previously treated metastatic pancreatic adenocarcinoma (CALGB 80603)

Background. The Cancer and Leukemia Group B (CALGB) conducted a phase II study evaluating sunitinib in patients with progressive metastatic pancreas adenocarcinoma following prior gemcitabinebased therapy (trial CALGB 80603; ClinicalTrials.gov identifier, NCT00397787). The primary endpoint was to determine the disease control rate (DCR) as measured by the Response Evaluation Criteria in Solid Tumors (complete response, partial response [PR], and stable disease) at 6 weeks. Patients and Methods. Patients aged >18 years with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 -2 and with progressive pancreas adenocarcinoma following treatment with gemcitabine were eligible. Sunitinib was dosed at 50 mg orally days 1-28, every 42 days (1 cycle). The statistical plan called for a three-stage design. A DCR >15% was considered worthy of further study. Results. In total, 77 patients were enrolled. Forty-two (54.6%) enrollees were male. The median age was 65 years. The ECOG performance status score distribution was: 0, 39%; 1, 50%; 2, 11%. The DCR was 21.6%; one patient (1.4%) had a PR and 15 patients (20.3%) had stable disease as their best response. The progression-free survival time was 1.31 months (95% confidence interval [CI] 1.25-1.38 months) and overall survival time was 3.68 months (95% CI, 3.06-4.24 months). Conclusions. The study met its primary endpoint; however sunitinib had minimal activity and moderate toxicity in a population of gemcitabine-refractory pancreas adenocarcinoma patients. For future studies, limiting enrollment to patients with an ECOG performance status score of 0-1 is recommended. © AlphaMed Press.

Authors
O'reilly, EM; Niedzwiecki, D; Hall, M; Hollis, D; Bekaii-Saab, T; Pluard, T; Douglas, K; Abou-Alfa, GK; Kindler, HL; Schilsky, RL; Goldberg, RM
MLA Citation
O'reilly, EM, Niedzwiecki, D, Hall, M, Hollis, D, Bekaii-Saab, T, Pluard, T, Douglas, K, Abou-Alfa, GK, Kindler, HL, Schilsky, RL, and Goldberg, RM. "A Cancer and Leukemia group B phase II study of sunitinib malate in patients with previously treated metastatic pancreatic adenocarcinoma (CALGB 80603)." Oncologist 15.12 (2010): 1310-1319.
PMID
21148613
Source
scival
Published In
The oncologist
Volume
15
Issue
12
Publish Date
2010
Start Page
1310
End Page
1319
DOI
10.1634/theoncologist.2010-0152

Multivitamin use is not associated with cancer recurrence or survival in patients with stage III colon cancer: Findings from CALGB 89803

Purpose: Multivitamin use is widespread in the United States, especially among patients with cancer. However, the influence of multivitamin supplementation on cancer recurrence and death after a curative resection of colon cancer is unknown. Patients and Methods: We conducted a prospective, observational study of 1,038 patients with stage III colon cancer enrolled in a randomized adjuvant chemotherapy trial. Patients reported on multivitamin use during and 6 months after adjuvant chemotherapy. Patients were observed until March 2009 for disease recurrence and death. To minimize bias by occult recurrence, we excluded patients who recurred or died within 90 days of their multivitamin assessment. Results: Among 1,038 patients, 518 (49.9%) reported multivitamin use during adjuvant chemotherapy. Compared with nonusers, the multivariate hazard ratio (HR) for disease-free survival was 0.94 (95% CI, 0.77 to 1.15) for patients who used multivitamins. Similarly, multivitamin use during adjuvant chemotherapy was not significantly associated with recurrence-free survival (multivariate HR, 0.93; 95% CI, 0.75 to 1.15) or overall survival (multivariate HR 0.92; 95% CI, 0.74 to 1.16). Multivitamin use reported 6 months after completion of adjuvant chemotherapy was also not associated with improved patient outcome, and consistent use both during and following adjuvant therapy conferred no benefit. Neither an increasing number of tablets nor increasing duration of use before cancer diagnosis was associated with cancer recurrence or mortality. Multivitamin use also did not improve the rates of grade 3 and higher GI toxicity. Conclusion: Multivitamin use during and after adjuvant chemotherapy was not significantly associated with improved outcomes in patients with stage III colon cancer. © 2010 by American Society of Clinical Oncology.

Authors
Ng, K; Meyerhardt, JA; Chan, JA; Niedzwiecki, D; Hollis, DR; Saltz, LB; Mayer, RJ; III, ABB; Schaefer, PL; Whittom, R; Hantel, A; Goldberg, RM; Fuchs, CS
MLA Citation
Ng, K, Meyerhardt, JA, Chan, JA, Niedzwiecki, D, Hollis, DR, Saltz, LB, Mayer, RJ, III, ABB, Schaefer, PL, Whittom, R, Hantel, A, Goldberg, RM, and Fuchs, CS. "Multivitamin use is not associated with cancer recurrence or survival in patients with stage III colon cancer: Findings from CALGB 89803." Journal of Clinical Oncology 28.28 (2010): 4354-4363.
PMID
20805450
Source
scival
Published In
Journal of Clinical Oncology
Volume
28
Issue
28
Publish Date
2010
Start Page
4354
End Page
4363
DOI
10.1200/JCO.2010.28.0362

Impact of smoking on patients with stage iii colon cancer: Results from cancer and leukemia group B 89803

BACKGROUND: Cigarette smoking has been shown to increase the risk of developing colorectal cancer, particularly smoking early in life. Little is known about the impact of tobacco use on colon cancer recurrence among colon cancer survivors. METHODS: The authors prospectively collected lifetime smoking history from stage III colon cancer patients enrolled in a phase 3 trial via self-report questionnaires during and 6 months after completion of adjuvant chemotherapy. Smoking status was defined as never, current, or past. Lifetime pack-years were defined as number of lifetime packs of cigarettes. Patients were followed for recurrence or death. RESULTS: Data on smoking history were captured on 1045 patients with stage III colon cancer receiving adjuvant therapy (46% never smokers; 44% past; 10% current). The adjusted hazard ratio (HR) for disease-free survival (DFS) was 0.99 (95% confidence interval [CI], 0.70-1.41), 1.17 (95% CI 0.89-1.55), and 1.22 (95% CI 0.92-1.61) for lifetime pack-years 0-10, 10-20, and 20+, respectively, compared with never smoking (P = .16). In a preplanned exploratory analysis of smoking intensity early in life, the adjusted HR for 12+ pack-years before age 30 years for DFS was 1.37 (95% CI, 1.02-1.84) compared with never smoking (P = .04). The adjusted HR for DFS was 1.18 (95% CI, 0.92-1.50) for past smokers and 1.10 (95% CI, 0.73-1.64) for current smokers, compared with never smokers. CONCLUSIONS: Total tobacco usage early in life may be an important, independent prognostic factor of cancer recurrences and mortality in patients with stage III colon cancer. © 2010 American Cancer Society.

Authors
McCleary, NJ; Niedzwiecki, D; Hollis, D; Saltz, LB; Schaefer, P; Whittom, R; Hantel, A; Benson, A; Goldberg, R; Meyerhardt, JA
MLA Citation
McCleary, NJ, Niedzwiecki, D, Hollis, D, Saltz, LB, Schaefer, P, Whittom, R, Hantel, A, Benson, A, Goldberg, R, and Meyerhardt, JA. "Impact of smoking on patients with stage iii colon cancer: Results from cancer and leukemia group B 89803." Cancer 116.4 (2010): 957-966.
PMID
20052723
Source
scival
Published In
Cancer
Volume
116
Issue
4
Publish Date
2010
Start Page
957
End Page
966
DOI
10.1002/cncr.24866

Optimization of vaccine responses with an E1, E2b and E3-deleted Ad5 vector circumvents pre-existing anti-vector immunity.

Recombinant serotype 5 adenovirus (Ad5) vectors lacking E1 expression induce robust immune responses against encoded transgenes in pre-clinical models, but have muted responses in human trials because of widespread pre-existing anti-adenovirus immunity. Attempts to circumvent Ad5-specific immunity by using alternative serotypes or modifying capsid components have not yielded profound clinical improvement. To address this issue, we explored a novel alternative strategy, specifically reducing the expression of structural Ad5 genes by creating E1 and E2b deleted recombinant Ad5 vectors. Our data show that [E1-, E2b-]vectors retaining the Ad5 serotype are potent immunogens in pre-clinical models despite the presence of significant Ad5-specific immunity, in contrast to [E1-] vectors. These pre-clinical studies with E1 and E2b-deleted recombinant Ad5 vectors suggest that anti-Ad immunity will no longer be a limiting factor, and that clinical trials to evaluate their performance are warranted.

Authors
Osada, T; Yang, XY; Hartman, ZC; Glass, O; Hodges, BL; Niedzwiecki, D; Morse, MA; Lyerly, HK; Amalfitano, A; Clay, TM
MLA Citation
Osada, T, Yang, XY, Hartman, ZC, Glass, O, Hodges, BL, Niedzwiecki, D, Morse, MA, Lyerly, HK, Amalfitano, A, and Clay, TM. "Optimization of vaccine responses with an E1, E2b and E3-deleted Ad5 vector circumvents pre-existing anti-vector immunity." Cancer Gene Ther 16.9 (September 2009): 673-682.
PMID
19229288
Source
pubmed
Published In
Cancer Gene Therapy
Volume
16
Issue
9
Publish Date
2009
Start Page
673
End Page
682
DOI
10.1038/cgt.2009.17

KRAS mutation, cancer recurrence, and patient survival in stage III colon cancer: Findings from CALGB 89803

Authors
Fuchs, C; Ogino, S; Meyerhardt, JA; Irahara, N; Niedzwiecki, D; Hollis, D; Saltz, LB; Mayer, RJ; Bertagnolli, MM
MLA Citation
Fuchs, C, Ogino, S, Meyerhardt, JA, Irahara, N, Niedzwiecki, D, Hollis, D, Saltz, LB, Mayer, RJ, and Bertagnolli, MM. "KRAS mutation, cancer recurrence, and patient survival in stage III colon cancer: Findings from CALGB 89803." May 20, 2009.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
27
Issue
15
Publish Date
2009

Presence of 18q loss of heterozygosity (LOH) and disease-free and overall survival in stage II colon cancer: CALGB Protocol 9581

Authors
Bertagnolli, MM; Niedzwiecki, D; Hall, M; Jewell, SD; Mayer, RJ; Goldberg, RM; Colacchio, TA; Warren, RS; Redston, M
MLA Citation
Bertagnolli, MM, Niedzwiecki, D, Hall, M, Jewell, SD, Mayer, RJ, Goldberg, RM, Colacchio, TA, Warren, RS, and Redston, M. "Presence of 18q loss of heterozygosity (LOH) and disease-free and overall survival in stage II colon cancer: CALGB Protocol 9581." May 20, 2009.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
27
Issue
15
Publish Date
2009

KRAS mutation, cancer recurrence, and patient survival in stage III colon cancer: Findings from CALGB 89803.

4037 Purpose: KRAS mutation in stage IV colorectal cancer predicts resistance to anti-EGFR targeted treatment (cetuximab or panitumumab). However, whether the presence of KRAS mutation independently predicts the survival of colon cancer patients remains uncertain.We conducted a prospective observational study of 508 cases identified among 1264 patients with stage III colon cancer who enrolled in a randomized adjuvant chemotherapy trial (5-fluorouracil, leucovorin with or without irinotecan) between April 1999 and May 2001 (CALGB 89803; Saltz et al. J Clin Oncol 2007). KRAS mutations were detected in 178 tumors (35%) by Pyrosequencing. Kaplan-Meier and Cox proportional hazard models were used to assess the significance of KRAS mutational status and adjusted for potential confounders including age, sex, tumor location, T stage, N stage, performance status, adjuvant chemotherapy arm and microsatellite instability (MSI) status.When compared to patients with wild-type KRAS, those with a mutation in KRAS did not experience any difference in disease-free (DFS), recurrence-free (RFS), or overall survival (OS) (log-rank P>0.56 for DFS, RFS, and OS). Five-year DFS was 62% for KRAS-mutated and 63% for KRAS-wild-type patients. Five-year RFS was 64% for KRAS-mutated and 66% for KRAS- wild-type patients. Five-year OS was 74% for KRAS-mutated and 73% for KRAS-wild-type patients. The effect of KRAS mutation on patient survival did not differ according to clinical features, chemotherapy arm or MSI status, and the effect of adjuvant chemotherapy assignment on outcome did not differ according to KRAS status.In this large clinical trial of chemotherapy in patients with stage III colon cancer, KRAS mutational status was not associated with any significant influence on disease-free or overall survival. No significant financial relationships to disclose.

Authors
Fuchs, C; Ogino, S; Meyerhardt, JA; Irahara, N; Niedzwiecki, D; Hollis, D; Saltz, LB; Mayer, RJ; Bertagnolli, MM
MLA Citation
Fuchs, C, Ogino, S, Meyerhardt, JA, Irahara, N, Niedzwiecki, D, Hollis, D, Saltz, LB, Mayer, RJ, and Bertagnolli, MM. "KRAS mutation, cancer recurrence, and patient survival in stage III colon cancer: Findings from CALGB 89803." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 27.15_suppl (May 2009): 4037-.
PMID
27961543
Source
epmc
Published In
Journal of Clinical Oncology
Volume
27
Issue
15_suppl
Publish Date
2009
Start Page
4037

Presence of 18q loss of heterozygosity (LOH) and disease-free and overall survival in stage II colon cancer: CALGB Protocol 9581.

4012 Background: LOH at 18q is associated with poorer overall survival in patients with colon cancer; however available studies are retrospective and vary in analysis methods. We recently completed an 18qLOH assay method validation study, and after standardizing technique, this prospective study investigated the role of 18qLOH among patients with low-risk stage II colon cancer.In Cancer and Leukemia Group B (CALGB) protocol 9581, we randomized 1738 stage II patients to post-operative treatment with a 500 mg loading dose of monoclonal antibody 17-1A followed by four infusions of 100 mg every 28 days or observation. The primary endpoint was overall survival (OS); disease free survival (DFS) was a secondary endpoint. Status of 18qLOH was assessed in patients with available tissue and interpretable PCR results. Patients were excluded if their tumors were uninformative for 18qLOH or if their tumors displayed microsatellite instability.We report 18qLOH data on 156 patients. Patient characteristics including treatment, age, gender, performance status, site and grade of tumor, were similar between all patients enrolled and the subset of patients with tumor samples analyzed. The DFS and OS for treated and observed patients were no different (5-yr DFS: 0.81 and 0.80, p= 0.96; 5-yr OS: 0.88 and 0.86, p=0.44 at a median of 6.8 yrs of follow-up) and the data were pooled across the study's arms. Of the tumors examined, 101 (65%) were positive for 18qLOH. A significantly lower proportion of patients with 18qLOH-positive tumors had proximal tumors (46.5% vs 65.5%; p=0.02). Significantly decreased DFS and OS were observed in patients with 18qLOH-positive tumors. Five-year DFS among patients with 18qLOH-positive tumors was 0.78 vs 0.93 among patients with 18qLOH-negative tumors [HR 0.39; 95% CI (0.16, 0.94); logrank p=0.03 based on 33 events]. Five-year OS among patients with 18qLOH-positive tumors was 0.85 vs 0.98 among patients with 18qLOH-negative tumors [HR 0.25; 95% CI (0.07, 0.83); logrank p=0.01 based on 24 events]. Conclusions LOH at 18q was prognostic for DFS and OS among patients with available tissue for analysis after resection of low-risk stage II colon cancer who were not treated with chemotherapy in the adjuvant setting. [Table: see text].

Authors
Bertagnolli, MM; Niedzwiecki, D; Hall, M; Jewell, SD; Mayer, RJ; Goldberg, RM; Colacchio, TA; Warren, RS; Redston, M
MLA Citation
Bertagnolli, MM, Niedzwiecki, D, Hall, M, Jewell, SD, Mayer, RJ, Goldberg, RM, Colacchio, TA, Warren, RS, and Redston, M. "Presence of 18q loss of heterozygosity (LOH) and disease-free and overall survival in stage II colon cancer: CALGB Protocol 9581." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 27.15_suppl (May 2009): 4012-.
PMID
27961506
Source
epmc
Published In
Journal of Clinical Oncology
Volume
27
Issue
15_suppl
Publish Date
2009
Start Page
4012

Induction of Wilms' tumor protein (WT1)-specific antitumor immunity using a truncated WT1-expressing adenovirus vaccine.

PURPOSE: Wilms' tumor protein (WT1) is overexpressed in most leukemias and many solid tumors and is a promising target for tumor immunotherapy. WT1 peptide-based cancer vaccines have been reported but have limited application due to HLA restriction of the peptides. We sought to vaccinate using adenoviral (Ad) vectors encoding tumor-associated antigens such as WT1 that can stimulate tumor-associated antigen-specific immunity across a broad array of HLA types and multiple class I and class II epitopes. EXPERIMENTAL DESIGN: We developed a novel Ad vector encoding a truncated version of WT1 (Ad-tWT1) lacking the highly conserved COOH terminus zinc finger domains and tested its ability to stimulate WT1-specific immune responses and antitumor immunity in two murine models of WT1-expressing tumors. RESULTS: Despite encoding a transcription factor, we found that Ad-tWT1-transduced murine and human dendritic cells showed cytoplasmic expression of the truncated WT1 protein. In addition, vaccination of C57BL/6 mice with Ad-tWT1 generated WT1-specific cell-mediated and humoral immune responses and conferred protection against challenge with the leukemia cell line, mWT1-C1498. Moreover, in a tumor therapy model, Ad-tWT1 vaccination of TRAMP-C2 tumor-bearing mice significantly suppressed tumor growth. CONCLUSIONS: This is the first report of a WT1-encoding Ad vector that is capable of inducing effective immunity against WT1-expressing malignancies. Based on these findings, Ad-tWT1 warrants investigation in human clinical trials to evaluate its applications as a vaccine for patients with WT1-expressing cancers.

Authors
Osada, T; Woo, CY; McKinney, M; Yang, XY; Lei, G; Labreche, HG; Hartman, ZC; Niedzwiecki, D; Chao, N; Amalfitano, A; Morse, MA; Lyerly, HK; Clay, TM
MLA Citation
Osada, T, Woo, CY, McKinney, M, Yang, XY, Lei, G, Labreche, HG, Hartman, ZC, Niedzwiecki, D, Chao, N, Amalfitano, A, Morse, MA, Lyerly, HK, and Clay, TM. "Induction of Wilms' tumor protein (WT1)-specific antitumor immunity using a truncated WT1-expressing adenovirus vaccine." Clin Cancer Res 15.8 (April 15, 2009): 2789-2796.
PMID
19351755
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
15
Issue
8
Publish Date
2009
Start Page
2789
End Page
2796
DOI
10.1158/1078-0432.CCR-08-2589

Multiagent chemotherapy for isolated colorectal liver metastases: a single-centered retrospective study.

BACKGROUND: Few studies identifying variables associated with prognosis after resection of colorectal liver metastases (CLM) account for treatment with multiagent chemotherapy (fluoropyrmidines with irinotecan, oxaliplatin, bevacizumab, and/or cetuximab). The objective of this retrospective study was to determine the effect of multiagent chemotherapy on long-term survival after resection of CLM. METHODS: Demographics, clinicopathologic tumor characteristics, treatments, and long-term outcomes were reviewed. RESULTS: From 1996 to 2006, 230 patients underwent resection of CLM. Treatment strategies before and after resection included fluoropyrimidine monotherapy (n = 34 and n = 39), multiagent chemotherapy (n = 81 and n = 73), and observation (n = 115 and n = 118). Prehepatectomy treatment strategy was not associated with overall survival. Actuarial 4-year survival was 63%, 39%, and 40% for patients treated with multiagent chemotherapy, fluoropyrimidine monotherapy, and observation after hepatectomy, p = 0.06. Posthepatectomy multiagent chemotherapy (p = 0.04, HR 0.52 [0.27-1.03]), duration of posthepatectomy chemotherapy treatment of 2 months or longer (p = 0.05, HR 0.49 [0.25-0.99]), carcino-embryonic antigen level >10 ng/mL (p = 0.03, HR 2.09, 95% CI [1.32-3.32]), and node positive primary tumor (p = 0.002, HR 1.79 [1.06-3.02]) were associated with overall survival in multivariate analysis. CONCLUSIONS: The association of posthepatectomy multiagent chemotherapy with overall survival in this retrospective study indicates the need for prospective randomized trials comparing multiagent chemotherapy and fluoropyrimidine monotherapy for CLM.

Authors
Reddy, SK; Broadwater, G; Niedzwiecki, D; Barbas, AS; Hurwitz, HI; Bendell, JC; Morse, MA; Clary, BM
MLA Citation
Reddy, SK, Broadwater, G, Niedzwiecki, D, Barbas, AS, Hurwitz, HI, Bendell, JC, Morse, MA, and Clary, BM. "Multiagent chemotherapy for isolated colorectal liver metastases: a single-centered retrospective study." J Gastrointest Surg 13.1 (January 2009): 74-84.
PMID
18685900
Source
pubmed
Published In
Journal of Gastrointestinal Surgery
Volume
13
Issue
1
Publish Date
2009
Start Page
74
End Page
84
DOI
10.1007/s11605-008-0617-5

Long-term follow-up of survival in Hodgkin's lymphoma

Authors
Canellos, GP; Niedzwiecki, D; Johnson, JL
MLA Citation
Canellos, GP, Niedzwiecki, D, and Johnson, JL. "Long-term follow-up of survival in Hodgkin's lymphoma." New England Journal of Medicine 361.24 (2009): 2390-2391.
PMID
20007568
Source
scival
Published In
The New England journal of medicine
Volume
361
Issue
24
Publish Date
2009
Start Page
2390
End Page
2391
DOI
10.1056/NEJMc0906731

Immunochemotherapy and autologous stem-cell transplantation for untreated patients with mantle-cell lymphoma: CALGB 59909

Purpose: Mantle-cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin's lymphoma with a poor prognosis. We explored the feasibility, safety, and effectiveness of an aggressive immunochemotherapy treatment program that included autologous stem-cell transplantation (ASCT) for patients up to age 69 years with newly diagnosed MCL. Patients and Methods: The primary end point was 2-year progression-free survival (PFS). A successful trial would yield a 2-year PFS of at least 50% and an event rate (early progression plus nonrelapse mortality) less than 20% at day +100 following ASCT. Seventy-eight patients were treated with two or three cycles of rituximab combined with methotrexate and augmented CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone). This treatment was followed by intensification with high doses of cytarabine and etoposide combined with rituximab and filgrastim to mobilize autologous peripheral-blood stem cells. Patients then received high doses of carmustine, etoposide, and cyclophosphamide followed by ASCT and two doses of rituximab. Results: There were two nonrelapse mortalities, neither during ASCT. With a median follow-up of 4.7 years, the 2-year PFS was 76% (95% CI, 64% to 85%), and the 5-year PFS was 56% (95% CI, 43% to 68%). The 5-year overall survival was 64% (95% CI, 50% to 75%). The event rate by day + 100 of ASCT was 5.1%. Conclusion: The Cancer and Leukemia Group B 59909 regimen is feasible, safe, and effective in patients with newly diagnosed MCL. The incorporation of rituximab with aggressive chemotherapy and ASCT may be responsible for the encouraging outcomes demonstrated in this study, which produced results comparable to similar treatment regimens. © 2009 by American Society of Clinical Oncology.

Authors
Damon, LE; Johnson, JL; Niedzwiecki, D; Cheson, BD; Hurd, DD; Bartlett, NL; LaCasce, AS; Blum, KA; Byrd, JC; Kelly, M; Stock, W; Linker, CA; Canellos, GP
MLA Citation
Damon, LE, Johnson, JL, Niedzwiecki, D, Cheson, BD, Hurd, DD, Bartlett, NL, LaCasce, AS, Blum, KA, Byrd, JC, Kelly, M, Stock, W, Linker, CA, and Canellos, GP. "Immunochemotherapy and autologous stem-cell transplantation for untreated patients with mantle-cell lymphoma: CALGB 59909." Journal of Clinical Oncology 27.36 (2009): 6101-6108.
PMID
19917845
Source
scival
Published In
Journal of Clinical Oncology
Volume
27
Issue
36
Publish Date
2009
Start Page
6101
End Page
6108
DOI
10.1200/JCO.2009.22.2554

KRAS mutation in stage III colon cancer and clinical outcome following intergroup trial CALGB 89803

Purpose: Alterations in the RAS and RAF pathway relate to epigenetic and epigenomic aberrations, and are important in colorectal carcinogenesis. KRAS mutation in metastatic colorectal cancer predicts resistance to anti-epidermal growth factor receptor (EGFR)-targeted therapy (cetuximab or panitumumab). It remains uncertain, however, whether KRAS mutation predicts prognosis or clinical outcome of colon cancer patients independent of anti-EGFR therapy. Methods: We conducted a study of 508 cases identified among 1,264 patients with stage III colon cancer who enrolled in a randomized adjuvant chemotherapy trial (5-fluorouracil, leucovorin with or without irinotecan) in 1999-2001 (CALGB 89803). KRAS mutations were detected in 178 tumors (35%) by pyrosequencing. Kaplan-Meier and Cox proportional hazard models assessed the prognostic significance of KRAS mutation and adjusted for potential confounders including age, sex, tumor location, tumor/ node stage, performance status, adjuvant chemotherapy arm, and microsatellite instability status. Results: Compared with patients with KRAS-wild-type tumors, patients with KRAS-mutated tumors did not experience any difference in disease-free, recurrence-free, or overall survival. The 5-year disease-free, recurrence-free, and overall survival rates (KRAS-mutated versus KRAS-wild-type patients) were 62% versus 63% (log-rank P = 0.89), 64% versus 66% (P = 0.84), and 75% versus 73% (P = 0.56), respectively. The effect of KRAS mutation on patient survival did not significantly differ according to clinical features, chemotherapy arm, or microsatellite instability status, and the effect of adjuvant chemotherapy assignment on outcome did not differ according to KRAS status. Conclusions: In this large trial of chemotherapy in stage III colon cancer patients, KRAS mutational status was not associated with any significant influence on disease-free or overall survival. © 2009 American Association for Cancer Research.

Authors
Ogino, S; Meyerhardt, JA; Irahara, N; Niedzwiecki, D; Hollis, D; Saltz, LB; Mayer, RJ; Schaefer, P; Whittom, R; Hantel, A; III, ABB; Goldberg, RM; Bertagnolli, MM; Fuchs, CS
MLA Citation
Ogino, S, Meyerhardt, JA, Irahara, N, Niedzwiecki, D, Hollis, D, Saltz, LB, Mayer, RJ, Schaefer, P, Whittom, R, Hantel, A, III, ABB, Goldberg, RM, Bertagnolli, MM, and Fuchs, CS. "KRAS mutation in stage III colon cancer and clinical outcome following intergroup trial CALGB 89803." Clinical Cancer Research 15.23 (2009): 7322-7329.
PMID
19934290
Source
scival
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
15
Issue
23
Publish Date
2009
Start Page
7322
End Page
7329
DOI
10.1158/1078-0432.CCR-09-1570

Randomized phase II study of gemcitabine administered at a fixed dose rate or in combination with cisplatin, docetaxel, or irinotecan in patients with metastatic pancreatic cancer: CALGB 89904

Purpose: The relative value of gemcitabine-based combination chemotherapy therapy and prolonged infusions of gemcitabine in patients with advanced pancreatic cancer remains controversial. We explored the efficacy and toxicity of gemcitabine administered at a fixed dose rate or in combination with cisplatin, docetaxel, or irinotecan in a multi-institutional, randomized, phase II study. Patients and Methods: Patients with metastatic pancreatic cancer were randomly assigned to one of the following four regimens: gemcitabine 1,000 mg/m2 on days 1, 8, and 15 with cisplatin 50 mg/m2 on days 1 and 15 (arm A); gemcitabine 1,500 mg/m2 at a rate of 10 mg/m 2/min on days 1, 8, and 15 (arm B); gemcitabine 1,000 mg/m 2 with docetaxel 40 mg/m2 on days 1 and 8 (arm C); or gemcitabine 1,000 mg/m2 with irinotecan 100 mg/m2 on days 1 and 8 (arm D). Patients were observed for response, toxicity, and survival. Results: Two hundred fifty-nine patients were enrolled onto the study, of whom 245 were eligible and received treatment. Anticipated rates of myelosuppression, fatigue, and expected regimenspecific toxicities were observed. The overall tumor response rates were 12% to 14%, and the median overall survival times were 6.4 to 7.1 months among the four regimens. Conclusion: Gemcitabine/cisplatin, fixed dose rate gemcitabine, gemcitabine/docetaxel, and gemcitabine/irinotecan have similar antitumor activity in metastatic pancreatic cancer. In light of recent negative randomized studies directly comparing several of these regimens with standard gemcitabine, none of these approaches can be recommended for routine use in patients with this disease. © 2009 by American Society of Clinical Oncology.

Authors
Kulke, MH; Tempero, MA; Niedzwiecki, D; Hollis, DR; Kindler, HL; Cusnir, M; Enzinger, PC; Gorsch, SM; Goldberg, RM; Mayer, RJ
MLA Citation
Kulke, MH, Tempero, MA, Niedzwiecki, D, Hollis, DR, Kindler, HL, Cusnir, M, Enzinger, PC, Gorsch, SM, Goldberg, RM, and Mayer, RJ. "Randomized phase II study of gemcitabine administered at a fixed dose rate or in combination with cisplatin, docetaxel, or irinotecan in patients with metastatic pancreatic cancer: CALGB 89904." Journal of Clinical Oncology 27.33 (2009): 5506-5512.
PMID
19858396
Source
scival
Published In
Journal of Clinical Oncology
Volume
27
Issue
33
Publish Date
2009
Start Page
5506
End Page
5512
DOI
10.1200/JCO.2009.22.1309

Erratum: A phase II prospective multi-institutional trial of adjuvant active specific immunotherapy following curative resection of colorectal cancer hepatic metastases: Cancer and leukemia group B study 89903 (Annals of Surgical Oncology (2008) 15 (158-164) DOI: 10.1245/S10434-007-9654-7)

Authors
Posner, MC; Niedzwiecki, D; Venook, AP; Hollis, DR; Kindler, HL; Martin, EW; Schilsky, RL; Goldberg, RM; Mayer, RJ
MLA Citation
Posner, MC, Niedzwiecki, D, Venook, AP, Hollis, DR, Kindler, HL, Martin, EW, Schilsky, RL, Goldberg, RM, and Mayer, RJ. "Erratum: A phase II prospective multi-institutional trial of adjuvant active specific immunotherapy following curative resection of colorectal cancer hepatic metastases: Cancer and leukemia group B study 89903 (Annals of Surgical Oncology (2008) 15 (158-164) DOI: 10.1245/S10434-007-9654-7)." Annals of Surgical Oncology 16.8 (2009): 2381--.
Source
scival
Published In
Annals of Surgical Oncology
Volume
16
Issue
8
Publish Date
2009
Start Page
2381-
DOI
10.1245/s10434-009-0466-9

Microsatellite instability predicts improved response to adjuvant therapy with irinotecan, fluorouracil, and leucovorin in stage III colon cancer: Cancer and leukemia group B protocol 89803

Purpose Colon cancers exhibiting DNA mismatch repair (MMR) defects demonstrate distinct clinical and pathologic features, including better prognosis and reduced response to fluorouracil (FU) -based chemotherapy. This prospective study investigated adjuvant chemotherapy containing FU and irinotecan in patients with MMR deficient (MMR-D) colon cancers. Patients and Methods Cancer and Leukemia Group B 89803 randomly assigned 1,264 patients with stage III colon cancer to postoperative weekly bolus FU/leucovorin (LV) or weekly bolus irinotecan, FU, and LV (IFL). The primary end point was overall survival; disease-free survival (DFS) was a secondary end point. Tumor expression of the MMR proteins, MLH1 and MSH2, was determined by immunohisto- chemistry (IHC). DNA microsatellite instability was also assessed using a panel of mono- and dinucleotide markers. Tumors with MMR defects were those demonstrating loss of MMR protein expression (MMR-D) and/or microsatellite instability high (MSI-H) genotype. Results Of 723 tumor cases examined by genotyping and IHC, 96 (13.3%) were MMR-D/MSI-H. Genotyping results were consistent with IHC in 702 cases (97.1%). IFL-treated patients with MMR-D/MSI-H tumors showed improved 5-year DFS as compared with those with mismatch repair intact tumors (0.76; 95% CI, 0.64 to 0.88 v 0.59; 95% CI, 0.53 to 0.64; P =.03). This relationship was not observed among patients treated with FU/LV. A trend toward longer DFS was observed in IFL-treated patients with MMR-D/MSI-H tumors as compared with those receiving FU/LV (0.57; 95% CI, 0.42 to 0.71 v 0.76; 95% CI, 0.64 to 0.88; P =.07; hazard ratio interaction between tumor status and treatment, 0.51; likelihood ratio P =.117). Conclusion Loss of tumor MMR function may predict improved outcome in patients treated with the IFL regimen as compared with those receiving FU/LV. © 2009 by American Society of Clinical Oncology.

Authors
Bertagnolli, MM; Niedzwiecki, D; Compton, CC; Hahn, HP; Hall, M; Damas, B; Jewell, SD; Mayer, RJ; Goldberg, RM; Saltz, LB; Warren, RS; Redston, M
MLA Citation
Bertagnolli, MM, Niedzwiecki, D, Compton, CC, Hahn, HP, Hall, M, Damas, B, Jewell, SD, Mayer, RJ, Goldberg, RM, Saltz, LB, Warren, RS, and Redston, M. "Microsatellite instability predicts improved response to adjuvant therapy with irinotecan, fluorouracil, and leucovorin in stage III colon cancer: Cancer and leukemia group B protocol 89803." Journal of Clinical Oncology 27.11 (2009): 1814-1821.
PMID
19273709
Source
scival
Published In
Journal of Clinical Oncology
Volume
27
Issue
11
Publish Date
2009
Start Page
1814
End Page
1821
DOI
10.1200/JCO.2008.18.2071

P27 Kip1 in stage III colon cancer: Implications for outcome following adjuvant chemotherapy in cancer and leukemia group B protocol 89803

Background: In retrospective studies, loss of p27 Kip1 (p27), a cyclin-dependent kinase inhibitor, has been associated with poor prognosis following colorectal cancer treatment. In a prospective study, we validated this relationship in patients enrolled on a trial of adjuvant chemotherapy for stage III colon cancer. Methods: Cancer and Leukemia Group B protocol 89803 randomized 1,264 stage III colon cancer patients to receive weekly bolus 5-fluorouracil/leucovorin or weekly bolus irinotecan, 5-fluo-rouracil, and leucovorin (lFL). The primary end point was overall survival (OS); disease-free survival was a secondary endpoint. Expression of p27 and DNA mismatch repair proteins were determined by immunohistochemistry in primary tumor and normal tissue from paraffin blocks. Data were analyzed using log-rank test. Results: Of 601 tumors analyzed, 207 (34.4%) showed p27 loss, 377 (62.8%) retained p27, and 17 (2.8%) were indeterminate. Patients with p27-negative tumors showed reduced OS [5-year OS 66%: 95% confidence interval (95% CI), 0.59-0.72 versus 75%: 95% CI, 0.70-0.79; log-rank P = 0.021]. This relationship was not influenced by treatment arm. Combination of p27 status with mismatch repair status, however, identified a small subset of patients that may benefit from lFL (n = 36; 5-year disease-free survival 81%: 95% CI, 0.64-0.98 versus 47%: 95% CI, 0.21-0.72; log-rank P = 0.042; 5-year OS 81%: 95% CI, 0.64-0.98 versus 60%: 95% CI, 0.35-0.85; log-rank P = 0.128). Conclusions: Loss of p27 is associated with reduced survival in stage III colon cancer but by itself does not indicate a significant difference in outcome between patients treated lFL or 5-fluorouracil/leucovorin. © 2009 American Association for Cancer Research.

Authors
Bertagnolli, MM; Warren, RS; Niedzwiecki, D; Mueller, E; Compton, CC; Redston, M; Hall, M; Hahn, HP; Jewell, SD; Mayer, RJ; Goldberg, RM; Saltz, LB; Loda, M
MLA Citation
Bertagnolli, MM, Warren, RS, Niedzwiecki, D, Mueller, E, Compton, CC, Redston, M, Hall, M, Hahn, HP, Jewell, SD, Mayer, RJ, Goldberg, RM, Saltz, LB, and Loda, M. "P27 Kip1 in stage III colon cancer: Implications for outcome following adjuvant chemotherapy in cancer and leukemia group B protocol 89803." Clinical Cancer Research 15.6 (2009): 2116-2122.
PMID
19276255
Source
scival
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
15
Issue
6
Publish Date
2009
Start Page
2116
End Page
2122
DOI
10.1158/1078-0432.CCR-08-2674

Depletion of human regulatory T cells specifically enhances antigen-specific immune responses to cancer vaccines.

CD4(+)CD25(high)FoxP3(+) regulatory T (Treg) cells limit antigen-specific immune responses and are a cause of suppressed anticancer immunity. In preclinical and clinical studies, we assessed the immune consequences of FoxP3(+) Treg-cell depletion in patients with advanced malignancies. We demonstrated that a CD25(high) targeting immunotoxin (denileukin diftitox) depleted FoxP3(+) Treg cells, decreased Treg-cell function, and enhanced antigen-specific T-cell responses in vitro. We then attempted to enhance antitumor immune responses in patients with carcinoembryonic antigen (CEA)-expressing malignancies by Treg-cell depletion. In a pilot study (n = 15), denileukin diftitox, given as a single dose or repeated dosing, was followed by immunizations with dendritic cells modified with the fowlpox vector rF-CEA(6D)-TRICOM. By flow cytometric analysis, we report the first direct evidence that circulating CD4(+)CD25(high)FoxP3(+) Treg cells are depleted after multiple doses of denileukin diftitox. Earlier induction of, and overall greater exposure to, the T-cell response to CEA was observed in the multiple-dose group, but not the single-dose group. These results indicate the potential for combining Treg-cell depletion with anticancer vaccines to enhance tumor antigen-specific immune responses and the need to explore dose and schedule of Treg depletion strategies in optimizing vaccine efforts.

Authors
Morse, MA; Hobeika, AC; Osada, T; Serra, D; Niedzwiecki, D; Lyerly, HK; Clay, TM
MLA Citation
Morse, MA, Hobeika, AC, Osada, T, Serra, D, Niedzwiecki, D, Lyerly, HK, and Clay, TM. "Depletion of human regulatory T cells specifically enhances antigen-specific immune responses to cancer vaccines." Blood 112.3 (August 1, 2008): 610-618.
PMID
18519811
Source
pubmed
Published In
Blood
Volume
112
Issue
3
Publish Date
2008
Start Page
610
End Page
618
DOI
10.1182/blood-2008-01-135319

The impact of smoking on cancer recurrence and survival in patients with stage III colon cancer: Findings from intergroup trial CALGB 89803

Authors
Jackson, NA; Fuchs, CS; Niedzwiecki, D; Hollis, DR; Saltz, LB; Mayer, RJ; Meyerhardt, JA
MLA Citation
Jackson, NA, Fuchs, CS, Niedzwiecki, D, Hollis, DR, Saltz, LB, Mayer, RJ, and Meyerhardt, JA. "The impact of smoking on cancer recurrence and survival in patients with stage III colon cancer: Findings from intergroup trial CALGB 89803." JOURNAL OF CLINICAL ONCOLOGY 26.15 (May 20, 2008).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
26
Issue
15
Publish Date
2008

The impact of smoking on cancer recurrence and survival in patients with stage III colon cancer: Findings from intergroup trial CALGB 89803.

4039 Background: Although tobacco use is linked to the development of colon cancer, little is known about its impact in colon cancer survivors. METHODS: We prospectively collected data on prior and current cigarette smoking on 1,045 patients with stage III colon cancer enrolled in a phase III adjuvant chemotherapy trial (bolus 5-FU/leucovorin ± irinotecan). Patients (pts) reported tobacco use in self- report questionnaires during (Q1) & 6 months after completion of adjuvant therapy (Q2). Smoking status was defined as never, current, or past. Lifetime pack years (pyr) were defined as # of packs of cigarettes over pt's lifetime. Since there was no difference in efficacy between the two treatments, data for all patients were combined. Cox proportional hazards were computed for disease-free survival (DFS, our primary endpoint) and overall survival (OS). DFS and OS were measured from completion of Q1 to event of interest, excluding events within the 1(st) 90 days to avoid biases of change in behavior due to impending event. RESULTS: Data on smoking history were captured on 1,045 patients of 1,264 in the phase III trial (460 [44%] past smokers; 107 [10%] current smokers; 478 [46%] never smokers). In analyses adjusted for age, N and T stage, grade of differentiation, and presence of bowel obstruction at dx, past smokers had hazard ratio (HR) for DFS of 1.15 (95% CI, 0.92-1.43; p=0.2) and current smokers had HR for DFS of 1.20 (95% CI, 0.85-1.70; p=0.3), compared to never smokers. Consistent with prior analyses, we defined pyr categories as 0, 0-10, 10-20, 20 or more. In unadjusted analyses, HR for DFS were 1.16 (95% CI, 0.89-1.52), 1.24 (95% CI, 0.85-1.83) and 1.33 (95% CI, 1.03-1.73) for lifetime pyr 0-10, 10-20 and 20+, respectively, compared to never smoking (p trend 0.04). In adjusted analyses, HR for 20+ pyr was 1.25 (95% CI, 0.96-1.63) compared to never smoking (p trend 0.15). HRs for OS were similar as DFS for smoking status and lifetime pyr. CONCLUSIONS: Lifetime total of tobacco usage may influence outcomes in patients with stage III colon cancer. Further research with larger datasets is warranted. No significant financial relationships to disclose.

Authors
Jackson, NA; Fuchs, CS; Niedzwiecki, D; Hollis, DR; Saltz, LB; Mayer, RJ; Meyerhardt, JA
MLA Citation
Jackson, NA, Fuchs, CS, Niedzwiecki, D, Hollis, DR, Saltz, LB, Mayer, RJ, and Meyerhardt, JA. "The impact of smoking on cancer recurrence and survival in patients with stage III colon cancer: Findings from intergroup trial CALGB 89803." J Clin Oncol 26.15_suppl (May 20, 2008): 4039-.
PMID
27949293
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
26
Issue
15_suppl
Publish Date
2008
Start Page
4039

LE-SN38 for metastatic colorectal cancer after progression on oxaliplatin: Results of CALGB 80402.

4109 Background: In patients (pts) with metastatic colorectal cancer (mCRC) after first-line progression on 5-fluorouracil (5-FU), irinotecan (IRI) improves survival over best supportive care or additional 5-FU. IRI provides limited survival benefit, commonly causes asthenia and diarrhea, and rarely causes fatal toxicities related to dehydration and sepsis. LE-SN38 is a liposomal formulation of SN38, the active metabolite of IRI. LE-SN38 was formulated in an attempt to improve the therapeutic index of IRI by preserving clinical activity without increasing overall toxicities. This single arm, open label Phase II study assesses the response rate (RR) and toxicity profile of LE-SN38 in pts with mCRC. METHODS: Pts had histologically or cytologically confirmed mCRC, measurable disease, and received one prior 5- FU/oxaliplatin (but not IRI) regimen for metastatic disease. Pts had ECOG PS 0-1, normal bone marrow, hepatic, and renal function. UGT1A1 genotype status was determined prior to registration and pts were eligible if homozygous for wild-type UGT1A1*1 or heterozygous for UGT1A1*28. Pts received LE-SN38 35mg/m(2) IV over 90 min every 21 days until disease progression for a minimum of 2 cycles. Tumor assessment by imaging was done every 2 cycles. The primary endpoint of this trial was RR. A RR of 15%, comparable to that of irinotecan, was considered worthy of further study. RESULTS: 30 pts (16 males, 14 females) were enrolled and treated from 1/06-1/07. Median age was 50-59y. Toxicities included Grade 4: leukocytes (7%), neutrophils/granulocytes (7%). Grade 3: hemoglobin (3%), lymphopenia (3%), neutrophils/granulocytes (7%), prothrombin time (PT) (3%), nausea (3%), gastrointestinal obstruction (3%), vomiting (3%), pain (3%). There was no Grade 3-4 diarrhea. There were no complete (CR) or partial responses (PR), but 11 pts had stable disease (SD) observed. Median PFS was 1.58 months (95% CI: 1.51, 2 months) and median OS was 9.07 months (95%CI: 6.67, 11.27 months). CONCLUSIONS: LE-SN38 did not meet the prespecified activity criteria for OR and PFS. Although LE-SN38 is associated with an acceptable toxicity profile, this formulation, dose and schedule of LE-SN38 does not merit further evaluation in previously treated pts with mCRC. No significant financial relationships to disclose.

Authors
Ocean, AJ; Niedzwiecki, D; Atkins, JN; Parker, B; O'Neil, BH; Lee, JW; Wadler, S; Goldberg, RM
MLA Citation
Ocean, AJ, Niedzwiecki, D, Atkins, JN, Parker, B, O'Neil, BH, Lee, JW, Wadler, S, and Goldberg, RM. "LE-SN38 for metastatic colorectal cancer after progression on oxaliplatin: Results of CALGB 80402." J Clin Oncol 26.15_suppl (May 20, 2008): 4109-.
PMID
27951078
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
26
Issue
15_suppl
Publish Date
2008
Start Page
4109

A phase II trial of sunitinib (S) in previously-treated pancreas adenocarcinoma (PAC), CALGB 80603.

4515 Background: S is an oral broad-spectrum tyrosine kinase (TK) inhibitor with potential utility in PAC given the perturbation of multiple signaling pathways and stromal alterations noted in PAC. CALGB conducted an NCI-sponsored phase II study of S in patients (pts) with previously-treated PAC. METHODS: Eligibility included: PAC previously treated with front-line gemcitabine (gem) therapy, or progression of disease (PD) during or within 3-months of completion of adjuvant therapy, or newly metastatic disease following therapy for locally advanced PAC; performance status 0-2; measurable disease by RECIST; no prior anti-VEGF therapy; no evidence of duodenal invasion on CT. S was dosed at 50 mg daily for 28 days followed by 14 days of rest (1 cycle). Re-staging was performed after each of the first 4 cycles of therapy. STUDY DESIGN: Single-arm, multi-center cooperative group, 3-stage design, with response criteria of at least stable disease (SD) in 1/19, 2/39, for expansion. Planned accrual was 64. Primary endpoint: Response rate (RECIST). Secondary endpoints: Duration of response, toxicity, PFS, and survival. RESULTS: From 11/06 to 11/07, 77 pts were accrued with the criteria met for full accrual (1 withdrew consent). Pt characteristics were: male 54%, female 46%, age: median 65 yrs, range 42- 87, and PS 0/1/2 45%/48%/7%. Prior therapy included: gem 61%, gem-based combination 37%, TK inhibitor 14%, radiation therapy 14%. Sites of disease were: liver 84%, lung 30%, other 19%. As of 12/07, 52 pts are evaluable for response. Response criteria for continuation were met at the two interim analyses. SD occurred in 7 pts [13%, 95% CI (3.6%, 22%)] and PD in 29 (56%). Number of cycles received was: 1- 86%; 2- 12%, 3- 2%. Dose modification was needed in 21%. Median PFS was 41 days (CI 37-57d), and median OS 97 days (CI 79-127d). Grade 3-5 toxicities included: hematologic 13% (G3), fatigue 12%, bleeding 6% (G3), nausea 4% (G3), Thrombosis/embolism 2% (G3), TTP/renal failure 2%, GI perforation 2% (G5). CONCLUSIONS: Preliminary analysis of a large cooperative group phase II study of S in previously-treated PAC suggests modest single agent activity and no new safety signals in this patient population. Final results will be presented. [Table: see text].

Authors
O'Reilly, EM; Niedzwiecki, D; Hollis, DR; Bekaii-Saab, TS; Pluard, T; Duffy, A; Overcash, F; Ivy, SP; Goldberg, RM
MLA Citation
O'Reilly, EM, Niedzwiecki, D, Hollis, DR, Bekaii-Saab, TS, Pluard, T, Duffy, A, Overcash, F, Ivy, SP, and Goldberg, RM. "A phase II trial of sunitinib (S) in previously-treated pancreas adenocarcinoma (PAC), CALGB 80603." J Clin Oncol 26.15_suppl (May 20, 2008): 4515-.
PMID
27949201
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
26
Issue
15_suppl
Publish Date
2008
Start Page
4515

A phase II trial of sunitinib (S) in previously-treated pancreas adenocarcinoma (PAC), CALGB 80603

Authors
O'Reilly, EM; Niedzwiecki, D; Hollis, DR; Bekaii-Saab, TS; Pluard, T; Duffy, A; Overcash, F; Ivy, SP; Goldberg, RM
MLA Citation
O'Reilly, EM, Niedzwiecki, D, Hollis, DR, Bekaii-Saab, TS, Pluard, T, Duffy, A, Overcash, F, Ivy, SP, and Goldberg, RM. "A phase II trial of sunitinib (S) in previously-treated pancreas adenocarcinoma (PAC), CALGB 80603." JOURNAL OF CLINICAL ONCOLOGY 26.15 (May 20, 2008).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
26
Issue
15
Publish Date
2008

LE-SN38 for metastatic colorectal cancer after progression on oxaliplatin: Results of CALGB 80402

Authors
Ocean, AJ; Niedzwiecki, D; Atkins, JN; Parker, B; O'Neil, BH; Lee, JW; Wadler, S; Goldberg, RM
MLA Citation
Ocean, AJ, Niedzwiecki, D, Atkins, JN, Parker, B, O'Neil, BH, Lee, JW, Wadler, S, and Goldberg, RM. "LE-SN38 for metastatic colorectal cancer after progression on oxaliplatin: Results of CALGB 80402." JOURNAL OF CLINICAL ONCOLOGY 26.15 (May 20, 2008).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
26
Issue
15
Publish Date
2008

Depletion of human regulatory T cells (Treg) and antigen-specific immune responses to cancer vaccines

Authors
Clay, TM; Hobeika, A; Osada, T; Serra, D; Niedzwiecki, D; Lyerly, HK; Morse, MA
MLA Citation
Clay, TM, Hobeika, A, Osada, T, Serra, D, Niedzwiecki, D, Lyerly, HK, and Morse, MA. "Depletion of human regulatory T cells (Treg) and antigen-specific immune responses to cancer vaccines." May 20, 2008.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
26
Issue
15
Publish Date
2008

Depletion of human regulatory T cells (Treg) and antigen-specific immune responses to cancer vaccines.

3010 Background: CD4+CD25+FoxP3+ regulatory T cells (Treg) limit antigen-specific immune responses and are a cause of suppressed anticancer immunity. Conversely, depletion of Treg leads to immune enhancement. The immunotoxin denileukin diftitox which selectively targets lymphocytes expressing CD25 may deplete FoxP3+ Treg.We evaluated the proliferative potential of PBMC to various antigens in vitro following exposure to denileukin diftitox. We then performed a pilot study in which patients with advanced CEA expressing malignancies, being immunized with autologous dendritic cells modified with a fowlpox vector encoding CEA (rF-CEA(6D)-TRICOM), received denileukin diftitox 18 mcg/kg, once, 4 days before the immunizations began, or 9 mcg/kg prior to each of the 4 immunizations. ELISPOT, cytokine flow cytometry, and ELISA were used to measure the T cell and antibody response.In vitro, escalating doses of denileukin diftitox depleted FoxP3+ Treg, decreased Treg function in vitro, and enhanced antigen-specific T cell responses. In the pilot study (n=15), denileukin diftitox was associated with a 74 ± 6% decrease in Treg in those receiving multiple doses, but not in those receiving a single dose. An earlier peak in the vaccine-induced CEA-specific T cell responses, and significant levels (>0.5%) of circulating CD8+ and CD4+ CEA-specific T cells were also seen in the multiple dose group. Conversely, a single dose of denileukin diftitox enhanced anti-CEA, but not antifowlpox vector, antibody responses. Multiple doses abolished the anti-CEA antibody response.These results indicate the potential for combining Treg depletion with anticancer vaccines to enhance tumor antigen specific immune responses. No significant financial relationships to disclose.

Authors
Clay, TM; Hobeika, A; Osada, T; Serra, D; Niedzwiecki, D; Lyerly, HK; Morse, MA
MLA Citation
Clay, TM, Hobeika, A, Osada, T, Serra, D, Niedzwiecki, D, Lyerly, HK, and Morse, MA. "Depletion of human regulatory T cells (Treg) and antigen-specific immune responses to cancer vaccines." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 26.15_suppl (May 2008): 3010-.
PMID
27947631
Source
epmc
Published In
Journal of Clinical Oncology
Volume
26
Issue
15_suppl
Publish Date
2008
Start Page
3010

THE USE, SAFETY, AND EFFICACY OF DACLIZUMAB FOR STEROID REFRACTORY GRAFT-VERSUS-HOST-DISEASE (GVHD) AFTER UNRELATED CORD BLOOD TRANSPLANTATION (UCBT)

Authors
Mohamed, A; Niedzwiecki, D; Baker, JH; Vinesett, R; Martin, PL; Driscoll, TA; Prasad, VK; Parikh, S; Kurtzberg, J; Szabolcs, P
MLA Citation
Mohamed, A, Niedzwiecki, D, Baker, JH, Vinesett, R, Martin, PL, Driscoll, TA, Prasad, VK, Parikh, S, Kurtzberg, J, and Szabolcs, P. "THE USE, SAFETY, AND EFFICACY OF DACLIZUMAB FOR STEROID REFRACTORY GRAFT-VERSUS-HOST-DISEASE (GVHD) AFTER UNRELATED CORD BLOOD TRANSPLANTATION (UCBT)." February 2008.
Source
wos-lite
Published In
Biology of Blood and Marrow Transplantation
Volume
14
Issue
2
Publish Date
2008
Start Page
77
End Page
77
DOI
10.1016/j.bbmt.2007.12.217

Immune reconstitution in children after unrelated cord blood transplantation.

There is a great need to learn more about the biology of immune recovery after UCBT. Fundamental gaps in knowledge remain regarding the biology and kinetics of developing antigen-specific protective immunity and understanding the impact of recipient age and immunosuppressive agents. However, there is also realistic hope that clinical translation of new immunotherapy strategies could enhance immune competence after UCBT either by having an impact on the thymic-independent early period or by fostering thymic recovery.

Authors
Szabolcs, P; Niedzwiecki, D
MLA Citation
Szabolcs, P, and Niedzwiecki, D. "Immune reconstitution in children after unrelated cord blood transplantation." Biol Blood Marrow Transplant 14.1 Suppl 1 (January 2008): 66-72. (Review)
PMID
18162223
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
14
Issue
1 Suppl 1
Publish Date
2008
Start Page
66
End Page
72
DOI
10.1016/j.bbmt.2007.10.016

Detailed analysis of cytomegalovirus (CMV)-specific T cells expanded for adoptive immunotherapy of CMV infection following allogeneic stem cell transplantation for malignant disease.

BACKGROUND: Cytomegalovirus (CMV) infection and its treatment causes significant morbidity following allogeneic stem cell transplantation (SCT) for malignancies. We studied the phenotype, function and growth kinetics of CMV pp65 antigen (Ag)-specific T cells expanded in a short-term culture for adoptive therapy. METHODS: Peripheral blood mononuclear cells (PBMC) from CMV-seropositive donors were cultured in various conditions with CMV pp65((495-503)) peptide to determine the most effective method for generating CMV-specific T cells. CMV-expanded cultures were tested for frequency, phenotype and functionality using peptide-MHC tetramer analysis, cytokine flow cytometry and cytolytic assays. A patient undergoing allogeneic SCT was administered CMV pp65-specific T cells generated from the donor based on these data, and recipient PBMC were analyzed following T-cell infusion. RESULTS: CMV pp65-specific T cells were consistently generated from CMV-seropositive donors at high frequencies (20-40% of CD8+ T cells), secreted interferon-gamma (IFN-gamma) in response to CMV peptide and had lytic activity against CMV peptide-expressing targets. Cultured CMV-specific T cells were infused into a SCT recipient without toxicity. DISCUSSION: Stimulating donor PBMC to generate functional, Ag-specific T cells for infusion into SCT recipients was accomplished consistently using readily available technology. We observed no toxicity in one patient receiving T cells and were able to monitor infused cells. These findings support further study of this approach as a prophylaxis against the risk of infection in patients receiving allogeneic transplantation from CMV-seropositive donors.

Authors
Hobeika, A; Osada, T; Serra, D; Peplinski, S; Hanson, K; Tanaka, Y; Niedzwiecki, D; Chao, N; Rizzieri, D; Lyerly, H; Clay, T; Morse, M
MLA Citation
Hobeika, A, Osada, T, Serra, D, Peplinski, S, Hanson, K, Tanaka, Y, Niedzwiecki, D, Chao, N, Rizzieri, D, Lyerly, H, Clay, T, and Morse, M. "Detailed analysis of cytomegalovirus (CMV)-specific T cells expanded for adoptive immunotherapy of CMV infection following allogeneic stem cell transplantation for malignant disease." Cytotherapy 10.3 (2008): 289-302.
PMID
18418774
Source
pubmed
Published In
Cytotherapy (Informa)
Volume
10
Issue
3
Publish Date
2008
Start Page
289
End Page
302
DOI
10.1080/14653240801927040

Association of family history with cancer recurrence and survival among patients with stage III colon cancer

Context: A family history of colorectal cancer in a first-degree relative increases the risk of developing colorectal cancer. However, the influence of family history on cancer recurrence and survival among patients with established disease remains uncertain. Objective: To examine the association of family history of colorectal cancer with cancer recurrence and survival of patients with colon cancer. Design, Setting, and Participants: Prospective observational study of 1087 patients with stage III colon cancer enrolled in a randomized adjuvant chemotherapy trial (CALGB 89803) between April 1999 and May 2001. Patients provided data on family history at baseline and were followed up until March 2007 for disease recurrence and death (median follow-up, 5.6 years). In a subset of patients, we assessed microsatellite instability (MSI) and expression of the mismatch repair (MMR) proteins MLH1 and MSH2 in tumor specimens. Main Outcome Measures: Disease-free survival, recurrence-free survival, and overall survival according to the presence or absence of a family history of colorectal cancer. Results: Among 1087 eligible patients, 195 (17.9%) reported a family history of colorectal cancer in a first-degree relative. Cancer recurrence or death occurred in 57 of 195 patients (29%; 95% confidence interval [CI], 23%-36%) with a family history of colorectal cancer and 343 of 892 patients (38%; 95% CI, 35%-42%) without a family history. Compared with patients without a family history, the adjusted hazard ratios (HRs) among those with 1 or more affected first-degree relatives were 0.72 (95% CI, 0.54-0.96) for disease-free survival, 0.74 (95% CI, 0.55-0.99) for recurrence-free survival, and 0.75 (95% CI, 0.54-1.05) for overall survival. This reduction in risk of cancer recurrence or death associated with a family history became stronger with an increasing number of affected first-degree relatives. Compared with participants without a family history of colorectal cancer, those with 1 affected relative had a multivariate HR of 0.77 (95% CI, 0.57-1.04) for disease-free survival. For participants with 2 or more affected relatives, we observed a greater reduction in risk (multivariate HR for disease-free survival, 0.49; 95% CI, 0.23-1.04; P for trend with increasing number of affected relatives=.01). The improved disease-free survival associated with a family history was independent of tumoral MSI or MMR status. Conclusion: Among patients with stage III colon cancer receiving adjuvant chemotherapy, a family history of colorectal cancer is associated with a significant reduction in cancer recurrence and death. ©2008 American Medical Association. All rights reserved.

Authors
Chan, JA; Meyerhardt, JA; Niedzwiecki, D; Hollis, D; Saltz, LB; Mayer, RJ; Thomas, J; Schaefer, P; Whittom, R; Hantel, A; Goldberg, RM; Warren, RS; Bertagnolli, M; Fuchs, CS
MLA Citation
Chan, JA, Meyerhardt, JA, Niedzwiecki, D, Hollis, D, Saltz, LB, Mayer, RJ, Thomas, J, Schaefer, P, Whittom, R, Hantel, A, Goldberg, RM, Warren, RS, Bertagnolli, M, and Fuchs, CS. "Association of family history with cancer recurrence and survival among patients with stage III colon cancer." JAMA - Journal of the American Medical Association 299.21 (2008): 2515-2523.
PMID
18523220
Source
scival
Published In
JAMA : the journal of the American Medical Association
Volume
299
Issue
21
Publish Date
2008
Start Page
2515
End Page
2523
DOI
10.1001/jama.299.21.2515

In reply

Authors
Tepper, JE; Niedzwiecki, D
MLA Citation
Tepper, JE, and Niedzwiecki, D. "In reply." Journal of Clinical Oncology 26.31 (2008): 5134--.
Source
scival
Published In
Journal of Clinical Oncology
Volume
26
Issue
31
Publish Date
2008
Start Page
5134-
DOI
10.1200/JCO.2008.19.0678

Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781

Purpose: The primary treatment modality for patients with carcinoma of the esophagus or gastroesophageal junction has been surgery, although primary radiation therapy with concurrent chemotherapy produces similar results. As both have curative potential, there has been great interest in the use of trimodality therapy. To this end, we compared survival, response, and patterns of failure of trimodality therapy to esophagectomy alone in patients with nonmetastatic esophageal cancer. Patients and Methods: Four hundred seventy-five eligible patients were planned for enrollment. Patients were randomly assigned to either esophagectomy with node dissection alone or cisplatin 100 mg/m 2 and fluorouracil 1,000 mg/m2/d for 4 days on weeks 1 and 5 concurrent with radiation therapy (50.4 Gy total: 1.8 Gy/fraction over 5.6 weeks) followed by esophagectomy with node dissection. Results: Fifty-six patients were enrolled between October 1997 and March 2000, when the trial was closed due to poor accrual. Thirty patients were randomly assigned to trimodality therapy and 26 were assigned to surgery alone. Patient and tumor characteristics were similar between groups. Treatment was generally well tolerated. Median follow-up was 6 years. An intent-to-treat analysis showed a median survival of 4.48 v 1.79 years in favor of trimodality therapy (exact stratified log-rank, P = .002). Five-year survival was 39% (95% CI, 21% to 57%) v 16% (95% CI, 5% to 33%) in favor of trimodality therapy. Conclusion: The results from this trial reflect a long-term survival advantage with the use of chemoradiotherapy followed by surgery in the treatment of esophageal cancer, and support trimodality therapy as a standard of care for patients with this disease. © 2008 by American Society of Clinical Oncology.

Authors
Tepper, J; Krasna, MJ; Niedzwiecki, D; Hollis, D; Reed, CE; Goldberg, R; Kiel, K; Willett, C; Sugarbaker, D; Mayer, R
MLA Citation
Tepper, J, Krasna, MJ, Niedzwiecki, D, Hollis, D, Reed, CE, Goldberg, R, Kiel, K, Willett, C, Sugarbaker, D, and Mayer, R. "Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781." Journal of Clinical Oncology 26.7 (2008): 1086-1092.
PMID
18309943
Source
scival
Published In
Journal of Clinical Oncology
Volume
26
Issue
7
Publish Date
2008
Start Page
1086
End Page
1092
DOI
10.1200/JCO.2007.12.9593

Meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future phase II trials

Purpose: Objective tumor response rates observed in phase II trials for metastatic melanoma have historically not provided a reliable indicator of meaningful survival benefits. To facilitate using overall survival (OS) or progression-free survival (PFS) as an endpoint for future phase II trials, we evaluated historical data from cooperative group phase II trials to attempt to develop benchmarks for OS and PFS as reference points for future phase II trials. Patients and Methods: Individual-level and trial-level data were obtained for patients enrolled onto 42 phase II trials (70 trial arms) that completed accrual in the years 1975 through 2005 and conducted by Southwest Oncology Group, Eastern Cooperative Oncology Group, Cancer and Leukemia Group B, North Central Cancer Treatment Group, and the Clinical Trials Group of the National Cancer Institute of Canada. Univariate and multivariate analyses were performed to identify prognostic variables, and between-trial(-arm) variability in 1-year OS rates and 6-month PFS rates were examined. Results: Statistically significant individual-level and trial-level prognostic factors found in a multivariate survival analysis for OS were performance status, presence of visceral disease, sex, and whether the trial excluded patients with brain metastases. Performance status, sex, and age were statistically significant prognostic factors for PFS. Controlling for these prognostic variables essentially eliminated between-trial variability in 1-year OS rates but not in 6-month PFS rates. Conclusion: Benchmarks are provided for 1-year OS or OS curves that make use of the distribution of prognostic factors of the patients in the phase II trial. A similar benchmark for 6-month PFS is provided, but its use is more problematic because of residual between-trial variation in this endpoint. © 2008 by American Society of Clinical Oncology.

Authors
Korn, EL; Liu, P-Y; Lee, SJ; Chapman, J-AW; Niedzwiecki, D; Suman, VJ; Moon, J; Sondak, VK; Atkins, MB; Eisenhauer, EA; Parulekar, W; Markovic, SN; Saxman, S; Kirkwood, JM
MLA Citation
Korn, EL, Liu, P-Y, Lee, SJ, Chapman, J-AW, Niedzwiecki, D, Suman, VJ, Moon, J, Sondak, VK, Atkins, MB, Eisenhauer, EA, Parulekar, W, Markovic, SN, Saxman, S, and Kirkwood, JM. "Meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future phase II trials." Journal of Clinical Oncology 26.4 (2008): 527-534.
PMID
18235113
Source
scival
Published In
Journal of Clinical Oncology
Volume
26
Issue
4
Publish Date
2008
Start Page
527
End Page
534
DOI
10.1200/JCO.2007.12.7837

Thalidomide has limited single-agent activity in relapsed or refractory indolent non-Hodgkin lymphomas: A phase II trial of the Cancer and Leukemia Group B

Thalidomide is an immunomodulatory agent with demonstrated activity in multiple myeloma, mantle cell lymphoma and lymphoplasmacytic lymphoma. Its activity is believed to be due modulation of the tumour milieu, including downregulation of angiogenesis and inflammatory cytokines. Between July 2001 and April 2004, 24 patients with relapsed/refractory indolent lymphomas received thalidomide 200 mg daily with escalation by 100 mg daily every 1-2 weeks as tolerated, up to a maximum of 800 mg daily. Patients had received a median of 2 (range, 1-4) prior regimens. Of 24 evaluable patients, two achieved a complete remission and one achieved a partial remission for an overall response rate of 12.5% (95% confidence interval: 2.6-32.4%). Eleven patients progressed during therapy. Grade 3-4 adverse effects included myelosuppression, fatigue, somnolence/depressed mood, neuropathy and dyspnea. Of concern was the occurrence of four thromboembolic events. Our results failed to demonstrate an important response rate to single agent thalidomide in indolent lymphomas and contrast with the higher activity level reported with the second generation immunomodulatory agent, lenalidomide. © 2008 The Authors.

Authors
Smith, SM; Grinblatt, D; Johnson, JL; Niedzwiecki, D; Rizzieri, D; Bartlett, NL; Cheson, BD
MLA Citation
Smith, SM, Grinblatt, D, Johnson, JL, Niedzwiecki, D, Rizzieri, D, Bartlett, NL, and Cheson, BD. "Thalidomide has limited single-agent activity in relapsed or refractory indolent non-Hodgkin lymphomas: A phase II trial of the Cancer and Leukemia Group B." British Journal of Haematology 140.3 (2008): 313-319.
PMID
18217897
Source
scival
Published In
British Journal of Haematology
Volume
140
Issue
3
Publish Date
2008
Start Page
313
End Page
319
DOI
10.1111/j.1365-2141.2007.06937.x

Association of dietary patterns with cancer recurrence and survival in patients with stage III colon cancer

Authors
Meyerhardt, JA; Niedzwiecki, D; Hollis, D; Saltz, LB; Hu, FB; Mayer, RJ; Nelson, H; Whittom, R; Hantel, A; Thomas, J; Fuchs, CS
MLA Citation
Meyerhardt, JA, Niedzwiecki, D, Hollis, D, Saltz, LB, Hu, FB, Mayer, RJ, Nelson, H, Whittom, R, Hantel, A, Thomas, J, and Fuchs, CS. "Association of dietary patterns with cancer recurrence and survival in patients with stage III colon cancer." Obstetrical and Gynecological Survey 63.2 (2008): 94-96.
Source
scival
Published In
Obstetrical and Gynecological Survey
Volume
63
Issue
2
Publish Date
2008
Start Page
94
End Page
96
DOI
10.1097/01.ogx.0000300472.76442.c2

Impact of body mass index and weight change after treatment on cancer recurrence and survival in patients with stage III colon cancer: Findings from cancer and leukemia group B 89803

Purpose: Obesity is a risk factor for the development of colon cancer. However, the influence of body mass index (BMI) on the outcome of patients with established colon cancer remains uncertain. Moreover, the impact of change in body habitus after diagnosis has not been studied. Patients and Methods: We conducted a prospective, observational study of 1,053 patients who had stage III colon cancer and who were enrolled on a randomized trial of adjuvant chemotherapy. Patients reported on height and weight during and 6 months after adjuvant chemotherapy. Patients were observed for cancer recurrence or death. Results: In this cohort of patients with stage III cancer, 35% of patients were overweight (BMI, 25 to 29.9 kg/m2), and 34% were obese (BMI ≥ 30 kg/m2). Increased BMI was not significantly associated with a higher risk of colon cancer recurrence or death (P trend = .54). Compared with normal-weight patients (BMI, 21 to 24.9 kg/m2), the multivariate hazard ratio for disease-free survival was 1.00 (95% CI, 0.72 to 1.40) for patients with class I obesity (BMI, 30 to 34.9 kg/m2) and 1.24 (95% CI, 0.84 to 1.83) for those with class II to III obesity (BMI ≥ 35 kg/m 2) after analysis was adjusted for tumor-related prognostic factors, physical activity, tobacco history, performance status, age, and sex. Similarly, after analysis was controlled for BMI, weight change (either loss or gain) during the time period between ongoing adjuvant therapy and 6 months after completion of therapy did not significantly impact on cancer recurrence and/or mortality. Conclusion: Neither BMI nor weight change was significantly associated with an increased risk of cancer recurrence and death in patients with colon cancer. © 2008 by American Society of Clinical Oncology.

Authors
Meyerhardt, JA; Niedzwiecki, D; Hollis, D; Saltz, LB; Mayer, RJ; Nelson, H; Whittom, R; Hantel, A; Thomas, J; Fuchs, CS
MLA Citation
Meyerhardt, JA, Niedzwiecki, D, Hollis, D, Saltz, LB, Mayer, RJ, Nelson, H, Whittom, R, Hantel, A, Thomas, J, and Fuchs, CS. "Impact of body mass index and weight change after treatment on cancer recurrence and survival in patients with stage III colon cancer: Findings from cancer and leukemia group B 89803." Journal of Clinical Oncology 26.25 (2008): 4109-4115.
PMID
18757324
Source
scival
Published In
Journal of Clinical Oncology
Volume
26
Issue
25
Publish Date
2008
Start Page
4109
End Page
4115
DOI
10.1200/JCO.2007.15.6687

Induction therapy for poor-prognosis anal canal carcinoma: A phase II study of the Cancer and Leukemia Group B (CALGB 9281)

Purpose: Although most patients with anal canal cancer are cured with sphincter-preserving, nonsurgical, combined-modality therapy, those with large tumors and lymph node involvement have a poor prognosis. To establish the safety and efficacy of induction chemotherapy with infusional fluorouracil (FU) plus cisplatin followed by FU plus mitomycin C with concurrent radiation in patients with poor-prognosis squamous cell cancers of the anal canal. Methods: Patients with previously untreated anal canal cancers with T3 or T4 tumors and/or extensive nodal involvement (bulky N2 or N3) received two 28-day cycles of induction treatment with infusional FU plus cisplatin followed by two 28-day cycles of FU plus mitomycin C with concurrent split-course radiation. A third cycle of FU and cisplatin with radiation boost was given to patients with persistent primary site disease or bulky N2 or N3 disease at presentation. Results: Forty-five assessable patients received protocol therapy. Treatment was generally well tolerated, and gastrointestinal and hematologic toxicities were the most common. Induction chemotherapy resulted in eight complete and 21 partial responses. After induction, combined-modality, and boost therapy, 37 (82%) of 45 assessable high-risk patients achieved a complete response. After 4 years of follow-up, 68% of patients are alive, 61% are disease-free, and 50% are colostomy- and disease-free. Conclusion: A combined-modality approach that includes induction treatment with FU and cisplatin followed by combined-modality therapy with FU, mitomycin C, and concurrent radiation results in long-term disease control in the majority of patients with poor-prognosis anal canal cancer. © 2008 by American Society of Clinical Oncology.

Authors
Meropol, NJ; Niedzwiecki, D; Shank, B; Colacchio, TA; Ellerton, J; Valone, F; Budinger, S; Day, JM; Hopkins, J; Tepper, J; Goldberg, RM; Mayer, RJ
MLA Citation
Meropol, NJ, Niedzwiecki, D, Shank, B, Colacchio, TA, Ellerton, J, Valone, F, Budinger, S, Day, JM, Hopkins, J, Tepper, J, Goldberg, RM, and Mayer, RJ. "Induction therapy for poor-prognosis anal canal carcinoma: A phase II study of the Cancer and Leukemia Group B (CALGB 9281)." Journal of Clinical Oncology 26.19 (2008): 3229-3234.
PMID
18490648
Source
scival
Published In
Journal of Clinical Oncology
Volume
26
Issue
19
Publish Date
2008
Start Page
3229
End Page
3234
DOI
10.1200/JCO.2008.16.2339

A phase II prospective multi-institutional trial of adjuvant active specific immunotherapy following curative resection of colorectal cancer hepatic metastases: Cancer and Leukemia Group B study 89903

Background: Patients with curatively resected colorectal cancer hepatic metastases often harbor occult metastatic disease and are at high risk of experiencing recurrence. This patient cohort is ideally suited to test novel therapies such as immunotherapy. We treated patients-post-hepatic resection-with anti-idiotype monoclonal antibody vaccines to the tumor-associated antigens carcinoembryonic antigen (CeaVac) and human milk fat globule (TriAb), both of which are co-expressed in more than 90% of colorectal cancer patients. Methods: Vaccinations commenced 6-12 weeks post-hepatic resection and consisted of four biweekly treatments of 2 mg CeaVac and TriAb, then monthly treatments for 2 years, then on every other month for 3 years. The primary endpoint was to investigate the proportion of patients recurrence-free at 2 years, and the objective of the study was to demonstrate that at least 58% would be recurrence-free at this time to consider the regimen worthy of further study. Results: Between July 2001 and October 2004, 56 patients were accrued; 52 patients with margin-negative resection were eligible for analysis. Hepatic lobectomy was performed in 56% of patients with a median of one metastasis (range 1-3). Of the 52 eligible patients, 49 were evaluable for the primary end point. Median follow-up was 3.1 years. The proportion of patients recurrence-free at 2 years was 39%, with a lower confidence bound (LCB) of 0.29. Median recurrence-free survival was 16 months. The 2-year overall survival was 94% (95% CI, 0.81, 0.98). Only 10% of patients had documented grade-3 adverse events. Conclusions: Anti-idiotype monoclonal antibody vaccine therapy with CeaVac and TriAb as an adjuvant to curative resection of colorectal cancer hepatic metastases is well tolerated but did not improve 2-year recurrence-free survival when compared with the expected value of 40% reported for hepatic resection alone. © 2007 Society of Surgical Oncology.

Authors
Posner, MC; Niedzwiecki, D; Venook, AP; Hollis, DR; Kindler, HL; Martin, EW; Schilsky, RL; Goldberg, RM
MLA Citation
Posner, MC, Niedzwiecki, D, Venook, AP, Hollis, DR, Kindler, HL, Martin, EW, Schilsky, RL, and Goldberg, RM. "A phase II prospective multi-institutional trial of adjuvant active specific immunotherapy following curative resection of colorectal cancer hepatic metastases: Cancer and Leukemia Group B study 89903." Annals of Surgical Oncology 15.1 (2008): 158-164.
PMID
18008108
Source
scival
Published In
Annals of Surgical Oncology
Volume
15
Issue
1
Publish Date
2008
Start Page
158
End Page
164
DOI
10.1245/s10434-007-9654-7

Long term disease-free survival and T cell and antibody responses in women with high-risk Her2+ breast cancer following vaccination against Her2.

BACKGROUND: The HER2-inhibiting antibody trastuzumab, in combination with chemotherapy, significantly improves survival of women with resected, HER2-overexpressing breast cancers, but is associated with toxicities including a risk of cardiomyopathy. Additionally, the beneficial effect of trastuzumab is expected to decrease once the drug is discontinued. We proposed to address these concerns by using cancer vaccines to stimulate HER2 intracellular domain (ICD)-specific T cell and antibody responses. METHODS: Subjects with stage II (> or = 6 +LN), III, or stage IV breast cancer with > 50% HER2 overexpressing tumor cells who were disease-free after surgery and adjuvant therapy were eligible. Vaccines consisted of immature, cultured DC (n = 3), mature cultured DC (n = 3), or mature Flt3-ligand mobilized peripheral blood DC (n = 1) loaded with ICD, or tetanus toxoid, keyhole limpet hemocyanin or CMV peptide as controls, and were administered intradermally/subcutaneously four times at 3 week intervals. ICD-specific T cell and antibody responses were measured. Cardiac function was determined by MUGA or ECHO; long term disease status was obtained from patient contact. RESULTS: All seven patients successfully underwent DC generation and five received all 4 immunizations. There were no toxicities greater than grade 1 or ejection fraction decrements below normal. Delayed-type hypersensitivity (DTH) reactions at the injection site occurred in 6/7 patients and HER2 specificity was detected by cytokine flow cytometry or ELISPOT in 5 patients. At more than 5 years of follow-up, 6/7 had detectable anti-ICD antibodies. One patient experienced a pulmonary recurrence at 4 years from their study immunizations. This recurrence was resected and they are without evidence of disease. All patients are alive and disease-free at 4.6-6.7 years of follow-up. CONCLUSION: Although this was a small pilot study, the well-tolerated nature of the vaccines, the lack of cardiac toxicity, significant immunogenicity, and a 100% 4.5-year survival rate suggest that vaccination with HER2 ICD protein-containing DC is appropriate for further study in this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT00005956.

Authors
Morse, MA; Hobeika, A; Osada, T; Niedzwiecki, D; Marcom, PK; Blackwell, KL; Anders, C; Devi, GR; Lyerly, HK; Clay, TM
MLA Citation
Morse, MA, Hobeika, A, Osada, T, Niedzwiecki, D, Marcom, PK, Blackwell, KL, Anders, C, Devi, GR, Lyerly, HK, and Clay, TM. "Long term disease-free survival and T cell and antibody responses in women with high-risk Her2+ breast cancer following vaccination against Her2. (Published online)" J Transl Med 5 (September 6, 2007): 42-.
PMID
17822557
Source
pubmed
Published In
Journal of Translational Medicine
Volume
5
Publish Date
2007
Start Page
42
DOI
10.1186/1479-5876-5-42

Partially matched, nonmyeloablative allogeneic transplantation: clinical outcomes and immune reconstitution.

PURPOSE: Allogeneic transplantation is typically limited to younger patients having a matched donor. To allow a donor to be found for nearly all patients, we have used a nonmyeloablative conditioning regimen in conjunction with stem cells from a related donor with one fully mismatched HLA haplotype. PATIENTS AND METHODS: Fludarabine, cyclophosphamide, and alemtuzumab were used as the preparatory regimen. Additional graft-versus-host disease (GVHD) prophylaxis included mycophenolate with or without cyclosporine. Patients with persistence of disease had a donor lymphocyte boost planned. Toxicities, engraftment, response, survival, and immune recovery are reported. RESULTS: Forty-nine patients with hematologic malignancies or marrow failure and no other available donors were enrolled. Ninety-four percent of patients had successful engraftment, and 8% had secondary graft failure. The treatment-related mortality rate was 10.2%, and 8% of patients had severe GVHD. Encouraging evidence of quantitative lymphocyte recovery through expansion of transplanted T cells was noted by 3 to 6 months. Seventy-five percent of patients attained a complete remission, and 1-year survival rate was 31% (95% CI, 18% to 44%). A standard-risk group of 19 patients with aplasia or in remission at transplantation demonstrated a 63% 1-year survival rate (95% CI, 38% to 80%) and 2.9-year median overall survival time (95% CI, 6.2 to 48 months). CONCLUSION: Nonmyeloablative therapy using haploidentical family member donors is feasible because the main obstacles of GVHD and graft rejection are manageable, allowing readily available stem-cell donors to be found for nearly all patients. Further qualitative and quantitative improvement in immune recovery is needed to address the high rate of relapse and risk of severe infections.

Authors
Rizzieri, DA; Koh, LP; Long, GD; Gasparetto, C; Sullivan, KM; Horwitz, M; Chute, J; Smith, C; Gong, JZ; Lagoo, A; Niedzwiecki, D; Dowell, JM; Waters-Pick, B; Liu, C; Marshall, D; Vredenburgh, JJ; Gockerman, J; Decastro, C; Moore, J; Chao, NJ
MLA Citation
Rizzieri, DA, Koh, LP, Long, GD, Gasparetto, C, Sullivan, KM, Horwitz, M, Chute, J, Smith, C, Gong, JZ, Lagoo, A, Niedzwiecki, D, Dowell, JM, Waters-Pick, B, Liu, C, Marshall, D, Vredenburgh, JJ, Gockerman, J, Decastro, C, Moore, J, and Chao, NJ. "Partially matched, nonmyeloablative allogeneic transplantation: clinical outcomes and immune reconstitution." J Clin Oncol 25.6 (February 20, 2007): 690-697.
PMID
17228020
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
25
Issue
6
Publish Date
2007
Start Page
690
End Page
697
DOI
10.1200/JCO.2006.07.0953

Addition of weekly oxaliplatin to standard preoperative chemoradiation for locally advanced rectal cancer - In reply

Authors
Ryan, DP; Niedzwiecki, D; Hollis, D; Tepper, J; Mayer, RJ
MLA Citation
Ryan, DP, Niedzwiecki, D, Hollis, D, Tepper, J, and Mayer, RJ. "Addition of weekly oxaliplatin to standard preoperative chemoradiation for locally advanced rectal cancer - In reply." JOURNAL OF CLINICAL ONCOLOGY 25.5 (February 10, 2007): 603-603.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
25
Issue
5
Publish Date
2007
Start Page
603
End Page
603
DOI
10.1200/JCO.2006.09.4805

A phase II prospective, multi-institutional trial (CALGB 89903) of adjuvant active specific immunotherapy following curative resection of colorectal cancer(CRC) hepatic metastases

Authors
Posner, MC; Niedzwiecki, D; Venook, AP; Hollis, DR; Schilsky, RL; Goldberg, RM; Mayer, RJ
MLA Citation
Posner, MC, Niedzwiecki, D, Venook, AP, Hollis, DR, Schilsky, RL, Goldberg, RM, and Mayer, RJ. "A phase II prospective, multi-institutional trial (CALGB 89903) of adjuvant active specific immunotherapy following curative resection of colorectal cancer(CRC) hepatic metastases." February 2007.
Source
wos-lite
Published In
Annals of Surgical Oncology
Volume
14
Issue
2
Publish Date
2007
Start Page
3
End Page
3

Association of dietary patterns with cancer recurrence and survival in patients with stage III colon cancer

Context: Dietary factors have been associated with the risk of developing colon cancer but the influence of diet on patients with established disease is unknown. Objective: To determine the association of dietary patterns with cancer recurrences and mortality of colon cancer survivors. Design, Setting, and Patients: Prospective observational study of 1009 patients with stage III colon cancer who were enrolled in a randomized adjuvant chemotherapy trial (CALGB 89803) between April 1999 and May 2001. Patients reported on dietary intake using a semiquantitative food frequency questionnaire during and 6 months after adjuvant chemotherapy. We identified 2 major dietary patterns, prudent and Western, by factor analysis. The prudent pattern was characterized by high intakes of fruits and vegetables, poultry, and fish; the Western pattern was characterized by high intakes of meat, fat, refined grains, and dessert. Patients were followed up for cancer recurrence or death. Main Outcome Measures: Disease-free survival, recurrence-free survival, and overall survival by dietary pattern. Results: During a median follow-up of 5.3 years for the overall cohort, 324 patients had cancer recurrence, 223 patients died with cancer recurrence, and 28 died without documented cancer recurrence. A higher intake of a Western dietary pattern after cancer diagnosis was associated with a significantly worse disease-free survival (colon cancer recurrences or death). Compared with patients in the lowest quintile of Western dietary pattern, those in the highest quintile experienced an adjusted hazard ratio (AHR) for disease-free survival of 3.25 (95% confidence interval [CI], 2.04-5.19; P for trend <.001). The Western dietary pattern was associated with a similar detriment in recurrence-free survival (AHR, 2.85; 95% CI, 1.75-4.63) and overall survival (AHR, 2.32; 95% CI, 1.36-3.96]), comparing highest to lowest quintiles (both with P for trend <.001). The reduction in disease-free survival with a Western dietary pattern was not significantly modified by sex, age, nodal stage, body mass index, physical activity level, base-line performance status, or treatment group. In contrast, the prudent dietary pattern was not significantly associated with cancer recurrence or mortality. Conclusions: Higher intake of a Western dietary pattern may be associated with a higher risk of recurrence and mortality among patients with stage III colon cancer treated with surgery and adjuvant chemotherapy. Further studies are needed to delineate which components of such a diet show the strongest association. ©2007 American Medical Association. All rights reserved.

Authors
Meyerhardt, JA; Niedzwiecki, D; Hollis, D; Saltz, LB; Hu, FB; Mayer, RJ; Nelson, H; Whittom, R; Hantel, A; Thomas, J; Fuchs, CS
MLA Citation
Meyerhardt, JA, Niedzwiecki, D, Hollis, D, Saltz, LB, Hu, FB, Mayer, RJ, Nelson, H, Whittom, R, Hantel, A, Thomas, J, and Fuchs, CS. "Association of dietary patterns with cancer recurrence and survival in patients with stage III colon cancer." Journal of the American Medical Association 298.7 (2007): 754-764.
PMID
17699009
Source
scival
Published In
JAMA : the journal of the American Medical Association
Volume
298
Issue
7
Publish Date
2007
Start Page
754
End Page
764
DOI
10.1001/jama.298.7.754

Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: Results of CALGB 89803

Purpose: Randomized studies have shown that irinotecan (CPT-11) extends survival in metastatic colorectal cancer patients when administered in second-line and when added to fluorouracil (FU) plus leucovorin (LV) in first-line therapy of metastatic colorectal cancer. When this study was initiated, FU plus LV was standard adjuvant treatment for stage III colon cancer. We evaluated the efficacy and safety of weekly bolus CPT-11 plus FU plus LV in the treatment of patients with completely resected stage III colon cancer. Methods: A total of 1,264 patients were randomly assigned to receive either standard weekly bolus FU plus LV regimen or weekly bolus CPT-11 plus FU plus LV. The primary end points of the study were overall survival (OS) and disease-free survival (DFS). Results: Treatment arms were well-balanced for patient characteristics and prognostic variables. There were no differences in either DFS or OS between the two treatment arms. Toxicity, including lethal toxicity, was significantly higher on the CPT-11 plus FU plus LV arm. Conclusion: The addition of CPT-11 to weekly bolus FU plus LV did not result in improvement in DFS or OS in stage III disease, but did increase both lethal and nonlethal toxicity. This trial demonstrates that advances in the treatment of metastatic disease do not necessarily translate into advances in adjuvant treatment, and it reinforces the need for randomized controlled adjuvant studies. © 2007 by American Society of Clinical Oncology.

Authors
Saltz, LB; Niedzwiecki, D; Hollis, D; Goldberg, RM; Hantel, A; Thomas, JP; Fields, ALA; Mayer, RJ
MLA Citation
Saltz, LB, Niedzwiecki, D, Hollis, D, Goldberg, RM, Hantel, A, Thomas, JP, Fields, ALA, and Mayer, RJ. "Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: Results of CALGB 89803." Journal of Clinical Oncology 25.23 (2007): 3456-3461.
PMID
17687149
Source
scival
Published In
Journal of Clinical Oncology
Volume
25
Issue
23
Publish Date
2007
Start Page
3456
End Page
3461
DOI
10.1200/JCO.2007.11.2144

Single agent bortezomib in the treatment of relapsed and refractory Hodgkin lymphoma: Cancer and leukemia Group B protocol 50206

Constitutive activation of nuclear factor-κB (NF-κB) has been described in patient-derived Reed-Sternberg cells and Hodgkin lymphoma (HL) cell lines and contributes to the proliferation and survival of HL. Therapeutic inhibition of the proteasome with bortezomib may inhibit over-expression of nuclear NF-κB by preventing degradation of IκB, which sequesters NF-κB in the cytoplasm. To evaluate this hypothesis, the Cancer and Leukemia Group B (CALGB) conducted a multi-institutional phase II trial of single agent bortezomib in patients with relapsed or refractory classical HL. Thirty patients received bortezomib 1.3 mg/m2 on days 1, 4, 8, 11 and every 21 days for a median of 2 cycles (range, 1-8). Patients were heavily pre-treated with a median of four prior therapies, and 83% were previously transplanted. No responses were observed, 9 patients had stable disease, and 21 progressed. The median progression-free and overall survivals were 1.4 months [95% CI, (1.28, 1.91)] and 14.8 months [95% CI (11.2, 22.3)], respectively. Grade 3-4 adverse events, primarily thrombocytopenia, occurred in 15 patients. Therefore, although well tolerated, 1.3 mg/m2 bortezomib administered biweekly has no single agent activity in relapsed/refractory classical HL.

Authors
Blum, KA; Johnson, JL; Niedzwiecki, D; Canellos, GP; Cheson, BD; Bartlett, NL
MLA Citation
Blum, KA, Johnson, JL, Niedzwiecki, D, Canellos, GP, Cheson, BD, and Bartlett, NL. "Single agent bortezomib in the treatment of relapsed and refractory Hodgkin lymphoma: Cancer and leukemia Group B protocol 50206." Leukemia and Lymphoma 48.7 (2007): 1313-1319.
PMID
17613759
Source
scival
Published In
Leukemia & Lymphoma (Informa)
Volume
48
Issue
7
Publish Date
2007
Start Page
1313
End Page
1319
DOI
10.1080/10428190701411458

Gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD), a salvage regimen in relapsed Hodgkin's lymphoma: CALGB 59804

Background: Because of high single-agent activity and modest toxicity, we hypothesized the combination of gemcitabine (G), vinorelbine (V), and pegylated liposomal doxorubicin (D) would be an effective salvage therapy for Hodgkin's lymphoma (HL). Patients and methods: A total of 91 patients participated. GVD was administered on days 1 and 8 every 21 days at doses of G 1000 mg/m2, V 20 mg/m2, and D 15 mg/m2 for transplant-naive patients, and G 800 mg/m2, V 15 mg/m2, and D 10 mg/m2 for post-transplant patients. Results: The dose-limiting toxicity was mucositis for the transplant-naive patients and febrile neutropenia for post-transplant patients. The overall response rate (RR) for all patients was 70% [95% confidence interval (CI) 59.8, 79.7], with 19% complete remissions. The 4-year event-free and overall survival rates in transplant-naive patients treated with GVD followed by autologous transplant were 52% (95% CI 0.34, 0.68) and 70% (95% CI 0.49, 0.84), and in the patients in whom prior transplant failed, these were 10% (95% CI 0.03, 0.22) and 34% (95% CI 0.17, 0.52), respectively. Conclusions: GVD is a well-tolerated, active regimen for relapsed HL with results similar to those reported for more toxic regimens. High RRs in patients in whom prior transplant failed confirms this regimen's activity even in heavily pretreated patients. © 2007 European Society for Medical Oncology.

Authors
Bartlett, NL; Niedzwiecki, D; Johnson, JL; Friedberg, JW; Johnson, KB; Besien, KV; Zelenetz, AD; Cheson, BD; Canellos, GP
MLA Citation
Bartlett, NL, Niedzwiecki, D, Johnson, JL, Friedberg, JW, Johnson, KB, Besien, KV, Zelenetz, AD, Cheson, BD, and Canellos, GP. "Gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD), a salvage regimen in relapsed Hodgkin's lymphoma: CALGB 59804." Annals of Oncology 18.6 (2007): 1071-1079.
PMID
17426059
Source
scival
Published In
Annals of Oncology
Volume
18
Issue
6
Publish Date
2007
Start Page
1071
End Page
1079
DOI
10.1093/annonc/mdm090

Revisiting the Cancer and Leukemia Group B/Southwest Oncology Group 80405 trial: A phase III trial of chemotherapy and biologic agents for patients with untreated advanced colorectal adenocarcinoma

Authors
Venook, AP; Blanke, CD; Niedzwiecki, D; Lenz, H-J; Taylor, JR; Hollis, DR; Sutherland, S; Goldberg, RM
MLA Citation
Venook, AP, Blanke, CD, Niedzwiecki, D, Lenz, H-J, Taylor, JR, Hollis, DR, Sutherland, S, and Goldberg, RM. "Revisiting the Cancer and Leukemia Group B/Southwest Oncology Group 80405 trial: A phase III trial of chemotherapy and biologic agents for patients with untreated advanced colorectal adenocarcinoma." Clinical Colorectal Cancer 6.7 (2007): 536-538.
PMID
17553204
Source
scival
Published In
Clinical colorectal cancer
Volume
6
Issue
7
Publish Date
2007
Start Page
536
End Page
538
DOI
10.3816/CCC.2007.n.021

Results of a phase II study of 506U78 in cutaneous T-cell lymphoma and peripheral T-cell lymphoma: CALGB 59901

Nelarabine (compound 506U78), a novel purine nucleoside, is a soluble pro-drug of 9-beta-d-arabinofuranosylguanine (ara-G). Nelarabine is rapidly demethoxylated in blood by adenosine deaminase to ara-G. Pre-clinical and clinical studies have demonstrated the selective cytotoxicity of ara-G to T-lineage derived cells. CALGB Protocol 59901 was a Phase II study of nelarabine in patients with systemically untreated cutaneous T-cell lymphoma (CTCL) or refractory/relapsed systemic T-cell lymphoma (STCL). The objectives were to determine response rate, remission duration and safety profile associated with nelarabine given at 1.5 g m-2 per day on days 1, 3 and 5 as an intravenous infusion every 21 days for a minimum of two cycles and to continue up to two cycles beyond CR up to a maximum of eight cycles. Nineteen patients were enrolled in the study: 11 CTCL and eight STCL patients. Grade 3 or 4 adverse events were documented in 50% and 28%, respectively. In particular, 33% of patients experienced Grade 3 or 4 neurologic toxicities. There were two partial remissions lasting 3 months and 5.5 months, respectively. Median event-free survival was 1.2 months and median overall survival was 3 months. Due to lack of efficacy and excessive toxicity, nelarabine is not recommended as monotherapy in adult patients with CTCL and STCL at this dose schedule.

Authors
Czuczman, M; Porcu, P; Johnson, J; Niedzwiecki, D; Kelly, M; Hsi, E; Cook, J; Canellos, G; Cheson, B
MLA Citation
Czuczman, M, Porcu, P, Johnson, J, Niedzwiecki, D, Kelly, M, Hsi, E, Cook, J, Canellos, G, and Cheson, B. "Results of a phase II study of 506U78 in cutaneous T-cell lymphoma and peripheral T-cell lymphoma: CALGB 59901." Leukemia and Lymphoma 48.1 (2007): 97-103.
PMID
17325852
Source
scival
Published In
Leukemia & Lymphoma (Informa)
Volume
48
Issue
1
Publish Date
2007
Start Page
97
End Page
103
DOI
10.1080/10428190600961058

In reply [2]

Authors
Ryan, DP; Niedzwiecki, D; Hollis, D; Tepper, J; Mayer, RJ
MLA Citation
Ryan, DP, Niedzwiecki, D, Hollis, D, Tepper, J, and Mayer, RJ. "In reply [2]." Journal of Clinical Oncology 25.5 (2007): 603--.
Source
scival
Published In
Journal of Clinical Oncology
Volume
25
Issue
5
Publish Date
2007
Start Page
603-

Immune reconstitution after unrelated cord blood transplantation.

Over the past years unrelated cord blood transplant (UCBT) has emerged as an effective alternative to unrelated donor blood and marrow transplantation. However, despite several advantages, its success is limited by the high incidence of opportunistic infections (OI), most of which are viral. Infection-related mortality is the primary cause of death after UCBT with most deaths occurring in the first 3-6 months post transplant. For several months, until recovery of the thymus is restored to support de novo T cell generation, protective antiviral immunity depends on the activity of post-thymic T cells infused within the cord blood (CB) grafts. However, almost all CB T cells are antigen inexperienced (naïve) lymphocytes that have been functionally altered by placental factors to protect pregnancy. CB T cells need to undergo in vivo priming, Th1/Tc1 maturation, and peripheral expansion before they can afford immunologic protection. This article provides an overview of what is currently known regarding the reconstitution of adaptive immunity following UCBT including our own data from prospective analyses of pediatric cohorts. Remarkable immunophenotypic changes are notable already in the first 2-3 weeks post-UCBT. These changes result from apparent 'homeostatic' peripheral T cell expansion in the lymphopenic environment. While we can identify patient- and graft-specific predictive factors, the concordant emergence of T cell subsets displaying the phenotype of Th1/Tc1 cytotoxic effector cells can be statistically linked to those UCBT recipients who will subsequently develop viral and other opportunistic infections. Antigen presenting dendritic cell reconstitution may also reflect alterations in immunocompetence due to OI and/or GVHD.

Authors
Szabolcs, P; Niedzwiecki, D
MLA Citation
Szabolcs, P, and Niedzwiecki, D. "Immune reconstitution after unrelated cord blood transplantation." Cytotherapy 9.2 (2007): 111-122. (Review)
PMID
17453963
Source
pubmed
Published In
Cytotherapy (Informa)
Volume
9
Issue
2
Publish Date
2007
Start Page
111
End Page
122
DOI
10.1080/14653240701231014

The CpG Island Methylator Phenotype and Chromosomal Instability Are Inversely Correlated in Sporadic Colorectal Cancer

Background & Aims: The CpG island methylator phenotype (CIMP) is one of the mechanisms involved in colorectal carcinogenesis (CRC). Although CIMP is probably the cause of high-frequency microsatellite instability (MSI-H) sporadic CRCs, its role in microsatellite stable (MSS) tumors is debated. The majority of MSS CRCs demonstrate chromosomal instability (CIN) with frequent loss of heterozygosity (LOH) at key tumor suppressor genes. We hypothesized that the majority of sporadic CRCs without CIN would be associated with CIMP. Methods: We tested 126 sporadic CRCs for MSI and LOH and categorized tumors into MSI, LOH, or MSI-/LOH- subgroups. Methylation status was evaluated using 6 CIMP-related markers (MINT1, MINT2, MINT31, p16INK4α, p14ARF, and hMLH1) and 6 tumor suppressor genes (PTEN, TIMP3, RUNX3, HIC1, APC, and RARβ2). BRAF V600E mutation analysis was performed using allele-specific polymerase chain reaction and DNA sequencing. Results: We observed frequent methylation at all 12 loci in all CRCs. BRAF V600E mutations correlated with the MSI (P < .0001) and MSI-/LOH- (P = .03) subgroups. MSI and MSI-/LOH- tumors exhibited more promoter methylation than CRCs with LOH (P < .0001). We also found an inverse correlation between the frequencies of methylation and LOH (ρ = -0.36; P < .0001). Conclusions: The associations between methylation frequencies at CIMP-related markers and MSI or MSI-/LOH- sporadic CRCs suggest that the majority of these tumors evolve through CIMP. These findings suggest that CIN and CIMP represent 2 independent and inversely related mechanisms of genetic and epigenetic instability in sporadic CRCs and confirm that MSI cancers arise as a consequence of CIMP. © 2007 AGA Institute.

Authors
Goel, A; Nagasaka, T; Arnold, CN; Inoue, T; Hamilton, C; Niedzwiecki, D; Compton, C; Mayer, RJ; Goldberg, R; Bertagnolli, MM; Boland, CR
MLA Citation
Goel, A, Nagasaka, T, Arnold, CN, Inoue, T, Hamilton, C, Niedzwiecki, D, Compton, C, Mayer, RJ, Goldberg, R, Bertagnolli, MM, and Boland, CR. "The CpG Island Methylator Phenotype and Chromosomal Instability Are Inversely Correlated in Sporadic Colorectal Cancer." Gastroenterology 132.1 (2007): 127-138.
PMID
17087942
Source
scival
Published In
Gastroenterology
Volume
132
Issue
1
Publish Date
2007
Start Page
127
End Page
138
DOI
10.1053/j.gastro.2006.09.018

Immuno-chemotherapy (IC) and autologous stem cell transplant (ASCT) for untreated patients (pts) with mantle cell lymphoma (MCL): CALGB 59909.

Authors
Damon, LE; Johnson, J; Niedzwiecki, D; Cheson, BD; Hurd, DD; Bartlett, NL; Byrd, JC; Kelly, M; Linker, C; Canellos, GP
MLA Citation
Damon, LE, Johnson, J, Niedzwiecki, D, Cheson, BD, Hurd, DD, Bartlett, NL, Byrd, JC, Kelly, M, Linker, C, and Canellos, GP. "Immuno-chemotherapy (IC) and autologous stem cell transplant (ASCT) for untreated patients (pts) with mantle cell lymphoma (MCL): CALGB 59909." November 16, 2006.
Source
wos-lite
Published In
Blood
Volume
108
Issue
11
Publish Date
2006
Start Page
774A
End Page
774A

Multivariate analysis of patient and graft specific factors among 330 recipients of unrelated cord blood transplant (UCBT) to predict risk of death from opportunistic infections in the first 6 months after UCBT.

Authors
Szabolcs, P; Peterson, BL; Niedzwiecki, D; Chao, N; Kurtzberg, J
MLA Citation
Szabolcs, P, Peterson, BL, Niedzwiecki, D, Chao, N, and Kurtzberg, J. "Multivariate analysis of patient and graft specific factors among 330 recipients of unrelated cord blood transplant (UCBT) to predict risk of death from opportunistic infections in the first 6 months after UCBT." November 16, 2006.
Source
wos-lite
Published In
Blood
Volume
108
Issue
11
Publish Date
2006
Start Page
810A
End Page
810A

Prospective comparison of patient experience with colon imaging tests.

PURPOSE: Patient experience varies with the currently available colon imaging tests, including air contrast barium enema, computed tomographic colonography, and colonoscopy. We examined differences in patient experience with colon imaging tests and whether they varied with gender, age, and race. SUBJECTS AND METHODS: Patients with fecal occult blood, hematochezia, iron-deficiency anemia, or a family history of colon cancer underwent air contrast barium enema followed 7 to 14 days later by computed tomographic colonography and colonoscopy. Validated patient experience questionnaires that measured the experience for each test and a separate questionnaire that obtained an overall summary measure were administered after testing. Eleven patient experiences including pain, embarrassment, difficulty with bowel preparation, and satisfaction with tests were examined. RESULTS: A total of 614 subjects completed all 3 imaging tests. The test most patients were willing to repeat was colonoscopy; it also was reported to be the least painful procedure. Patients were least satisfied with air contrast barium enema, and fewer would undergo air contrast barium enema compared with computed tomographic colonography or colonoscopy. There were limited racial and gender differences in perceptions of the tests. Younger adults perceived air contrast barium enema to be more painful than older adults. CONCLUSION: Taking into account a wide variety of patient experience measures, patients preferred colonoscopy to air contrast barium enema and computed tomographic colonography. This finding has important implications for physicians considering different colon imaging tests.

Authors
Bosworth, HB; Rockey, DC; Paulson, EK; Niedzwiecki, D; Davis, W; Sanders, LL; Yee, J; Henderson, J; Hatten, P; Burdick, S; Sanyal, A; Rubin, DT; Sterling, M; Akerkar, G; Bhutani, MS; Binmoeller, K; Garvie, J; Bini, EJ; McQuaid, K; Foster, WL; Thompson, WM; Dachman, A; Halvorsen, R
MLA Citation
Bosworth, HB, Rockey, DC, Paulson, EK, Niedzwiecki, D, Davis, W, Sanders, LL, Yee, J, Henderson, J, Hatten, P, Burdick, S, Sanyal, A, Rubin, DT, Sterling, M, Akerkar, G, Bhutani, MS, Binmoeller, K, Garvie, J, Bini, EJ, McQuaid, K, Foster, WL, Thompson, WM, Dachman, A, and Halvorsen, R. "Prospective comparison of patient experience with colon imaging tests." Am J Med 119.9 (September 2006): 791-799.
PMID
16945615
Source
pubmed
Published In
American Journal of Medicine
Volume
119
Issue
9
Publish Date
2006
Start Page
791
End Page
799
DOI
10.1016/j.amjmed.2006.02.013

Comparison of radiologists and technologists in the performance of air-contrast barium enemas.

OBJECTIVE: The purpose of this study was to determine whether the rate of polyp detection and the quality of air-contrast barium enema (ACBE) procedures performed by technologists differ from those performed by radiologists. CONCLUSION: Our results showed that well-trained certified technologists can perform ACBE similar in overall quality and accuracy to ACBE performed by attending physicians and residents. Training technologists to perform ACBE may help to alleviate the radiology staffing shortage in the United States.

Authors
Thompson, WM; Foster, WL; Paulson, EK; Niedzwiecki, D; Low, VHS; Fulford, LB; Broomer, BW; Sanders, L; Rockey, DC
MLA Citation
Thompson, WM, Foster, WL, Paulson, EK, Niedzwiecki, D, Low, VHS, Fulford, LB, Broomer, BW, Sanders, L, and Rockey, DC. "Comparison of radiologists and technologists in the performance of air-contrast barium enemas." AJR Am J Roentgenol 187.3 (September 2006): 706-709.
PMID
16928934
Source
pubmed
Published In
AJR. American journal of roentgenology
Volume
187
Issue
3
Publish Date
2006
Start Page
706
End Page
709
DOI
10.2214/AJR.05.0526

Phase II study of the farnesyltransferase inhibitor R115777 in advanced melanoma: CALGB 500104.

8014 Background: Ras-based signaling is thought to be critical in the genesis of melanoma. Farneslytransferase (FT) inhibitors (FTIs) have been developed as a pharmacologic strategy to inhibit Ras function. Additional farnesylated proteins are also important for the malignant process, and FTIs inhibit melanoma cell line proliferation in vitro. These considerations motivated the development of a phase II trial of the FTI R115777 in patients with melanoma. Farnesylated proteins are also important for T cell activation. The interest in future combinations of targeted agents and immunotherapeutics in this disease prompted analysis of T cell function ex vivo. METHODS: A 3-stage design was pursued with a maximum of 40 patients planned and early stopping if there were no responders in the first 14, or fewer than 2 responders in the first 28 patients. Eligibility included intact organ function, PS≤1, no prior chemotherapy, at most 1 prior immunotherapy, no brain metastases, and presence of at least 2 cutaneous lesions amenable to excisional biopsy. R115777 (300 mg orally) was administered twice per day for 21 days of a 28-day cycle. Patients were evaluated every 2 cycles by RECIST criteria. Blood was obtained pre-treatment and during week 7 for analysis of HDJ-2 farnesylation and for T cell IFN-γ production in response to SEA. In addition, tumor biopsies were performed pre- and post-treatment when feasible to directly measure FT activity. RESULTS: 14 patients were enrolled. 2 patients had grade 3 toxicities, which included myelosuppression, nausea/vomiting, elevated BUN, and anorexia. There were no clinical responses, and only 4 patients went on to a second course of treatment. All analyzed patients showed HDJ-2 gel shift in peripheral blood cells, as well as marked inhibition of FT activity (by 85-98%) in tumor tissue. T cell production of IFN-γ was also suppressed. CONCLUSIONS: Despite potent target inhibition, the FTI R115777 showed no evidence for clinical activity as a single agent in this cohort of 14 metastatic melanoma patients. Inhibition of T cell function has implications for future combination therapies and suggests the possibility for FTIs as candidate immunosuppressive agents. New therapeutic approaches for melanoma, or logically selected combination therapies, are needed. [Table: see text].

Authors
Gajewski, TF; Niedzwiecki, D; Johnson, J; Linette, G; Bucher, C; Blaskovich, M; Sebti, S; Haluska, F
MLA Citation
Gajewski, TF, Niedzwiecki, D, Johnson, J, Linette, G, Bucher, C, Blaskovich, M, Sebti, S, and Haluska, F. "Phase II study of the farnesyltransferase inhibitor R115777 in advanced melanoma: CALGB 500104." J Clin Oncol 24.18_suppl (June 20, 2006): 8014-.
PMID
27955577
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
24
Issue
18_suppl
Publish Date
2006
Start Page
8014

Microsatellite instability predicts improved response to adjuvant therapy with irinotecan, 5-fluorouracil and leucovorin in stage III colon cancer.

10003 Background: Colon cancers exhibiting a high level of microsatellite instability (MSI-H) show distinct clinicopathological features, including both better prognosis and reduced response to 5-fluorouracil (5-FU)-based chemotherapy. We investigated the impact of adjuvant chemotherapy containing irinotecan in patients with MSI-H colon cancers. METHODS: CALGB protocol 89803 randomized 1264 patients with resected stage III colon cancer to receive post-operative 5-FU and leucovorin (LV) with or without irinotecan. Paraffin blocks containing primary tumor and normal tissue were collected. Microsatellite instablility was assessed using a panel of mono- and di-nucleotide markers. Disease free survival (DFS) was measured from trial entry until documented disease progression or death from any cause. A statistical significance level of 0.2 was used in screening to generate hypotheses regarding MSI status and outcome. Median follow-up at analysis was 3.8 years. Overall C89803 showed no advantage for addition of irinotecan to 5-FU/LV. RESULTS: Patients with and without tumor samples analyzed did not differ by treatment, age, gender, primary site, T-stage, differentiation, # positive nodes, or mucinous type. Of 482 tumors analyzed, 75 (16%) demonstrated MSI-H. MSI-H cancers were more likely to be located in the proximal colon (p<0.0001), of high histologic grade (p<0.0001) and mucinous histology (p<0.0001), and also had increased numbers of tumor-containing lymph nodes (mean # positive nodes/case = 3.5 for MSI Low/Stable vs. 4.7 for MSI-H; p = 0.04). At the time of analysis 143 of 482 patients (36%) analyzed experienced tumor recurrence and/or death due to any cause. For patients with MSI-H tumors, DFS was better in those treated with irinotecan in addition to 5-FU/LV (logrank p=0.18). Among patients with MSI Low/Stable tumors there was no difference in DFS between those treated with and without irinotecan (logrank p =0.39). CONCLUSIONS: Early results from CALGB protocol 89803 indicate that addition of postoperative irinotecan to 5-FU/LV may improve DFS in patients with stage III colon cancers that exhibit MSI-H. Longer follow-up is required to confirm this finding. [Table: see text].

Authors
Bertagnolli, MM; Compton, CC; Niedzwiecki, D; Warren, RS; Jewell, S; Bailey, GP; Mayer, RJ; Goldberg, R; Saltz, L; Redston, M
MLA Citation
Bertagnolli, MM, Compton, CC, Niedzwiecki, D, Warren, RS, Jewell, S, Bailey, GP, Mayer, RJ, Goldberg, R, Saltz, L, and Redston, M. "Microsatellite instability predicts improved response to adjuvant therapy with irinotecan, 5-fluorouracil and leucovorin in stage III colon cancer." J Clin Oncol 24.18_suppl (June 20, 2006): 10003-.
PMID
27955350
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
24
Issue
18_suppl
Publish Date
2006
Start Page
10003

A phase II study of bortezomib in relapsed Hodgkin lymphoma: Preliminary results of CALGB 50206.

7576 Background: Constitutive NF-κB activation has been described in both Hodgkin lymphoma (HL) cell lines and patient-derived Reed-Sternberg cells. In vitro, therapeutic targeting of NF-κB with proteasome inhibitors like bortezomib leads to apoptosis of HL cell lines, providing a rationale for clinical trials with this agent. METHODS: From 3/15/2004 until 2/23/2005, the CALGB conducted a phase II trial of bortezomib in patients (pts) with relapsed and refractory classical HL to assess response rate and toxicity. Eligibility requirements included at least one prior systemic therapy, measurable disease, absolute neutrophil count ≥ 750/μL, platelets ≥ 75,000/μl, and creatinine ≤ 2.5 mg/dl. Pts able to undergo a stem cell transplant with curative intent or with pre-existing sensory neuropathy ≥ grade 2 were not eligible. Bortezomib was administered at 1.3 mg/m(2) days 1, 4, 8, and 11 every 21 days for 2-8 cycles, or until disease progression. RESULTS: 30 pts received a median of 2 cycles (range, 1-8). For 25 pts with available data, 80% had stage IV disease with a median of 4 prior therapies (range 2-8, 92% with prior stem cell transplant). For 29 pts with complete response data, 2 pts were not evaluable due to adverse events (bleeding gastric ulcer and grade 4 dyspnea) during cycle 1 leading to a discontinuation of therapy prior to restaging. In the remaining 27, no responses were observed [95% CI (0.0, 0.13)]; 18 pts progressed, and 9 pts had stable disease. Median follow-up is 4.4 (range, 0.6 -16.4) months. The median progression-free and overall survival times are 1.4 [95% CI (1.3, 2.8)] and 11.6 months [95% CI (6.6, ongoing)], respectively. Toxicity data are available for 26 pts. Grade 3-4 events included thrombocytopenia (27%), lymphopenia (8%), dyspnea (8%), anemia (4%), diarrhea (4%), hypotension (4%), rash (4%), and hyperbilirubinemia (4%). Both instances of grade 3-4 dyspnea occurred in pts with disease progression in the lung. 27% developed grade 2 sensory or motor neuropathy. CONCLUSIONS: Although well-tolerated, bortezomib has no single agent efficacy in relapsed classical HL at the current dose and schedule. No significant financial relationships to disclose.

Authors
Blum, KA; Johnson, JL; Niedzwiecki, D; Cannellos, GP; Cheson, BD; Bartlett, NL
MLA Citation
Blum, KA, Johnson, JL, Niedzwiecki, D, Cannellos, GP, Cheson, BD, and Bartlett, NL. "A phase II study of bortezomib in relapsed Hodgkin lymphoma: Preliminary results of CALGB 50206." J Clin Oncol 24.18_suppl (June 20, 2006): 7576-.
PMID
27955434
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
24
Issue
18_suppl
Publish Date
2006
Start Page
7576

Superiority of trimodality therapy to surgery alone in esophageal cancer: Results of CALGB 9781.

4012 Background: CALGB 9781 was a prospective randomized Intergroup trial of trimodality therapy versus surgery alone for the treatment of stages 1-3 esophageal cancer. METHODS: Five-hundred patients were targeted for enrollment with three years of follow-up planned. The primary endpoint was overall survival. All patents had EGD with biopsy, barium esophagogram and CT. Additional staging by EUS and/or thoracoscopy/laparoscopy was recommended. Patients were randomized to treatment with either surgery alone or cisplatin (100mg/m(2)) and 5FU (1000 mg/m(2)/d × 4d) weeks 1 and 5 concurrent with radiation therapy (50.4 Gy- 1.8 Gy/fx over 5.6 weeks) followed by esophagectomy with lymph node dissection. RESULTS: A total of 56 patients were entered on study between October 1997 and March 2000 when the trial was closed due to poor accrual. Thirty patients were randomized to trimodality therapy and 26 to surgery alone. Patient characteristics were similar between groups. Surgical staging was conducted in just over 50% of patients in both groups. The primary toxicities of Gr 3 or greater with preoperative therapy were hematopoietic (54%), and esophagitis/dysphagia (40%). There were 14 and 17 patients with surgical complications on the trimodality and surgery alone arms, respectively, with 2 post-surgical deaths (within 30 days), both on the surgery alone arm. Postoperative hospital stays were 11.5 and 10 days, respectively. Median follow-up is 6 years. An intent- to- treat analysis showed a median survival of 4.5 yrs vs 1.8 yrs in favor of trimodality therapy (log-rank p=0.02). A log rank test with stratifications by N stage, staging approach and histology demonstrated a p-value of 0.005. 5-year survival was 39% (95% CI [21%, 57%]) vs 16% (95% CI [5%, 33%]) in favor of trimodality therapy. Analysis of progression-free survival is underway. CONCLUSIONS: This randomized study demonstrates a long-term survival advantage with the use of chemoradiation therapy followed by surgery in the treatment of esophageal cancer. Although accrual was well below that planned, the observed survival difference is statistically significant and suggests that trimodality therapy is an appropriate standard of care for patients with this disease. No significant financial relationships to disclose.

Authors
Tepper, JE; Krasna, M; Niedzwiecki, D; Hollis, D; Reed, C; Goldberg, R; Rich, T; Kiel, K; Mayer, R
MLA Citation
Tepper, JE, Krasna, M, Niedzwiecki, D, Hollis, D, Reed, C, Goldberg, R, Rich, T, Kiel, K, and Mayer, R. "Superiority of trimodality therapy to surgery alone in esophageal cancer: Results of CALGB 9781." J Clin Oncol 24.18_suppl (June 20, 2006): 4012-.
PMID
27953697
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
24
Issue
18_suppl
Publish Date
2006
Start Page
4012

Phase III study of irinotecan/5FU/LV (FOLFIRI) or oxaliplatin/5FU/LV (FOLFOX) ± cetuximab for patients (pts) with untreated metastatic adenocarcinoma of the colon or rectum (MCRC): CALGB 80203 preliminary results.

3509 Background: FOLFIRI or FOLFOX are 1st-line treatments (Rx) for MCRC. Cetuximab is an IgG1 Mab that targets the epidermal growth factor receptor (EGFR) and is approved as monotherapy or in combination with irinotecan in irinotecan-refractory, EGFR + pts with MCRC. CALGB 80203 randomized untreated MCRC pts to FOLFOX or FOLFIRI ± cetuximab (independent of EGFR status.) Methods: Pts with performance status 0-1 with tumor blocks available for EGFR analysis received either irinotecan 180 mg/m(2) over 1.5 hours (h) or oxaliplatin 85 mg/m(2) over 2h combined with LV 400 mg/m(2) over 2h and 5FU 400 mg/m(2) bolus, then 46-48h CI 5FU 2400 mg/m(2) q o w. Cetuximab dose: 400 mg/m(2) loading dose, then 250 mg/m(2) qw. Rx continued until progression or toxicity; subsequent Rx was not mandated although information was collected on such rx. Accrual goal was 2200 pts with intended 1° endpt of overall survival (OS). 80203 closed administratively in 1/05 (due to slow accrual) with 238 pts accrued. 2° endpts of response rate (RR), progression free survival (PFS), duration of R and toxicity are now able to be analyzed. RESULTS: Accrual: FOLFIRI (A) - 61; FOLFIRI + cetuximab (B) - 59: FOLFOX (C) - 60; FOLFOX + cetuximab (D) - 58; approx median follow-up (f/u) is 12 months. RR (CR + PR, not all yet confirmed): A - 34%; B - 42%; C - 32%; D - 55%. RR was similar in the FOLFIRI or FOLFOX arms (A+B v. C+D; 38% v. 43%, p=0.44; chi-square) while C225 containing arms (B+D) v. non-C225 arms (A+C) had a superior RR (49% v. 33%; p=0.014, chi-square) It is too early to tell if there are differences in PFS, duration of response or OS. No significant differences in gr III diarrhea or any gr IV toxicities were seen. CONCLUSIONS: These results suggest that FOLFIRI and FOLFOX are similar in efficacy for pts with untreated MCRC and that adding cetuximab to either in1st-line Rx appears to increase response rates. PFS and duration of response do not appear different at this analysis. Further f/u and an analysis of prospective companion correlative studies may help to further clarify these results. [Table: see text].

Authors
Venook, A; Niedzwiecki, D; Hollis, D; Sutherland, S; Goldberg, R; Alberts, S; Benson, A; Wade, J; Schilsky, R; Mayer, R
MLA Citation
Venook, A, Niedzwiecki, D, Hollis, D, Sutherland, S, Goldberg, R, Alberts, S, Benson, A, Wade, J, Schilsky, R, and Mayer, R. "Phase III study of irinotecan/5FU/LV (FOLFIRI) or oxaliplatin/5FU/LV (FOLFOX) ± cetuximab for patients (pts) with untreated metastatic adenocarcinoma of the colon or rectum (MCRC): CALGB 80203 preliminary results." J Clin Oncol 24.18_suppl (June 20, 2006): 3509-.
PMID
27953330
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
24
Issue
18_suppl
Publish Date
2006
Start Page
3509

Microsatellite instability predicts improved response to adjuvant therapy with irinotecan, 5-fluorouracil and leucovorin in stage III colon cancer.

Authors
Bertagnolli, MM; Compton, CC; Niedzwiecki, D; Warren, RS; Jewell, S; Bailey, GP; Mayer, RJ; Goldberg, R; Saltz, L; Redston, M
MLA Citation
Bertagnolli, MM, Compton, CC, Niedzwiecki, D, Warren, RS, Jewell, S, Bailey, GP, Mayer, RJ, Goldberg, R, Saltz, L, and Redston, M. "Microsatellite instability predicts improved response to adjuvant therapy with irinotecan, 5-fluorouracil and leucovorin in stage III colon cancer." June 20, 2006.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
24
Issue
18
Publish Date
2006
Start Page
541S
End Page
541S

Superiority of trimodality therapy to surgery alone in esophageal cancer: Results of CALGB 9781.

Authors
Tepper, JE; Krasna, M; Niedzwiecki, D; Hollis, D; Reed, C; Goldberg, R; Rich, T; Kiel, K; Mayer, R
MLA Citation
Tepper, JE, Krasna, M, Niedzwiecki, D, Hollis, D, Reed, C, Goldberg, R, Rich, T, Kiel, K, and Mayer, R. "Superiority of trimodality therapy to surgery alone in esophageal cancer: Results of CALGB 9781." June 20, 2006.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
24
Issue
18
Publish Date
2006
Start Page
181S
End Page
181S

Phase III study of irinotecan/5FU/LV (FOLFIRI) or oxaliplatin/5FU/LV (FOLFOX) +/- cetuximab for patients (pts) with untreated metastatic adenocarcinoma of the colon or rectum (MCRC): CALGB 80203 preliminary results.

Authors
Venook, A; Niedzwiecki, D; Hollis, D; Sutherland, S; Goldberg, R; Alberts, S; Benson, A; Wade, J; Schilsky, R; Mayer, R
MLA Citation
Venook, A, Niedzwiecki, D, Hollis, D, Sutherland, S, Goldberg, R, Alberts, S, Benson, A, Wade, J, Schilsky, R, and Mayer, R. "Phase III study of irinotecan/5FU/LV (FOLFIRI) or oxaliplatin/5FU/LV (FOLFOX) +/- cetuximab for patients (pts) with untreated metastatic adenocarcinoma of the colon or rectum (MCRC): CALGB 80203 preliminary results." June 20, 2006.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
24
Issue
18
Publish Date
2006
Start Page
148S
End Page
148S

Phase II study of the farnesyltransferase inhibitor R115777 in advanced melanoma: CALGB 500104.

Authors
Gajewski, TF; Niedzwiecki, D; Johnson, J; Linette, G; Bucher, C; Blaskovich, M; Sebti, S; Haluska, F
MLA Citation
Gajewski, TF, Niedzwiecki, D, Johnson, J, Linette, G, Bucher, C, Blaskovich, M, Sebti, S, and Haluska, F. "Phase II study of the farnesyltransferase inhibitor R115777 in advanced melanoma: CALGB 500104." June 20, 2006.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
24
Issue
18
Publish Date
2006
Start Page
456S
End Page
456S

A phase II study of bortezomib in relapsed Hodgkin lymphoma: Preliminary results of CALGB 50206.

Authors
Blum, KA; Johnson, JL; Niedzwiecki, D; Cannellos, GP; Cheson, BD; Bartlett, NL
MLA Citation
Blum, KA, Johnson, JL, Niedzwiecki, D, Cannellos, GP, Cheson, BD, and Bartlett, NL. "A phase II study of bortezomib in relapsed Hodgkin lymphoma: Preliminary results of CALGB 50206." June 20, 2006.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
24
Issue
18
Publish Date
2006
Start Page
440S
End Page
440S

Phase I/II study of preoperative oxaliplatin, fluorouracil, and external-beam radiation therapy in patients with locally advanced rectal cancer: Cancer and Leukemia Group B 89901.

PURPOSE: The addition of oxaliplatin to fluorouracil in patients with advanced colorectal cancer improves survival. This phase I/II study evaluated the addition of weekly oxaliplatin to preoperative continuous infusion fluorouracil (FU) and external-beam radiation therapy (RT) in patients with locally advanced rectal adenocarcinoma. PATIENTS AND METHODS: Patients with clinical T3/T4 rectal adenocarcinoma and no evidence of metastases were treated with weekly oxaliplatin, continuous infusion FU 200 mg/m2 intravenously, and RT. A total of 6 weekly doses of oxaliplatin were planned. RT dose was 1.8 Gy/fraction to a total dose of 50.4 Gy. In the phase I portion, oxaliplatin was escalated from 30 to 60 mg/m2. RESULTS: Forty-four patients were entered onto the study, 18 on the phase I portion and 26 on the phase II portion. The maximum-tolerated dose (MTD) for oxaliplatin was determined to be 60 mg/m2. At the MTD, 12 patients experienced grade 3 or 4 diarrhea, two patients experienced grade 3 neutropenia, and one patient experienced grade 3 thrombocytopenia. Fifty-six percent of patients entered at the MTD completed all 6 weeks of oxaliplatin. Eight (25%) of 32 patients enrolled at the phase II dose experienced a pathologic complete response. CONCLUSION: In this multicenter study, the addition of oxaliplatin to intravenous continuous infusion FU and RT for patients with locally advanced rectal cancer was associated with a high pathologic complete response rate but more toxicity than when FU is used alone. A regimen of weekly oxaliplatin, continuous infusion FU, and radiation therapy is now being evaluated by the National Surgical Adjuvant Breast and Bowel Project.

Authors
Cancer and Leukemia Group B 89901, ; Ryan, DP; Niedzwiecki, D; Hollis, D; Mediema, BE; Wadler, S; Tepper, JE; Goldberg, RM; Mayer, RJ
MLA Citation
Cancer and Leukemia Group B 89901, , Ryan, DP, Niedzwiecki, D, Hollis, D, Mediema, BE, Wadler, S, Tepper, JE, Goldberg, RM, and Mayer, RJ. "Phase I/II study of preoperative oxaliplatin, fluorouracil, and external-beam radiation therapy in patients with locally advanced rectal cancer: Cancer and Leukemia Group B 89901." J Clin Oncol 24.16 (June 1, 2006): 2557-2562.
PMID
16636336
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
24
Issue
16
Publish Date
2006
Start Page
2557
End Page
2562
DOI
10.1200/JCO.2006.05.6754

A randomized phase III comparative trial of immediate consolidation with high-dose chemotherapy and autologous peripheral blood progenitor cell support compared to observation with delayed consolidation in women with metastatic breast cancer and only bone metastases following intensive induction chemotherapy.

The prognosis for patients with metastatic breast cancer remains poor. Metastatic breast cancer confined to the bones may have a better prognosis, especially hormone receptor-positive disease. We performed a prospective, randomized clinical trial to compare immediate consolidation with high-dose chemotherapy and hematopoietic support versus observation with high-dose consolidation at the time of disease progression in women with metastatic breast cancer and only bone metastases. The patients received chemotherapy with doxorubicin, 5-fluorouracil and methotrexate before randomization. In all, 85 patients were enrolled and 69 were randomized. The median follow-up is 8.1 years from randomization. The median event-free survival (EFS) for the immediate transplant arm is 12 months and for the observation arm is 4.3 months (P<0.0001). The median overall survival for the immediate transplant arm is 2.97 years and for the observation arm 1.81 years, a difference that is not statistically significant. Immediate high-dose chemotherapy and radiation therapy as consolidation offers a clinically and statistically significant improvement in EFS compared with radiation therapy alone following induction chemotherapy for women with metastatic breast cancer confined to the bones.

Authors
Vredenburgh, JJ; Madan, B; Coniglio, D; Ross, M; Broadwater, G; Niedzwiecki, D; Edwards, J; Marks, L; Vandemark, R; McDonald, C; Affronti, ML; Peters, WP
MLA Citation
Vredenburgh, JJ, Madan, B, Coniglio, D, Ross, M, Broadwater, G, Niedzwiecki, D, Edwards, J, Marks, L, Vandemark, R, McDonald, C, Affronti, ML, and Peters, WP. "A randomized phase III comparative trial of immediate consolidation with high-dose chemotherapy and autologous peripheral blood progenitor cell support compared to observation with delayed consolidation in women with metastatic breast cancer and only bone metastases following intensive induction chemotherapy." Bone Marrow Transplant 37.11 (June 2006): 1009-1015.
PMID
16633363
Source
pubmed
Published In
Bone Marrow Transplantation
Volume
37
Issue
11
Publish Date
2006
Start Page
1009
End Page
1015
DOI
10.1038/sj.bmt.1705367

Causes of errors in polyp detection at air-contrast barium enema examination.

PURPOSE: To retrospectively determine the cause of errors in air-contrast barium enema (ACBE) examination for detection of polyps 6 mm or larger. MATERIALS AND METHODS: The study had institutional review board approval. Informed consent was waived for this HIPAA-compliant study. ABCE findings in 41 subjects with 56 missed polyps were evaluated by two radiologists to determine if the cause of errors was perceptual or technical. A comparison was made between total number of polyps in the proximal and distal colon and those missed at each location (Fisher exact test). The 288 ACBE examinations were assessed on a scale of 0-4 (0, excellent; 4, very poor) for six colonic segments (paired t test). RESULTS: Of 17 polyps 1 cm or larger not detected in 15 subjects, 11 (65%) were missed because of technical errors and six (35%) because of perceptual errors. Eight (72%) technical and four (67%) perceptual errors occurred proximal to the splenic flexure. One 3.5-cm cecal carcinoma was not diagnosed prospectively (perceptual error). Of 39 6-9-mm polyps not detected in 26 subjects, 35 (90%) were missed because of technical errors and four (10%) because of perceptual errors. Eighty percent of technical and 75% of perceptual errors were in the proximal colon. When the proportion of polyps in the proximal and distal colon was compared, 22 (63%) of 35 polyps in the distal colon and 15 (26%) of 58 in the proximal colon were detected (P = .0009). There were no detectable differences in the quality of studies in subjects whose polyps were detected and subjects whose polyps were missed (P > .05). CONCLUSION: Technical errors were more common than perceptual errors. The majority of missed polyps were in the proximal colon. Detection rates of polypoid lesions might increase if the quality of ACBE examination can be improved, especially in the proximal colon.

Authors
Thompson, WM; Foster, WL; Paulson, EK; Niedzwiecki, D; Low, VHS; Fulford, LB; Broomer, BW; Sanders, L; Rockey, DC
MLA Citation
Thompson, WM, Foster, WL, Paulson, EK, Niedzwiecki, D, Low, VHS, Fulford, LB, Broomer, BW, Sanders, L, and Rockey, DC. "Causes of errors in polyp detection at air-contrast barium enema examination." Radiology 239.1 (April 2006): 139-148.
PMID
16507754
Source
pubmed
Published In
Radiology
Volume
239
Issue
1
Publish Date
2006
Start Page
139
End Page
148
DOI
10.1148/radiol.2391050610

Hepatic arterial infusion versus systemic therapy for hepatic metastases from colorectal cancer: a randomized trial of efficacy, quality of life, and molecular markers (CALGB 9481).

PURPOSE: Hepatic metastases derive most of their blood supply from the hepatic artery; therefore, for patients with hepatic metastases from colorectal cancer, hepatic arterial infusion (HAI) of chemotherapy may improve outcome. METHODS: In a multi-institutional trial, 135 patients were randomly assigned to receive HAI versus systemic bolus fluorouracil and leucovorin. The primary end point was survival; secondary end points were response, recurrence, toxicity, quality of life, cost, and the influence of molecular markers. RESULTS: Overall survival was significantly longer for HAI versus systemic treatment (median, 24.4 v 20 months; P = .0034), as were response rates (47% and 24%; P = .012) and time to hepatic progression (THP; 9.8 v 7.3 months; P = .034). Time to extrahepatic progression (7.7 v 14.8 months; P = .029) was significantly shorter in the HAI group. Quality-of-life measurements showed improved physical functioning in the HAI group at the 3- and 6-month follow-up assessments. Toxicity included grade > or = 3 neutropenia (2% and 45%; P < .01), stomatitis (0% and 24%; P < .01), and bilirubin elevation (18.6% and 0; P < .01) in the HAI and systemic treatment groups, respectively. A greater proportion of men versus women receiving HAI experienced biliary toxicity (37% and 15%, respectively; P = .05). For HAI patients with thymidylate synthase levels in tumor less than or > or = 4, the median survival was 24 and 14 months, respectively (P = .17). CONCLUSION: HAI therapy increased overall survival, response rate, THP, and was associated with better physical functioning compared with systemic therapy. Additional studies need to address the overall benefit and cost of new chemotherapy agents versus HAI alone or the combination of HAI with new agents.

Authors
Kemeny, NE; Niedzwiecki, D; Hollis, DR; Lenz, H-J; Warren, RS; Naughton, MJ; Weeks, JC; Sigurdson, ER; Herndon, JE; Zhang, C; Mayer, RJ
MLA Citation
Kemeny, NE, Niedzwiecki, D, Hollis, DR, Lenz, H-J, Warren, RS, Naughton, MJ, Weeks, JC, Sigurdson, ER, Herndon, JE, Zhang, C, and Mayer, RJ. "Hepatic arterial infusion versus systemic therapy for hepatic metastases from colorectal cancer: a randomized trial of efficacy, quality of life, and molecular markers (CALGB 9481)." J Clin Oncol 24.9 (March 20, 2006): 1395-1403.
PMID
16505413
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
24
Issue
9
Publish Date
2006
Start Page
1395
End Page
1403
DOI
10.1200/JCO.2005.03.8166

Analysis of micrometastatic disease in sentinel lymph nodes from resectable colon cancer: results of Cancer and Leukemia Group B Trial 80001.

PURPOSE: To determine whether sentinel lymph node (LN) sampling (SLNS) could reduce the number of nodes required to characterize micrometastatic disease (MMD) in patients with potentially curable colon cancer. PATIENTS AND METHODS: Cancer and Leukemia Group B 80001 was a study to determine whether SLNS could identify a subset of LNs that predicted the status of the nodal basin for resectable colon cancer and, therefore, could be extensively evaluated for the presence of micrometastases. Patients enrolled onto this study underwent SLNS after injection of 1% isosulfan blue, and both sentinel nodes (SNs) and non-SNs obtained during primary tumor resection were sectioned at multiple levels and stained using anti-carcinoembryonic antigen and anticytokeratin antibodies. RESULTS: Using standard histopathology, SNs failed to predict the presence of nodal disease in 13 (54%) of 24 node-positive patients. Immunostains were performed for patients whose LNs were negative by standard histopathology. Depending on the immunohistochemical criteria used to assign LN positivity, SN examination resulted in either an unacceptably high false-positive rate (20%) or a low sensitivity for detection of MMD (40%). CONCLUSION: By examining both SNs and non-SNs, this multi-institutional study showed that SNs did not accurately predict the presence of either conventionally defined nodal metastases or MMD. As a result, SLNS is not a useful technique for the study of MMD in patients with colon cancer.

Authors
Redston, M; Compton, CC; Miedema, BW; Niedzwiecki, D; Dowell, JM; Jewell, SD; Fleshman, JM; Bem, J; Mayer, RJ; Bertagnolli, MM; Leukemia Group B Trial 80001,
MLA Citation
Redston, M, Compton, CC, Miedema, BW, Niedzwiecki, D, Dowell, JM, Jewell, SD, Fleshman, JM, Bem, J, Mayer, RJ, Bertagnolli, MM, and Leukemia Group B Trial 80001, . "Analysis of micrometastatic disease in sentinel lymph nodes from resectable colon cancer: results of Cancer and Leukemia Group B Trial 80001." J Clin Oncol 24.6 (February 20, 2006): 878-883.
PMID
16418493
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
24
Issue
6
Publish Date
2006
Start Page
878
End Page
883
DOI
10.1200/JCO.2005.03.6038

Non-myeloablative allogeneic transplantation with alemtuzumab, fludarabine and cyclophosphamide using 3-6/6 HLA matched donors

Authors
Rizzieri, D; Chute, J; Horwitz, M; Gasparetto, C; Sullivan, K; Long, G; Morris, A; Niedzwiecki, D; Nelson, C
MLA Citation
Rizzieri, D, Chute, J, Horwitz, M, Gasparetto, C, Sullivan, K, Long, G, Morris, A, Niedzwiecki, D, and Nelson, C. "Non-myeloablative allogeneic transplantation with alemtuzumab, fludarabine and cyclophosphamide using 3-6/6 HLA matched donors." February 2006.
Source
wos-lite
Published In
Biology of Blood and Marrow Transplantation
Volume
12
Issue
2
Publish Date
2006
Start Page
34
End Page
34
DOI
10.1016/j.bbmt.2005.11.104

Phase 2 study of the g209-2M melanoma peptide vaccine and low-dose interleukin-2 in advanced melanoma: Cancer and Leukemia Group B 509901.

High-dose interleukin-2 (IL-2) is the only approved immunologic therapy for advanced melanoma, but response rates are low and significant toxicities limit treatment to otherwise healthy patients. g209-2M is a nanopeptide engineered to mimic an epitope of the gp100 melanocyte differentiation protein that is recognized in a human leukocyte antigen (HLA)-restricted manner by melanoma tumor-infiltrating lymphocytes in some patients. Previous reports indicated that administration of the g209-2M peptide could induce g209-reactive circulating T cells in patients with melanoma and that the combination of g209-2M and high-dose IL-2 might be a more active treatment than high-dose IL-2 alone. Low-dose IL-2 is not active but has significant biologic effects, and because of a different toxicity profile, it can be offered to most patients. The primary objective of this cooperative group phase 2 study was to determine the activity of the combination of g209-2M and low-dose IL-2 in advanced melanoma. Twenty-six HLA appropriate patients with advanced melanoma received subcutaneous g209-2M peptide once every 3 weeks and subcutaneous IL-2 (5 million IU/m) daily for 5 days during the first and second weeks. Patients were monitored for tumor response, toxicity, and induction of g209-reactive circulating T cells. There were no objective responses. There were no toxic deaths and no grade 4 toxicities. More than half of the patients experienced some grade 2 toxicity and one quarter experienced grade 3 toxicity. There was no convincing evidence by enzyme-linked immunospot or tetramer analysis of induction of g209-reactive circulating T cells. The combination of g209-2M and low-dose IL-2 is safe and tolerable but inactive against advanced melanoma. Absence of evidence of immunization raises concerns for peptide-based immunization strategies with concurrent IL-2.

Authors
Roberts, JD; Niedzwiecki, D; Carson, WE; Chapman, PB; Gajewski, TF; Ernstoff, MS; Hodi, FS; Shea, C; Leong, SP; Johnson, J; Zhang, D; Houghton, A; Haluska, FG; Cancer and Leukemia Group B,
MLA Citation
Roberts, JD, Niedzwiecki, D, Carson, WE, Chapman, PB, Gajewski, TF, Ernstoff, MS, Hodi, FS, Shea, C, Leong, SP, Johnson, J, Zhang, D, Houghton, A, Haluska, FG, and Cancer and Leukemia Group B, . "Phase 2 study of the g209-2M melanoma peptide vaccine and low-dose interleukin-2 in advanced melanoma: Cancer and Leukemia Group B 509901." J Immunother 29.1 (January 2006): 95-101.
PMID
16365605
Source
pubmed
Published In
Journal of Immunotherapy
Volume
29
Issue
1
Publish Date
2006
Start Page
95
End Page
101

Second malignancy risk associated with treatment of Hodgkin's lymphoma: Meta-analysis of the randomised trials

Background: Despite several investigations, second malignancy risks (SMR) following radiotherapy alone (RT), chemotherapy alone (CT) and combined chemoradiotherapy (CRT) for Hodgkin's lymphoma (HL) remain controversial. Patients and Methods: We sought individual patient data from randomised trials comparing RT versus CRT, CT versus CRT, RT versus CT or involved-field (IF) versus extended-field (EF) RT for untreated HL. Overall SMR (including effects of salvage treatment) were compared using Peto's method. Results: Data for between 53% and 69% of patients were obtained for the four comparisons. (i) RT versus CRT (15 trials, 3343 patients): SMR were lower with CRT than with RT as initial treatment (odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.62-0.98 and P = 0.03). (ii) CT versus CRT (16 trials, 2861 patients): SMR were marginally higher with CRT than with CT as initial treatment (OR = 1.38, CI 1.00-1.89 and P = 0.05). (iii) IF-RT versus EF-RT (19 trials, 3221 patients): no significant difference in SMR (P = 0.28) although more breast cancers occurred with EF-RT (P = 0.04 and OR = 3.25). Conclusions: Administration of CT in addition to RT as initial therapy for HL decreases overall SMR by reducing relapse and need for salvage therapy. Administration of RT additional to CT marginally increases overall SMR in advanced stages. Breast cancer risk (but not SMR in general) was substantially higher after EF-RT. Caution is needed in applying these findings to current therapies. © 2006 Oxford University Press.

Authors
Franklin, J; Pluetschow, A; Paus, M; Specht, L; Anselmo, A-P; Aviles, A; Biti, G; Bogatyreva, T; Bonadonna, G; Brillant, C; Cavalieri, E; Diehl, V; Eghbali, H; Fermé, C; Henry-Amar, M; Hoppe, R; Howard, S; Meyer, R; Niedzwiecki, D; Pavlovsky, S; Radford, J; Raemaekers, J; Ryder, D; Schiller, P; Shakhtarina, S; Valagussa, P; Wilimas, J; Yahalom, J
MLA Citation
Franklin, J, Pluetschow, A, Paus, M, Specht, L, Anselmo, A-P, Aviles, A, Biti, G, Bogatyreva, T, Bonadonna, G, Brillant, C, Cavalieri, E, Diehl, V, Eghbali, H, Fermé, C, Henry-Amar, M, Hoppe, R, Howard, S, Meyer, R, Niedzwiecki, D, Pavlovsky, S, Radford, J, Raemaekers, J, Ryder, D, Schiller, P, Shakhtarina, S, Valagussa, P, Wilimas, J, and Yahalom, J. "Second malignancy risk associated with treatment of Hodgkin's lymphoma: Meta-analysis of the randomised trials." Annals of Oncology 17.12 (2006): 1749-1760.
PMID
16984979
Source
scival
Published In
Annals of Oncology
Volume
17
Issue
12
Publish Date
2006
Start Page
1749
End Page
1760
DOI
10.1093/annonc/mdl302

Prolonged follow-up after initial therapy with 2-chlorodeoxyadenosine in patients with indolent non-Hodgkin lymphoma: Results of cancer and leukemia group B study 9153

BACKGROUND. The objective of this study was to determine the efficacy and toxicity of 2-chlorodeoxyadenosine (2-CdA) in patients with untreated, indolent non-Hodgkin lymphoma (NHL). METHODS. For this multicenter, single-arm, Phase II study, 44 patients with treatment-naive, stage III or IV, indolent NHL (International Working Formulation subtypes A, B, and C) were enrolled. Patients received 0.14 mg/kg per day of 2-CdA as a 2-hour bolus infusion for 5 consecutive days every 28 days until maximal response or a total of 6 cycles. RESULTS. Thirty-eight patients were eligible for response evaluation. The overall response rate was 100% (95% confidence interval [95% CI], 90.8-100%), and the complete response rate was 31.6% (95% CI, 17.5-48.7%). In the intent-to-treat population, the median failure-free survival was 2.0 years (95% CI, 1.3-3.4 years), and the overall survival rate was 7.0 years (95% CI, 4.3-9.4 years). Six patients had sustained remissions that lasted a median of 8.7 years (range, from 5.9 years to ≥11 years). Although 68% of patients experienced at least 1 grade 3 or 4 event, consisting primarily of myelosuppression, severe infections were rare, with only 8 grade 3 infections. Four late malignancies (prostate adenocarcinoma, ductal carcinoma in situ, and myelodysplasia) and 4 patients with large cell transformation were reported. CONCLUSIONS. 2-CdA is an active, well-tolerated therapy for patients with untreated, indolent NHL. © 2006 American Cancer Society.

Authors
Blum, KA; Johnson, JL; Niedzwiecki, D; Piro, LD; Saven, A; Peterson, BA; Byrd, JC; Cheson, BD
MLA Citation
Blum, KA, Johnson, JL, Niedzwiecki, D, Piro, LD, Saven, A, Peterson, BA, Byrd, JC, and Cheson, BD. "Prolonged follow-up after initial therapy with 2-chlorodeoxyadenosine in patients with indolent non-Hodgkin lymphoma: Results of cancer and leukemia group B study 9153." Cancer 107.12 (2006): 2817-2825.
PMID
17120198
Source
scival
Published In
Cancer
Volume
107
Issue
12
Publish Date
2006
Start Page
2817
End Page
2825
DOI
10.1002/cncr.22344

Phase II study of temozolomide and thalidomide in patients with metastatic melanoma in the brain: High rate of thromboembolic events (CALGB 500102)

BACKGROUND. Preliminary studies suggesting that extended-dose temozolomide with thalidomide is safe and active in patients with metastatic melanoma have led to frequent use of this oral regimen. To confirm these observations the combination was tested in a multicenter Phase II trial in patients with melanoma brain metastases. METHODS. Eligible patients had melanoma brain metastases, with or without systemic metastases. The primary endpoint was response rate in brain metastases. Patients received temozolomide at a dose of 75 mg/m 2/day for 6 weeks with a 2-week rest between cycles, and thalidomide (escalated to 400 mg/day for patients age <70 years or to 200 mg/day for patients age ≥70 years). A 2-stage design required ≥3 responses in the first 21 patients before enrolling 29 additional patients in the second stage. RESULTS. Sixteen eligible patients were enrolled. No objective responses were observed. The median survival was 23.9 weeks. Seven patients withdrew because of tumor progression; 7 were removed during Cycle 1 because of adverse events, including allergic reaction (1 patient), severe fatigue (1 patient), sudden death (1 patient), and thromboembolic events (pulmonary embolism in 3 patients and deep vein thrombosis in 1 patient); 2 patients withdrew when the study was suspended and subsequently closed. No associations could be established between baseline characteristics and toxicity. CONCLUSIONS. The proportion of patients with lethal or potentially life-threatening adverse events was high (0.31, 95% confidence interval, 0.11-0.59), and the absence of objective responses made it unlikely that further accrual would demonstrate the efficacy of the regimen. These observations provide little support for the use of this combination for melanoma brain metastases unless safe and effective methods to prevent thrombosis are developed. © 2006 American Cancer Society.

Authors
Krown, SE; Niedzwiecki, D; Hwu, W-J; Hodgson, L; Houghton, AN; Haluska, FG
MLA Citation
Krown, SE, Niedzwiecki, D, Hwu, W-J, Hodgson, L, Houghton, AN, and Haluska, FG. "Phase II study of temozolomide and thalidomide in patients with metastatic melanoma in the brain: High rate of thromboembolic events (CALGB 500102)." Cancer 107.8 (2006): 1883-1890.
PMID
16986123
Source
scival
Published In
Cancer
Volume
107
Issue
8
Publish Date
2006
Start Page
1883
End Page
1890
DOI
10.1002/cncr.22239

Sequential doxorubicin and topotecan in relapsed/refractory aggressive non-Hodgkin's lymphoma: Results of CALGB 59906

Topoisomerase enzymes are critical components of genomic replication and function to minimize torsional stress on DNA. Sequential administration of a topoisomerase II inhibitor followed by a topoisomerase I inhibitor is potentially synergistic due to increased target enzyme levels. Patients with relapsed or refractory aggressive non-Hodgkin's lymphomas (NHL) were eligible for this phase II study of doxorubicin 25 mg/m2 intravenous (IV) on day 1 and topotecan 1.75 mg/ m2/day IV on days 3 - 5, every 21 days. The trial objectives included the overall response rate, progression-free survival, and toxicity. Twenty-six patients were enrolled and 25 patients are assessable for toxicity and response. The median age was 58 (range 23 - 74) years. The patients had received a median of two (range one to five) prior regimens, including five patients with a prior stem cell transplant. Five patients (20%, 95% confidence interval 0.07, 0.42) responded with two (8%) complete remissions and three (12%) partial remissions; an additional four (16%) patients had stable disease. Both patients achieving a complete remission had Burkitt's lymphoma. There were no treatment-related deaths. In conclusion, the combination of doxorubicin and topotecan is well tolerated and has modest activity in relapsed/refractory NHL, with occasional patients having a prolonged remission. The activity in Burkitt's lymphoma should be investigated further.

Authors
Smith, SM; Johnson, JL; Niedzwiecki, D; Eder, JP; Canellos, G; Cheson, BD; Bartlett, NL
MLA Citation
Smith, SM, Johnson, JL, Niedzwiecki, D, Eder, JP, Canellos, G, Cheson, BD, and Bartlett, NL. "Sequential doxorubicin and topotecan in relapsed/refractory aggressive non-Hodgkin's lymphoma: Results of CALGB 59906." Leukemia and Lymphoma 47.8 (2006): 1511-1517.
PMID
16966261
Source
scival
Published In
Leukemia & Lymphoma (Informa)
Volume
47
Issue
8
Publish Date
2006
Start Page
1511
End Page
1517
DOI
10.1080/10428190600581385

Impact of physical activity on cancer recurrence and survival in patients with stage III colon cancer: Findings from CALGB 89803

Purpose: Regular physical activity reduces the risk of developing colon cancer, however, its influence on patients with established disease is unknown. Patients and Methods: We conducted a prospective observational study of 832 patients with stage III colon cancer enrolled in a randomized adjuvant chemotherapy trial. Patients reported on various recreational physical activities approximately 6 months after completion of therapy and were observed for recurrence or death. To minimize bias by occult recurrence, we excluded patients who experienced recurrence or died within 90 days of their physical activity assessment. Results: Compared with patients engaged in less than three metabolic equivalent task (MET) -hours per week of physical activity, the adjusted hazard ratio for disease-free survival was 0.51 (95% CI, 0.26 to 0.97) for 18 to 26.9 MET-hours per week and 0.55 (95% CI, 0.33 to 0.91) for 27 or more MET-hours per week. The adjusted P for trend was .01. Postdiagnosis activity was associated with similar improvements in recurrence-free survival (P for trend = .03) and overall survival (P for trend = .01). The benefit associated with physical activity was not significantly modified by sex, body mass index, number of positive lymph nodes, age, baseline performance status, or chemotherapy received. Moreover, the benefit remained unchanged even after excluding participants who developed cancer recurrence or died within 6 months of activity assessment. Conclusion: Beyond surgical resection and postoperative adjuvant chemotherapy for stage III colon cancer, for patients who survive and are recurrence free approximately 6 months after adjuvant chemotherapy, physical activity appears to reduce the risk of cancer recurrence and mortality. © 2006 by American Society of Clinical Oncology.

Authors
Meyerhardt, JA; Heseltine, D; Niedzwiecki, D; Hollis, D; Saltz, LB; Mayer, RJ; Thomas, J; Nelson, H; Whittom, R; Hantel, A; Schilsky, RL; Fuchs, CS
MLA Citation
Meyerhardt, JA, Heseltine, D, Niedzwiecki, D, Hollis, D, Saltz, LB, Mayer, RJ, Thomas, J, Nelson, H, Whittom, R, Hantel, A, Schilsky, RL, and Fuchs, CS. "Impact of physical activity on cancer recurrence and survival in patients with stage III colon cancer: Findings from CALGB 89803." Journal of Clinical Oncology 24.22 (2006): 3535-3541.
PMID
16822843
Source
scival
Published In
Journal of Clinical Oncology
Volume
24
Issue
22
Publish Date
2006
Start Page
3535
End Page
3541
DOI
10.1200/JCO.2006.06.0863

Cancer and Leukemia Group B Gastrointestinal Cancer Committee

The Cancer and Leukemia Group B Gastrointestinal Cancer Committee was organized in the late 1970s under the leadership of Michael Perry and Philip Schein and began full-scale operations in the mid-1980s. Today, it is a multidisciplinary team of surgeons, radiation and medical oncologists, statisticians, quality-of-life experts, pharmacogeneticists, basic scientists, and community oncologists who design studies that are conducted across the United States. The Committee has done trials in patients with esophageal, gastric, pancreatic, colon, rectal, and anal cancers. New initiatives are under way in hepatocellular cancer, cholangiocarcinoma, and neuroendocrine tumors originating in the gastrointestinal tract. The Committee has increasingly concentrated on translational studies using tumor blocks, germ-line DNA, and plasma to evaluate biological correlates of tumor response and clinical outcomes. A broad program of pharmacogenomics has been incorporated for virtually all studies, including trials that prospectively use polymorphisms in drug-metabolizing genes to assign treatments. Future efforts aim to evolve new standards of care, evaluate new therapies, and answer relevant biological questions in gastrointestinal cancer. © 2006 American Association for Cancer Research.

Authors
Goldberg, RM; Niedzwiecki, D; Bertagnolli, M; Blackstock, AW; Tepper, JE; Mayer, RJ
MLA Citation
Goldberg, RM, Niedzwiecki, D, Bertagnolli, M, Blackstock, AW, Tepper, JE, and Mayer, RJ. "Cancer and Leukemia Group B Gastrointestinal Cancer Committee." Clinical Cancer Research 12.11 II (2006): 3589s-3595s.
PMID
16740790
Source
scival
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
12
Issue
11 II
Publish Date
2006
Start Page
3589s
End Page
3595s
DOI
10.1158/1078-0432.CCR-06-9004

Partially HLA matched, non-myeloablative allogeneic transplantation

Authors
Rizzieri, DA; Koh, LP; Long, GD; Gasparetto, C; Sullivan, KM; Horwitz, M; Chute, J; Gong, JZ; Lagoo, AS; Niedzwiecki, D; Lu, CX; Marshall, D; Dowell, JM; Chao, NJ
MLA Citation
Rizzieri, DA, Koh, LP, Long, GD, Gasparetto, C, Sullivan, KM, Horwitz, M, Chute, J, Gong, JZ, Lagoo, AS, Niedzwiecki, D, Lu, CX, Marshall, D, Dowell, JM, and Chao, NJ. "Partially HLA matched, non-myeloablative allogeneic transplantation." November 16, 2005.
Source
wos-lite
Published In
Blood
Volume
106
Issue
11
Publish Date
2005
Start Page
812A
End Page
812A

Outcome and immune reconstitution following T cell depleted nonmyeloablative allogeneic transplantation using matched donors

Authors
Rizzieri, DA; Koh, LP; Long, GD; Gasparetto, C; Gong, JZ; Lagoo, AS; Niedzwiecki, D; Sullivan, KM; Chute, J; Horwitz, M; Ashley, M; Chao, NJ
MLA Citation
Rizzieri, DA, Koh, LP, Long, GD, Gasparetto, C, Gong, JZ, Lagoo, AS, Niedzwiecki, D, Sullivan, KM, Chute, J, Horwitz, M, Ashley, M, and Chao, NJ. "Outcome and immune reconstitution following T cell depleted nonmyeloablative allogeneic transplantation using matched donors." November 16, 2005.
Source
wos-lite
Published In
Blood
Volume
106
Issue
11
Publish Date
2005
Start Page
576A
End Page
576A

Cancer and Leukemia Group B/Southwest Oncology Group trial 80405: a phase III trial of chemotherapy and biologics for patients with untreated advanced colorectal adenocarcinoma.

Authors
Venook, AP; Blanke, CD; Niedzwiecki, D; Lenz, H-J; Taylor, JR; Hollis, DR; Sutherland, S; Goldberg, RM
MLA Citation
Venook, AP, Blanke, CD, Niedzwiecki, D, Lenz, H-J, Taylor, JR, Hollis, DR, Sutherland, S, and Goldberg, RM. "Cancer and Leukemia Group B/Southwest Oncology Group trial 80405: a phase III trial of chemotherapy and biologics for patients with untreated advanced colorectal adenocarcinoma." Clin Colorectal Cancer 5.4 (November 2005): 292-294.
PMID
16356309
Source
pubmed
Published In
Clinical colorectal cancer
Volume
5
Issue
4
Publish Date
2005
Start Page
292
End Page
294

Tenascin and microvessel stromal changes in patients with non-Hodgkin's lymphoma are isolated to the sites of disease and vary in correlation to disease activity.

This study investigated stromal changes in expression of tenascin and vasculogenesis in lymphoma. Documenting the dynamic nature of the stromal changes in lymphoma in relation to response to therapy is helpful in planning new therapies directed at these targets. Two hundred and sixty one samples from 111 patients with varying types of non-Hodgkin's lymphoma were reviewed and examined using immunohistochemistry techniques. Samples were stained for factor VIII - related antigen for microvessel density (MVD) analysis and anti-tenascin antibody for qualitative assessment of the stromal expression. Multiple samples from the same patient were taken at the same point in time to assess whether stromal changes were limited to sites of disease. Multiple samples were examined over the course of a patient's illness to assess whether the stromal changes were modulated according to disease activity. There was a significant increase in tenascin expression and MVD in the sites of disease compared with uninvolved sites (p = 0.01 and p < 0.0001, respectively). In patients who responded to therapy, there was a decrease in the expression of tenascin (p = 0.0049) and MVD (p < 0.0001), and in those with disease progression there was an increase in the tenascin expression (p = 0.0050) and MVD (p < 0.0001). Our results suggest stromal changes are isolated to the sites of disease within patients, allowing targeted therapies to be developed. Further, stromal changes correlate with disease response over the course of the patient's disease. This new finding may have implications for the timing of anti-stromally directed therapies.

Authors
Rizzieri, DA; Wadleigh, M; Wikstrand, CJ; Mann, KP; Sen, F; Peterson, BL; Niedzwiecki, D; Proia, AD; Bigner, DD
MLA Citation
Rizzieri, DA, Wadleigh, M, Wikstrand, CJ, Mann, KP, Sen, F, Peterson, BL, Niedzwiecki, D, Proia, AD, and Bigner, DD. "Tenascin and microvessel stromal changes in patients with non-Hodgkin's lymphoma are isolated to the sites of disease and vary in correlation to disease activity." Leuk Lymphoma 46.10 (October 2005): 1455-1462.
PMID
16194891
Source
pubmed
Published In
Leukemia & Lymphoma (Informa)
Volume
46
Issue
10
Publish Date
2005
Start Page
1455
End Page
1462
DOI
10.1080/10428190500158060

Distinct hematopoietic progenitor compartments are delineated by the expression of aldehyde dehydrogenase and CD34.

A broad range of hematopoietic stem cells and progenitors reside within a fraction of umbilical cord blood (UCB) that exhibits low light scatter properties (SSC(lo)) and high expression of aldehyde dehydrogenase (ALDH(br)). Many SSC(lo) ALDH(br) cells coexpress CD34; however, other cells express either ALDH or CD34. To investigate the developmental potential of these cell subsets, purified ALDH(br) CD34+, ALDH(neg) CD34+, and ALDH(br) CD34(neg) UCB cells were characterized within a variety of in vivo and in vitro assays. Primitive progenitors capable of multilineage development were monitored in long- and short-term repopulation assays performed on nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice, and in primary and secondary long-term culture assays. These progenitors were highly enriched within the ALDH(br) CD34+ fraction. This cell fraction also enriched short-term myeloid progenitors that were detected in vitro. By comparison, ALDH(neg) CD34+ cells contained few primitive progenitors and had diminished short-term myeloid potential but exhibited enhanced short-term natural killer (NK) cell development in vitro. The ALDH(br) CD34(neg) cells were not efficiently supported by any of the assays used. These studies suggested that in particular the expression of ALDH delineated distinct CD34+ stem cell and progenitor compartments. The differential expression of ALDH may provide a means to explore normal and malignant processes associated with myeloid and lymphoid development.

Authors
Storms, RW; Green, PD; Safford, KM; Niedzwiecki, D; Cogle, CR; Colvin, OM; Chao, NJ; Rice, HE; Smith, CA
MLA Citation
Storms, RW, Green, PD, Safford, KM, Niedzwiecki, D, Cogle, CR, Colvin, OM, Chao, NJ, Rice, HE, and Smith, CA. "Distinct hematopoietic progenitor compartments are delineated by the expression of aldehyde dehydrogenase and CD34." Blood 106.1 (July 1, 2005): 95-102.
PMID
15790790
Source
pubmed
Published In
Blood
Volume
106
Issue
1
Publish Date
2005
Start Page
95
End Page
102
DOI
10.1182/blood-2004-09-3652

Influence of regular aspirin use on survival for patients with stage III colon cancer: Findings from Intergroup trial CALGB 89803.

Authors
Fuchs, C; Meyerhardt, JA; Heseltine, DL; Niedzwiecki, D; Hollis, D; Chan, AT; Saltz, LB; Schilsky, RL; Mayer, RJ
MLA Citation
Fuchs, C, Meyerhardt, JA, Heseltine, DL, Niedzwiecki, D, Hollis, D, Chan, AT, Saltz, LB, Schilsky, RL, and Mayer, RJ. "Influence of regular aspirin use on survival for patients with stage III colon cancer: Findings from Intergroup trial CALGB 89803." June 1, 2005.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
23
Issue
16
Publish Date
2005
Start Page
253S
End Page
253S

The impact of physical activity on patients with stage III colon cancer: Findings from Intergroup trial CALGB 89803.

Authors
Meyerhardt, JA; Heseltine, D; Niedzwiecki, D; Hollis, D; Saltz, LB; Mayer, RJ; Schilsky, RL; Fuchs, CS
MLA Citation
Meyerhardt, JA, Heseltine, D, Niedzwiecki, D, Hollis, D, Saltz, LB, Mayer, RJ, Schilsky, RL, and Fuchs, CS. "The impact of physical activity on patients with stage III colon cancer: Findings from Intergroup trial CALGB 89803." June 1, 2005.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
23
Issue
16
Publish Date
2005
Start Page
254S
End Page
254S

Phase II study of dose-adjusted EPOCH-R in untreated de novo CD20+ diffuse large B-cell lymphoma (DLBCL)-CALGB 50103.

Authors
Wilson, WH; Porcu, P; Hurd, D; Martin, SE; Czuczman, M; Niedzwiecki, D; Saint Louis, JD; Johnson, JL; Cheson, B; Canellos, GP; Zelenetz, AD
MLA Citation
Wilson, WH, Porcu, P, Hurd, D, Martin, SE, Czuczman, M, Niedzwiecki, D, Saint Louis, JD, Johnson, JL, Cheson, B, Canellos, GP, and Zelenetz, AD. "Phase II study of dose-adjusted EPOCH-R in untreated de novo CD20+ diffuse large B-cell lymphoma (DLBCL)-CALGB 50103." June 1, 2005.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
23
Issue
16
Publish Date
2005
Start Page
567S
End Page
567S

Influence of regular aspirin use on survival for patients with stage III colon cancer: Findings from Intergroup trial CALGB 89803.

3530 Background: Regular aspirin use reduces the risk of colorectal neoplasia. In animals, aspirin and COX-2 inhibitors appear to inhibit tumor growth. The effect of aspirin use on outcome in patients with established colon cancer is unknown.We prospectively studied aspirin use in 830 pts with stage III colon cancer enrolled in a randomized trial of post-operative adjuvant chemotherapy (5-fluorouracil/leucovorin +/- irinotecan). Patients completed a detailed survey of medication use and lifestyle midway through adjuvant therapy and then again 6 months after completion of therapy. We computed Cox proportional hazards for recurrence-free (RFS), disease-free (DFS) and overall survival (OS) according to aspirin use. Time intervals were measured from completion of the 2(nd) questionnaire to recurrence or death, excluding events within the 1(st) 60 days to avoid bias from analgesic use due to underlying disease. Median follow-up after the last questionnaire was 2.4 years.Among 830 patients who completed both questionnaires, 72 (8.7%) pts reported aspirin use both midway and 6 months after adjuvant therapy (consistent users). Compared to those who did not report consistent use, consistent aspirin users experienced a hazard ratio (HR) for disease recurrence (RFS) of 0.45 (95% CI, 0.21-0.97), after adjustment for age, gender, baseline performance status, N stage, T stage, preoperative CEA, bowel obstruction, perforation, tumor differentiation, and treatment arm. After identical adjustment, consistent aspirin use was associated with a HR for disease recurrence and/or death (DFS) of 0.48 (95% CI, 0.24-0.99) and a HR for death (OS) of 0.52 (95% CI, 0.19-1.46). Regular users of either celecoxib or rofecoxib (n=35; 4.3%) experienced a HR for recurrence of 0.56 (95% CI, 0.21-1.54). To assess whether these associations reflected a non-specific analgesic effect, we assessed regular acetaminophen use and found no recurrence or survival benefit.Consistent aspirin use may be associated with improved outcome in patients with stage III colon cancer. Ongoing randomized trials are assessing the addition of COX-2 inhibitors to chemotherapy in patients with advanced disease. [Table: see text].

Authors
Fuchs, C; Meyerhardt, JA; Heseltine, DL; Niedzwiecki, D; Hollis, D; Chan, AT; Saltz, LB; Schilsky, RL; Mayer, RJ
MLA Citation
Fuchs, C, Meyerhardt, JA, Heseltine, DL, Niedzwiecki, D, Hollis, D, Chan, AT, Saltz, LB, Schilsky, RL, and Mayer, RJ. "Influence of regular aspirin use on survival for patients with stage III colon cancer: Findings from Intergroup trial CALGB 89803." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 23.16_suppl (June 2005): 3530-.
PMID
27944416
Source
epmc
Published In
Journal of Clinical Oncology
Volume
23
Issue
16_suppl
Publish Date
2005
Start Page
3530

Phase II study of dose-adjusted EPOCH-R in untreated de novo CD20+ diffuse large B-cell lymphoma (DLBCL)-CALGB 50103.

6530 Background: DA-EPOCH-R is a rationally designed regimen based on schedule optimization and pharmacodynamic dosing. Studies suggest it overcomes adverse effects of tumor proliferation and bcl-2 in de novo DLBCL and adjusts for differences in patient drug clearance. An NCI study in 83 untreated de novo DLBCL patients shows a PFS and OS of 82% at 32 months median follow-up and no relapses beyond 2 years. PFS is 94% for low (0-2) and 57% for high (3-5) IPI at 3 years. Hence, CALGB undertook a confirmatory phase II study.Eligibility: untreated de novo CD20+ DLBCL; ≥ 18 years; stage II-IV; ECOG PS 0-2; and adequate organ function unless due to disease. Patients received DA-EPOCH-R + filgrastim for 6-8 cycles, based on response, and no patients received radiation. Endpoints were PFS, OS and toxicity. Study design is a cooperative group prospective phase II.Of 78 patients, 5 were ineligible. Patient characteristics are median age (range) 58 (23-80) years, and IPI of low (0-2) in 60% and high (3-5) in 40% of patients. Treatment was administered in 18 centers and toxicity assessed in 72 patients. The pharmacodynamic endpoint of grade 4 neutropenia occurred in 96% of patients. Febrile neutropenia occurred in 33% of patients. Grade 4 anemia and thrombocytopenia occurred in 11% and 15% of patients, respectively. Gastrointestinal, thrombosis or neurological toxicities were rare at grade 4 (0-3%) and infrequent at grade 3 (0-14%). No patients had cardiac failure and there was one treatment associated death from CNS hemorrhage. Ninety percent of patients completed at least 6 cycles and 20% received 8 cycles. ORR was 100% with 68% CR and 32% PR. With a median (range) follow-up of 11 (2.4-22.8) months, 10 patients progressed (8 in the first year) with similar rates in CR's (6/49) and PR's (4/23). At 18 months, PFS is 80% overall, and 93% and 46%, respectively, in low (0-2) and high (3-5) IPI. Survival is 88% at 18 months.DA-EPOCH-R can be administered in a cooperative group with acceptable toxicity. Preliminary survival results are encouraging and consistent with the NCI study. A CALGB randomized phase III study of DA-EPOCH-R versus R-CHOP with microarray tumor analysis will begin early next year. [Table: see text].

Authors
Wilson, WH; Porcu, P; Hurd, D; Martin, SE; Czuczman, M; Niedzwiecki, D; Saint Louis, JD; Johnson, JL; Cheson, B; Canellos, GP; Zelenetz, AD
MLA Citation
Wilson, WH, Porcu, P, Hurd, D, Martin, SE, Czuczman, M, Niedzwiecki, D, Saint Louis, JD, Johnson, JL, Cheson, B, Canellos, GP, and Zelenetz, AD. "Phase II study of dose-adjusted EPOCH-R in untreated de novo CD20+ diffuse large B-cell lymphoma (DLBCL)-CALGB 50103." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 23.16_suppl (June 2005): 6530-.
PMID
27943874
Source
epmc
Published In
Journal of Clinical Oncology
Volume
23
Issue
16_suppl
Publish Date
2005
Start Page
6530

The impact of physical activity on patients with stage III colon cancer: Findings from Intergroup trial CALGB 89803.

3534 Background: Regular physical activity (PA) is strongly associated with a reduced risk of developing colon cancer. The influence of PA on the outcome of patients with established colon cancer is unknown.We prospectively studied recreational PA among 816 patients with stage III colon cancer enrolled in a randomized trial of post-operative adjuvant chemotherapy (bolus 5-fluorouracil/leucovorin +/- irinotecan). Patients completed detailed surveys of various non-occupational activities midway through adjuvant therapy (Q1) and then again 6 months after completion of therapy (12-14 months after enrollment, Q2). Levels of PA were measured as total metabolic equivalent tasks (MET)-hours-per-week scores & divided into quintiles. We computed Cox proportional hazards for disease-free survival (DFS) and overall survival (OS) according to quintiles of PA as measured on Q2. DFS and OS were measured from completion of Q2 to recurrence or death (DFS) and death (OS), excluding events within the 1(st) 90 days to avoid biases of decreased activity due to underlying disease. Median follow-up after the post-chemotherapy questionnaire was 2.4 years.Levels of PA were associated with significantly improved DFS among patients with stage III colon cancer. After adjustment for age, gender, baseline performance status, N stage, T stage, preoperative CEA, bowel obstruction and perforation, level of differentiation, treatment arm, and body mass index, the hazard ratio (HR) for DFS for individuals in the highest quintile (>25 MET-hours/week, eg. jog 3-4 hours/week or brisk walk [3-4 mph] daily) was 0.65 (95% CI, 0.38-1.11; p for trend = 0.02) compared to those in the lowest quintile of PA. This relationship varied by gender with a HR = 0.33 [95% CI, 0.11-0.99] for women (p for trend = 0.046) and a HR= 0.89 [95% CI, 0.44-1.78] for men (p for trend = 0.3). Data on OS is not yet mature, though the p trend among all patients with increasing PA is 0.02.Increased PA appears to be associated with DFS and OS among patients with stage III colon cancer. Follow-up data will be more mature at the time of presentation, as will analyses on the impact of PA on treatment-related toxicities No significant financial relationships to disclose.

Authors
Meyerhardt, JA; Heseltine, D; Niedzwiecki, D; Hollis, D; Saltz, LB; Mayer, RJ; Schilsky, RL; Fuchs, CS
MLA Citation
Meyerhardt, JA, Heseltine, D, Niedzwiecki, D, Hollis, D, Saltz, LB, Mayer, RJ, Schilsky, RL, and Fuchs, CS. "The impact of physical activity on patients with stage III colon cancer: Findings from Intergroup trial CALGB 89803." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 23.16_suppl (June 2005): 3534-.
PMID
27944410
Source
epmc
Published In
Journal of Clinical Oncology
Volume
23
Issue
16_suppl
Publish Date
2005
Start Page
3534

Phase I study of immunization with dendritic cells modified with fowlpox encoding carcinoembryonic antigen and costimulatory molecules.

PURPOSE: To determine the safety and immunologic and clinical efficacy of a dendritic cell vaccine modified to hyperexpress costimulatory molecules and tumor antigen. EXPERIMENTAL DESIGN: In this phase I study, we administered one or two cycles of four triweekly s.c./intradermal injections of ex vivo generated dendritic cells modified with a recombinant fowlpox vector encoding carcinoembryonic antigen (CEA) and a triad of costimulatory molecules [rF-CEA(6D)-TRICOM]. Controls consisted of immature dendritic cells loaded with tetanus toxoid and a HLA A2-restricted peptide derived from cytomegalovirus pp65 protein. RESULTS: Fourteen patients (11 with colorectal cancer and 3 with non-small cell lung cancer) were enrolled and 12 completed at least one cycle of immunization. There were no grade 3/4 toxicities directly referable to the immunizations. One patient had a decrease in the CEA level from 46 to 6.8 and a minor regression in adenopathy that occurred several months after completion of the immunizations. Five other patients were stable through at least one cycle of immunization (3 months). Direct analysis of peripheral blood mononuclear cells using the ELISpot assay showed an increase in the frequency of CEA-specific T cells in 10 patients (range, 10-541 CEA-specific cells/10(5) peripheral blood mononuclear cells). There was a trend for a greater peak frequency of CEA-specific T cells among those with either a minor response or a stable disease following at least one cycle of therapy. A second cycle was not associated with higher T-cell frequencies. Cytokine flow cytometry showed CEA-specific immune response among both CD4(+) and CD8(+) T cells in all immune responders. CONCLUSION: This immunization strategy is safe and activates potent CEA-specific immune responses.

Authors
Morse, MA; Clay, TM; Hobeika, AC; Osada, T; Khan, S; Chui, S; Niedzwiecki, D; Panicali, D; Schlom, J; Lyerly, HK
MLA Citation
Morse, MA, Clay, TM, Hobeika, AC, Osada, T, Khan, S, Chui, S, Niedzwiecki, D, Panicali, D, Schlom, J, and Lyerly, HK. "Phase I study of immunization with dendritic cells modified with fowlpox encoding carcinoembryonic antigen and costimulatory molecules." Clin Cancer Res 11.8 (April 15, 2005): 3017-3024.
PMID
15837756
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
11
Issue
8
Publish Date
2005
Start Page
3017
End Page
3024
DOI
10.1158/1078-0432.CCR-04-2172

Telomerase mRNA-transfected dendritic cells stimulate antigen-specific CD8+ and CD4+ T cell responses in patients with metastatic prostate cancer.

Telomerase reverse transcriptase (hTERT) represents an attractive target for cancer immunotherapy because hTERT is reactivated in most human tumors. A clinical trial was initiated in which hTERT mRNA-transfected dendritic cells (DC) were administered to 20 patients with metastatic prostate cancer. Nine of these subjects received DC transfected with mRNA encoding a chimeric lysosome-associated membrane protein-1 (LAMP) hTERT protein, allowing for concomitant induction of hTERT-specific CD8+ and CD4+ T cell responses. Treatment was well tolerated. Intense infiltrates of hTERT-specific T cells were noted at intradermal injection sites after repeated vaccination. In 19 of 20 subjects, expansion of hTERT-specific CD8+ T cells was measured in the peripheral blood of study subjects, with 0.9-1.8% of CD8+ T cells exhibiting Ag specificity. Patients immunized with the chimeric LAMP hTERT vaccine developed significantly higher frequencies of hTERT-specific CD4+ T cells than subjects receiving DC transfected with the unmodified hTERT template. Moreover, CTL-mediated killing of hTERT targets was enhanced in the LAMP hTERT group, suggesting that an improved CD4+ response could augment a CTL response. Vaccination was further associated with a reduction of prostate-specific Ag velocity and molecular clearance of circulating micrometastases. Our findings provide a rationale for further development of hTERT-transfected DC vaccines in the treatment of prostate and other cancers.

Authors
Su, Z; Dannull, J; Yang, BK; Dahm, P; Coleman, D; Yancey, D; Sichi, S; Niedzwiecki, D; Boczkowski, D; Gilboa, E; Vieweg, J
MLA Citation
Su, Z, Dannull, J, Yang, BK, Dahm, P, Coleman, D, Yancey, D, Sichi, S, Niedzwiecki, D, Boczkowski, D, Gilboa, E, and Vieweg, J. "Telomerase mRNA-transfected dendritic cells stimulate antigen-specific CD8+ and CD4+ T cell responses in patients with metastatic prostate cancer." J Immunol 174.6 (March 15, 2005): 3798-3807.
PMID
15749921
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
174
Issue
6
Publish Date
2005
Start Page
3798
End Page
3807

The impact of immune reconstitution on the development of opportunistic infections (OI) after unrelated umbilical cord blood transplantation (UUCBT). A multivariate analysis of host, graft, and day+50 immune profile

Authors
Szabolcs, P; Park, K; Marti, L; Reese, M; Lee, Y; DeOliveira, D; Sanders, L; Niedzwiecki, D
MLA Citation
Szabolcs, P, Park, K, Marti, L, Reese, M, Lee, Y, DeOliveira, D, Sanders, L, and Niedzwiecki, D. "The impact of immune reconstitution on the development of opportunistic infections (OI) after unrelated umbilical cord blood transplantation (UUCBT). A multivariate analysis of host, graft, and day+50 immune profile." BONE MARROW TRANSPLANTATION 35 (March 2005): S93-S93.
Source
wos-lite
Published In
Bone Marrow Transplantation
Volume
35
Publish Date
2005
Start Page
S93
End Page
S93

Dendritic cell and T-cell subsets correlate with the development and site of acute GVHD following unrelated cord blood transplantation in children: A multivariate analysis

Authors
Szabolcs, P; Park, KD; Niedzwiecki, D; Sanders, L; Lee, YA; Marti, L; Reese, MI; Kurtzberg, J
MLA Citation
Szabolcs, P, Park, KD, Niedzwiecki, D, Sanders, L, Lee, YA, Marti, L, Reese, MI, and Kurtzberg, J. "Dendritic cell and T-cell subsets correlate with the development and site of acute GVHD following unrelated cord blood transplantation in children: A multivariate analysis." February 2005.
Source
wos-lite
Published In
Biology of Blood and Marrow Transplantation
Volume
11
Issue
2
Publish Date
2005
Start Page
81
End Page
81
DOI
10.1016/j.bbmt.2004.12.240

Analysis of air contrast barium enema, computed tomographic colonography, and colonoscopy: prospective comparison.

BACKGROUND: The usefulness of currently available colon imaging tests, including air contrast barium enema (ACBE), computed tomographic colonography (CTC), and colonoscopy, to detect colon polyps and cancers is uncertain. We aimed to assess the sensitivity of these three imaging tests. METHODS: Patients with faecal occult blood, haematochezia, iron-deficiency anaemia, or a family history of colon cancer underwent three separate colon-imaging studies--ACBE, followed 7-14 days later by CTC and colonoscopy on the same day. The primary outcome was detection of colonic polyps and cancers. Outcomes were assessed by building an aggregate view of the colon, taking into account results of all three tests. FINDINGS: 614 patients completed all three imaging tests. When analysed on a per-patient basis, for lesions 10 mm or larger in size (n=63), the sensitivity of ACBE was 48% (95% CI 35-61), CTC 59% (46-71, p=0.1083 for CTC vs ACBE), and colonoscopy 98% (91-100, p<0.0001 for colonoscopy vs CTC). For lesions 6-9 mm in size (n=116), sensitivity was 35% for ACBE (27-45), 51% for CTC (41-60, p=0.0080 for CTC vs ACBE), and 99% for colonoscopy (95-100, p<0.0001 for colonoscopy vs CTC). For lesions of 10 mm or larger in size, the specificity was greater for colonoscopy (0.996) than for either ACBE (0.90) or CTC (0.96) and declined for ACBE and CTC when smaller lesions were considered. INTERPRETATION: Colonoscopy was more sensitive than other tests, as currently undertaken, for detection of colonic polyps and cancers. These data have important implications for diagnostic use of colon imaging tests.

Authors
Rockey, DC; Paulson, E; Niedzwiecki, D; Davis, W; Bosworth, HB; Sanders, L; Yee, J; Henderson, J; Hatten, P; Burdick, S; Sanyal, A; Rubin, DT; Sterling, M; Akerkar, G; Bhutani, MS; Binmoeller, K; Garvie, J; Bini, EJ; McQuaid, K; Foster, WL; Thompson, WM; Dachman, A; Halvorsen, R
MLA Citation
Rockey, DC, Paulson, E, Niedzwiecki, D, Davis, W, Bosworth, HB, Sanders, L, Yee, J, Henderson, J, Hatten, P, Burdick, S, Sanyal, A, Rubin, DT, Sterling, M, Akerkar, G, Bhutani, MS, Binmoeller, K, Garvie, J, Bini, EJ, McQuaid, K, Foster, WL, Thompson, WM, Dachman, A, and Halvorsen, R. "Analysis of air contrast barium enema, computed tomographic colonography, and colonoscopy: prospective comparison." Lancet 365.9456 (January 22, 2005): 305-311.
PMID
15664225
Source
pubmed
Published In
The Lancet
Volume
365
Issue
9456
Publish Date
2005
Start Page
305
End Page
311
DOI
10.1016/S0140-6736(05)17784-8

Enumerating antigen-specific T-cell responses in peripheral blood: a comparison of peptide MHC Tetramer, ELISpot, and intracellular cytokine analysis.

Detection of the circulating antigen-specific T-cell response to immunization is an important biologic end point in clinical trials of cancer vaccines. Typically employed assays are peptide MHC tetramer, ELISpot, and intracellular cytokine analysis. Although there is no agreement on the definition of a positive response in these assays, many groups have chosen a number of T cells greater than 2 standard deviations above the mean of the negative controls. The authors wished to determine how well this cutoff performed for each of these assays in detecting positive and negative T-cell responses to a model antigen, the immunodominant HLA-A*0201-restricted epitope of cytomegalovirus (CMV) pp65. For each assay, the mean + 2 standard deviations of the response for CMV seronegatives was the point that best separated the two groups. Using this value, each assay had a sensitivity of 87.5% and specificity of 95% to 100% and exhibited a high degree of concordance (kappa 0.76-0.9) with the other two. The authors conclude that currently available immunologic assays perform well in detecting biologically relevant levels of antigen-specific T cells. These assays will better define the quantity and quality of protective immune responses to viral disease and offer insight into the requirements for protective anti-cancer immunity.

Authors
Hobeika, AC; Morse, MA; Osada, T; Ghanayem, M; Niedzwiecki, D; Barrier, R; Lyerly, HK; Clay, TM
MLA Citation
Hobeika, AC, Morse, MA, Osada, T, Ghanayem, M, Niedzwiecki, D, Barrier, R, Lyerly, HK, and Clay, TM. "Enumerating antigen-specific T-cell responses in peripheral blood: a comparison of peptide MHC Tetramer, ELISpot, and intracellular cytokine analysis." J Immunother 28.1 (January 2005): 63-72.
PMID
15614046
Source
pubmed
Published In
Journal of Immunotherapy
Volume
28
Issue
1
Publish Date
2005
Start Page
63
End Page
72

Preliminary analysis of cancer and leukemia group B (CALGB) 80003: A phase II trial of gemcitabine, 5-fluorouracil (5FU), and radiation therapy (RT) in locally advanced non-metastatic pancreatic adenocarcinoma

Authors
Mamon, HJ; Niedzwiecki, D; Hollis, DR; Tan, B; Smith, J; Blackstock, AW; Tepper, JE; Goldberg, RM; Mayer, RJ; Fuchs, CS
MLA Citation
Mamon, HJ, Niedzwiecki, D, Hollis, DR, Tan, B, Smith, J, Blackstock, AW, Tepper, JE, Goldberg, RM, Mayer, RJ, and Fuchs, CS. "Preliminary analysis of cancer and leukemia group B (CALGB) 80003: A phase II trial of gemcitabine, 5-fluorouracil (5FU), and radiation therapy (RT) in locally advanced non-metastatic pancreatic adenocarcinoma." 2005.
Source
wos-lite
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
63
Issue
2
Publish Date
2005
Start Page
S13
End Page
S13
DOI
10.1016/j.ijrobp.2005.07.028

Epigenetic inactivation of RUNX3 in microsatellite unstable sporadic colon cancers.

Runt domain transcription factors are important targets of TGF-beta superfamily proteins and play a crucial role in mammalian development. Three mammalian runt-related genes, RUNX1, RUNX2 and RUNX3, have been described. RUNX3 has been shown to be a putative tumor suppressor gene localized to chromosome 1p36, a region showing frequent loss of heterozygosity events in colon, gastric, breast and ovarian cancers. Because of the important role of TGF-beta signaling in the human colon, we hypothesized that RUNX3 may serve as a key tumor suppressor in human colon cancers and colon cancer-derived cell lines. We examined RUNX3 expression and the frequency of RUNX3 promoter hypermethylation in 17 colon cancer cell lines and 91 sporadic colorectal cancers. Semiquantitative analysis of RUNX3 transcripts was performed by RT-PCR and de novo methylation of the RUNX3 promoter was studied by a methylation-specific PCR (MSP) assay. Nineteen of 91 informative tumors (21%) and 11 of 17 (65%) colon cancer cell lines exhibited hypermethylation of the RUNX3 promoter. Interestingly, RUNX3 promoter hypermethylation was more common in tumors exhibiting high frequency of microsatellite instability (MSI-H) (33% of MSI-H vs. 12% of MSI-L/MSS tumors; p = 0.012). Hypermethylation of the RUNX3 promoter correlated with loss of mRNA transcripts in all cell lines. RUNX3 promoter methylation was reversed and its expression restored in SW48 and HCT15 colon cancer cells after treatment with the demethylating agent 5-aza-2'-deoxycytidine, indicating that loss of expression is caused by epigenetic inactivation in colon carcinogenesis. This is the first demonstration of frequent de novo hypermethylation of the RUNX3 promoter in sporadic colon cancers. The significant association of RUNX3 promoter hypermethylation with MSI-H colon cancers suggests that RUNX3 is a novel target of methylation, along with the hMLH1 gene, in the evolution of MSI-H colorectal cancers.

Authors
Goel, A; Arnold, CN; Tassone, P; Chang, DK; Niedzwiecki, D; Dowell, JM; Wasserman, L; Compton, C; Mayer, RJ; Bertagnolli, MM; Boland, CR
MLA Citation
Goel, A, Arnold, CN, Tassone, P, Chang, DK, Niedzwiecki, D, Dowell, JM, Wasserman, L, Compton, C, Mayer, RJ, Bertagnolli, MM, and Boland, CR. "Epigenetic inactivation of RUNX3 in microsatellite unstable sporadic colon cancers." Int J Cancer 112.5 (December 10, 2004): 754-759.
PMID
15386381
Source
pubmed
Published In
International Journal of Cancer
Volume
112
Issue
5
Publish Date
2004
Start Page
754
End Page
759
DOI
10.1002/ijc.20472

Sequential topoisomerase I (topo I) and topoisomerase II (topo II) inhibitors in relapsed/refractory aggressive NHL: Results of CALGB 59906, a phase II study of doxorubicin and topotecan.

Authors
Smith, SM; Johnson, JL; Niedzwiecki, D; Eder, JP; Canellos, GP; Cheson, BD; Bartlett, NL
MLA Citation
Smith, SM, Johnson, JL, Niedzwiecki, D, Eder, JP, Canellos, GP, Cheson, BD, and Bartlett, NL. "Sequential topoisomerase I (topo I) and topoisomerase II (topo II) inhibitors in relapsed/refractory aggressive NHL: Results of CALGB 59906, a phase II study of doxorubicin and topotecan." November 16, 2004.
Source
wos-lite
Published In
Blood
Volume
104
Issue
11
Publish Date
2004
Start Page
685A
End Page
686A

Dose dense, high intensity induction therapy followed by early high dose chemotherapy (HDT) and autologous hematopoietic stem cell transplantation (AHSCT) for mantle cell lymphoma (MCL).

Authors
Koh, LP; Gockerman, JP; Moore, JO; DeCastro, C; Long, GD; Gasparetto, C; Niedzwiecki, D; Edwards, J; Prosnitz, L; Horwitz, M; Chute, J; Morris, A; Lassiter, M; Loftis, J; Davis, P; Chao, NJ; Rizzieri, DA
MLA Citation
Koh, LP, Gockerman, JP, Moore, JO, DeCastro, C, Long, GD, Gasparetto, C, Niedzwiecki, D, Edwards, J, Prosnitz, L, Horwitz, M, Chute, J, Morris, A, Lassiter, M, Loftis, J, Davis, P, Chao, NJ, and Rizzieri, DA. "Dose dense, high intensity induction therapy followed by early high dose chemotherapy (HDT) and autologous hematopoietic stem cell transplantation (AHSCT) for mantle cell lymphoma (MCL)." November 16, 2004.
Source
wos-lite
Published In
Blood
Volume
104
Issue
11
Publish Date
2004
Start Page
261A
End Page
261A

CALGB 59901: Results of a phase II study of 506U78 in CTCL and PTCL.

Authors
Czuczman, MS; Porcu, P; Johnson, J; Niedzwiecki, D; Canellos, GP; Cheson, BD
MLA Citation
Czuczman, MS, Porcu, P, Johnson, J, Niedzwiecki, D, Canellos, GP, and Cheson, BD. "CALGB 59901: Results of a phase II study of 506U78 in CTCL and PTCL." November 16, 2004.
Source
wos-lite
Published In
Blood
Volume
104
Issue
11
Publish Date
2004
Start Page
682A
End Page
682A

Intense immunochemotherapy (IC) and autologous stem, cell transplant (ASCT) for untreated patients (pts) with mantle cell lymphoma (MCL): CALGB 59909. A preliminary report.

Authors
Damon, L; Niedzwiecki, D; Johnson, J; Cheson, B; Hurd, D; Barlett, N; Kelly, M; Linker, C; Canellos, G
MLA Citation
Damon, L, Niedzwiecki, D, Johnson, J, Cheson, B, Hurd, D, Barlett, N, Kelly, M, Linker, C, and Canellos, G. "Intense immunochemotherapy (IC) and autologous stem, cell transplant (ASCT) for untreated patients (pts) with mantle cell lymphoma (MCL): CALGB 59909. A preliminary report." November 16, 2004.
Source
wos-lite
Published In
Blood
Volume
104
Issue
11
Publish Date
2004
Start Page
255A
End Page
256A

Dendritic and T cell subsets correlate with the development and site of acute GVHD following unrelated cord blood transplantation. A multivariate analysis of host, graft, and day+50 immune profile.

Authors
Szabolcs, P; Park, KD; Marti, L; Lee, YA; Reese, M; Sanders, L; Niedzwiecki, D; Kurtzberg, J
MLA Citation
Szabolcs, P, Park, KD, Marti, L, Lee, YA, Reese, M, Sanders, L, Niedzwiecki, D, and Kurtzberg, J. "Dendritic and T cell subsets correlate with the development and site of acute GVHD following unrelated cord blood transplantation. A multivariate analysis of host, graft, and day+50 immune profile." November 16, 2004.
Source
wos-lite
Published In
Blood
Volume
104
Issue
11
Publish Date
2004
Start Page
281A
End Page
281A

Sentinel node staging of resectable colon cancer: results of a multicenter study.

OBJECTIVE AND SUMMARY BACKGROUND DATA: Sentinel lymph node (LN) sampling, a technique widely used to manage breast cancer and melanoma, seeks to select LNs that accurately predict regional node status and can be extensively examined to identify nodal metastatic disease not detected by standard histopathological staging. For patients with resectable colon cancer, improved identification of LN disease would significantly advance patient care by identifying patients likely to benefit from adjuvant therapy. This study, conducted by 25 surgeons at 13 institutions, examined whether sentinel node (SN) sampling accurately predicted LN status for patients with resectable colon cancer. METHODS: SN sampling involved peritumor injection of 1% isosulfan blue, followed by identification of all LN visualized within 10 minutes. SN sampling was performed on 79 of 91 patients enrolled, followed by multilevel sectioning (MLS) of the nodes and examination by a single study pathologist. RESULTS: By standard histopathology, 7 patients had primary disease that was either benign or not colon cancer and were therefore excluded from further studies. Of 72 colon cancer cases studied, 48 (66%) were node-negative and 24 (33%) contained nodal metastases. SNs were successfully located in 66 cases (92%), with an average of 2.1 nodes per patient. SNs were negative in 14 of 24 node-positive cases (58%). MLS revealed tumor in a SN in 1 of these cases, bringing the false-negative rate of SN examination to 54%. CONCLUSION: This multi-institutional study found that for patients with node-positive colon cancer, SN examination with MLS failed to predict nodal status in 54% of cases. We conclude that SN sampling with MLS, used alone, is unlikely to improve risk stratification for resectable colon cancer.

Authors
Bertagnolli, M; Miedema, B; Redston, M; Dowell, J; Niedzwiecki, D; Fleshman, J; Bem, J; Mayer, R; Zinner, M; Compton, C
MLA Citation
Bertagnolli, M, Miedema, B, Redston, M, Dowell, J, Niedzwiecki, D, Fleshman, J, Bem, J, Mayer, R, Zinner, M, and Compton, C. "Sentinel node staging of resectable colon cancer: results of a multicenter study." Ann Surg 240.4 (October 2004): 624-628.
PMID
15383790
Source
pubmed
Published In
Annals of Surgery
Volume
240
Issue
4
Publish Date
2004
Start Page
624
End Page
628

APC promoter hypermethylation contributes to the loss of APC expression in colorectal cancers with allelic loss on 5q.

INTRODUCTION: Germ-line mutations of the APC gene are associated with familial adenomatous polyposis, and somatic mutations occur frequently in sporadic colorectal cancer. However, to abrogate APC function, both alleles must be inactivated. Recently, it has been demonstrated that epigenetic modification of the APC promoter influences APC silencing. Here we examined the influence of APC methylation on APC expression in tumors with and without LOH at the APC locus. MATERIAL AND METHODS: 137 sporadic colorectal cancer specimens were investigated for LOH at the 5q locus. The methylation status of the APC promoter was determined by methylation-specific PCR. APC expression was performed by immunohistochemistry. RESULTS: Expression was reduced or lost in 110 of 137 (80%) tumors and LOH at 5q was found in 13 of 132 (10%) tumors. There was no difference in 5q LOH between tumors with or without intact APC expression. Vice versa, there was no difference in the APC expression in tumors with 5q LOH. Aberrant APC promoter methylation was detected in 33 of 118 (28%) tumors investigated. Of the tumors with 5q LOH for which methylation data were available, 4 of 11 (36%) were methylated versus 28 of 105 (27%) of those without LOH. No difference in methylation was observed in tumors without 5q LOH and normal APC expression and those without 5q LOH and reduced or missing APC expression. Importantly, none of the tumors with 5q LOH and normal APC staining were aberrantly methylated, whereas 50% of the cancers with LOH at 5q and reduced or absent staining were hypermethylated. CONCLUSIONS: This report suggests that tumors with 5q LOH and reduced APC expression are more frequently hypermethylated at the APC promoter compared to those tumors with 5q LOH and normal APC expression. The association among APC promoter methylation status, 5q LOH, and reduced or lost APC expression suggests that de novo methylation plays an important role as a "second hit" in silencing APC expression in colorectal neoplasia.

Authors
Arnold, CN; Goel, A; Niedzwiecki, D; Dowell, JM; Wasserman, L; Compton, C; Mayer, RJ; Bertagnolli, MM; Boland, CR
MLA Citation
Arnold, CN, Goel, A, Niedzwiecki, D, Dowell, JM, Wasserman, L, Compton, C, Mayer, RJ, Bertagnolli, MM, and Boland, CR. "APC promoter hypermethylation contributes to the loss of APC expression in colorectal cancers with allelic loss on 5q." Cancer Biol Ther 3.10 (October 2004): 960-964.
PMID
15326380
Source
pubmed
Published In
Cancer Biology and Therapy
Volume
3
Issue
10
Publish Date
2004
Start Page
960
End Page
964

A randomized phase II study of gemcitabine/cisplatin, gemcitabine fixed dose rate infusion, gemcitabine/docetaxel, or gemcitabinefirinotecan in patients with metastatic pancreatic cancer (CALGB 89904).

Authors
Kulke, MH; Niedzwiecki, D; Tempero, MA; Hollis, DR; Mayer, RJ
MLA Citation
Kulke, MH, Niedzwiecki, D, Tempero, MA, Hollis, DR, and Mayer, RJ. "A randomized phase II study of gemcitabine/cisplatin, gemcitabine fixed dose rate infusion, gemcitabine/docetaxel, or gemcitabinefirinotecan in patients with metastatic pancreatic cancer (CALGB 89904)." July 15, 2004.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
22
Issue
14
Publish Date
2004
Start Page
316S
End Page
316S

A phase I/II study of preoperative oxaliplatin (0), 5-fluorouracil (5-FU), and external beam radiation therapy (XRT) in locally advanced rectal cancer: CALGB 89901.

Authors
Ryan, DP; Niedzwiecki, D; Hollis, D; Miedema, BE; Wadler, S; Tepper, JE; Mayer, RJ
MLA Citation
Ryan, DP, Niedzwiecki, D, Hollis, D, Miedema, BE, Wadler, S, Tepper, JE, and Mayer, RJ. "A phase I/II study of preoperative oxaliplatin (0), 5-fluorouracil (5-FU), and external beam radiation therapy (XRT) in locally advanced rectal cancer: CALGB 89901." July 15, 2004.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
22
Issue
14
Publish Date
2004
Start Page
260S
End Page
260S

Sentinel node staging of resectable colon cancer: Results of CALGB 80001.

Authors
Bertagnolli, MM; Redston, M; Miedema, B; Dowell, J; Niedzwiecki, D; Mayer, R; Fleshman, J; Bem, J; Compton, C
MLA Citation
Bertagnolli, MM, Redston, M, Miedema, B, Dowell, J, Niedzwiecki, D, Mayer, R, Fleshman, J, Bem, J, and Compton, C. "Sentinel node staging of resectable colon cancer: Results of CALGB 80001." July 15, 2004.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
22
Issue
14
Publish Date
2004
Start Page
246S
End Page
246S

Phase III trial of adjuvant immunotherapy with MOAb 17-1A following resection for stage II adenocarcinoma of the colon (CALGB 9581).

Authors
Colacchio, TA; Niedzwiecki, D; Compton, C; Warren, R; Benson, AIB; Goldberg, R; Kerr, D; Fields, A; Hollis, D; Mayer, R
MLA Citation
Colacchio, TA, Niedzwiecki, D, Compton, C, Warren, R, Benson, AIB, Goldberg, R, Kerr, D, Fields, A, Hollis, D, and Mayer, R. "Phase III trial of adjuvant immunotherapy with MOAb 17-1A following resection for stage II adenocarcinoma of the colon (CALGB 9581)." July 15, 2004.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
22
Issue
14
Publish Date
2004
Start Page
250S
End Page
250S

Irinotecan plus fluorouracil/leucovorin (IFL) versus fluorouracil/leucovorin alone (FL) in stage III colon cancer (intergroup trial CALGB C89803).

Authors
Saltz, LB; Niedzwiecki, D; Hollis, D; Goldberg, RM; Hantel, A; Thomas, JP; Fields, ALA; Carver, G; Mayer, RJ
MLA Citation
Saltz, LB, Niedzwiecki, D, Hollis, D, Goldberg, RM, Hantel, A, Thomas, JP, Fields, ALA, Carver, G, and Mayer, RJ. "Irinotecan plus fluorouracil/leucovorin (IFL) versus fluorouracil/leucovorin alone (FL) in stage III colon cancer (intergroup trial CALGB C89803)." July 15, 2004.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
22
Issue
14
Publish Date
2004
Start Page
245S
End Page
245S

A phase I/II study of preoperative oxaliplatin (O), 5-fluorouracil (5-FU), and external beam radiation therapy (XRT) in locally advanced rectal cancer: CALGB 89901.

3560 Background: 5FU and XRT administered preoperatively is a standard regimen for patients with T3/T4 rectal cancer. Preclinical data demonstrate radiation sensitization for O and 5FU. The aims were to determine the MTD of weekly O with 5FU and XRT and to determine the pathological response at the MTD.Eligibility criteria included adenocarcinoma of the rectum within 12 cm of the anal verge; T3/T4 disease as demonstrated by endorectal USG or MRI; no metastatic disease; adequate bone marrow, liver, and kidney function. 5FU 200 mg/m2 was administered over 24 hours daily. XRT was delivered at 1.8 Gy per day, 5 days/week (28 fractions total). O was administered over 1 hour on day 1 of each week. Surgical resection was recommended 4-6 weeks after chemoradiation. DLTs included grade 4 neutropenia, grade 3/4 thrombocytopenia or grade 3/4 nonhematologic toxicity requiring > 7 days interruption in therapy. A traditional phase I accrual design was followed. The MTD is the dose level below the level where 2 of 6 patients experience DLT or a maximum dose of O of 60 mg/m2.18 patients (7 women, 15 caucasian, median age 56.5) were enrolled to 4 dose levels of O (30, 40, 50, 60mg/m2). No DLTs were observed in the first 3 dose levels. 2 patients were replaced in dose level 2 (1 hypersensitivity reaction, 1 colonic obstruction). The third patient enrolled at dose level 4 experienced a DLT (diarrhea week 4) and a patient at this level was replaced due to disease related bowel perforation. Three additional patients were enrolled at dose level 4 without any DLTs. Two patients experienced grade 3 neutropenia. No patient experienced grade 3 thrombocytopenia or neuropathy. Grade 3 diarrhea occurred in one patient each at the 30 and 50 mg/m2 dose levels during weeks 4 and 1, respectively, and 3 patients at 60 mg/m2 during weeks 2, 3, and 4, respectively. An additional 19 patients have been accrued at dose level 4.The recommended phase II dose of weekly O when administered with 5FU and XRT is 60mg/m2. Updated toxicity and pathological response rate for 25 patients treated at the MTD will be available in Spring 2004. [Table: see text].

Authors
Ryan, DP; Niedzwiecki, D; Hollis, D; Miedema, BE; Wadler, S; Tepper, JE; Mayer, RJ
MLA Citation
Ryan, DP, Niedzwiecki, D, Hollis, D, Miedema, BE, Wadler, S, Tepper, JE, and Mayer, RJ. "A phase I/II study of preoperative oxaliplatin (O), 5-fluorouracil (5-FU), and external beam radiation therapy (XRT) in locally advanced rectal cancer: CALGB 89901." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 22.14_suppl (July 2004): 3560-.
PMID
28016617
Source
epmc
Published In
Journal of Clinical Oncology
Volume
22
Issue
14_suppl
Publish Date
2004
Start Page
3560

Phase III trial of adjuvant immunotherapy with MOAb 17-1A following resection for stage II adenocarcinoma of the colon (CALGB 9581).

3522 Background: MoAb 17-1A targets a cell surface antigen expressed on many adenocarcinomas and improved survival in early trials of adjuvant therapy in Stage III colon cancer. The primary clinical objective of this study was to determine whether adjuvant treatment with MoAb 17-1A improved overall (OS) and failure-free survival (FFS) in patients who have had resection of a stage II (pT3NO or pT4bNO) colon cancer. The secondary objective was to investigate a panel of prognostic biological markers for potential association with OS and FFS after adjuvant therapy in these patients.Patients were randomized to either treatment with MoAb 17-1A or observation only with stratification according to degree of differentiation, vascular or lymphatic invasion, and preoperative serum CEA. Therapy consisted of an initial 2-hour infusion of 500 mg of MoAb 17-1A (cycle 1) followed by a lower dose (100 mg) every 28 days for four doses. The study was activated 5/31/97 and closed to accrual on 5/31/02 because of the discontinuation of the drug supply.The final patient accrual was 1738 of 2100 targeted, with 865 on the treatment arm and 873 on the observation arm. Study results were released by the CALGB Data and Safety Monitoring Board after futility boundaries for OS and FFS were met at the fifth planned interim analysis in July 2003. As of December 2003 there were 93 (11%) Grade 3 toxicities, 18 (2%) Grade 4 toxicities, and no deaths due to treatment. Median follow-up was 32 months on MoAB17-1A and 34 months on Observation. Two hundred eleven (211) failures and 116 deaths have been observed. These comprised 104 failures and 55 deaths on the MoAB 17-1A arm and 107 failures and 61 deaths on the observation arm. Median OS and FFS have not been reached. There were no significant differences between treatment arms (OS p=0.36; FFS p=0.49). Preliminary data on marker prevalence will be available by May 2004.MoAb 17-1A does not appear to prolong OS or FFS in patients with Stage II colon cancer following resection. No significant financial relationships to disclose.

Authors
Colacchio, TA; Niedzwiecki, D; Compton, C; Warren, R; Benson, AI; Goldberg, R; Kerr, D; Fields, A; Hollis, D; Mayer, R
MLA Citation
Colacchio, TA, Niedzwiecki, D, Compton, C, Warren, R, Benson, AI, Goldberg, R, Kerr, D, Fields, A, Hollis, D, and Mayer, R. "Phase III trial of adjuvant immunotherapy with MOAb 17-1A following resection for stage II adenocarcinoma of the colon (CALGB 9581)." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 22.14_suppl (July 2004): 3522-.
PMID
28016523
Source
epmc
Published In
Journal of Clinical Oncology
Volume
22
Issue
14_suppl
Publish Date
2004
Start Page
3522

Irinotecan plus fluorouracil/leucovorin (IFL) versus fluorouracil/leucovorin alone (FL) in stage III colon cancer (intergroup trial CALGB C89803).

3500 Background: Irinotecan prolongs survival in second line 5FU-refractory metastatic colorectal cancer (MCRC). First line irinotecan, weekly bolus 5FU, and leucovorin (IFL) was superior to daily x 5 bolus 5FU and leucovorin alone (FL) in a phase III trial in MCRC in terms of response rate, progression free survival and overall survival (OS). We conducted a phase III randomized study to evaluate whether IFL was also superior to weekly bolus FL after curative resection for stage III colon cancer.Eligible patients had TxN1-2M0 disease, Zubrod 0-2, and no prior chemotherapy. Patients (pts) received either IFL (irinotecan 125mg/m2 over 90 minutes followed by leucovorin 20 mg/m2 IV bolus and then 5FU 500mg/m2 IV bolus, given 4 weeks on, 2 weeks off, x 5 cycles (30 weeks total)) or the Roswell Park schedule of FL (leucovorin 500mg/m2 IV over 2 hours plus 5FU 500 mg/m2 at 1 hour after start of leucovorin, given 6 weeks on, two weeks off, x 4 cycles (32 weeks total)). Pts were stratified for N1 vs. N2 disease, high vs. low grade histology, and preoperative CEA of < 5 ng/ml, ≥ 5ng/ml, or unknown.1264 pts were randomized between April, 1999 and April, 2001. Median follow up is 2.6 years, and 67% of total expected deaths and 85% of total expected failures have occurred. Median OS and failure-free survival (FFS) have not yet been reached. IFL shows no improvement over FL in terms of either OS (p=0.88) or FFS (p=0.84) Futility boundaries for both of these endpoints have been exceeded. Toxicities are shown in the table. 18 deaths occurred on the IFL arm during treatment vs. 6 deaths on the FL arm (p=0.008).In stage III colon cancer, IFL, as compared to FL, is associated with a greater degree of neutropenia, neutropenic fever, and death on treatment, with no associated clinical benefit. Weekly bolus IFL should not be used in the management of stage III colon cancer. [Figure: see text] [Table: see text].

Authors
Saltz, LB; Niedzwiecki, D; Hollis, D; Goldberg, RM; Hantel, A; Thomas, JP; Fields, AL; Carver, G; Mayer, RJ
MLA Citation
Saltz, LB, Niedzwiecki, D, Hollis, D, Goldberg, RM, Hantel, A, Thomas, JP, Fields, AL, Carver, G, and Mayer, RJ. "Irinotecan plus fluorouracil/leucovorin (IFL) versus fluorouracil/leucovorin alone (FL) in stage III colon cancer (intergroup trial CALGB C89803)." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 22.14_suppl (July 2004): 3500-.
PMID
28016485
Source
epmc
Published In
Journal of Clinical Oncology
Volume
22
Issue
14_suppl
Publish Date
2004
Start Page
3500

Sentinel node staging of resectable colon cancer: Results of CALGB 80001.

3506 The most important outcome predictor for resectable colon cancer (RCC) is the status of locoregional lymph nodes. This information is critical, as patients with positive nodes may benefit from post-operative adjuvant therapy. A subset of patients with node-negative RCC experiences a poor outcome, suggesting that improved staging would benefit this population by identifying patients who should receive additional treatment. CALGB 80001, a study conducted by 25 surgery-pathology teams at 12 institutions, was designed to determine whether sentinel lymph node sampling (SLNS) could identify a subset of lymph nodes that predict the status of the nodal basin for RCC, and therefore could be extensively evaluated for the presence of metastases. SLNS was performed on 79 of 91 patients enrolled, followed by multilevel sectioning (MLS) of the nodes, and examination by H&E as well as IHC to identify cells positive for cytokeratin (CK) and carcinoembryonic antigen (CEA). Sentinel nodes (SN) were successfully located in 66 of 72 colon cancer cases (92%), with an average of 2.0 sentinel nodes per patient. SNs were negative in 14 of 25 node-positive cases (56%). MLS revealed tumor in a SN in one of these cases, bringing the sensitivity of SN examination by H&E and MLS to 48%. Results of further sentinel node studies are as follows: [Figure: see text] The addition of IHC for CK and CEA doubled the total number of node positive colon cancer cases from 25 to 50 of 62 (40 to 81%).These results show that SN examined by H&E and MLS failed to predict nodal status in 52% of cases. Analysis of SNs from colon cancer is unlikely to predict the nodal status of the patient, and studies to examine micrometastatic disease should involve all draining nodes removed. No significant financial relationships to disclose.

Authors
Bertagnolli, MM; Redston, M; Miedema, B; Dowell, J; Niedzwiecki, D; Mayer, R; Fleshman, J; Bem, J; Compton, C
MLA Citation
Bertagnolli, MM, Redston, M, Miedema, B, Dowell, J, Niedzwiecki, D, Mayer, R, Fleshman, J, Bem, J, and Compton, C. "Sentinel node staging of resectable colon cancer: Results of CALGB 80001." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 22.14_suppl (July 2004): 3506-.
PMID
28016487
Source
epmc
Published In
Journal of Clinical Oncology
Volume
22
Issue
14_suppl
Publish Date
2004
Start Page
3506

A randomized phase II study of gemcitabine/cisplatin, gemcitabine fixed dose rate infusion, gemcitabine/docetaxel, or gemcitabine/irinotecan in patients with metastatic pancreatic cancer (CALGB 89904).

4011 Background: In the treatment of advanced pancreatic cancer, chemotherapy regimens utilizing prolonged infusions of gemcitabine or combinations of gemcitabine and other agents have been associated with higher objective tumor response rates and, in some cases, improvements in progression-free survival when compared with gemcitabine administered as a standard 30-minute infusion. Comparisons between these novel regimens have been limited. We therefore performed a randomized phase II study of four investigational chemotherapy regimens in pts with documented metastatic pancreatic cancer.Pts were randomized to receive one of the following four treatments: gem 1000 mg/m2 d 1, 8, 15 with cisplatin 50 mg/m2 d1, 15 q 28d (Arm A); gem 1500 mg/m2 at a fixed dose rate of 10 mg/m2/minute d1, 8, 15 q 28d (Arm B); gem 1000 mg/m2 d1, 8 with docetaxel 40 mg/m2 d1, 8 q 21d (Arm C); or gem 1000 mg/m2 d1, 8 with irinotecan 100 mg/m2 d1, 8 q 21d (Arm D). Planned follow up per pt is 6 months.Two hundred and fifty-one pts (61-65 per arm) were enrolled, with the following characteristics: median age 60.7 (range (31-84); M/F = 157/94; ECOG PS 0/1/2 = 49/86/18. Median follow-up time is 4.8 months. Pts were followed for overall survival, tumor response, time to tumor progression, and toxicity. The major toxicities experienced by 198 enrolled pts for whom data is currently available are shown in Table 1. Three pts experienced treatment related deaths: 1 (2%) in Arm A and 2 (4%) in Arm B.While the specific toxicities differ to some degree between regimens, all four regimens have acceptable toxicity profiles. Accrual to the trial has been completed. Updated toxicity data, as well as preliminary data for survival, response, and time to tumor progression will be presented at the annual meeting. [Figure: see text] [Table: see text].

Authors
Kulke, MH; Niedzwiecki, D; Tempero, MA; Hollis, DR; Mayer, RJ
MLA Citation
Kulke, MH, Niedzwiecki, D, Tempero, MA, Hollis, DR, and Mayer, RJ. "A randomized phase II study of gemcitabine/cisplatin, gemcitabine fixed dose rate infusion, gemcitabine/docetaxel, or gemcitabine/irinotecan in patients with metastatic pancreatic cancer (CALGB 89904)." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 22.14_suppl (July 2004): 4011-.
PMID
28016443
Source
epmc
Published In
Journal of Clinical Oncology
Volume
22
Issue
14_suppl
Publish Date
2004
Start Page
4011

Low-dose weekly paclitaxel for recurrent or refractory aggressive non-Hodgkin lymphoma.

BACKGROUND: Many patients with recurrent, intermediate or high-grade non-Hodgkin lymphoma (NHL) may not respond to or are not candidates for aggressive salvage chemotherapy. Effective, less toxic regimens are needed. Although high-dose taxanes have not been reported to be very effective for the treatment of lymphoma, different delivery rates may allow for different mechanisms of action to be manifest and result in a different toxicity profile and response rate. The current study tested this hypothesis by using low-dose, weekly paclitaxel in patients with recurrent or refractory NHL. METHODS: Adults age > 18 years with refractory or recurrent, aggressive NHL who were not considered curable with standard high-dose therapy received paclitaxel at a dose of 80 mg/m2 weekly for 5 weeks for 2 cycles. RESULTS: Thirty-four patients with refractory NHL and 4 patients with recurrent disease were treated. Approximately 45% of the patients had achieved a prior disease remission. The median number of prior regimens received was 3, 74% of the patients had an International Prognostic Index of > or = 3 at the time of study entry, and 29% had failed high-dose therapy with autologous hematopoietic support. Only one patient encountered severe toxicity (sepsis). Myelosuppression was reported to occur in approximately 20% of patients. A total of 10 patients (26%) achieved a complete disease response and 4 patients (11%) achieved a partial response. CONCLUSIONS: In the current study, low-dose, weekly paclitaxel therapy was found to provide a well tolerated and less toxic approach to the treatment of refractory NHL, with encouraging responses noted in heavily pretreated patients. However, evaluation in patients with an earlier stage of disease is warranted.

Authors
Rizzieri, DA; Sand, GJ; McGaughey, D; Moore, JO; DeCastro, C; Chao, NJ; Vredenburgh, JJ; Gasparetto, C; Long, GD; Anderson, E; Foster, T; Toaso, B; Adams, D; Niedzwiecki, D; Gockerman, JP
MLA Citation
Rizzieri, DA, Sand, GJ, McGaughey, D, Moore, JO, DeCastro, C, Chao, NJ, Vredenburgh, JJ, Gasparetto, C, Long, GD, Anderson, E, Foster, T, Toaso, B, Adams, D, Niedzwiecki, D, and Gockerman, JP. "Low-dose weekly paclitaxel for recurrent or refractory aggressive non-Hodgkin lymphoma." Cancer 100.11 (June 1, 2004): 2408-2414.
PMID
15160345
Source
pubmed
Published In
Cancer
Volume
100
Issue
11
Publish Date
2004
Start Page
2408
End Page
2414
DOI
10.1002/cncr.20245

Frequent inactivation of PTEN by promoter hypermethylation in microsatellite instability-high sporadic colorectal cancers.

Loss of PTEN tumor suppressor function is observed in tumors of breast, prostate, thyroid, and endometrial origin. Allelic losses in the proximity of the PTEN locus (10q23) also occur in sporadic colorectal cancers (CRCs), but biallelic inactivation of this site has not been frequently demonstrated. We hypothesized that alternative mechanisms of PTEN allelic inactivation, such as promoter hypermethylation, might be operative in CRC and that PTEN inactivation may be related to recognized forms of genomic instability. We characterized a cohort of 273 sporadic CRCs by determining their microsatellite instability (MSI) status. Of these, 146 cancers were examined for PTEN promoter methylation by methylation-specific PCR. Mutations at the poly(A)6 repeat sequences in PTEN exons 7 and 8 and deletions at the 10q23 locus were also identified using microsatellite analysis. The presence of PTEN protein was determined by immunostaining, and the results were correlated with the promoter methylation status. We observed that PTEN promoter hypermethylation was a frequent occurrence in MSI-high (MSI-H) tumors (19.1% of MSI-H versus 2.2% of MSI-low/microsatellite stable tumors; P = 0.002). A PTEN mutation or a deletion event was present in 60% of the tumors with promoter region hypermethylation. Hypermethylation of the PTEN promoter correlated significantly with either decreased or complete loss of PTEN protein expression (P = 0.004). This is the first demonstration of PTEN inactivation as a result of promoter hypermethylation in MSI-H sporadic CRCs. These data suggest that this silencing mechanism plays a major role in PTEN inactivation and, in colon cancer, may be more important than either allelic losses or inactivating mutations. The significant correlation of PTEN hypermethylation with MSI-H tumors further suggests that PTEN is an additional important "target" of methylation along with the hMLH1 gene in the evolution of MSI-H CRCs and also confers the "second hit" in the biallelic inactivation mechanism for some proportion of tumors.

Authors
Goel, A; Arnold, CN; Niedzwiecki, D; Carethers, JM; Dowell, JM; Wasserman, L; Compton, C; Mayer, RJ; Bertagnolli, MM; Boland, CR
MLA Citation
Goel, A, Arnold, CN, Niedzwiecki, D, Carethers, JM, Dowell, JM, Wasserman, L, Compton, C, Mayer, RJ, Bertagnolli, MM, and Boland, CR. "Frequent inactivation of PTEN by promoter hypermethylation in microsatellite instability-high sporadic colorectal cancers." Cancer Res 64.9 (May 1, 2004): 3014-3021.
PMID
15126336
Source
pubmed
Published In
Cancer Research
Volume
64
Issue
9
Publish Date
2004
Start Page
3014
End Page
3021

How important is bleomycin in the adriamycin + bleomycin + vinblastine + dacarbazine regimen?

Authors
Canellos, GP; Duggan, D; Johnson, J; Niedzwiecki, D
MLA Citation
Canellos, GP, Duggan, D, Johnson, J, and Niedzwiecki, D. "How important is bleomycin in the adriamycin + bleomycin + vinblastine + dacarbazine regimen?." J Clin Oncol 22.8 (April 15, 2004): 1532-1533. (Letter)
PMID
15084636
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
22
Issue
8
Publish Date
2004
Start Page
1532
End Page
1533
DOI
10.1200/JCO.2004.99.010

Intensive chemotherapy with and without cranial radiation for Burkitt leukemia and lymphoma: final results of Cancer and Leukemia Group B Study 9251.

BACKGROUND: The objective of the current study was to evaluate the efficacy of intensive chemotherapy with and without cranial radiation for central nervous system (CNS) prophylaxis in adults with Burkitt leukemia or lymphoma. METHODS: Patients received 18 weeks of therapy. Prophylactic cranial radiation (2400 centigrays) and 12 doses of triple intrathecal chemotherapy were administered to the first cohort of patients. A subsequent cohort received the same therapy, with the exceptions that intrathecal therapy was reduced to six doses and radiotherapy was administered only to high-risk individuals. RESULTS: The median follow-up durations were 6.8 years in Cohort 1 and 4.1 years in Cohort 2. Three occurrences of transverse myelitis, 2 severe neuropathies, 3 cases of aphasia, and 1 case of blindness were documented in the first cohort of 52 patients (Cohort 1). In the subsequent cohort of 40 patients (Cohort 2), none of these occurrences were observed, and patients experienced less neurologic toxicity overall (61% vs. 26%; P=0.001). Responses were similar, and the 3-year event-free survival rate was 0.52 (95% confidence interval, 0.38-0.65) for Cohort 1 and 0.45 (0.29-0.60) for Cohort 2. CONCLUSIONS: Intensive, short-duration chemotherapy with less intensive CNS prophylaxis led to control at this sanctuary site with little neurotoxicity and may be curative for adults with Burkitt leukemia or lymphoma.

Authors
Rizzieri, DA; Johnson, JL; Niedzwiecki, D; Lee, EJ; Vardiman, JW; Powell, BL; Barcos, M; Bloomfield, CD; Schiffer, CA; Peterson, BA; Canellos, GP; Larson, RA
MLA Citation
Rizzieri, DA, Johnson, JL, Niedzwiecki, D, Lee, EJ, Vardiman, JW, Powell, BL, Barcos, M, Bloomfield, CD, Schiffer, CA, Peterson, BA, Canellos, GP, and Larson, RA. "Intensive chemotherapy with and without cranial radiation for Burkitt leukemia and lymphoma: final results of Cancer and Leukemia Group B Study 9251." Cancer 100.7 (April 1, 2004): 1438-1448.
PMID
15042678
Source
pubmed
Published In
Cancer
Volume
100
Issue
7
Publish Date
2004
Start Page
1438
End Page
1448
DOI
10.1002/cncr.20143

Immune reconstitution and the risk of opportunistic infections after unrelated cord blood transplantation. A multivariate analysis

Authors
Szaboles, P; Park, KD; Reese, M; Marti, L; Sanders, L; Niedzwiecki, D; Lee, Y; DeOliveira, D; Kurtzberg, J
MLA Citation
Szaboles, P, Park, KD, Reese, M, Marti, L, Sanders, L, Niedzwiecki, D, Lee, Y, DeOliveira, D, and Kurtzberg, J. "Immune reconstitution and the risk of opportunistic infections after unrelated cord blood transplantation. A multivariate analysis." March 24, 2004.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
18
Issue
5
Publish Date
2004
Start Page
A829
End Page
A829

Impact of body mass index on outcomes and treatment-related toxicity in patients with stage II and III rectal cancer: findings from Intergroup Trial 0114.

PURPOSE: To study the relationship between body mass index (BMI) and rates of sphincter-preserving operations, overall survival, cancer recurrence, and treatment-related toxicities in patients with rectal cancer. PATIENTS AND METHODS: We evaluated a nested cohort of 1,688 patients with stage II and III rectal cancer participating in a randomized trial of postoperative fluorouracil-based chemotherapy and radiation therapy. RESULTS: Obese patients were more likely to undergo an abdominoperineal resection (APR) than normal-weight patients (odds ratio, 1.77; 95% CI, 1.27 to 2.46). When analyzed by sex, increasing adiposity in men was a strong predictor of having an APR (P <.0001). Obese men with rectal cancer were also more likely than normal-weight men to have a local recurrence (hazard ratio [HR], 1.61; 95% CI, 1.00 to 2.59). In contrast, obesity was not predictive of cancer recurrence in women, nor was BMI predictive of overall mortality in either men or women. Underweight patients had an increased risk of death (HR, 1.43; 95% CI, 1.08 to 1.89) compared with normal-weight patients but no increase in cancer recurrences. Among all study participants, obese patients had a significantly lower rate of grade 3 to 4 leukopenia, neutropenia, and stomatitis and a lower rate of any grade 3 or worse toxicity when compared with normal-weight individuals. CONCLUSION: Increasing BMI in male patients with rectal cancer is associated with a decreased likelihood of sphincter preservation and a higher chance of local recurrence. For both men and women, overweight and obese patients experience less toxicity associated with adjuvant chemoradiotherapy, suggesting that actual body weight dosing of fluorouracil for obese patients is justified.

Authors
Meyerhardt, JA; Tepper, JE; Niedzwiecki, D; Hollis, DR; McCollum, AD; Brady, D; O'Connell, MJ; Mayer, RJ; Cummings, B; Willett, C; Macdonald, JS; Benson, AB; Fuchs, CS
MLA Citation
Meyerhardt, JA, Tepper, JE, Niedzwiecki, D, Hollis, DR, McCollum, AD, Brady, D, O'Connell, MJ, Mayer, RJ, Cummings, B, Willett, C, Macdonald, JS, Benson, AB, and Fuchs, CS. "Impact of body mass index on outcomes and treatment-related toxicity in patients with stage II and III rectal cancer: findings from Intergroup Trial 0114." J Clin Oncol 22.4 (February 15, 2004): 648-657.
PMID
14966087
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
22
Issue
4
Publish Date
2004
Start Page
648
End Page
657
DOI
10.1200/JCO.2004.07.121

The impact of immune reconstitution in the early post grafting period on the development of opportunistic infections after unrelated cord blood transplantation. A multivariate analysis of host, graft, and day +50 immune profile

Authors
Szabolcs, P; Park, KD; Marti, L; Reese, M; Lee, YA; Oliveira, DD; Sanders, L; Niedzwiecki, D; Kutzberg, J
MLA Citation
Szabolcs, P, Park, KD, Marti, L, Reese, M, Lee, YA, Oliveira, DD, Sanders, L, Niedzwiecki, D, and Kutzberg, J. "The impact of immune reconstitution in the early post grafting period on the development of opportunistic infections after unrelated cord blood transplantation. A multivariate analysis of host, graft, and day +50 immune profile." February 2004.
Source
crossref
Published In
Biology of Blood and Marrow Transplantation
Volume
10
Publish Date
2004
Start Page
24
End Page
24
DOI
10.1016/j.bbmt.2003.12.099

Impact of hospital procedure volume on surgical operation and long-term outcomes in high-risk curatively resected rectal cancer: findings from the Intergroup 0114 Study.

PURPOSE: Prior studies have demonstrated superior outcomes after a curative surgical resection of rectal cancer at hospitals where the volume of such surgeries is high. However, because these studies often lack detailed information on tumor and treatment characteristics as well as cancer recurrence, the true nature of this relation remains uncertain. PATIENTS AND METHODS: We studied a nested cohort of 1,330 patients with stage II and stage III rectal cancer participating in a multicenter, adjuvant chemoradiotherapy trial. We analyzed differences in rates of sphincter-preserving operations, overall survival, and cancer recurrence by hospital surgical volume. RESULTS: We observed a significant difference in the rates of abdominoperineal resections across tertiles of hospital procedure volume (46.3% for patients resected at low-volume, 41.3% at medium-volume, and 31.8% at high-volume hospitals; P <.0001), even after adjustment for tumor distance from the anal verge. However, this higher rate of sphincter-sparing operations at high-volume centers was not accompanied by any increase in recurrence rates. Hospital surgical volume did not predict overall, disease-free, recurrence-free, or local recurrence-free survival. However, among patients who did not complete the planned adjuvant chemoradiotherapy (270 patients), those who underwent surgery at low-volume hospitals had a significant increase in cancer recurrence (adjusted hazard ratio, 1.94; 95% CI, 1.01 to 3.72; P =.04 for the trend) and a nonsignificant trend toward increased overall mortality (P =.08) and local recurrence (P =.10). In contrast, no significant volume-outcome relation was noted among patients who did complete postoperative therapy. CONCLUSION: Using prospectively recorded data, we found that hospital surgical volume had no significant effect on rectal cancer recurrence or survival when patients completed standard adjuvant therapy. Sphincter-preserving surgery was more commonly performed at high-volume centers.

Authors
Meyerhardt, JA; Tepper, JE; Niedzwiecki, D; Hollis, DR; Schrag, D; Ayanian, JZ; O'Connell, MJ; Weeks, JC; Mayer, RJ; Willett, CG; MacDonald, JS; Benson, AB; Fuchs, CS
MLA Citation
Meyerhardt, JA, Tepper, JE, Niedzwiecki, D, Hollis, DR, Schrag, D, Ayanian, JZ, O'Connell, MJ, Weeks, JC, Mayer, RJ, Willett, CG, MacDonald, JS, Benson, AB, and Fuchs, CS. "Impact of hospital procedure volume on surgical operation and long-term outcomes in high-risk curatively resected rectal cancer: findings from the Intergroup 0114 Study." J Clin Oncol 22.1 (January 1, 2004): 166-174.
PMID
14701779
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
22
Issue
1
Publish Date
2004
Start Page
166
End Page
174
DOI
10.1200/JCO.2004.04.172

Evaluation of microsatellite instability, hMLH1 expression and hMLH1 promoter hypermethylation in defining the MSI phenotype of colorectal cancer.

INTRODUCTION: About 15% of all colorectal cancers (CRCs) demonstrate high levels of microsatellite instability (MSI-H) and are currently best identified by molecular analysis of microsatellite markers. Most sporadic CRCs with MSI-H are known to be associated with the methylation of the hMLH1 promoter. Promoter methylation coincided with lack of hMLH1 expression. We aimed to investigate the association between MSI status, hMLH1 protein expression and methylation status of the hMLH1 promoter, and to determine the usefulness of each method in defining the MSI phenotype in sporadic CRCs. MATERIALS AND METHODS: CRCs from 173 patients from the Cancer and Leukemia Group B (CALGB) were assessed for their MSI status. An additional cohort of 18 MSI-H tumors from the University of California San Diego (UCSD) was included in the analysis of the MSI-H subgroup. MSI testing was performed by PCR using five standard MSI markers. hMLH1 promoter analysis was investigated by methylation specific PCR (MSP), and expression of the MMR genes hMLH1 and hMSH2 was examined by immunohistochemistry (IHC). RESULTS: Of the 173 CALGB tumors, 111 (64%) were MSS, 35 (20%) were MSI-L and 27 (16%) MSI-H, respectively. Data on hMLH1 protein expression, hMSH2 protein expression and hMLH1 methylation are available on 128, 173 and 81 of these tumors, respectively. Presence of hMLH1 and hMSH2 protein expression was significantly associated with MSI status. Four of 45 (8.9%) MSI-H tumors and 0 of 146 (0%) MSS/MSI-L tumors did not express hMSH2 (p = 0.0028). hMLH1 protein expression was present in 107 of 108 (99%) MSS and MSI-L tumors versus 11 of 20 (55%) MSI-H tumors (p < 0.0001). Of 61 MSS and MSI-L cancers studied for methylation, 11 (18%) were methylated at the hMLH1 promoter whereas 14 of 20 (70%) MSI-H cancers were methylated (p = 0.0001). In 27 MSI-H tumors studied for hMLH1 protein expression and methylation, 93% of tumors with loss of expression (93%) were also methylated while 42% (5/12) with positive immunostaining for hMLH1 were methylated at the hMLH1 promoter (p = 0.009). CONCLUSIONS: Promoter methylation and hMLH1 expression are significantly associated with the MSI-H phenotype in CRC. Promoter methylation analysis provides a useful means to screen for MSI-H tumors. Our data further suggests that hMLH1 promoter methylation analysis alone cannot replace MSI testing, as a significant number of MSI-H tumors could be potentially overseen by such an approach. We suggest that phenotypic evaluation of CRC is performed most reliably with MSI testing, although expression analysis and investigation of the promoter methylation status may complement the screening process.

Authors
Arnold, CN; Goel, A; Compton, C; Marcus, V; Niedzwiecki, D; Dowell, JM; Wasserman, L; Inoue, T; Mayer, RJ; Bertagnolli, MM; Boland, CR
MLA Citation
Arnold, CN, Goel, A, Compton, C, Marcus, V, Niedzwiecki, D, Dowell, JM, Wasserman, L, Inoue, T, Mayer, RJ, Bertagnolli, MM, and Boland, CR. "Evaluation of microsatellite instability, hMLH1 expression and hMLH1 promoter hypermethylation in defining the MSI phenotype of colorectal cancer." Cancer Biol Ther 3.1 (January 2004): 73-78.
PMID
14726676
Source
pubmed
Published In
Cancer Biology and Therapy
Volume
3
Issue
1
Publish Date
2004
Start Page
73
End Page
78

Unrelated umbilical cord blood transplantation in adult patients.

Since January 1996, we have administered myeloablative therapy followed by infusion of unrelated umbilical cord blood cells in 57 adult patients with high-risk disease. The median age was 31 years (range, 18-58 years), and the median weight was 70 kg (range, 46-110 kg). Two patients were treated for genetic disorders and 55 for advanced hematologic malignancies. The preparative regimens were total body irradiation or busulfan based, both with antithymocyte globulin. HLA matching between donor and recipient was 3 of 6 in 3 patients, 4 of 6 in 44 patients, 5 of 6 in 8 patients, and 6 of 6 in 2 patients. The median nucleated cell dose was 1.50 x 10(7)/kg (range, 0.54-2.78 x 10(7)/kg), and the median CD34(+) cell dose was 1.37 x 10(5)/kg (range, 0.02-12.45 x 10(5)/kg). All patients received granulocyte colony-stimulating factor after transplantation until neutrophil recovery. Graft-versus-host disease prophylaxis consisted of cyclosporine and steroids. The median number of days to an absolute neutrophil count of 500/microL was 26 (range, 12-55 days). The median time to an untransfused platelet count of >20000/microL was 84 days (range, 35-167 days). Seventeen patients developed grade II to IV acute GVHD. The median survival of the entire group was 91 days (range, 10-2251 days). Eleven patients were alive at a median follow-up of 1670 days (range, 67-2251 days), 1 with autologous recovery and 1 with relapsed lymphoma. The actuarial projected 3-year survival is 19%. Infection was the primary cause of death. These results suggest that unrelated umbilical cord blood transplantation is a viable option for adult patients and should be explored in patients with earlier-stage disease.

Authors
Long, GD; Laughlin, M; Madan, B; Kurtzberg, J; Gasparetto, C; Morris, A; Rizzieri, D; Smith, C; Vredenburgh, J; Halperin, EC; Broadwater, G; Niedzwiecki, D; Chao, NJ
MLA Citation
Long, GD, Laughlin, M, Madan, B, Kurtzberg, J, Gasparetto, C, Morris, A, Rizzieri, D, Smith, C, Vredenburgh, J, Halperin, EC, Broadwater, G, Niedzwiecki, D, and Chao, NJ. "Unrelated umbilical cord blood transplantation in adult patients." Biol Blood Marrow Transplant 9.12 (December 2003): 772-780.
PMID
14677117
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
9
Issue
12
Publish Date
2003
Start Page
772
End Page
780
DOI
10.1016/j.bbmt.2003.08.007

Phase I trial with pharmocokinetics, dosimetry, toxicity and response of anti-stromal therapy using I-131 labeled chimeric anti-tenascin therapy for lymphoma.

Authors
Rizzieri, DA; Akabani, G; Zalutsky, M; Coleman, RE; Toaso, B; Anderson, E; Lagoo, A; Clayton, S; Niedzwiecki, D; Moore, JO; Gockerman, JP; DeCastro, C; Chao, NJ; Gasparetto, C; Bigner, DD
MLA Citation
Rizzieri, DA, Akabani, G, Zalutsky, M, Coleman, RE, Toaso, B, Anderson, E, Lagoo, A, Clayton, S, Niedzwiecki, D, Moore, JO, Gockerman, JP, DeCastro, C, Chao, NJ, Gasparetto, C, and Bigner, DD. "Phase I trial with pharmocokinetics, dosimetry, toxicity and response of anti-stromal therapy using I-131 labeled chimeric anti-tenascin therapy for lymphoma." November 16, 2003.
Source
wos-lite
Published In
Blood
Volume
102
Issue
11
Publish Date
2003
Start Page
635A
End Page
636A

Clinical outcome and immune reconstitution following alemtuzumab T cell depleted nonmyeloablative allogeneic immunotherapy using HLA mis-matched (3-5/6) related hematopoietic stem cells.

Authors
Rizzieri, DA; Koh, LP; Long, GD; Gasparetto, C; Vredenburgh, JJ; Buckley, PJ; Gong, G; Lagoo, A; Davis, P; Lassiter, M; Rooney, B; Niedzwiecki, D; Waters-Pick, B; Burleson, J; Thompson, M; Johns, A; Folz, RJ; Horwtiz, ME; Sullivan, K; Morris, A; Chao, NJ
MLA Citation
Rizzieri, DA, Koh, LP, Long, GD, Gasparetto, C, Vredenburgh, JJ, Buckley, PJ, Gong, G, Lagoo, A, Davis, P, Lassiter, M, Rooney, B, Niedzwiecki, D, Waters-Pick, B, Burleson, J, Thompson, M, Johns, A, Folz, RJ, Horwtiz, ME, Sullivan, K, Morris, A, and Chao, NJ. "Clinical outcome and immune reconstitution following alemtuzumab T cell depleted nonmyeloablative allogeneic immunotherapy using HLA mis-matched (3-5/6) related hematopoietic stem cells." November 16, 2003.
Source
wos-lite
Published In
Blood
Volume
102
Issue
11
Publish Date
2003
Start Page
482A
End Page
482A

Low-dose weekly paclitaxel for relapsed or refractory aggressive non-Hodgkins lymphoma.

Authors
Rizzieri, DA; Sand, GJ; McGaughey, D; Moore, J; DeCastro, C; Chao, N; Vredenburgh, J; Gasparetto, C; Anderson, L; Foster, T; Niedzwiecki, D; Gockerman, J
MLA Citation
Rizzieri, DA, Sand, GJ, McGaughey, D, Moore, J, DeCastro, C, Chao, N, Vredenburgh, J, Gasparetto, C, Anderson, L, Foster, T, Niedzwiecki, D, and Gockerman, J. "Low-dose weekly paclitaxel for relapsed or refractory aggressive non-Hodgkins lymphoma." November 16, 2003.
Source
wos-lite
Published In
Blood
Volume
102
Issue
11
Publish Date
2003
Start Page
641A
End Page
641A

Analysis of surgical salvage after failure of primary therapy in rectal cancer: results from Intergroup Study 0114.

PURPOSE: Intergroup Study 0114 was designed to study the effect of various chemotherapy regimens delivered after potentially curative surgical resection of T3, T4, and/or node-positive rectal cancer. A subset analysis was undertaken to investigate the prevalence and influence of salvage therapy among patients with recurrent disease. PATIENTS AND METHODS: Adjuvant therapy consisted of two cycles of fluorouracil (FU)-based chemotherapy followed by pelvic irradiation with chemotherapy and two more cycles of chemotherapy after radiation therapy. A total of 1,792 patients were entered onto the study and 1,696 were assessable. After a median of 8.9 years of follow-up, 715 patients (42%) had disease recurrence, and an additional 10% died without evidence of disease. Five hundred patients with follow-up information available had a single organ or single site of first recurrence (73.5% of all recurrences). RESULTS: A total of 171 patients (34% of those with a single organ or single site of recurrence) had a potentially curative resection of the metastatic or locally recurrent disease. Single-site first recurrences in the liver, lung, or pelvis occurred in 448 patients (90% of the single-site recurrences), with 159 (35%) of these undergoing surgical resection for attempted cure. Overall survival differed significantly between the resected and nonresected groups (P <.0001), with overall 5-year probabilities of.27 and.06, respectively. Controlling for worst performance status at the time of recurrence does not alter this relationship. Patients who underwent salvage surgery had significantly increased survival (P <.001) for each site. CONCLUSION: Attempted surgical salvage of rectal cancer recurrence is performed commonly in the United States. The chance of a long-term cure with such intervention is approximately 27%.

Authors
Tepper, JE; O'Connell, M; Hollis, D; Niedzwiecki, D; Cooke, E; Mayer, RJ; Intergroup Study 0114,
MLA Citation
Tepper, JE, O'Connell, M, Hollis, D, Niedzwiecki, D, Cooke, E, Mayer, RJ, and Intergroup Study 0114, . "Analysis of surgical salvage after failure of primary therapy in rectal cancer: results from Intergroup Study 0114." J Clin Oncol 21.19 (October 1, 2003): 3623-3628.
PMID
14512393
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
21
Issue
19
Publish Date
2003
Start Page
3623
End Page
3628
DOI
10.1200/JCO.2003.03.018

Immunological and clinical responses in metastatic renal cancer patients vaccinated with tumor RNA-transfected dendritic cells.

Autologous dendritic cells transfected with total renal tumor RNA have been shown to be potent stimulators of CTLs and antitumor immunity in vitro. A Phase I trial was conducted to evaluate this strategy for feasibility, safety, and efficacy to induce tumor-specific T-cell responses in subjects with metastatic renal cell carcinoma. Renal tumor RNA-transfected dendritic cells were administered to 10 evaluable study patients with no evidence of dose-limiting toxicity or vaccine-related adverse effects including autoimmunity. In six of seven evaluable subjects, expansion of tumor-specific T cells was detected after immunization. The vaccine-induced T-cell reactivities were directed against a broad set of renal tumor-associated antigens, including telomerase reverse transcriptase, G250, and oncofetal antigen, but not against self-antigens expressed by normal renal tissues. Although most patients underwent secondary therapies after vaccination, tumor-related mortality of the study subjects was unexpectedly low with only 3 of 10 patients dying from disease after a mean follow-up of 19.8 months. These data provide a scientific rationale for continued clinical investigation of this polyvalent vaccine strategy in the treatment of metastatic renal cell carcinoma and, potentially, other cancers.

Authors
Su, Z; Dannull, J; Heiser, A; Yancey, D; Pruitt, S; Madden, J; Coleman, D; Niedzwiecki, D; Gilboa, E; Vieweg, J
MLA Citation
Su, Z, Dannull, J, Heiser, A, Yancey, D, Pruitt, S, Madden, J, Coleman, D, Niedzwiecki, D, Gilboa, E, and Vieweg, J. "Immunological and clinical responses in metastatic renal cancer patients vaccinated with tumor RNA-transfected dendritic cells." Cancer Res 63.9 (May 1, 2003): 2127-2133.
PMID
12727829
Source
pubmed
Published In
Cancer Research
Volume
63
Issue
9
Publish Date
2003
Start Page
2127
End Page
2133

Early T cell reconstitution along with graft and patient characteristics impact on opportunistic infections following unrelated cord blood transplantation in children

Authors
Szabolcs, P; Park, KD; Marti, L; Reese, M; Sanders, L; Niedzwiecki, D; Kurtzberg, J
MLA Citation
Szabolcs, P, Park, KD, Marti, L, Reese, M, Sanders, L, Niedzwiecki, D, and Kurtzberg, J. "Early T cell reconstitution along with graft and patient characteristics impact on opportunistic infections following unrelated cord blood transplantation in children." April 14, 2003.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
17
Issue
7
Publish Date
2003
Start Page
C59
End Page
C59

Characterization of sporadic colon cancer by patterns of genomic instability.

Colorectal cancer (CRC) can progress through two pathways of genomic instability: chromosomal (CIN) and microsatellite instability (MSI). We hypothesized that these two pathways are not always independent and that some tumors therefore show a significant degree of overlap between these two mechanisms. We classified 209 high-risk stage II and stage III sporadic CRCs based on their MSI status, using a National Cancer Institute-recommended panel of microsatellite markers, and also identified MSI-associated mutations of CRC target genes such as TGFbetaRII. Evidence for CIN was gathered by identifying loss of heterozygosity (LOH) events on chromosomal arms 1p, 2p, 3p, 5q, 17p, and 18q, which are regions harboring mismatch-repair and tumor-suppressor genes that are significant in CRC development. Results of all molecular markers tested were correlated with clinicopathological variables of the cohort, including treatment outcome. Of the 209 cases, 65% cancers were microsatellite stable, 21% were MSI-low, and 14% were MSI-high (MSI-H). Overall, 51% of the tumors had at least one LOH event, with most frequent chromosomal losses observed on 18q (72.5%), followed by 5q (22%), 17p (21%), and 3p (14%). Interestingly, we observed a significant degree of overlap between MSI and CIN pathways. Of 107 cancers with LOH events, 7 (6.5%) were also MSI-H, and of 30 cancers that were MSI-H, 7 (23.3%) also had one or more LOH events. We also found that 37.8% of microsatellite-stable cancers had no LOH events identified, thus comprising a subgroup of tumors that were not representative of either of these two pathways of genomic instability. Our data suggest that molecular mechanisms of genomic instability are not necessarily independent and may not be fully defined by either the MSI or CIN pathways.

Authors
Goel, A; Arnold, CN; Niedzwiecki, D; Chang, DK; Ricciardiello, L; Carethers, JM; Dowell, JM; Wasserman, L; Compton, C; Mayer, RJ; Bertagnolli, MM; Boland, CR
MLA Citation
Goel, A, Arnold, CN, Niedzwiecki, D, Chang, DK, Ricciardiello, L, Carethers, JM, Dowell, JM, Wasserman, L, Compton, C, Mayer, RJ, Bertagnolli, MM, and Boland, CR. "Characterization of sporadic colon cancer by patterns of genomic instability." Cancer Res 63.7 (April 1, 2003): 1608-1614.
PMID
12670912
Source
pubmed
Published In
Cancer Research
Volume
63
Issue
7
Publish Date
2003
Start Page
1608
End Page
1614

Immunological and clinical responses in patients with metastatic renal cell carcinoma to vaccination with tumor RNA transfected dendritic cells.

Authors
Zhen, S; Dannull, J; Coleman, D; Higgins, J; Yancey, D; Pruitt, S; Weizer, A; Niedzwiecki, D; Gilboa, E; Vieweg, J
MLA Citation
Zhen, S, Dannull, J, Coleman, D, Higgins, J, Yancey, D, Pruitt, S, Weizer, A, Niedzwiecki, D, Gilboa, E, and Vieweg, J. "Immunological and clinical responses in patients with metastatic renal cell carcinoma to vaccination with tumor RNA transfected dendritic cells." November 16, 2002.
Source
wos-lite
Published In
Blood
Volume
100
Issue
11
Publish Date
2002
Start Page
867A
End Page
867A

Early T cell reconstitution along with graft and patient characteristics impact on opportunistic infections following unrelated cord blood transplantation in children.

Authors
Szabolcs, P; Park, KD; Reese, M; Marti, L; Sanders, L; Niedzwiecki, D; Kurtzberg, J
MLA Citation
Szabolcs, P, Park, KD, Reese, M, Marti, L, Sanders, L, Niedzwiecki, D, and Kurtzberg, J. "Early T cell reconstitution along with graft and patient characteristics impact on opportunistic infections following unrelated cord blood transplantation in children." November 16, 2002.
Source
wos-lite
Published In
Blood
Volume
100
Issue
11
Publish Date
2002
Start Page
841A
End Page
841A

Long-term follow-up of Hodgkin's disease trial.

Authors
Canellos, GP; Niedzwiecki, D
MLA Citation
Canellos, GP, and Niedzwiecki, D. "Long-term follow-up of Hodgkin's disease trial." N Engl J Med 346.18 (May 2, 2002): 1417-1418. (Letter)
PMID
11986425
Source
pubmed
Published In
The New England journal of medicine
Volume
346
Issue
18
Publish Date
2002
Start Page
1417
End Page
1418
DOI
10.1056/NEJM200205023461821

Adjuvant therapy in rectal cancer: analysis of stage, sex, and local control--final report of intergroup 0114.

PURPOSE: The gastrointestinal Intergroup studied postoperative adjuvant chemotherapy and radiation therapy in patients with T3/4 and N+ rectal cancer after potentially curative surgery to try to improve chemotherapy and to determine the risk of systemic and local failure. PATIENTS AND METHODS: All patients had a potentially curative surgical resection and were treated with two cycles of chemotherapy followed by chemoradiation therapy and two additional cycles of chemotherapy. Chemotherapy regimens were bolus fluorouracil (5-FU), 5-FU and leucovorin, 5-FU and levamisole, and 5-FU, leucovorin, and levamisole. Pelvic irradiation was given to a dose of 45 Gy to the whole pelvis and a boost to 50.4 to 54 Gy. RESULTS: One thousand six hundred ninety-five patients were entered and fully assessable, with a median follow-up of 7.4 years. There was no difference in overall survival (OS) or disease-free survival (DFS) by drug regimen. DFS and OS decreased between years 5 and 7 (from 54% to 50% and 64% to 56%, respectively), although recurrence-free rates had only a small decrease. The local recurrence rate was 14% (9% in low-risk [T1 to N2+] and 18% in high-risk patients [T3N+, T4N]). Overall, 7-year survival rates were 70% and 45% for the low-risk and high-risk groups, respectively. Males had a poorer overall survival rate than females. CONCLUSION: There is no advantage to leucovorin- or levamisole-containing regimens over bolus 5-FU alone in the adjuvant treatment of rectal cancer when combined with irradiation. Local and distant recurrence rates are still high, especially in T3N+ and T4 patients, even with full adjuvant chemoradiation therapy.

Authors
Tepper, JE; O'Connell, M; Niedzwiecki, D; Hollis, DR; Benson, AB; Cummings, B; Gunderson, LL; Macdonald, JS; Martenson, JA; Mayer, RJ
MLA Citation
Tepper, JE, O'Connell, M, Niedzwiecki, D, Hollis, DR, Benson, AB, Cummings, B, Gunderson, LL, Macdonald, JS, Martenson, JA, and Mayer, RJ. "Adjuvant therapy in rectal cancer: analysis of stage, sex, and local control--final report of intergroup 0114." J Clin Oncol 20.7 (April 1, 2002): 1744-1750.
PMID
11919230
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
20
Issue
7
Publish Date
2002
Start Page
1744
End Page
1750
DOI
10.1200/JCO.2002.07.132

Transplantation of unrelated umbilical cord blood in adult patients.

Authors
Long, GD; Laughlin, M; Madan, B; Kurtzberg, J; Rubinstein, P; Gasparetto, C; Morris, A; Rizzieri, D; Smith, C; Vredenburgh, J; Halperin, EC; Broadwater, G; Niedzwiecki, D; Chao, NJ
MLA Citation
Long, GD, Laughlin, M, Madan, B, Kurtzberg, J, Rubinstein, P, Gasparetto, C, Morris, A, Rizzieri, D, Smith, C, Vredenburgh, J, Halperin, EC, Broadwater, G, Niedzwiecki, D, and Chao, NJ. "Transplantation of unrelated umbilical cord blood in adult patients." LEUKEMIA 16.3 (March 2002): 411-411.
Source
wos-lite
Published In
Leukemia
Volume
16
Issue
3
Publish Date
2002
Start Page
411
End Page
411

Autologous dendritic cells transfected with prostate-specific antigen RNA stimulate CTL responses against metastatic prostate tumors.

Autologous dendritic cells (DCs) transfected with mRNA encoding prostate-specific antigen (PSA) are able to stimulate potent, T cell-mediated antitumor immune responses in vitro. A phase I trial was performed to evaluate this strategy for safety, feasibility, and efficacy to induce T cell responses against the self-protein PSA in patients with metastatic prostate cancer. In 13 study subjects, escalating doses of PSA mRNA-transfected DCs were administered with no evidence of dose-limiting toxicity or adverse effects, including autoimmunity. Induction of PSA-specific T cell responses was consistently detected in all patients, suggesting in vivo bioactivity of the vaccine. Vaccination was further associated with a significant decrease in the log slope PSA in six of seven subjects; three patients that could be analyzed exhibited a transient molecular clearance of circulating tumor cells. The demonstration of vaccine safety, successful in vivo induction of PSA-specific immunity, and impact on surrogate clinical endpoints provides a scientific rationale for further clinical investigation of RNA-transfected DCs in the treatment of human cancer.

Authors
Heiser, A; Coleman, D; Dannull, J; Yancey, D; Maurice, MA; Lallas, CD; Dahm, P; Niedzwiecki, D; Gilboa, E; Vieweg, J
MLA Citation
Heiser, A, Coleman, D, Dannull, J, Yancey, D, Maurice, MA, Lallas, CD, Dahm, P, Niedzwiecki, D, Gilboa, E, and Vieweg, J. "Autologous dendritic cells transfected with prostate-specific antigen RNA stimulate CTL responses against metastatic prostate tumors." J Clin Invest 109.3 (February 2002): 409-417.
PMID
11828001
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
109
Issue
3
Publish Date
2002
Start Page
409
End Page
417
DOI
10.1172/JCI14364

Radiolabeled anti-tenascin antibody for refractory non-Hodgkins lymphoma (NHL).

Authors
Rizzieri, DA; Akabani, G; Coleman, RE; Zalutsky, MR; Niedzwiecki, D; Payne, N; Wikstrand, C; Bigner, DD
MLA Citation
Rizzieri, DA, Akabani, G, Coleman, RE, Zalutsky, MR, Niedzwiecki, D, Payne, N, Wikstrand, C, and Bigner, DD. "Radiolabeled anti-tenascin antibody for refractory non-Hodgkins lymphoma (NHL)." BLOOD 98.11 (November 16, 2001): 247B-247B.
Source
wos-lite
Published In
Blood
Volume
98
Issue
11
Publish Date
2001
Start Page
247B
End Page
247B

Durable engraftment of mismatched unrelated cord blood following a non-myeloablative preparative regimen for adults.

Authors
Rizzieri, DA; Long, GD; Vredenburgh, JJ; Gasparetto, C; Morris, A; Niedzwiecki, D; Lassiter, M; Loftis, J; Davis, P; McDonald, C; Stenzel, T; Waters-Pick, B; Kurtzberg, J; Chao, NJ
MLA Citation
Rizzieri, DA, Long, GD, Vredenburgh, JJ, Gasparetto, C, Morris, A, Niedzwiecki, D, Lassiter, M, Loftis, J, Davis, P, McDonald, C, Stenzel, T, Waters-Pick, B, Kurtzberg, J, and Chao, NJ. "Durable engraftment of mismatched unrelated cord blood following a non-myeloablative preparative regimen for adults." BLOOD 98.11 (November 16, 2001): 185A-185A.
Source
wos-lite
Published In
Blood
Volume
98
Issue
11
Publish Date
2001
Start Page
185A
End Page
185A

Non-myeloablative allogeneic transplantation using T depleted matched sibling peripheral blood stem cells.

Authors
Rizzieri, DA; Long, GD; Vredenburgh, JJ; Gasparetto, C; Morris, A; Lassiter, M; Loftis, J; Davis, P; McDonald, C; Stenzel, T; Niedzwiecki, D; Chao, NJ
MLA Citation
Rizzieri, DA, Long, GD, Vredenburgh, JJ, Gasparetto, C, Morris, A, Lassiter, M, Loftis, J, Davis, P, McDonald, C, Stenzel, T, Niedzwiecki, D, and Chao, NJ. "Non-myeloablative allogeneic transplantation using T depleted matched sibling peripheral blood stem cells." BLOOD 98.11 (November 16, 2001): 420A-421A.
Source
wos-lite
Published In
Blood
Volume
98
Issue
11
Publish Date
2001
Start Page
420A
End Page
421A

Dose dense, high intensity therapy for mantle cell lymphoma.

Authors
Rizzieri, DA; Gockerman, JP; Moore, JO; DeCastro, C; Long, GD; Vredenburgh, JJ; Niedzwiecki, D; Edwards, J; Prosnitz, L; Gasparetto, C; Morris, A; Lassiter, M; Davis, P; Chao, NJ
MLA Citation
Rizzieri, DA, Gockerman, JP, Moore, JO, DeCastro, C, Long, GD, Vredenburgh, JJ, Niedzwiecki, D, Edwards, J, Prosnitz, L, Gasparetto, C, Morris, A, Lassiter, M, Davis, P, and Chao, NJ. "Dose dense, high intensity therapy for mantle cell lymphoma." BLOOD 98.11 (November 16, 2001): 681A-682A.
Source
wos-lite
Published In
Blood
Volume
98
Issue
11
Publish Date
2001
Start Page
681A
End Page
682A

Low dose, weekly, paclitaxel as salvage therapy for non-Hodgkins lymphoma (NHL).

Authors
Rizzieri, DA; DeCastro, C; Gockerman, JP; Niedzwiecki, D; Vredenburgh, JJ; Gasparetto, C; Long, G; Payne, N; Ibom, V; Chao, NJ; Moore, JO
MLA Citation
Rizzieri, DA, DeCastro, C, Gockerman, JP, Niedzwiecki, D, Vredenburgh, JJ, Gasparetto, C, Long, G, Payne, N, Ibom, V, Chao, NJ, and Moore, JO. "Low dose, weekly, paclitaxel as salvage therapy for non-Hodgkins lymphoma (NHL)." BLOOD 98.11 (November 16, 2001): 246B-246B.
Source
wos-lite
Published In
Blood
Volume
98
Issue
11
Publish Date
2001
Start Page
246B
End Page
246B

Non-myeloablative transplantation using CAMPATH 1H for T depletion of mismatched, related donor peripheral blood stem cells.

Authors
Rizzieri, DA; Long, GD; Vredenburgh, JJ; Gasparetto, C; Morris, A; Lassiter, M; Loftis, J; Davis, P; McDonald, C; Stenzel, T; Niedzwiecki, D; Chao, NJ
MLA Citation
Rizzieri, DA, Long, GD, Vredenburgh, JJ, Gasparetto, C, Morris, A, Lassiter, M, Loftis, J, Davis, P, McDonald, C, Stenzel, T, Niedzwiecki, D, and Chao, NJ. "Non-myeloablative transplantation using CAMPATH 1H for T depletion of mismatched, related donor peripheral blood stem cells." BLOOD 98.11 (November 16, 2001): 669A-669A.
Source
wos-lite
Published In
Blood
Volume
98
Issue
11
Publish Date
2001
Start Page
669A
End Page
669A

Reconstitution of T cell and dendritic cell immunity 50 days post unrelated cord blood transplant predicts the incidence of opportunistic infections and acute GVHD in children.

Authors
Szabolcs, P; Park, KD; Reese, M; Marti, L; Broadwater, G; Niedzwiecki, D; DeOliveira, D; Kurtzberg, J
MLA Citation
Szabolcs, P, Park, KD, Reese, M, Marti, L, Broadwater, G, Niedzwiecki, D, DeOliveira, D, and Kurtzberg, J. "Reconstitution of T cell and dendritic cell immunity 50 days post unrelated cord blood transplant predicts the incidence of opportunistic infections and acute GVHD in children." BLOOD 98.11 (November 16, 2001): 204A-204A.
Source
wos-lite
Published In
Blood
Volume
98
Issue
11
Publish Date
2001
Start Page
204A
End Page
204A

Increased microvessel density in non-Hodgkin's lymphoma (NHL) is localized to the site of disease changes in accordance with disease response.

Authors
Wadleigh, M; Niedzwiecki, D; Davis, P; Payne, N; Sen, F; Mann, KP; Proia, A; Hollis, D; Rizzieri, DA
MLA Citation
Wadleigh, M, Niedzwiecki, D, Davis, P, Payne, N, Sen, F, Mann, KP, Proia, A, Hollis, D, and Rizzieri, DA. "Increased microvessel density in non-Hodgkin's lymphoma (NHL) is localized to the site of disease changes in accordance with disease response." BLOOD 98.11 (November 16, 2001): 236B-236B.
Source
wos-lite
Published In
Blood
Volume
98
Issue
11
Publish Date
2001
Start Page
236B
End Page
236B

High dose cyclophosphamide plus recombinant human granulocyte-colony stimulating factor (rhG-CSF) in the treatment of follicular, low grade non-Hodgkin's lymphoma: CALGB 9150.

The main objectives of this study were to determine the feasibility of administering high doses of cyclophosphamide plus recombinant human granulocyte-colony stimulating factor (rhG-CSF) every 14-21 days to patients with follicular small cleaved cell lymphoma. For each patient, the treatment was not considered feasible if fewer than four cycles of cyclophosphamide chemotherapy could be administered on schedule (i.e. at least every 29 days) or (1) hospitalization of the patient for longer than three days was necessary for neutropenic fever (38 degrees C) or bacteriologically documented infection in > 50% of the cycles, or (2) grade > or = 2 hemorrhage in association with thrombocytopenia of grade > or = 3 severity occurred in > 50% of the cycles or (3) non-hematologic toxicity (excluding nausea/vomiting and alopecia) of grade > or = 3 occurred in > 50% of cycles. The goal was to have a treatment program feasible in 75% or more of the treated patients. The secondary objectives were to determine the toxicities, the complete and partial response rates, and the time to treatment failure (TTF). The trial also attempted to assess the effectiveness of this treatment program in eradicating Bcl-2 rearrangements by PCR, and to assess complete remission duration in relationship to PCR results in patients who respond to this chemotherapy program. Patients were required to have histologically documented non-Hodgkin's lymphoma of the subtypes follicular, predominantly small cleaved cell (IWF-B) or follicular mixed, (IWF-C). Patients were required to have Stage IV disease including histologic evidence of bone marrow involvement. Measurable disease was required and patients were also required to have one of the following risk factors: > or = 2 extranodal sites, node or nodal group > or = 5 cm. Submission of fresh bone marrow for molecular genetic studies for the presence of Bcl-2-Ig fusion DNA was mandatory in previously untreated patients. Patients had to be between 18 and physiologic age 55 years (carefully selected patients over age 55 years were also eligible), expected survival > 2 years, performance status 0-1, and have adequate renal, hepatic and bone marrow function, and a cardiac ejection fraction > or = 50%. Cyclophosphamide 4.5 g/m2 i.v. was given with mesna every 14 days with rhG-CSF support. Twenty-nine patients were accrued to this trial. The median follow-up time is 5.0 years, with a range of 2.5-6.7 years. The overall response rate was 75% (9 CRs 37.5%, 9PRs 37.5%). The median duration of survival is 5.53 years. The 1-year estimated probability of freedom from treatment failure was 50% and of survival at 1 year was 92%. No strong association was observed between TTF and age, symptomatic stage, histology performance status, number of extranodal sites or baseline Bcl-2 status. At 3 years the survival of all patients was 78% and failure free survival was 17%. 15 (62%) of the 24 eligible previously untreated patients met the criteria for feasibility specified in the protocol. The 95% CI for the feasibility rate is (44 and 82%). Twenty-two of the 24 (92%) previously untreated patients had specimens submitted for testing for Bcl-2 rearrangements. Thirteen of the 22 (59%) were found to have rearrangements at baseline. Post-treatment specimens were submitted for seven of the 13 patients. Four of the seven converted to Bcl-2 negative following treatment. Eight of 13 Bcl-2 positive patients (62%) had a clinical response to treatment. The 95% exact binomial CI for the total response rate in this subgroup is (28 and 88%). This study demonstrates that repetitive doses of cyclophosphamide at 4.5 g/m2 every two weeks with rhG-CSF support can be administered to selected younger patients with advanced follicular lymphoma with morphologic involvement of the bone marrow with acceptable non-hematologic toxicity.

Authors
Lichtman, SM; Petroni, G; Schilsky, RL; Johnson, JL; Perri, RT; Niedzwiecki, D; Sklar, J; Barcos, M; Peterson, BA
MLA Citation
Lichtman, SM, Petroni, G, Schilsky, RL, Johnson, JL, Perri, RT, Niedzwiecki, D, Sklar, J, Barcos, M, and Peterson, BA. "High dose cyclophosphamide plus recombinant human granulocyte-colony stimulating factor (rhG-CSF) in the treatment of follicular, low grade non-Hodgkin's lymphoma: CALGB 9150." Leuk Lymphoma 42.6 (November 2001): 1255-1264.
PMID
11911406
Source
pubmed
Published In
Leukemia & Lymphoma (Informa)
Volume
42
Issue
6
Publish Date
2001
Start Page
1255
End Page
1264
DOI
10.3109/10428190109097750

Nicotinamide adenine dinucleotide (NAD) and its metabolites inhibit T lymphocyte proliferation: role of cell surface NAD glycohydrolase and pyrophosphatase activities.

The presence of NAD-metabolizing enzymes (e.g., ADP-ribosyltransferase (ART)2) on the surface of immune cells suggests a potential immunomodulatory activity for ecto-NAD or its metabolites at sites of inflammation and cell lysis where extracellular levels of NAD may be high. In vitro, NAD inhibits mitogen-stimulated rat T cell proliferation. To investigate the mechanism of inhibition, the effects of NAD and its metabolites on T cell proliferation were studied using ART2a+ and ART2b+ rat T cells. NAD and ADP-ribose, but not nicotinamide, inhibited proliferation of mitogen-activated T cells independent of ART2 allele-specific expression. Inhibition by P2 purinergic receptor agonists was comparable to that induced by NAD and ADP-ribose; these compounds were more potent than P1 agonists. Analysis of the NAD-metabolizing activity of intact rat T cells demonstrated that ADP-ribose was the predominant metabolite, consistent with the presence of cell surface NAD glycohydrolase (NADase) activities. Treatment of T cells with phosphatidylinositol-specific phospholipase C removed much of the NADase activity, consistent with at least one NADase having a GPI anchor; ART2- T cell subsets contained NADase activity that was not releasable by phosphatidylinositol-specific phospholipase C treatment. Formation of AMP from NAD and ADP-ribose also occurred, a result of cell surface pyrophosphatase activity. Because AMP and its metabolite, adenosine, were less inhibitory to rat T cell proliferation than was NAD or ADP-ribose, pyrophosphatases may serve a regulatory role in modifying the inhibitory effect of ecto-NAD on T cell activation. These data suggest that T cells express multiple NAD and adenine nucleotide-metabolizing activities that together modulate immune function.

Authors
Bortell, R; Moss, J; McKenna, RC; Rigby, MR; Niedzwiecki, D; Stevens, LA; Patton, WA; Mordes, JP; Greiner, DL; Rossini, AA
MLA Citation
Bortell, R, Moss, J, McKenna, RC, Rigby, MR, Niedzwiecki, D, Stevens, LA, Patton, WA, Mordes, JP, Greiner, DL, and Rossini, AA. "Nicotinamide adenine dinucleotide (NAD) and its metabolites inhibit T lymphocyte proliferation: role of cell surface NAD glycohydrolase and pyrophosphatase activities." J Immunol 167.4 (August 15, 2001): 2049-2059.
PMID
11489987
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
167
Issue
4
Publish Date
2001
Start Page
2049
End Page
2059

Recommendation for caution with irinotecan, fluorouracil, and leucovorin for colorectal cancer.

Authors
Sargent, DJ; Niedzwiecki, D; O'Connell, MJ; Schilsky, RL
MLA Citation
Sargent, DJ, Niedzwiecki, D, O'Connell, MJ, and Schilsky, RL. "Recommendation for caution with irinotecan, fluorouracil, and leucovorin for colorectal cancer." N Engl J Med 345.2 (July 12, 2001): 144-145. (Letter)
PMID
11450666
Source
pubmed
Published In
The New England journal of medicine
Volume
345
Issue
2
Publish Date
2001
Start Page
144
End Page
145
DOI
10.1056/NEJM200107123450213

Phase II study of oral eniluracil, 5-fluorouracil, and leucovorin in patients with advanced colorectal carcinoma

BACKGROUND. The oral administration of 5-fluorouracil (5-FU) is hindered by erratic bioavailability due to catabolism of 5-FU by the enzyme dihydropyrimidine dehydrogenase (DPD) in the gastrointestinal tract. Eniluracil is a potent inactivator of DPD which results in 100% oral bioavailability of 5-FU. Leucovorin (LV) is another biochemical modulator of 5-FU that potentiates inhibition of thymidylate synthase, the primary target of 5-FU. The goal of this study was to determine the antitumor activity and toxicity of an oral regimen containing eniluracil, 5-FU, and LV in patients with colorectal carcinoma. METHODS. Sixty eligible patients who had previously untreated, measurable, metastatic colorectal carcinoma were treated with oral eniluracil 50 mg on Days 1-7, 5-FU 20 mg/m 2 on Days 2-6, and LV 50 mg on Days 2-6. Cycles were repeated at 28-day intervals. RESULTS. The overall response rate was 13% (95% confidence interval [CI] = 6, 25%), with 1 complete response and 7 partial responses. Three additional patients had partial responses that were not confirmed at subsequent evaluations. The median time to progression of disease was 4.4 months (95% CI = 3.45, 7.69) and the median survival time was 12.6 months (95% CI = 9.1, 14.75). Grade 3-5 toxicity (1 toxic death) occurred in 51 patients (85%). Grade 4 neutropenia occurred in 25 patients (42%), and 18 patients (30%) had Grade 3-4 diarrhea. Twenty-one patients (35%) were hospitalized for toxicity, and 12 (20%) had febrile neutropenia. Baseline creatinine clearance was associated inversely with severe toxicity (P = 0.001). CONCLUSIONS. Although antitumor activity was observed, the frequent occurrence of severe toxicity with this regimen limited its clinical utility. Alternate schedules with a more favorable therapeutic index are undergoing clinical testing and should be pursued. The high level of toxicity observed with orally administered low dose 5-FU underscored the potency of eniluracil as a biochemical modulator. © 2001 American Cancer Society.

Authors
Meropol, NJ; Niedzwiecki, D; Hollis, D; Schilsky, RL; Mayer, RJ
MLA Citation
Meropol, NJ, Niedzwiecki, D, Hollis, D, Schilsky, RL, and Mayer, RJ. "Phase II study of oral eniluracil, 5-fluorouracil, and leucovorin in patients with advanced colorectal carcinoma." Cancer 91.7 (April 1, 2001): 1256-1263.
Source
scopus
Published In
Cancer
Volume
91
Issue
7
Publish Date
2001
Start Page
1256
End Page
1263
DOI
10.1002/1097-0142(20010401)91:7<1256::AID-CNCR1126>3.0.CO;2-V

Phase II study of oral eniluracil, 5-fluorouracil, and leucovorin in patients with advanced colorectal carcinoma.

BACKGROUND: The oral administration of 5-fluorouracil (5-FU) is hindered by erratic bioavailability due to catabolism of 5-FU by the enzyme dihydropyrimidine dehydrogenase (DPD) in the gastrointestinal tract. Eniluracil is a potent inactivator of DPD which results in 100% oral bioavailability of 5-FU. Leucovorin (LV) is another biochemical modulator of 5-FU that potentiates inhibition of thymidylate synthase, the primary target of 5-FU. The goal of this study was to determine the antitumor activity and toxicity of an oral regimen containing eniluracil, 5-FU, and LV in patients with colorectal carcinoma. METHODS: Sixty eligible patients who had previously untreated, measurable, metastatic colorectal carcinoma were treated with oral eniluracil 50 mg on Days 1-7, 5-FU 20 mg/m(2) on Days 2-6, and LV 50 mg on Days 2-6. Cycles were repeated at 28-day intervals. RESULTS: The overall response rate was 13% (95% confidence interval [CI] = 6, 25%), with 1 complete response and 7 partial responses. Three additional patients had partial responses that were not confirmed at subsequent evaluations. The median time to progression of disease was 4.4 months (95% CI = 3.45, 7.69) and the median survival time was 12.6 months (95% CI = 9.1, 14.75). Grade 3-5 toxicity (1 toxic death) occurred in 51 patients (85%). Grade 4 neutropenia occurred in 25 patients (42%), and 18 patients (30%) had Grade 3-4 diarrhea. Twenty-one patients (35%) were hospitalized for toxicity, and 12 (20%) had febrile neutropenia. Baseline creatinine clearance was associated inversely with severe toxicity (P = 0.001). CONCLUSIONS: Although antitumor activity was observed, the frequent occurrence of severe toxicity with this regimen limited its clinical utility. Alternate schedules with a more favorable therapeutic index are undergoing clinical testing and should be pursued. The high level of toxicity observed with orally administered low dose 5-FU underscored the potency of eniluracil as a biochemical modulator.

Authors
Meropol, NJ; Niedzwiecki, D; Hollis, D; Schilsky, RL; Mayer, RJ; Cancer and Leukemia Group B,
MLA Citation
Meropol, NJ, Niedzwiecki, D, Hollis, D, Schilsky, RL, Mayer, RJ, and Cancer and Leukemia Group B, . "Phase II study of oral eniluracil, 5-fluorouracil, and leucovorin in patients with advanced colorectal carcinoma." Cancer 91.7 (April 1, 2001): 1256-1263.
PMID
11283924
Source
pubmed
Published In
Cancer
Volume
91
Issue
7
Publish Date
2001
Start Page
1256
End Page
1263

Microsatellite high (MSI-H) tumors are not associated with LOH at the APC locus compared to microsatellite-low/stable (MSI-L/MSS) tumors

Authors
Arnold, CN; Goel, A; Chang, DK; Wasserman, L; Compton, C; Niedzwiecki, D; Mayer, RJ; Bertagnolli, MM; Boland, CR
MLA Citation
Arnold, CN, Goel, A, Chang, DK, Wasserman, L, Compton, C, Niedzwiecki, D, Mayer, RJ, Bertagnolli, MM, and Boland, CR. "Microsatellite high (MSI-H) tumors are not associated with LOH at the APC locus compared to microsatellite-low/stable (MSI-L/MSS) tumors." GASTROENTEROLOGY 120.5 (April 2001): A296-A296.
Source
wos-lite
Published In
Gastroenterology
Volume
120
Issue
5
Publish Date
2001
Start Page
A296
End Page
A296

A panel of mono- and dinucleotide microsatellite markers is required for reliable determination of the MSI status in colorectal cancer

Authors
Arnold, CN; Goel, A; Carethers, JM; Wasserman, L; Compton, C; Niedzwiecki, D; Mayer, RJ; Bertagnolli, MM; Boland, CR
MLA Citation
Arnold, CN, Goel, A, Carethers, JM, Wasserman, L, Compton, C, Niedzwiecki, D, Mayer, RJ, Bertagnolli, MM, and Boland, CR. "A panel of mono- and dinucleotide microsatellite markers is required for reliable determination of the MSI status in colorectal cancer." GASTROENTEROLOGY 120.5 (April 2001): A599-A599.
Source
wos-lite
Published In
Gastroenterology
Volume
120
Issue
5
Publish Date
2001
Start Page
A599
End Page
A599

Chromosomal vs microsatellite instability in colorectal cancers: Evidence for previously unrecognized pathways

Authors
Goel, A; Arnold, CN; Chang, DK; Ricciardiello, L; Chauhan, DP; Carethers, JM; Wasserman, L; Compton, C; Niedzwiecki, D; Mayer, RJ; Bertagnolli, MM; Boland, CR
MLA Citation
Goel, A, Arnold, CN, Chang, DK, Ricciardiello, L, Chauhan, DP, Carethers, JM, Wasserman, L, Compton, C, Niedzwiecki, D, Mayer, RJ, Bertagnolli, MM, and Boland, CR. "Chromosomal vs microsatellite instability in colorectal cancers: Evidence for previously unrecognized pathways." GASTROENTEROLOGY 120.5 (April 2001): A163-A163.
Source
wos-lite
Published In
Gastroenterology
Volume
120
Issue
5
Publish Date
2001
Start Page
A163
End Page
A163

Somatic frameshift mutations in MBD4 (MED1) are not exclusively associated with microsatellite high (MSI-H) colorectal tumors

Authors
Goel, A; Arnold, CN; Ricciardiello, L; Chang, DK; Wasserman, L; Compton, C; Niedzwiecki, D; Mayer, RJ; Bertagnolli, MM; Boland, R
MLA Citation
Goel, A, Arnold, CN, Ricciardiello, L, Chang, DK, Wasserman, L, Compton, C, Niedzwiecki, D, Mayer, RJ, Bertagnolli, MM, and Boland, R. "Somatic frameshift mutations in MBD4 (MED1) are not exclusively associated with microsatellite high (MSI-H) colorectal tumors." GASTROENTEROLOGY 120.5 (April 2001): A293-A293.
Source
wos-lite
Published In
Gastroenterology
Volume
120
Issue
5
Publish Date
2001
Start Page
A293
End Page
A293

Impact of number of nodes retrieved on outcome in patients with rectal cancer.

PURPOSE: We postulated that the pathologic evaluation of the lymph nodes of surgical specimens from patients with rectal cancer can have a substantial impact on time to relapse and survival. PATIENTS AND METHODS: We analyzed data from 1,664 patients with T3, T4, or node-positive rectal cancer treated in a national intergroup trial of adjuvant therapy with chemotherapy and radiation therapy. Associations between the number of lymph nodes found by the pathologist in the surgical specimen and the time to relapse and survival outcomes were investigated. RESULTS: Patients were divided into groups by nodal status and the corresponding quartiles of numbers of nodes examined. The number of nodes examined was significantly associated with time to relapse and survival among patients who were node-negative. For the first through fourth quartiles, the 5-year relapse rates were 0.37, 0.34, 0.26, and 0.19 (P: = .003), and the 5-year survival rates were 0.68, 0.73, 0.72, and 0.82 (P: = .02). No significant differences were found by quartiles among patients determined to be node-positive. We propose that observed differences are primarily related to the incorrect determination of nodal status in node-negative patients. Approximately 14 nodes need to be studied to define nodal status accurately. CONCLUSION: These results suggest that the pathologic assessment of lymph nodes in surgical specimens is often inaccurate and that examining greater number of nodes increases the likelihood of proper staging. Some patients who might benefit from adjuvant therapy are misclassified as node-negative due to incomplete sampling of lymph nodes.

Authors
Tepper, JE; O'Connell, MJ; Niedzwiecki, D; Hollis, D; Compton, C; Benson, AB; Cummings, B; Gunderson, L; Macdonald, JS; Mayer, RJ
MLA Citation
Tepper, JE, O'Connell, MJ, Niedzwiecki, D, Hollis, D, Compton, C, Benson, AB, Cummings, B, Gunderson, L, Macdonald, JS, and Mayer, RJ. "Impact of number of nodes retrieved on outcome in patients with rectal cancer." J Clin Oncol 19.1 (January 1, 2001): 157-163.
PMID
11134208
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
19
Issue
1
Publish Date
2001
Start Page
157
End Page
163
DOI
10.1200/JCO.2001.19.1.157

Preoperative mobilization of circulating dendritic cells by Flt3 ligand administration to patients with metastatic colon cancer.

PURPOSE: To evaluate preoperative dendritic cell (DC) mobilization and tumor infiltration after administration of Flt3 ligand (Flt3L) to patients with metastatic colon cancer. PATIENTS AND METHODS: Twelve patients with colon cancer metastatic to the liver or lung received Flt3L (20 microg/kg/d subcutaneously for 14 days for one to three cycles at monthly intervals) before attempted metastasectomy. The number and phenotype of DCs mobilized into peripheral-blood mononuclear cells (PBMCs) were evaluated by flow cytometry. After surgical resection, metastatic tumor tissue was evaluated for DC infiltration. In vivo immune responses to recall antigens were measured. RESULTS: After Flt3L administration, on average, the total number of leukocytes in the peripheral blood increased from 5.9 +/- 1.0 x 10(3)/mm(3) to 11.2 +/- 3.8 x 10(3)/mm(3) (mean +/- SD, P: =. 0001). The percentage of CD11c(+)CD14(-) DCs in PBMCs increased from 2.4% +/- 1.8% to 8.8% +/- 4.7% (P: =.004). Delayed-type hypersensitivity (DTH) responses to recall antigens (CANDIDA:, mumps, and tetanus) showed marginally significant increases in reactivity after Flt3L administration (P: =.06, P: =.03, and P: =.08, respectively). An increase in the number of DCs was observed at the periphery of the tumors of patients who received Flt3L compared with those of patients who had not. CONCLUSION: Flt3L is capable of mobilizing DCs into the peripheral blood of patients with metastatic colon cancer and may be associated with increases in DC infiltration in the peritumoral regions. Flt3L mobilization is associated with a trend toward increased DTH responses to recall antigens in vivo. The use of Flt3L to increase circulating DCs for cancer immunotherapy should be considered.

Authors
Morse, MA; Nair, S; Fernandez-Casal, M; Deng, Y; St Peter, M; Williams, R; Hobeika, A; Mosca, P; Clay, T; Cumming, RI; Fisher, E; Clavien, P; Proia, AD; Niedzwiecki, D; Caron, D; Lyerly, HK
MLA Citation
Morse, MA, Nair, S, Fernandez-Casal, M, Deng, Y, St Peter, M, Williams, R, Hobeika, A, Mosca, P, Clay, T, Cumming, RI, Fisher, E, Clavien, P, Proia, AD, Niedzwiecki, D, Caron, D, and Lyerly, HK. "Preoperative mobilization of circulating dendritic cells by Flt3 ligand administration to patients with metastatic colon cancer." J Clin Oncol 18.23 (December 1, 2000): 3883-3893.
PMID
11099317
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
18
Issue
23
Publish Date
2000
Start Page
3883
End Page
3893
DOI
10.1200/JCO.2000.18.23.3883

Predictive value of day+50 immune reconstitution on the incidence of opportunistic infections and acute GVHD following unrelated cord blood transplants in children.

Authors
Szabolcs, P; Park, KD; Reese, M; Niedzwiecki, D; Chao, NJ; Kurtzberg, J
MLA Citation
Szabolcs, P, Park, KD, Reese, M, Niedzwiecki, D, Chao, NJ, and Kurtzberg, J. "Predictive value of day+50 immune reconstitution on the incidence of opportunistic infections and acute GVHD following unrelated cord blood transplants in children." BLOOD 96.11 (November 16, 2000): 789A-789A.
Source
wos-lite
Published In
Blood
Volume
96
Issue
11
Publish Date
2000
Start Page
789A
End Page
789A

Phase II study of infusional chemotherapy with doxorubicin, vincristine and etoposide plus cyclophosphamide and prednisone (I-CHOPE) in resistant diffuse aggressive non-Hodgkin's lymphoma: CALGB 9255. Cancer and Leukemia Group B.

BACKGROUND: Patients with resistant diffuse aggressive non-Hodgkin's lymphoma (DA-NHL) have a poor prognosis. Studies have suggested infusional therapy may be beneficial. PATIENTS AND METHODS: This trial used an infusional regimen called I-CHOPE in resistant patients who had previously received only bolus CHOPE or CHOP regimen. Resistance was defined as: a) primary refractory disease, b) progression on therapy, c) partial response, d) complete remission lasting less than one year. Eligibility criteria included a diagnosis of DA-NHL (IWF E-H), no prior irradiation and adequate organ function. RESULTS: Thirty-seven patients were entered and twenty-nine were eligible. Reasons for ineligibility were incorrect histology (5) and other (3). The median age was 57 years (range 29-81) with 21 males. The performance status scores were: 0 (12 patients); 1 (9 patients); 2 (8 patients). Prior therapy consisted of standard CHOP (26 patients), bolus CHOPE (2 patients), high dose CHOP (1 patient). Therapy consisted of a 120 hour continuous intravenous infusion of doxorubicin 10 mg/m2/day, vincristine 0.28 mg/m2/day (maximum 0.4 mg/day), and etoposide 48 mg/m2/day. Cyclophosphamide 750 mg/m2 was given as an i.v. bolus day 6 and prednisone was given at 100 mg/day p.o. on days 1-5. G-CSF was allowed for myelosuppression. The overall response rate was 48% (CR 17%; PR 31%). Freedom from progression was 24% at six months and 8% at one year. Survival was 69% at six months and 40% at one year. In an exploratory analysis a prior CR or PR predicted response to I-CHOPE. Twelve of sixteen patients who had a CR/PR on previous therapy responded while two of thirteen who had no prior response, responded to I-CHOPE (P = 0.003). The toxicity was tolerable with grade 3-4 hematologic toxicity being leucopenia 94% and thrombocytopenia 41%. The grade 3-4 non-hematologic toxicities were infection in 28%, phlebitis in 11%, and stomatitis in 15%. CONCLUSIONS: I-CHOPE can induce responses in this group of patients with a poor prognosis, but most were seen in those who had previously had a response to bolus chemotherapy.

Authors
Lichtman, SM; Niedzwiecki, D; Barcos, M; Carlisle, TL; Cooper, MR; Johnson, JL; Peterson, BA
MLA Citation
Lichtman, SM, Niedzwiecki, D, Barcos, M, Carlisle, TL, Cooper, MR, Johnson, JL, and Peterson, BA. "Phase II study of infusional chemotherapy with doxorubicin, vincristine and etoposide plus cyclophosphamide and prednisone (I-CHOPE) in resistant diffuse aggressive non-Hodgkin's lymphoma: CALGB 9255. Cancer and Leukemia Group B." Ann Oncol 11.9 (September 2000): 1141-1146.
PMID
11061609
Source
pubmed
Published In
Annals of Oncology
Volume
11
Issue
9
Publish Date
2000
Start Page
1141
End Page
1146

Markers of angiogenesis, factor VIII and tenascin, correlate with disease activity in patients with Non-Hodgkin's Lymphoma.

Authors
Rizzieri, DA; Wikstrand, CJ; Mann, KP; Sen, F; Proia, AD; Niedzwiecki, D; Bigner, DD; Vredenburgh, J
MLA Citation
Rizzieri, DA, Wikstrand, CJ, Mann, KP, Sen, F, Proia, AD, Niedzwiecki, D, Bigner, DD, and Vredenburgh, J. "Markers of angiogenesis, factor VIII and tenascin, correlate with disease activity in patients with Non-Hodgkin's Lymphoma." BLOOD 94.10 (November 15, 1999): 253B-253B.
Source
wos-lite
Published In
Blood
Volume
94
Issue
10
Publish Date
1999
Start Page
253B
End Page
253B

Safety of nifedipine in angina pectoris: a meta-analysis.

-Our objective was to compare cardiovascular event rates in patients with stable angina receiving nifedipine as monotherapy or combination therapy and in active drug controls. A MEDLARS search of published articles from 1966 to 1995 in English, French, German, Italian, or Spanish, supplemented by a manual search of bibliographies, identified 60 randomized controlled trials that met protocol criteria. Blinded articles were extracted by 2 physicians. The pooled risks of death, withdrawal, and cardiovascular event were computed and expressed as odds ratios (ORs) for all nifedipine formulations and relative to same study control drug regimens. Thirty cardiovascular events were reported in 2635 nifedipine exposures (1.14%) and 19 events in 2655 other active drug exposures (0.72%). Unadjusted ORs for nifedipine versus controls were 1.40 (95% CI, 0.56 to 3.49) for major events (death, nonfatal myocardial infarction, stroke, revascularization procedure), 1.75 (95% CI, 0.83 to 3.67) for increased angina, and 1.61 (95% CI, 0.91 to 2.87) for all events (major events plus increased angina). Episodes of increased angina were more frequent on immediate-release nifedipine (OR, 4.19 [95% CI, 1.41 to 12.49]) and on nifedipine monotherapy (OR, 2.61 [95% CI, 1.30 to 5.26]). The OR for immediate-release nifedipine was significantly higher than that for sustained-release/extended-release nifedipine (P=0.001), and the OR for nifedipine monotherapy was higher than that for nifedipine combination therapy (P=0.03). Increased risks of cardiovascular events in patients with stable angina on nifedipine were due primarily to more episodes of increased angina, confined to the immediate-release formulation and to nifedipine monotherapy.

Authors
Stason, WB; Schmid, CH; Niedzwiecki, D; Whiting, GW; Caubet, JF; Cory, D; Luo, D; Ross, SD; Chalmers, TC
MLA Citation
Stason, WB, Schmid, CH, Niedzwiecki, D, Whiting, GW, Caubet, JF, Cory, D, Luo, D, Ross, SD, and Chalmers, TC. "Safety of nifedipine in angina pectoris: a meta-analysis." Hypertension 33.1 (January 1999): 24-31.
PMID
9931077
Source
pubmed
Published In
Hypertension
Volume
33
Issue
1
Publish Date
1999
Start Page
24
End Page
31

Safety of nifedipine in angina pectoris: A meta-analysis

Our objective was to compare cardiovascular event rates in patients with stable angina receiving nifedipine as monotherapy or combination therapy and in active drug controls. A MEDLARS search of published articles from 1966 to 1995 in English, French, German, Italian, or Spanish, supplemented by a manual search of bibliographies, identified 60 randomized controlled trials that met protocol criteria. Blinded articles were extracted by 2 physicians. The pooled risks of death, withdrawal, and cardiovascular event were computed and expressed as odds ratios (ORs) for all nifedipine formulations and relative to same study control drug regimens. Thirty cardiovascular events were reported in 2635 nifedipine exposures (1.14%) and 19 events in 2655 other active drug exposures (0.72%). Unadjusted ORs for nifedipine versus controls were 1.40 (95% CI, 0.56 to 3.49) for major events (death, nonfatal myocardial infarction, stroke, revascularization procedure), 1.75 (95% CI, 0.83 to 3.67) for increased angina, and 1.61 (95% CI, 0.91 to 2.87) for all events (major events plus increased angina). Episodes of increased angina were more frequent on immediate-release nifedipine (OR, 4.19 [95% CI, 1.41 to 12.49]) and on nifedipine monotherapy (OR, 2.61 [95% CI, 1.30 to 5.26]). The OR for immediate-release nifedipine was significantly higher than that for sustained-release/extended-release nifedipine (P=0.001), and the OR for nifedipine monotherapy was higher than that for nifedipine combination therapy (P=0.03). Increased risks of cardiovascular events in patients with stable angina on nifedipine were due primarily to more episodes of increased angina, confined to the immediate-release formulation and to nifedipine monotherapy.

Authors
Stason, WB; Schmid, CH; Niedzwiecki, D; Whiting, GW; Caubet, J-F; Cory, D; Luo, D; Ross, SD; Chalmers, TC
MLA Citation
Stason, WB, Schmid, CH, Niedzwiecki, D, Whiting, GW, Caubet, J-F, Cory, D, Luo, D, Ross, SD, and Chalmers, TC. "Safety of nifedipine in angina pectoris: A meta-analysis." Hypertension 33.1 I (1999): 24-31.
Source
scival
Published In
Hypertension
Volume
33
Issue
1 I
Publish Date
1999
Start Page
24
End Page
31

Erratum: Safety of nifedipine in patients with hypertension: A meta- analysis (Hypertension 30 (7-14))

Authors
Stason, WB; Schmid, CH; Niedzwiecki, D; Whiting, GW; Caubet, J-F; Luo, D; Ross, SD; Chalmers, TC
MLA Citation
Stason, WB, Schmid, CH, Niedzwiecki, D, Whiting, GW, Caubet, J-F, Luo, D, Ross, SD, and Chalmers, TC. "Erratum: Safety of nifedipine in patients with hypertension: A meta- analysis (Hypertension 30 (7-14))." Hypertension 34.3 (1999): 531--.
Source
scival
Published In
Hypertension
Volume
34
Issue
3
Publish Date
1999
Start Page
531-

Insulin-like growth factor-1 is a radial cell-associated neurotrophin that promotes neuronal recruitment from the adult songbird edpendyma/subependyma.

In the adult songbird forebrain, neurons continue to be produced from precursor cells in the forebrain ependymal/subependymal zone (SZ), from which they migrate upon radial guide fibers. The new neurons and their radial cell partners may coderive from a common SZ progenitor, which may be the radial cell itself. On this basis, we asked whether radial cells might provide trophic support for the migration or survival of newly generated neurons. We focused upon the insulin-like growth factors (IGFs) IGF-1 and IGF-2, which have previously been shown to support the survival and differentiation of neural progenitor cells. We found that IGF-1 immunoreactivity was expressed heavily by adult zebra finch radial cells and their fibers, with little expression otherwise. IGF-2, in contrast, was expressed by parenchymal astrocytes and exhibited little radial cell expression. Despite their distinct distributions, IGF-1 and IGF-2 exerted similar trophic effects on finch SZ cells in vitro; both greatly increased the number of neurons migrating from explants of the adult finch SZ, relative to explants raised in low-insulin, IGF-1-deficient media. However, neither factor extended neuronal survival. These results suggest that in neurogenic regions of the adult avian forebrain, IGF-1 acts as a radial cell-associated neuronal differentiation and/or departure factor, which may serve to regulate neuronal recruitment into the adult brain.

Authors
Jiang, J; McMurtry, J; Niedzwiecki, D; Goldman, SA
MLA Citation
Jiang, J, McMurtry, J, Niedzwiecki, D, and Goldman, SA. "Insulin-like growth factor-1 is a radial cell-associated neurotrophin that promotes neuronal recruitment from the adult songbird edpendyma/subependyma." J Neurobiol 36.1 (July 1998): 1-15.
PMID
9658334
Source
pubmed
Published In
Journal of Neurobiology
Volume
36
Issue
1
Publish Date
1998
Start Page
1
End Page
15

Safety of nifedipine in patients with hypertension: a meta-analysis.

Our objective was to compare cardiovascular event rates in patients with mild or moderate hypertension who received nifedipine with active drug controls. We performed a MEDLARS search using the MeSH heading "hypertension" and the text word "nifedipine" to identify all articles that were published between 1966 and August 1995 in English, French, German, Italian, and Spanish languages and that involved human subjects. The computerized search was supplemented by a manual search of article bibliographies. Review of 1880 citations revealed 98 randomized controlled clinical trials that met protocol criteria. Articles were extracted independently by two doctors who were blinded for author, institution, and treatment regimen, using a structured, pretested extraction form. Differences of opinion were resolved by consensus. Fourteen events occurred in 5198 exposures (0.27%) to nifedipine and 24 events in 5402 exposures (0.44%) to other active drug controls. Unadjusted odds ratios for nifedipine versus controls were 0.49 (95% confidence interval [CI], 0.22-1.09) for definitive events (death, nonfatal myocardial infarction or stroke, revascularization procedure) and 0.61 (95% CI, 0.31-1.17) for all events (definitive plus increased angina). The odds ratio for nifedipine monotherapy (sustained- or extended-release in 91% of exposures) was nonsignificantly higher for definitive and all events (odds ratio, 1.40; 95% CI, 0.49-4.03 and odds ratio, 1.39; 95% CI, 0.59-3.32, respectively). The odds ratio for nifedipine in combination with another drug was significantly lower for definitive and all events (odds ratio, 0.09; 95% CI, 0.01-0.66 and odds ratio, 0.15; 95% CI, 0.03-0.65, respectively). Differences in odds ratio for nifedipine monotherapy and combined therapy were statistically significant (P=.02 for definitive events and P=.001 for all events). Results support the safety of sustained- and extended-release nifedipine in the treatment of mild or moderate hypertension when it is used in combination with other drugs.

Authors
Stason, WB; Schmid, CH; Niedzwiecki, D; Whiting, GW; Caubet, JF; Luo, D; Ross, SD; Chalmers, TC
MLA Citation
Stason, WB, Schmid, CH, Niedzwiecki, D, Whiting, GW, Caubet, JF, Luo, D, Ross, SD, and Chalmers, TC. "Safety of nifedipine in patients with hypertension: a meta-analysis." Hypertension 30.1 Pt 1 (July 1997): 7-14.
PMID
9231814
Source
pubmed
Published In
Hypertension
Volume
30
Issue
1 Pt 1
Publish Date
1997
Start Page
7
End Page
14

Safety of nifedipine in patients with hypertension: A meta-analysis

Our objective was to compare cardiovascular event rates in patients with mild or moderate hypertension who received nifedipine with active drug controls. We performed a MEDLARS search using the MeSH heading 'hypertension' and the text word 'nifedipine' to identify all articles that were published between 1966 and August 1995 in English, French, German, Italian, and Spanish languages and that involved human subjects. The computerized search was supplemented by a manual search of article bibliographies. Review of 1880 citations revealed 98 randomized controlled clinical trials that met protocol criteria. Articles were extracted independently by two doctors who were blinded for author, institution, and treatment regimen, using a structured, pretested extraction form. Differences of opinion were resolved by consensus. Fourteen events occurred in 5198 exposures (0.27%) to nifedipine and 24 events in 5402 exposures (0.44%) to other active drug controls. Unadjusted odds ratios for nifedipine versus controls were 0.49 (95% confidence interval [CI], 0.22-1.09) for definitive events (death, nonfatal myocardial infarction or stroke, revascularization procedure) and 0.61 (95% CI, 0.311.17) for all events (definitive plus increased angina). The odds ratio for nifedipine monotherapy (sustained- or extended release in 91% of exposures) was nonsignificantly higher for definitive and all events (odds ratio, 1.40; 95% CI, 0.49-4.03 and odds ratio, 1.39; 95% CI, 0.59-3.32, respectively). The odds ratio for nifedipine in combination with another drug was significantly lower for definitive and all events (odds ratio, 0.09; 95% CI, 0.01-0.66 and odds ratio, 0.15; 95% CI, 0.03-0.65, respectively). Differences in odds ratio for nifedipine monotherapy and combined therapy were statistically significant (P=.02 for definitive events and P=.001 for all events). Results support the safety of sustained- and extended-release nifedipine in the treatment of mild or moderate hypertension when it is used in combination with other drugs.

Authors
Stason, WB; Schmid, CH; Niedzwiecki, D; Whiting, GW; Luo, D; Ross, SD; Chalmers, TC
MLA Citation
Stason, WB, Schmid, CH, Niedzwiecki, D, Whiting, GW, Luo, D, Ross, SD, and Chalmers, TC. "Safety of nifedipine in patients with hypertension: A meta-analysis." Hypertension 30.1 (1997): 7-14.
Source
scival
Published In
Hypertension
Volume
30
Issue
1
Publish Date
1997
Start Page
7
End Page
14

Ependymal/subependymal zone cells of postnatal and adult songbird brain generate both neurons and nonneuronal siblings in vitro and in vivo

The songbird forebrain continues to generate neurons in adulthood, from precursor cells located in the ependymal/subependymal zone (SZ) over the mediocaudal neostriatum. Precursor mitosis is followed by migration of neuronal daughter cells into the underlying forebrain, along radial fibers derived from the SZ. To define the ontogeny of both the new neurons and their radial guide cells, we employed retroviral insertion of the lacZ gene into neostriatal SZ precursor cells derived from postnatal and adult songbirds. We found that single SZ cells generate both neurons and substrate glia in vitro, and in an analogous fashion, both neurons and radial cells in vivo. This suggests that newly generated neurons and radial cells of the adult avian brain derive from a common pluripotential progenitor.

Authors
Goldman, SA; Zukhar, A; Barami, K; Mikawa, T; Niedzwiecki, D
MLA Citation
Goldman, SA, Zukhar, A, Barami, K, Mikawa, T, and Niedzwiecki, D. "Ependymal/subependymal zone cells of postnatal and adult songbird brain generate both neurons and nonneuronal siblings in vitro and in vivo." Journal of Neurobiology 30.4 (August 1, 1996): 505-520.
Source
scopus
Published In
Journal of Neurobiology
Volume
30
Issue
4
Publish Date
1996
Start Page
505
End Page
520
DOI
10.1002/(SICI)1097-4695(199608)30:4<505::AID-NEU6>3.0.CO;2-7

Ependymal/subependymal zone cells of postnatal and adult songbird brain generate both neurons and nonneuronal siblings in vitro and in vivo.

The songbird forebrain continues to generate neurons in adulthood, from precursor cells located in the ependymal /subependymal zone (SZ) over the mediocaudal neostriatum. Precursor mitosis is followed by migration of neuronal daughter cells into the underlying forebrain, along radial fibers derived from the SZ. To define the ontogeny of both the new neurons and their radial guide cells, we employed retroviral insertion of the lacZ gene into neostriatal SZ precursor cells derived from postnatal and adult songbirds. We found that single SZ cells generate both neurons and substrate glia in vitro, and in an analogous fashion, both neurons and radial cells in vivo. This suggests that newly generated neurons and radial cells of the adult avian brain derive from a common pluripotential progenitor.

Authors
Goldman, SA; Zukhar, A; Barami, K; Mikawa, T; Niedzwiecki, D
MLA Citation
Goldman, SA, Zukhar, A, Barami, K, Mikawa, T, and Niedzwiecki, D. "Ependymal/subependymal zone cells of postnatal and adult songbird brain generate both neurons and nonneuronal siblings in vitro and in vivo." J Neurobiol 30.4 (August 1996): 505-520.
PMID
8844514
Source
pubmed
Published In
Journal of Neurobiology
Volume
30
Issue
4
Publish Date
1996
Start Page
505
End Page
520
DOI
10.1002/(SICI)1097-4695(199608)30:4<505::AID-NEU6>3.0.CO;2-7

Pain and depression in patients with newly diagnosed pancreas cancer.

PURPOSE: To evaluate the prevalence of pain and depression, their correlation, and their effect on quality of life in patients with recently diagnosed adenocarcinoma of the pancreas (PC). MATERIALS AND METHODS: Cross-sectional pain and psychosocial distress were assessed using validated instruments, including the Memorial Pain Assessment Card (MPAC), Beck Depression Inventory (BDI), Hopelessness Scale (BHS), and Functional Living Index-Cancer (FLIC). Patients were evaluated before their first operation for PC or first treatment with chemotherapy at a large tertiary-care cancer center. RESULTS: One hundred thirty patients with proven PC were studied: 83 before their operation and 47 before their first chemotherapy treatment. At the time of study entrance, 37% of patients had no pain and an additional 34% had pain that was mild or less severe. Only 29% of patients had moderate, strong, or severe pain. Chemotherapy patients reported significantly more intense pain than did preoperative patients (P = .02). Symptoms of depression were assessed using the BDI and BHS scales. A substantial minority of patients (38%) had BDI scores > or = 15, which suggests high levels of depressive symptoms. There was a significant correlation between increasing pain and depressive symptoms among those who experienced pain. Quality of life was assessed using the Weekly Activity Checklist (WAC) and the FLIC. Compared with patients who had no pain or mild pain, patients with moderate or greater pain had significantly impaired functional activity (P = .03) and poorer quality-of-life scores (P = .02) when compared with those with lesser degrees of pain. There were significant correlations between increasing pain and depression and between pain and depressive symptoms and impaired quality of life and function. CONCLUSION: Our results indicate that moderate or severe pain and symptoms of depression are not as prevalent in recently diagnosed PC patients as is generally believed. However, one third have inadequate pain control despite the use of oral analgesics. These patients can be identified by the use of a simple self-report instrument (the MPAC card). Quality of life and function are adversely affected by moderate or greater levels of perceived pain intensity. A simple and rapid assessment is possible and can identify high-risk patients in need of intervention that may improve quality of life.

Authors
Kelsen, DP; Portenoy, RK; Thaler, HT; Niedzwiecki, D; Passik, SD; Tao, Y; Banks, W; Brennan, MF; Foley, KM
MLA Citation
Kelsen, DP, Portenoy, RK, Thaler, HT, Niedzwiecki, D, Passik, SD, Tao, Y, Banks, W, Brennan, MF, and Foley, KM. "Pain and depression in patients with newly diagnosed pancreas cancer." J Clin Oncol 13.3 (March 1995): 748-755.
PMID
7884435
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
13
Issue
3
Publish Date
1995
Start Page
748
End Page
755
DOI
10.1200/JCO.1995.13.3.748

Amplification of HER-2/neu gene in human gastric adenocarcinomas: correlation with primary site.

Adenocarcinomas of the proximal stomach including the gastroesophageal junction are extremely virulent cancers which are increasing rapidly in incidence. Stage-for-stage proximal gastric cancers have a worse prognosis than do tumors of the body or antrum of the stomach. To further explore biological differences based on site, we studied 80 patients with locally advanced primary tumours of the proximal (n = 40) and distal stomach (n = 40) for amplification of the HER-2/neu proto-oncogene. None of 40 patients with proximal lesions had overexpression of HER-2/neu, whereas four of 40 (10%) distal adenocarcinomas had a 16-24-fold gene amplification (P = 0.04). In the adenocarcinomas from two patients, gene rearrangements were found in addition to amplification. HER-2/neu gene product p185 over-expression was found only in the amplified cases. All four patients with distal tumors and amplification had rapid progression of disease (median survival: 4.3 months). While it is unclear why HER-2/neu amplification is seen only in distal tumors, these data further support the hypothesis that biological differences between proximal and distal lesions are present. As is the case for other tumours, HER-2/neu amplification is associated with a poor prognosis for the individual patient.

Authors
Albino, AP; Jaehne, J; Altorki, N; Blundell, M; Urmacher, C; Lauwers, G; Niedzwiecki, D; Kelsen, DP
MLA Citation
Albino, AP, Jaehne, J, Altorki, N, Blundell, M, Urmacher, C, Lauwers, G, Niedzwiecki, D, and Kelsen, DP. "Amplification of HER-2/neu gene in human gastric adenocarcinomas: correlation with primary site." Eur J Surg Oncol 21.1 (February 1995): 56-60.
PMID
7851555
Source
pubmed
Published In
EJSO - European Journal of Surgical Oncology
Volume
21
Issue
1
Publish Date
1995
Start Page
56
End Page
60

Thymic epithelial defects and predisposition to autoimmune disease in BB rats.

We report an association between thymic epithelial defects and predisposition to autoimmunity. Diabetes-prone (DP) BB rats develop spontaneous hyperglycemia and are deficient in T cell subsets expressing the RT6 alloantigen. Diabetes resistant (DR) BB rats become diabetic if depleted of RT6+ T cells. The inciting immune system defects are unknown. We made the following observations: 1) Regions of thymic cortex and medulla devoid of thymic epithelium exist in DP-BB, DR-BB, and Lewis rats, all of which are susceptible to autoimmune disorders. Such defects were absent in eight normal rat strains. 2) Thymic epithelial defects are absent at birth, but present in BB rats at 4 weeks of age. 3) The genetic predisposition to thymic epithelial defects is an autosomal dominant trait. 4) The observation of thymic defects in (DP x WF)F1 rats led to the prediction that such animals, which never develop spontaneous autoimmunity, might be susceptible to its induction. Following depletion of RT6+ T cells we observed diabetes in 91%, and thyroiditis in 43%, of treated F1 animals (n = 23). Pancreatic insulitis was uniformly present. Because thymic epithelium participates in the positive and negative selection of developing thymocytes, we propose that thymic epithelial defects may play an important role in the predisposition of BB rats to autoimmunity.

Authors
Doukas, J; Mordes, JP; Swymer, C; Niedzwiecki, D; Mason, R; Rozing, J; Rossini, AA; Greiner, DL
MLA Citation
Doukas, J, Mordes, JP, Swymer, C, Niedzwiecki, D, Mason, R, Rozing, J, Rossini, AA, and Greiner, DL. "Thymic epithelial defects and predisposition to autoimmune disease in BB rats." Am J Pathol 145.6 (December 1994): 1517-1525.
PMID
7992854
Source
pubmed
Published In
The American journal of pathology
Volume
145
Issue
6
Publish Date
1994
Start Page
1517
End Page
1525

Intraportal injection of monoclonal antibody in nude mice bearing hepatic metastases.

Using a model for hepatic human colorectal carcinoma metastases in athymic mice, we compared the selective [intraportal (ip)] and systemic [intravenous (iv)] injection of radiolabeled monoclonal antibody (mAb) strongly reactive against the cell line. Percent injected dose of radiolabeled antibody per gram (%id/g) of tumor or normal tissues was measured at selected time points (up to 5 days postinjection) within 3 dose levels: 0.1, 1.0, and 2.0 micrograms (micrograms). At each dose level, 3-9 animals were studied in each of 3 groups: animals receiving ip injection (group HT-29-15 ip), those receiving intravenous injection (group HT-29-15 iv), and those receiving isotype-matched control antibody via the intraportal route (group BL-3 ip). Significantly greater (P < 0.005) %id/g in tumor was seen in group HT-29-15 ip at all time points and dose levels compared to those in groups HT-29-15 iv or BL-3 ip. However, immediately after injection of mAb, there was no difference in tumor %id/g between groups HT-29-15 ip and HT-29-15 iv at the highest dose level. There was no increase in %id/g of mAb in normal liver and blood after ip injection compared to iv injection beyond day 1. Therefore ip injection resulted in higher tumor to liver and tumor to blood ratios compared to iv (P < 0.005). We conclude that delivery of mAb to hepatic metastases can be enhanced by selective injection; this has important implications in the design of future clinical trials utilizing radiolabeled mAb in the diagnosis and treatment of hepatic metastases.

Authors
Rivoire, ML; Yoshida, K; Voiglio, EJ; Divgi, CR; Niedzwiecki, D; Chapman, D; Cohen, AM; Sigurdson, ER
MLA Citation
Rivoire, ML, Yoshida, K, Voiglio, EJ, Divgi, CR, Niedzwiecki, D, Chapman, D, Cohen, AM, and Sigurdson, ER. "Intraportal injection of monoclonal antibody in nude mice bearing hepatic metastases." J Surg Oncol 54.2 (October 1993): 71-77.
PMID
8412162
Source
pubmed
Published In
Journal of Surgical Oncology
Volume
54
Issue
2
Publish Date
1993
Start Page
71
End Page
77

Phase I clinical and pharmacology study of topotecan given daily for 5 consecutive days to patients with advanced solid tumors, with attempt at dose intensification using recombinant granulocyte colony-stimulating factor.

BACKGROUND: Topotecan has been shown in previous studies to be a specific inhibitor of topoisomerase I, a nuclear enzyme required for DNA replication and transcription. PURPOSE: Our objectives in this phase I clinical trial were to determine the maximum tolerated dose, dose-limiting toxic effects, and recommended phase II dose of topotecan and to define the pharmacokinetics of topotecan in humans. METHODS: Forty-three patients with advanced, incurable solid tumors were treated. Doses ranged from 0.5 to 2.0 mg/m2 daily for five days [corrected], with treatment cycles repeated initially every 28 days. Following the identification of the standard maximum tolerated dose, further dose escalations were attempted by following topotecan cycles with recombinant granulocyte colony-stimulating factor (rG-CSF). RESULTS: The maximum tolerated dose without rG-CSF for patients without prior cytotoxic therapy was 1.75 mg/m2 daily. The maximum tolerated dose for previously treated patients was 1.50 mg/m2 daily. The dose-limiting toxic effect was myelosuppression, with granulocytopenia being most commonly observed. Use of rG-CSF did not permit topotecan dose intensification, since thrombocytopenia and fatigue rapidly emerged as dose-limiting toxic effects. Plasma half-lives of topotecan (lactone form) were approximately 10 and 100 minutes for distribution and elimination phases, respectively. CONCLUSIONS: The doses of topotecan recommended for use in phase II clinical trials in solid tumors are 1.5 and 1.25 mg/m2 daily in previously untreated and previously treated patients, respectively. Based on observed rates of recovery from myelosuppression, treatment should be possible on a 21-day cycle. Dose intensification was not possible with the use of rG-CSF; however, rG-CSF may be a useful addition to the regimens of those few patients who experience either prolonged granulocytopenia or neutropenic sepsis or those who are not able to receive their second treatment cycle by day 21.

Authors
Saltz, L; Sirott, M; Young, C; Tong, W; Niedzwiecki, D; Tzy-Jyun, Y; Tao, Y; Trochanowski, B; Wright, P; Barbosa, K
MLA Citation
Saltz, L, Sirott, M, Young, C, Tong, W, Niedzwiecki, D, Tzy-Jyun, Y, Tao, Y, Trochanowski, B, Wright, P, and Barbosa, K. "Phase I clinical and pharmacology study of topotecan given daily for 5 consecutive days to patients with advanced solid tumors, with attempt at dose intensification using recombinant granulocyte colony-stimulating factor." J Natl Cancer Inst 85.18 (September 15, 1993): 1499-1507.
PMID
7689654
Source
pubmed
Published In
Journal of the National Cancer Institute
Volume
85
Issue
18
Publish Date
1993
Start Page
1499
End Page
1507

Octreotide as an antineoplastic agent in the treatment of functional and nonfunctional neuroendocrine tumors.

BACKGROUND: Although patients with neuroendocrine tumors typically exhibit an indolent clinical course, the pace of disease accelerates and the prognosis deteriorates once objective progression of disease begins. Thirty-four patients with advanced neuroendocrine tumors were treated with octreotide as antineoplastic therapy. This treatment was begun only after documentation of clear objective progression of disease. METHODS: A Phase II trial was performed at a tertiary comprehensive cancer center. RESULTS: The median survival for this patient population from the start of octreotide therapy has not been reached, with a median follow-up of 29 months (range, 1-47 months). No major objective tumor regressions were seen. Seventeen patients (50%) experienced a computed tomography-documented stabilization of disease that was maintainable for a minimum of 2 months (median, 5 months; range, 0-27 months). Of the 34 patients, 20 patients received octreotide as their first antineoplastic therapy. The median survival for these 20 patients has not been reached, with a median follow-up also of 29 months (range, 12-41 months). CONCLUSIONS: Octreotide may influence the natural history of neuroendocrine tumors. The survival in patients treated with octreotide, as measured from the time of progression of disease, compares favorably with that of historical controls. Proof of a survival advantage for patients treated with octreotide would require a multicenter, randomized trial.

Authors
Saltz, L; Trochanowski, B; Buckley, M; Heffernan, B; Niedzwiecki, D; Tao, Y; Kelsen, D
MLA Citation
Saltz, L, Trochanowski, B, Buckley, M, Heffernan, B, Niedzwiecki, D, Tao, Y, and Kelsen, D. "Octreotide as an antineoplastic agent in the treatment of functional and nonfunctional neuroendocrine tumors." Cancer 72.1 (July 1, 1993): 244-248.
PMID
8389666
Source
pubmed
Published In
Cancer
Volume
72
Issue
1
Publish Date
1993
Start Page
244
End Page
248

Decreased polyglutamylation of methotrexate in acute lymphoblastic leukemia blasts in adults compared to children with this disease.

We compared blast cells from adult and pediatric patients with untreated acute lymphoblastic leukemia (ALL) (as separated groups of T-lineage cell and B-lineage cell ALL) to determine if methotrexate (MTX) polyglutamate formation in adult patients might be a contributing cause to the known difference in clinical outcome, since MTX is a key drug in chemotherapy regimens. Adult B-lineage cell ALL blasts and blasts from the patients with T-lineage cell ALL accumulated lower amounts of total MTX and polyglutamates, especially long-chain MTX polyglutamates (glu3-6) than pediatric B-lineage cell ALL blasts. In view of the importance of polyglutamylation of MTX as a determinant of cytotoxicity of this drug, decreased formation of MTX polyglutamates is likely a contributing cause to the lower cure rate in adult ALL and T-lineage cell ALL as compared to childhood B-lineage cell ALL.

Authors
Göker, E; Lin, JT; Trippett, T; Elisseyeff, Y; Tong, WP; Niedzwiecki, D; Tan, C; Steinherz, P; Schweitzer, BI; Bertino, JR
MLA Citation
Göker, E, Lin, JT, Trippett, T, Elisseyeff, Y, Tong, WP, Niedzwiecki, D, Tan, C, Steinherz, P, Schweitzer, BI, and Bertino, JR. "Decreased polyglutamylation of methotrexate in acute lymphoblastic leukemia blasts in adults compared to children with this disease." Leukemia 7.7 (July 1993): 1000-1004.
PMID
7686600
Source
pubmed
Published In
Leukemia
Volume
7
Issue
7
Publish Date
1993
Start Page
1000
End Page
1004

A pilot study of hepatic artery floxuridine combined with systemic 5-fluorouracil and leucovorin. A potential adjuvant program after resection of colorectal hepatic metastases.

BACKGROUND: Most patients with colorectal carcinoma metastatic to the liver have relapses after surgical resection of hepatic metastases with failures divided equally between hepatic and extrahepatic sites. A pilot study was begun using a regimen combining intrahepatic floxuridine (FUDR) and systemic 5-fluorouracil (5-FU) and leucovorin (LV) to determine its safety and efficacy. METHODS: Because this was a pilot study, 21 patients with unresectable hepatic metastases from colorectal carcinoma were treated to assess the regimen's toxicity. Eight patients had liver metastases that were resected completely; then they received treatment. FUDR was given by hepatic arterial pump through a 14-day continuous infusion at 0.25 mg/kg/day. Systemic therapy consisted of LV 200 mg/m2 and 5-FU 280 mg/m2 using a bolus dose of 5-FU for 5 days with escalation of the 5-FU dose in separate patient cohorts. The maximally tolerated 5-FU dose was 325 mg/m2. RESULTS: The median survival in the 21 unresectable patients was 16 months with a partial response rate of 56% (10 of 18 evaluable patients; 95% confidence interval, 38-79%). The major systemic toxicity was diarrhea, Grade 3 or 4, in 54% of patients being treated in the 4-week regimen and 19%, in the 5-week regimen. The level of hepatic toxicity was similar to that in previous studies using intrahepatic chemotherapy alone, i.e., 48% of patients had a 200% increase in alkaline phosphatase levels and 10% had bilirubin elevations of more than 3.0 mg/dl (one patient had documented biliary sclerosis). All eight patients treated with adjuvant therapy were alive without disease after a median follow-up of 23 months. CONCLUSIONS: Systemic 5-FU and LV can be combined safely with intraarterial FUDR without loss of efficacy or increased biliary toxicity. Eight patients treated with this regimen as adjuvant therapy after liver metastasis resection were alive and disease-free after a median follow-up of 23 months.

Authors
Kemeny, N; Conti, JA; Sigurdson, E; Cohen, A; Seiter, K; Lincer, R; Niedzwiecki, D; Botet, J; Chapman, D; Costa, P
MLA Citation
Kemeny, N, Conti, JA, Sigurdson, E, Cohen, A, Seiter, K, Lincer, R, Niedzwiecki, D, Botet, J, Chapman, D, and Costa, P. "A pilot study of hepatic artery floxuridine combined with systemic 5-fluorouracil and leucovorin. A potential adjuvant program after resection of colorectal hepatic metastases." Cancer 71.6 (March 15, 1993): 1964-1971.
PMID
8443746
Source
pubmed
Published In
Cancer
Volume
71
Issue
6
Publish Date
1993
Start Page
1964
End Page
1971

Phase II trial of postoperative adjuvant intraperitoneal cisplatin and fluorouracil and systemic fluorouracil chemotherapy in patients with resected gastric cancer.

PURPOSE: This study was performed to assess the short- and long-term toxicities and the impact on relapse pattern and survival of postoperative intraperitoneal (IP) cisplatin and fluorouracil (FU) plus systemic intravenous (IV) FU as adjuvant therapy for gastric cancer patients who are at high risk for recurrence after potentially curative resection (T2N1-2M0 or T3-4N(any)M0). PATIENTS AND METHODS: Starting 14 to 28 days after potentially curative resection of primary gastric cancers, 35 patients were given IP cisplatin 25 mg/m2 and FU 750 mg daily for 4 days; FU 750 mg/m2 was concurrently given as a continuous 24-hour i.v. infusion. Five cycles of therapy delivered at 1-month intervals were used. RESULTS: After a median follow-up of 24 months, 51% of patients remain alive and free of disease. Sixteen patients have recurred; 13 of 16 had an intraabdominal component, whereas three had extraabdominal failure only. Two major treatment-related toxicities were noted: neutropenia and a late toxicity of peritoneal fibrosis (sclerosing encapsulating peritonitis [SEP]). There was one postoperative death. Eleven patients underwent second laparotomy: five patients had SEP, two patients had bowel obstruction from adhesions unrelated to SEP, and four patients had recurrent cancer. Potential causes of SEP included an alkaline pH of infused FU and cisplatin that possibly led to activation of cisplatin before infusion. CONCLUSION: IP cisplatin and FU and concurrent systemic FU is a tolerable adjuvant therapy in the postoperative setting for patients with resected gastric cancer. The recommended dosage schedule with this technique is cisplatin 25 mg/m2 and FU 750 mg total dose IP with FU 500 mg/m2 as a continuous 24-hour infusion daily for days 1 to 4. SEP as a late toxicity, which was observed in 15% of patients, is treatable by surgical lysis of adhesions.

Authors
Atiq, OT; Kelsen, DP; Shiu, MH; Saltz, L; Tong, W; Niedzwiecki, D; Trochanowski, B; Lin, S; Toomasi, F; Brennan, M
MLA Citation
Atiq, OT, Kelsen, DP, Shiu, MH, Saltz, L, Tong, W, Niedzwiecki, D, Trochanowski, B, Lin, S, Toomasi, F, and Brennan, M. "Phase II trial of postoperative adjuvant intraperitoneal cisplatin and fluorouracil and systemic fluorouracil chemotherapy in patients with resected gastric cancer." J Clin Oncol 11.3 (March 1993): 425-433.
PMID
8445416
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
11
Issue
3
Publish Date
1993
Start Page
425
End Page
433
DOI
10.1200/JCO.1993.11.3.425

Randomized trial of hepatic arterial floxuridine, mitomycin, and carmustine versus floxuridine alone in previously treated patients with liver metastases from colorectal cancer.

PURPOSE: This study was designed to determine if hepatic arterial therapy with floxuridine (F), mitomycin, and carmustine (BCNU) (FMB) is superior to hepatic arterial therapy with F alone in previously treated patients with hepatic metastases from colorectal cancer. PATIENTS AND METHODS: Ninety-five patients were randomized to intrahepatic FMB versus intrahepatic F. All patients had tumor progression after systemic chemotherapy (either therapeutic or adjuvant). RESULTS: There was no significant difference in response rate (47% FMB v 33% F; P = .17). Median survival was similar in the two groups, 19.1 months for the FMB group compared with 14.0 months for the F group (P = .23). The overall median survival was 16.8 months. In patients who received prior adjuvant therapy, there was no difference between the two groups, but response rate was high in both (50% FMB v 62% F). The response rate for all patients who had received only prior adjuvant therapy versus all those who had received prior therapy for metastatic disease was 57% and 35%, respectively (P = .066). In the subset of patients whose disease had progressed with prior systemic chemotherapy, the response rate to FMB was greater than that to F (47% v 23%; P = .035). CONCLUSION: The overall partial response rate of 39% and the overall survival of 16.8 months from initiation of intrahepatitis therapy show that hepatic arterial therapy is a reasonable treatment option for patients whose tumor does not respond to systemic therapy or whose disease progresses after adjuvant therapy for colorectal cancer.

Authors
Kemeny, N; Cohen, A; Seiter, K; Conti, JA; Sigurdson, ER; Tao, Y; Niedzwiecki, D; Botet, J; Budd, A
MLA Citation
Kemeny, N, Cohen, A, Seiter, K, Conti, JA, Sigurdson, ER, Tao, Y, Niedzwiecki, D, Botet, J, and Budd, A. "Randomized trial of hepatic arterial floxuridine, mitomycin, and carmustine versus floxuridine alone in previously treated patients with liver metastases from colorectal cancer." J Clin Oncol 11.2 (February 1993): 330-335.
PMID
8426211
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
11
Issue
2
Publish Date
1993
Start Page
330
End Page
335
DOI
10.1200/JCO.1993.11.2.330

Octreotide as an antineoplastic agent in the treatment of functional and nonfunctional neuroendocrine tumors

Background. Although patients with neuroendocrine tumors typically exhibit an indolent clinical course, the pace of disease accelerates and the prognosis deteriorates once objective progression of disease begins. Thirty‐four patients with advanced neuroendocrine tumors were treated with octreotide as antineoplastic therapy. This treatment was begun only after documentation of clear objective progression of disease. Methods. A Phase II trial was performed at a tertiary comprehensive cancer center. Results. The median survival for this patient population from the start of octreotide therapy has not been reached, with a median follow‐up of 29 months (range, 1–47 months). No major objective tumor regressions were seen. Seventeen patients (50%) experienced a computed tomography‐documented stabilization of disease that was maintainable for a minimum of 2 months (median, 5 months; range, 0–27 months). Of the 34 patients, 20 patients received octreotide as their first antineoplastic therapy. The median survival for these 20 patients has not been reached, with a median follow‐up also of 29 months (range, 12–41 months). Conclusions. Octreotide may influence the natural history of neuroendocrine tumors. The survival in patients treated with octreotide, as measured from the time of progression of disease, compares favorably with that of historical controls. Proof of a survival advantage for patients treated with octreotide would require a multicenter, randomized trial. Copyright © 1993 American Cancer Society

Authors
Saltz, L; Trochanowski, B; Buckley, M; Heffernan, B; Niedzwiecki, D; Tao, Y; Kelsen, D
MLA Citation
Saltz, L, Trochanowski, B, Buckley, M, Heffernan, B, Niedzwiecki, D, Tao, Y, and Kelsen, D. "Octreotide as an antineoplastic agent in the treatment of functional and nonfunctional neuroendocrine tumors." Cancer 72.1 (January 1, 1993): 244-248.
Source
scopus
Published In
Cancer
Volume
72
Issue
1
Publish Date
1993
Start Page
244
End Page
248
DOI
10.1002/1097-0142(19930701)72:1<244::AID-CNCR2820720143>3.0.CO;2-Q

A pilot study of hepatic artery floxuridine combined with systemic 5‐fluorouracil and leucovorin. A potential adjuvant program after resection of colorectal hepatic metastases

Background. Most patients with colorectal carcinoma metastatic to the liver have relapses after surgical resection of hepatic metastases with failures divided equally between hepatic and extrahepatic sites. A pilot study was begun using a regimen combining intrahepatic floxuridine (FUDR) and systemic 5‐fluorouracil (5‐FU) and leucovorin (LV) to determine its sa fety and efficacy. Methods. Because this was a pilot study, 21 patients with unresectable hepatic metastases from colorectal carcinoma were treated to assess the regimen's toxicity. Eight patients had liver metastases that were resected completely; then they received treatment. FUDR was given by hepatic arterial pump through a 14‐day continuous infusion at 0.25 mg/kg/day. Systemic therapy consisted of LV 200 mg/m 2 and 5‐FU 280 mg/m 2 using a bolus dose of 5‐FU for 5 days with escalation of the 5‐FU dose in separate patient cohorts. The maximally tolerated 5‐FU dose was 325 mg/m 2 . Results. The median survival in the 21 unresectable patients was 16 months with a partial response rate of 56% (10 of 18 evaluable patients; 95% confidence interval, 38–79%). The major systemic toxicity was diarrhea, Grade 3 or 4, in 54% of patients being treated in the 4‐week regimen and 19%, in the 5‐week regimen. The level of hepatic toxicity was similar to that in previous studies using intrahepatic chemotherapy alone, i.e., 48% of patients had a 200% increase in alkaline phosphatase levels and 10% had bilirubin elevations of more than 3.0 mg/dl (one patient had documented biliary sclerosis). All eight patients treated with adjuvant therapy were alive without disease after a median follow‐up of 23 months. Conclusions. Systemic 5‐FU and LV can be combined safely with intraarterial FUDR without loss of efficacy or increased biliary toxicity. Eight patients treated with this regimen as adjuvant therapy after liver metastasis resection were alive and disease‐free after a median follow‐up of 23 months. Copyright © 1993 American Cancer Society

Authors
Kemeny, N; Conti, JA; Sigurdson, E; Cohen, A; Seiter, K; Lincer, R; Niedzwiecki, D; Botet, J; Chapman, D; Costa, P; Budd, A
MLA Citation
Kemeny, N, Conti, JA, Sigurdson, E, Cohen, A, Seiter, K, Lincer, R, Niedzwiecki, D, Botet, J, Chapman, D, Costa, P, and Budd, A. "A pilot study of hepatic artery floxuridine combined with systemic 5‐fluorouracil and leucovorin. A potential adjuvant program after resection of colorectal hepatic metastases." Cancer 71.6 (January 1, 1993): 1964-1971.
Source
scopus
Published In
Cancer
Volume
71
Issue
6
Publish Date
1993
Start Page
1964
End Page
1971
DOI
10.1002/1097-0142(19930315)71:6<1964::AID-CNCR2820710607>3.0.CO;2-T

Histologic predictors of survival in acquired immunodeficiency syndrome-associated Kaposi's sarcoma.

The relationship between 22 histologic variables and survival was investigated in 93 patients with acquired immunodeficiency syndrome (AIDS)-associated Kaposi's sarcoma (KS). All the patients were homosexual men in whom KS was the initial manifestation of AIDS. All patients were followed for at least 12 months or until death. Histologic specimens of the initial KS biopsy were reviewed in a blind manner by two of the authors and were evaluated for the presence of a number of histologic features. In a univariate analysis nodular lesions of KS (upsilon patch or plaque lesions), the absence of hemosiderin, the absence of irregular vascular spaces, and the presence of spindle cell nodules were all significantly associated with increased length of survival. Two variables previously shown to be related to survival (CD4:CD8 cell ratio, initial lesion on lower extremities) were included in a multivariate analysis (Cox model) in addition to the histologic variables. Complete data were available from 85 patients. In the multivariate analysis a higher helper to suppressor T-cell ratio, initial lesion on lower extremities, presence of spindle cell nodules, and nodular histology (upsilon patch or plaque histology) were all significantly associated with increased length of survival. These data suggest that in AIDS-associated KS, as in reticuloendothelial neoplasms, histologic features may be useful in identifying prognostically different subgroups of patients.

Authors
Niedt, GW; Myskowski, PL; Urmacher, C; Niedzwiecki, D; Chapman, D; Krown, SE; Safai, B
MLA Citation
Niedt, GW, Myskowski, PL, Urmacher, C, Niedzwiecki, D, Chapman, D, Krown, SE, and Safai, B. "Histologic predictors of survival in acquired immunodeficiency syndrome-associated Kaposi's sarcoma." Hum Pathol 23.12 (December 1992): 1419-1426.
PMID
1468779
Source
pubmed
Published In
Human Pathology
Volume
23
Issue
12
Publish Date
1992
Start Page
1419
End Page
1426

Intrinsic resistance to methotrexate in human soft tissue sarcoma cell lines.

A human fibrosarcoma cell line, HT-1080, and four new cell lines (HS-16, HS-28, HS-30, and HS-42) were established from untreated patients with mesenchymal chondrosarcoma, peripheral nerve sheath sarcoma, malignant hemangiopericytoma, and mixed mesodermal tumor, respectively, and were used for analysis of mechanisms of intrinsic resistance to methotrexate. All four new cell lines were resistant to methotrexate as determined by inhibition of thymidylate synthase in whole cells and by growth inhibition, as compared with HT-1080, a methotrexate sensitive cell line. Methotrexate uptake, level of dihydrofolate reductase, and inhibition of this enzyme by methotrexate in the four cell lines were comparable to HT-1080 cells. However, levels of long chain polyglutamates (glu3-5) of methotrexate achieved after a 24-h incubation with this drug were much lower in the four new cell lines as compared to the HT-1080 cell line (5- to 20-fold lower). The low levels of methotrexate polyglutamates formed is likely the major cause of intrinsic methotrexate resistance in these new sarcoma cell lines.

Authors
Li, WW; Lin, JT; Schweitzer, BI; Tong, WP; Niedzwiecki, D; Bertino, JR
MLA Citation
Li, WW, Lin, JT, Schweitzer, BI, Tong, WP, Niedzwiecki, D, and Bertino, JR. "Intrinsic resistance to methotrexate in human soft tissue sarcoma cell lines." Cancer Res 52.14 (July 15, 1992): 3908-3913.
PMID
1377601
Source
pubmed
Published In
Cancer Research
Volume
52
Issue
14
Publish Date
1992
Start Page
3908
End Page
3913

In vitro neurogenesis by neuronal precursor cells derived from the adult songbird brain.

The vocal control nucleus of the adult songbird forebrain, HVc, exhibits de novo neurogenesis in adulthood, with the production of new neurons from precursor cells located in the overlying ventricular zone (Goldman and Nottebohm, 1983). We previously established that explants derived from neurogenic regions of the adult canary forebrain could be maintained in vitro, under conditions that permitted the migration and differentiation of those new neurons previously generated in vivo (Goldman, 1990). However, we found no evidence for continued neuronal mitogenesis in these cultures, which were raised in high concentrations of serum. In the present study, we investigated the permissive conditions for in vitro neurogenesis by these adult forebrain-derived ventricular zone explants. When HVc explants derived from adult zebra finches were maintained in low-serum medium, in vitro neurogenesis could be demonstrated by 3H-thymidine uptake as long as 5 days after explantation. Immunocytochemistry for microtubule-associated protein-2 followed by autoradiography confirmed the neuronal identity of these 3H-thymidine-incorporating cells. In vitro neuronal production occurred in an inverse relation to the serum concentration: Over the range of 2.5-25% fetal bovine serum, neuronal 3H-thymidine labeling was most frequent in those cultures exposed to the lowest serum levels. This facilitation of in vitro neuronal mitogenesis by serum depletion suggests that fetal serum may contain factors that inhibit the division of adult-derived neuronal precursor cells, either directly or by agents released by serum-stimulated glial or ependymal cells.

Authors
Goldman, SA; Zaremba, A; Niedzwiecki, D
MLA Citation
Goldman, SA, Zaremba, A, and Niedzwiecki, D. "In vitro neurogenesis by neuronal precursor cells derived from the adult songbird brain." J Neurosci 12.7 (July 1992): 2532-2541.
PMID
1613545
Source
pubmed
Published In
The Journal of neuroscience : the official journal of the Society for Neuroscience
Volume
12
Issue
7
Publish Date
1992
Start Page
2532
End Page
2541

Intrapleural cisplatin and mitomycin for malignant mesothelioma following pleurectomy: pharmacokinetic studies.

PURPOSE: Intrapleural cisplatin-based chemotherapy has been used in the treatment of patients with malignant pleural mesothelioma and malignant pleural effusions, but the pharmacokinetics of this form of chemotherapy have not been previously evaluated. We performed pharmacokinetic studies on 12 patients who received both intrapleural cisplatin and mitomycin immediately following pleurectomy/decortication for malignant pleural mesothelioma. PATIENTS AND METHODS: Simultaneous pleural fluid and plasma samples were collected at 15 and 30 minutes, and at 1, 2, 3, 4, and 24 hours after administration of the intrapleural chemotherapy (cisplatin 100 mg/m2 and mitomycin 8 mg/m2), and after cisplatin (total and free) and mitomycin levels were measured. The mean peak levels, the areas under the concentration-time curve (AUC) and the drug half-lives (t1/2s) in plasma and pleural fluid were compared using the paired t test. Differences were considered significant if P less than or equal to .05. RESULTS: Systemic absorption was rapid, with peak plasma levels being reached within 1 hour of administration of the intrapleural chemotherapy. Peak plasma levels measured after intrapleural chemotherapy approximated those reportedly attained during systemic administration of these drugs at similar doses. However, the mean peak cisplatin and mitomycin levels, and their mean AUCs, were significantly higher in the pleural fluid than in the plasma. There was a three- to fivefold advantage (on a logarithmic scale) for pleural to plasma AUCs for both cisplatin and mitomycin. The mean t1/2s for cisplatin and mitomycin were significantly longer in the plasma than in the pleural fluid. CONCLUSIONS: The pharmacokinetics of intrapleural cisplatin-based chemotherapy are analogous to those of intraperitoneal chemotherapy. Our findings show that intrapleural cisplatin-based chemotherapy has a distinct local pharmacologic advantage, but also produces significant and sustained drug plasma levels.

Authors
Rusch, VW; Niedzwiecki, D; Tao, Y; Menendez-Botet, C; Dnistrian, A; Kelsen, D; Saltz, L; Markman, M
MLA Citation
Rusch, VW, Niedzwiecki, D, Tao, Y, Menendez-Botet, C, Dnistrian, A, Kelsen, D, Saltz, L, and Markman, M. "Intrapleural cisplatin and mitomycin for malignant mesothelioma following pleurectomy: pharmacokinetic studies." J Clin Oncol 10.6 (June 1992): 1001-1006.
PMID
1588364
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
10
Issue
6
Publish Date
1992
Start Page
1001
End Page
1006
DOI
10.1200/JCO.1992.10.6.1001

Biochemical modulation of bolus fluorouracil by PALA in patients with advanced colorectal cancer.

PURPOSE: N-(phosphonacetyl)-L-aspartic acid (PALA) is a pyrimidine synthesis inhibitor that modulates fluorouracil (FU) cytotoxicity. Two previous studies of patients with colorectal carcinoma documented complete response (CR) and partial response (PR) rates of 40% and 43% using weekly low-dose PALA followed by a 24-hour FU infusion. We investigated whether comparable results could be obtained with biochemical modulation by low-dose PALA using bolus instead of infusional FU. PATIENTS AND METHODS: Forty-five patients without prior chemotherapy who had advanced colorectal carcinoma were treated with PALA 250 mg/m2 followed 24 hours later by bolus FU at three dose levels, 600, 700, 800 mg/m2, repeated weekly for 6 weeks followed by a 2-week break. RESULTS: The CR and PR rate was 15 of 43 patients or 35% (95% confidence interval [CI], 21% to 49%), with an overall median survival of 18 months. Grade 3 or 4 diarrhea was the major toxicity observed in 24% of patients receiving FU at 700 mg/m2 and in 43% of patients receiving 800 mg/m2. Hematologic toxicity was observed only with an FU dose of 800 mg/m2, and 29% (four of 14) of patients developed grade 4 leukopenia. We also noted the development of ascites in six patients, mild hyperbilirubinemia in 16 patients, and a decreased albumin level in 22 patients; these abnormalities occurred more frequently in responding patients. CONCLUSIONS: The observed response rate, median survival, and toxicity in this study are similar to those obtained with PALA plus infusional FU and with other methods of FU modulation. Larger phase III studies are needed to compare bolus FU/PALA regimens with other PALA and non-PALA-containing combinations. Our future focus will be attenuate this regimen's toxicity while maintaining or improving its response rates and survival.

Authors
Kemeny, N; Conti, JA; Seiter, K; Niedzwiecki, D; Botet, J; Martin, D; Costa, P; Wiseberg, J; McCulloch, W
MLA Citation
Kemeny, N, Conti, JA, Seiter, K, Niedzwiecki, D, Botet, J, Martin, D, Costa, P, Wiseberg, J, and McCulloch, W. "Biochemical modulation of bolus fluorouracil by PALA in patients with advanced colorectal cancer." J Clin Oncol 10.5 (May 1992): 747-752.
PMID
1569447
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
10
Issue
5
Publish Date
1992
Start Page
747
End Page
752
DOI
10.1200/JCO.1992.10.5.747

FAMTX versus etoposide, doxorubicin, and cisplatin: a random assignment trial in gastric cancer.

PURPOSE: The chemotherapy regimens of high-dose methotrexate, high-dose fluorouracil (FU), Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and leucovorin (FAMTX) and etoposide, Adriamycin, and cisplatin (EAP) have both been reported in nonrandom assignment trials to have high overall response rates and substantial complete response rates in patients with gastric cancer, as well as major toxicities of myelosuppression. Here we report a prospective, stratified, random-assignment comparison of the two combinations in previously untreated patients with advanced gastric cancer. PATIENTS AND METHODS: Sixty patients were entered onto the trial, 30 receiving EAP and 30 FAMTX. All patients had measurable or assessable tumor masses. Patient entry was stopped at the point when significant toxicity differences were seen at interim analysis. RESULTS: Response rates were similar between the two arms (FAMTX, 33% [95% confidence interval (CI), 16% to 50%]; EAP, 20% [95% Cl, 6% to 34%]). Three FAMTX and no EAP patients had complete remissions. The median survival for the two arms were similar (EAP, 6.1 months; FAMTX, 7.3 months). At 1 year, 7% of EAP and 17% of FAMTX patients were alive. EAP caused significantly more myelosuppression (leukopenia, P = .002; anemia, P = .03; thrombocytopenia, P = .0001) than did FAMTX. EAP also resulted in significantly longer hospitalizations per study month (8 v 5 days). Four EAP patients died of lethal toxicity, whereas no FAMTX patients died of treatment-related causes (P = .04). CONCLUSIONS: FAMTX is at least as active as EAP and is significantly less toxic. Although both regimens remain investigational, the toxicities of FAMTX are more manageable. Further studies involving FAMTX in both the adjuvant and advanced disease setting are underway.

Authors
Kelsen, D; Atiq, OT; Saltz, L; Niedzwiecki, D; Ginn, D; Chapman, D; Heelan, R; Lightdale, C; Vinciguerra, V; Brennan, M
MLA Citation
Kelsen, D, Atiq, OT, Saltz, L, Niedzwiecki, D, Ginn, D, Chapman, D, Heelan, R, Lightdale, C, Vinciguerra, V, and Brennan, M. "FAMTX versus etoposide, doxorubicin, and cisplatin: a random assignment trial in gastric cancer." J Clin Oncol 10.4 (April 1992): 541-548.
PMID
1548519
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
10
Issue
4
Publish Date
1992
Start Page
541
End Page
548
DOI
10.1200/JCO.1992.10.4.541

Validation of gallium-67-citrate single-photon emission computed tomography in biopsy-confirmed residual Hodgkin's disease in the mediastinum.

In a retrospective study of a series of 30 adult patients during restaging of Hodgkin's disease after therapy, computed tomography (CT) and biopsy results were correlated with 67Ga SPECT in order to determine the value of SPECT imaging in monitoring recurrent mediastinal Hodgkin's disease. SPECT had an overall accuracy of 93% (28/30) and correctly identified active disease in 24 of 25, 96% of histopathologically proven recurrent Hodgkin's disease. Thus in this post-therapy setting, we have confirmed the high sensitivity of 67GA SPECT scans in patients selected for biopsy. Gallium-67 may prove particularly useful in detecting residual disease activity in patients in whom biopsy was positive but the interpretations of the CT scans were uncertain in regard to presence of tumors [8/30 (27%)]. In this group of patients, we found SPECT particularly helpful. A larger prospective series is under way to assess this possibility.

Authors
Kostakoglu, L; Yeh, SD; Portlock, C; Heelan, R; Yao, TJ; Niedzwiecki, D; Larson, SM
MLA Citation
Kostakoglu, L, Yeh, SD, Portlock, C, Heelan, R, Yao, TJ, Niedzwiecki, D, and Larson, SM. "Validation of gallium-67-citrate single-photon emission computed tomography in biopsy-confirmed residual Hodgkin's disease in the mediastinum." J Nucl Med 33.3 (March 1992): 345-350.
PMID
1740700
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
33
Issue
3
Publish Date
1992
Start Page
345
End Page
350

Treatment of unresectable primary liver cancer with intrahepatic fluorodeoxyuridine and mitomycin C through an implantable pump.

Ten patients with unresectable primary liver cancer, eight of whom had elevated serum alpha-fetoprotein levels, were treated with intrahepatic fluorodeoxyuridine (FUDR) and mitomycin C administered through an implantable pump. Four patients had a partial response, and two had a minor response. The median survival from initiation of treatment was 14.5 months (range, 2 to 32 months), with patients receiving therapy for a median of 11.2 months. In general, the therapy was well tolerated; only one patient had treatment-related biliary sclerosis. In conclusion, the combination of intrahepatic FUDR and mitomycin C was an effective palliative regimen for unresectable primary liver cancer, even in the presence of elevated serum alpha-fetoprotein levels. Further studies are needed to confirm these findings and compare this regimen with other methods of treatment for hepatocellular carcinoma.

Authors
Atiq, OT; Kemeny, N; Niedzwiecki, D; Botet, J
MLA Citation
Atiq, OT, Kemeny, N, Niedzwiecki, D, and Botet, J. "Treatment of unresectable primary liver cancer with intrahepatic fluorodeoxyuridine and mitomycin C through an implantable pump." Cancer 69.4 (February 15, 1992): 920-924.
PMID
1370918
Source
pubmed
Published In
Cancer
Volume
69
Issue
4
Publish Date
1992
Start Page
920
End Page
924

Adjuvant chemotherapy for colorectal hepatic metastases: role of route of administration and timing.

Improved results in the adjuvant and therapeutic treatment of colon cancer has led to renewed interest in the role of adjuvant chemotherapy following liver resection for colorectal hepatic metastases. However, little is known about the most effective method or timing of delivery of adjuvant chemotherapy. Sixty-nine BD-IX rats underwent a right hepatic lobectomy following tumour inoculation via a splenic injection of 10(7) K12/TRb colon cancer cells. The rats were then randomized to receive systemic FUdR (1 mg kg-1 d-1 for 7 d) or regional (hepatic artery or portal vein) FUdR (2 mg kg-1 d-1 for 7 d) immediately or 72 h following tumour injection. On Day 28, a laprotomy was performed, and tumour nodules in the liver were counted. The animals were followed to death, and at autopsy the cause of death from hepatic or extrahepatic metastases was determined. All methods of FUdR infusion were superior to no treatment. Immediate portal vein (PV) FUdR infusion delayed the appearance of hepatic tumour (P = 0.003), changed the cause of death from hepatic to extrahepatic disease (P = 0.019), and prolonged survival (P < 0.05). Infusion of FUdR via the PV 72 h later did not delay the appearance of hepatic tumours nor prolong survival. In contrast, delayed HA FUdR infusion controlled hepatic metastases (P = 0.04) and improved survival (P < 0.05).

Authors
Sutanto-Ward, E; Sigurdson, ER; Tremiterra, S; Lincer, R; Chapman, D; Niedzwiecki, D
MLA Citation
Sutanto-Ward, E, Sigurdson, ER, Tremiterra, S, Lincer, R, Chapman, D, and Niedzwiecki, D. "Adjuvant chemotherapy for colorectal hepatic metastases: role of route of administration and timing." Surg Oncol 1.1 (February 1992): 87-95.
PMID
1341240
Source
pubmed
Published In
Surgical Oncology
Volume
1
Issue
1
Publish Date
1992
Start Page
87
End Page
95

A randomized trial of intrahepatic infusion of fluorodeoxyuridine with dexamethasone versus fluorodeoxyuridine alone in the treatment of metastatic colorectal cancer.

To decrease the toxicity of hepatic arterial fluorodeoxyuridine (FUDR) administered through an Infusaid pump (Shiley Infusaid, Inc., Norwood, MA), 50 patients with liver metastases from colorectal cancer were selected randomly to receive FUDR, 0.3 mg/kg/d, for 14 of 28 days, with or without a total dose of 20 mg of hepatic arterial dexamethasone for 14 of 28 days. Patients were stratified according to the percentage of liver involvement by tumor and the perfusion pattern on macroaggrated albumin perfusion scan (MAA) scan. There was a trend toward decreased frequency of bilirubin levels in the group receiving dexamethasone plus FUDR versus the group receiving FUDR alone (9% and 30%, respectively, had a 200% or greater increase from baseline; P = 0.07). Patients in the group treated with dexamethasone and FUDR received higher doses of FUDR in the second, third, fifth, and sixth months than those receiving FUDR alone; however, this was statistically significant only in the fifth month (percentages of planned dose received: 42% and 19%, respectively; P = 0.05), and there was no overall difference for the total 6-month period. The complete and partial response rates were increased in patients receiving dexamethasone and FUDR versus FUDR alone (8% and 63% versus 4% and 36%, respectively; P = 0.03), and there was a trend toward increased survival with the addition of dexamethasone (median, 23 months and 15 months, respectively; P = 0.06). In conclusion, the use of hepatic arterial dexamethasone is associated with an increased response rate and a trend toward increased survival and decreased bilirubin levels. Therefore, the authors recommend additional investigation of the use of dexamethasone with chemotherapy to treat hepatic metastases.

Authors
Kemeny, N; Seiter, K; Niedzwiecki, D; Chapman, D; Sigurdson, E; Cohen, A; Botet, J; Oderman, P; Murray, P
MLA Citation
Kemeny, N, Seiter, K, Niedzwiecki, D, Chapman, D, Sigurdson, E, Cohen, A, Botet, J, Oderman, P, and Murray, P. "A randomized trial of intrahepatic infusion of fluorodeoxyuridine with dexamethasone versus fluorodeoxyuridine alone in the treatment of metastatic colorectal cancer." Cancer 69.2 (January 15, 1992): 327-334.
PMID
1303612
Source
pubmed
Published In
Cancer
Volume
69
Issue
2
Publish Date
1992
Start Page
327
End Page
334

Treatment of unresectable primary liver cancer with intrahepatic fluorodeoxyuridine and mitomycin C through an implantable pump

Ten patients with unresectable primary liver cancer, eight of whom had elevated serum alpha‐fetoprotein levels, were treated with intrahepatic fluorodeoxyuridine (FUDR) and mitomycin C administered through an implantable pump. Four patients had a partial response, and two had a minor response. The median survival from initiation of treatment was 14.5 months (range, 2 to 32 months), with patients receiving therapy for a median of 11.2 months. In general, the therapy was well tolerated; only one patient had treatment‐related biliary sclerosis. In conclusion, the combination of intrahepatic FUDR and mitomycin C was an effective palliative regimen for unresectable primary liver cancer, even in the presence of elevated serum alpha‐fetoprotein levels. Further studies are needed to confirm these findings and compare this regimen with other methods of treatment for hepatocellular carcinoma. Cancer 1992; 69:920–924. Copyright © 1992 American Cancer Society

Authors
Atiq, OT; Kemeny, N; Niedzwiecki, D; Botet, J
MLA Citation
Atiq, OT, Kemeny, N, Niedzwiecki, D, and Botet, J. "Treatment of unresectable primary liver cancer with intrahepatic fluorodeoxyuridine and mitomycin C through an implantable pump." Cancer 69.4 (January 1, 1992): 920-924.
Source
scopus
Published In
Cancer
Volume
69
Issue
4
Publish Date
1992
Start Page
920
End Page
924
DOI
10.1002/1097-0142(19920215)69:4<920::AID-CNCR2820690414>3.0.CO;2-Y

A randomized trial of intrahepatic infusion of fluorodeoxyuridine with dexamethasone versus fluorodeoxyuridine alone in the treatment of metastatic colorectal cancer

To decrease the toxicity of hepatic arterial fluorodeoxyuridine (FUDR) administered through an Infusaid pump (Shiley Infusaid, Inc., Norwood, MA), 50 patients with liver metastases from colorectal cancer were selected randomly to receive FUDR, 0.3 mg/kg/d, for 14 of 28 days, with or without a total dose of 20 mg of hepatic arterial dexamethasone for 14 of 28 days. Patients were stratified according to the percentage of liver involvement by tumor and the perfusion pattern on macroaggrated albumin perfusion scan (MAA) scan. There was a trend toward decreased frequency of bilirubin levels in the group receiving dexamethasone plus FUDR versus the group receiving FUDR alone (9% and 30%, respectively, had a 200% or greater increase from baseline; P = 0.07). Patients in the group treated with dexamethasone and FUDR received higher doses of FUDR in the second, third, fifth, and sixth months than those receiving FUDR alone; however, this was statistically significant only in the fifth month (percentages of planned dose received: 42% and 19%, respectively; P = 0.05), and there was no overall difference for the total 6‐month period. The complete and partial response rates were increased in patients receiving dexamethasone and FUDR versus FUDR alone (8% and 63% versus 4% and 36%, respectively; P = 0.03), and there was a trend toward increased survival with the addition of dexamethasone (median, 23 months and 15 months, respectively; P = 0.06). In conclusion, the use of hepatic arterial dexamethasone is associated with an increased response rate and a trend toward increased survival and decreased bilirubin levels. Therefore, the authors recommend additional investigation of the use of dexamethasone with chemotherapy to treat hepatic metastases. Copyright © 1992 American Cancer Society

Authors
Kemeny, N; Seiter, K; Niedzwiecki, D; Chapman, D; Sigurdson, E; Cohen, A; Botet, J; Oderman, P; Murray, P
MLA Citation
Kemeny, N, Seiter, K, Niedzwiecki, D, Chapman, D, Sigurdson, E, Cohen, A, Botet, J, Oderman, P, and Murray, P. "A randomized trial of intrahepatic infusion of fluorodeoxyuridine with dexamethasone versus fluorodeoxyuridine alone in the treatment of metastatic colorectal cancer." Cancer 69.2 (January 1, 1992): 327-334.
Source
scopus
Published In
Cancer
Volume
69
Issue
2
Publish Date
1992
Start Page
327
End Page
334
DOI
10.1002/1097-0142(19920115)69:2<327::AID-CNCR2820690209>3.0.CO;2-U

A new syndrome: ascites, hyperbilirubinemia, and hypoalbuminemia after biochemical modulation of fluorouracil with N-phosphonacetyl-L-aspartate (PALA)

OBJECTIVE: To report a new syndrome of ascites, hyperbilirubinemia, and hypoalbuminemia after treatment with N-phosphonacetyl-L-aspartate (PALA) and fluorouracil for metastatic colorectal cancer. DESIGN: Retrospective analysis. SETTING: Regional cancer treatment center. PATIENTS: Forty-four previously untreated patients with metastatic colorectal cancer in a phase I-II trial of PALA-fluorouracil. MEASUREMENTS AND MAIN RESULTS: One or more transient hepatic abnormalities frequently occurred in 15 of the 17 responding patients. Within the first 10 weeks of treatment, 5 patients developed ascites, 12 had a decrease in the serum albumin level, 6 developed bilirubin elevations, and 7 had transaminase elevations, all in the presence of a complete or partial tumor response. Prolongations of the prothrombin time and elevations of serum glucose levels were also seen. CONCLUSIONS: An unusual syndrome of ascites, hyperbilirubinemia, and hypoalbuminemia is associated with a PALA-fluorouracil regimen. These abnormalities, which may be related to decreased hepatic protein synthesis, occurred more often in patients whose tumor was responding to chemotherapy. Clinicians must recognize that in patients undergoing chemotherapy with these agents, ascites and elevated liver function tests may be secondary to drug administration and are not necessarily due to disease progression.

Authors
Kemeny, N; Seiter, K; Martin, D; Urmacher, C; Niedzwiecki, D; Kurtz, RC; Costa, P; Murray, M
MLA Citation
Kemeny, N, Seiter, K, Martin, D, Urmacher, C, Niedzwiecki, D, Kurtz, RC, Costa, P, and Murray, M. "A new syndrome: ascites, hyperbilirubinemia, and hypoalbuminemia after biochemical modulation of fluorouracil with N-phosphonacetyl-L-aspartate (PALA)." Ann Intern Med 115.12 (December 15, 1991): 946-951.
PMID
1824554
Source
pubmed
Published In
Annals of internal medicine
Volume
115
Issue
12
Publish Date
1991
Start Page
946
End Page
951

A phase III comparison trial of streptozotocin, mitomycin, and 5-fluorouracil with cisplatin, cytosine arabinoside, and caffeine in patients with advanced pancreatic carcinoma.

Conventional chemotherapy for unresectable or metastatic adenocarcinoma of the pancreas has had little effect on palliation or survival. Almost all studies of systemic therapy have involved empiric use of a variety of Phase II or conventional agents alone or in combination. On the basis of recent studies using a human tumor pancreatic cancer (PC) xenograft in nude mice, a Phase I clinical trial of cisplatin, high-dose cytosine arabinoside (Ara-C), and caffeine (CAC) was performed in patients with advanced incurable PC. A tolerable dose and schedule of the three agents were developed. Seven of 18 patients with measurable disease in this Phase I trial had partial responses to CAC. A Phase III comparison of CAC versus standard treatment using streptozotocin, mitomycin, and 5-fluorouracil (SMF) was performed. Eighty-two patients with advanced PC were entered into this random assignment trial. The two treatment arms were well balanced for the usual prognostic factors. Although the acute (e.g., nausea and vomiting) toxicities of CAC were greater than those of SMF, both groups of patients tolerated treatment resonably well. Ninety percent of patients were evaluable for response. Two patients (5.5%) on the CAC treatment arm (95% confidence interval [CI], 0% to 15%) and four patients (10.2%) on the SMF treatment arm (95% CI, 1% to 22%) had objective responses (partial response in measurable disease or improvement in evaluable disease). No complete remissions were observed. The 95% confidence limits of response for CAC and SMF overlapped. The median duration of survival for all patients on the SMF treatment arm was 10 months, although it was 5 months on the CAC treatment arm (P = 0.008). In this Phase III comparison, CAC was not superior to conventional therapy with SMF in terms of response and was inferior for survival. Neither regimen is effective treatment for advanced PC.

Authors
Kelsen, D; Hudis, C; Niedzwiecki, D; Dougherty, J; Casper, E; Botet, J; Vinciguerra, V; Rosenbluth, R
MLA Citation
Kelsen, D, Hudis, C, Niedzwiecki, D, Dougherty, J, Casper, E, Botet, J, Vinciguerra, V, and Rosenbluth, R. "A phase III comparison trial of streptozotocin, mitomycin, and 5-fluorouracil with cisplatin, cytosine arabinoside, and caffeine in patients with advanced pancreatic carcinoma." Cancer 68.5 (September 1, 1991): 965-969.
PMID
1833042
Source
pubmed
Published In
Cancer
Volume
68
Issue
5
Publish Date
1991
Start Page
965
End Page
969

Role of folylpolyglutamates in biochemical modulation of fluoropyrimidines by leucovorin.

The growth-inhibitory effect of fluoropyrimidines combined with a short-term exposure to leucovorin and the pattern of polyglutamylation of folates were compared between parental CCRF-CEM cells and a cell line with impaired ability to form polyglutamates (CCRF-CEM/P). The combination of leucovorin with 5-fluorouracil or 5-fluorodeoxyuridine increased the growth inhibition of CCRF-CEM cells compared to the fluoropyrimidine alone in the parent cell line but not in CCRF-CEM/P cells. In addition, leucovorin produced a significant increase in the inhibition of intracellular thymidylate synthase activity caused by 5-fluorouracil or 5-fluorodeoxyuridine as compared to these drugs alone in CCRF-CEM cells, but no increase in inhibition over that produced by the single drugs alone was observed in CCRF-CEM/P cells. Although levels of 5,10-methylene tetrahydrofolate after leucovorin administration were similar in both cell lines, polyglutamylation of this coenzyme was decreased in the CCRF-CEM/P cell line. The inability of CCRF-CEM/P cells to form significant levels of polyglutamates of N5,N10-methylenete-trahydrofolate, may be responsible for the lack of enhanced cell kill observed when a short exposure to leucovorin is used with fluoropyrimidines.

Authors
Romanini, A; Lin, JT; Niedzwiecki, D; Bunni, M; Priest, DG; Bertino, JR
MLA Citation
Romanini, A, Lin, JT, Niedzwiecki, D, Bunni, M, Priest, DG, and Bertino, JR. "Role of folylpolyglutamates in biochemical modulation of fluoropyrimidines by leucovorin." Cancer Res 51.3 (February 1, 1991): 789-793.
PMID
1988119
Source
pubmed
Published In
Cancer Research
Volume
51
Issue
3
Publish Date
1991
Start Page
789
End Page
793

A phase III comparison trial of streptozotocin, mitomycin, and 5‐fluorouracil with cisplatin, cytosine arabinoside, and caffeine in patients with advanced pancreatic carcinoma

Conventional chemotherapy for unresectable or metastatic adenocarcinoma of the pancreas has had little effect on palliation or survival. Almost all studies of systemic therapy have involved empiric use of a variety of Phase II or conventional agents alone or in combination. On the basis of recent studies using a human tumor pancreatic cancer (PC) xenograft in nude mice, a Phase I clinical trial of cisplatin, high‐dose cytosine arabinoside (Ara‐C), and caffeine (CAC) was performed in patients with advanced incurable PC. A tolerable dose and schedule of the three agents were developed. Seven of 18 patients with measurable disease in this Phase I trial had partial responses to CAC. A Phase III comparison of CAC versus standard treatment using streptozotocin, mitomycin, and 5‐fluorouracil (SMF) was performed. Eighty‐two patients with advanced PC were entered into this random assignment trial. The two treatment arms were well balanced for the usual prognostic factors. Although the acute (e.g., nausea and vomiting) toxicities of CAC were greater than those of SMF, both groups of patients tolerated treatment reasonably well. Ninety percent of patients were evaluable for response. Two patients (5.5%) on the CAC treatment arm (95% confidence interval [CI], 0% to 15%) and four patients (10.2%) on the SMF treatment arm (95% CI, 1% to 22%) had objective responses (partial response in measurable disease or improvement in evaluable disease). No complete remissions were observed. The 95% confidence limits of response for CAC and SMF overlapped. The median duration of survival for all patients on the SMF treatment arm was 10 months, although it was 5 months on the CAC treatment arm (P = 0.008). In this Phase III comparison, CAC was not superior to conventional therapy with SMF in terms of response and was inferior for survival. Neither regimen is effective treatment for advanced PC. Copyright © 1991 American Cancer Society

Authors
Kelsen, D; Hudis, C; Niedzwiecki, D; Dougherty, J; Casper, E; Botet, J; Vinciguerra, V; Rosenbluth, R
MLA Citation
Kelsen, D, Hudis, C, Niedzwiecki, D, Dougherty, J, Casper, E, Botet, J, Vinciguerra, V, and Rosenbluth, R. "A phase III comparison trial of streptozotocin, mitomycin, and 5‐fluorouracil with cisplatin, cytosine arabinoside, and caffeine in patients with advanced pancreatic carcinoma." Cancer 68.5 (January 1, 1991): 965-969.
Source
scopus
Published In
Cancer
Volume
68
Issue
5
Publish Date
1991
Start Page
965
End Page
969
DOI
10.1002/1097-0142(19910901)68:5<965::AID-CNCR2820680509>3.0.CO;2-2

Basis for natural resistance to methotrexate in human acute non-lymphocytic leukemia.

The basis of intrinsic resistance of blasts from patients with acute non-lymphocytic leukemia (ANLL) to methotrexate was studied. MTX polyglutamate formation was measured in blast cells from 19 patients with ANLL and in 7 pediatric patients with acute lymphocytic leukemia (ALL), after in vitro incubation for 24 h with 3H-methotrexate. There was no significant differences seen in the total amount of MTX plus polyglutamates measured between ANLL and ALL blasts, indicating that transport defects do not account for intrinsic MTX resistance in ANLL. However, there were significant differences between the amounts of long chain MTX polyglutamates found in ANLL cells as compared to ALL cells. Most, but not all, ANLL blasts were unable to form long chain polyglutamates. In as much as the level of MTX polyglutamates found in blast cells after MTX administration allows for retention of this drug, this property may explain, at least in part, the refractoriness of most patients with ANLL to methotrexate.

Authors
Lin, JT; Tong, WP; Trippett, TM; Niedzwiecki, D; Tao, Y; Tan, C; Steinherz, P; Schweitzer, BI; Bertino, JR
MLA Citation
Lin, JT, Tong, WP, Trippett, TM, Niedzwiecki, D, Tao, Y, Tan, C, Steinherz, P, Schweitzer, BI, and Bertino, JR. "Basis for natural resistance to methotrexate in human acute non-lymphocytic leukemia." Leuk Res 15.12 (1991): 1191-1196.
PMID
1722550
Source
pubmed
Published In
Leukemia Research
Volume
15
Issue
12
Publish Date
1991
Start Page
1191
End Page
1196

Relationship and prognostic value of endogenous interferon-alpha, beta 2-microglobulin, and neopterin serum levels in patients with Kaposi sarcoma and AIDS.

We investigated whether elevated serum levels of beta 2-microglobulin and neopterin were related to the abnormal in vivo production of interferon described in patients with human immunodeficiency virus (HIV) infection, and whether these factors might add to measurements of CD4+ T cells in predicting survival and tumor regression in patients with Kaposi sarcoma associated with AIDS. beta 2-Microglobulin and neopterin levels were strongly correlated (r = 0.82), and were each significantly higher in patients with detectable serum interferon-alpha activity. Inverse correlations were observed between prognosis and levels of these serum products. Prediction by CD4+ T-cell count of tumor regression after treatment with interferon-alpha and zidovudine was improved by each of two factors: (a) the presence or absence of endogenous interferon-alpha activity, and (b) a combined variable reflecting relative levels of the interferon-inducible products, beta 2-microglobulin and neopterin. The level of beta 2-microglobulin was the single best predictor of survival. When beta 2-microglobulin was not considered, the endogenous interferon-alpha variable was the best predictor of survival, and the prediction was enhanced by addition of the combined variable, or the neopterin value alone. We conclude that serologic markers, which directly or indirectly reflect activation of the endogenous interferon system, may be valuable adjuncts to CD4+ T-cell counts in assessing prognosis and selecting and evaluating treatments for patients with Kaposi sarcoma and AIDS.

Authors
Krown, SE; Niedzwiecki, D; Bhalla, RB; Flomenberg, N; Bundow, D; Chapman, D
MLA Citation
Krown, SE, Niedzwiecki, D, Bhalla, RB, Flomenberg, N, Bundow, D, and Chapman, D. "Relationship and prognostic value of endogenous interferon-alpha, beta 2-microglobulin, and neopterin serum levels in patients with Kaposi sarcoma and AIDS." J Acquir Immune Defic Syndr 4.9 (1991): 871-880.
PMID
1895208
Source
pubmed
Published In
Journal of Acquired Immune Deficiency Syndromes
Volume
4
Issue
9
Publish Date
1991
Start Page
871
End Page
880

Preoperative therapy for esophageal cancer: a randomized comparison of chemotherapy versus radiation therapy.

Ninety-six patients with operable epidermoid cancer of the esophagus were entered into a phase III, random assignment study designed to compare the efficacy of two preoperative approaches (chemotherapy [CT] or radiation therapy [RT]). Major study end points were objective response rates, surgical outcome, and recurrence pattern. Patients were randomly assigned to receive either two cycles of cisplatin, vindesine, and bleomycin or 55 Gy of radiation before a planned surgical procedure. Postoperative crossover therapy (radiation to those receiving preoperative CT and vice versa) was given to patients with T3Nany or unresectable tumors. Objective response rates of the primary tumor to preoperative therapy were similar (RT 64%, CT 55%), as were operability rates (RT 77%, CT 75%), resection rates (RT 65%, CT 58%), and operative mortality (RT 13.5%, CT 11.1%). Significantly higher doses of CT could be administered when CT was given as initial therapy, rather than after RT/surgery. Local failure or persistence occurred in 33% of operable patients. The median survival for all patients was 11 months; 20% remain alive without disease (median follow-up, 34 months). Because of the crossover design, it was not possible to analyze survival according to the preoperative therapy arm alone. This study suggests that since CT is as effective in treating local tumor as RT, but can also potentially treat systemic disease, investigational programs using CT before surgery as part of initial treatment for localized esophageal cancer should continue. However, if a significant impact on overall survival is to be achieved, more effective chemotherapy regimens or schedules need to be identified. Outside of carefully designed clinical trials, surgery alone or radiation alone remain standard therapy.

Authors
Kelsen, DP; Minsky, B; Smith, M; Beitler, J; Niedzwiecki, D; Chapman, D; Bains, M; Burt, M; Heelan, R; Hilaris, B
MLA Citation
Kelsen, DP, Minsky, B, Smith, M, Beitler, J, Niedzwiecki, D, Chapman, D, Bains, M, Burt, M, Heelan, R, and Hilaris, B. "Preoperative therapy for esophageal cancer: a randomized comparison of chemotherapy versus radiation therapy." J Clin Oncol 8.8 (August 1990): 1352-1361.
PMID
1696309
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
8
Issue
8
Publish Date
1990
Start Page
1352
End Page
1361
DOI
10.1200/JCO.1990.8.8.1352

Estimation and inference in pharmacokinetic models: the effectiveness of model reformulation and resampling methods for functions of parameters.

It is well known that high parameter estimate correlations and asymptotic variance estimates can cause estimation and inference problems in the analysis of pharmacokinetic models. In this paper we show that analysis of three important functions of pharmacokinetic parameters, the half-life, mean residence time, and the area under the curve, can sometimes be greatly improved by reformulating the model to address collinearity and by using the bootstrap to form confidence intervals. The resultant estimators can be more accurate than the original ones, and resultant confidence intervals can be narrower. Of the three measures, the half-life estimator is much better behaved than the estimators of mean residence time and area under the curve under collinearity, suggesting that it (or measures like it) should be used more often.

Authors
Niedzwiecki, D; Simonoff, JS
MLA Citation
Niedzwiecki, D, and Simonoff, JS. "Estimation and inference in pharmacokinetic models: the effectiveness of model reformulation and resampling methods for functions of parameters." J Pharmacokinet Biopharm 18.4 (August 1990): 361-377.
PMID
2231325
Source
pubmed
Published In
Journal of pharmacokinetics and biopharmaceutics
Volume
18
Issue
4
Publish Date
1990
Start Page
361
End Page
377

Interferon-alpha with zidovudine: safety, tolerance, and clinical and virologic effects in patients with Kaposi sarcoma associated with the acquired immunodeficiency syndrome (AIDS)

OBJECTIVE: To evaluate safety, tolerance, and potential efficacy of interferon-alpha and zidovudine combination therapy in patients with Kaposi sarcoma and the acquired immunodeficiency syndrome (AIDS). DESIGN: Open, phase-I study with randomization between two preparations of interferon-alpha. SETTING: Outpatient clinic of a cancer research center. PATIENTS: Forty-three patients with Kaposi sarcoma associated with AIDS. INTERVENTIONS: Patients were treated with interferon-alpha, 4.5, 9, or 18 million U/d, and zidovudine, 100 or 200 mg orally every 4 hours. MEASUREMENTS AND MAIN RESULTS: Neutropenia was the major dose-limiting toxicity. Fatigue, liver enzyme elevation, anemia, and thrombocytopenia were dose-limiting in some patients. Maximum tolerated dosages for interferon-alpha 2a with zidovudine, respectively, were 4.5 million U/d with 200 mg every 4 hours or 18 million U/d with 100 mg every 4 hours. An interferon-alpha n1 [corrected] dosage of 9 million U/d with zidovudine dosages of either 100 or 200 mg every 4 hours induced dose-limiting toxicity in most patients. Of 37 evaluable patients, 17 (46%; 95% CI, 30% to 62%) showed complete or partial tumor regression. Antitumor effects occurred more frequently in patients with baseline CD4 counts above 200 x 10(6) cells/L (65%) than in patients with lower baseline counts (30%, P = 0.05). Effects on CD4 cells were related to both initial CD4 count and interferon dose. Increased skin test reactivity and decreased serum human immunodeficiency virus (HIV) p24 antigen and virus recovery from blood cells were seen. CONCLUSIONS: Combined therapy with interferon-alpha and zidovudine can be safely administered to patients with AIDS and Kaposi sarcoma. The observed effects on tumor growth, HIV replication, and immune function support further studies of the combination in patients at various stages of HIV infection.

Authors
Krown, SE; Gold, JW; Niedzwiecki, D; Bundow, D; Flomenberg, N; Gansbacher, B; Brew, BJ
MLA Citation
Krown, SE, Gold, JW, Niedzwiecki, D, Bundow, D, Flomenberg, N, Gansbacher, B, and Brew, BJ. "Interferon-alpha with zidovudine: safety, tolerance, and clinical and virologic effects in patients with Kaposi sarcoma associated with the acquired immunodeficiency syndrome (AIDS)." Ann Intern Med 112.11 (June 1, 1990): 812-821.
PMID
1971504
Source
pubmed
Published In
Annals of internal medicine
Volume
112
Issue
11
Publish Date
1990
Start Page
812
End Page
821

Toxoplasma gondii serology in HIV-infected patients: the development of central nervous system toxoplasmosis in AIDS.

Central nervous system (CNS) toxoplasmosis is an important infectious complication of AIDS which requires prolonged treatment. Most cases occur in patients with serologic evidence of prior exposure and therefore appear to result from reactivation of a previously acquired infection. Antibody to Toxoplasma gondii was found in 130 out of 411 patients with AIDS (32%). Of these, CNS toxoplasmosis developed in 31 (24%). By survival analysis, the estimated probability of ever developing CNS infection in antibody-positive individuals was 28%, occurring in 26% of patients within 2 years of the onset of AIDS. All patients with HIV infection should be tested for antibody to T. gondii and monitored for any neurologic change. Methods of prophylaxis for CNS toxoplasmosis in these high-risk patients need to be developed.

Authors
Grant, IH; Gold, JW; Rosenblum, M; Niedzwiecki, D; Armstrong, D
MLA Citation
Grant, IH, Gold, JW, Rosenblum, M, Niedzwiecki, D, and Armstrong, D. "Toxoplasma gondii serology in HIV-infected patients: the development of central nervous system toxoplasmosis in AIDS." AIDS 4.6 (June 1990): 519-521.
PMID
2386617
Source
pubmed
Published In
AIDS
Volume
4
Issue
6
Publish Date
1990
Start Page
519
End Page
521

Anticipatory immune suppression and nausea in women receiving cyclic chemotherapy for ovarian cancer.

Nausea and immune function were assessed in 20 cancer patients in the hospital prior to chemotherapy and compared with assessments conducted at home. Proliferative responses to T-cell mitogens were lower for cells isolated from hospital blood samples than for home samples obtained several days earlier. Patients also experienced increased nausea in the hospital. Hierarchical multiple regression analyses indicated that decreased immune function in the hospital was not related to increased anxiety. The observed anticipatory immune suppression is consistent with the hypothesis that chemotherapy patients may develop conditioned immune suppression as well as conditioned nausea after repeated pairings of hospital stimuli with the emetic and immunosuppressive effects of chemotherapy.

Authors
Bovbjerg, DH; Redd, WH; Maier, LA; Holland, JC; Lesko, LM; Niedzwiecki, D; Rubin, SC; Hakes, TB
MLA Citation
Bovbjerg, DH, Redd, WH, Maier, LA, Holland, JC, Lesko, LM, Niedzwiecki, D, Rubin, SC, and Hakes, TB. "Anticipatory immune suppression and nausea in women receiving cyclic chemotherapy for ovarian cancer." J Consult Clin Psychol 58.2 (April 1990): 153-157.
PMID
2335631
Source
pubmed
Published In
Journal of Consulting and Clinical Psychology
Volume
58
Issue
2
Publish Date
1990
Start Page
153
End Page
157

Randomized study of continuous infusion fluorouracil versus fluorouracil plus cisplatin in patients with metastatic colorectal cancer.

One hundred twenty-two chemotherapy-naive patients with histologically confirmed colorectal adenocarcinoma were entered into a randomized trial comparing infusional fluorouracil (FU) versus cisplatin (CDDP) and FU. In both groups, patients received continuous infusion FU 1,000 mg/m2/d for 5 consecutive days every 4 weeks. Patients randomized to CDDP/FU also received CDDP 20 mg/m2 intravenous (IV) bolus on days 1 to 5 of each cycle. Patients were comparable in terms of age, performance status, baseline laboratory values, dominant sites of measurable disease, and percent of liver involvement. The partial response rate was significantly greater in patients who received CDDP/FU versus FU alone (25% v 3%, P = .001). Patients who received CDDP/FU experienced significantly greater toxicity compared with FU alone: grades 3 and 4 hematologic toxicity occurred in 22% and 0% of patients, respectively (P = .0001); grades 2 to 4 nausea and vomiting occurred in 80% and 15% of patients, respectively (P = .0001). There were no significant differences in either the duration of response (median, 6 and 4.7 months for CDDP/FU and FU groups, respectively) or survival (median 10, and 12 months, respectively). Compared with infusional FU alone, CDDP/FU provided a significantly greater partial response rate with increased toxicity, but it did not improve overall survival in patients with advanced colorectal carcinoma. Therefore, the use of CDDP/FU as routine therapy for the treatment of colorectal carcinoma cannot be recommended.

Authors
Kemeny, N; Israel, K; Niedzwiecki, D; Chapman, D; Botet, J; Minsky, B; Vinciguerra, V; Rosenbluth, R; Bosselli, B; Cochran, C
MLA Citation
Kemeny, N, Israel, K, Niedzwiecki, D, Chapman, D, Botet, J, Minsky, B, Vinciguerra, V, Rosenbluth, R, Bosselli, B, and Cochran, C. "Randomized study of continuous infusion fluorouracil versus fluorouracil plus cisplatin in patients with metastatic colorectal cancer." J Clin Oncol 8.2 (February 1990): 313-318.
PMID
2405107
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
8
Issue
2
Publish Date
1990
Start Page
313
End Page
318
DOI
10.1200/JCO.1990.8.2.313

Metastatic adenocarcinomas of unknown primary site. Prognostic variables and treatment results.

As part of a Phase II chemotherapy trial using mitomycin-C, adriamycin, and vindesine, 57 patients with adenocarcinoma of unknown primary site were assessed for prognostic variables predictive of response and survival. They were also evaluated for response and toxicity, usefulness of screening techniques, and eventual definition of primary site and pattern of progression. Only gender predicted response, with women being more likely to respond than men. Visceral metastases below the diaphragm, or the presence of liver metastases, predicted poor survival. Responding patients were highly likely to relapse first at sites of initial disease. Hemolytic-uremic syndrome was the most severe toxicity; other side effects were moderate. The response rate was 30% (three complete responders), which is similar to other current regimens. This study suggests that patients with better prognosis characteristics of single site of disease and without intraabdominal tumor may benefit from a policy of expectant observation after local control has been established. Patients with multiple sites of disease and/or intraabdominal tumor are appropriate candidates for investigational chemotherapy.

Authors
Kambhu, SA; Kelsen, DP; Fiore, J; Niedzwiecki, D; Chapman, D; Vinciguerra, V; Rosenbluth, R
MLA Citation
Kambhu, SA, Kelsen, DP, Fiore, J, Niedzwiecki, D, Chapman, D, Vinciguerra, V, and Rosenbluth, R. "Metastatic adenocarcinomas of unknown primary site. Prognostic variables and treatment results." Am J Clin Oncol 13.1 (February 1990): 55-60.
PMID
2106257
Source
pubmed
Published In
American Journal of Clinical Oncology: Cancer Clinical Trials
Volume
13
Issue
1
Publish Date
1990
Start Page
55
End Page
60

Histology of early lesions of AIDS-associated Kaposi's sarcoma.

The original cutaneous biopsy specimens of 93 patients who presented themselves to the Memorial Sloan-Kettering Cancer Center with acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma (KS) were systematically reviewed for 23 histologic variables. KS was the initial manifestation of AIDS in all of the patients. The vast majority of patients presented with plaque histology of KS. Early lesions of KS were characterized by the presence of dilated vascular spaces haphazardly arranged in the biopsy specimen, a sparse inflammatory cell infiltrate composed of lymphocytes (usually without plasma cells), and aggregates of cuboidal cells with the appearance of epithelioid cells. Individually necrotic tumor cells were present in nearly every case. Spindle cells arranged in fascicles or nodules were seen in a minority of cases. These data provide an overview of the different histologic patterns seen in initial lesions of AIDS-associated KS and may lead to better understanding of the pathogenesis of this tumor.

Authors
Niedt, GW; Myskowski, PL; Urmacher, C; Niedzwiecki, D; Chapman, D; Safai, B
MLA Citation
Niedt, GW, Myskowski, PL, Urmacher, C, Niedzwiecki, D, Chapman, D, and Safai, B. "Histology of early lesions of AIDS-associated Kaposi's sarcoma." Mod Pathol 3.1 (January 1990): 64-70.
PMID
2308922
Source
pubmed
Published In
Modern Pathology
Volume
3
Issue
1
Publish Date
1990
Start Page
64
End Page
70

Carboplatin-based chemotherapy with pharmacokinetic analysis for patients with hemodialysis-dependent renal insufficiency.

Three patients with renal insufficiency requiring hemodialysis were treated with carboplatin at 100 mg/m2 in combination with etoposide for advanced germ-cell tumor (GCT, two cases) or Adriamycin + vinblastine for a transitional-cell carcinoma of the ureter (one case). Hemodialysis was performed 24 h after the administration of carboplatin. Both patients with GCT achieved a complete response, and the patient with transitional-cell carcinoma of the ureter was inevaluable for response but his disease has not progressed. The dose of carboplatin was increased in one patient as renal function improved on therapy. In two patients, the pharmacokinetics of carboplatin were determined; the pre-dialysis half-lives, AUC, and total body clearances of free carboplatin-derived platinum were estimated to be 32 and 18.3 h, 4.93 and 6.17 mg ml-1 min, and 18.2 and 18.7 ml/min, respectively. The dialysis elimination half-lives (t1/2 beta) of 2 and 3 h, respectively, for these two patients were markedly lower than the predialysis values, indicating that carboplatin was dialyzed. In summary, carboplatin can be given to patients with severe renal insufficiency. Adequate AUCs were achieved and dialysis limited systemic exposure to free carboplatin.

Authors
Motzer, RJ; Niedzwiecki, D; Isaacs, M; Menendez-Botet, C; Tong, WP; Flombaum, C; Scher, HI; Bosl, GJ
MLA Citation
Motzer, RJ, Niedzwiecki, D, Isaacs, M, Menendez-Botet, C, Tong, WP, Flombaum, C, Scher, HI, and Bosl, GJ. "Carboplatin-based chemotherapy with pharmacokinetic analysis for patients with hemodialysis-dependent renal insufficiency." Cancer Chemother Pharmacol 27.3 (1990): 234-238.
PMID
2176133
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
27
Issue
3
Publish Date
1990
Start Page
234
End Page
238

[Intraportal injection of specific monoclonal antibody in nude mice with liver metastasis].

To assess the importance of monoclonal antibody route of administration, we compared the selective (intraportal) and systemic injection of specific radiolabeled monoclonal antibody, using a murine model of hepatic metastases from a human colorectal carcinoma. Tumor uptake was studied over time after injection of 0.1, 1.0 or 2.0 micrograms of a specific antibody (HT29-15) or an isotype-matched control (BL-3). Significantly higher tumor uptake and tumor/liver or tumor/blood uptake ratios were seen in animals receiving intraportal injection for all tested doses. Intraportal injection of specific monoclonal antibody resulted in significant improvement in metastases uptake; these findings could be applied to the diagnosis and treatment of hepatic metastases from colorectal cancer using radiolabeled monoclonal antibodies.

Authors
Rivoire, M; Yoshida, K; Divgi, C; Niedzwiecki, D; Chapman, D; Sigurdson, E
MLA Citation
Rivoire, M, Yoshida, K, Divgi, C, Niedzwiecki, D, Chapman, D, and Sigurdson, E. "[Intraportal injection of specific monoclonal antibody in nude mice with liver metastasis]." Chirurgie 116.8-9 (1990): 721-729.
PMID
2129990
Source
pubmed
Published In
Chirurgie
Volume
116
Issue
8-9
Publish Date
1990
Start Page
721
End Page
729

Intrahepatic mitomycin C as a salvage treatment for patients with hepatic metastases from colorectal carcinoma.

Sixty-four evaluable patients with hepatic metastases from colorectal carcinoma, who did not have evidence of extrahepatic disease, were treated with intrahepatic (IH) mitomycin C (M) after disease progression or intolerance to treatment with IH fluorodeoxyuridine (FUDR). Eleven patients (17%) had a partial response (PR) to IH M and ten (16%) patients had stable disease. Patients who responded to IH FUDR were more likely to respond to IH M when compared with those who progressed on IH FUDR (47% versus 13%, respectively; P = 0.013). Those who were switched to IH M because of hepatotoxicity on IH FUDR also were more likely to respond to IH M than those who were switched because of progression on IH FUDR (75% versus 27%, respectively; P = 0.022). Baseline laboratory values, the percent of tumorous liver involvement, prior history of systemic chemotherapy, and the interval from diagnosis to initiation of IH M did not help predict response. Toxicity was mild and well tolerated. The overall median survival time of the 64 evaluable patients was 9.0 months from the start of IH M therapy. We conclude that IH M has some salvage benefit in patients with hepatic metastases.

Authors
Schneider, A; Kemeny, N; Chapman, D; Niedzwiecki, D; Oderman, P
MLA Citation
Schneider, A, Kemeny, N, Chapman, D, Niedzwiecki, D, and Oderman, P. "Intrahepatic mitomycin C as a salvage treatment for patients with hepatic metastases from colorectal carcinoma." Cancer 64.11 (December 1, 1989): 2203-2206.
PMID
2529960
Source
pubmed
Published In
Cancer
Volume
64
Issue
11
Publish Date
1989
Start Page
2203
End Page
2206

Advanced pancreatic cancer: a phase I-II trial of cisplatin, high-dose cytarabine, and caffeine.

In a phase I-II study, 28 patients with advanced pancreatic adenocarcinoma were treated with cisplatin, high-dose cytarabine (ARA-C), and caffeine. This clinical trial was based on a nude mouse-human tumor xenograft model, which demonstrated synergism of these agents by inhibiting the growth of human pancreatic tumors. Toxic effects noted in the clinical study included myelosuppression, moderate nausea and vomiting, and mild renal insufficiency. No toxic effects were directly attributable to caffeine. Eighteen of the 28 patients had measurable or assessable disease; seven (39%) had partial responses (95% confidence intervals, 18%-63%). The median response duration was 6.2 months. Median survival for responders was 9.5 months with two patients surviving for more than 18 months. Median survival for all patients was 6.1 months. The combination of cisplatin, ARA-C, and caffeine is an active and tolerable regimen in the treatment of advanced pancreatic cancer. A phase III trial in which this regimen is being compared with standard therapy is in progress.

Authors
Dougherty, JB; Kelsen, D; Kemeny, N; Magill, G; Botet, J; Niedzwiecki, D
MLA Citation
Dougherty, JB, Kelsen, D, Kemeny, N, Magill, G, Botet, J, and Niedzwiecki, D. "Advanced pancreatic cancer: a phase I-II trial of cisplatin, high-dose cytarabine, and caffeine." J Natl Cancer Inst 81.22 (November 15, 1989): 1735-1738.
PMID
2681796
Source
pubmed
Published In
Journal of the National Cancer Institute
Volume
81
Issue
22
Publish Date
1989
Start Page
1735
End Page
1738

Flow cytometry as a predictive indicator in patients with operable gastric cancer.

Adenocarcinoma of the proximal portion of the stomach (gastroesophageal [GE] junction and cardia) is increasing in incidence. The inferior survival of patients with GE-cardia lesions as compared with patients with tumors located in the body and antrum has been attributed to anatomic features. To determine if a biological difference could explain the varying prognosis, flow cytometric studies were performed prospectively in 50 patients with operable gastric cancer and analyzed for association with site, histology, gender, age, stage, and disease-free survival. DNA aneuploidy significantly correlated with tumor location: 96% of GE-cardia carcinomas were aneuploid as compared with 48% of body-antrum tumors (P = .0008). Nodal involvement was more common in aneuploid tumors (P = .0548), and women were more likely to have diploid tumors than were men (P = .0233). The median disease-free survival for patients with diploid tumors was 18.5 months as compared with 5.4 months for patients with aneuploid carcinomas (P = .076). Furthermore, within the body-antrum of the stomach, patients with diploid tumors had a significantly better disease-free survival than did those with aneuploid tumors from the same site (18.4 v 4.7 months, P = .0185). These results indicate there is a difference in the DNA content of gastric tumors located in different sites within the stomach and that DNA content correlates with prognosis.

Authors
Nanus, DM; Kelsen, DP; Niedzwiecki, D; Chapman, D; Brennan, M; Cheng, E; Melamed, M
MLA Citation
Nanus, DM, Kelsen, DP, Niedzwiecki, D, Chapman, D, Brennan, M, Cheng, E, and Melamed, M. "Flow cytometry as a predictive indicator in patients with operable gastric cancer." J Clin Oncol 7.8 (August 1989): 1105-1112.
PMID
2754450
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
7
Issue
8
Publish Date
1989
Start Page
1105
End Page
1112
DOI
10.1200/JCO.1989.7.8.1105

Cisplatin and 5-fluorouracil infusion for metastatic colorectal carcinoma. Differences in survival in two patient groups with similar response rates.

Because of reported synergism between 5-fluorouracil (5-FU) and cisplatin (CDDP) in L1210 leukemic mice and activity of this combination in clinical studies, a trial was initiated in previously untreated patients with advanced colorectal carcinoma. Cisplatin at 20 mg/m2 and 5-FU as a continuous infusion at 1000 mg/m2 were both administered for 5 consecutive days every 4 weeks. Forty-one patients were treated at Memorial Sloan-Kettering Cancer Center (MSKCC) and 46 were treated by the Community Clinical Oncology Program (CCOP) physicians. A 50% reduction in measurable disease was seen in 12 of 35 (34%) MSKCC patients and in nine of 41 (22%) of the CCOP patients with 95% confidence intervals of 0.18 to 0.50 and 0.10 to 0.35 in the two groups, respectively. The predominant toxicities were as follows: nausea and vomiting, 32%; mucositis, 26%; leukocyte counts less than 2000 cells/mm3, 17%; platelet counts less than 25,000 cells/mm3, 8%; and severe neurotoxicity, 5%. Dose attenuation was similar in the two groups. The median survival was 16.4 months for the MSKCC group and 9.6 months for the CCOP group (P = 0.0003). Although the baseline characteristics (age, sex, performance status, and baseline lactic dehydrogenase [LDH] and alkaline phosphatase) were similar, on further examination differences between the two groups were evident. In the MSKCC group, 14% of patients with liver metastases had greater than 50% of their liver involved with tumor whereas this occurred in 41% of the CCOP group (P = 0.03). The LDH values greater than 500 U/l were observed in 10% of patients in the MSKCC group and in 37% of the patients in the CCOP group (P = 0.007). Characteristics which reflect the bulk of disease, such as the percent of liver involvement, need to be analyzed in order to evaluate purported survival differences in randomized and nonrandomized trials of colorectal carcinoma.

Authors
Kemeny, N; Niedzwiecki, D; Reichman, B; Botet, J; Vinciguerra, V; Michaelson, R; Rosenbluth, R; Deonarine, S
MLA Citation
Kemeny, N, Niedzwiecki, D, Reichman, B, Botet, J, Vinciguerra, V, Michaelson, R, Rosenbluth, R, and Deonarine, S. "Cisplatin and 5-fluorouracil infusion for metastatic colorectal carcinoma. Differences in survival in two patient groups with similar response rates." Cancer 63.6 (March 15, 1989): 1065-1069.
PMID
2917309
Source
pubmed
Published In
Cancer
Volume
63
Issue
6
Publish Date
1989
Start Page
1065
End Page
1069

Prognostic variables in patients with hepatic metastases from colorectal cancer. Importance of medical assessment of liver involvement.

Variation in response rates to chemotherapy and survival in patients with hepatic metastases from colorectal carcinoma may be due to patient selection factors. The prognostic importance of 13 factors were analyzed in 112 patients with only hepatic metastases, who were eligible for hepatic artery infusional chemotherapy. When individually analyzed, six factors were found to significantly (less than 0.001) affect survival: the percentage of tumor involvement of the liver, assessed medically or surgically; initial serum albumin and lactic dehydrogenase; initial Karnofsky performance status; and weight loss. Patients with less than or equal to 30% liver involvement had a median survival of 24 months versus 10 months if they had greater than 30% involvement. There was a highly significant agreement between medical and surgical assessment of liver involvement (P = 0.0001). When the variables affecting survival were studied together by multivariable analyses, the most important factor was the medical assessment of liver involvement accomplished by evaluation of radionuclide liver scan and CTT scans. The next two most important factors in the model were the ability of the patient to obtain a tumor response and the presence or absence of weight loss. Only one factor helped predict response to chemotherapy, the type of perfusion seen on a 99Technetium-macroaggregated albumin (MAA) arterial flow scan. Forty-five percent of patients with good perfusion had a partial response while 13% of patients with poor perfusion had a tumor response (P = 0.006). We recommend that future studies, dealing with patients who have hepatic metastases from colorectal carcinoma and are eligible for hepatic arterial infusion, document and stratify for the following factors: the percentage of liver involvement, the presence or absence of weight loss, and the type of perfusion seen on MAA scans.

Authors
Kemeny, N; Niedzwiecki, D; Shurgot, B; Oderman, P
MLA Citation
Kemeny, N, Niedzwiecki, D, Shurgot, B, and Oderman, P. "Prognostic variables in patients with hepatic metastases from colorectal cancer. Importance of medical assessment of liver involvement." Cancer 63.4 (February 15, 1989): 742-747.
PMID
2521570
Source
pubmed
Published In
Cancer
Volume
63
Issue
4
Publish Date
1989
Start Page
742
End Page
747

Prognostic variables in patients with hepatic metastases from colorectal cancer. Importance of medical assessment of liver involvement

Variation in response rates to chemotherapy and survival in patients with hepatic metastases from colorectal carcinoma may be due to patient selection factors. The prognostic importance of 13 factors were analyzed in 112 patients with only hepatic metastases, who were eligible for hepatic artery infusional chemotherapy. When individually analyzed, six factors were found to significantly ( < 0.001) affect survival: the percentage of tumor involvement of the liver, assessed medically or surgically; initial serum albumin and lactic dehydrogenase; initial Karnofsky performance status; and weight loss. Patients with ≦30% liver involvement had a median survival of 24 months versus 10 months if they had > 30% involvement. There was a highly significant agreement between medical and surgical assessment of liver involvement (P = 0.0001). When the variables affecting survival were studied together by multivariable analyses, the most important factor was the medical assessment of liver involvement accomplished by evaluation of radionuclide liver scan and CTT scans. The next two most important factors in the model were the ability of the patient to obtain a tumor response and the presence or absence of weight loss. Only one factor helped predict response to chemotherapy, the type of perfusion seen on a 99 Technetium‐macroaggregated albumin (MAA) arterial flow scan. Forty‐five percent of patients with good perfusion had a partial response while 13% of patients with poor perfusion had a tumor response (P = 0.006). We recommend that future studies, dealing with patients who have hepatic metastases from colorectal carcinoma and are eligible for hepatic arterial infusion, document and stratify for the following factors: the percentage of liver involvement, the presence or absence of weight loss, and the type of perfusion seen on MAA scans. Copyright © 1989 American Cancer Society

Authors
Kemeny, N; Niedzwiecki, D; Shurgot, B; Oderman, P
MLA Citation
Kemeny, N, Niedzwiecki, D, Shurgot, B, and Oderman, P. "Prognostic variables in patients with hepatic metastases from colorectal cancer. Importance of medical assessment of liver involvement." Cancer 63.4 (January 1, 1989): 742-747.
Source
scopus
Published In
Cancer
Volume
63
Issue
4
Publish Date
1989
Start Page
742
End Page
747
DOI
10.1002/1097-0142(19890215)63:4<742::AID-CNCR2820630423>3.0.CO;2-T

Intrahepatic mitomycin C as a salvage treatment for patients with hepatic metastases from colorectal carcinoma

Sixty‐four evaluable patients with hepatic metastases from colorectal carcinoma, who did not have evidence of extrahepatic disease, were treated with intrahepatic (IH) mitomycin C (M) after disease progression or intolerance to treatment with IH fluorodeoxyuridine (FUDR). Eleven patients (17%) had a partial response (PR) to IH M and ten (16%) patients had stable disease. Patients who responded to IH FUDR were more likely to respond to IH M when compared with those who progressed on IH FUDR (47% versus 13%, respectively; P = 0.013). Those who were switched to IH M because of hepatotoxicity on IH FUDR also were more likely to respond to IH M than those who were switched because of progression on IH FUDR (75% versus 27%, respectively; P = 0.022). Baseline laboratory values, the percent of tumorous liver involvement, prior history of systemic chemotherapy, and the interval from diagnosis to initiation of IH M did not help predict response. Toxicity was mild and well tolerated. The overall median survival time of the 64 evaluable patients was 9.0 months from the start of IH M therapy. We conclude that IH M has some salvage benefit in patients with hepatic metastases. Copyright © 1989 American Cancer Society

Authors
Schneider, A; Kemeny, N; Chapman, D; Niedzwiecki, D; Oderman, P
MLA Citation
Schneider, A, Kemeny, N, Chapman, D, Niedzwiecki, D, and Oderman, P. "Intrahepatic mitomycin C as a salvage treatment for patients with hepatic metastases from colorectal carcinoma." Cancer 64.11 (January 1, 1989): 2203-2206.
Source
scopus
Published In
Cancer
Volume
64
Issue
11
Publish Date
1989
Start Page
2203
End Page
2206
DOI
10.1002/1097-0142(19891201)64:11<2203::AID-CNCR2820641103>3.0.CO;2-O

Cisplatin and 5‐fluorouracil infusion for metastatic colorectal carcinoma. Differences in survival in two patient groups with similar response rates

Because of reported synergism between 5‐fluorourcil (5‐FU) and cisplatin (CDDP) in L1210 leukemic mice and activity of this combination in clinical studies, a trial was initiated in previously untreated patients with advanced colorectal carcinoma. Cisplatin at 20 mg/m 2 and 5‐FU as a continuous infusion at 1000 mg/m 2 were both administered for 5 consecutive days every 4 weeks. Forty‐one patients were treated at Memorial Sloan‐Kettering Cancer Center (MSKCC) and 46 were treated by the Community Clinical Oncology Program (CCOP) physicians. A 50% reduction in measurable disease was seen in 12 of 35 (34%) MSKCC patients and in nine of 41 (22%) of the CCOP patients with 95% confidence intervals of 0.18 to 0.50 and 0.10 to 035 in the two groups, respectively. The predominant toxicities were as follows: nausea and vomiting, 32%; mucositis, 26%; leukocyte counts < 2000 cells/mm3, 17%; platelet counts < 25,000 cells/mm 3 , 8%; and severe neurotoxicity, 5%. Dose attenuation was similar in the two groups. The median survival was 16.4 months for the MSKCC group and 9.6 months for the CCOP group (P = 0.0003). Although the baseline characteristics (age, sex, performance status, and baseline lactic dehydrogenase [LDH] and alkaline phosphatase) were similar, on further examination differences between the two groups were evident. In the MSKCC group, 14% of patients with liver metastases had > 50% of their liver involved with tumor wheras this occurred in 41% of the CCOP group (P = 0.03). The LDH values > 500 U/I were observed in 10% of patients in the MSKCC group and in 37% of the patients in the CCOP group (P = 0.007). Characteristics which reflect the bulk of disease, such as the percent of liver involvement, need to be analyzed in order to evaluate purported survival differences in randomized and nonrandomized trials of colorectal carcinoma. Copyright © 1989 American Cancer Society

Authors
Kemeny, N; Niedzwiecki, D; Reichman, B; Botet, J; Vinciguerra, V; Michaelson, R; Rosenbluth, R; Deonarine, S
MLA Citation
Kemeny, N, Niedzwiecki, D, Reichman, B, Botet, J, Vinciguerra, V, Michaelson, R, Rosenbluth, R, and Deonarine, S. "Cisplatin and 5‐fluorouracil infusion for metastatic colorectal carcinoma. Differences in survival in two patient groups with similar response rates." Cancer 63.6 (January 1, 1989): 1065-1069.
Source
scopus
Published In
Cancer
Volume
63
Issue
6
Publish Date
1989
Start Page
1065
End Page
1069
DOI
10.1002/1097-0142(19890315)63:6<1065::AID-CNCR2820630604>3.0.CO;2-4

A phase II trial of streptozotocin and adriamycin in advanced APUD tumors.

Thirty-three patients with advanced carcinoid tumors, islet cell carcinomas, or medullary carcinomas of the thyroid were entered into a phase II trial combining streptozotocin (STZ) and Adriamycin. Thirty-one patients are evaluable for response, and 29 are evaluable for survival. Six (19%) patients achieved objective partial responses (95% confidence limits: 5.4-33). The median duration of response for partial responders was 282 days. The median survival for responders and nonresponders was 16.2 months and 7.8 months, respectively, with an overall median survival of 10.9 months. At 10.9 months median follow-up, 4 (14%) of 29 patients are surviving. Toxicity was mild, except that nausea or vomiting occurred in 25 of 31 patients evaluable for toxicity. With this dose and schedule of administration, STZ and Adriamycin produce modest response rates with objective palliation of disease in patients with advanced amine precursor uptake and decarboxylation (APUD) tumors.

Authors
Frame, J; Kelsen, D; Kemeny, N; Cheng, E; Niedzwiecki, D; Heelan, R; Lippermann, R
MLA Citation
Frame, J, Kelsen, D, Kemeny, N, Cheng, E, Niedzwiecki, D, Heelan, R, and Lippermann, R. "A phase II trial of streptozotocin and adriamycin in advanced APUD tumors." Am J Clin Oncol 11.4 (August 1988): 490-495.
PMID
2841843
Source
pubmed
Published In
American Journal of Clinical Oncology: Cancer Clinical Trials
Volume
11
Issue
4
Publish Date
1988
Start Page
490
End Page
495

AIDS-associated Kaposi's sarcoma: variables associated with survival.

The records of 187 consecutive patients with acquired immunodeficiency syndrome (AIDS)-associated Kaposi's sarcoma were analyzed retrospectively for a number of prognostic variables. In a multivariate analysis, the initial site of disease was found to be related to survival. Initial lesions on the skin of the lower extremities or in the lymph nodes were associated with longer survival (p = 0.005 and p = 0.01, respectively). Higher helper/suppressor T cell ratios were strongly associated with longer survival (p less than 0.0001). Age and serum IgG antibody levels to cytomegalovirus did not appear to correlate. These results suggest that there are different subgroups of patients with AIDS-associated Kaposi's sarcoma, and that the initial site of disease, as well as immunologic parameters, may be useful in prognosis.

Authors
Myskowski, PL; Niedzwiecki, D; Shurgot, BA; Kaufman, D; Krown, SE; Nisce, L; Safai, B
MLA Citation
Myskowski, PL, Niedzwiecki, D, Shurgot, BA, Kaufman, D, Krown, SE, Nisce, L, and Safai, B. "AIDS-associated Kaposi's sarcoma: variables associated with survival." J Am Acad Dermatol 18.6 (June 1988): 1299-1306.
PMID
2968378
Source
pubmed
Published In
Journal of The American Academy of Dermatology
Volume
18
Issue
6
Publish Date
1988
Start Page
1299
End Page
1306

Heterogeneity of tardive dyskinesia. A multivariate analysis.

To determine whether tardive dyskinesia (TD) is a single abnormal movement syndrome or multiple syndromes involving different anatomical areas, we examined 228 out-patients diagnosed with TD at the Connecticut Mental Health Center in New Haven. Application of factor analysis to the seven anatomical severity scores of the Abnormal Involuntary Movement Scale yielded three statistically independent factors involving abnormal movements primarily of the jaw-tongue, face-lips, and extremities-trunk. Using logistic regression to predict the severity of these factors, we found that the severity of the orofacial scores was positively associated with age, schizoaffective or affective disorder, and living alone, while severity of non-orofacial movement was positively associated with current neuroleptic dose, non-use of psychiatric medication, and living alone. Our findings suggest that orofacial and non-orofacial dyskinetic movements may involve distinct clinical syndromes of TD, each having a different set of prognostic and, possibly, aetiological determinants.

Authors
Glazer, WM; Morgenstern, H; Niedzwiecki, D; Hughes, J
MLA Citation
Glazer, WM, Morgenstern, H, Niedzwiecki, D, and Hughes, J. "Heterogeneity of tardive dyskinesia. A multivariate analysis." Br J Psychiatry 152 (February 1988): 253-259.
PMID
3262396
Source
pubmed
Published In
The British journal of psychiatry : the journal of mental science
Volume
152
Publish Date
1988
Start Page
253
End Page
259

Heterogeneity of tardive dyskinesia. A multivariate analysis

To determine whether tardive dyskinesia (TD) is a single abnormal movement syndrome or multiple syndromes involving different anatomical areas, we examined 228 out-patients diagnosed with TD at the Connecticut Mental Health Center in New Haven. Application of factor analysis to the seven anatomical severity scores of the Abnormal Involuntary Movement Scale yielded three statistically independent factors involving abnormal movements primarily of the jaw-tongue, face-lips, and extremities-trunk. Using logistic regression to predict the severity of these factors, we found that the severity of the orofacial scores was positively associated with age, schizoaffective or affective disorder, and living alone, while severity of non-orofacial movement was positively associated with current neuroleptic dose, non-use of psychiatric medication, and living alone. Our findings suggest that orofacial and non-orofacial dyskinetic movements may involve distinct clinical syndromes of TD, each having a different set of prognostic and, possibly, aetiological determinants.

Authors
Glazer, WM; Morgenstern, H; Niedzwiecki, D; Hughes, J
MLA Citation
Glazer, WM, Morgenstern, H, Niedzwiecki, D, and Hughes, J. "Heterogeneity of tardive dyskinesia. A multivariate analysis." British Journal of Psychiatry 152.FEB. (January 1, 1988): 253-259.
Source
scopus
Published In
The British journal of psychiatry : the journal of mental science
Volume
152
Issue
FEB.
Publish Date
1988
Start Page
253
End Page
259

Randomized trial of combined modality therapy with and without thymosin fraction v in the treatment of small cell lung cancer

A randomized trial of thymosin fraction V (60 mg/m2 s.c. twice weekly) given during induction chemotherapy and radiation therapy was performed in 91 patients with small cell carcinoma of the lung. Induction chemotherapy consisted of four cycles of an alternating combination of drugs (cyclophosphamide/Adriamycin/vincristine and cisplatin/etoposide). Radiation to the primary complex was given to patients with limited disease. All patients received prophylactic cranial irradiation. There were 35 patients with limited disease (18 randomized to thymosin and 17 to no thymosin) and 56 with extensive disease (28 thymosin and 28 no thymosin). Pretreatment immunological parameters were comparable between the two groups. For limited disease patients the overall response rate was 100%, including 66% (21 of 32) complete responders. The median duration of response was 19 mo (range, 5-57 mo) and survival 21 mo (range, 4 days to 57 mo). The 3-yr survival was 32%. For ED patients the overall response to rate was 95% with 29% (13 of 48) complete. The median duration of response was 10 mo and the median duration of survival 12 mo with 13% alive at 2 yr. A comparison of the thymosin-versus no thymosin-treated patients revealed no difference in response rate, response duration, or survival whether analyzed as a whole or by extent of disease. An analysis based on pretreatment immune function and total white blood cell and absolute lymphocyte count revealed no difference in the survival distributions. No differences in the pattern of toxicity were observed between the thymosin- versus no thymosin-treated patients. The addition of thymosin fraction V during induction chemotherapy and consolidation radiotherapy did not alter outcome.

Authors
Scher, HI; Shank, B; Chapman, R; Geller, N; Pinsky, C; Gralla, R; Kelsen, D; Bosl, G; Golbey, R; Petroni, G; Niedzwiecki, D; Martini, N; Heelan, R; Hollander, P; Hilaris, B; Oettgen, H; Wittes, RE
MLA Citation
Scher, HI, Shank, B, Chapman, R, Geller, N, Pinsky, C, Gralla, R, Kelsen, D, Bosl, G, Golbey, R, Petroni, G, Niedzwiecki, D, Martini, N, Heelan, R, Hollander, P, Hilaris, B, Oettgen, H, and Wittes, RE. "Randomized trial of combined modality therapy with and without thymosin fraction v in the treatment of small cell lung cancer." Cancer Research 48.6 (1988): 1663-1670.
PMID
2830968
Source
scival
Published In
Cancer Research
Volume
48
Issue
6
Publish Date
1988
Start Page
1663
End Page
1670

Significance of a fall in serum CEA concentration in patients treated with cytotoxic chemotherapy for disseminated colorectal cancer.

'Tumour response', defined as clinical or radiological evidence of tumour shrinkage is frequently regarded as an objective of chemotherapy, rather than as a predictor of prolonged survival. This study has assessed whether a fall in the serum CEA concentration after chemotherapy for disseminated colorectal cancer is a predictor of prolonged survival and compared it with tumour response as a predictor of survival. There was a 37% improvement in median survival among patients whose serum CEA concentration fell after chemotherapy (70% of patients treated) compared with patients whose serum CEA did not fall. The use of greater than 25% clinical or radiological tumour shrinkage as a predictor of prolonged survival identified a smaller proportion (36%) of patients in whom there was a 52% prolongation in median survival compared with patients whose tumours shrank less than 25%, or did not shrink. Proportional hazards regression analysis suggested that tumour shrinkage was a stronger predictor of survival. A fall in serum CEA concentration, however, identified a group of patients whose tumours did not shrink, but who had a 27% improvement in median survival compared with those whose tumours did not shrink and whose serum CEA concentration did not fall. Monitoring of the serum CEA during the first two months of treatment appears to provide a sensitive and economical means of identifying those patients whose survival is likely to be prolonged by chemotherapy for colorectal cancer.

Authors
Allen-Mersh, TG; Kemeny, N; Niedzwiecki, D; Shurgot, B; Daly, JM
MLA Citation
Allen-Mersh, TG, Kemeny, N, Niedzwiecki, D, Shurgot, B, and Daly, JM. "Significance of a fall in serum CEA concentration in patients treated with cytotoxic chemotherapy for disseminated colorectal cancer." Gut 28.12 (December 1987): 1625-1629.
PMID
3428690
Source
pubmed
Published In
Gut
Volume
28
Issue
12
Publish Date
1987
Start Page
1625
End Page
1629

Phase I and clinical pharmacology study of trimetrexate administered weekly for three weeks.

Trimetrexate, a new antifolate compound, was administered by 30-min infusions weekly for 3 weeks to 29 patients with solid tumors in a Phase I study. Thrombocytopenia was dose limiting, but highly variable among patients at a given dose level; other toxicity was mild and uncommon. Twenty-three patients participated in pharmacokinetic studies and five patients participated in a study of the effects of trimetrexate on [6-3H]-deoxyuridine incorporation into hematopoietic cell DNA. The median total body clearance of trimetrexate for each dose level was independent of dose but the total body clearance varied widely among patients at a given dose level. The magnitude of the fall in platelet count in individual patients correlated well with the amount of exposure to trimetrexate, but not with the extent of prior therapy. The amount of [6-3H]deoxyuridine incorporation into hematopoietic cell DNA at 72 h after drug administration correlated with the total body clearance of trimetrexate. The total body clearance of trimetrexate was reduced in patients with impaired hepatic synthetic function, as judged by low pretreatment serum albumin concentrations. The recommended Phase II starting dose on this schedule is 130 mg/m2 weekly for 3 weeks; patients with hypoalbuminemia should be treated at lower doses.

Authors
Fanucchi, MP; Walsh, TD; Fleisher, M; Lokos, G; Williams, L; Cassidy, C; Vidal, P; Chou, TC; Niedzwiecki, D; Young, CW
MLA Citation
Fanucchi, MP, Walsh, TD, Fleisher, M, Lokos, G, Williams, L, Cassidy, C, Vidal, P, Chou, TC, Niedzwiecki, D, and Young, CW. "Phase I and clinical pharmacology study of trimetrexate administered weekly for three weeks." Cancer Res 47.12 (June 15, 1987): 3303-3308.
PMID
2953412
Source
pubmed
Published In
Cancer Research
Volume
47
Issue
12
Publish Date
1987
Start Page
3303
End Page
3308

Evaluation of new anticancer agents against human pancreatic carcinomas in nude mice.

Heterotransplantation of human cancers in nude mice has provided an in vivo model for studying the biologic characteristics of human tumors, particularly their response to chemotherapy. In an effort to identify cytotoxic agents effective against pancreatic carcinoma, this model was used to evaluate the efficacy of three new anticancer agents--menogarol, 4'-epirubicin, and taxol--against two human transplanted pancreatic tumors. Relative area (tumor length X width) differed significantly between menogarol-treated and control groups (p = 0.034). A marked response was also observed in the tumors to 4'-epirubicin (p = 0.01). Taxol was ineffective in controlling tumor growth; by the fourth week, the size of treated tumors was similar to that of the control group (p = 0.55). No toxicity was observed in either the menogarol- or taxol-treated animals. Animals bearing the P2 tumor, and treated with 4' epirubicin displayed severe toxicity by day 18 with death by day 21 in most animals. For the second tumor, Capan-1, relative area differed significantly between the menogarol-treated and the control group (p = 0.003). In animals given 4'-epirubicin, a smaller difference was observed when comparing the relative areas (p = 0.09). Animals treated with taxol again showed no difference in the tumors when compared with controls (p = 1.0). The use of the nude mouse system has evolved so that tumor-oriented trials are now feasible with the hope of clinical applicability. This study illustrates that at least two agents--menogarol and 4'-epirubicin--may have some antitumor activity against pancreatic carcinoma in this system.

Authors
Sternberg, CN; Sordillo, PP; Cheng, E; Chuang, YJ; Niedzwiecki, D
MLA Citation
Sternberg, CN, Sordillo, PP, Cheng, E, Chuang, YJ, and Niedzwiecki, D. "Evaluation of new anticancer agents against human pancreatic carcinomas in nude mice." Am J Clin Oncol 10.3 (June 1987): 219-221.
PMID
2884864
Source
pubmed
Published In
American Journal of Clinical Oncology: Cancer Clinical Trials
Volume
10
Issue
3
Publish Date
1987
Start Page
219
End Page
221

The impact of neuroleptic medication on tardive dyskinesia: a meta-analysis of published studies.

To quantify the impact of chronic exposure to neuroleptic medication on the occurrence of tardive dyskinesia (TD), we conducted a meta-analysis of data collected from 21 studies published between 1966 and 1985. The observed prevalence of dyskinesia was greater among exposed subjects in all 21 studies; we estimate that, on the average, the occurrence rate was 2.9 times greater in exposed persons than would be expected if they had been unexposed. We estimate that 65 per cent of exposed cases and 51 per cent of all cases in these investigations were caused by long-term neuroleptic exposure. Among adult United States residents in 1980, we estimate that there were approximately 193,000 neuroleptic-induced TD cases of which about 60 per cent occurred in outpatients. We also observed substantial heterogeneity of effect (rate ratio) across studies, however, partially explained, by changes and differences in the rate of dyskinesia, by differences in the frequency of certain effect modifiers, and by differences in diagnostic methods. Methodologic limitations of the studies and their possible effects on our results are discussed.

Authors
Morgenstern, H; Glazer, WM; Niedzwiecki, D; Nourjah, P
MLA Citation
Morgenstern, H, Glazer, WM, Niedzwiecki, D, and Nourjah, P. "The impact of neuroleptic medication on tardive dyskinesia: a meta-analysis of published studies." Am J Public Health 77.6 (June 1987): 717-724.
PMID
2883905
Source
pubmed
Published In
American journal of public health
Volume
77
Issue
6
Publish Date
1987
Start Page
717
End Page
724

Toxicity, elimination, and metabolism of 10-ethyl-10-deazaaminopterin in rats and dogs.

10-Ethyl-10-deazaaminopterin (10-EdAM) is an antifolate compound with greater therapeutic activity than methotrexate against transplanted tumors in mice. When given weekly for 3 weeks, the 10% lethal dose in rats was 125 mg/kg (i.p.) and in dogs it was 2.5 mg/kg (i.v.). The major histopathological findings in intoxicated animals were damage to the mucosa of the gastrointestinal tract in rats and dogs and hypocellularity of the marrow in rats. The elimination of 50 mg/kg of 10-EdAM from the plasma of rats was triexponential with a terminal phase t1/2 of 18.5 h but a mean residence time of 0.7 h. The primary route of elimination in rats was biliary secretion of parent compound and eventual excretion of the parent compound and the deglutamate metabolite in the feces; the 7-hydroxy metabolite was also present in plasma, bile, and feces. Biliary elimination was independent of dose over a 5-fold range. The elimination of 10-EdAM from the plasma of dogs was also triexponential with a mean terminal phase t1/2 of 9.1 h and a mean residence time of 2.5 h; nonrenal clearance was the primary route of elimination. The pharmacokinetic parameters were independent of dose over the range of 0.25 to 5.0 mg/kg. High tissue concentrations of 10-EdAM were observed initially in liver, kidney, and small intestine of rats, while concentrations in bone marrow were low. Some polyglutamate formation was observed in these tissues as early as 0.5 h after drug administration but declined over 72 h.

Authors
Fanucchi, MP; Kinahan, JJ; Samuels, LL; Hancock, C; Chou, TC; Niedzwiecki, D; Farag, F; Vidal, PM; DeGraw, JI; Sternberg, SS
MLA Citation
Fanucchi, MP, Kinahan, JJ, Samuels, LL, Hancock, C, Chou, TC, Niedzwiecki, D, Farag, F, Vidal, PM, DeGraw, JI, and Sternberg, SS. "Toxicity, elimination, and metabolism of 10-ethyl-10-deazaaminopterin in rats and dogs." Cancer Res 47.9 (May 1, 1987): 2334-2339.
PMID
2436760
Source
pubmed
Published In
Cancer Research
Volume
47
Issue
9
Publish Date
1987
Start Page
2334
End Page
2339

High-dose human lymphoblastoid interferon in metastatic colorectal cancer: clinical results and modification of biological responses.

A total of 22 patients with advanced measurable colorectal carcinoma were treated with human lymphoblastoid interferon, 15 X 10(6) U/m2 im 3 times a week, in a trial designed to evaluate therapeutic activity, toxic effects, and biological response modification. One partial response (4.5% response rate) was observed which lasted 4 months. Sixty-eight percent of the patients required dose reduction for excessive toxicity, primarily constitutional symptoms. One patient developed phenobarbital toxicity, a previously undescribed side effect thought to be related to interferon-induced depression of hepatic microsomal enzymes required for drug metabolism. Treatment was associated with an increase in peripheral blood natural killer (NK) cell activity and the activity of an interferon-induced enzyme, 2'-5' oligoadenylate synthetase. The increase in NK cell activity was observed only in patients whose pretreatment NK cell activity was below normal. No induction of serum factors inducing differentiation of myeloid leukemic cell lines was documented. We conclude that human lymphoblastoid interferon, at the dose and schedule tested, has minimal antitumor activity as a single agent in advanced colorectal cancer and induces unacceptable toxicity in the majority of such patients. Recent literature suggesting a possible role for interferon alpha in combination with other drugs in the treatment of colorectal cancer is discussed.

Authors
Krown, SE; Mintzer, D; Cunningham-Rundles, S; Niedzwiecki, D; Krim, M; Einzig, AI; Gabrilove, JL; Shurgot, B; Gessula, J
MLA Citation
Krown, SE, Mintzer, D, Cunningham-Rundles, S, Niedzwiecki, D, Krim, M, Einzig, AI, Gabrilove, JL, Shurgot, B, and Gessula, J. "High-dose human lymphoblastoid interferon in metastatic colorectal cancer: clinical results and modification of biological responses." Cancer Treat Rep 71.1 (January 1987): 39-45.
PMID
3791267
Source
pubmed
Published In
Cancer Treatment Reports
Volume
71
Issue
1
Publish Date
1987
Start Page
39
End Page
45

Pharmacokinetics of cis-diamminedichloroplatinum(II) after administration in hypertonic saline.

Nephrotoxicity, the dose-limiting toxicity of cis-diamminedichloroplatinum(II) (CDDP), is ameliorated when administered in hypertonic saline with normal saline hydration. To determine whether the diminished nephrotoxicity is associated with alteration of the pharmacokinetics of CDDP, we examined the pharmacokinetics of free and total platinum, platinum renal excretion, and urine electrolytes in patients given CDDP in hypertonic saline and in patients given CDDP in a conventional manner. The pharmacokinetics of free and total platinum for equal doses of CDDP were similar regardless of the vehicle of administration and the method of hydration. CDDP given in a vehicle of high chloride concentration with normal saline hydration resulted in a statistically significant increase in both urine volume and chloruresis compared to the conventional regimen. The decreased nephrotoxicity associated with administration of CDDP in hypertonic saline with saline diuresis may be related to increased chloruresis, urinary volume, or a combination of both, but did not appear to be related to an alteration in the pharmacokinetics.

Authors
Bajorin, DF; Bosl, GJ; Alcock, NW; Niedzwiecki, D; Gallina, E; Shurgot, B
MLA Citation
Bajorin, DF, Bosl, GJ, Alcock, NW, Niedzwiecki, D, Gallina, E, and Shurgot, B. "Pharmacokinetics of cis-diamminedichloroplatinum(II) after administration in hypertonic saline." Cancer Res 46.11 (November 1986): 5969-5972.
PMID
3756934
Source
pubmed
Published In
Cancer Research
Volume
46
Issue
11
Publish Date
1986
Start Page
5969
End Page
5972

Etoposide in prostatic cancer: experimental studies and phase II trial in patients with bidimensionally measurable disease.

Etoposide, a semisynthetic derivative of podophyllotoxin, was evaluated concurrently in vitro against a human derived hormone-resistant cell line, PC-3, and in vivo in bidimensionally measurable hormone-resistant human prostatic cancer. In vitro, a dose-response relationship was observed, with 74% inhibition at 10 micrograms/ml (1 h incubation) and greater than 99% inhibition at 90 micrograms/ml, both in the range of clinically achievable concentrations. In vivo, 1 PR (5%, 95% confidence limits 0-12%) of 18+ months was observed in 20 adequately treated patients. The results confirm the limited role of etoposide in hormone-refractory disease and the need for new model systems for evaluation of potential chemotherapeutic compounds in this disease.

Authors
Scher, HI; Sternberg, C; Heston, WD; Watson, RC; Niedzwiecki, D; Smart, T; Hollander, P; Yagoda, A
MLA Citation
Scher, HI, Sternberg, C, Heston, WD, Watson, RC, Niedzwiecki, D, Smart, T, Hollander, P, and Yagoda, A. "Etoposide in prostatic cancer: experimental studies and phase II trial in patients with bidimensionally measurable disease." Cancer Chemother Pharmacol 18.1 (1986): 24-26.
PMID
3757155
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
18
Issue
1
Publish Date
1986
Start Page
24
End Page
26

Pharmacokinetics of intravenous (IV) and oral (PO) idarubicin (4DMDR) in children with cancer

Authors
Hancock, C; Bacha, D; Niedzwiecki, D
MLA Citation
Hancock, C, Bacha, D, and Niedzwiecki, D. "Pharmacokinetics of intravenous (IV) and oral (PO) idarubicin (4DMDR) in children with cancer." Proceedings of the American Association for Cancer Research VOL. 26 (1985): No.-621.
Source
scival
Published In
Proceedings of the American Association for Cancer Research
Volume
VOL. 26
Publish Date
1985
Start Page
No.
End Page
621

Pharmacokinetics of idarubicin (4-DMDR) with or without cytarabine (ARA-C) in patients (pts) with relapsed leukemia

Authors
Hancock, C; Niedzwiecki, D; Merke, D
MLA Citation
Hancock, C, Niedzwiecki, D, and Merke, D. "Pharmacokinetics of idarubicin (4-DMDR) with or without cytarabine (ARA-C) in patients (pts) with relapsed leukemia." Proceedings of the American Association for Cancer Research VOL. 26 (1985): No.-622.
Source
scival
Published In
Proceedings of the American Association for Cancer Research
Volume
VOL. 26
Publish Date
1985
Start Page
No.
End Page
622
Show More