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Kelley, Michael John

Overview:

1.     A major theme throughout my career has been the biology of and improving outcomes for patients with lung cancer.  Early publications examined the relationship between specific genetic alterations in lung cancer and clinically relevant applications including differential drug sensitivity, differentiation of metastases from second primary cancers, and application of patient-specific mutations as epitopes for immunotherapy.  Correlation of alteration of p16 with drug sensitivity led to identification of a class of CDK4 inhibitor. I served as the primary investigator or co-investigator in all of these studies.  I led a study that demonstrated that tubulin mutations are uncommon in lung cancer and described the artifactual detection of pseudogenes as the origin of a prior report claiming association of tubulin mutation with taxane sensitivity, thus correcting the scientific record. 


2.   A second area of continuing interest in lung cancer is the conduct of therapeutic and prevention clinical trials.  These trials have primarily been translation of hypotheses derived primarily from laboratory-based biological observations including the GRP autocrine growth factor in small cell lung cancer, a phase I study of a pulmonary toxin in non-small cell lung cancer, mutation-specific immunotherapy, and a putative chemopreventive agent for smokers.  More recently, I have been an active member of the Respiratory Committee of CALGB/Alliance including serving as principal investigator on a trial testing the addition of irinotecan to treatment of patients with small cell lung cancer. 


3.  Through my clinical practice, I identified a large family with the May-Hegglin anomaly, an autosomal dominant platelet condition characterized as thrombocytopenia, leukocyte inclusions, and giant platelets.  While the condition had been described in the early 1900s, the genetic basis was unknown.  I conceptualized and led a project to identify the underlying molecular basis of this frequently misdiagnosed disorder through classical genetics.  I then extended that observation to related genetic conditions (now known as MYH9-assocaited disorders) characterized by varying degrees of hematological abnormalities, hearing loss and renal disease.  Analysis of the spectrum of observed mutations and phenotypes resulted in identification of a genotype-phenotype association for the most medically significant aspects of the disorders.  Working with Dan Kiehart’s lab, we described the effect of commonly observed mutations of MYH9 on assembly of non-muscle myosin.  An animal model of the most common MYH9 mutation was created in my lab and demonstrated hematological abnormalities similar to those found in humans. 


4.  I described genetic linkage for a rare familial cancer syndrome characterized by very high penetrance of chordoma.  Subsequent linkage analysis resolved a phenotype mis-assignment and resulted in identification of germline gene duplication of the T-box gene, Brachyury in about half of affected families.  I then confirmed another groups report that a common coding region SNP of the Brachyury gene as well as additional genetic variants are associated with an increased risk for development of chordoma independent of amplification of the Brachyury gen.   To study the biology of chordoma, I established the origin of existing putative chordoma cell lines and working criteria for identification of possible new chordoma cell lines.  Using two confirmed chordoma cell lines, I screened all regulatory-approved drugs for anti-growth activity to determine whether any could be repurposed for clinical use in patients. 


5.  Beginning in 2007, I began to transition my career to a leadership position within the Department of Veterans Affairs as the National Program Director for Oncology.  This led to opportunities to utilize the vast and detailed clinical data sets of nearly 1 million patients with cancer to address questions that have been difficult to study either through randomized trials or in less robust datasets.  The use of surgery to treat early stage non-small cell lung cancer is a standard treatment for which I observed a racial disparity.  The lower rate of use of surgery among African Americans was not explained by association with comorbidity.  In another study, I described the rate of use of adjuvant chemotherapy as having increased temporally after publication of randomized trials showing a modest benefit to its use.  I showed that initially this chemotherapy was primarily carboplatin-based, despite all positive trials having used cisplatin.  Cisplatin use has subsequently increased though there is not a demonstrable improvement is survival associated with its use.  I also showed that survival overall, regardless of use of chemotherapy, has improved suggesting that the application of clinical trial data for adjuvant chemotherapy is improving outcome.  In a related study, I found that elderly patients benefit as much as younger patients from adjuvant chemotherapy.  Patients with stage III non-small cell lung cancer are frequently treated with concurrent chemoradiotherapy, for which there are two commonly used chemotherapy regimens: cisplatin-etoposide and carboplatin-paclitaxel.  I examined the outcome and toxicity of patients treated with these two regimens and found that while there was no significant difference in survival, there was more toxicity associated with cisplatin-etoposide.  This finding may impact one current clinical guideline recommendation that favors cisplatin-etoposide over carboplatin-paclitaxel.  Finally, in stage IV disease, a similar observation was made that cisplatin-based chemotherapy is associated with greater toxicity but not improved survival. 


Complete List of Published Work in MyBibliography:   http://www.ncbi.nlm.nih.gov/sites/myncbi/michael.kelley.1/bibliography/4...

Positions:

Professor of Medicine

Medicine, Medical Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1985

M.D. — University of Michigan at Ann Arbor

Grants:

Chordoma Foundation Brachyury Mouse Model Project

Administered By
Medicine, Medical Oncology
AwardedBy
Chordoma Foundation
Role
Principal Investigator
Start Date
January 01, 2016
End Date
December 31, 2017

Chordoma Genetically Engineered Mouse Model

Administered By
Medicine, Medical Oncology
AwardedBy
Chordoma Foundation
Role
Principal Investigator
Start Date
July 01, 2014
End Date
June 30, 2015

IPA - David Alcorta

Administered By
Medicine, Medical Oncology
AwardedBy
Veterans Administration Medical Center
Role
Principal Investigator
Start Date
July 01, 2013
End Date
October 01, 2013

Young Smokers' Reactions to Genetic Risk for Lung Cancer

Administered By
School of Nursing
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
August 01, 2007
End Date
July 31, 2013

IPA - David Alcorta

Administered By
Medicine, Medical Oncology
AwardedBy
Veterans Administration Medical Center
Role
Principal Investigator
Start Date
July 01, 2011
End Date
May 01, 2013

IPA - Sufeng Li

Administered By
Medicine, Medical Oncology
AwardedBy
Veterans Administration Medical Center
Role
Principal Investigator
Start Date
July 01, 2011
End Date
October 31, 2012

Genetic Determinants of Susceptibility to Kidney Disease in African Americans

Administered By
Medicine, Nephrology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 22, 2009
End Date
July 31, 2012

IPA - Sufeng Li

Administered By
Medicine, Medical Oncology
AwardedBy
Veterans Administration Medical Center
Role
Principal Investigator
Start Date
July 01, 2009
End Date
June 30, 2011

Quit-smoking program for lung cancer patients' families

Administered By
Duke Cancer Institute
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
May 10, 2003
End Date
April 30, 2010

IPA Enyu Ding

Administered By
Medicine, Medical Oncology
AwardedBy
Veterans Administration Medical Center
Role
Principal Investigator
Start Date
June 01, 2007
End Date
August 31, 2009

IPA - Sufeng Li

Administered By
Medicine, Medical Oncology
AwardedBy
Veterans Administration Medical Center
Role
Principal Investigator
Start Date
April 01, 2007
End Date
March 31, 2009

Biomarker Studies for Novel Anti-Cancer Agents

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
May 28, 2003
End Date
February 29, 2008

Phase I/II Trial of ZD1839 and Celecoxib in Ex-Smokers

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 26, 2002
End Date
August 31, 2007

Mentored Clinical Research Scholar Program

Administered By
Medicine, Infectious Diseases
AwardedBy
National Institutes of Health
Role
Co-Mentor
Start Date
September 30, 2002
End Date
September 29, 2006

Measurement of Hypoxia in Non-Small Cell Lung Carcinoma

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 2002
End Date
March 31, 2006

Genetic Analysis of Hereditary Macrothrombocytopenias

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
February 15, 2001
End Date
November 30, 2004
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Publications:

Implementation of Lung Cancer Screening in the Veterans Health Administration.

The US Preventive Services Task Force recommends annual lung cancer screening (LCS) with low-dose computed tomography for current and former heavy smokers aged 55 to 80 years. There is little published experience regarding implementing this recommendation in clinical practice.To describe organizational- and patient-level experiences with implementing an LCS program in selected Veterans Health Administration (VHA) hospitals and to estimate the number of VHA patients who may be candidates for LCS.This clinical demonstration project was conducted at 8 academic VHA hospitals among 93 033 primary care patients who were assessed on screening criteria; 2106 patients underwent LCS between July 1, 2013, and June 30, 2015.Implementation Guide and support, full-time LCS coordinators, electronic tools, tracking database, patient education materials, and radiologic and nodule follow-up guidelines.Description of implementation processes; percentages of patients who agreed to undergo LCS, had positive findings on results of low-dose computed tomographic scans (nodules to be tracked or suspicious findings), were found to have lung cancer, or had incidental findings; and estimated number of VHA patients who met the criteria for LCS.Of the 4246 patients who met the criteria for LCS, 2452 (57.7%) agreed to undergo screening and 2106 (2028 men and 78 women; mean [SD] age, 64.9 [5.1] years) underwent LCS. Wide variation in processes and patient experiences occurred among the 8 sites. Of the 2106 patients screened, 1257 (59.7%) had nodules; 1184 of these patients (56.2%) required tracking, 42 (2.0%) required further evaluation but the findings were not cancer, and 31 (1.5%) had lung cancer. A variety of incidental findings, such as emphysema, other pulmonary abnormalities, and coronary artery calcification, were noted on the scans of 857 patients (40.7%).It is estimated that nearly 900 000 of a population of 6.7 million VHA patients met the criteria for LCS. Implementation of LCS in the VHA will likely lead to large numbers of patients eligible for LCS and will require substantial clinical effort for both patients and staff.

Authors
Kinsinger, LS; Anderson, C; Kim, J; Larson, M; Chan, SH; King, HA; Rice, KL; Slatore, CG; Tanner, NT; Pittman, K; Monte, RJ; McNeil, RB; Grubber, JM; Kelley, MJ; Provenzale, D; Datta, SK; Sperber, NS; Barnes, LK; Abbott, DH; Sims, KJ; Whitley, RL; Wu, RR; Jackson, GL
MLA Citation
Kinsinger, LS, Anderson, C, Kim, J, Larson, M, Chan, SH, King, HA, Rice, KL, Slatore, CG, Tanner, NT, Pittman, K, Monte, RJ, McNeil, RB, Grubber, JM, Kelley, MJ, Provenzale, D, Datta, SK, Sperber, NS, Barnes, LK, Abbott, DH, Sims, KJ, Whitley, RL, Wu, RR, and Jackson, GL. "Implementation of Lung Cancer Screening in the Veterans Health Administration." JAMA internal medicine 177.3 (March 2017): 399-406.
PMID
28135352
Source
epmc
Published In
JAMA Internal Medicine
Volume
177
Issue
3
Publish Date
2017
Start Page
399
End Page
406
DOI
10.1001/jamainternmed.2016.9022

BRCA testing within the Department of Veterans Affairs: concordance with clinical practice guidelines.

Guideline-concordant cancer care is a priority within the Department of Veterans Affairs (VA). In 2009, the VA expanded its capacity to treat breast cancer patients within VA medical centers (VAMCs). We sought to determine whether male and female Veterans diagnosed with breast cancer received BRCA testing as recommended by the National Comprehensive Cancer Network (NCCN) guidelines on Genetic/Familial High-Risk Assessment in Breast and Ovarian Cancer (v. 1.2010-1.2012). Using the 2011-2012 VA Central Cancer Registry and BRCA test orders from Myriad Genetics, we conducted a retrospective study. The outcome variable was a recommendation for genetic counseling or BRCA testing, determined by chart review. Independent variables expected to predict testing included region, site of care, and patient characteristics. We performed descriptive analysis of all patients and conducted multivariable logistic regression on patients who sought care at VAMCs that offered BRCA testing. Of the 462 Veterans who met NCCN testing criteria, 126 (27 %) received guideline-concordant care, either a referral for counseling or actual testing. No BRCA testing was recommended in 49 (50 %) VAMCs that provide cancer treatment. Surprisingly, patients with second primary breast cancer were less likely to be referred/tested (OR 0.39; CI 0.17, 0.89; p = 0.025). For patients under age 51, a yearly increase in age decreased likelihood of referral or testing (OR 0.85; CI 0.76, 0.94; p < 0.001). There were no differences in testing by race. In conclusion, there was significant underutilization and lack of access to BRCA testing for Veterans diagnosed with breast cancer. Our research suggests the need for clinical decision support tools to facilitate delivery of guideline-concordant cancer care and improve Veteran access to BRCA testing.

Authors
Chun, DS; Berse, B; Venne, VL; DuVall, SL; Filipski, KK; Kelley, MJ; Meyer, LJ; Icardi, MS; Lynch, JA
MLA Citation
Chun, DS, Berse, B, Venne, VL, DuVall, SL, Filipski, KK, Kelley, MJ, Meyer, LJ, Icardi, MS, and Lynch, JA. "BRCA testing within the Department of Veterans Affairs: concordance with clinical practice guidelines." Familial cancer 16.1 (January 2017): 41-49.
PMID
27589855
Source
epmc
Published In
Familial Cancer
Volume
16
Issue
1
Publish Date
2017
Start Page
41
End Page
49
DOI
10.1007/s10689-016-9921-5

Phase II Study of Dasatinib in Previously Treated Patients with Advanced Non-Small Cell Lung Cancer.

The Src pathway in activated in about one-third of non-small cell lung cancer (NSCLC) tumors. Dasatinib has Src-inhibitor activity. We examined the activity of dasatinib in 37 patients with advanced, previously treated NSCLC. Among the 29 patients who underwent pre-treatment biopsy for RNA biomarker analysis, 25 were treated with dasatinib 70 mg twice daily. There were no responses. Five patients discontinued treatment due to toxicity. Three patients had minor biopsy-related pneumothoraces. Given the lack of responses, no biomarkers were analyzed. Dasatinib 70 mg twice daily does not have activity nor is it well tolerated in unselected patients with advanced stage, previously treated NSCLC.

Authors
Kelley, MJ; Jha, G; Shoemaker, D; Herndon, JE; Gu, L; Barry, WT; Crawford, J; Ready, N
MLA Citation
Kelley, MJ, Jha, G, Shoemaker, D, Herndon, JE, Gu, L, Barry, WT, Crawford, J, and Ready, N. "Phase II Study of Dasatinib in Previously Treated Patients with Advanced Non-Small Cell Lung Cancer." Cancer investigation 35.1 (January 2017): 32-35.
PMID
27911119
Source
epmc
Published In
Cancer Investigation (Informa)
Volume
35
Issue
1
Publish Date
2017
Start Page
32
End Page
35
DOI
10.1080/07357907.2016.1253710

Epidermal Growth Factor Receptor Mutational Testing and Erlotinib Treatment Among Veterans Diagnosed With Lung Cancer in the United States Department of Veterans Affairs.

We examined mutational testing of the epidermal growth factor gene (EGFR) and erlotinib treatment among veterans diagnosed with non-small-cell lung cancer in the United States Department of Veterans Affairs (VA). Our objectives were to identify the prevalence of clinically actionable EGFR mutations, to determine whether testing and treatment were guideline concordant, to evaluate the impact of testing and treatment on survival, and to estimate the rate of testing.Test results were linked to electronic health records from VA Corporate Data Warehouse and the VA Central Cancer Registry. We analyzed patient demographic and clinical characteristics, prevalence of EGFR mutations, and timing of EGFR mutational testing and erlotinib treatment based on pharmacy records. Overall survival was assessed by Kaplan-Meier analysis.Among 973 patients tested at 70 VA medical centers between 2011 and 2013, 64 (7%) had sensitizing EGFR mutations, 694 (71%) were EGFR wild type, and 168 (17%) had clinically insignificant polymorphisms or variants of unknown significance. Results were not documented in 47 tests (5%). Erlotinib administration was in agreement with test results in 843 cases (87%).Veterans have a much lower rate of sensitizing EGFR mutations than the reported average of 10% to 15%, which correlates with a high rate of smoking among veterans. This may partially explain clinicians' reluctance to prescribe EGFR testing, which results in underutilization. Although test results appear to have influenced erlotinib treatment decisions, we documented a substantial number of cases where treatment was not applied in accordance with clinical guidelines, potentially resulting in worse outcomes and unnecessary cost.

Authors
Lynch, JA; Berse, B; Chun, D; Rivera, D; Filipski, KK; Kulich, S; Viernes, B; DuVall, SL; Kelley, MJ
MLA Citation
Lynch, JA, Berse, B, Chun, D, Rivera, D, Filipski, KK, Kulich, S, Viernes, B, DuVall, SL, and Kelley, MJ. "Epidermal Growth Factor Receptor Mutational Testing and Erlotinib Treatment Among Veterans Diagnosed With Lung Cancer in the United States Department of Veterans Affairs." Clinical lung cancer (December 7, 2016).
PMID
28038980
Source
epmc
Published In
Clinical lung cancer
Publish Date
2016
DOI
10.1016/j.cllc.2016.11.018

Colorectal Cancer Statistics From the Veterans Affairs Central Cancer Registry.

Colorectal cancer (CRC) is a common and potentially deadly disease. Although the United States has robust cancer data reporting, information from the Department of Veterans Affairs (VA) healthcare system has often been underrepresented in national cancer data sources. We describe veterans with incident CRC in terms of their patient and tumor characteristics and mortality.Patients diagnosed or treated with CRC at any VA institution in the fiscal years 2009 to 2012 were identified using 3 data sources: (1) VA Central Cancer Registry (VACCR); (2) VA Corporate Data Warehouse; and (3) VA Reports and Measures Portal. The CRC frequencies within the VA population and survival curves were examined descriptively and compared with the national projections using Surveillance, Epidemiology, and End Results program data.A total of 12,551 veterans with CRC were included in the present analysis. The median age at diagnosis was 65.5 years. Approximately 97% (n = 12,229) of the CRC cases were diagnosed among men. Approximately 44% (n = 5517) of the patients were diagnosed with localized disease. The 3-year survival rate was associated with age (P < .01) and stage (P < .01) at diagnosis. We identified a possible decrease in VA CRC incidence over time.Although the VA CRC patient population was heavily skewed toward the male gender, the patient and tumor characteristics were similar between the incident CRC cases reported by the VACCR and those reported to the Surveillance, Epidemiology, and End Results program. This suggests that research findings resulting from the VACCR might have applicability beyond the VA healthcare system setting.

Authors
Zullig, LL; Smith, VA; Jackson, GL; Danus, S; Schnell, M; Lindquist, J; Provenzale, D; Weinberger, M; Kelley, MJ; Bosworth, HB
MLA Citation
Zullig, LL, Smith, VA, Jackson, GL, Danus, S, Schnell, M, Lindquist, J, Provenzale, D, Weinberger, M, Kelley, MJ, and Bosworth, HB. "Colorectal Cancer Statistics From the Veterans Affairs Central Cancer Registry." Clinical colorectal cancer 15.4 (December 2016): e199-e204.
PMID
27301717
Source
epmc
Published In
Clinical colorectal cancer
Volume
15
Issue
4
Publish Date
2016
Start Page
e199
End Page
e204
DOI
10.1016/j.clcc.2016.04.005

Survival With Stereotactic Body Radiation Therapy (SBRT) and Conventional Radiation Therapy (CRT) in Stage I Non-Small Cell Lung Cancer Patients in the Veterans Affairs System

Authors
Boyer, MJ; Williams, C; Kelley, MJ; Salama, JK
MLA Citation
Boyer, MJ, Williams, C, Kelley, MJ, and Salama, JK. "Survival With Stereotactic Body Radiation Therapy (SBRT) and Conventional Radiation Therapy (CRT) in Stage I Non-Small Cell Lung Cancer Patients in the Veterans Affairs System." October 1, 2016.
Source
wos-lite
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
96
Issue
2
Publish Date
2016
Start Page
S9
End Page
S9

Outcome Analysis of Treatment in Stage IIA, T3N0 Rectal Adenocarcinoma in the Veterans Health Administration (VHA)

Authors
Hall, WA; Lans, D; Arce-Lara, C; Kelley, MJ; Santana-Davila, R; Marcus, DM; Tsai, S; Ridolfi, T; Erickson, BA; Gore, EM
MLA Citation
Hall, WA, Lans, D, Arce-Lara, C, Kelley, MJ, Santana-Davila, R, Marcus, DM, Tsai, S, Ridolfi, T, Erickson, BA, and Gore, EM. "Outcome Analysis of Treatment in Stage IIA, T3N0 Rectal Adenocarcinoma in the Veterans Health Administration (VHA)." October 1, 2016.
Source
wos-lite
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
96
Issue
2
Publish Date
2016
Start Page
E186
End Page
E186

Survival With Stereotactic Body Radiation Therapy (SBRT) and Conventional Radiation Therapy (CRT) in Stage I Non-Small Cell Lung Cancer Patients in the Veterans Affairs System

Authors
Boyer, MJ; Williams, C; Kelley, MJ; Salama, JK
MLA Citation
Boyer, MJ, Williams, C, Kelley, MJ, and Salama, JK. "Survival With Stereotactic Body Radiation Therapy (SBRT) and Conventional Radiation Therapy (CRT) in Stage I Non-Small Cell Lung Cancer Patients in the Veterans Affairs System." October 1, 2016.
Source
wos-lite
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
96
Issue
2
Publish Date
2016
Start Page
S9
End Page
S9

Pharmacogenetic Discovery in CALGB (Alliance) 90401 and Mechanistic Validation of a VAC14 Polymorphism that Increases Risk of Docetaxel-Induced Neuropathy.

Discovery of SNPs that predict a patient's risk of docetaxel-induced neuropathy would enable treatment individualization to maximize efficacy and avoid unnecessary toxicity. The objectives of this analysis were to discover SNPs associated with docetaxel-induced neuropathy and mechanistically validate these associations in preclinical models of drug-induced neuropathy.A genome-wide association study was conducted in metastatic castrate-resistant prostate cancer patients treated with docetaxel, prednisone and randomized to bevacizumab or placebo on CALGB 90401. SNPs were genotyped on the Illumina HumanHap610-Quad platform followed by rigorous quality control. The inference was conducted on the cumulative dose at occurrence of grade 3+ sensory neuropathy using a cause-specific hazard model that accounted for early treatment discontinuation. Genes with SNPs significantly associated with neuropathy were knocked down in cellular and mouse models of drug-induced neuropathy.A total of 498,081 SNPs were analyzed in 623 Caucasian patients, 50 (8%) of whom experienced grade 3+ neuropathy. The 1,000 SNPs most associated with neuropathy clustered in relevant pathways including neuropathic pain and axonal guidance. An SNP in VAC14 (rs875858) surpassed genome-wide significance (P = 2.12 × 10-8, adjusted P = 5.88 × 10-7). siRNA knockdown of VAC14 in stem cell-derived peripheral neuronal cells increased docetaxel sensitivity as measured by decreased neurite processes (P = 0.0015) and branches (P < 0.0001). Prior to docetaxel treatment, VAC14 heterozygous mice had greater nociceptive sensitivity than wild-type litter mate controls (P = 0.001).VAC14 should be prioritized for further validation of its potential role as a predictor of docetaxel-induced neuropathy and biomarker for treatment individualization. Clin Cancer Res; 22(19); 4890-900. ©2016 AACR.

Authors
Hertz, DL; Owzar, K; Lessans, S; Wing, C; Jiang, C; Kelly, WK; Patel, J; Halabi, S; Furukawa, Y; Wheeler, HE; Sibley, AB; Lassiter, C; Weisman, L; Watson, D; Krens, SD; Mulkey, F; Renn, CL; Small, EJ; Febbo, PG; Shterev, I; Kroetz, DL; Friedman, PN; Mahoney, JF; Carducci, MA; Kelley, MJ; Nakamura, Y; Kubo, M; Dorsey, SG; Dolan, ME; Morris, MJ; Ratain, MJ; McLeod, HL
MLA Citation
Hertz, DL, Owzar, K, Lessans, S, Wing, C, Jiang, C, Kelly, WK, Patel, J, Halabi, S, Furukawa, Y, Wheeler, HE, Sibley, AB, Lassiter, C, Weisman, L, Watson, D, Krens, SD, Mulkey, F, Renn, CL, Small, EJ, Febbo, PG, Shterev, I, Kroetz, DL, Friedman, PN, Mahoney, JF, Carducci, MA, Kelley, MJ, Nakamura, Y, Kubo, M, Dorsey, SG, Dolan, ME, Morris, MJ, Ratain, MJ, and McLeod, HL. "Pharmacogenetic Discovery in CALGB (Alliance) 90401 and Mechanistic Validation of a VAC14 Polymorphism that Increases Risk of Docetaxel-Induced Neuropathy." Clinical cancer research : an official journal of the American Association for Cancer Research 22.19 (October 2016): 4890-4900.
PMID
27143689
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
22
Issue
19
Publish Date
2016
Start Page
4890
End Page
4900
DOI
10.1158/1078-0432.ccr-15-2823

Impact of Race on Treatment and Survival among U.S. Veterans with Early-Stage Lung Cancer.

Numerous reports suggest lower rates of surgical procedures and poorer survival for black patients with early-stage (stage I or II) NSCLC than for white patients. This study examined treatment trends among blacks and whites with early-stage NSCLC and determined whether racial disparities exist in survival among patients receiving similar treatment.A retrospective analysis of 18,466 patients in the Veteran Affairs Central Cancer Registry in whom stage I or II NSCLC was diagnosed in 2001-2010 was conducted. Patients were categorized as receiving an operation, radiation, or other/no treatment. Overall survival (OS) and lung cancer-specific survival (LCSS) were evaluated using Kaplan-Meier and multivariable Cox regression analyses.There was a statistically significant disparity between black and white patients receiving an operation that decreased over time to similar rates (p = 0.01). No significant racial differences in receipt of radiation were noted. Race was not associated with OS among all patients (hazard ratio [HR] = 0.97, 95% confidence interval [CI]: 0.93-1.02). Among patients who received an operation, no racial difference in OS was observed (HR = 0.94, 95% CI: 0.87-1.01), but the HR for blacks versus whites was 0.90 (95% CI: 0.82-0.98) for radiation treatment and 0.89 (95% CI: 0.81-0.97) for other/no treatment. Race was not associated with LCSS among all patients combined or within each treatment category.A racial disparity in the rate of operation was no longer apparent at the end of the study period. There was no racial difference in OS or LCSS among all patients in this equal access health care system. Long-documented racial differences in lung cancer treatment and mortality result from disparity of access to health care and delivery of recommended treatment.

Authors
Williams, CD; Salama, JK; Moghanaki, D; Karas, TZ; Kelley, MJ
MLA Citation
Williams, CD, Salama, JK, Moghanaki, D, Karas, TZ, and Kelley, MJ. "Impact of Race on Treatment and Survival among U.S. Veterans with Early-Stage Lung Cancer." Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 11.10 (October 2016): 1672-1681.
PMID
27296104
Source
epmc
Published In
Journal of Thoracic Oncology
Volume
11
Issue
10
Publish Date
2016
Start Page
1672
End Page
1681
DOI
10.1016/j.jtho.2016.05.030

Readiness for Implementation of Lung Cancer Screening. A National Survey of Veterans Affairs Pulmonologists.

To mitigate the potential harms of screening, professional societies recommend that lung cancer screening be conducted in multidisciplinary programs with the capacity to provide comprehensive care, from screening through pulmonary nodule evaluation to treatment of screen-detected cancers. The degree to which this standard can be met at the national level is unknown.To assess the readiness of clinical facilities in a national healthcare system for implementation of comprehensive lung cancer screening programs, as compared with the ideal described in policy recommendations.This was a cross-sectional, self-administered survey of staff pulmonologists in pulmonary outpatient clinics in Veterans Health Administration facilities.The facility-level response rate was 84.1% (106 of 126 facilities with pulmonary clinics); 88.7% of facilities showed favorable provider perceptions of the evidence for lung cancer screening, and 73.6% of facilities had a favorable provider-perceived local context for screening implementation. All elements of the policy-recommended infrastructure for comprehensive screening programs were present in 36 of 106 facilities (34.0%); the most common deficiencies were the lack of on-site positron emission tomography scanners or radiation oncology services. Overall, 26.5% of Veterans Health Administration facilities were ideally prepared for lung cancer screening implementation (44.1% if the policy recommendations for on-site positron emission tomography scanners and radiation oncology services were waived).Many facilities may be less than ideally positioned for the implementation of comprehensive lung cancer screening programs. To ensure safe, effective screening, hospitals may need to invest resources or coordinate care with facilities that can offer comprehensive care for screening through downstream evaluation and treatment of screen-detected cancers.

Authors
Tukey, MH; Clark, JA; Bolton, R; Kelley, MJ; Slatore, CG; Au, DH; Wiener, RS
MLA Citation
Tukey, MH, Clark, JA, Bolton, R, Kelley, MJ, Slatore, CG, Au, DH, and Wiener, RS. "Readiness for Implementation of Lung Cancer Screening. A National Survey of Veterans Affairs Pulmonologists." Annals of the American Thoracic Society 13.10 (October 2016): 1794-1801.
PMID
27409524
Source
epmc
Published In
Annals of the American Thoracic Society
Volume
13
Issue
10
Publish Date
2016
Start Page
1794
End Page
1801

Metformin, Diabetes, and Survival among U.S. Veterans with Colorectal Cancer.

Metformin has been associated with improved colorectal cancer survival, but investigations are limited by small numbers of patients and confounding by diabetic severity. We examined the association between metformin use and overall survival (OS) in patients with diabetes and colorectal cancer in a large population of U.S. veterans, while adjusting for measures of diabetic severity.Patients diagnosed with colorectal cancer from January 2001 to December 2008 were identified from the Veterans Affairs Central Cancer Registry. Multivariable models were used to examine the adjusted association of OS with diabetes and use of antidiabetic medications.There were 21,352 patients diagnosed with colorectal cancer identified (n = 16,355 nondiabetic patients, n = 2,038 diabetic patients on metformin, n = 2,136 diabetic patients on medications other than metformin, n = 823 diabetic patients not on antidiabetic medication). Diabetic patients had a significantly worse OS than nondiabetic patients, but metformin users had only a 10% increase in death (HRadj 1.10; 95% CI, 1.03-1.17, P = 0.004), as compared with 22% for users of other antidiabetic medications (HRadj 1.22; 95% CI, 1.15-1.29, P < 0.0001). Among colorectal cancer patients with diabetes, metformin users had a 13% improved OS versus patients taking other antidiabetic medications (HRadj 0.87; 95% CI, 0.79-0.95, P = 0.003), while diabetic patients not on any antidiabetic medications did not differ with respect to OS (HRadj 1.02; 95% CI, 0.90-1.15, P = 0.76).Among diabetics with colorectal cancer, metformin use is associated with improved survival, despite adjustments for diabetes severity and other risk factors.These data lend further support to the conduct of randomized studies of possible anticancer effects of metformin among patients with colorectal cancer. Cancer Epidemiol Biomarkers Prev; 25(10); 1418-25. ©2016 AACR.

Authors
Paulus, JK; Williams, CD; Cossor, FI; Kelley, MJ; Martell, RE
MLA Citation
Paulus, JK, Williams, CD, Cossor, FI, Kelley, MJ, and Martell, RE. "Metformin, Diabetes, and Survival among U.S. Veterans with Colorectal Cancer." Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 25.10 (October 2016): 1418-1425.
PMID
27496094
Source
epmc
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
25
Issue
10
Publish Date
2016
Start Page
1418
End Page
1425
DOI
10.1158/1055-9965.epi-16-0312

Survival With Stereotactic Body Radiation Therapy (SBRT) and Conventional Radiation Therapy (CRT) in Stage I Non-Small Cell Lung Cancer Patients in the Veterans Affairs System.

Authors
Boyer, MJ; Williams, C; Kelley, MJ; Salama, JK
MLA Citation
Boyer, MJ, Williams, C, Kelley, MJ, and Salama, JK. "Survival With Stereotactic Body Radiation Therapy (SBRT) and Conventional Radiation Therapy (CRT) in Stage I Non-Small Cell Lung Cancer Patients in the Veterans Affairs System." International journal of radiation oncology, biology, physics 96.2S (October 2016): S9-.
PMID
27676046
Source
epmc
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
96
Issue
2S
Publish Date
2016
Start Page
S9
DOI
10.1016/j.ijrobp.2016.06.037

Outcome Analysis of Treatment in Stage IIA, T3N0 Rectal Adenocarcinoma in the Veterans Health Administration (VHA).

Authors
Hall, WA; Lans, D; Arce-Lara, C; Kelley, MJ; Santana-Davila, R; Marcus, DM; Tsai, S; Ridolfi, T; Erickson, BA; Gore, EM
MLA Citation
Hall, WA, Lans, D, Arce-Lara, C, Kelley, MJ, Santana-Davila, R, Marcus, DM, Tsai, S, Ridolfi, T, Erickson, BA, and Gore, EM. "Outcome Analysis of Treatment in Stage IIA, T3N0 Rectal Adenocarcinoma in the Veterans Health Administration (VHA)." International journal of radiation oncology, biology, physics 96.2S (October 2016): E186-.
Website
http://hdl.handle.net/10161/13069
PMID
27674006
Source
epmc
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
96
Issue
2S
Publish Date
2016
Start Page
E186
DOI
10.1016/j.ijrobp.2016.06.1058

Second line treatment of small cell lung cancer: more is better?

Authors
Humeniuk, MS; Kelley, MJ
MLA Citation
Humeniuk, MS, and Kelley, MJ. "Second line treatment of small cell lung cancer: more is better?." Annals of translational medicine 4.Suppl 1 (October 2016): S65-.
PMID
27868033
Source
epmc
Published In
Annals of translational medicine
Volume
4
Issue
Suppl 1
Publish Date
2016
Start Page
S65

Abstract 2037: A discovery study to identify clinical and genetic risk factors for bevacizumab (BEV)-related gastrointestinal (GI) hemorrhage (HEM) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated on CALGB 90401 (Alliance)

Authors
Patel, JN; Jiang, C; Owzar, K; Hertz, DL; Mulkey, FA; Kelly, WK; Halabi, S; Furukawa, Y; Lassiter, C; Dorsey, SG; Friedman, PN; Small, EJ; Carducci, MA; Mahoney, JF; Kelley, MJ; Nakamura, Y; Kubo, M; Ratain, MJ; Morris, MJ; McLeod, HL
MLA Citation
Patel, JN, Jiang, C, Owzar, K, Hertz, DL, Mulkey, FA, Kelly, WK, Halabi, S, Furukawa, Y, Lassiter, C, Dorsey, SG, Friedman, PN, Small, EJ, Carducci, MA, Mahoney, JF, Kelley, MJ, Nakamura, Y, Kubo, M, Ratain, MJ, Morris, MJ, and McLeod, HL. "Abstract 2037: A discovery study to identify clinical and genetic risk factors for bevacizumab (BEV)-related gastrointestinal (GI) hemorrhage (HEM) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated on CALGB 90401 (Alliance)." July 15, 2016.
Source
crossref
Published In
Cancer Research
Volume
76
Issue
14 Supplement
Publish Date
2016
Start Page
2037
End Page
2037
DOI
10.1158/1538-7445.AM2016-2037

Veterans health administration hepatitis B testing and treatment with anti-CD20 antibody administration.

To evaluate pretreatment hepatitis B virus (HBV) testing, vaccination, and antiviral treatment rates in Veterans Affairs patients receiving anti-CD20 Ab for quality improvement.We performed a retrospective cohort study using a national repository of Veterans Health Administration (VHA) electronic health record data. We identified all patients receiving anti-CD20 Ab treatment (2002-2014). We ascertained patient demographics, laboratory results, HBV vaccination status (from vaccination records), pharmacy data, and vital status. The high risk period for HBV reactivation is during anti-CD20 Ab treatment and 12 mo follow up. Therefore, we analyzed those who were followed to death or for at least 12 mo after completing anti-CD20 Ab. Pretreatment serologic tests were used to categorize chronic HBV (hepatitis B surface antigen positive or HBsAg+), past HBV (HBsAg-, hepatitis B core antibody positive or HBcAb+), resolved HBV (HBsAg-, HBcAb+, hepatitis B surface antibody positive or HBsAb+), likely prior vaccination (isolated HBsAb+), HBV negative (HBsAg-, HBcAb-), or unknown. Acute hepatitis B was defined by the appearance of HBsAg+ in the high risk period in patients who were pretreatment HBV negative. We assessed HBV antiviral treatment and the incidence of hepatitis, liver failure, and death during the high risk period. Cumulative hepatitis, liver failure, and death after anti-CD20 Ab initiation were compared by HBV disease categories and differences compared using the χ(2) test. Mean time to hepatitis peak alanine aminotransferase, liver failure, and death relative to anti-CD20 Ab administration and follow-up were also compared by HBV disease group.Among 19304 VHA patients who received anti-CD20 Ab, 10224 (53%) had pretreatment HBsAg testing during the study period, with 49% and 43% tested for HBsAg and HBcAb, respectively within 6 mo pretreatment in 2014. Of those tested, 2% (167/10224) had chronic HBV, 4% (326/7903) past HBV, 5% (427/8110) resolved HBV, 8% (628/8110) likely prior HBV vaccination, and 76% (6022/7903) were HBV negative. In those with chronic HBV infection, ≤ 37% received HBV antiviral treatment during the high risk period while 21% to 23% of those with past or resolved HBV, respectively, received HBV antiviral treatment. During and 12 mo after anti-CD20 Ab, the rate of hepatitis was significantly greater in those HBV positive vs negative (P = 0.001). The mortality rate was 35%-40% in chronic or past hepatitis B and 26%-31% in hepatitis B negative. In those pretreatment HBV negative, 16 (0.3%) developed acute hepatitis B of 4947 tested during anti-CD20Ab treatment and follow-up.While HBV testing of Veterans has increased prior to anti-CD20 Ab, few HBV+ patients received HBV antivirals, suggesting electronic health record algorithms may enhance health outcomes.

Authors
Hunt, CM; Beste, LA; Lowy, E; Suzuki, A; Moylan, CA; Tillmann, HL; Ioannou, GN; Lim, JK; Kelley, MJ; Provenzale, D
MLA Citation
Hunt, CM, Beste, LA, Lowy, E, Suzuki, A, Moylan, CA, Tillmann, HL, Ioannou, GN, Lim, JK, Kelley, MJ, and Provenzale, D. "Veterans health administration hepatitis B testing and treatment with anti-CD20 antibody administration." World journal of gastroenterology 22.19 (May 2016): 4732-4740.
Website
http://hdl.handle.net/10161/11950
PMID
27217704
Source
epmc
Published In
World journal of gastroenterology : WJG
Volume
22
Issue
19
Publish Date
2016
Start Page
4732
End Page
4740
DOI
10.3748/wjg.v22.i19.4732

CLINICAL IMPACT OF THE 21-GENE RS TEST WITHIN THE VETERANS HEALTH CARE ADMINISTRATION

Authors
Lynch, J; Chun, DS; Berse, B; Venne, V; Efimova, O; DuVall, S; Filipski, KK; Kelley, MJ
MLA Citation
Lynch, J, Chun, DS, Berse, B, Venne, V, Efimova, O, DuVall, S, Filipski, KK, and Kelley, MJ. "CLINICAL IMPACT OF THE 21-GENE RS TEST WITHIN THE VETERANS HEALTH CARE ADMINISTRATION." May 2016.
Source
wos-lite
Published In
Value in Health
Volume
19
Issue
3
Publish Date
2016
Start Page
A312
End Page
A312

Colorectal cancer survivorship statistics: A Veterans Affairs Central Cancer Registry analysis.

Authors
Zullig, LL; Smith, V; Danus, S; Schnell, M; Lindquist, J; Provenzale, DT; Jackson, GL; Weinberger, M; Kelley, MJ; Bosworth, HB
MLA Citation
Zullig, LL, Smith, V, Danus, S, Schnell, M, Lindquist, J, Provenzale, DT, Jackson, GL, Weinberger, M, Kelley, MJ, and Bosworth, HB. "Colorectal cancer survivorship statistics: A Veterans Affairs Central Cancer Registry analysis." January 20, 2016.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
34
Issue
3
Publish Date
2016

Comparison of Quality Oncology Practice Initiative (QOPI) Measure Adherence Between Oncology Fellows, Advanced Practice Providers, and Attending Physicians.

Quality improvement measures are uniformly applied to all oncology providers, regardless of their roles. Little is known about differences in adherence to these measures between oncology fellows, advance practice providers (APP), and attending physicians. We investigated conformance across Quality Oncology Practice Initiative (QOPI) measures for oncology fellows, advance practice providers, and attending physicians at the Durham Veterans Affairs Medical Center (DVAMC). Using data collected from the Spring 2012 and 2013 QOPI cycles, we abstracted charts of patients and separated them based on their primary provider. Descriptive statistics and the chi-square test were calculated for each QOPI measure between fellows, advanced practice providers (APPs), and attending physicians. A total of 169 patients were reviewed. Of these, 31 patients had a fellow, 39 had an APP, and 99 had an attending as their primary oncology provider. Fellows and attending physicians performed similarly on 90 of 94 QOPI metrics. High-performing metrics included several core QOPI measures including documenting consent for chemotherapy, recommending adjuvant chemotherapy when appropriate, and prescribing serotonin antagonists when prescribing emetogenic chemotherapies. Low-performing metrics included documentation of treatment summary and taking action to address problems with emotional well-being by the second office visit. Attendings documented the plan for oral chemotherapy more often (92 vs. 63%, P=0.049). However, after the chart audit, we found that fellows actually documented the plan for oral chemotherapy 88% of the time (p=0.73). APPs and attendings performed similarly on 88 of 90 QOPI measures. The quality of oncology care tends to be similar between attendings and fellows overall; some of the significant differences do not remain significant after a second manual chart review, highlighting that the use of manual data collection for QOPI analysis is an imperfect system, and there may be significant inter-observer variability.

Authors
Zhu, J; Zhang, T; Shah, R; Kamal, AH; Kelley, MJ
MLA Citation
Zhu, J, Zhang, T, Shah, R, Kamal, AH, and Kelley, MJ. "Comparison of Quality Oncology Practice Initiative (QOPI) Measure Adherence Between Oncology Fellows, Advanced Practice Providers, and Attending Physicians." Journal of cancer education : the official journal of the American Association for Cancer Education 30.4 (December 2015): 774-778.
PMID
25686787
Source
epmc
Published In
Journal of Cancer Education
Volume
30
Issue
4
Publish Date
2015
Start Page
774
End Page
778
DOI
10.1007/s13187-015-0798-z

A National Survey of Pulmonologists' Views on Low-Dose Computed Tomography Screening for Lung Cancer.

Multiple guidelines now recommend low-dose computed tomography (LDCT) screening for lung cancer. Given their central role in the planning of LDCT screening programs, pulmonologists' beliefs about LDCT screening will affect the safety, cost-effectiveness, and success of LDCT screening implementation.To assess pulmonologists' propensity to offer lung cancer screening and their perceptions about LDCT screening.We performed a national web-based survey, administered July 2013 to February 2014, among all staff pulmonologists active in Veterans Health Administration pulmonary clinics. The primary outcome was screening propensity (on the basis of responses to clinical vignettes) in relation to guidelines. Using bivariate and multinomial logistic regression, we assessed how perceptions of the evidence, trade-offs, and barriers to implementation of LDCT screening programs affected propensity to screen.Of 573 eligible pulmonologists e-mailed, 286 (49.9%) participated. Approximately one-half (52.4%) had a propensity for guideline-concordant screening, 22.7% for overscreening, and 24.9% for underscreening. In bivariate analyses, guideline concordance was associated with acceptance of trial evidence, guidelines, and the efficacy of screening. In multivariable models, underscreeners were more likely to cite the potential harms of screening (e.g., false-positive findings, radiation exposure, incidental findings, unfavorable cost-benefit ratio), as influential factors (relative risk, 3.9; 95% confidence interval, 1.5-9.67) and were less influenced by trial evidence and guidelines (relative risk, 0.06; 95% confidence interval, 0.02-0.2), as compared with guideline-concordant screeners. Local resource availability did not significantly affect screening propensity, but insufficient infrastructure and personnel were commonly perceived barriers to implementation.Pulmonologists have varied perceptions of the evidence and trade-offs of LDCT screening, leading to the potential for over- and underscreening. To minimize potential harms as LDCT screening is widely implemented, physicians must understand which patients are appropriate candidates and engage those patients in a shared decision-making process regarding the trade-offs of LDCT screening.

Authors
Iaccarino, JM; Clark, J; Bolton, R; Kinsinger, L; Kelley, M; Slatore, CG; Au, DH; Wiener, RS
MLA Citation
Iaccarino, JM, Clark, J, Bolton, R, Kinsinger, L, Kelley, M, Slatore, CG, Au, DH, and Wiener, RS. "A National Survey of Pulmonologists' Views on Low-Dose Computed Tomography Screening for Lung Cancer." Annals of the American Thoracic Society 12.11 (November 2015): 1667-1675.
PMID
26368003
Source
epmc
Published In
Annals of the American Thoracic Society
Volume
12
Issue
11
Publish Date
2015
Start Page
1667
End Page
1675
DOI
10.1513/annalsats.201507-467oc

Hepatitis B Testing Prior to Administration of Rituximab, Ofatumumab and Obinutuzumab in the National Veterans Affairs Health Healthcare System, 2002-2014

Authors
Hunt, CM; Beste, LA; Ioannou, GN; Lowy, E; Provenzale, DT; Kelley, MJ; Suzuki, A; Moylan, CA; Oloruntoba, OO; Tillmann, HL; Lim, JK; Ross, D
MLA Citation
Hunt, CM, Beste, LA, Ioannou, GN, Lowy, E, Provenzale, DT, Kelley, MJ, Suzuki, A, Moylan, CA, Oloruntoba, OO, Tillmann, HL, Lim, JK, and Ross, D. "Hepatitis B Testing Prior to Administration of Rituximab, Ofatumumab and Obinutuzumab in the National Veterans Affairs Health Healthcare System, 2002-2014." October 2015.
Source
wos-lite
Published In
Hepatology
Volume
62
Publish Date
2015
Start Page
478A
End Page
479A

Chemotherapy at the End of Life (EOL) for Patients with Lung Cancer within the VA System

Authors
Santana-Davila, R; Kelley, MJ; Williams, CD; Eaton, K; Whittle, JC
MLA Citation
Santana-Davila, R, Kelley, MJ, Williams, CD, Eaton, K, and Whittle, JC. "Chemotherapy at the End of Life (EOL) for Patients with Lung Cancer within the VA System." JOURNAL OF THORACIC ONCOLOGY 10.9 (September 2015): S789-S790.
Source
wos-lite
Published In
Journal of Thoracic Oncology
Volume
10
Issue
9
Publish Date
2015
Start Page
S789
End Page
S790

Early-Stage Lung Cancer Treatment and Survival: Impact of Race

Authors
Williams, CD; Kelley, MJ
MLA Citation
Williams, CD, and Kelley, MJ. "Early-Stage Lung Cancer Treatment and Survival: Impact of Race." JOURNAL OF THORACIC ONCOLOGY 10.9 (September 2015): S281-S281.
Source
wos-lite
Published In
Journal of Thoracic Oncology
Volume
10
Issue
9
Publish Date
2015
Start Page
S281
End Page
S281

Improved Survival in Patients with Stage I-II NSCLC Treated with Surgery or Radiotherapy in the Department of Veterans Affairs

Authors
Salama, JK; Williams, CD; Moghanaki, D; Kelley, MJ
MLA Citation
Salama, JK, Williams, CD, Moghanaki, D, and Kelley, MJ. "Improved Survival in Patients with Stage I-II NSCLC Treated with Surgery or Radiotherapy in the Department of Veterans Affairs." JOURNAL OF THORACIC ONCOLOGY 10.9 (September 2015): S280-S281.
Source
wos-lite
Published In
Journal of Thoracic Oncology
Volume
10
Issue
9
Publish Date
2015
Start Page
S280
End Page
S281

Effect of age on the efficacy of adjuvant chemotherapy for resected non-small cell lung cancer.

BACKGROUND: Adjuvant chemotherapy after surgical resection improves outcomes for patients with early-stage non-small cell lung cancer (NSCLC). To the authors' knowledge, there are no published prospective trials to date of adjuvant chemotherapy after surgical resection administered exclusively in older patients. In the current study, the authors sought to evaluate the efficacy of adjuvant chemotherapy in older patients in a Veterans Health Administration cohort. METHODS: Patients who underwent surgical resection for American Joint Committee on Cancer stages IB to III NSCLC between 2001 and 2011 were analyzed. Data regarding patient demographics and comorbidities, tumor characteristics, and primary treatment were collected. Patients were divided into 2 groups based on age at diagnosis: those aged <70 years and those aged ≥70 years. The primary exposure was use of adjuvant chemotherapy. A Cox proportional hazards model was used to estimate the significance of patient characteristics. Survival curves were estimated using the Kaplan-Meier method and group comparisons were performed using the log-rank test. RESULTS: The analysis included 7593 patients who underwent surgical resection for stage IB to stage III NSCLC. Among these, 2897 patients (38%) were aged ≥70 years. The percentage of older patients who received adjuvant chemotherapy was approximately one-half that of younger patients who did so (15.3% vs 31.6%; P<.0001). Carboplatin-based doublets were used most often in all patients (64.6%). Both younger patients (hazard ratio, 0.79; 95% confidence interval, 0.72-0.86) and older patients (hazard ratio, 0.81; 95% confidence interval, 0.71-0.92) were found to have a lower risk of death with receipt of adjuvant chemotherapy. CONCLUSIONS: Older patients derive a similar magnitude of benefit from adjuvant chemotherapy as younger patients and therefore adjuvant chemotherapy should not be withheld based on age alone.

Authors
Ganti, AK; Williams, CD; Gajra, A; Kelley, MJ
MLA Citation
Ganti, AK, Williams, CD, Gajra, A, and Kelley, MJ. "Effect of age on the efficacy of adjuvant chemotherapy for resected non-small cell lung cancer." Cancer 121.15 (August 2015): 2578-2585.
PMID
25873330
Source
epmc
Published In
Cancer
Volume
121
Issue
15
Publish Date
2015
Start Page
2578
End Page
2585
DOI
10.1002/cncr.29360

Implementation of gene expression testing for breast cancer patients within the Veterans Health Administration.

Authors
Lynch, JA; Berse, B; Filipski, KK; Freedman, AN; DuVall, S; Venne, V; Kelley, MJ
MLA Citation
Lynch, JA, Berse, B, Filipski, KK, Freedman, AN, DuVall, S, Venne, V, and Kelley, MJ. "Implementation of gene expression testing for breast cancer patients within the Veterans Health Administration." May 20, 2015.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
33
Issue
15
Publish Date
2015

Utilization of BRCA1/BRCA2 testing in Veterans Health Administration.

Authors
Chun, D; Lynch, JA; DuVall, SL; Filipski, KK; Kelley, MJ; Berse, B; Venne, V
MLA Citation
Chun, D, Lynch, JA, DuVall, SL, Filipski, KK, Kelley, MJ, Berse, B, and Venne, V. "Utilization of BRCA1/BRCA2 testing in Veterans Health Administration." May 20, 2015.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
33
Issue
15
Publish Date
2015

Epidermal growth factor receptor (EGFR) testing among veterans diagnosed with lung cancer in the VA

Authors
Lynch, JA; Berse, B; Filipski, KK; Kulich, S; Freedman, AN; DuVall, SL; Kelley, MJ
MLA Citation
Lynch, JA, Berse, B, Filipski, KK, Kulich, S, Freedman, AN, DuVall, SL, and Kelley, MJ. "Epidermal growth factor receptor (EGFR) testing among veterans diagnosed with lung cancer in the VA." May 20, 2015.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
33
Issue
15
Publish Date
2015

Comparing a medical records-based and a claims-based index for measuring comorbidity in patients with lung or colon cancer.

Ascertaining comorbid conditions in cancer patients is important for research and clinical quality measurement, and is particularly important for understanding care and outcomes for older patients and those with multi-morbidity. We compared the medical records-based ACE-27 index and the claims-based Charlson index in predicting receipt of therapy and survival for lung and colon cancer patients.We calculated the Charlson index using administrative data and the ACE-27 score using medical records for Veterans Affairs patients diagnosed with stage I/II non-small cell lung or stage III colon cancer from January 2003 to December 2004. We compared the proportion of patients identified by each index as having any comorbidity. We used multivariable logistic regression to ascertain the predictive power of each index regarding delivery of guideline-recommended therapies and two-year survival, comparing the c-statistic and the Akaike information criterion (AIC).Overall, 97.2% of lung and 90.9% of colon cancer patients had any comorbidity according to the ACE-27 index, versus 59.5% and 49.7%, respectively, according to the Charlson. Multivariable models including the ACE-27 index outperformed Charlson-based models when assessing receipt of guideline-recommended therapies, with higher c-statistics and lower AICs. Neither index was clearly superior in prediction of two-year survival.The ACE-27 index measured using medical records captured more comorbidity and outperformed the Charlson index measured using administrative data for predicting receipt of guideline-recommended therapies, demonstrating the potential value of more detailed comorbidity data. However, the two indices had relatively similar performance when predicting survival.

Authors
Kehl, KL; Lamont, EB; McNeil, BJ; Bozeman, SR; Kelley, MJ; Keating, NL
MLA Citation
Kehl, KL, Lamont, EB, McNeil, BJ, Bozeman, SR, Kelley, MJ, and Keating, NL. "Comparing a medical records-based and a claims-based index for measuring comorbidity in patients with lung or colon cancer." Journal of geriatric oncology 6.3 (May 2015): 202-210.
PMID
25662785
Source
epmc
Published In
Journal of Geriatric Oncology
Volume
6
Issue
3
Publish Date
2015
Start Page
202
End Page
210
DOI
10.1016/j.jgo.2015.01.005

Bevacizumab and the risk of arterial and venous thromboembolism in patients with metastatic, castration-resistant prostate cancer treated on Cancer and Leukemia Group B (CALGB) 90401 (Alliance).

Bevacizumab is associated with an increased risk of arterial thromboembolism (ATE); however, its effect on venous thromboembolism (VTE) remains controversial. Scant data exist on the factors that increase the risk of ATE/VTE in patients with prostate cancer. The authors investigated the association of bevacizumab treatment and clinical factors with ATE/VTE risk in patients who were treated on Cancer and Leukemia Group B (CALGB) trial 90401.Patients with metastatic, castration-resistant prostate cancer were randomized to receive docetaxel and prednisone with or without bevacizumab once every 21 days. Cycle-to-event Cox regression models were used to investigate the association of bevacizumab with the incidence of grade 3 or greater (≥ 3) ATE and VTE. Age, prior ATE/VTE, baseline antiplatelet/anticoagulant use, and VTE risk score (based on leukocyte count, hemoglobin, platelet count, body mass index, and tumor location) were evaluated in univariate and multivariable analyses.Of 1008 randomized patients, the odds of experiencing grade ≥ 3 ATE were significantly greater in those who received bevacizumab compared with those who received placebo (odds ratio, 2.79; P = .02), whereas an opposite trend was noted for grade ≥ 3 VTE (odds ratio, 0.60; P = .08). In the multivariable analysis, bevacizumab treatment (hazard ratio [HR], 3.00; P = .01) and age (HR, 1.06; P = .02) were significantly associated with the risk of ATE; whereas age (HR, 1.05; P = .01) and VTE risk score (HR, 1.83; P = .03) were significantly associated with the risk of VTE.Bevacizumab was significantly associated with a greater risk of ATE in patients with metastatic, castration-resistant prostate cancer, but it was not significantly associated with the risk of VTE. Understanding clinical factors that increase the risk for experiencing ATE/VTE is essential to mitigate the risks and reduce the burden of these prevalent complications in cancer care.

Authors
Patel, JN; Jiang, C; Hertz, DL; Mulkey, FA; Owzar, K; Halabi, S; Ratain, MJ; Friedman, PN; Small, EJ; Carducci, MA; Mahoney, JF; Kelley, MJ; Morris, MJ; Kelly, WK; McLeod, HL
MLA Citation
Patel, JN, Jiang, C, Hertz, DL, Mulkey, FA, Owzar, K, Halabi, S, Ratain, MJ, Friedman, PN, Small, EJ, Carducci, MA, Mahoney, JF, Kelley, MJ, Morris, MJ, Kelly, WK, and McLeod, HL. "Bevacizumab and the risk of arterial and venous thromboembolism in patients with metastatic, castration-resistant prostate cancer treated on Cancer and Leukemia Group B (CALGB) 90401 (Alliance)." Cancer 121.7 (April 2015): 1025-1031.
PMID
25417775
Source
epmc
Published In
Cancer
Volume
121
Issue
7
Publish Date
2015
Start Page
1025
End Page
1031
DOI
10.1002/cncr.29169

A preliminary exploration of college smokers' reactions to nicotine dependence genetic susceptibility feedback.

INTRODUCTION: Many young smokers underestimate their risk for becoming addicted to cigarettes. We explored whether informing light college smokers (i.e., fewer than 5 cigarettes/day) of their genetic predisposition to nicotine dependence influenced their perceived risks and worry about becoming addicted, their ability to quit (i.e., self-efficacy), their desire to quit, and smoking cessation. METHODS: College smokers (n = 142) received educational materials on mechanisms and consequences of nicotine addiction and were offered genetic susceptibility testing for nicotine dependence. Participants who accepted testing were randomized to receive feedback or no feedback (i.e., control). Tested participants learned they were above or not above average genetic risk for nicotine dependence. All participants responded to questions about perceived risks and worry about becoming addicted, efficacy to quit, and desire to quit. Cessation was assessed during a 1-month follow-up. RESULTS: Efficacy beliefs, worry about becoming addicted, and desire to quit did not differ by study condition or feedback. Perceived risk for becoming addicted was highest among tested participants informed they were above average risk for nicotine dependence. Overall, self-reported 30- but not 7-day quit rate was higher among participants who underwent genetic testing compared with control participants. CONCLUSIONS: This pilot study is the first to show that among light college smokers, receipt of genetic susceptibility feedback to nicotine dependence potentially curbs smoking without producing detrimental effects.

Authors
Lipkus, IM; Schwartz-Bloom, R; Kelley, MJ; Pan, W
MLA Citation
Lipkus, IM, Schwartz-Bloom, R, Kelley, MJ, and Pan, W. "A preliminary exploration of college smokers' reactions to nicotine dependence genetic susceptibility feedback." Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco 17.3 (March 2015): 337-343.
PMID
25173776
Source
epmc
Published In
Nicotine and Tobacco Research (OUP)
Volume
17
Issue
3
Publish Date
2015
Start Page
337
End Page
343
DOI
10.1093/ntr/ntu155

Cisplatin and etoposide versus carboplatin and paclitaxel with concurrent radiotherapy for stage III non-small-cell lung cancer: an analysis of Veterans Health Administration data.

The optimal chemotherapy regimen to use with radiotherapy in stage III non-small-cell lung cancer is unknown. Here, we compare the outcome of patents treated within the Veterans Health Administration with either etoposide-cisplatin (EP) or carboplatin-paclitaxel (CP).We identified patients treated with EP and CP with concurrent radiotherapy from 2001 to 2010. Survival rates were compared using Cox proportional hazards regression models with adjustments for confounding provided by propensity score methods and an instrumental variables analysis. Comorbidities and treatment complications were identified through administrative data.A total of 1,842 patients were included; EP was used in 27% (n = 499). Treatment with EP was not associated with a survival advantage in a Cox proportional hazards model (hazard ratio [HR], 0.97; 95% CI, 0.85 to 1.10), a propensity score matched cohort (HR, 1.07; 95% CI, 0.91 to 1.24), or a propensity score adjusted model (HR, 0.97; 95% CI, 0.85 to 1.10). In an instrumental variables analysis, there was no survival advantage for patients treated in centers where EP was used more than 50% of the time as compared with centers where EP was used in less than 10% of the patients (HR, 1.07; 95% CI, 0.90 to 1.26). Patients treated with EP, compared with patients treated with CP, had more hospitalizations (2.4 v 1.7 hospitalizations, respectively; P < .001), outpatient visits (17.6 v 12.6 visits, respectively; P < .001), infectious complications (47.3% v 39.4%, respectively; P = .0022), acute kidney disease/dehydration (30.5% v 21.2%, respectively; P < .001), and mucositis/esophagitis (18.6% v 14.4%, respectively; P = .0246).After accounting for prognostic variables, patients treated with EP versus CP had similar overall survival, but EP was associated with increased morbidity.

Authors
Santana-Davila, R; Devisetty, K; Szabo, A; Sparapani, R; Arce-Lara, C; Gore, EM; Moran, A; Williams, CD; Kelley, MJ; Whittle, J
MLA Citation
Santana-Davila, R, Devisetty, K, Szabo, A, Sparapani, R, Arce-Lara, C, Gore, EM, Moran, A, Williams, CD, Kelley, MJ, and Whittle, J. "Cisplatin and etoposide versus carboplatin and paclitaxel with concurrent radiotherapy for stage III non-small-cell lung cancer: an analysis of Veterans Health Administration data." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 33.6 (February 2015): 567-574.
PMID
25422491
Source
epmc
Published In
Journal of Clinical Oncology
Volume
33
Issue
6
Publish Date
2015
Start Page
567
End Page
574
DOI
10.1200/jco.2014.56.2587

Comparison of Quality Oncology Practice Initiative (QOPI) Measure Adherence Between Oncology Fellows, Advanced Practice Providers, and Attending Physicians

© 2015, Springer Science+Business Media New York.Quality improvement measures are uniformly applied to all oncology providers, regardless of their roles. Little is known about differences in adherence to these measures between oncology fellows, advance practice providers (APP), and attending physicians. We investigated conformance across Quality Oncology Practice Initiative (QOPI) measures for oncology fellows, advance practice providers, and attending physicians at the Durham Veterans Affairs Medical Center (DVAMC). Using data collected from the Spring 2012 and 2013 QOPI cycles, we abstracted charts of patients and separated them based on their primary provider. Descriptive statistics and the chi-square test were calculated for each QOPI measure between fellows, advanced practice providers (APPs), and attending physicians. A total of 169 patients were reviewed. Of these, 31 patients had a fellow, 39 had an APP, and 99 had an attending as their primary oncology provider. Fellows and attending physicians performed similarly on 90 of 94 QOPI metrics. High-performing metrics included several core QOPI measures including documenting consent for chemotherapy, recommending adjuvant chemotherapy when appropriate, and prescribing serotonin antagonists when prescribing emetogenic chemotherapies. Low-performing metrics included documentation of treatment summary and taking action to address problems with emotional well-being by the second office visit. Attendings documented the plan for oral chemotherapy more often (92 vs. 63 %, P = 0.049). However, after the chart audit, we found that fellows actually documented the plan for oral chemotherapy 88 % of the time (p = 0.73). APPs and attendings performed similarly on 88 of 90 QOPI measures. The quality of oncology care tends to be similar between attendings and fellows overall; some of the significant differences do not remain significant after a second manual chart review, highlighting that the use of manual data collection for QOPI analysis is an imperfect system, and there may be significant inter-observer variability.

Authors
Zhu, J; Zhang, T; Shah, R; Kamal, AH; Kelley, MJ
MLA Citation
Zhu, J, Zhang, T, Shah, R, Kamal, AH, and Kelley, MJ. "Comparison of Quality Oncology Practice Initiative (QOPI) Measure Adherence Between Oncology Fellows, Advanced Practice Providers, and Attending Physicians." Journal of Cancer Education 30.4 (2015): 774-778.
Source
scival
Published In
Journal of Cancer Education
Volume
30
Issue
4
Publish Date
2015
Start Page
774
End Page
778
DOI
10.1007/s13187-015-0798-z

Adjuvant Chemotherapy for Older Patients With Early-Stage Non-Small Cell Lung Cancer

Authors
Ganti, A; Williams, C; Gajra, A; Kelley, MJ
MLA Citation
Ganti, A, Williams, C, Gajra, A, and Kelley, MJ. "Adjuvant Chemotherapy for Older Patients With Early-Stage Non-Small Cell Lung Cancer." November 15, 2014.
Source
wos-lite
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
90
Publish Date
2014
Start Page
S12
End Page
S13

Characterization of T gene sequence variants and germline duplications in familial and sporadic chordoma.

Chordoma is a rare bone cancer that is believed to originate from notochordal remnants. We previously identified germline T duplication as a major susceptibility mechanism in several chordoma families. Recently, a common genetic variant in T (rs2305089) was significantly associated with the risk of sporadic chordoma. We sequenced all T exons in 24 familial cases and 54 unaffected family members from eight chordoma families (three with T duplications), 103 sporadic cases, and 160 unrelated controls. We also measured T copy number variation in all sporadic cases. We confirmed the association between the previously reported variant rs2305089 and risk of familial [odds ratio (OR) = 2.6, 95% confidence interval (CI) = 0.93, 7.25, P = 0.067] and sporadic chordoma (OR = 2.85, 95% CI = 1.89, 4.29, P < 0.0001). We also identified a second common variant, rs1056048, that was strongly associated with chordoma in families (OR = 4.14, 95% CI = 1.43, 11.92, P = 0.0086). Among sporadic cases, another common variant (rs3816300) was significantly associated with risk when jointly analyzed with rs2305089. The association with rs3816300 was significantly stronger in cases with early age onset. In addition, we identified three rare variants that were only observed among sporadic chordoma cases, all of which have potential functional relevance based on in silico predictions. Finally, we did not observe T duplication in any sporadic chordoma case. Our findings further highlight the importance of the T gene in the pathogenesis of both familial and sporadic chordoma and suggest a complex susceptibility related to T.

Authors
Kelley, MJ; Shi, J; Ballew, B; Hyland, PL; Li, W-Q; Rotunno, M; Alcorta, DA; Liebsch, NJ; Mitchell, J; Bass, S; Roberson, D; Boland, J; Cullen, M; He, J; Burdette, L; Yeager, M; Chanock, SJ; Parry, DM; Goldstein, AM; Yang, XR
MLA Citation
Kelley, MJ, Shi, J, Ballew, B, Hyland, PL, Li, W-Q, Rotunno, M, Alcorta, DA, Liebsch, NJ, Mitchell, J, Bass, S, Roberson, D, Boland, J, Cullen, M, He, J, Burdette, L, Yeager, M, Chanock, SJ, Parry, DM, Goldstein, AM, and Yang, XR. "Characterization of T gene sequence variants and germline duplications in familial and sporadic chordoma." Human genetics 133.10 (October 2014): 1289-1297.
PMID
24990759
Source
epmc
Published In
Human Genetics
Volume
133
Issue
10
Publish Date
2014
Start Page
1289
End Page
1297
DOI
10.1007/s00439-014-1463-z

Molecular characterization of chordoma xenografts generated from a novel primary chordoma cell source and two chordoma cell lines.

Chordoma cells can generate solid-like tumors in xenograft models that express some molecular characteristics of the parent tumor, including positivity for brachyury and cytokeratins. However, there is a dearth of molecular markers that relate to chordoma tumor growth, as well as the cell lines needed to advance treatment. The objective in this study was to isolate a novel primary chordoma cell source and analyze the characteristics of tumor growth in a mouse xenograft model for comparison with the established U-CH1 and U-CH2b cell lines.Primary cells from a sacral chordoma, called "DVC-4," were cultured alongside U-CH1 and U-CH2b cells for more than 20 passages and characterized for expression of CD24 and brachyury. While brachyury is believed essential for driving tumor formation, CD24 is associated with healthy nucleus pulposus cells. Each cell type was subcutaneously implanted in NOD/SCID/IL2Rγ(null) mice. The percentage of solid tumors formed, time to maximum tumor size, and immunostaining scores for CD24 and brachyury (intensity scores of 0-3, heterogeneity scores of 0-1) were reported and evaluated to test differences across groups.The DVC-4 cells retained chordoma-like morphology in culture and exhibited CD24 and brachyury expression profiles in vitro that were similar to those for U-CH1 and U-CH2b. Both U-CH1 and DVC-4 cells grew tumors at rates that were faster than those for U-CH2b cells. Gross tumor developed at nearly every site (95%) injected with U-CH1 and at most sites (75%) injected with DVC-4. In contrast, U-CH2b cells produced grossly visible tumors in less than 50% of injected sites. Brachyury staining was similar among tumors derived from all 3 cell types and was intensely positive (scores of 2-3) in a majority of tissue sections. In contrast, differences in the pattern and intensity of staining for CD24 were noted among the 3 types of cell-derived tumors (p < 0.05, chi-square test), with evidence of intense and uniform staining in a majority of U-CH1 tumor sections (score of 3) and more than half of the DVC-4 tumor sections (scores of 2-3). In contrast, a majority of sections from U-CH2b cells stained modestly for CD24 (scores of 1-2) with a predominantly heterogeneous staining pattern.This is the first report on xenografts generated from U-CH2b cells in which a low tumorigenicity was discovered despite evidence of chordoma-like characteristics in vitro. For tumors derived from a primary chordoma cell and U-CH1 cell line, similarly intense staining for CD24 was observed, which may correspond to their similar potential to grow tumors. In contrast, U-CH2b tumors stained less intensely for CD24. These results emphasize that many markers, including CD24, may be useful in distinguishing among chordoma cell types and their tumorigenicity in vivo.

Authors
Karikari, IO; Gilchrist, CL; Jing, L; Alcorta, DA; Chen, J; Richardson, WJ; Gabr, MA; Bell, RD; Kelley, MJ; Bagley, CA; Setton, LA
MLA Citation
Karikari, IO, Gilchrist, CL, Jing, L, Alcorta, DA, Chen, J, Richardson, WJ, Gabr, MA, Bell, RD, Kelley, MJ, Bagley, CA, and Setton, LA. "Molecular characterization of chordoma xenografts generated from a novel primary chordoma cell source and two chordoma cell lines." Journal of neurosurgery. Spine 21.3 (September 2014): 386-393.
Website
http://hdl.handle.net/10161/8887
PMID
24905390
Source
epmc
Published In
Journal of neurosurgery. Spine
Volume
21
Issue
3
Publish Date
2014
Start Page
386
End Page
393
DOI
10.3171/2014.4.spine13262

Acting in the face of uncertainty.

Authors
Atkins, D; Ross, D; Kelley, M
MLA Citation
Atkins, D, Ross, D, and Kelley, M. "Acting in the face of uncertainty." Annals of internal medicine 161.4 (August 2014): 300-301.
PMID
24934826
Source
epmc
Published In
Annals of internal medicine
Volume
161
Issue
4
Publish Date
2014
Start Page
300
End Page
301
DOI
10.7326/m14-1344

Use and impact of adjuvant chemotherapy in patients with resected non-small cell lung cancer.

BACKGROUND: Despite clinical trials demonstrating improved survival with adjuvant chemotherapy (AC) for patients with American Joint Committee on Cancer stages I to III non-small cell lung cancer (NSCLC), it is unclear whether this survival benefit extends to broader populations. The current study evaluated patterns of AC use and examined the impact of AC on survival. METHODS: A retrospective analysis was conducted of patients in the Veterans Affairs Central Cancer Registry diagnosed with stages IB to IIIA NSCLC between 2001 and 2008. Descriptive statistics were used to examine patterns of AC use over an 8-year time period. Cox proportional hazards regression analyses were used to estimate hazards ratios (HR) and 95% confidence intervals (95% CIs) to compare mortality risk among patients treated with and without AC. RESULTS: Among 14,306 patients with stages IB to IIIA NSCLC, 4929 underwent surgery and 22% of these received AC. The percentages of patients diagnosed in 2001 through 2003, 2004 through 2005, and 2006 through 2008 receiving AC were 7.0%, 29.8%, and 29.5%, respectively. There was no survival benefit with AC noted for patients diagnosed between 2001 and 2003, but AC was associated with improved survival for the period between 2004 and 2005 (HR, 0.78; 95% CI, 0.67-0.91) and 2006 through 2008 (HR, 0.79; 95% CI, 0.69-0.91). Of those patients receiving AC, 89% received platinum-doublet chemotherapy. Carboplatin remained the most common agent, although cisplatin use reached 43% in the period between 2006 and 2008. The HR for cisplatin relative to carboplatin was 0.96 (95% CI, 0.80-1.15). CONCLUSIONS: There was a significant increase in the use of AC between 2001 and 2008 and AC was associated with an improvement in overall survival.

Authors
Williams, CD; Gajra, A; Ganti, AK; Kelley, MJ
MLA Citation
Williams, CD, Gajra, A, Ganti, AK, and Kelley, MJ. "Use and impact of adjuvant chemotherapy in patients with resected non-small cell lung cancer." Cancer 120.13 (July 2014): 1939-1947.
PMID
24668613
Source
epmc
Published In
Cancer
Volume
120
Issue
13
Publish Date
2014
Start Page
1939
End Page
1947
DOI
10.1002/cncr.28679

Cancer Incidence in HIV-Infected Versus Uninfected Veterans: Comparison of Cancer Registry and ICD-9 Code Diagnoses.

Given the growing interest in the cancer burden in persons living with HIV/AIDS, we examined the validity of data sources for cancer diagnoses (cancer registry versus International Classification of Diseases, Ninth Revision [ICD-9 codes]) and compared the association between HIV status and cancer risk using each data source in the Veterans Aging Cohort Study (VACS), a prospective cohort of HIV-infected and uninfected veterans from 1996 to 2008.We reviewed charts to confirm potential incident cancers at four VACS sites. In the entire cohort, we calculated cancer-type-specific age-, sex-, race/ethnicity-, and calendar-period-standardized incidence rates and incidence rate ratios (IRR) (HIV-infected versus uninfected). We calculated standardized incidence ratios (SIR) to compare VACS and Surveillance, Epidemiology, and End Results rates.Compared to chart review, both Veterans Affairs Central Cancer Registry (VACCR) and ICD-9 diagnoses had approximately 90% sensitivity; however, VACCR had higher positive predictive value (96% versus 63%). There were 6,010 VACCR and 13,386 ICD-9 incident cancers among 116,072 veterans. Although ICD-9 rates tended to be double VACCR rates, most IRRs were in the same direction and of similar magnitude, regardless of data source. Using either source, all cancers combined, most viral-infection-related cancers, lung cancer, melanoma, and leukemia had significantly elevated IRRs. Using ICD-9, eight additional IRRs were significantly elevated, most likely due to false positive diagnoses. Most ICD-9 SIRs were significantly elevated and all were higher than the corresponding VACCR SIR.ICD-9 may be used with caution for estimating IRRs, but should be avoided when estimating incidence or SIRs. Elevated cancer risk based on VACCR diagnoses among HIV-infected veterans was consistent with other studies.

Authors
Park, LS; Tate, JP; Rodriguez-Barradas, MC; Rimland, D; Goetz, MB; Gibert, C; Brown, ST; Kelley, MJ; Justice, AC; Dubrow, R
MLA Citation
Park, LS, Tate, JP, Rodriguez-Barradas, MC, Rimland, D, Goetz, MB, Gibert, C, Brown, ST, Kelley, MJ, Justice, AC, and Dubrow, R. "Cancer Incidence in HIV-Infected Versus Uninfected Veterans: Comparison of Cancer Registry and ICD-9 Code Diagnoses." Journal of AIDS & clinical research 5.7 (July 2014): 1000318-.
PMID
25580366
Source
epmc
Published In
Journal of AIDS and Clinical Research
Volume
5
Issue
7
Publish Date
2014
Start Page
1000318
DOI
10.4172/2155-6113.1000318

A genome-wide association study (GWAS) of docetaxel-induced neutropenia in CALGB 90401/60404 (Alliance)

Authors
Hertz, DL; Jiang, C; Owzar, K; Halabi, S; Kelly, WK; Mulkey, F; Patel, JN; Carducci, MA; Kelley, MJ; Stadler, WM; Mohamed, MK; Morris, MJ; Nakamura, Y; Zembutsu, H; Ratain, MJ; McLeod, HL
MLA Citation
Hertz, DL, Jiang, C, Owzar, K, Halabi, S, Kelly, WK, Mulkey, F, Patel, JN, Carducci, MA, Kelley, MJ, Stadler, WM, Mohamed, MK, Morris, MJ, Nakamura, Y, Zembutsu, H, Ratain, MJ, and McLeod, HL. "A genome-wide association study (GWAS) of docetaxel-induced neutropenia in CALGB 90401/60404 (Alliance)." May 20, 2014.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
32
Issue
15
Publish Date
2014

Metformin (M), diabetes (DM), and colorectal cancer (CRC) survival among US veterans.

Authors
Paulus, JK; Cossor, FI; Williams, CD; Martell, RE; Kelley, MJ
MLA Citation
Paulus, JK, Cossor, FI, Williams, CD, Martell, RE, and Kelley, MJ. "Metformin (M), diabetes (DM), and colorectal cancer (CRC) survival among US veterans." May 20, 2014.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
32
Issue
15
Publish Date
2014

Association between metformin (M) use and survival among non-small cell lung cancer (NSCLC) patients (pts).

Authors
Fortune-Greeley, AK; Williams, CD; Paulus, JK; Kelley, MJ
MLA Citation
Fortune-Greeley, AK, Williams, CD, Paulus, JK, and Kelley, MJ. "Association between metformin (M) use and survival among non-small cell lung cancer (NSCLC) patients (pts)." May 20, 2014.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
32
Issue
15
Publish Date
2014

Cisplatin versus carboplatin-based regimens for the treatment of patients with metastatic lung cancer. An analysis of Veterans Health Administration data.

While platinum-based doublet chemotherapy is standard of care for patients presenting with metastatic non-small-cell lung cancer, the optimal platinum agent (cisplatin versus carboplatin) is unclear. We therefore compared survival and toxicity among persons receiving these agents at Department of Veterans Affairs hospitals.We used the Veterans Affairs Central Cancer Registry to identify veterans presented between 2001 and 2008 with metastatic non-small-cell lung cancer, then selected those receiving initial platinum doublet chemotherapy. We compared survival between those receiving cisplatin and carboplatin using multivariable Cox proportional hazards models and propensity score analyses to adjust for imbalances in demographics and clinical characteristics.We identified 4352 eligible persons; 4061 (93%) received carboplatin. Patients treated with cisplatin were younger (median age 61 versus 63, p < 0.01) and had less comorbidities (summary comorbidity score > 2, 7.7% versus 12.8%, p = 0.01) and higher eGFR (87 versus 84 mL/min/1.73 m). Median survival was similar for persons receiving cisplatin and carboplatin (8.1 versus 7.5 months, p = 0.54). In an adjusted survival analyses, the use of cisplatin was not associated with a better survival (hazard ratio 0.98, 95% confidence interval 0.84-1.14, p = 0.79). We performed subgroup analysis defined by histology and second agent, the hazard ratio for mortality ranged spanned 1 and none of these approached statistical significance (all p values > 0.20). Cisplatin-treated patients were more likely to have more hospitalization (1.7 versus 1.3, p < 0.01) and outpatient visits (11 versus 9.6, p < 0.01). Cisplatin-treated patient had more subsequent encounters for infection (41.6% versus 34.3%, p < 0.01) and acute kidney injury/dehydration (29.2% versus 15.5%, p < 0.01) CONCLUSIONS:: Patients receiving cisplatin and carboplatin-based doublets did not have significantly different survival, but cisplatin use was associated with an increase morbidity and healthcare use.

Authors
Santana-Davila, R; Szabo, A; Arce-Lara, C; Williams, CD; Kelley, MJ; Whittle, J
MLA Citation
Santana-Davila, R, Szabo, A, Arce-Lara, C, Williams, CD, Kelley, MJ, and Whittle, J. "Cisplatin versus carboplatin-based regimens for the treatment of patients with metastatic lung cancer. An analysis of Veterans Health Administration data." Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 9.5 (May 2014): 702-709.
PMID
24662458
Source
epmc
Published In
Journal of Thoracic Oncology
Volume
9
Issue
5
Publish Date
2014
Start Page
702
End Page
709
DOI
10.1097/jto.0000000000000146

Cisplatin versus Carboplatin-Based Regimens for the Treatment of Patients with Metastatic Lung Cancer. An Analysis of Veterans Health Administration Data

Authors
Santana-Davila, R; Szabo, A; Arce-Lara, C; Williams, CD; Kelley, MJ; Whittle, J
MLA Citation
Santana-Davila, R, Szabo, A, Arce-Lara, C, Williams, CD, Kelley, MJ, and Whittle, J. "Cisplatin versus Carboplatin-Based Regimens for the Treatment of Patients with Metastatic Lung Cancer. An Analysis of Veterans Health Administration Data." JOURNAL OF THORACIC ONCOLOGY 9.5 (May 2014): 702-709.
Source
wos-lite
Published In
Journal of Thoracic Oncology
Volume
9
Issue
5
Publish Date
2014
Start Page
702
End Page
709
DOI
10.1097/JTO.0000000000000146

Characterization of T gene sequence variants and germline duplications in familial and sporadic chordoma.

Chordoma is a rare bone cancer that is believed to originate from notochordal remnants. We previously identified germline T duplication as a major susceptibility mechanism in several chordoma families. Recently, a common genetic variant in T (rs2305089) was significantly associated with the risk of sporadic chordoma. We sequenced all T exons in 24 familial cases and 54 unaffected family members from eight chordoma families (three with T duplications), 103 sporadic cases, and 160 unrelated controls. We also measured T copy number variation in all sporadic cases. We confirmed the association between the previously reported variant rs2305089 and risk of familial [odds ratio (OR) = 2.6, 95% confidence interval (CI) = 0.93, 7.25, P = 0.067] and sporadic chordoma (OR = 2.85, 95% CI = 1.89, 4.29, P < 0.0001). We also identified a second common variant, rs1056048, that was strongly associated with chordoma in families (OR = 4.14, 95% CI = 1.43, 11.92, P = 0.0086). Among sporadic cases, another common variant (rs3816300) was significantly associated with risk when jointly analyzed with rs2305089. The association with rs3816300 was significantly stronger in cases with early age onset. In addition, we identified three rare variants that were only observed among sporadic chordoma cases, all of which have potential functional relevance based on in silico predictions. Finally, we did not observe T duplication in any sporadic chordoma case. Our findings further highlight the importance of the T gene in the pathogenesis of both familial and sporadic chordoma and suggest a complex susceptibility related to T.

Authors
Kelley, MJ; Shi, J; Ballew, B; Hyland, PL; Li, WQ; Rotunno, M; Alcorta, DA; Liebsch, NJ; Mitchell, J; Bass, S; Roberson, D; Boland, J; Cullen, M; He, J; Burdette, L; Yeager, M; Chanock, SJ; Parry, DM; Goldstein, AM; Yang, XR
MLA Citation
Kelley, MJ, Shi, J, Ballew, B, Hyland, PL, Li, WQ, Rotunno, M, Alcorta, DA, Liebsch, NJ, Mitchell, J, Bass, S, Roberson, D, Boland, J, Cullen, M, He, J, Burdette, L, Yeager, M, Chanock, SJ, Parry, DM, Goldstein, AM, and Yang, XR. "Characterization of T gene sequence variants and germline duplications in familial and sporadic chordoma." Human genetics 133.10 (January 1, 2014): 1289-1297.
Source
scopus
Published In
Human Genetics
Volume
133
Issue
10
Publish Date
2014
Start Page
1289
End Page
1297
DOI
10.1007/s00439-014-1463-z

Feasibility of using an epigenetic marker of risk for lung cancer, methylation of p16, to promote smoking cessation among US veterans.

Providing smokers feedback using epigenetic markers of lung cancer risk has yet to be tested as a strategy to motivate smoking cessation. Epigenetic modification of Rb-p16 (p16) due to tobacco exposure is associated with increased risk of developing lung cancer. This study examined the acceptance of testing for methylated p16 and the understanding of test results in smokers at risk for development of lung cancer.Thirty-five current smokers with airways obstruction viewed an educational presentation regarding p16 function followed by testing for the presence of methylated p16 in sputum. Participants were offered smoking cessation assistance and asked to complete surveys at the time of enrolment regarding their understanding of the educational material, perception of risk associated with smoking and desire to quit. Participants were notified of their test result and follow-up surveys were administered 2 and 10 weeks after notification of their test result.Twenty per cent of participants had methylated p16. Participants showed high degree of understanding of educational materials regarding the function and risk associated with p16 methylation. Sixty-seven per cent and 57% of participants with low-risk and high-risk test results, respectively, reported that the information was more likely to motivate them to quit smoking. Smoking cessation rates were similar between methylated and non-methylated participants.Testing for an epigenetic marker of lung cancer risk is accepted and understood by active smokers. A low-risk test result does not decrease motivation to stop smoking.NCT01038492.

Authors
Shofer, S; Beyea, M; Li, S; Bastian, LA; Wahidi, MM; Kelley, M; Lipkus, IM
MLA Citation
Shofer, S, Beyea, M, Li, S, Bastian, LA, Wahidi, MM, Kelley, M, and Lipkus, IM. "Feasibility of using an epigenetic marker of risk for lung cancer, methylation of p16, to promote smoking cessation among US veterans." BMJ open respiratory research 1.1 (January 2014): e000032-.
PMID
25478181
Source
epmc
Published In
BMJ Open Respiratory Research
Volume
1
Issue
1
Publish Date
2014
Start Page
e000032
DOI
10.1136/bmjresp-2014-000032

Cisplatin versus carboplatin-based regimens for the treatment of patients with metastatic lung cancer. An analysis of veterans health administration data

BACKGROUND:: While platinum-based doublet chemotherapy is standard of care for patients presenting with metastatic non-small-cell lung cancer, the optimal platinum agent (cisplatin versus carboplatin) is unclear. We therefore compared survival and toxicity among persons receiving these agents at Department of Veterans Affairs hospitals. METHODS:: We used the Veterans Affairs Central Cancer Registry to identify veterans presented between 2001 and 2008 with metastatic non-small-cell lung cancer, then selected those receiving initial platinum doublet chemotherapy. We compared survival between those receiving cisplatin and carboplatin using multivariable Cox proportional hazards models and propensity score analyses to adjust for imbalances in demographics and clinical characteristics. RESULTS:: We identified 4352 eligible persons; 4061 (93%) received carboplatin. Patients treated with cisplatin were younger (median age 61 versus 63, p < 0.01) and had less comorbidities (summary comorbidity score > 2, 7.7% versus 12.8%, p = 0.01) and higher eGFR (87 versus 84 mL/min/1.73 m). Median survival was similar for persons receiving cisplatin and carboplatin (8.1 versus 7.5 months, p = 0.54). In an adjusted survival analyses, the use of cisplatin was not associated with a better survival (hazard ratio 0.98, 95% confidence interval 0.84-1.14, p = 0.79). We performed subgroup analysis defined by histology and second agent, the hazard ratio for mortality ranged spanned 1 and none of these approached statistical significance (all p values > 0.20). Cisplatin-treated patients were more likely to have more hospitalization (1.7 versus 1.3, p < 0.01) and outpatient visits (11 versus 9.6, p < 0.01). Cisplatin-treated patient had more subsequent encounters for infection (41.6% versus 34.3%, p < 0.01) and acute kidney injury/dehydration (29.2% versus 15.5%, p < 0.01) CONCLUSIONS:: Patients receiving cisplatin and carboplatin-based doublets did not have significantly different survival, but cisplatin use was associated with an increase morbidity and healthcare use. © 2014 by the International Association for the Study of Lung Cancer.

Authors
Santana-Davila, R; Szabo, A; Arce-Lara, C; Williams, CD; Kelley, MJ; Whittle, J
MLA Citation
Santana-Davila, R, Szabo, A, Arce-Lara, C, Williams, CD, Kelley, MJ, and Whittle, J. "Cisplatin versus carboplatin-based regimens for the treatment of patients with metastatic lung cancer. An analysis of veterans health administration data." Journal of Thoracic Oncology 9.5 (2014): 702-709.
Source
scival
Published In
Journal of Thoracic Oncology
Volume
9
Issue
5
Publish Date
2014
Start Page
702
End Page
709
DOI
10.1097/JTO.0000000000000146

Use and impact of adjuvant chemotherapy in patients with resected non-small cell lung cancer

BACKGROUND Despite clinical trials demonstrating improved survival with adjuvant chemotherapy (AC) for patients with American Joint Committee on Cancer stages I to III non-small cell lung cancer (NSCLC), it is unclear whether this survival benefit extends to broader populations. The current study evaluated patterns of AC use and examined the impact of AC on survival. METHODS A retrospective analysis was conducted of patients in the Veterans Affairs Central Cancer Registry diagnosed with stages IB to IIIA NSCLC between 2001 and 2008. Descriptive statistics were used to examine patterns of AC use over an 8-year time period. Cox proportional hazards regression analyses were used to estimate hazards ratios (HR) and 95% confidence intervals (95% CIs) to compare mortality risk among patients treated with and without AC. RESULTS Among 14,306 patients with stages IB to IIIA NSCLC, 4929 underwent surgery and 22% of these received AC. The percentages of patients diagnosed in 2001 through 2003, 2004 through 2005, and 2006 through 2008 receiving AC were 7.0%, 29.8%, and 29.5%, respectively. There was no survival benefit with AC noted for patients diagnosed between 2001 and 2003, but AC was associated with improved survival for the period between 2004 and 2005 (HR, 0.78; 95% CI, 0.67-0.91) and 2006 through 2008 (HR, 0.79; 95% CI, 0.69-0.91). Of those patients receiving AC, 89% received platinum-doublet chemotherapy. Carboplatin remained the most common agent, although cisplatin use reached 43% in the period between 2006 and 2008. The HR for cisplatin relative to carboplatin was 0.96 (95% CI, 0.80-1.15). CONCLUSIONS There was a significant increase in the use of AC between 2001 and 2008 and AC was associated with an improvement in overall survival. Cancer 2014;120:1939-1947. © 2014 American Cancer Society.

Authors
Williams, CD; Gajra, A; Ganti, AK; Kelley, MJ
MLA Citation
Williams, CD, Gajra, A, Ganti, AK, and Kelley, MJ. "Use and impact of adjuvant chemotherapy in patients with resected non-small cell lung cancer." Cancer 120.13 (2014): 1939-1947.
Source
scival
Published In
Cancer
Volume
120
Issue
13
Publish Date
2014
Start Page
1939
End Page
1947
DOI
10.1002/cncr.28679

Comparison of QOPI measure conformance between oncology fellows and attending physicians

Authors
Zhang, T; Kamal, A; Kelley, MJ
MLA Citation
Zhang, T, Kamal, A, and Kelley, MJ. "Comparison of QOPI measure conformance between oncology fellows and attending physicians." November 1, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
31
Issue
31
Publish Date
2013

Tools to accurately identify veterans who undergo molecular diagnostic testing

Authors
Kelley, MJ; Lynch, JA
MLA Citation
Kelley, MJ, and Lynch, JA. "Tools to accurately identify veterans who undergo molecular diagnostic testing." November 1, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
31
Issue
31
Publish Date
2013

Epigenetic assay detects early stage non-small cell lung cancer in sputum

Authors
Van Neste, L; Moreau, F; Kelley, MJ; Belinsky, SA; Bigley, J; Van Criekinge, W
MLA Citation
Van Neste, L, Moreau, F, Kelley, MJ, Belinsky, SA, Bigley, J, and Van Criekinge, W. "Epigenetic assay detects early stage non-small cell lung cancer in sputum." EUROPEAN JOURNAL OF CANCER 49 (November 2013): S36-S36.
Source
wos-lite
Published In
European Journal of Cancer
Volume
49
Publish Date
2013
Start Page
S36
End Page
S36

Comparison of QOPI measure conformance between oncology fellows and attending physicians.

162 Background: Quality improvement measures are uniformly applied to all oncology providers, regardless of their positions. Little is known about differences in conformance to these measures between oncology fellows and attending physicians. In order to tailor improvement interventions to these groups, we investigated conformance across QOPI measures for oncology fellows and attending physicians at the Durham VA Medical Center (DVAMC).Using data collected from the Spring 2013 QOPI cycle, we abstracted information from patients who had received care at the DVAMC between 2011 and 2013 and separated them based on their provider. To validate the data, we abstracted a subset of patient charts, limited to oral chemotherapy quality measures. Descriptive statistics and the Chi square test were calculated for each measure between the two groups.A total of 97 patients were reviewed at DVAMC. Of these, 21 had a fellow and 47 had an attending as their main provider. Fellows and attendings performed similarly on 119 of 125 QOPI measures (core, end of life, symptom, colorectal, and NSCLC modules). Fellows were less likely to assess pain on the most recent visits when compared to attendings (52% vs. 77%, p=0.046) but more likely to document a management plan if the patient had moderate or severe pain (86% vs 75%, p=0.09). Attendings documented the plan for oral chemotherapy more often (93% vs. 60%, p=0.07). However, after the chart audit, we found that fellows actually documented the plan for oral chemotherapy 80% of the time (p=0.21). Fellows were more likely to document smoking status (95% vs. 64%, p=0.007) and to address smoking cessation (86% vs. 62%, p=0.048).Patient care practices tend to be similar between attendings and fellows overall; some of the significant differences may not remain significant after chart audit. Fellows generally mirror behaviors of attending physicians, and attendings have an important role in modeling best practice behaviors for fellows. Different quality measure standards may not be necessary between fellows and attendings.

Authors
Kamal, A; Kelley, MJ
MLA Citation
Kamal, A, and Kelley, MJ. "Comparison of QOPI measure conformance between oncology fellows and attending physicians." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 31.31_suppl (November 2013): 162-.
PMID
28136392
Source
epmc
Published In
Journal of Clinical Oncology
Volume
31
Issue
31_suppl
Publish Date
2013
Start Page
162

A genome-wide association study (GWAS) of docetaxel-induced peripheral neuropathy in CALGB 90401 (Alliance)

Authors
Hertz, DL; Owzar, K; Halabi, S; Kelly, WK; Zembutsu, H; Jiang, C; Patel, JN; Watson, D; Shterev, I; Kroetz, DL; Friedman, PN; Mahoney, JF; Carducci, MA; Kelley, MJ; Small, EJ; Febbo, PG; Nakamura, Y; Kubo, M; Ratain, MJ; McLeod, HL
MLA Citation
Hertz, DL, Owzar, K, Halabi, S, Kelly, WK, Zembutsu, H, Jiang, C, Patel, JN, Watson, D, Shterev, I, Kroetz, DL, Friedman, PN, Mahoney, JF, Carducci, MA, Kelley, MJ, Small, EJ, Febbo, PG, Nakamura, Y, Kubo, M, Ratain, MJ, and McLeod, HL. "A genome-wide association study (GWAS) of docetaxel-induced peripheral neuropathy in CALGB 90401 (Alliance)." May 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

Patterns of second-line chemotherapy and its effect on survival in patients treated within the Veterans Health Administration (VHA)

Authors
Santana-Davila, R; File, DM; Arce-Lara, CE; Kelley, MJ; Williams, CD; Whittle, JC
MLA Citation
Santana-Davila, R, File, DM, Arce-Lara, CE, Kelley, MJ, Williams, CD, and Whittle, JC. "Patterns of second-line chemotherapy and its effect on survival in patients treated within the Veterans Health Administration (VHA)." May 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

Current status of the implementation of gene expression testing in breast cancer management in the United States

Authors
Lynch, JA; Fiore, L; Kelley, MJ; Borzecki, A; Lathan, CS; Hassett, M; Rugo, HS; Khoury, MJ; Freedman, AN
MLA Citation
Lynch, JA, Fiore, L, Kelley, MJ, Borzecki, A, Lathan, CS, Hassett, M, Rugo, HS, Khoury, MJ, and Freedman, AN. "Current status of the implementation of gene expression testing in breast cancer management in the United States." May 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

Evolution of the Quality Oncology Practice Initiative supportive care quality measures portfolio and conformance at a Veterans Affairs medical center.

A growing set of quality measures is being implemented to evaluate all components of cancer care, from diagnosis through the end of life. We investigated the Quality Oncology Practice Initiative (QOPI) quality measures portfolio. Additionally, we explored the effect of quality measure type on conformance.We performed QOPI data collections twice per year from fall 2007 through fall 2010 and spring 2012, using chart review of the Durham Veterans Administration outpatient oncology clinic. We categorized QOPI measures as nontreatment-related supportive care (NTSC), treatment-related supportive care (TSC), diagnostic, or therapeutic. Descriptive statistics and χ(2) were used to compare longitudinal conformance.The majority of QOPI measures in spring 2012 assess processes of chemotherapy treatment (therapeutic, 54.3%; TSC, 8.7%) or diagnostic modalities (19.6%). Measures targeting NTSC are few (17.4%) but increased from three measures in fall 2007 to eight measures in spring 2012. During those 5 years, average conformance to NTSC, TSC, diagnostic, and therapeutic measures was 71.4%, 86.1%, 89.3%, and 75.4%, respectively (P < .001). Within the NTSC measures, emotional well-being and constipation assessment were least documented (41.0% and 46.3%, respectively). In spring 2012, NTSC measure conformance (75.8%) remained significantly lower than diagnostic measure conformance (91.5%; P < .001).Most QOPI quality measures assess diagnosis or treatment processes of care and not supportive care. Aggregate conformance to the NTSC measures was lower than that of other categories. The differential conformance demonstrates the necessity of standardized documentation methods and quality improvement efforts that remain commensurate with the increasing portfolio of supportive care measures.

Authors
Nipp, RD; Kelley, MJ; Williams, CD; Kamal, AH
MLA Citation
Nipp, RD, Kelley, MJ, Williams, CD, and Kamal, AH. "Evolution of the Quality Oncology Practice Initiative supportive care quality measures portfolio and conformance at a Veterans Affairs medical center." Journal of oncology practice 9.3 (May 2013): e86-e89.
PMID
23942507
Source
epmc
Published In
Journal of Oncology Practice
Volume
9
Issue
3
Publish Date
2013
Start Page
e86
End Page
e89
DOI
10.1200/jop.2013.000923

Abstract 352: Murine model of chordoma: Sonic Hedgehog promoter-driven Cre activation of Brachyury (T) expression induces spinal disk abnormalities and perinatal lethal developmental defects.

Authors
Alcorta, DA; Maier, JA; Harfe, BD; Kelley, MJ
MLA Citation
Alcorta, DA, Maier, JA, Harfe, BD, and Kelley, MJ. "Abstract 352: Murine model of chordoma: Sonic Hedgehog promoter-driven Cre activation of Brachyury (T) expression induces spinal disk abnormalities and perinatal lethal developmental defects." April 15, 2013.
Source
crossref
Published In
Cancer Research
Volume
73
Issue
8 Supplement
Publish Date
2013
Start Page
352
End Page
352
DOI
10.1158/1538-7445.AM2013-352

Influence of comorbidity on racial differences in receipt of surgery among US veterans with early-stage non-small-cell lung cancer.

It is unclear why racial differences exist in the frequency of surgery for lung cancer treatment. Comorbidity is an important consideration in selection of patients for lung cancer treatment, including surgery. To assess whether comorbidity contributes to the observed racial differences, we evaluated racial differences in the prevalence of comorbidity and their impact on receipt of surgery.A total of 1,314 patients (1,135 white, 179 black) in the Veterans Health Administration diagnosed with early-stage non-small-cell lung cancer in 2007 were included. The effect of comorbidity on surgery was determined by using generalized linear models with a logit link accounting for patient clustering within Veterans Administration Medical Centers.Compared with whites, blacks had greater prevalence of hypertension, liver disease, renal disease, illicit drug abuse, and poor performance status, but lower prevalence of respiratory disease. The impact of most individual comorbidities on receipt of surgery was similar between blacks and whites, and comorbidity did not influence the race-surgery association in a multivariable analysis. The proportion of blacks not receiving surgery as well as refusing surgery was greater than that among whites.Blacks had a greater prevalence of several comorbid conditions and poor performance status; however, the overall comorbidity score did not differ by race. In general, the effect of comorbidity on receipt of surgery was similar in blacks and whites. Racial differences in comorbidity do not fully explain why blacks undergo lung cancer surgery less often than whites.

Authors
Williams, CD; Stechuchak, KM; Zullig, LL; Provenzale, D; Kelley, MJ
MLA Citation
Williams, CD, Stechuchak, KM, Zullig, LL, Provenzale, D, and Kelley, MJ. "Influence of comorbidity on racial differences in receipt of surgery among US veterans with early-stage non-small-cell lung cancer." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 31.4 (February 2013): 475-481.
PMID
23269988
Source
epmc
Published In
Journal of Clinical Oncology
Volume
31
Issue
4
Publish Date
2013
Start Page
475
End Page
481
DOI
10.1200/jco.2012.44.1170

Phase II study of induction cisplatin and irinotecan followed by concurrent carboplatin, etoposide, and thoracic radiotherapy for limited-stage small-cell lung cancer, CALGB 30206.

INTRODUCTION: We sought to determine the efficacy of using both irinotecan- and etoposide-containing regimens sequentially for patients with untreated limited-stage small-cell lung cancer. METHODS: Patients with untreated, measurable, limited-stage small-cell lung cancer with performance status 0 to 2, and adequate organ function were eligible. Treatment consisted of induction with cisplatin 30 mg/m and irinotecan 65 mg/m intravenously on day 1 and 8, every 21 days for two cycles. Beginning day 43, daily chest irradiation to 70 Gy was administered concurrently with carboplatin area under curve 5 on day 1, and etoposide 100 mg/m on days 1 to 3, every 21 days for three cycles. The primary objective was to differentiate between 45% and 60% 2-year survival. RESULTS: Two induction cycles were delivered to 72 of 75 eligible patients (96%) and all planned treatment was delivered to 59 patients (79%). Cisplatin and irinotecan induction chemotherapy resulted in complete responses in 7% and partial responses in 64% (response rate 71%, 95% confidence interval [CI], 59%-81%). The best response to all therapy included 88% complete or partial responses (95% CI, 78%-94%). With median follow-up of 57 months, the median progression-free survival and overall survival are 12.6 (95% CI, 9.4-14.7) and 18.1 months (15.8-22.9), respectively. The 1- and 2-year survival was 69% and 31%, respectively. Frequent (>20%) grade 3 and 4 toxicities were neutropenia in 84%, hemoglobin in 36%, platelets in 51%, esophagitis in 22%, and dehydration in 24%. There were no fatal toxicities. CONCLUSIONS: This treatment regimen of irinotecan-cisplatin induction chemotherapy followed by 70 Gy concurrent radiation and etoposide-carboplatin had tolerable toxicity but did not meet the preplanned 2-year survival target for further development.

Authors
Kelley, MJ; Bogart, JA; Hodgson, LD; Ansari, RH; Atkins, JN; Pang, H; Green, MR; Vokes, EE
MLA Citation
Kelley, MJ, Bogart, JA, Hodgson, LD, Ansari, RH, Atkins, JN, Pang, H, Green, MR, and Vokes, EE. "Phase II study of induction cisplatin and irinotecan followed by concurrent carboplatin, etoposide, and thoracic radiotherapy for limited-stage small-cell lung cancer, CALGB 30206." J Thorac Oncol 8.1 (January 2013): 102-108.
PMID
23196276
Source
pubmed
Published In
Journal of Thoracic Oncology
Volume
8
Issue
1
Publish Date
2013
Start Page
102
End Page
108
DOI
10.1097/JTO.0b013e31827628e1

The Role of Brachyury in Notochordal and Non-Notochordal Malignancy

Authors
Kelley, M
MLA Citation
Kelley, M. "The Role of Brachyury in Notochordal and Non-Notochordal Malignancy." ONCOLOGIST 18 (2013): S1-S1.
Source
wos-lite
Published In
The oncologist
Volume
18
Publish Date
2013
Start Page
S1
End Page
S1

Phase II study of induction cisplatin and irinotecan followed by concurrent carboplatin, etoposide, and thoracic radiotherapy for limited-stage small-cell lung cancer, CALGB 30206

INTRODUCTION: We sought to determine the efficacy of using both irinotecan-and etoposide-containing regimens sequentially for patients with untreated limited-stage small-cell lung cancer. METHODS: Patients with untreated, measurable, limited-stage small-cell lung cancer with performance status 0 to 2, and adequate organ function were eligible. Treatment consisted of induction with cisplatin 30 mg/m and irinotecan 65 mg/m intravenously on day 1 and 8, every 21 days for two cycles. Beginning day 43, daily chest irradiation to 70 Gy was administered concurrently with carboplatin area under curve 5 on day 1, and etoposide 100 mg/m on days 1 to 3, every 21 days for three cycles. The primary objective was to differentiate between 45% and 60% 2-year survival. RESULTS: Two induction cycles were delivered to 72 of 75 eligible patients (96%) and all planned treatment was delivered to 59 patients (79%). Cisplatin and irinotecan induction chemotherapy resulted in complete responses in 7% and partial responses in 64% (response rate 71%, 95% confidence interval [CI], 59%-81%). The best response to all therapy included 88% complete or partial responses (95% CI, 78%-94%). With median follow-up of 57 months, the median progression-free survival and overall survival are 12.6 (95% CI, 9.4-14.7) and 18.1 months (15.8-22.9), respectively. The 1-and 2-year survival was 69% and 31%, respectively. Frequent (>20%) grade 3 and 4 toxicities were neutropenia in 84%, hemoglobin in 36%, platelets in 51%, esophagitis in 22%, and dehydration in 24%. There were no fatal toxicities. CONCLUSIONS: This treatment regimen of irinotecan-cisplatin induction chemotherapy followed by 70 Gy concurrent radiation and etoposide-carboplatin had tolerable toxicity but did not meet the preplanned 2-year survival target for further development. Copyright © 2012 by the International Association for the Study of Lung Cancer.

Authors
Kelley, MJ; Bogart, JA; Hodgson, LD; Ansari, RH; Atkins, JN; Pang, H; Green, MR; Vokes, EE
MLA Citation
Kelley, MJ, Bogart, JA, Hodgson, LD, Ansari, RH, Atkins, JN, Pang, H, Green, MR, and Vokes, EE. "Phase II study of induction cisplatin and irinotecan followed by concurrent carboplatin, etoposide, and thoracic radiotherapy for limited-stage small-cell lung cancer, CALGB 30206." Journal of Thoracic Oncology 8.1 (2013): 102-108.
Source
scival
Published In
Journal of Thoracic Oncology
Volume
8
Issue
1
Publish Date
2013
Start Page
102
End Page
108
DOI
10.1097/JTO.0b013e31827628e1

Assessment of the Impact of Adjunctive Proactive Telephone Counseling to Promote Smoking Cessation Among Lung Cancer Patients' Social Networks

Authors
Bastian, LA; Fish, LJ; Peterson, BL; Biddle, AK; Garst, J; Lyna, P; Molner, S; Bepler, G; Kelley, M; Keefe, FJ; McBride, CM
MLA Citation
Bastian, LA, Fish, LJ, Peterson, BL, Biddle, AK, Garst, J, Lyna, P, Molner, S, Bepler, G, Kelley, M, Keefe, FJ, and McBride, CM. "Assessment of the Impact of Adjunctive Proactive Telephone Counseling to Promote Smoking Cessation Among Lung Cancer Patients' Social Networks." AMERICAN JOURNAL OF HEALTH PROMOTION 27.3 (2013): 181-190.
PMID
23286595
Source
wos-lite
Published In
American journal of health promotion : AJHP
Volume
27
Issue
3
Publish Date
2013
Start Page
181
End Page
190
DOI
10.4278/ajhp.101122-QUAN-387

Identification of repurposed small molecule drugs for chordoma therapy

Chordoma is a rare, slow growing malignant tumor arising from remnants of the fetal notochord. Surgery is the first choice for chordoma treatment, followed by radiotherapy, although postoperative complications remain significant. Recurrence of the disease occurs frequently due to the anatomy of the tumor location and violation of the tumor margins at the initial surgery. Currently, there are no effective drugs available for patients with chordoma. Due to the rarity of the disease, there is limited opportunity to test agents in clinical trials and no concerted effort to develop agents for chordoma in the pharmaceutical industry. To rapidly and efficiently identify small molecules that inhibit chordoma cell growth, we screened the NCGC Pharmaceutical Collection (NPC) containing approximately 2800 clinically approved and investigational drugs at 15 different concentrations in chordoma cell lines, U-CH1 and U-CH2. We identified a group of drugs including bortezomib, 17-AA G, digitoxin, staurosporine, digoxin, rubitecan, and trimetrexate that inhibited chordoma cell growth, with potencies from 10 to 370 nM in U-CH1 cells, but less potently in U-CH2 cells. Most of these drugs also induced caspase 3/7 activity with a similar rank order as the cytotoxic effect on U-CH1 cells. Cantharidin, digoxin, digitoxin, staurosporine, and bortezomib showed similar inhibitory effect on cell lines and 3 primary chordoma cell cultures. The combination treatment of bortezomib with topoisomerase I and II inhibitors increased the therapeutic potency in U-CH2 and patient-derived primary cultures. Our results provide information useful for repurposing currently approved drugs for chordoma and potential approach of combination therapy. © 2013 Landes Bioscience.

Authors
Xia, M; Huang, R; Sakamuru, S; Alcorta, D; Cho, M-H; Lee, D-H; Park, DM; Kelley, MJ; Sommer, J; Austin, CP
MLA Citation
Xia, M, Huang, R, Sakamuru, S, Alcorta, D, Cho, M-H, Lee, D-H, Park, DM, Kelley, MJ, Sommer, J, and Austin, CP. "Identification of repurposed small molecule drugs for chordoma therapy." Cancer Biology and Therapy 14.7 (2013): 638-647.
PMID
23792643
Source
scival
Published In
Cancer Biology and Therapy
Volume
14
Issue
7
Publish Date
2013
Start Page
638
End Page
647
DOI
10.4161/cbt.24596

Persistence of quality improvement in a Veterans Affairs (VA) academic practice assessed by Quality Oncology Practice Initiative (QOPI)

Authors
Kiernan, KL; Williams, CD; Kamal, A; Kelley, MJ
MLA Citation
Kiernan, KL, Williams, CD, Kamal, A, and Kelley, MJ. "Persistence of quality improvement in a Veterans Affairs (VA) academic practice assessed by Quality Oncology Practice Initiative (QOPI)." JOURNAL OF CLINICAL ONCOLOGY 30.34 (December 1, 2012).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
30
Issue
34
Publish Date
2012

Impact of race on early-stage lung cancer treatment and survival

Authors
Williams, CD; Provenzale, DT; Stechuchak, KM; Kelley, MJ
MLA Citation
Williams, CD, Provenzale, DT, Stechuchak, KM, and Kelley, MJ. "Impact of race on early-stage lung cancer treatment and survival." JOURNAL OF CLINICAL ONCOLOGY 30.34 (December 1, 2012).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
30
Issue
34
Publish Date
2012

The evolution of supportive care quality measures portfolio and conformance

Authors
Nipp, RD; Kelley, MJ; Williams, CD; Kamal, A
MLA Citation
Nipp, RD, Kelley, MJ, Williams, CD, and Kamal, A. "The evolution of supportive care quality measures portfolio and conformance." JOURNAL OF CLINICAL ONCOLOGY 30.34 (December 1, 2012).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
30
Issue
34
Publish Date
2012

The evolution of supportive care quality measures portfolio and conformance.

259 Background: A growing set of quality measures is being implemented to evaluate all components of cancer care ranging from diagnosis through the end-of-life (EOL). With an increasing emphasis from ASCO and others on the regular delivery of supportive care principles throughout the cancer trajectory, we investigated our longitudinal Quality Oncology Practice Initiative (QOPI) data to understand the trends in supportive and EOL measures.We performed twice-yearly QOPI data collections from 2007 through Spring 2012 using chart review of the Durham Veterans Administration (VA) outpatient oncology clinic, staffed by VA and Duke faculty as well as Duke fellows. QOPI measures were categorized as non-treatment related supportive care (SC) (NTSC), treatment-related SC (TSC), diagnostic (D), or therapeutic (T). Descriptive statistics and chi square were used to compare longitudinal conformance.The majority of QOPI measures assess processes of chemotherapy treatment (49.1% T and 11.1% TSC) or diagnostic modalities (21.1% D). Measures targeting NTSC are few (18.6%), but increased from two SC measures in 2007 to eight in Spring 2012, including the addition of two EOL measures. Over the five years, average conformance to NTSC, TSC, D, and T measures was 71.4%, 86.1%, 89.3%, and 75.4%, respectively (p<0.001). Within the NTSC measures, emotional well-being, and constipation assessment were least documented (41.0%, and 46.3% respectively). In Spring 2012, SC measure conformance (76.0%) remained significantly lower than D measure conformance (91.5%) (p<0.001). Potential explanations include heterogenous and non-standardized ways to document non-treatment measures despite an increasing emphasis within cancer care on supportive and palliative care.Most QOPI quality measures assess diagnosis or treatment processes of cancer care. Aggregate conformance to the NTSC measures was lower than other categories over five years. This disparity persists in the latest 2012 collection, and novel SC measures have been added. The differential conformance demonstrates the necessity of quality improvement efforts that stay commiserate with the increasing portfolio of SC measures.

Authors
Kelley, MJ; Williams, CD; Kamal, A
MLA Citation
Kelley, MJ, Williams, CD, and Kamal, A. "The evolution of supportive care quality measures portfolio and conformance." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 30.34_suppl (December 2012): 259-.
PMID
28147103
Source
epmc
Published In
Journal of Clinical Oncology
Volume
30
Issue
34_suppl
Publish Date
2012
Start Page
259

Persistence of quality improvement in a Veterans Affairs (VA) academic practice assessed by Quality Oncology Practice Initiative (QOPI).

209 Background: The success of quality improvement (QI) efforts is usually assessed initially within a year of implementation but performance may later decline. We sought to determine the longer-term effectiveness of practice improvement interventions and the characteristics of interventions associated with persistent improvement.The Durham VA Hem-Onc fellowship program affiliated with Duke University participated in QOPI twice yearly in 2007 to 2010 and Spring (Sp) 2012. Four interventions were implemented focused on treatment planning (TP; Sp07), treatment summary (TS; Fa07), consent (C; Sp07), and aprepitant use (A; Sp09). Effectiveness was determined by reassessment of 4, 3, 1, and 1 measures, respectively. The TP, TS, and C interventions were policy-dictated use of templated documentation or written consent, and, for TP and C, required conformance prior to chemotherapy administration; TS is not linked to a process. The A intervention modified order set templates to include A for highly emetogenic regimens. For each measure, we compared conformance pre-intervention with post-intervention conformance and, for quality indicators not targeted for improvement, the baseline with each subsequent assessment using chi-square.Considering only measures in the core or symptom management modules with unchanged or similar definitions throughout the study period, 13 of 28 measures had conformance > 85% in the baseline 2007 data. TP conformance increased from 64% to 88, 94, 92, and 96% in subsequent years (p < 0.01). TS was 45% at baseline, 43% (p = NS) in the first post-intervention year, decreased to 24% for two years (p < 0.01) and then increased to 38% (p = NS). C increased from 64% to 97, 91, 94, and 100% (p < 0.01). Conformance with A increased from 9% to 78 and 86% (p < 0.01). Among measures not targeted by intervention, smoking assessment and counseling increased in later years.In this single practice experience, QI improvement interventions integrated into physician processes resulted in substantial and persistent improvement while no improvement was observed as a result of policy-required use of standard documentation alone.

Authors
Williams, CD; Kamal, A; Kelley, MJ
MLA Citation
Williams, CD, Kamal, A, and Kelley, MJ. "Persistence of quality improvement in a Veterans Affairs (VA) academic practice assessed by Quality Oncology Practice Initiative (QOPI)." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 30.34_suppl (December 2012): 209-.
PMID
28147003
Source
epmc
Published In
Journal of Clinical Oncology
Volume
30
Issue
34_suppl
Publish Date
2012
Start Page
209

Impact of race on early-stage lung cancer treatment and survival.

232 Background: Studies have documented racial differences along the lung cancer continuum and equity in care is essential to quality improvement. The purpose of this study was to investigate the influence of race on lung cancer treatment and survival among early-stage non-small cell lung cancer patients in an equal access healthcare system. We hypothesize that patients receiving similar treatment will have similar survival.Data were from the External Peer Review Program (EPRP) Lung Cancer Special Study, which was a cross-sectional study conducted to assess the quality of care among patients diagnosed with lung cancer and receiving care at a VA facility. All patients were diagnosed between October 1, 2006 and December 31, 2007. Analyses were restricted to patients with Stage I/II NSCLC (n=1,426; 1,229 whites, 197 blacks). Multivariate logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95%CI).The proportion of blacks who had surgery was significantly less than that among whites (OR: 0.56, 95% CI 0.39-0.79). There was no racial difference in receipt of adjuvant therapy (chemotherapy and/or radiation therapy) among patients who had surgery (p=0.08). Among patients who did not undergo surgery, blacks were more likely to refuse surgery (OR: 2.30, 95% CI 1.29-4.13); however, the proportion of patients with contraindications to surgery and those receiving palliative treatment were similar in both race groups. The 2-year survival rate was 69% and race was not a predictor of survival when controlling for receipt of surgery along with other covariates (p=0.76). The 2-year survival rate was 82% among patients who had surgery, and 48% among patients who did not have surgery. Specifically among patients who did not have surgery due to refusal, the survival rate was 55%.We observed a racial disparity in surgery, partially due to the greater rate of refusal among blacks, but not adjuvant or palliative treatment. Race did not have a major impact on 2-year survival for patients with early-stage lung cancer. These findings stress the need to better understand patient preferences regarding surgery and identify ways to reduce this variation in surgery to improve quality of lung cancer care.

Authors
Provenzale, DT; Stechuchak, KM; Kelley, MJ
MLA Citation
Provenzale, DT, Stechuchak, KM, and Kelley, MJ. "Impact of race on early-stage lung cancer treatment and survival." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 30.34_suppl (December 2012): 232-.
PMID
28146913
Source
epmc
Published In
Journal of Clinical Oncology
Volume
30
Issue
34_suppl
Publish Date
2012
Start Page
232

Cancer incidence among patients of the U.S. Veterans Affairs Health Care System.

OBJECTIVE: Approximately 40,000 incident cancer cases are reported in the Veterans Affairs Central Cancer Registry (VACCR) annually (approximately 3% of U.S. cancer cases). Our objective was to provide the first comprehensive description of cancer incidence as reported in VACCR. METHODS: Data were obtained from VACCR for incident cancers diagnosed in VA. Analyses focused on 2007 data. Cancer incidence among VA patients was compared to the general U.S. cancer population. RESULTS: In 2007, 97.5% of VA cancers were diagnosed among men. Approximately 78.5% of newly diagnosed patients were White, 19.0% Black, and 2.5% were another race. Median age at diagnosis was 66 years. The geographic distribution of cancer patients in VA aligns that of VA users. The most commonly diagnosed cancers were similar between VA and the U.S. male cancer population. The five most frequently diagnosed cancers among VA cancer patients were: prostate (31.8%), lung/bronchus (18.8%), colon/rectum (8.6%), urinary bladder (3.6%), and skin melanomas (3.4%). VA patients were diagnosed at an earlier stage of disease for the three most commonly diagnosed cancers--lung/bronchus, colon/rectum, and prostate--compared to the U.S. male cancer population. CONCLUSIONS: Registry data indicate that incident cancers in VA in 2007 approximately mirrored those observed among U.S. men.

Authors
Zullig, LL; Jackson, GL; Dorn, RA; Provenzale, DT; McNeil, R; Thomas, CM; Kelley, MJ
MLA Citation
Zullig, LL, Jackson, GL, Dorn, RA, Provenzale, DT, McNeil, R, Thomas, CM, and Kelley, MJ. "Cancer incidence among patients of the U.S. Veterans Affairs Health Care System." Mil Med 177.6 (June 2012): 693-701.
PMID
22730846
Source
pubmed
Published In
Military medicine
Volume
177
Issue
6
Publish Date
2012
Start Page
693
End Page
701

Mouse models of MYH9-related disease: Mutations in nonmuscle myosin II-A

We have generated 3 mouse lines, each with a different mutation in the non-muscle myosin II-A gene, Myh9 (R702C, D1424N, and E1841K). Each line develops MYH9-related disease similar to that found in human patients. R702C mutant human cDNA fused with green fluorescent protein was introduced into the first coding exon of Myh9, and D1424N and E1841K mutations were introduced directly into the corresponding exons. Homozygous R702C mice die at embryonic day 10.5-11.5, whereas homozygous D1424N and E1841K mice are viable. All heterozygous and homozygous mutant mice show macrothrombocytopenia with prolonged bleeding times, a defect in clot retraction, and increased extramedullary megakaryocytes. Studies of cultured megakaryocytes and live-cell imaging of megakaryocytes in the BM show that heterozygous R702C megakaryocytes form fewer and shorter proplatelets with less branching and larger buds. The results indicate that disrupted proplatelet formation contributes to the macrothrombocytopenia in mice and most probably in humans. We also observed premature cataract formation, kidney abnormalities, including albuminuria, focal segmental glomerulosclerosis and progressive kidney disease, and mild hearing loss. Our results show that heterozygous mice with mutations in the myosin motor or filament-forming domain manifest similar hematologic, eye, and kidney phenotypes to humans with MYH9-related disease.

Authors
Zhang, Y; Conti, MA; Malide, D; Dong, F; Wang, A; Shmist, YA; Liu, C; Zerfas, P; Daniels, MP; Chan, C-C; Kozin, E; Kachar, B; Kelley, MJ; Kopp, JB; Adelstein, RS
MLA Citation
Zhang, Y, Conti, MA, Malide, D, Dong, F, Wang, A, Shmist, YA, Liu, C, Zerfas, P, Daniels, MP, Chan, C-C, Kozin, E, Kachar, B, Kelley, MJ, Kopp, JB, and Adelstein, RS. "Mouse models of MYH9-related disease: Mutations in nonmuscle myosin II-A." Blood 119.1 (2012): 238-250.
PMID
21908426
Source
scival
Published In
Blood
Volume
119
Issue
1
Publish Date
2012
Start Page
238
End Page
250
DOI
10.1182/blood-2011-06-358853

Proactive recruitment of cancer patients' social networks into a smoking cessation trial.

BACKGROUND: This report describes the characteristics associated with successful enrollment of smokers in the social networks (i.e., family and close friends) of patients with lung cancer into a smoking cessation intervention. METHODS: Lung cancer patients from four clinical sites were asked to complete a survey enumerating their family members and close friends who smoke, and provide permission to contact these potential participants. Family members and close friends identified as smokers were interviewed and offered participation in a smoking cessation intervention. Repeated measures logistic regression model examined characteristics associated with enrollment. RESULTS: A total of 1062 eligible lung cancer patients were identified and 516 patients consented and completed the survey. These patients identified 1325 potentially eligible family and close friends. Of these, 496 consented and enrolled in the smoking cessation program. Network enrollment was highest among patients who were white and had late-stage disease. Social network members enrolled were most likely to be female, a birth family, immediate family, or close friend, and live in close geographic proximity to the patient. CONCLUSIONS: Proactive recruitment of smokers in the social networks of lung cancer patients is challenging. In this study, the majority of family members and friends declined to participate. Enlisting immediate female family members and friends, who live close to the patient as agents to proactively recruit other network members into smoking cessation trials could be used to extend reach of cessation interventions to patients' social networks. Moreover, further consideration should be given to the appropriate timing of approaching network smokers to consider cessation.

Authors
Bastian, LA; Fish, LJ; Peterson, BL; Biddle, AK; Garst, J; Lyna, P; Molner, S; Bepler, G; Kelley, M; Keefe, FJ; McBride, CM
MLA Citation
Bastian, LA, Fish, LJ, Peterson, BL, Biddle, AK, Garst, J, Lyna, P, Molner, S, Bepler, G, Kelley, M, Keefe, FJ, and McBride, CM. "Proactive recruitment of cancer patients' social networks into a smoking cessation trial." Contemporary clinical trials 32.4 (July 2011): 498-504. (Academic Article)
PMID
21382509
Source
manual
Published In
Contemporary Clinical Trials
Volume
32
Issue
4
Publish Date
2011
Start Page
498
End Page
504
DOI
10.1016/j.cct.2011.03.006

Automated extraction of Quality Oncology Practice Initiative (QOPI) quality measures from the Veterans Health Administration (VHA) electronic health record system

Authors
Williams, CD; Kelley, MJ
MLA Citation
Williams, CD, and Kelley, MJ. "Automated extraction of Quality Oncology Practice Initiative (QOPI) quality measures from the Veterans Health Administration (VHA) electronic health record system." 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

Automated extraction of Quality Oncology Practice Initiative (QOPI) quality measures from the Veterans Health Administration (VHA) electronic health record system.

e16560 Background: ASCO's QOPI is a program that requires manual data abstraction of medical record data to measure quality of cancer care, a necessary component of quality improvement programs. Improving quality of care for veterans is a long-standing goal of the VHA. The VHA's electronic health record (EHR) is a fully integrated health information system used in all VA healthcare settings. It is unknown whether automated data extraction from the VHA EHR is feasible to assess quality of cancer care.Using non-small cell lung cancer (NSCLC) as an example, we examined the quality measure data elements needed to assess the fall 2010 QOPI measures. We then determined which data elements could be electronically collated from the VHA EHR. To complement and improve upon this method, we designed and implemented a note template in the VHA EHR at the Durham VA Medical Center. This template allows the oncologist to enter at the time of care delivery those required data elements not currently electronically retrievable from the EHR in a structured format suitable for automated retrieval.Based on data currently in the EHR not including data in the note template, data elements for 7/25 (28%) core measures, 7/9 (78%) symptom/toxicity management measures, 9/16 (56%) end-of-life measures and 0/9 (0%) NSCLC QOPI measures can be obtained automatically. Combined with data from the note template, data elements for 16/25 (64%) Core measures, 9/9 (100%) symptom/toxicity management measures, 14/16 (88%) end-of-life measures and 100% (9/9) NSCLC QOPI measures are able to be obtained electronically.A majority of data required to assess adherence with QOPI measures are readily available in the VHA EHR, particularly for measures common for all cancers. A note template is useful for structuring and capturing electronic data for cancer-specific measures. A comparison of manually abstracted data from the Fall 2010 QOPI data collection to electronically captured data will be available by June 2011. Embedding quality measures into the VHA's EHR system will allow real time quality assessment and improvement in cancer care.

Authors
Williams, CD; Kelley, MJ
MLA Citation
Williams, CD, and Kelley, MJ. "Automated extraction of Quality Oncology Practice Initiative (QOPI) quality measures from the Veterans Health Administration (VHA) electronic health record system." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 29.15_suppl (May 2011): e16560-.
PMID
28022056
Source
epmc
Published In
Journal of Clinical Oncology
Volume
29
Issue
15_suppl
Publish Date
2011
Start Page
e16560

Retraction: A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer. N Engl J Med 2006;355:570-80.

To the Editor: We would like to retract our article, "A Genomic Strategy to Refine Prognosis in Early-Stage Non-Small-Cell Lung Cancer,"(1) which was published in the Journal on August 10, 2006. Using a sample set from a study by the American College of Surgeons Oncology Group (ACOSOG) and a collection of samples from a study by the Cancer and Leukemia Group B (CALGB), we have tried and failed to reproduce results supporting the validation of the lung metagene model described in the article. We deeply regret the effect of this action on the work of other investigators.

Authors
Potti, A; Mukherjee, S; Petersen, R; Dressman, HK; Bild, A; Koontz, J; Kratzke, R; Watson, MA; Kelley, M; Ginsburg, GS; West, M; Harpole, DH; Nevins, JR
MLA Citation
Potti, A, Mukherjee, S, Petersen, R, Dressman, HK, Bild, A, Koontz, J, Kratzke, R, Watson, MA, Kelley, M, Ginsburg, GS, West, M, Harpole, DH, and Nevins, JR. "Retraction: A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer. N Engl J Med 2006;355:570-80." N Engl J Med 364.12 (March 24, 2011): 1176-.
PMID
21366430
Source
pubmed
Published In
The New England journal of medicine
Volume
364
Issue
12
Publish Date
2011
Start Page
1176
DOI
10.1056/NEJMc1101915

Retraction: Genomic signatures to guide the use of chemotherapeutics.

Authors
Potti, A; Dressman, HK; Bild, A; Riedel, RF; Chan, G; Sayer, R; Cragun, J; Cottrill, H; Kelley, MJ; Petersen, R; Harpole, D; Marks, J; Berchuck, A; Ginsburg, GS; Febbo, P; Lancaster, J; Nevins, JR
MLA Citation
Potti, A, Dressman, HK, Bild, A, Riedel, RF, Chan, G, Sayer, R, Cragun, J, Cottrill, H, Kelley, MJ, Petersen, R, Harpole, D, Marks, J, Berchuck, A, Ginsburg, GS, Febbo, P, Lancaster, J, and Nevins, JR. "Retraction: Genomic signatures to guide the use of chemotherapeutics." Nat Med 17.1 (January 2011): 135-.
PMID
21217686
Source
pubmed
Published In
Nature Medicine
Volume
17
Issue
1
Publish Date
2011
Start Page
135
DOI
10.1038/nm0111-135

Erratum: Genomic signatures to guide the use of chemotherapeutics (Nature Medicine (2006) 12 (1294-1300))

Authors
Potti, A; Dressman, HK; Bild, A; Riedel, RF; Chan, G; Sayer, R; Cragun, J; Cottrill, H; Kelley, MJ; Petersen, R; Harpole, D; Marks, J; Berchuck, A; Ginsburg, GS; Febbo, P; Lancaster, J; Nevins, JR
MLA Citation
Potti, A, Dressman, HK, Bild, A, Riedel, RF, Chan, G, Sayer, R, Cragun, J, Cottrill, H, Kelley, MJ, Petersen, R, Harpole, D, Marks, J, Berchuck, A, Ginsburg, GS, Febbo, P, Lancaster, J, and Nevins, JR. "Erratum: Genomic signatures to guide the use of chemotherapeutics (Nature Medicine (2006) 12 (1294-1300))." Nature Medicine 17.1 (2011): 135--.
Source
scival
Published In
Nature Medicine
Volume
17
Issue
1
Publish Date
2011
Start Page
135-
DOI
10.1038/nm0111-135

Surveillance for hepatocellular carcinoma

Authors
Kelley, MJ
MLA Citation
Kelley, MJ. "Surveillance for hepatocellular carcinoma." Annals of Internal Medicine 155.4 (2011): 274--.
PMID
21844558
Source
scival
Published In
Annals of internal medicine
Volume
155
Issue
4
Publish Date
2011
Start Page
274-
DOI
10.7326/0003-4819-155-4-201108160-00016

Lung cancer management in 2010.

The introduction of newer therapies and approaches for management has led to a renewed excitement in the field of lung cancer. This trend has continued in 2010 with the adoption of the new staging system recommended by the International Association for the Study of Lung Cancer (IASLC). Novel targets, such as EML4-ALK, have been identified and agents targeting these abnormalities have shown promise in uncontrolled clinical trials, while other strategies, including combining targeted agents with cytotoxic chemotherapy in unselected patients, have not proven to be successful. This review summarizes important recent clinical advances that could have a significant impact on the future care of patients with lung cancer.

Authors
Ganti, AK; Huang, CH; Klein, MA; Keefe, S; Kelley, MJ
MLA Citation
Ganti, AK, Huang, CH, Klein, MA, Keefe, S, and Kelley, MJ. "Lung cancer management in 2010." Oncology (Williston Park, N.Y.) 25.1 (2011): 64-73.
PMID
21361246
Source
scival
Published In
Oncology
Volume
25
Issue
1
Publish Date
2011
Start Page
64
End Page
73

Lung cancer management in 2010

The introduction of newer therapies and approaches for management has led to a renewed excitement in the field of lung cancer. This trend has continued in 2010 with the adoption of the new staging system recommended by the International Association for the Study of Lung Cancer (IASLC). Novel targets, such as EML4-ALK, have been identified and agents targeting these abnormalities have shown promise in uncontrolled clinical trials, while other strategies, including combining targeted agents with cytotoxic chemotherapy in unselected patients, have not proven to be successful. This review summarizes important recent clinical advances that could have a significant impact on the future care of patients with lung cancer.

Authors
Ganti, AK; Huang, CH; Klein, MA; Keefe, S; Kelley, MJ
MLA Citation
Ganti, AK, Huang, CH, Klein, MA, Keefe, S, and Kelley, MJ. "Lung cancer management in 2010." Oncology 25.1 (2011).
Source
scival
Published In
Oncology
Volume
25
Issue
1
Publish Date
2011

Mutations in the Motor and Rod Domains of Murine Nonmuscle Myosin II-A Cause Similar Defects and Mimic Human MYH9-Related Disease

Authors
Zhang, Y; Conti, M; Malide, D; Dong, F; Wang, A; Shmist, Y; Liu, C; Zerfas, P; Daniels, M; Chan, C-C; Kozin, E; Kachar, B; Kelley, M; Kopp, J; Adelstein, RS
MLA Citation
Zhang, Y, Conti, M, Malide, D, Dong, F, Wang, A, Shmist, Y, Liu, C, Zerfas, P, Daniels, M, Chan, C-C, Kozin, E, Kachar, B, Kelley, M, Kopp, J, and Adelstein, RS. "Mutations in the Motor and Rod Domains of Murine Nonmuscle Myosin II-A Cause Similar Defects and Mimic Human MYH9-Related Disease." 2011.
Source
wos-lite
Published In
Molecular Biology of the Cell
Volume
22
Publish Date
2011

Quality of nonmetastatic colorectal cancer care in the Department of Veterans Affairs.

PURPOSE: The Veterans Affairs (VA) healthcare system treats approximately 3% of patients with cancer in the United States each year. We measured the quality of nonmetastatic colorectal cancer (CRC) care in VA as indicated by concordance with National Comprehensive Cancer Network practice guidelines (six indicators) and timeliness of care (three indicators). PATIENTS AND METHODS: A retrospective medical record abstraction was done for 2,492 patients with incident stages I to III CRC diagnosed between October 1, 2003, and March 31, 2006, who underwent definitive CRC surgery. Patients were treated at one or more of 128 VA medical centers. The proportion of patients receiving guideline-concordant care and time intervals between care processes were calculated. RESULTS: More than 80% of patients had preoperative carcinoembryonic antigen determination (ie, stages II to III disease) and documented clear surgical margins (ie, stages II to III disease). Between 72% and 80% of patients had appropriate referral to a medical oncologist (ie, stages II to III disease), preoperative computed tomography scan of the abdomen and pelvis (ie, stages II to III disease), and adjuvant fluorouracil-based chemotherapy (ie, stage III disease). Less than half of patients with stages I to III CRC (43.5%) had a follow-up colonoscopy 7 to 18 months after surgery. The mean number of days between major treatment events included the following: 26.6 days (standard deviation [SD], 38.2; median, 20 days) between diagnosis and initiation of treatment (in stages II to III disease); 64.8 [corrected] days (SD, 54.9; median, 50 days) between definitive surgery and start of adjuvant chemotherapy (in stages II to III disease); and 444.2 [corrected] days (SD, 182.1; median, 393 days) between definitive surgery and follow-up colonoscopies (in stages I to III disease). CONCLUSION: Although there is opportunity for improvement in the area of cancer surveillance, the VA performs well in meeting established guidelines for diagnosis and treatment of CRC.

Authors
Jackson, GL; Melton, LD; Abbott, DH; Zullig, LL; Ordin, DL; Grambow, SC; Hamilton, NS; Zafar, SY; Gellad, ZF; Kelley, MJ; Provenzale, D
MLA Citation
Jackson, GL, Melton, LD, Abbott, DH, Zullig, LL, Ordin, DL, Grambow, SC, Hamilton, NS, Zafar, SY, Gellad, ZF, Kelley, MJ, and Provenzale, D. "Quality of nonmetastatic colorectal cancer care in the Department of Veterans Affairs." J Clin Oncol 28.19 (July 1, 2010): 3176-3181.
PMID
20516431
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
28
Issue
19
Publish Date
2010
Start Page
3176
End Page
3181
DOI
10.1200/JCO.2009.26.7948

A pathway-based classification of human breast cancer.

The hallmark of human cancer is heterogeneity, reflecting the complexity and variability of the vast array of somatic mutations acquired during oncogenesis. An ability to dissect this heterogeneity, to identify subgroups that represent common mechanisms of disease, will be critical to understanding the complexities of genetic alterations and to provide a framework to develop rational therapeutic strategies. Here, we describe a classification scheme for human breast cancer making use of patterns of pathway activity to build on previous subtype characterizations using intrinsic gene expression signatures, to provide a functional interpretation of the gene expression data that can be linked to therapeutic options. We show that the identified subgroups provide a robust mechanism for classifying independent samples, identifying tumors that share patterns of pathway activity and exhibit similar clinical and biological properties, including distinct patterns of chromosomal alterations that were not evident in the heterogeneous total population of tumors. We propose that this classification scheme provides a basis for understanding the complex mechanisms of oncogenesis that give rise to these tumors and to identify rational opportunities for combination therapies.

Authors
Gatza, ML; Lucas, JE; Barry, WT; Kim, JW; Wang, Q; Crawford, MD; Datto, MB; Kelley, M; Mathey-Prevot, B; Potti, A; Nevins, JR
MLA Citation
Gatza, ML, Lucas, JE, Barry, WT, Kim, JW, Wang, Q, Crawford, MD, Datto, MB, Kelley, M, Mathey-Prevot, B, Potti, A, and Nevins, JR. "A pathway-based classification of human breast cancer." Proc Natl Acad Sci U S A 107.15 (April 13, 2010): 6994-6999.
PMID
20335537
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
107
Issue
15
Publish Date
2010
Start Page
6994
End Page
6999
DOI
10.1073/pnas.0912708107

Methylthioadenosine phosphorylase and activated insulin-like growth factor-1 receptor/insulin receptor: potential therapeutic targets in chordoma.

Currently there is no effective chemotherapy for chordoma. Recent studies report co-expression of insulin-like growth factor-1 receptor (IGF1R) and its cognate ligand in chordoma, but it is unknown whether this receptor tyrosine kinase is activated in these tumours. Additionally, genetic studies have confirmed frequent deletions of chromosome 9p in chordomas, which encompasses the cyclin-dependent kinase inhibitor 2A (CDKN2A) locus. Another gene in this region, methylthioadenosine phosphorylase (MTAP), is an essential enzyme of the purine salvage pathway and has therapeutic relevance because MTAP-deficient cells are particularly sensitive to inhibitors of de novo purine synthesis. We investigated whether these pathways might be potential therapeutic targets for chordoma. Paraffin-embedded tissue samples from 30 chordomas were analysed by immunohistochemistry for expression of the phosphorylated isoforms of IGF1R or the insulin receptor (pIGF1R/pIR) and selected downstream signalling molecules, including BCL2-associated agonist of cell death protein (BAD). Expression of CDKN2A and MTAP proteins was also assessed. Skeletal chondrosarcomas, benign notochordal cell tumours, and fetal notochord were studied for comparison. Phosphorylated IGF1R/IR was detected in 41% of chordomas, together with activated downstream signalling molecules, and pIGF1R/pIR was absent in benign notochordal cell tumours and fetal notochord. Thirty-nine per cent of chordomas were negative for MTAP immunoreactivity. Patients with pIGF1R/pIR-positive tumours showed significantly decreased median disease-free survival in multivariate survival analysis (p = 0.036), whereas phosphorylation of BAD at serine-99 was found to be associated with a favourable prognosis (p = 0.002). Approximately 40% of chordomas demonstrate evidence of activation of the IGF1R/IR signalling pathway or loss of a key enzyme in the purine salvage pathway. Aberrant signalling cascades and disrupted metabolic pathways such as these may represent opportunities for novel targeted therapeutic approaches for the treatment of chordoma.

Authors
Sommer, J; Itani, DM; Homlar, KC; Keedy, VL; Halpern, JL; Holt, GE; Schwartz, HS; Coffin, CM; Kelley, MJ; Cates, JMM
MLA Citation
Sommer, J, Itani, DM, Homlar, KC, Keedy, VL, Halpern, JL, Holt, GE, Schwartz, HS, Coffin, CM, Kelley, MJ, and Cates, JMM. "Methylthioadenosine phosphorylase and activated insulin-like growth factor-1 receptor/insulin receptor: potential therapeutic targets in chordoma." J Pathol 220.5 (April 2010): 608-617.
PMID
20140939
Source
pubmed
Published In
The Journal of Pathology
Volume
220
Issue
5
Publish Date
2010
Start Page
608
End Page
617
DOI
10.1002/path.2679

Phosphorylated epidermal growth factor receptor and cyclooxygenase-2 expression in localized non-small cell lung cancer.

PURPOSE: The prognostic significance of epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) expression remains unestablished, although EGFR and COX-2 are frequently overexpressed in non-small cell lung cancer (NSCLC). Considering the importance of EGFR activation after ligand binding, however, the expression of phosphorylated EGFR (p-EGFR) may have more significance in predicting tumor aggressiveness in NSCLC than either EGFR or COX-2 expression. PATIENTS AND METHODS: We studied the relationships between p-EGFR, EGFR, and COX-2 overexpression and examined their association with prognosis in localized NSCLC. The expression of p-EGFR, EGFR, and COX-2 was studied by immunohistochemistry in 77 surgically-resected stage I/II NSCLC cases. EGFR mutational status was determined by sequencing exons 18-21. Correlation of expression with clinical outcome and other biomarkers, including Ki-67 and microvessel density (MVD), was also examined. RESULTS: Out of the 77 patients, EGFR overexpression was observed in 37 (48.1%), p-EGFR expression was found in 22 (28.6%), and COX-2 overexpression was seen in 45 (58.4%). Expression of p-EGFR was associated with COX-2 overexpression (P = 0.047), but not EGFR overexpression or high Ki-67 (P = 0.087 and P = 0.092, respectively). COX-2 overexpression was significantly associated with high Ki-67 (P = 0.011). Expression of p-EGFR correlated with lower disease-free survival (P = 0.045), but not overall survival. Neither EGFR nor COX-2 overexpression was associated with prognosis. CONCLUSION: p-EGFR appears to be a better indicator for lower disease-free survival than EGFR overexpression itself in localized NSCLC. Pathways other than EGFR activation may influence COX-2 overexpression.

Authors
Kim, SJ; Rabbani, ZN; Dong, F; Vollmer, RT; Schreiber, E-G; Dewhirst, MW; Vujaskovic, Z; Kelley, MJ
MLA Citation
Kim, SJ, Rabbani, ZN, Dong, F, Vollmer, RT, Schreiber, E-G, Dewhirst, MW, Vujaskovic, Z, and Kelley, MJ. "Phosphorylated epidermal growth factor receptor and cyclooxygenase-2 expression in localized non-small cell lung cancer." Med Oncol 27.1 (March 2010): 91-97.
PMID
19235531
Source
pubmed
Published In
Medical Oncology
Volume
27
Issue
1
Publish Date
2010
Start Page
91
End Page
97
DOI
10.1007/s12032-009-9178-z

A phase II study of dasatinib in patients with chemosensitive relapsed small cell lung cancer (Cancer and Leukemia Group B 30602).

INTRODUCTION: SRC is an oncogene with an essential role in the invasiveness and metastasis of solid tumors including small cell lung cancer. Dasatinib is a potent inhibitor of SRC as well as other tyrosine kinases. The primary objective of this study was to determine the efficacy of second-line dasatinib in patients with chemosensitive (relapse or progression > or =90 days after completing first-line therapy) small cell lung cancer. METHODS: Patients with measurable disease; performance status 0 to 1; no more than one prior platinum-based chemotherapy regimen; and adequate hematologic, hepatic, and renal function were eligible. Dasatinib was administered orally at 70 mg twice daily continuously (1 cycle = 21 days) until disease progression or unacceptable toxicity. Response was determined after every two cycles. Patients were followed until disease progression or death. The study was prospectively designed to simultaneously discriminate between complete plus partial response rates of 5% versus 20% and progression-free survival (PFS) rates at 6 weeks of 50% versus 70.7% in 53 evaluable patients with at least 92% power. The study was to be terminated early and declared negative if 1 or less objective response and 14 or fewer instances of PFS > or =6 weeks were observed among the initial 27 patients; however, patient accrual continued while the initial 27 patients were evaluated. RESULTS: Between April 2007 and December 2008, 45 patients were enrolled, but one patient never received any protocol therapy and one patient was ineligible: male/female, 17/26; white/black/unknown, 40/2/1; median age, 64 years (range, 35-84 years); and performance status 0/1, 12/31. No objective response was recorded among the 43 eligible and treated patients. Among the initial 27 patients, only 13 instances of PFS > or =6 weeks were observed. With a median follow-up time of 7.1 months, median estimated overall survival and PFS times for the 43 eligible and treated patients were 17.0 and 5.9 weeks, respectively. Common reasons for removal of patients from protocol treatment were progressive disease (65%) and adverse events (26%). Toxicity was generally mild to moderate: grade 3 events of >5% frequency included fatigue and pleural and pericardial effusions; and no grade 4 or 5 events were encountered. CONCLUSIONS: Dasatinib did not reach our specified efficacy criteria in this clinical setting, and the study was terminated.

Authors
Miller, AA; Pang, H; Hodgson, L; Ramnath, N; Otterson, GA; Kelley, MJ; Kratzke, RA; Vokes, EE; Cancer and Leukemia Group B (CALGB),
MLA Citation
Miller, AA, Pang, H, Hodgson, L, Ramnath, N, Otterson, GA, Kelley, MJ, Kratzke, RA, Vokes, EE, and Cancer and Leukemia Group B (CALGB), . "A phase II study of dasatinib in patients with chemosensitive relapsed small cell lung cancer (Cancer and Leukemia Group B 30602)." J Thorac Oncol 5.3 (March 2010): 380-384.
PMID
20087228
Source
pubmed
Published In
Journal of Thoracic Oncology
Volume
5
Issue
3
Publish Date
2010
Start Page
380
End Page
384
DOI
10.1097/JTO.0b013e3181cee36e

Developing and sustaining quality improvement partnerships in the VA: the Colorectal Cancer Care Collaborative.

OBJECTIVE: The Veterans Affairs (VA) Quality Enhancement Research Initiative (QUERI) seeks to develop partnerships between VA health services researchers and clinical managers, with the goal of designing and evaluating interventions to improve the quality of VA health care. METHODS: In the present report we describe one such initiative aimed at enhancing the continuum of colorectal cancer (CRC) care, including diagnosis, treatment and surveillance-the Colorectal Cancer Care Collaborative (C4). RESULTS: We describe the process and thinking that led to two parallel quality improvement "collaboratives" that addressed (1) CRC screening and diagnostic follow-up and (2) the guideline concordance and timeliness of CRC treatment. Additionally, we discuss ongoing effort to spread lessons learned during the first stages of the project, which initially occurred at only a subset of VA facilities, throughout the VA health care system. The description of this initiative is organized around key questions that must be answered when developing, sustaining and spreading multi-component quality improvement interventions. CONCLUSION: We conclude with a discussion of lessons learned that we believe would apply to similar initiatives elsewhere, even if they address different clinical issues in health care settings with different organizational structures.

Authors
Jackson, GL; Powell, AA; Ordin, DL; Schlosser, JE; Murawsky, J; Hersh, J; Ponte, G; Zullig, LL; Erb, F; Parlier, R; Haggstrom, DA; Koets, N; Mills, PD; Francis, J; Kelley, MJ; Davies, ML; Provenzale, D; VA Colorectal Cancer Care Planning Committee Members,
MLA Citation
Jackson, GL, Powell, AA, Ordin, DL, Schlosser, JE, Murawsky, J, Hersh, J, Ponte, G, Zullig, LL, Erb, F, Parlier, R, Haggstrom, DA, Koets, N, Mills, PD, Francis, J, Kelley, MJ, Davies, ML, Provenzale, D, and VA Colorectal Cancer Care Planning Committee Members, . "Developing and sustaining quality improvement partnerships in the VA: the Colorectal Cancer Care Collaborative." J Gen Intern Med 25 Suppl 1 (January 2010): 38-43.
PMID
20077150
Source
pubmed
Published In
Journal of General Internal Medicine
Volume
25 Suppl 1
Publish Date
2010
Start Page
38
End Page
43
DOI
10.1007/s11606-009-1155-x

Molecular characterization of putative chordoma cell lines.

Immortal tumor cell lines are an important model system for cancer research, however, misidentification and cross-contamination of cell lines are a common problem. Seven chordoma cell lines are reported in the literature, but none has been characterized in detail. We analyzed gene expression patterns and genomic copy number variations in five putative chordoma cell lines (U-CH1, CCL3, CCL4, GB60, and CM319). We also created a new chordoma cell line, U-CH2, and provided genotypes for cell lines for identity confirmation. Our analyses revealed that CCL3, CCL4, and GB60 are not chordoma cell lines, and that CM319 is a cancer cell line possibly derived from chordoma, but lacking expression of key chordoma biomarkers. U-CH1 and U-CH2 both have gene expression profiles, copy number aberrations, and morphology consistent with chordoma tumors. These cell lines also harbor genetic changes, such as loss of p16, MTAP, or PTEN, that make them potentially useful models for studying mechanisms of chordoma pathogenesis and for evaluating targeted therapies.

Authors
Brüderlein, S; Sommer, JB; Meltzer, PS; Li, S; Osada, T; Ng, D; Möller, P; Alcorta, DA; Kelley, MJ
MLA Citation
Brüderlein, S, Sommer, JB, Meltzer, PS, Li, S, Osada, T, Ng, D, Möller, P, Alcorta, DA, and Kelley, MJ. "Molecular characterization of putative chordoma cell lines." Sarcoma 2010 (2010): 630129-.
PMID
21253487
Source
pubmed
Published In
Sarcoma
Volume
2010
Publish Date
2010
Start Page
630129
DOI
10.1155/2010/630129

Treatment outcomes of different prognostic groups of patients on cancer and leukemia group B trial 39801: induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for unresectable stage III non-small cell lung cancer.

BACKGROUND: In Cancer and Leukemia Group B 39801, we evaluated whether induction chemotherapy before concurrent chemoradiotherapy would result in improved survival and demonstrated no significant benefit from the addition of induction chemotherapy. The primary objective of this analysis was to dichotomize patients into prognostic groups using factors predictive of survival and to investigate whether induction chemotherapy was beneficial in either prognostic group. PATIENTS AND METHODS: A Cox proportional hazard model was used to assess the impact on survival of the following factors: (>or=70 versus <70 years), gender, race, stage (IIIB versus IIIA), hemoglobin (hgb) (<13 versus >or=13 g/dl), performance status (PS) (1 versus 0), weight loss (>or=5% versus <5%), treatment arm, and the interaction between weight loss and hgb. RESULTS: Factors predictive of decreased survival were weight loss >or=5%, age >or=70 years, PS of 1, and hgb <13 g/dl (p < 0.05). Patients were classified as having >or=2 poor prognostic factors (n = 165) or or=2 versus patients with or=2 factors (HR = 0.86, 95% CI, 0.63-1.17; p = 0.34) or

Authors
Stinchcombe, TE; Hodgson, L; Herndon, JE; Kelley, MJ; Cicchetti, MG; Ramnath, N; Niell, HB; Atkins, JN; Akerley, W; Green, MR; Vokes, EE; Cancer and Leukemia Group B,
MLA Citation
Stinchcombe, TE, Hodgson, L, Herndon, JE, Kelley, MJ, Cicchetti, MG, Ramnath, N, Niell, HB, Atkins, JN, Akerley, W, Green, MR, Vokes, EE, and Cancer and Leukemia Group B, . "Treatment outcomes of different prognostic groups of patients on cancer and leukemia group B trial 39801: induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for unresectable stage III non-small cell lung cancer." J Thorac Oncol 4.9 (September 2009): 1117-1125.
PMID
19652624
Source
pubmed
Published In
Journal of Thoracic Oncology
Volume
4
Issue
9
Publish Date
2009
Start Page
1117
End Page
1125
DOI
10.1097/JTO.0b013e3181b27b33

Identification of prognostic groups in patients (pts) with unresectable stage III non-small cell lung cancer (NSCLC) treated with chemoradiotherapy on Cancer and Leukemia and Group B trial (CALGB) 39801

Authors
Stinchcombe, TE; Hodgson, L; Herndon, IIJE; Kelley, M; Cicchetti, MG; Ramnath, N; Niell, H; Atkins, JN; Akerley, W; Green, MR; Vokes, EE
MLA Citation
Stinchcombe, TE, Hodgson, L, Herndon, IIJE, Kelley, M, Cicchetti, MG, Ramnath, N, Niell, H, Atkins, JN, Akerley, W, Green, MR, and Vokes, EE. "Identification of prognostic groups in patients (pts) with unresectable stage III non-small cell lung cancer (NSCLC) treated with chemoradiotherapy on Cancer and Leukemia and Group B trial (CALGB) 39801." JOURNAL OF THORACIC ONCOLOGY 4.9 (September 2009): S522-S523.
Source
wos-lite
Published In
Journal of Thoracic Oncology
Volume
4
Issue
9
Publish Date
2009
Start Page
S522
End Page
S523

Clinical factors predictive of overall survival (OS) and the identification of prognostic groups in patients (pts) with unresectable stage III non-small cell lung cancer (NSCLC) treated with chemoradiotherapy on Cancer and Leukemia and Group B trial (CALGB) 39801

Authors
Stinchcombe, TE; Hodgson, L; Herndon, JE; Kelley, MJ; Cicchetti, M; Ramnath, N; Niell, HB; Atkins, JN; Green, MR; Vokes, EE
MLA Citation
Stinchcombe, TE, Hodgson, L, Herndon, JE, Kelley, MJ, Cicchetti, M, Ramnath, N, Niell, HB, Atkins, JN, Green, MR, and Vokes, EE. "Clinical factors predictive of overall survival (OS) and the identification of prognostic groups in patients (pts) with unresectable stage III non-small cell lung cancer (NSCLC) treated with chemoradiotherapy on Cancer and Leukemia and Group B trial (CALGB) 39801." May 20, 2009.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
27
Issue
15
Publish Date
2009

Clinical factors predictive of overall survival (OS) and the identification of prognostic groups in patients (pts) with unresectable stage III non-small cell lung cancer (NSCLC) treated with chemoradiotherapy on Cancer and Leukemia and Group B trial (CALGB) 39801.

7535 Background: CALGB 39801 was designed to test whether treatment with induction chemotherapy and concurrent chemoradiotherapy (arm B) would improve OS in comparison to identical chemoradiotherapy alone (arm A), and demonstrated no significant benefit in OS for induction therapy. The objective of this analysis was to identify factors predictive of OS, and to use relevant factors to dichotomize pts into prognostic groups.Between July 1998 and May 2002, 331 pts were studied and included in a Cox proportional hazard regression analysis investigating previously identified prognostic factors: age (< 70 vs. ≥ 70 years), gender, race/ethnicity, hemoglobin (hgb) (< 13 vs. ≥13), performance status (PS) (0 vs.1), pretreatment weight loss (wt loss) (<5% vs. ≥ 5%), and treatment arm.Cox regression analysis identified weight loss ≥ 5%, age ≥ 70, PS of 1, and hgb < 13 as predictive of worse survival (p<0.05), but not treatment arm (p=0.55). The median survival for pts with 0 (n=66), 1 (n=100), 2 (n=100), or ≥ 3 (n=65) risk factors were 24, 18, 10, and 8 months, respectively (p=0.0001). The pts were dichotomized into "poor prognosis" (PP) defined as ≥2 factors (n=165) and "good prognosis" (GP) defined as ≤ 1 factors (n=166). The hazard ratio (HR) for overall survival for the PP in comparison GP was 1.88 (95% CI, 1.49 to 2.37; p-value < 0.0001); the median survival times (MST) observed were 9 and 18 months, respectively (p<0.0001). The reasons for discontinuing treatment, and the rates of hematologic and non-hematologic adverse events were similar between the two groups. In the PP group the OS was similar between arms A (n=82) and B (n=83) (HR=0.97, 95% CI, 0.70 to 1.4; p=0.34); MST of 8.7 and 9.5 months, respectively. In the GP the OS was similar between arms A (n=79) and B (n=87) (HR=0.86, 95% CI, 0.63 to 1.1; p=0.87); MST of 19.3 and 17.6 months, respectively.Factors predictive of OS can be used to dichotomize pts into prognostic groups. Induction chemotherapy was not beneficial in either prognostic group. No significant financial relationships to disclose.

Authors
Stinchcombe, TE; Hodgson, L; Herndon, JE; Kelley, MJ; Cicchetti, M; Ramnath, N; Niell, HB; Atkins, JN; Green, MR; Vokes, EE
MLA Citation
Stinchcombe, TE, Hodgson, L, Herndon, JE, Kelley, MJ, Cicchetti, M, Ramnath, N, Niell, HB, Atkins, JN, Green, MR, and Vokes, EE. "Clinical factors predictive of overall survival (OS) and the identification of prognostic groups in patients (pts) with unresectable stage III non-small cell lung cancer (NSCLC) treated with chemoradiotherapy on Cancer and Leukemia and Group B trial (CALGB) 39801." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 27.15_suppl (May 2009): 7535-.
PMID
27963304
Source
epmc
Published In
Journal of Clinical Oncology
Volume
27
Issue
15_suppl
Publish Date
2009
Start Page
7535

Methylthioadenosine Phosphorylase and Activated Insulin-Like Growth Factor 1-Receptor: Potential Therapeutic Targets in Chordoma

Authors
Sommer, JB; Itani, DM; Homlar, KC; Olson, SJ; Holt, GE; Schwartz, HS; Coffin, CM; Kelley, MJ; Cates, JM
MLA Citation
Sommer, JB, Itani, DM, Homlar, KC, Olson, SJ, Holt, GE, Schwartz, HS, Coffin, CM, Kelley, MJ, and Cates, JM. "Methylthioadenosine Phosphorylase and Activated Insulin-Like Growth Factor 1-Receptor: Potential Therapeutic Targets in Chordoma." LABORATORY INVESTIGATION 89 (January 2009): 22A-22A.
Source
wos-lite
Published In
Laboratory Investigation
Volume
89
Publish Date
2009
Start Page
22A
End Page
22A

Methylthioadenosine Phosphorylase and Activated Insulin-Like Growth Factor 1-Receptor: Potential Therapeutic Targets in Chordoma

Authors
Sommer, JB; Itani, DM; Homlar, KC; Olson, SJ; Holt, GE; Schwartz, HS; Coffin, CM; Kelley, MJ; Cates, JM
MLA Citation
Sommer, JB, Itani, DM, Homlar, KC, Olson, SJ, Holt, GE, Schwartz, HS, Coffin, CM, Kelley, MJ, and Cates, JM. "Methylthioadenosine Phosphorylase and Activated Insulin-Like Growth Factor 1-Receptor: Potential Therapeutic Targets in Chordoma." MODERN PATHOLOGY 22 (January 2009): 22A-22A.
Source
wos-lite
Published In
Modern Pathology
Volume
22
Publish Date
2009
Start Page
22A
End Page
22A

Persistent Smoking After a Diagnosis of Lung Cancer Is Associated With Higher Reported Pain Levels

The purpose of this study was to evaluate the impact of smoking status after a diagnosis of lung cancer on reported pain levels. We conducted a telephone survey of patients with lung cancer identified from 4 participating sites between September 2004 and July 2006. Patients were asked to rate their usual pain level over the past week on a 0 to 10 rating scale on which 0 was "no pain" and 10 "pain as bad as you can imagine." We operationally defined persistent smokers as patients who reported continuing to smoke after their lung cancer diagnosis. A logistic regression analysis was used to test the hypothesis that persistent smokers report higher usual pain levels than nonsmokers. Overall, 893 patients completed the survey. The majority (76%) was found to have advanced cancer (stages IIIb and IV). The mean age was 63 years (SD = 10). Seventeen percent of the patients studied were categorized as persistent smokers. The mean pain score for the study sample was 3.1 (SD = 2.7) and 41% reported moderate (4 to 6) or severe pain (7 to 10). A greater proportion of persistent smokers reported moderate or severe pain than nonsmokers or former smokers (P < .001). Logistic regression analysis revealed that smoking status was associated with the usual pain even after adjusting for age, perceived health status, and other lung cancer symptoms such as dyspnea, fatigue, and trouble eating. In conclusion, patients who continue to smoke after a diagnosis of lung cancer report higher levels of usual pain than nonsmokers or former smokers. More research is needed to understand the mechanisms that relate nicotine intake to pain and disease progression in late-stage lung cancer. Perspective: This article examines the relationship between pain and persistent smoking in patients with lung cancer. Although more research is needed to understand the mechanisms that relate nicotine intake to pain and disease progression, physicians can promote smoking cessation in patients with lung cancer to improve health and quality of life. © 2009 American Pain Society.

Authors
Daniel, M; Keefe, FJ; Lyna, P; Peterson, B; Garst, J; Kelley, M; Bepler, G; Bastian, LA
MLA Citation
Daniel, M, Keefe, FJ, Lyna, P, Peterson, B, Garst, J, Kelley, M, Bepler, G, and Bastian, LA. "Persistent Smoking After a Diagnosis of Lung Cancer Is Associated With Higher Reported Pain Levels." Journal of Pain 10.3 (2009): 323-328.
PMID
19254679
Source
scival
Published In
The Journal of Pain
Volume
10
Issue
3
Publish Date
2009
Start Page
323
End Page
328
DOI
10.1016/j.jpain.2008.10.006

T (brachyury) gene duplication confers major susceptibility to familial chordoma

Using high-resolution array-CGH, we identified unique duplications of a region on 6q27 in four multiplex families with at least three cases of chordoma, a cancer of presumed notochordal origin. The duplicated region contains only the T (brachyury) gene, which is important in notochord development and is expressed in most sporadic chordomas. Our findings highlight the value of screening for complex genomic rearrangements in searches for cancer-susceptibility genes. © 2009 Nature America, Inc. All rights reserved.

Authors
Yang, XR; Ng, D; Alcorta, DA; Liebsch, NJ; Sheridan, E; Li, S; Goldstein, AM; Parry, DM; Kelley, MJ
MLA Citation
Yang, XR, Ng, D, Alcorta, DA, Liebsch, NJ, Sheridan, E, Li, S, Goldstein, AM, Parry, DM, and Kelley, MJ. "T (brachyury) gene duplication confers major susceptibility to familial chordoma." Nature Genetics 41.11 (2009): 1176-1178.
PMID
19801981
Source
scival
Published In
Nature Genetics
Volume
41
Issue
11
Publish Date
2009
Start Page
1176
End Page
1178
DOI
10.1038/ng.454

Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice.

Tumors contain oxygenated and hypoxic regions, so the tumor cell population is heterogeneous. Hypoxic tumor cells primarily use glucose for glycolytic energy production and release lactic acid, creating a lactate gradient that mirrors the oxygen gradient in the tumor. By contrast, oxygenated tumor cells have been thought to primarily use glucose for oxidative energy production. Although lactate is generally considered a waste product, we now show that it is a prominent substrate that fuels the oxidative metabolism of oxygenated tumor cells. There is therefore a symbiosis in which glycolytic and oxidative tumor cells mutually regulate their access to energy metabolites. We identified monocarboxylate transporter 1 (MCT1) as the prominent path for lactate uptake by a human cervix squamous carcinoma cell line that preferentially utilized lactate for oxidative metabolism. Inhibiting MCT1 with alpha-cyano-4-hydroxycinnamate (CHC) or siRNA in these cells induced a switch from lactate-fueled respiration to glycolysis. A similar switch from lactate-fueled respiration to glycolysis by oxygenated tumor cells in both a mouse model of lung carcinoma and xenotransplanted human colorectal adenocarcinoma cells was observed after administration of CHC. This retarded tumor growth, as the hypoxic/glycolytic tumor cells died from glucose starvation, and rendered the remaining cells sensitive to irradiation. As MCT1 was found to be expressed by an array of primary human tumors, we suggest that MCT1 inhibition has clinical antitumor potential.

Authors
Sonveaux, P; Végran, F; Schroeder, T; Wergin, MC; Verrax, J; Rabbani, ZN; De Saedeleer, CJ; Kennedy, KM; Diepart, C; Jordan, BF; Kelley, MJ; Gallez, B; Wahl, ML; Feron, O; Dewhirst, MW
MLA Citation
Sonveaux, P, Végran, F, Schroeder, T, Wergin, MC, Verrax, J, Rabbani, ZN, De Saedeleer, CJ, Kennedy, KM, Diepart, C, Jordan, BF, Kelley, MJ, Gallez, B, Wahl, ML, Feron, O, and Dewhirst, MW. "Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice." J Clin Invest 118.12 (December 2008): 3930-3942.
PMID
19033663
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
118
Issue
12
Publish Date
2008
Start Page
3930
End Page
3942
DOI
10.1172/JCI36843

Improving quality at university based hematology/oncology fellowship continuity clinic with the quality oncology practice initiative (QOPI).

6578 Background: Quality imporvement is an important component of improving cancer care and is now an ACGME requirement of fellowship training. The feasibility of integrating QI activities into fellowship training is not known. METHODS: The Hematology/Oncology fellowship program at Duke University voluntarily participated in QOPI in Spring and Fall of 2007 in an effort to evaluate this quality improvement tool for compliance with ACGME requirements. For each round of chart abstractions, all patients seen in this clinic with lung cancer and colorectal cancer (charts identified by ICD-9 codes) within two years were screened for inclusion by the VA chief attending and 1-2 fellows; this screening process required approximately 6 hours.. EMR's of eligible patients were abstracted using the QOPI online tool by attending and fellow physicians. Each attending and fellow physician was assigned 6 to 8 patient charts to abstract data, and each chart required an average of 15 minutes. RESULTS: During the Spring 2007 survey, there were multiple areas identified for improvement. A template was created within the electronic medical record based on this data to improve documentation. A specific hem/onc treatment note was implemented for all patients who are to receive chemotherapy or biotherapy (oral and IV) for their cancers. The template addressed areas for improvement including chemotherapy cycles, pain assessment and consent. Comparison of surveys revealed improvement in documentation of pain assessment (78% increase to 87%), chemotherapy intent discussion (72% increase to 86.5%) and number of chemotherapy cycles documented (54% increase to 90%). CONCLUSIONS: QOPI participation is viable option to comply with ACGME requirements. Participation may improve performance through increased awareness of quality measures. Implementation of required template into electronic medical record improves documentation. No significant financial relationships to disclose.

Authors
Coscio, AM; Anguiano, A; Kuderer, NM; Kelley, M
MLA Citation
Coscio, AM, Anguiano, A, Kuderer, NM, and Kelley, M. "Improving quality at university based hematology/oncology fellowship continuity clinic with the quality oncology practice initiative (QOPI)." J Clin Oncol 26.15_suppl (May 20, 2008): 6578-.
PMID
27949857
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
26
Issue
15_suppl
Publish Date
2008
Start Page
6578

Improving quality at university based hematology/oncology fellowship continuity clinic with the quality oncology practice initiative (QOPI)

Authors
Coscio, AM; Anguiano, A; Kuderer, NM; Kelley, M
MLA Citation
Coscio, AM, Anguiano, A, Kuderer, NM, and Kelley, M. "Improving quality at university based hematology/oncology fellowship continuity clinic with the quality oncology practice initiative (QOPI)." 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

Corrigendum: Genomic signatures to guide the use of chemotherapeutics (Nature Medicine (2006) 12, (1294-1300))

Authors
Potti, A; Dressman, HK; Bild, A; Riedel, RF; Chan, G; Sayer, R; Cragun, J; Cottrill, H; Kelley, MJ; Petersen, R; Harpole, D; Marks, J; Berchuck, A; Ginsburg, GS; Febbo, P; Lancaster, J; Nevins, JR
MLA Citation
Potti, A, Dressman, HK, Bild, A, Riedel, RF, Chan, G, Sayer, R, Cragun, J, Cottrill, H, Kelley, MJ, Petersen, R, Harpole, D, Marks, J, Berchuck, A, Ginsburg, GS, Febbo, P, Lancaster, J, and Nevins, JR. "Corrigendum: Genomic signatures to guide the use of chemotherapeutics (Nature Medicine (2006) 12, (1294-1300))." Nature Medicine 14.8 (2008): 889--.
Source
scival
Published In
Nature Medicine
Volume
14
Issue
8
Publish Date
2008
Start Page
889-
DOI
10.1038/nm0808-889

Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III Non-small-cell lung cancer: Cancer and Leukemia Group B.

PURPOSE: Standard therapy for unresectable stage III non-small-cell lung cancer includes concomitant chemoradiotherapy. In Cancer and Leukemia Group B 39801, we evaluated whether induction chemotherapy before concurrent chemoradiotherapy would result in improved survival. PATIENTS AND METHODS: Between July 1998 and May 2002, 366 patients were randomly assigned to arm A, which involved immediate concurrent chemoradiotherapy with carboplatin area under the concentration-time curve (AUC) of 2 and paclitaxel 50 mg/m2 given weekly during 66 Gy of chest radiotherapy, or arm B, which involved two cycles of carboplatin AUC 6 and paclitaxel 200 mg/m2 administered every 21 days followed by identical chemoradiotherapy. The accrual goal was 360 patients. RESULTS: Thirty-four percent of patients were female, 66% were male, and the median age was 63 years. Grade 3 or 4 toxicities during induction chemotherapy on arm B consisted mainly of neutropenia (18% and 20%, respectively). During concurrent chemoradiotherapy, there was no difference in severity of in-field toxicities of esophagitis (grade 3 and 4 were, respectively, 30% and 2% for arm A v 28% and 8% for arm B) and dyspnea (grade 3 and 4 were, respectively, 11% and 3% for arm A v 15% and 4% for arm B). Survival differences were not statistically significant (P = .3), with a median survival on arm A of 12 months (95% CI, 10 to 16 months) versus 14 months (95% CI, 11 to 16 months) on arm B and a 2-year survival of 29% (95% CI, 22% to 35%) and 31% (95% CI, 25% to 38%). Age, weight loss before therapy, and performance status were statistically significant predictive factors. CONCLUSION: The addition of induction chemotherapy to concurrent chemoradiotherapy added toxicity and provided no survival benefit over concurrent chemoradiotherapy alone. The median survival achieved in each of the treatment groups is low, and the routine use of weekly carboplatin and paclitaxel with simultaneous radiotherapy should be re-examined.

Authors
Vokes, EE; Herndon, JE; Kelley, MJ; Cicchetti, MG; Ramnath, N; Neill, H; Atkins, JN; Watson, DM; Akerley, W; Green, MR; Cancer and Leukemia Group B,
MLA Citation
Vokes, EE, Herndon, JE, Kelley, MJ, Cicchetti, MG, Ramnath, N, Neill, H, Atkins, JN, Watson, DM, Akerley, W, Green, MR, and Cancer and Leukemia Group B, . "Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III Non-small-cell lung cancer: Cancer and Leukemia Group B." J Clin Oncol 25.13 (May 1, 2007): 1698-1704.
PMID
17404369
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
25
Issue
13
Publish Date
2007
Start Page
1698
End Page
1704
DOI
10.1200/JCO.2006.07.3569

Erratum: Genomic signatures to guide the use of chemotherapeutics (Nature (2006) 12, (1294-1300))

Authors
Potti, A; Dressman, HK; Bild, A; Riedel, RF; Chan, G; Sayer, R; Cragun, J; Cottrill, H; Kelley, MJ; Petersen, R; Harpole, D; Marks, J; Berchuck, A; Ginsburg, GS; Febbo, P; Lancaster, J; Nevins, JR
MLA Citation
Potti, A, Dressman, HK, Bild, A, Riedel, RF, Chan, G, Sayer, R, Cragun, J, Cottrill, H, Kelley, MJ, Petersen, R, Harpole, D, Marks, J, Berchuck, A, Ginsburg, GS, Febbo, P, Lancaster, J, and Nevins, JR. "Erratum: Genomic signatures to guide the use of chemotherapeutics (Nature (2006) 12, (1294-1300))." Nature Medicine 13.11 (2007): 1388--.
Source
scival
Published In
Nature Medicine
Volume
13
Issue
11
Publish Date
2007
Start Page
1388-
DOI
10.1038/nm1107-1388

Lung cancer chemoprevention: ACCP evidence-based clinical practice guidelines (2nd edition)

Background: Lung cancer is the most common cause of cancer death in the United States. Cigarette smoking is the main risk factor. Former smokers are at a substantially increased risk for lung cancer compared with lifetime never-smokers. Chemoprevention is the use of specific agents to reverse, suppress, or prevent the process of carcinogenesis. This article reviews the major agents that have been studied for chemoprevention. Methods: Articles of primary, secondary, and tertiary prevention trials were reviewed and summarized to obtain recommendations. Results: None of the phase III trials with the agents beta carotene, retinol, 13-cis-retinoic acid, α-tocopherol, N-acetylcysteine, or acetylsalicylic acid has demonstrated beneficial, reproducible results. For facilitating the evaluation of promising agents and for lessening the need for a large sample size, extensive time commitment, and expense, focus is now turning toward the assessment of surrogate end point biomarkers for lung carcinogenesis. With the understanding of important cellular signaling pathways, various inhibitors that may prevent or reverse lung carcinogenesis are being developed. Conclusions: By integrating biological knowledge, more trials can be performed in a reasonable time frame. The future of lung cancer chemoprevention should entail the evaluation of single agents or combinations that target various pathways while working toward identification and validation of intermediate end points.

Authors
Gray, J; Mao, JT; Szabo, E; Kelley, M; Kurie, J; Bepler, G
MLA Citation
Gray, J, Mao, JT, Szabo, E, Kelley, M, Kurie, J, and Bepler, G. "Lung cancer chemoprevention: ACCP evidence-based clinical practice guidelines (2nd edition)." Chest 132.3 SUPPL. (2007): 56S-68S.
PMID
17873160
Source
scival
Published In
Chest
Volume
132
Issue
3 SUPPL.
Publish Date
2007
Start Page
56S
End Page
68S
DOI
10.1378/chest.07-1348

Phase II study of carboplatin, irinotecan, and thalidomide combination in patients with extensive stage small-cell lung cancer.

Authors
Riedel, RF; Crawford, J; Dunphy, F; Herndon, JE; Garst, J; Kelley, MJ
MLA Citation
Riedel, RF, Crawford, J, Dunphy, F, Herndon, JE, Garst, J, and Kelley, MJ. "Phase II study of carboplatin, irinotecan, and thalidomide combination in patients with extensive stage small-cell lung cancer." Lung cancer (Amsterdam, Netherlands) 54.3 (December 2006): 431-432. (Academic Article)
PMID
17005294
Source
manual
Published In
Lung Cancer
Volume
54
Issue
3
Publish Date
2006
Start Page
431
End Page
432

Genomic signatures to guide the use of chemotherapeutics.

Using in vitro drug sensitivity data coupled with Affymetrix microarray data, we developed gene expression signatures that predict sensitivity to individual chemotherapeutic drugs. Each signature was validated with response data from an independent set of cell line studies. We further show that many of these signatures can accurately predict clinical response in individuals treated with these drugs. Notably, signatures developed to predict response to individual agents, when combined, could also predict response to multidrug regimens. Finally, we integrated the chemotherapy response signatures with signatures of oncogenic pathway deregulation to identify new therapeutic strategies that make use of all available drugs. The development of gene expression profiles that can predict response to commonly used cytotoxic agents provides opportunities to better use these drugs, including using them in combination with existing targeted therapies.

Authors
Potti, A; Dressman, HK; Bild, A; Riedel, RF; Chan, G; Sayer, R; Cragun, J; Cottrill, H; Kelley, MJ; Petersen, R; Harpole, D; Marks, J; Berchuck, A; Ginsburg, GS; Febbo, P; Lancaster, J; Nevins, JR
MLA Citation
Potti, A, Dressman, HK, Bild, A, Riedel, RF, Chan, G, Sayer, R, Cragun, J, Cottrill, H, Kelley, MJ, Petersen, R, Harpole, D, Marks, J, Berchuck, A, Ginsburg, GS, Febbo, P, Lancaster, J, and Nevins, JR. "Genomic signatures to guide the use of chemotherapeutics." Nat Med 12.11 (November 2006): 1294-1300.
PMID
17057710
Source
pubmed
Published In
Nature Medicine
Volume
12
Issue
11
Publish Date
2006
Start Page
1294
End Page
1300
DOI
10.1038/nm1491

Impact of a multidisciplinary thoracic oncology clinic on the timeliness of care.

BACKGROUND: Multidisciplinary clinics have been recommended for the evaluation of patients with lung cancer. Evidence to support this recommendation, however, is limited. A single-center, retrospective review of lung cancer patients at a Veterans Affairs hospital was performed comparing timeliness of diagnostic and treatment decisions during the operation of a multidisciplinary thoracic oncology clinic (MTOC) with a period after it closed (non-MTOC), during which only a weekly multidisciplinary conference was held. METHODS: Patients were identified from a tumor registry. Manual chart reviews were performed on all patients. Outcome measures included time from initial presentation to diagnosis (TTD) and time from diagnosis to treatment initiation (TTT). RESULTS: Three hundred forty-five patients (244 in MTOC, 101 in non-MTOC) diagnosed with lung cancer between 1999 and 2003 were included in the study. Baseline characteristics were similar between the two groups. Median TTD was 48 days (95% confidence interval [CI]: 37-61) and 47 days (95% CI: 39-55) in the MTOC (n = 164) and non-MTOC cohorts (n = 89), respectively (p = 0.09). Median TTT was 22 days (95% CI: 20-27) and 23 days (95% CI: 20-34) in the MTOC (n = 165) and non-MTOC cohorts (n = 89), respectively (p = 0.71). There was no difference in overall survival. CONCLUSION: Retrospective comparison of sequential cohorts failed to reveal benefit in the timeliness of care measures during the time period of MTOC operation. Potential confounders include the absence of a surgeon in the MTOC setting, an ongoing weekly multidisciplinary conference in the non-MTOC cohort, and existing infrastructures based on previous MTOC experiences and past provider experience. Confirmation of these findings in other health care settings is warranted, preferably in a prospective fashion.

Authors
Riedel, RF; Wang, X; McCormack, M; Toloza, E; Montana, GS; Schreiber, G; Kelley, MJ
MLA Citation
Riedel, RF, Wang, X, McCormack, M, Toloza, E, Montana, GS, Schreiber, G, and Kelley, MJ. "Impact of a multidisciplinary thoracic oncology clinic on the timeliness of care." J Thorac Oncol 1.7 (September 2006): 692-696.
PMID
17409938
Source
pubmed
Published In
Journal of Thoracic Oncology
Volume
1
Issue
7
Publish Date
2006
Start Page
692
End Page
696

A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer.

BACKGROUND: Clinical trials have indicated a benefit of adjuvant chemotherapy for patients with stage IB, II, or IIIA--but not stage IA--non-small-cell lung cancer (NSCLC). This classification scheme is probably an imprecise predictor of the prognosis of an individual patient. Indeed, approximately 25 percent of patients with stage IA disease have a recurrence after surgery, suggesting the need to identify patients in this subgroup for more effective therapy. METHODS: We identified gene-expression profiles that predicted the risk of recurrence in a cohort of 89 patients with early-stage NSCLC (the lung metagene model). We evaluated the predictor in two independent groups of 25 patients from the American College of Surgeons Oncology Group (ACOSOG) Z0030 study and 84 patients from the Cancer and Leukemia Group B (CALGB) 9761 study. RESULTS: The lung metagene model predicted recurrence for individual patients significantly better than did clinical prognostic factors and was consistent across all early stages of NSCLC. Applied to the cohorts from the ACOSOG Z0030 trial and the CALGB 9761 trial, the lung metagene model had an overall predictive accuracy of 72 percent and 79 percent, respectively. The predictor also identified a subgroup of patients with stage IA disease who were at high risk for recurrence and who might be best treated by adjuvant chemotherapy. CONCLUSIONS: The lung metagene model provides a potential mechanism to refine the estimation of a patient's risk of disease recurrence and, in principle, to alter decisions regarding the use of adjuvant chemotherapy in early-stage NSCLC.

Authors
Potti, A; Mukherjee, S; Petersen, R; Dressman, HK; Bild, A; Koontz, J; Kratzke, R; Watson, MA; Kelley, M; Ginsburg, GS; West, M; Harpole, DH; Nevins, JR
MLA Citation
Potti, A, Mukherjee, S, Petersen, R, Dressman, HK, Bild, A, Koontz, J, Kratzke, R, Watson, MA, Kelley, M, Ginsburg, GS, West, M, Harpole, DH, and Nevins, JR. "A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer." N Engl J Med 355.6 (August 10, 2006): 570-580.
PMID
16899777
Source
pubmed
Published In
The New England journal of medicine
Volume
355
Issue
6
Publish Date
2006
Start Page
570
End Page
580
DOI
10.1056/NEJMoa060467

A genomic strategy to refine prognosis in early stage non-small cell lung carcinoma (NSCLC).

Authors
Harpole, DH; Petersen, R; Mukherjee, S; Bild, A; Dressman, H; Kratzke, R; Kelley, MJ; Garst, J; Crawford, J; Nevins, JR; Potti, A
MLA Citation
Harpole, DH, Petersen, R, Mukherjee, S, Bild, A, Dressman, H, Kratzke, R, Kelley, MJ, Garst, J, Crawford, J, Nevins, JR, and Potti, A. "A genomic strategy to refine prognosis in early stage non-small cell lung carcinoma (NSCLC)." June 20, 2006.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
24
Issue
18
Publish Date
2006
Start Page
370S
End Page
370S

A genomic strategy to combinatorial therapeutics in solid tumors.

Authors
Potti, A; Dressman, HK; Bild, A; Riedel, R; Kelley, M; Ginsburg, G; Lancaster, J; Nevins, J; Febbo, P
MLA Citation
Potti, A, Dressman, HK, Bild, A, Riedel, R, Kelley, M, Ginsburg, G, Lancaster, J, Nevins, J, and Febbo, P. "A genomic strategy to combinatorial therapeutics in solid tumors." June 20, 2006.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
24
Issue
18
Publish Date
2006
Start Page
86S
End Page
86S

A genomic strategy to combinatorial therapeutics in solid tumors.

2031 Background: For most advanced solid tumors, the response rate to cytotoxic drugs is generally low, highlighting the importance of identifying those patients most likely to respond, either to single agents or combinations of cytotoxic or targeted therapies.We have made use of in vitro drug response data generated on the NCI-60 panel of cancer cell lines, coupled with Affymetrix U133 2.0 plus gene expression data, to develop genomic predictors of chemotherapy sensitivity. These models were then validated in independent cancer cell lines as well as response data from patient treatment studies.Predictive models making use of gene expression data were developed for docetaxel, adriamycin, 5-flourouracil, cyclophosphamide, paclitaxel, and topotecan. These models were shown to accurately predict sensitivity to the drugs in an independent set (n = 30) of cancer cell lines. Importantly, three of the predictors (docetaxel, topotecan, paclitaxel) also accurately (> 80%) predicted response in patient studies. When evaluated in a large collection of human cancers (n = 381), these gene expression signatures of drug response identified patterns of predicted sensitivity suggesting potential opportunities for novel combinations. We also combined the predictions of chemotherapy sensitivity with predictions of pathway deregulation (Bild A, Nature 2005), to develop further opportunities for combination therapy. For instance, this analysis revealed a significant relationship between PI3 kinase pathway deregulation and docetaxel resistance (p = 0.001), and a correlation between docetaxel sensitivity and the activation of the Rb/E2F pathway (p = 0.009). Furthermore, cell lines showing an increased probability of PI3 kinase and Rb/E2F activation were also more likely to respond to a PI3 kinase (LY-294002) inhibitor (p = 0.01) or R-Roscovitine (p = 0.03), a cell cycle inhibitor, respectively.The development and validation of chemotherapeutic response predictors, together with oncogenic pathway signatures that can guide the use of targeted agents, provides an opportunity to develop effective combinatorial therapeutic strategies geared to the individual patient. No significant financial relationships to disclose.

Authors
Potti, A; Dressman, HK; Bild, A; Riedel, R; Kelley, M; Ginsburg, G; Lancaster, J; Nevins, J; Febbo, P
MLA Citation
Potti, A, Dressman, HK, Bild, A, Riedel, R, Kelley, M, Ginsburg, G, Lancaster, J, Nevins, J, and Febbo, P. "A genomic strategy to combinatorial therapeutics in solid tumors." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 24.18_suppl (June 2006): 2031-.
PMID
27952715
Source
epmc
Published In
Journal of Clinical Oncology
Volume
24
Issue
18_suppl
Publish Date
2006
Start Page
2031

A genomic strategy to refine prognosis in early stage non-small cell lung carcinoma (NSCLC).

7026 Background. Although stage-specific classification identifies appropriate populations for adjuvant chemotherapy, this is likely an imprecise predictor for the individual patient with early stage NSCLC.Using previously-described methodologies that employ DNA microarray data, multiple gene expression profiles ('metagenes') that predict risk of recurrence in patients with stage I disease were identified. This analysis used an initial 'test' cohort of patients with NSCLC (n = 89) that represented an equal mix of squamous cell and adenocarcinoma. Also, each histologic subset had equal number of patients who survived more than 5 years and those who died within 2.5 years of initial diagnosis. The performance of the metagene-based model generated on the training cohort was then evaluated in independent 'validation' sets, including two multi-center cooperative group studies (ACOSOG Z0030 and CALGB 9761). Importantly, the CALGB validation was performed in a blinded fashion.Classification tree analyses that sample multiple gene expression profiles were used to develop a model of recurrence, termed the Lung Metagene Model, that accurately assesses prognosis (risk of recurrence and survival), performing significantly (p<0.001, odds ratio: 16.1, multivariate analysis) better than pathologic stage, T-size, nodal status, age, gender, histologic subtype and smoking history. The accuracy of prognosis using the Lung Metagene Model exceeded 90% (leave-one-out cross validation) in the initial training set (n = 89), 72% in the ACOSOG (n = 25), and 81% in the CALGB (n = 84) datasets. The prognostic accuracy was consistent across histologic subtypes and stages of NSCLC. Importantly, this provides an opportunity to re-classify stage IA patients to identify a subset of 'high risk' patients that may benefit from adjuvant chemotherapy. Further, stage IB and II patients identified as 'low risk' for recurrence, and who present co-morbidities, could potentially be candidates for observation, and those patients predicted to be at 'high risk' may benefit from novel therapeutic trials.The Lung Metagene Model provides a mechanism to refine the estimation of an individual patient's risk for disease recurrence and thus guide the use of adjuvant chemotherapy in NSCLC. No significant financial relationships to disclose.

Authors
Harpole, DH; Petersen, R; Mukherjee, S; Bild, A; Dressman, H; Kratzke, R; Kelley, MJ; Garst, J; Crawford, J; Nevins, JR; Potti, A
MLA Citation
Harpole, DH, Petersen, R, Mukherjee, S, Bild, A, Dressman, H, Kratzke, R, Kelley, MJ, Garst, J, Crawford, J, Nevins, JR, and Potti, A. "A genomic strategy to refine prognosis in early stage non-small cell lung carcinoma (NSCLC)." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 24.18_suppl (June 2006): 7026-.
PMID
27953212
Source
epmc
Published In
Journal of Clinical Oncology
Volume
24
Issue
18_suppl
Publish Date
2006
Start Page
7026

Gene expression models for recurrence risk prediction coupled with patterns of oncogenic pathway deregulation provide a novel therapeutic strategy for patients with non-small cell lung carcinoma.

Authors
Potti, A; Bild, A; Prince, R; Mukherjee, S; Dressman, H; Harpole, D; Kelley, M; Nevins, J
MLA Citation
Potti, A, Bild, A, Prince, R, Mukherjee, S, Dressman, H, Harpole, D, Kelley, M, and Nevins, J. "Gene expression models for recurrence risk prediction coupled with patterns of oncogenic pathway deregulation provide a novel therapeutic strategy for patients with non-small cell lung carcinoma." December 15, 2005.
Source
wos-lite
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
11
Issue
24
Publish Date
2005
Start Page
8997S
End Page
8998S

Erythropoietin and erythropoietin receptor expression in early stage non-small cell lung cancer: Prognostic significance.

Authors
Amin, K; Haroon, ZA; Kim, SJ; Li, SF; Rabbani, ZN; Vollmer, RT; Wang, XFF; Kelley, MJ; Arcasoy, MO
MLA Citation
Amin, K, Haroon, ZA, Kim, SJ, Li, SF, Rabbani, ZN, Vollmer, RT, Wang, XFF, Kelley, MJ, and Arcasoy, MO. "Erythropoietin and erythropoietin receptor expression in early stage non-small cell lung cancer: Prognostic significance." November 16, 2005.
Source
wos-lite
Published In
Blood
Volume
106
Issue
11
Publish Date
2005
Start Page
145B
End Page
145B

Corroboration of a familial chordoma locus on chromosome 7q and evidence of genetic heterogeneity using single nucleotide polymorphisms (SNPs).

Chordoma, a rare bone tumor originating from notochordal remnants, has a genetic predisposition in some families. Previously, we performed linkage analysis using microsatellite (STR) markers on 3 unrelated chordoma kindreds (16 patients with chordoma) and reported significant evidence for linkage to chromosome 7q33 (Z(max) = 4.78) with a minimal disease gene region of 11 cM. In our present study, we performed linkage analysis in these 3 families using chromosome 7 single nucleotide polymorphisms (SNPs). Parametric and nonparametric multipoint analyses showed significant linkage to 7q markers with p < 0.001 and Z(max) = 2.77, respectively. The minimal disease gene region was not reduced by combined SNP and STR haplotype analysis compared to the previous STR haplotype analysis alone. We genotyped members of a fourth chordoma family with SNP and STR markers for chromosome 7q and for 1p36, the location of a previously reported chordoma locus. Affected members of this family did not share a common haplotype on 7q, and the family did not show evidence of linkage to 1p36. Thus, we corroborated a chordoma locus on chromosome 7q in the 3 original families and demonstrated evidence for genetic heterogeneity in the fourth family. Our study also provided insights into some limitations and analytical complexities associated with using a dense SNP marker set in linkage analysis of complex pedigrees.

Authors
Yang, X'R'; Beerman, M; Bergen, AW; Parry, DM; Sheridan, E; Liebsch, NJ; Kelley, MJ; Chanock, S; Goldstein, AM
MLA Citation
Yang, X'R', Beerman, M, Bergen, AW, Parry, DM, Sheridan, E, Liebsch, NJ, Kelley, MJ, Chanock, S, and Goldstein, AM. "Corroboration of a familial chordoma locus on chromosome 7q and evidence of genetic heterogeneity using single nucleotide polymorphisms (SNPs)." Int J Cancer 116.3 (September 1, 2005): 487-491.
PMID
15818627
Source
pubmed
Published In
International Journal of Cancer
Volume
116
Issue
3
Publish Date
2005
Start Page
487
End Page
491
DOI
10.1002/ijc.21006

Expression of HIF-1alpha, CA IX, VEGF, and MMP-9 in surgically resected non-small cell lung cancer.

Endogenous hypoxia markers have been studied as prognostic indicators because they appear to be associated with tumor aggressiveness. This study was undertaken to compare the expression of two endogenous hypoxia markers, Hypoxia-inducible factor-1alpha (HIF-1alpha) and carbonic anhydrase IX (CA IX), with regard to their prognostic significance. We also compared spatial distribution of HIF-1alpha and CA IX and examined their relationship with expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-9, which may be regulated by hypoxia. We studied 74 resected stage I/II non-small cell lung cancers (NSCLCs) for expression of HIF-1alpha, CA IX, VEGF, and MMP-9 by immunohistochemistry, and the extent of tumor necrosis. Univariate and multivariate analyses were performed to assess prognostic implications of these markers for disease free survival. HIF-1alpha expression was strongly correlated with CA IX (r=0.667, p<0.001) and was co-localized with CA IX in corresponding areas. HIF-1alpha and CA IX expression were higher in areas with moderate to severe tumor necrosis relative to areas with minimal necrosis, suggesting their relationship with hypoxia. VEGF expression also showed a modest relationship with HIF-1alpha (p=0.07); however, there was no relationship between HIF-1alpha and MMP-9 expression (p>0.99). Expression of HIF-1alpha and CA IX above the median value was significantly associated with shorter disease free survival in univariate analysis (p<0.05). However, only high CA IX expression and pathologic stage were independent prognostic indicators in a multivariate analysis. Of the markers considered in this study, CA IX expression status was the most reliable hypoxia marker for predicting tumor aggressiveness.

Authors
Kim, SJ; Rabbani, ZN; Dewhirst, MW; Vujaskovic, Z; Vollmer, RT; Schreiber, E-G; Oosterwijk, E; Kelley, MJ
MLA Citation
Kim, SJ, Rabbani, ZN, Dewhirst, MW, Vujaskovic, Z, Vollmer, RT, Schreiber, E-G, Oosterwijk, E, and Kelley, MJ. "Expression of HIF-1alpha, CA IX, VEGF, and MMP-9 in surgically resected non-small cell lung cancer." Lung Cancer 49.3 (September 2005): 325-335.
PMID
15935515
Source
pubmed
Published In
Lung Cancer
Volume
49
Issue
3
Publish Date
2005
Start Page
325
End Page
335
DOI
10.1016/j.lungcan.2005.03.036

Genotype-phenotype correlation in MYH9-related thrombocytopenia.

Mutation of the non-muscle myosin heavy chain type II-A results in MYH9-related hereditary macrothrombocytopenia (HMTC), including four autosomal dominant platelet disorders: May-Hegglin anomaly (MHA), Sebastian (SBS), Fechtner (FS) and Epstein (EPS) syndrome. Denaturing high-performance liquid chromatography (DHPLC) was optimised for rapid screening of the seven exons harbouring all but one of the previously reported mutations of MYH9. Individuals from 13 families with phenotypes suggestive of MYH9-related HMTC were screened for mutations by DHPLC followed by direct sequencing of samples with aberrant column retention time. Mutations were identified in all 13 families. Six distinct missense heterozygous mutations were found in 10 families, including six families with MHA or SBS (E1841K, D1424N), three families with FS (R702H, R1165C, and D1424Y), and one family with EPS (S96L). A truncating mutation (R1933X) was found in three MHA families. A review of all published mutations suggests that mutation in the C-terminal coiled coil region or truncation of the tailpiece is associated with haematological-only phenotype, while mutation of the head ATPase domain frequently is associated with nephropathy and/or hearing loss. Mutations of other regions have intermediate expression of non-haematological characteristics. Further study is required to confirm these associations and understand the molecular basis for this genotype-phenotype relationship.

Authors
Dong, F; Li, S; Pujol-Moix, N; Luban, NLC; Shin, SW; Seo, JH; Ruiz-Saez, A; Demeter, J; Langdon, S; Kelley, MJ
MLA Citation
Dong, F, Li, S, Pujol-Moix, N, Luban, NLC, Shin, SW, Seo, JH, Ruiz-Saez, A, Demeter, J, Langdon, S, and Kelley, MJ. "Genotype-phenotype correlation in MYH9-related thrombocytopenia." Br J Haematol 130.4 (August 2005): 620-627.
PMID
16098078
Source
pubmed
Published In
British Journal of Haematology
Volume
130
Issue
4
Publish Date
2005
Start Page
620
End Page
627
DOI
10.1111/j.1365-2141.2005.05658.x

P-339 Multidisciplinary versus traditional evaluation in sequentialpatient cohorts with lung cancer

Authors
Riedel, R; Wang, X; McCormack, M; Toloza, E; Montana, G; Schreiber, G; Kelley, M
MLA Citation
Riedel, R, Wang, X, McCormack, M, Toloza, E, Montana, G, Schreiber, G, and Kelley, M. "P-339 Multidisciplinary versus traditional evaluation in sequentialpatient cohorts with lung cancer." July 2005.
Source
crossref
Published In
Lung Cancer
Volume
49
Publish Date
2005
Start Page
S205
End Page
S205
DOI
10.1016/S0169-5002(05)80833-5

Expression of phosphorylated epidermal growth factor receptor (p-EGFR) in early stage non-small cell lung cancer: its relationship with overexpression of EGFR and cyclooxygenase-2 (COX-2), and survival

Authors
Kim, SJ; Rabbani, ZN; Vollmer, RT; Schreiber, EG; Dewhirst, MW; Vujaskovic, Z; Kelley, MJ
MLA Citation
Kim, SJ, Rabbani, ZN, Vollmer, RT, Schreiber, EG, Dewhirst, MW, Vujaskovic, Z, and Kelley, MJ. "Expression of phosphorylated epidermal growth factor receptor (p-EGFR) in early stage non-small cell lung cancer: its relationship with overexpression of EGFR and cyclooxygenase-2 (COX-2), and survival." June 1, 2005.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
23
Issue
16
Publish Date
2005
Start Page
864S
End Page
864S

Expression of phosphorylated epidermal growth factor receptor (p-EGFR) in early stage non-small cell lung cancer: its relationship with overexpression of EGFR and cyclooxygenase-2 (COX-2), and survival.

9614 Background: Epidermal growth factor receptor (EGFR) is widely overexpressed in various cancers, and reported to relate with growth and invasion of cancer cells. However, clinical significance of EGFR overexpression is still controversial because its correlation with prognosis is not universal. Thus, activated form of EGFR (phosphorylated EGFR, p-EGFR) may better predict prognosis. We determined the association of p-EGFR and prognosis, and its relationship with EGFR and COX-2, and other biomarkers.We immunohistochemically examined the expression of p-EGFR, EGFR, and COX-2 in 77 resected stage I/II non-small cell lung cancers (NSCLCs). Their correlation with prognosis and other biomarkers was also assessed including Ki-67, vascular endothelial growth factor (VEGF), and microvessel density (MVD).EGFR overexpression, defined as membranous staining in more than 10% of cancer cells, was found in 37 patients (48.1%). 45 patients (58.4%) showed COX-2 overexpression, cytoplasmic granular staining in more than 10%. 28.6% of patients were positive expression of p-EGFR, cytoplasmic staining in more than 5% of cells (22/77). Expression of p-EGFR was significantly associated with COX-2 overexpression (p = 0.047), and showed a modest relationship with EGFR overexpression and high Ki-67 (p = 0.087, and 0.092, respectively). COX-2 overexpression also had a clear correlation with high Ki-67 expression (p = 0.011). However, no correlation was found between EGFR and COX-2 overexpression. VEGF expression and MVD showed no association with p-EGFR, EGFR, and COX-2 overexpression. Positive expression of p-EGFR was significantly related with a short disease free survival (p = 0.045), but not with overall survival. However, neither EGFR nor COX-2 overexpression were associated with prognosis (p > 0.05).Expression of p-EGFR may better predict increased malignant potential and worse prognosis of early stage NSCLC than EGFR overexpression itself and this may be related with COX-2 overexpression and high proliferative activity of cancer cells No significant financial relationships to disclose.

Authors
Kim, SJ; Rabbani, ZN; Vollmer, RT; Schreiber, EG; Dewhirst, MW; Vujaskovic, Z; Kelley, MJ
MLA Citation
Kim, SJ, Rabbani, ZN, Vollmer, RT, Schreiber, EG, Dewhirst, MW, Vujaskovic, Z, and Kelley, MJ. "Expression of phosphorylated epidermal growth factor receptor (p-EGFR) in early stage non-small cell lung cancer: its relationship with overexpression of EGFR and cyclooxygenase-2 (COX-2), and survival." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 23.16_suppl (June 2005): 9614-.
PMID
27943731
Source
epmc
Published In
Journal of Clinical Oncology
Volume
23
Issue
16_suppl
Publish Date
2005
Start Page
9614

Retrospective family study of childhood medulloblastoma.

Medulloblastoma is the most common malignant central nervous system tumor of childhood and can occur sporadically or in association with inherited cancer susceptibility syndromes such as the nevoid basal cell carcinoma syndrome (NBCCS). To determine whether an association existed between the risk of developing medulloblastoma and undiagnosed syndromes, we retrospectively reviewed clinical data on 33 patients with medulloblastoma from a single institution and compared them with their unaffected relatives (n = 46). Six patients had tumors showing desmoplastic histology. Two of the six met diagnostic criteria for NBCCS. One NBCCS patient had a missense mutation of patched-1 (PTCH1); the other had no identifiable PTCH1 mutation. Two patients with isolated desmoplastic medulloblastoma had an insertion and splice site mutation, respectively, in suppressor of fused (SUFU). All patients with nondesmoplastic medulloblastoma histology received molecular testing for SUFU. None of these patients had an identifiable mutation in PTCH1 or SUFU. We performed a clinical evaluation for Greig cephalopolysyndactyly syndrome (GCPS) in four medulloblastoma families, who exhibited macrocephaly as the only finding consistent with the diagnosis of GCPS. Molecular analysis of GLI3 in these four families was negative. There was a paucity of clinical findings among the majority of medulloblastoma patients in this study group to suggest a definable cancer genetic syndrome. We conclude that clinically recognizable syndromes are uncommon among patients with medulloblastoma, however, PTCH1 and SUFU mutations are present at a low but significant frequency.

Authors
Ng, D; Stavrou, T; Liu, L; Taylor, MD; Gold, B; Dean, M; Kelley, MJ; Dubovsky, EC; Vezina, G; Nicholson, HS; Byrne, J; Rutka, JT; Hogg, D; Reaman, GH; Goldstein, AM
MLA Citation
Ng, D, Stavrou, T, Liu, L, Taylor, MD, Gold, B, Dean, M, Kelley, MJ, Dubovsky, EC, Vezina, G, Nicholson, HS, Byrne, J, Rutka, JT, Hogg, D, Reaman, GH, and Goldstein, AM. "Retrospective family study of childhood medulloblastoma." Am J Med Genet A 134.4 (May 1, 2005): 399-403.
PMID
15759260
Source
pubmed
Published In
American Journal of Medical Genetics Part A
Volume
134
Issue
4
Publish Date
2005
Start Page
399
End Page
403
DOI
10.1002/ajmg.a.30653

Safety and efficacy of weekly oral oltipraz in chronic smokers.

Cigarette smoking is thought to contribute to carcinogenesis by formation of DNA adducts of tobacco smoke constituents leading to genotoxic damage. The dithiolethione, oltipraz, is a putative cancer chemopreventive agent that induces phase II detoxifying enzymes in preclinical models and reduces aflatoxin adducts in humans living in areas with high dietary levels. To determine if oltipraz could reduce adduct levels of tobacco smoke constituents in the lungs and other target organs, chronic smokers were enrolled to one of three arms: 400 or 200 mg/wk oral oltipraz or placebo. Endobronchial tissue and bronchoalveolar lavage were done before and after 12 weeks of drug treatment; peripheral blood, urine, and oral saline rinse were also collected. Toxicity was assessed every 4 weeks. Fifty-nine of the 77 enrolled subjects completed the study. Of those receiving oltipraz, 15% experienced grade 2/3 toxicity, which was predominantly gastrointestinal. All subject withdrawals occurred in the oltipraz groups. There was no significant difference between pre- and post-polycyclic aromatic hydrocarbon-DNA adduct levels in lung epithelial cells measured by immunoperoxidase staining between treatment and placebo groups. Likewise, no significant differences were found in polycyclic aromatic hydrocarbon or benzo(a)pyrene-7,8-diol-9,10-epoxide adducts measured in blood, oral lining cells, or bladder lining cells. There was also no increase in mRNA or enzymatic activity of phase II enzymes and no change in glutathione levels. Thus, despite moderate drug-related toxicity, there was no significant effect on pharmacodynamic or surrogate risk biomarkers. Other agents with lower toxicity and greater activity to induce phase II enzymes are needed to definitively test the detoxification-induction paradigm in smokers.

Authors
Kelley, MJ; Glaser, EM; Herndon, JE; Becker, F; Bhagat, R; Zhang, Y-J; Santella, RM; Carmella, SG; Hecht, SS; Gallot, L; Schilder, L; Crowell, JA; Perloff, M; Folz, RJ; Bergan, RC
MLA Citation
Kelley, MJ, Glaser, EM, Herndon, JE, Becker, F, Bhagat, R, Zhang, Y-J, Santella, RM, Carmella, SG, Hecht, SS, Gallot, L, Schilder, L, Crowell, JA, Perloff, M, Folz, RJ, and Bergan, RC. "Safety and efficacy of weekly oral oltipraz in chronic smokers." Cancer Epidemiol Biomarkers Prev 14.4 (April 2005): 892-899.
PMID
15824161
Source
pubmed
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
14
Issue
4
Publish Date
2005
Start Page
892
End Page
899
DOI
10.1158/1055-9965.EPI-04-0585

Rod mutations associated with MYH9-related disorders disrupt nonmuscle myosin-IIA assembly.

MYH9-related disorders are autosomal dominant syndromes, variably affecting platelet formation, hearing, and kidney function, and result from mutations in the human nonmuscle myosin-IIA heavy chain gene. To understand the mechanisms by which mutations in the rod region disrupt nonmuscle myosin-IIA function, we examined the in vitro behavior of 4 common mutant forms of the rod (R1165C, D1424N, E1841K, and R1933Stop) compared with wild type. We used negative-stain electron microscopy to analyze paracrystal morphology, a model system for the assembly of individual myosin-II molecules into bipolar filaments. Wild-type tail fragments formed ordered paracrystal arrays, whereas mutants formed aberrant aggregates. In mixing experiments, the mutants act dominantly to interfere with the proper assembly of wild type. Using circular dichroism, we find that 2 mutants affect the alpha-helical coiled-coil structure of individual molecules, and 2 mutants disrupt the lateral associations among individual molecules necessary to form higher-order assemblies, helping explain the dominant effects of these mutants. These results demonstrate that the most common mutations in MYH9, lesions in the rod, cause defects in nonmuscle myosin-IIA assembly. Further, the application of these methods to biochemically characterize rod mutations could be extended to other myosins responsible for disease.

Authors
Franke, JD; Dong, F; Rickoll, WL; Kelley, MJ; Kiehart, DP
MLA Citation
Franke, JD, Dong, F, Rickoll, WL, Kelley, MJ, and Kiehart, DP. "Rod mutations associated with MYH9-related disorders disrupt nonmuscle myosin-IIA assembly." Blood 105.1 (January 1, 2005): 161-169.
PMID
15339844
Source
pubmed
Published In
Blood
Volume
105
Issue
1
Publish Date
2005
Start Page
161
End Page
169
DOI
10.1182/blood-2004-06-2067

Erratum: A retrospective family study of childhood medulloblastoma (American Journal of Medical Genetics 134A, 4 (399-403) DOI 10.1002/ajmg.a. 30653)

Authors
Ng, D; Stavrou, T; Liu, L; Taylor, MD; Gold, B; Dean, M; Kelley, MJ; Dubovsky, EC; Vezina, G; Nicholson, HS; Byrne, J; Rutka, JT; Hogg, D; Reaman, GH; Goldstein, AM
MLA Citation
Ng, D, Stavrou, T, Liu, L, Taylor, MD, Gold, B, Dean, M, Kelley, MJ, Dubovsky, EC, Vezina, G, Nicholson, HS, Byrne, J, Rutka, JT, Hogg, D, Reaman, GH, and Goldstein, AM. "Erratum: A retrospective family study of childhood medulloblastoma (American Journal of Medical Genetics 134A, 4 (399-403) DOI 10.1002/ajmg.a. 30653)." American Journal of Medical Genetics 136 A.2 (2005): 226--.
Source
scival
Published In
American Journal of Medical Genetics Part A
Volume
136 A
Issue
2
Publish Date
2005
Start Page
226-
DOI
10.1002/ajmg.a.30821

Immunization with mutant p53- and K-ras-derived peptides in cancer patients: Immune response and clinical outcome

Purpose: To determine the ability to induce tumor-specific immunity with individual mutant K-ras- or p53-derived peptides and to monitor clinical outcome. Patients and Methods: Patients in varying stages of disease underwent genetic analysis for mutations in K-ras and p53. Thirty-nine patients were enrolled. Seventeen-mer peptides were custom synthesized to the corresponding mutation. Baseline immunity was assessed for cytotoxic T-lymphocyte (CTL) response and interferon gamma (IFN-γ) release from mutant peptide-primed lymphocytes. Patients' peripheral-blood mononuclear cells were pulsed with the corresponding peptide, irradiated, and applied intravenously. Patients were observed for CTL, IFN-γ, interleukin (IL)-2, IL-5, and granulocyte-macrophage colony-stimulating factor responses, for treatment-related toxicity, and for tumor response. Results: No toxicity was observed. Ten (26%) of 38 patients had detectable CTL against mutant p53 or K-ras, and two patients were positive for CTL at baseline. Positive IFN-γ responses occurred in 16 patients (42%) after vaccination, whereas four patients had positive IFN-γ reaction before vaccination. Of 29 patients with evident disease, five experienced a period of stable disease. Favorable prognostic markers were detectable CTL activity and a positive IFN-γ reaction but not IL-5 release. Median survival times of 393 v 98 days for a positive versus negative CTL response (P = .04), respectively, and of 470 v 88 days for a positive versus negative IFN-γ response (P = .02), respectively, were detected. Conclusion: Custom-made peptide vaccination is feasible without any toxicity. CTL and cytokine responses specific to a given mutation can be induced or enhanced with peptide vaccines. Cellular immunity to mutant p53 and K-ras oncopeptides is associated with longer survival. © 2005 by American Society of Clinical Oncology.

Authors
Carbone, DP; Ciernik, IF; Kelley, MJ; Smith, MC; Nadaf, S; Kavanaugh, D; Maher, VE; Stipanov, M; Contois, D; Johnson, BE; Pendleton, CD; Seifert, B; Carter, C; Read, EJ; Greenblatt, J; Top, LE; Kelsey, MI; Minna, JD; Berzofsky, JA
MLA Citation
Carbone, DP, Ciernik, IF, Kelley, MJ, Smith, MC, Nadaf, S, Kavanaugh, D, Maher, VE, Stipanov, M, Contois, D, Johnson, BE, Pendleton, CD, Seifert, B, Carter, C, Read, EJ, Greenblatt, J, Top, LE, Kelsey, MI, Minna, JD, and Berzofsky, JA. "Immunization with mutant p53- and K-ras-derived peptides in cancer patients: Immune response and clinical outcome." Journal of Clinical Oncology 23.22 (2005): 5099-5107.
PMID
15983396
Source
scival
Published In
Journal of Clinical Oncology
Volume
23
Issue
22
Publish Date
2005
Start Page
5099
End Page
5107
DOI
10.1200/JCO.2005.03.158

Carbonic anhydrase IX in early-stage non-small cell lung cancer.

PURPOSE: Tumor hypoxia is associated with poor prognosis and increased tumor aggressiveness. Carbonic anhydrase (CA) IX, an endogenous marker for tumor hypoxia, catalyzes the hydration of carbon dioxide into carbonic acid and contributes to the pH regulation of tumor cells. Therefore, CA IX might allow tumors to acclimate to a hypoxic microenvironment, promoting tumor cell proliferation. We hypothesized that CA IX expression is related to tumor cell proliferation and poor disease-free survival in patients with early-stage non-small-cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: CA IX expression was measured in 75 resected NSCLC tumors to assess prognostic implications for disease-free survival. The relationship of CA IX expression with microvessel density (MVD) and proliferation (Ki-67) index was assessed via colocalization analysis. RESULTS: All patients had operable NSCLC (stage I, 58; stage II, 17). CA IX expression was present in 54 (72%) of 75 patients and was associated with tumor necrosis (P < 0.05). CA IX-positive tumor areas showed greater cell proliferation as measured by Ki-67 index (P < 0.05) and less MVD (P < 0.05) than did CA IX-negative areas in colocalization analysis. The percentage of CA IX-positive tumor cells was significantly related to postoperative recurrence and poor disease-free survival (P < 0.05). Ki-67 index and pathologic stage were also independent prognostic factors for worse disease-free survival (P < 0.05). CONCLUSIONS: CA IX expression of tumor cells may be an indicator for poor disease-free survival in early-stage NSCLC.

Authors
Kim, SJ; Rabbani, ZN; Vollmer, RT; Schreiber, E-G; Oosterwijk, E; Dewhirst, MW; Vujaskovic, Z; Kelley, MJ
MLA Citation
Kim, SJ, Rabbani, ZN, Vollmer, RT, Schreiber, E-G, Oosterwijk, E, Dewhirst, MW, Vujaskovic, Z, and Kelley, MJ. "Carbonic anhydrase IX in early-stage non-small cell lung cancer." Clin Cancer Res 10.23 (December 1, 2004): 7925-7933.
PMID
15585626
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
10
Issue
23
Publish Date
2004
Start Page
7925
End Page
7933
DOI
10.1158/1078-0432.CCR-04-0636

Induction chemotherapy followed by concomitant chemoradiotherapy (CT/XRT) versus CT/XRT alone for regionally advanced unresectable non-small cell lung cancer (NSCLC): Initial analysis of a randomized phase III trial

Authors
Vokes, EE; Herndon, JE; Kelley, MJ; Watson, D; Cicchetti, MG; Green, MR
MLA Citation
Vokes, EE, Herndon, JE, Kelley, MJ, Watson, D, Cicchetti, MG, and Green, MR. "Induction chemotherapy followed by concomitant chemoradiotherapy (CT/XRT) versus CT/XRT alone for regionally advanced unresectable non-small cell lung cancer (NSCLC): Initial analysis of a randomized phase III trial." July 15, 2004.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
22
Issue
14
Publish Date
2004
Start Page
618S
End Page
618S

Induction chemotherapy followed by concomitant chemoradiotherapy (CT/XRT) versus CT/XRT alone for regionally advanced unresectable non-small cell lung cancer (NSCLC): Initial analysis of a randomized phase III trial.

7005 Background: Standard therapy for unresectable stage III NSCLC includes concomitant chemoradiotherapy. In CALGB 39801, we evaluated whether the addition of induction chemotherapy prior to CT/XRT would result in improved survival.Between 10/1998 and 5/2002, 366 stage III patients (pts) were randomized to either immediate CT/XRT [carboplatin AUC of 2 and paclitaxel 50 mg/m2 each given weekly during 66 Gy chest XRT to; arm 1 (182 pts)] or two cycles of carboplatin AUC 6 and paclitaxel 200 mg/m2 given q 21 days x 2 cycles followed by identical CT/XRT; arm 2 (184 pts). The accrual goal was 360 patients. 290 deaths were required to have 80% power to detect a 40% increase in median survival assuming a one-tailed log-rank test conducted at the 0.025 level of significance.34% of pts were female, 66% male and 63% were age 60 or older. Grade 3 or 4 toxicities during induction chemotherapy consisted mainly of neutropenia (17%/21%). During CT/XRT, grade 3/4 neutropenia was noted in 11%/4% (arm 1) versus 21%/6% (arm 2), grade 3 anemia was 5% vs 11%, grade 3/4 fatigue 16%/1% vs 16%/4%, esophagitis 30%/1% vs 28%/7%, and dyspnea 9%/3% vs 15%/4%. Overall, 4 toxicities were experienced by 24% of patients on arm 1 versus 41% on arm 2 (p=0.001). With 254 of 290 targeted deaths, median survival on arm 1 is 11.4 months versus 14 months on arm 2 (p=0.154). One year survival estimates are 48% (41%-57%) and 54% (47%-62%) respectively.The median survival achieved in each of the treatment groups is low compared to other recent experiences in the literature. The reason(s) for this are uncertain. The addition of induction chemotherapy to immediate concurrent CT/XRT is associated with a 2.6 month increase in median survival. However these findings are not sufficient to reject the null hypothesis of no treatment difference between the two study arms. Further follow up of this data set is required. Our results do not support the use of induction chemotherapy followed by CT/XRT as evidence based standard of care for patients with unresectable stage III NSCLC. [Table: see text].

Authors
Vokes, EE; Herndon, JE; Kelley, MJ; Watson, D; Cicchetti, MG; Green, MR
MLA Citation
Vokes, EE, Herndon, JE, Kelley, MJ, Watson, D, Cicchetti, MG, and Green, MR. "Induction chemotherapy followed by concomitant chemoradiotherapy (CT/XRT) versus CT/XRT alone for regionally advanced unresectable non-small cell lung cancer (NSCLC): Initial analysis of a randomized phase III trial." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 22.14_suppl (July 2004): 7005-.
PMID
28016284
Source
epmc
Published In
Journal of Clinical Oncology
Volume
22
Issue
14_suppl
Publish Date
2004
Start Page
7005

Ultrastructural analysis of granulocyte inclusions in genetically confirmed MYH9-related disorders.

BACKGROUND AND OBJECTIVES: MYH9-related disorders are autosomal dominant hereditary macrothrombocytopenias caused by mutations in the MYH9 gene. This gene encodes the non-muscular myosin heavy chain type II A (MHCIIA). Among these disorders, May-Hegglin anomaly (MHA), Sebastian syndrome (SS), and Fechtner syndrome (FS) are associated with different types of ribosome inclusions in granulocytes. FS also exhibits Alport-like manifestations: nephropathy, neurosensory deafness, and cataracts. The aim of our study was to assess the granulocyte inclusion ultrastructure in genetically confirmed MYH9-related disorders. DESIGN AND METHODS: Ten individuals were studied. All fulfilled the clinical and laboratory findings to be diagnosed as having an MYH9-related disorder. The ultrastructure of 50 granulocyte sections for each patient was examined, and the percentages of the different types of inclusion were established. Mutations of the MYH9 gene were also analyzed. RESULTS: The patients were classified as having MHA if the inclusions contained parallel longitudinal filaments. If not, they were classified as having SS or FS. FS patients also showed Alport-like manifestations. In all syndromes we observed a wide variability of the inclusion ultrastructure. Moreover, a small number of inclusions typical of other syndromes was observed. A new cross-striated inclusion variant was identified in SS. A significant number of pure ribosome aggregates were identified in all syndromes. INTERPRETATION AND CONCLUSIONS: Like other MYH9-related traits, the variation and partial overlap in the inclusion ultrastructure could be attributed to specific changes in the polymerization, assembly, or stability of the MHCIIA. These changes might be associated with MYH9 gene mutations as well as with its heterogeneous expression.

Authors
Pujol-Moix, N; Kelley, MJ; Hernández, A; Muñiz-Diaz, E; Español, I
MLA Citation
Pujol-Moix, N, Kelley, MJ, Hernández, A, Muñiz-Diaz, E, and Español, I. "Ultrastructural analysis of granulocyte inclusions in genetically confirmed MYH9-related disorders." Haematologica 89.3 (March 2004): 330-337.
PMID
15020273
Source
pubmed
Published In
Haematologica
Volume
89
Issue
3
Publish Date
2004
Start Page
330
End Page
337

Molecular classification and molecular genetics of human lung cancers.

Recent advances in the molecular classification of lung carcinomas and the identification of causative genetic alterations will likely lead to improvements in the diagnosis and treatment of patients with lung cancer. It is now possible to identify gene expression profiles that associate with patient outcome in lung carcinomas, in particular adenocarcinoma. Furthermore, patient survival has been shown to correlate with lung cancer oligonucleotide microarray expression profiles. Large-scale microarray technology may allow for the identification of useful biomarkers for early cancer detection. Oligonucleotide microarray data can be optimized by relating them to protein expression levels in tissue microarrays, by annotation with mutational data, and with results of testing for post-translational modification of cellular proteins. These data may be useful in tailoring chemotherapeutic protocols to individual tumors and identifying new targets for therapeutic intervention.

Authors
Meyerson, M; Franklin, WA; Kelley, MJ
MLA Citation
Meyerson, M, Franklin, WA, and Kelley, MJ. "Molecular classification and molecular genetics of human lung cancers." Semin Oncol 31.1 Suppl 1 (February 2004): 4-19. (Review)
PMID
14981576
Source
pubmed
Published In
Seminars in Oncology
Volume
31
Issue
1 Suppl 1
Publish Date
2004
Start Page
4
End Page
19

Molecular classification and molecular genetics of human lung cancers

Authors
Meyerson, M; Franklin, WA; Kelley, MJ
MLA Citation
Meyerson, M, Franklin, WA, and Kelley, MJ. "Molecular classification and molecular genetics of human lung cancers." SEMINARS IN ONCOLOGY 31.1 (February 2004): 4-19.
Source
wos-lite
Published In
Seminars in Oncology
Volume
31
Issue
1
Publish Date
2004
Start Page
4
End Page
19
DOI
10.1053/j.seminoncol.2003.12.009

Molecular Classification and Molecular Genetics of Human Lung Cancers

Recent advances in the molecular classification of lung carcinomas and the identification of causative genetic alterations will likely lead to improvements in the diagnosis and treatment of patients with lung cancer. It is now possible to identify gene expression profiles that associate with patient outcome in lung carcinomas, in particular adenocarcinoma. Furthermore, patient survival has been shown to correlate with lung cancer oligonucleotide microarray expression profiles. Large-scale microarray technology may allow for the identification of useful biomarkers for early cancer detection. Oligonucleotide microarray data can be optimized by relating them to protein expression levels in tissue microarrays, by annotation with mutational data, and with results of testing for post-translational modification of cellular proteins. These data may be useful in tailoring chemotherapeutic protocols to individual tumors and identifying new targets for therapeutic intervention. © 2004 Elsevier Inc. All rights reserved.

Authors
Meyerson, M; Franklin, WA; Kelley, MJ
MLA Citation
Meyerson, M, Franklin, WA, and Kelley, MJ. "Molecular Classification and Molecular Genetics of Human Lung Cancers." Seminars in Oncology 31.1 SUPPL. 1 (2004): 4-19.
Source
scival
Published In
Seminars in Oncology
Volume
31
Issue
1 SUPPL. 1
Publish Date
2004
Start Page
4
End Page
19
DOI
10.1053/j.seminoncol.2003.10.016

Platelet transmission electron microscopy in genetically confirmed MYH9-related disorders.

Authors
Pujol-Moix, N; Kelley, MJ; Muniz-Diaz, E; Ortega, JJ; Arilla, M; Espanol, I
MLA Citation
Pujol-Moix, N, Kelley, MJ, Muniz-Diaz, E, Ortega, JJ, Arilla, M, and Espanol, I. "Platelet transmission electron microscopy in genetically confirmed MYH9-related disorders." November 16, 2003.
Source
wos-lite
Published In
Blood
Volume
102
Issue
11
Publish Date
2003
Start Page
788A
End Page
789A

Genetic heterogeneity in familial chordoma

Authors
Yang, RX; Kelley, MJ; McMaster, M; Liebsch, NJ; Bergen, AW; Beerman, M; Haque, K; Goldstein, AM; Parry, DM
MLA Citation
Yang, RX, Kelley, MJ, McMaster, M, Liebsch, NJ, Bergen, AW, Beerman, M, Haque, K, Goldstein, AM, and Parry, DM. "Genetic heterogeneity in familial chordoma." November 2003.
Source
wos-lite
Published In
The American Journal of Human Genetics
Volume
73
Issue
5
Publish Date
2003
Start Page
495
End Page
495

Serum CYFRA 21-1 in advanced stage non-small cell lung cancer: an early measure of response.

OBJECTIVES: Our objective was to test the prognostic importance of both the pretreatment level and change in serum CYFRA 21-1 after one cycle of chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) and to compare these two CYFRA variables to routine clinical stage and response as measured by imaging. PATIENTS AND METHODS: Our patients consisted of 58 with advanced NSCLC who were treated with chemotherapy. Fourteen were stage IIIa, 8 stage IIIb, and 36 stage IV, and none had received previous treatment. The choice of chemotherapy was left to the discretion of the treating physicians. We collected two serum samples, one before the first cycle of chemotherapy and the second before the second cycle, and analyzed these for serum CYFRA 21-1 using an electrochemiluminescence immunoassay and the ElecSys 2010 system (Roche Diagnostics Corp., Indianapolis, IN). We expressed changes in CYFRA in terms of the natural ratio logarithm of post-treatment to pretreatment CYFRA, and we used the Cox proportional hazards model to analyze survival time. RESULTS: Patients experienced an average drop of 27% in serum CYFRA after the first cycle of chemotherapy. Furthermore, the Cox model demonstrated that both the initial natural logarithm of serum CYFRA and presence of >27% drop in CYFRA were significantly related to subsequent survival (model P 0.1). CONCLUSION: In advanced stage NSCLC, the initial level of serum CYFRA appears to provide more prognostic information than clinical stage. Furthermore, a drop of >27% in CYFRA after one cycle of therapy adds prognostic information, so that this threshold appears to be an early measure of response to chemotherapy.

Authors
Vollmer, RT; Govindan, R; Graziano, SL; Gamble, G; Garst, J; Kelley, MJ; Christenson, RH
MLA Citation
Vollmer, RT, Govindan, R, Graziano, SL, Gamble, G, Garst, J, Kelley, MJ, and Christenson, RH. "Serum CYFRA 21-1 in advanced stage non-small cell lung cancer: an early measure of response." Clinical cancer research : an official journal of the American Association for Cancer Research 9.5 (May 2003): 1728-1733. (Academic Article)
PMID
12738727
Source
manual
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
9
Issue
5
Publish Date
2003
Start Page
1728
End Page
1733

Ritterazine B, a new cytotoxic natural compound, induces apoptosis in cancer cells.

PURPOSE: Ritterazine B, one of the ritterazine analogues extracted from Ritterella tokioka, has been shown to be chemically similar to cephalostatin 1, and among the ritterazine derivatives is the most cytotoxic to P388 murine leukemia cells. The objective of this study was to determine the cytotoxicity of ritterazine B to non-small-cell lung cancer (NSCLC) cells in vitro and its effects on the cell cycle and apoptosis. METHODS: The cytotoxicity of ritterazine B against PC14 NSCLC cells was investigated using a 4-day MTT assay. Morphological changes in cells after exposure to this compound were evaluated by phase-contrast microscopy. The effects on the cell cycle of HL-60 leukemia cells and PC14 cells were elucidated by flow cytometry and an in vitro CDK/cyclin kinase assay. Induction of apoptosis in HL-60 cells was assessed using the TUNEL assay and Hoechst 33342 staining. In addition, molecules involved in apoptosis were evaluated by Western blotting. RESULTS: Ritterazine B exerted strong cytotoxic effects against PC14 cells with a mean GI(50) of 75.1 n M. Cell cycle analysis showed that ritterazine B caused accumulation of HL-60 and PC14 cells at the G2/M checkpoint. Furthermore, ritterazine B-treated HL-60 cells became multinucleated, and at a concentration of 20 n M this resulted in the onset of apoptosis. Neither cleavage of caspase target molecules nor phosphorylation of bcl-2 were observed in ritterazine B-treated HL-60 cells. CONCLUSIONS: These results indicate that ritterazine B might be a potent inducer of apoptosis acting via a novel antimitotic mechanism.

Authors
Komiya, T; Fusetani, N; Matsunaga, S; Kubo, A; Kaye, FJ; Kelley, MJ; Tamura, K; Yoshida, M; Fukuoka, M; Nakagawa, K
MLA Citation
Komiya, T, Fusetani, N, Matsunaga, S, Kubo, A, Kaye, FJ, Kelley, MJ, Tamura, K, Yoshida, M, Fukuoka, M, and Nakagawa, K. "Ritterazine B, a new cytotoxic natural compound, induces apoptosis in cancer cells." Cancer Chemother Pharmacol 51.3 (March 2003): 202-208.
PMID
12655437
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
51
Issue
3
Publish Date
2003
Start Page
202
End Page
208
DOI
10.1007/s00280-002-0558-8

Assessment of the scope and quality of clinical practice guidelines in lung cancer.

STUDY OBJECTIVES: To provide an evidence-based background for developing the American College of Chest Physicians (ACCP) lung cancer guidelines, a systematic review of the literature was performed to identify published lung cancer guidelines and evaluate their quality. DESIGN, SETTING, AND PARTICIPANTS: A systematic search was performed for relevant literature from MEDLINE, Cancerlit, CINAHL, HealthStar, the Cochrane Library, and the National Guidelines Clearinghouse published from January 1989 to July 2001. MEASUREMENT AND RESULTS: From 369 citations, 51 relevant guidelines were identified. Each guideline was evaluated by at least four reviewers using the Appraisal of Guidelines for Research and Evaluation (AGREE) instrument and was coded for clinical topics covered. The recommendations included in each guideline also were abstracted. Of the 51 guidelines evaluated, 27 (53%) were evidence-based. Clinical topics identified by the ACCP for their guideline effort each were represented by at least one existing guideline. Of the 880 clinical recommendations abstracted from the guidelines, only 253 (29%) were evidence-based. The AGREE instrument rates guidelines along six domains. As a group, the guidelines performed well in the scope and purpose domain, with only six guidelines (12%) scoring < 50%. For the remaining domains, however, the guidelines did not perform as well, as follows: for stakeholder involvement, 41 guidelines (80%) scored < 50%; for rigor of development, 29 guidelines (57%) scored < 50%; for clarity and presentation, 17 guidelines (33%) scored < 50%; for applicability, 46 guidelines (90%) scored < 50%; and for editorial independence, 47 guidelines (92%) scored < 50%. After considering the domain scores, the reviewers recommended only 19 of the guidelines (37%). CONCLUSIONS: All major clinical lung cancer topics are covered by at least one guideline, but no single guideline addresses all areas. Furthermore, although existing guidelines may accurately reflect clinical practice, most performed poorly when evaluated for quality. Future guideline efforts that address each item of the AGREE instrument would add substantially to the literature.

Authors
Harpole, LH; Kelley, MJ; Schreiber, G; Toloza, EM; Kolimaga, J; McCrory, DC
MLA Citation
Harpole, LH, Kelley, MJ, Schreiber, G, Toloza, EM, Kolimaga, J, and McCrory, DC. "Assessment of the scope and quality of clinical practice guidelines in lung cancer." Chest 123.1 Suppl (January 2003): 7S-20S. (Review)
PMID
12527562
Source
pubmed
Published In
Chest
Volume
123
Issue
1 Suppl
Publish Date
2003
Start Page
7S
End Page
20S

Prevention of lung cancer: summary of published evidence.

STUDY OBJECTIVES: To describe empiric research related to lung cancer prevention strategies, including chemoprevention aimed at reducing lung cancer incidence and various smoking avoidance and cessation interventions aimed at reducing smoking rates. DESIGN, SETTING, AND PARTICIPANTS: Systematic searches of MEDLINE, HealthStar, and Cochrane Library databases to July 2001 and print bibliographies. For chemoprevention studies, we considered only randomized controlled trials (RCTs) with lung cancer incidence as an end point. For studies of smoking avoidance or cessation, we selected systematic reviews and meta-analyses, and searched for individual RCTs only where high-quality and current reviews and meta-analyses were not available. MEASUREMENT AND RESULTS: Chemoprevention of lung cancer has been studied in five RCTs of primary prevention, no RCTs of secondary prevention, and five RCTs of tertiary prevention. None of these trials has shown evidence for efficacy of any agents tested, including retinol (vitamin A), beta-carotene, N-acetylcysteine, and selenium. There is a great deal of evidence about a wide variety of clinician-based and community-based efforts at smoking avoidance or cessation. Certain approaches have been shown to be effective (eg, mass media public education campaigns, direct restrictions on smoking, clinician-based approaches ranging from brief clinician advice to more in-depth sessions, and "life-skills training" in schools). Some approaches have intermediate or short-term effectiveness (ie, youth access restrictions and school-based interventions), and others have been shown to be ineffective (ie, acupuncture and provider education) or have been insufficiently studied (ie, provider feedback). CONCLUSIONS: There are no agents that have been proven to be effective for preventing lung cancer. Several clinician-based and community-based interventions show promise for reducing lung cancer incidence through smoking avoidance and prevention.

Authors
Kelley, MJ; McCrory, DC
MLA Citation
Kelley, MJ, and McCrory, DC. "Prevention of lung cancer: summary of published evidence." Chest 123.1 Suppl (January 2003): 50S-59S. (Review)
PMID
12527564
Source
pubmed
Published In
Chest
Volume
123
Issue
1 Suppl
Publish Date
2003
Start Page
50S
End Page
59S

Screening for lung cancer: a review of the current literature.

STUDY OBJECTIVES: To review the available data on the early detection of lung cancer, with a focus on three technologies: chest x-ray (CXR), sputum cytology, and low-dose CT (LDCT) scanning. DESIGN, SETTING, PARTICIPANTS: Review of published clinical studies of early detection technologies. The best available evidence on each topic was selected for analysis. Randomized trials were used to evaluate CXR and sputum cytology. Cohort studies, as well as studies providing evidence regarding rates of overdiagnosis and efficacy of initial treatment, were considered in evaluation of LDCT. Study design and results were summarized in evidence tables. Statistical analyses of combined data were not performed. MEASUREMENT AND RESULTS: Five randomized trials of CXR with or without sputum cytology have been conducted, each which reports disease-specific mortality as well as other end points. None of these studies provide support for the use of either CXR or sputum cytology for the early detection of lung cancer in asymptomatic individuals. Eight completed and ongoing trials of LDCT were identified. All of these studies report the frequency and stage distribution of lung cancers found during initial ("prevalence") screening, and several studies also report rates of detection at the time of annual follow-up. No outcome data on survival or treatment are available. A number of studies support the hypothesis of "overdiagnosis"--that some lung cancers detected by LDCT may behave in an indolent manner. CONCLUSIONS: The use of either CXR or sputum cytology for the early detection of lung cancer is not supported by the published evidence. The evidence for LDCT appears promising, in that the technology typically identifies lung cancer at an early stage, although corollary studies suggest that these findings in isolation may be misleading. Further high-quality research is needed to better define the role of LDCT in the evaluation of asymptomatic high-risk individuals.

Authors
Bach, PB; Kelley, MJ; Tate, RC; McCrory, DC
MLA Citation
Bach, PB, Kelley, MJ, Tate, RC, and McCrory, DC. "Screening for lung cancer: a review of the current literature." Chest 123.1 Suppl (January 2003): 72S-82S. (Review)
PMID
12527566
Source
pubmed
Published In
Chest
Volume
123
Issue
1 Suppl
Publish Date
2003
Start Page
72S
End Page
82S

Assessment of the scope and quality of clinical practice guidelines in lung cancer

Authors
Harpole, LH; Kelley, MJ; Schreiber, G; Toloza, EM; Kolimaga, J; McCrory, DC
MLA Citation
Harpole, LH, Kelley, MJ, Schreiber, G, Toloza, EM, Kolimaga, J, and McCrory, DC. "Assessment of the scope and quality of clinical practice guidelines in lung cancer." CHEST 123.1 (January 2003): 7S-20S.
Source
wos-lite
Published In
Chest
Volume
123
Issue
1
Publish Date
2003
Start Page
7S
End Page
20S
DOI
10.1378/chest.123.1_suppl.7S

Prevention of lung cancer - Summary of published evidence

Authors
Kelley, MJ; McCrory, DC
MLA Citation
Kelley, MJ, and McCrory, DC. "Prevention of lung cancer - Summary of published evidence." CHEST 123.1 (January 2003): 50S-59S.
Source
wos-lite
Published In
Chest
Volume
123
Issue
1
Publish Date
2003
Start Page
50S
End Page
59S
DOI
10.1378/chest.123.1_suppl.50S

Screening for lung cancer - A review of the current literature

Authors
Bach, PB; Kelley, MJ; Tate, RC; McCrory, DC
MLA Citation
Bach, PB, Kelley, MJ, Tate, RC, and McCrory, DC. "Screening for lung cancer - A review of the current literature." CHEST 123.1 (January 2003): 72S-82S.
Source
wos-lite
Published In
Chest
Volume
123
Issue
1
Publish Date
2003
Start Page
72S
End Page
82S
DOI
10.1378/chest.123.1_suppl.72S

Screening for lung cancer: A review of the current literature

Study objectives: To review the available data on the early detection of lung cancer, with a focus on three technologies: chest x-ray (CXR), sputum cytology, and low-dose CT (LDCT) scanning. Design, setting, participants: Review of published clinical studies of early detection technologies. The best available evidence on each topic was selected for analysis. Randomized trials were used to evaluate CXR and sputum cytology. Cohort studies, as well as studies providing evidence regarding rates of overdiagnosis and efficacy of initial treatment, were considered in evaluation of LDCT. Study design and results were summarized in evidence tables. Statistical analyses of combined data were not performed. Measurement and results: Five randomized trials of CXR with or without sputum cytology have been conducted, each which reports disease-specific mortality as well as other end points. None of these studies provide support for the use of either CXR or sputum cytology for the early detection of lung cancer in asymptomatic individuals. Eight completed and ongoing trials of LDCT were identified. All of these studies report the frequency and stage distribution of lung cancers found during initial ("prevalence") screening, and several studies also report rates of detection at the time of annual follow-up. No outcome data on survival or treatment are available. A number of studies support the hypothesis of "overdiagnosis" - that some lung cancers detected by LDCT may behave in an indolent manner. Conclusions: The use of either CXR or sputum cytology for the early detection of lung cancer is not supported by the published evidence. The evidence for LDCT appears promising, in that the technology typically identifies lung cancer at an early stage, although corollary studies suggest that these findings in isolation may be misleading. Further high-quality research is needed to better define the role of LDCT in the evaluation of asymptomatic high-risk individuals.

Authors
Bach, PB; Kelley, MJ; Tate, RC; McCrory, DC
MLA Citation
Bach, PB, Kelley, MJ, Tate, RC, and McCrory, DC. "Screening for lung cancer: A review of the current literature." Chest 123.1 SUPPL. (2003): 72S-82S.
Source
scival
Published In
Chest
Volume
123
Issue
1 SUPPL.
Publish Date
2003
Start Page
72S
End Page
82S

Prevention of lung cancer: Summary of published evidence

Study objectives: To describe empiric research related to lung cancer prevention strategies, including chemoprevention aimed at reducing lung cancer incidence and various smoking avoidance and cessation interventions aimed at reducing smoking rates. Design, setting, and participants: Systematic searches of MEDLINE, HealthStar, and Cochrane Library databases to July 2001 and print bibliographies. For chemoprevention studies, we considered only randomized controlled trials (RCTs) with lung cancer incidence as an end point. For studies of smoking avoidance or cessation, we selected systematic reviews and meta-analyses, and searched for individual RCTs only where high-quality and current reviews and meta-analyses were not available. Measurement and results: Chemoprevention of lung cancer has been studied in five RCTs of primary prevention, no RCTs of secondary prevention, and five RCTs of tertiary prevention. None of these trials has shown evidence for efficacy of any agents tested, including retinol (vitamin A), β-carotene, N-acetylcysteine, and selenium. There is a great deal of evidence about a wide variety of clinician-based and community-based efforts at smoking avoidance or cessation. Certain approaches have been shown to be effective (eg, mass media public education campaigns, direct restrictions on smoking, clinician-based approaches ranging from brief clinician advice to more in-depth sessions, and "life-skills training" in schools). Some approaches have intermediate or short-term effectiveness (ie, youth access restrictions and school-based interventions), and others have been shown to be ineffective (ie, acupuncture and provider education) or have been insufficiently studied (ie, provider feedback). Conclusions: There are no agents that have been proven to be effective for preventing lung cancer. Several clinician-based and community-based interventions show promise for reducing lung cancer incidence through smoking avoidance and prevention.

Authors
Kelley, MJ; McCrory, DC
MLA Citation
Kelley, MJ, and McCrory, DC. "Prevention of lung cancer: Summary of published evidence." Chest 123.1 SUPPL. (2003): 50S-59S.
Source
scival
Published In
Chest
Volume
123
Issue
1 SUPPL.
Publish Date
2003
Start Page
50S
End Page
59S

Assessment of the scope and quality of clinical practice guidelines in lung cancer

Study objectives: To provide an evidence-based background for developing the American College of Chest Physicians (ACCP) lung cancer guidelines, a systematic review of the literature was performed to identify published lung cancer guidelines and evaluate their quality. Design, setting, and participants: A systematic search was performed for relevant literature from MEDLINE, Cancerlit, CINAHL, HealthStar, the Cochrane Library, and the National Guidelines Clearinghouse published from January 1989 to July 2001. Measurement and results: From 369 citations, 51 relevant guidelines were identified. Each guideline was evaluated by at least four reviewers using the Appraisal of Guidelines for Research and Evaluation (AGREE) instrument and was coded for clinical topics covered. The recommendations included in each guideline also were abstracted. Of the 51 guidelines evaluated, 27 (53%) were evidence-based. Clinical topics identified by the ACCP for their guideline effort each were represented by at least one existing guideline. Of the 880 clinical recommendations abstracted from the guidelines, only 253 (29%) were evidence-based. The AGREE instrument rates guidelines along six domains. As a group, the guidelines performed well in the scope and purpose domain, with only six guidelines (12%) scoring < 50%. For the remaining domains, however, the guidelines did not perform as well, as follows: for stakeholder involvement, 41 guidelines (80%) scored < 50%; for rigor of development, 29 guidelines (57%) scored < 50%; for clarity and presentation, 17 guidelines (33%) scored < 50%; for applicability, 46 guidelines (90%) scored < 50%; and for editorial independence, 47 guidelines (92%) scored < 50%. After considering the domain scores, the reviewers recommended only 19 of the guidelines (37%). Conclusions: All major clinical lung cancer topics are covered by at least one guideline, but no single guideline addresses all areas. Furthermore, although existing guidelines may accurately reflect clinical practice, most performed poorly when evaluated for quality. Future guideline efforts that address each item of the AGREE instrument would add substantially to the literature.

Authors
Harpole, LH; Kelley, MJ; Schreiber, G; Toloza, EM; Kolimaga, J; McCrory, DC
MLA Citation
Harpole, LH, Kelley, MJ, Schreiber, G, Toloza, EM, Kolimaga, J, and McCrory, DC. "Assessment of the scope and quality of clinical practice guidelines in lung cancer." Chest 123.1 SUPPL. (2003): 7S-20S.
Source
scival
Published In
Chest
Volume
123
Issue
1 SUPPL.
Publish Date
2003
Start Page
7S
End Page
20S

Etiology of the mutational spectrum of ras genes in human carcinomas.

Authors
Kelley, MJ; Littman, SJ
MLA Citation
Kelley, MJ, and Littman, SJ. "Etiology of the mutational spectrum of ras genes in human carcinomas." J Natl Cancer Inst 94.20 (October 16, 2002): 1516-1517.
PMID
12381698
Source
pubmed
Published In
Journal of the National Cancer Institute
Volume
94
Issue
20
Publish Date
2002
Start Page
1516
End Page
1517

Randomized controlled clinical trial of weekly oltipraz in smokers.

Authors
Kelley, MJ; Folz, RJ; Glaser, EM; Herndon, JE; Crowell, JA; Perloff, M; Ferdman, E; Gallot, L; Becker, R; Bergan, RC
MLA Citation
Kelley, MJ, Folz, RJ, Glaser, EM, Herndon, JE, Crowell, JA, Perloff, M, Ferdman, E, Gallot, L, Becker, R, and Bergan, RC. "Randomized controlled clinical trial of weekly oltipraz in smokers." October 2002.
Source
wos-lite
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
11
Issue
10
Publish Date
2002
Start Page
1169S
End Page
1169S

Re: Genetic analysis of the beta-tubulin gene, TUBB, in non-small-cell lung cancer - Response

Authors
Kelley, MJ
MLA Citation
Kelley, MJ. "Re: Genetic analysis of the beta-tubulin gene, TUBB, in non-small-cell lung cancer - Response." JOURNAL OF THE NATIONAL CANCER INSTITUTE 94.10 (May 15, 2002): 777-777.
Source
wos-lite
Published In
Journal of the National Cancer Institute
Volume
94
Issue
10
Publish Date
2002
Start Page
777
End Page
777

Replication of linkage results using MALDI-TOF detection of single nucleotide polymorphisms (SNPS)

The utility of MALDI-TOF MS detection of single nucleotide polymorphisms (SNP) was discussed. The study was carried out by genotyped and analyzed 40 SNPs on chromosomes 22 using the Homogeneous Mass EXTEND (hME) assay in one large 4 generation family consisting of 26 individuals. It was observed that, for the chromosome 22 SNP assays analyzed, the assays were originally genotyped up to four times for a single assay. Three mismatched were also found among 1,451 comparisons that equal to 0.21% and the overall missing data after considering all attempts was 3.1%.

Authors
Gundry, R; Hayden, D; Boyce, P; Voltz, A; Luong, E; Pugh, E; Kelley, M; Fan, R; Bailey-Wilson, JE; Witmer, D; Doheny, K
MLA Citation
Gundry, R, Hayden, D, Boyce, P, Voltz, A, Luong, E, Pugh, E, Kelley, M, Fan, R, Bailey-Wilson, JE, Witmer, D, and Doheny, K. "Replication of linkage results using MALDI-TOF detection of single nucleotide polymorphisms (SNPS)." Proceedings 50th ASMS Conference on Mass Spectrometry and Allied Topics (2002): 399-401.
Source
scival
Published In
Proceedings 50th ASMS Conference on Mass Spectrometry and Allied Topics
Publish Date
2002
Start Page
399
End Page
401

Genetic analysis of the beta-tubulin gene, TUBB, in non-small-cell lung cancer.

Authors
Kelley, MJ; Li, S; Harpole, DH
MLA Citation
Kelley, MJ, Li, S, and Harpole, DH. "Genetic analysis of the beta-tubulin gene, TUBB, in non-small-cell lung cancer." J Natl Cancer Inst 93.24 (December 19, 2001): 1886-1888.
PMID
11752014
Source
pubmed
Published In
Journal of the National Cancer Institute
Volume
93
Issue
24
Publish Date
2001
Start Page
1886
End Page
1888

Ritterazine B, a new cytotoxic marine product, induces apoptosis and G2/M arrest.

Authors
Komiya, T; Tamura, K; Fukuoka, M; Kelley, MJ; Kubo, A; Kaye, FJ; Matsunaga, S; Fusetani, N; Nakagawa, K
MLA Citation
Komiya, T, Tamura, K, Fukuoka, M, Kelley, MJ, Kubo, A, Kaye, FJ, Matsunaga, S, Fusetani, N, and Nakagawa, K. "Ritterazine B, a new cytotoxic marine product, induces apoptosis and G2/M arrest." CLINICAL CANCER RESEARCH 7.11 (November 2001): 3716S-3716S.
Source
wos-lite
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
7
Issue
11
Publish Date
2001
Start Page
3716S
End Page
3716S

A familial chordoma locus maps to chromosome 7q33.

Authors
Yang, X; Kelley, MJ; Korczak, JF; Sheridan, E; Goldstein, AM; Parry, DM
MLA Citation
Yang, X, Kelley, MJ, Korczak, JF, Sheridan, E, Goldstein, AM, and Parry, DM. "A familial chordoma locus maps to chromosome 7q33." AMERICAN JOURNAL OF HUMAN GENETICS 69.4 (October 2001): 512-512.
Source
wos-lite
Published In
The American Journal of Human Genetics
Volume
69
Issue
4
Publish Date
2001
Start Page
512
End Page
512

A comparison of single nucleotide polymorphism(SNP) and microsatellite genome scans for May-Hegglin anomaly(MHA).

Authors
Pugh, EW; Witmer, PD; Wanyee, JW; Fan, YT; Ibay, GP; Voltz, A; Luong, E; Goldstein, JL; Nussbaum, RL; Korczak, JF; Kelley, MJ; Doheny, KD
MLA Citation
Pugh, EW, Witmer, PD, Wanyee, JW, Fan, YT, Ibay, GP, Voltz, A, Luong, E, Goldstein, JL, Nussbaum, RL, Korczak, JF, Kelley, MJ, and Doheny, KD. "A comparison of single nucleotide polymorphism(SNP) and microsatellite genome scans for May-Hegglin anomaly(MHA)." AMERICAN JOURNAL OF HUMAN GENETICS 69.4 (October 2001): 181-181.
Source
wos-lite
Published In
The American Journal of Human Genetics
Volume
69
Issue
4
Publish Date
2001
Start Page
181
End Page
181

Familial chordoma, a tumor of notochordal remnants, is linked to chromosome 7q33.

Chordoma is a rare tumor originating from notochordal remnants that is usually diagnosed during midlife. We performed a genomewide analysis for linkage in a family with 10 individuals affected by chordoma. The maximum two-point LOD score based on only the affected individuals was 2.21, at recombination fraction 0, at marker D7S2195 on chromosome 7q. Combined analysis of additional members of this family (11 affected individuals) and of two unrelated families (one with 2 affected individuals and the other with 3 affected individuals), with 20 markers on 7q, showed a maximum two-point LOD score of 4.05 at marker D7S500. Multipoint analysis based on only the affected individuals gave a maximum LOD score of 4.78, with an approximate 2-LOD support interval from marker D7S512 to marker D7S684. Haplotype analysis of the three families showed a minimal disease-gene region from D7S512 to D7S684, a distance of 11.1 cM and approximately 7.1 Mb. No loss of heterozygosity was found at markers D7S1804, D7S1824, and D7S2195 in four tumor samples from affected family members. These results map a locus for familial chordoma to 7q33. Further analysis of this region, to identify this gene, is ongoing.

Authors
Kelley, MJ; Korczak, JF; Sheridan, E; Yang, X; Goldstein, AM; Parry, DM
MLA Citation
Kelley, MJ, Korczak, JF, Sheridan, E, Yang, X, Goldstein, AM, and Parry, DM. "Familial chordoma, a tumor of notochordal remnants, is linked to chromosome 7q33." Am J Hum Genet 69.2 (August 2001): 454-460.
PMID
11452362
Source
pubmed
Published In
The American Journal of Human Genetics
Volume
69
Issue
2
Publish Date
2001
Start Page
454
End Page
460
DOI
10.1086/321982

Genetic changes in contralateral bronchioloalveolar carcinomas of the lung.

OBJECTIVE: The pattern of metastases and recurrence of bronchioloalveolar carcinoma (BAC) differs from adenocarcinoma of the lung, occurring more frequently within the lung without extrapulmonary involvement. Analyses of genetic differences of contralateral BACs may help to explain these clinical differences. METHODS: We compared paired tumors from 5 patients with contralateral metachronous BACs for loss of heterozygosity (LOH) on 6 chromosomal arms (2q, 3p, 5q, 9p, 13q and 17p) and mutational analysis of p53 and K-ras. RESULTS: Two patients, patients 1 and 2, had discordant patterns of LOH on 2 and 3 of the chromosome arms, respectively. In addition, patient 2 had a detectable K-ras mutation in his initial tumor but not in his second. These results suggest that in patients 1 and 2, the contralateral tumors were clonally unrelated. Patient 3 had no mutations in the K-ras or p53 gene and no LOH on any of the 5 informative chromosome arms. Patient 4 had LOH of 9p and mutated K-ras in both the first and the second tumor, with a mutation in the p53 gene in the first but not in the second tumor. Patient 5 had LOH of 17p and the same p53 mutations in both the first and the second tumor, with a mutation of K-ras in the first tumor but not in the second. CONCLUSIONS: The preponderance of evidence suggests that in patients 3, 4 and 5, the paired tumors were clonally related. The different patterns of LOH and mutations in clinically similar contralateral metachronous BACs provide evidence of genetic heterogeneity in the tumors of this patient group.

Authors
Shin, SW; Breathnach, OS; Linnoila, RI; Williams, J; Gillespie, JW; Kelley, MJ; Johnson, BE
MLA Citation
Shin, SW, Breathnach, OS, Linnoila, RI, Williams, J, Gillespie, JW, Kelley, MJ, and Johnson, BE. "Genetic changes in contralateral bronchioloalveolar carcinomas of the lung." Oncology 60.1 (2001): 81-87.
PMID
11150913
Source
pubmed
Published In
Oncology
Volume
60
Issue
1
Publish Date
2001
Start Page
81
End Page
87

Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9.

The authors had previously mapped a new locus-DFNA17, for nonsyndromic hereditary hearing impairment-to chromosome 22q12.2-q13. 3. DFNA17 spans a 17- to 23-cM region, and MYH9, a nonmuscle-myosin heavy-chain gene, is located within the linked region. Because of the importance of myosins in hearing, MYH9 was tested as a candidate gene for DFNA17. Expression of MYH9 in the rat cochlea was confirmed using reverse transcriptase-PCR and immunohistochemistry. MYH9 was immunolocalized in the organ of Corti, the subcentral region of the spiral ligament, and the Reissner membrane. Sequence analysis of MYH9 in a family with DFNA17 identified, at nucleotide 2114, a G-->A transposition that cosegregated with the inherited autosomal dominant hearing impairment. This missense mutation changes codon 705 from an invariant arginine (R) to histidine (H), R705H, within a highly conserved SH1 linker region. Previous studies have shown that modification of amino acid residues within the SH1 helix causes dysfunction of the ATPase activity of the motor domain in myosin II. Both the precise role of MYH9 in the cochlea and the mechanism by which the R705H mutation leads to the DFNA17 phenotype (progressive hearing impairment and cochleosaccular degeneration) remain to be elucidated.

Authors
Lalwani, AK; Goldstein, JA; Kelley, MJ; Luxford, W; Castelein, CM; Mhatre, AN
MLA Citation
Lalwani, AK, Goldstein, JA, Kelley, MJ, Luxford, W, Castelein, CM, and Mhatre, AN. "Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9." Am J Hum Genet 67.5 (November 2000): 1121-1128.
PMID
11023810
Source
pubmed
Published In
The American Journal of Human Genetics
Volume
67
Issue
5
Publish Date
2000
Start Page
1121
End Page
1128
DOI
10.1016/S0002-9297(07)62942-5

Mutation of MYH9, encoding non-muscle myosin heavy chain A, in May-Hegglin anomaly.

May-Hegglin anomaly (MHA) is an autosomal dominant macrothrombocytopenia of unclear pathogenesis characterized by thrombocytopenia, giant platelets and leukocyte inclusions. Studies have indicated that platelet structure and function are normal, suggesting a defect in megakaryocyte fragmentation. The disorder has been linked to chromosome 22q12-13. Here we screen a candidate gene in this region, encoding non-muscle myosin heavy chain A (MYH9), for mutations in ten families. In each family, we identified one of three sequence variants within either the -helical coiled coil or the tailpiece domain that co-segregated with disease status. The E1841K mutation was found in 5 families and occurs at a conserved site in the rod domain. This mutation was not found in 40 normal individuals. Four families had a nonsense mutation that resulted in truncation of most of the tailpiece. One family had a T1155I mutation present in an affected mother and daughter, but not in the mother's parents, thus representing a new mutation. Among the 30 affected individuals, 21 unaffected individuals and 13 spouses in the 10 families, there was correlation of a variant of MYH9 with the presence of MHA. The identification of MYH9 as the disease gene for MHA establishes the pathogenesis of the disorder, should provide further insight into the processes of normal platelet formation and may facilitate identification of the genetic basis of related disorders.

Authors
Kelley, MJ; Jawien, W; Ortel, TL; Korczak, JF
MLA Citation
Kelley, MJ, Jawien, W, Ortel, TL, and Korczak, JF. "Mutation of MYH9, encoding non-muscle myosin heavy chain A, in May-Hegglin anomaly." Nat Genet 26.1 (September 2000): 106-108.
PMID
10973260
Source
pubmed
Published In
Nature Genetics
Volume
26
Issue
1
Publish Date
2000
Start Page
106
End Page
108
DOI
10.1038/79069

Autosomal dominant macrothrombocytopenia with leukocyte inclusions (May-Hegglin anomaly) is linked to chromosome 22q12-13.

Macrothrombocytopenia with leukocyte inclusions (May-Hegglin anomaly) is a rare autosomal dominant disorder characterized by thrombocytopenia, giant platelets, and Döhle body-like inclusions in leukocytes. To determine the genetic basis of this disorder, we performed a genome-wide screen for linkage in three families with May-Hegglin anomaly. For the pooled analysis of the three families, three markers on chromosome 22 had two-point logarithm-of-difference (lod) scores greater than 3, with a maximum lod score of 3.91 at a recombination fraction (theta) of 0.076 for marker D22S683. Within the largest family (MHA-1), the maximum lod score was 5.36 at theta=0 at marker D22S445. Fine mapping of recombination events using eight adjacent markers indicated that the minimal disease region of family MHA-1 alone is in the approximately 26 cM region from D22S683 to the telomere. The maximum lod score for the three families combined was 5.84 at theta=0 for marker IL2RB. With the assumption of locus homogeneity, haplotype analysis of family MHA-4 indicated the disease region is centromeric to marker D22S1045. These data best support a minimal disease region from D22S683 to D22S1045, a span of about 1 Mb of DNA that contains 17 known genes and 4 predicted genes. Further analysis of this region will identify the genetic basis of May-Hegglin anomaly, facilitating subsequent characterization of the biochemical role of the disease gene in platelet formation.

Authors
Kelley, MJ; Jawien, W; Lin, A; Hoffmeister, K; Pugh, EW; Doheny, KF; Korczak, JF
MLA Citation
Kelley, MJ, Jawien, W, Lin, A, Hoffmeister, K, Pugh, EW, Doheny, KF, and Korczak, JF. "Autosomal dominant macrothrombocytopenia with leukocyte inclusions (May-Hegglin anomaly) is linked to chromosome 22q12-13." Hum Genet 106.5 (May 2000): 557-564.
PMID
10914687
Source
pubmed
Published In
Human Genetics
Volume
106
Issue
5
Publish Date
2000
Start Page
557
End Page
564

MEN1 gene mutation analysis of high-grade neuroendocrine lung carcinoma.

Neuroendocrine tumors of the lung consist of a spectrum of neoplasms, including typical carcinoids, atypical carcinoids, large-cell neuroendocrine carcinomas (LCNEC), and small-cell lung carcinomas (SCLC). We previously reported frequent inactivation of the gene responsible for multiple endocrine neoplasia type 1 (MEN1) in both typical and atypical carcinoid tumors. In the present study, we extend the analysis of human NE lung tumors to include 9 primary SCLCs, 36 SCLC cell lines, and 13 primary LCNECs for MEN1 gene inactivation. In SCLC, loss of heterozygosity (LOH) at the MEN1 gene on chromosome band 11q13 was detected in one primary tumor and two cell lines. The coding sequence and splice junctions of the MEN1 gene were screened for mutations in all 44 tumors and cell lines, and no mutations were detected. Northern blot analysis of 13 SCLC cell lines showed the MEN1 transcript to be present and of normal size. In LCNECs, a somatic frameshift in the MEN1 gene (1226delC) was found in one of 13 tumors, representing the first mutation observed outside the spectrum of neoplasms associated with MEN1. Interestingly, neither a deletion nor a mutation was detected in the other allele, and wild-type mRNA sequence was expressed in the tumor, suggesting that the MEN1 gene was not inactivated by a conventional two-hit mechanism. The data support the hypothesis that SCLC and lung carcinoids develop via distinct molecular pathways; however, further investigation is necessary to determine the significance of the MEN1 gene mutation observed in a single case of LCNEC. Published 2000 Wiley-Liss, Inc.

Authors
Debelenko, LV; Swalwell, JI; Kelley, MJ; Brambilla, E; Manickam, P; Baibakov, G; Agarwal, SK; Spiegel, AM; Marx, SJ; Chandrasekharappa, SC; Collins, FS; Travis, WD; Emmert-Buck, MR
MLA Citation
Debelenko, LV, Swalwell, JI, Kelley, MJ, Brambilla, E, Manickam, P, Baibakov, G, Agarwal, SK, Spiegel, AM, Marx, SJ, Chandrasekharappa, SC, Collins, FS, Travis, WD, and Emmert-Buck, MR. "MEN1 gene mutation analysis of high-grade neuroendocrine lung carcinoma." Genes Chromosomes Cancer 28.1 (May 2000): 58-65.
PMID
10738303
Source
pubmed
Published In
Genes, Chromosomes and Cancer
Volume
28
Issue
1
Publish Date
2000
Start Page
58
End Page
65

Genetic changes in contralateral bronchioloalveolar carcinomas of the lung

Objective: The pattern of metastases and recurrence of bronchioloalveolar carcinoma (BAC) differs from adenocarcinoma of the lung, occurring more frequently within the lung without extrapulmonary involvement. Analyses of genetic differences of contralateral BACs may help to explain these clinical differences. Methods: We compared paired tumors from 5 patients with contralateral metachronous BACs for loss of heterozygosity (LOH) on 6 chromosomal arms (2q, 3p, 5q, 9p, 13q and 17p) and mutational analysis of p53 and K-ras. Results: Two patients, patients 1 and 2, had discordant patterns of LOH on 2 and 3 of the chromosome arms, respectively. In addition, patient 2 had a detectable K-ras mutation in his initial tumor but not in his second. These results suggest that in patients 1 and 2, the contralateral tumors were clonally unrelated. Patient 3 had no mutations in the K-ras or p53 gene and no LOH on any of the 5 informative chromosome arms. Patient 4 had LOH of 9p and mutated K-ras in both the first and the second tumor, with a mutation in the p53 gene in the first but not in the second tumor. Patient 5 had LOH of 17p and the same p53 mutations in both the first and the second tumor, with a mutation of K-ras in the first tumor but not in the second. Conclusions: The preponderance of evidence suggests that in patients 3, 4 and 5, the paired tumors were clonally related. The different patterns of LOH and mutations in clinically similar contralateral metachronous BACs provide evidence of genetic heterogeneity in the tumors of this patient group. Copyright © 2001 S. Karger AG.

Authors
Shin, SW; Breathnach, OS; Linnoila, RI; Williams, J; Gillespie, JW; Kelley, MJ; Johnson, BE
MLA Citation
Shin, SW, Breathnach, OS, Linnoila, RI, Williams, J, Gillespie, JW, Kelley, MJ, and Johnson, BE. "Genetic changes in contralateral bronchioloalveolar carcinomas of the lung." Oncology 60.1 (2000): 81-87.
Source
scival
Published In
Oncology
Volume
60
Issue
1
Publish Date
2000
Start Page
81
End Page
87

The p16 status of tumor cell lines identifies small molecule inhibitors specific for cyclin-dependent kinase 4.

Loss of p16 functional activity leading to disruption of the p16/cyclin-dependent kinase (CDK) 4:cyclin D/retinoblastoma pathway is the most common event in human tumorigenesis, suggesting that compounds with CDK4 kinase inhibitory activity may be useful to regulate cancer cell growth. To identify such inhibitors, the 60 cancer cell lines of the National Cancer Institute drug screen panel were examined for p16 alterations (biallelic deletion, intragenic mutations, or absent p16 protein), and the growth-inhibitory activity of more than 50,000 compounds against these 60 cell lines was compared with their p16 status. One compound, 3-amino thioacridone (3-ATA; NSC 680434), whose growth-inhibitory activity correlated with the p16 status of the cell lines had an IC50 of 3.1 microM in a CDK4 kinase assay. In addition, four compounds structurally related to 3-ATA inhibited CDK4 kinase with IC50s ranging from 0.2-2.0 microM. All five of these compounds were less potent inhibitors of cell division cycle 2 and CDK2 kinases, with IC50s 30- to 500-fold higher than that for CDK4. ATP competition experiments demonstrated a noncompetitive mode of inhibition for 3-ATA (K(i) = 5.5 microM) and a linear mixed mode for benzothiadiazine (NSC 645787; K(i) = 0.73 microM). We have successfully demonstrated a novel approach to identify specific CDK4 kinase inhibitors that may selectively induce growth inhibition of p16-altered tumors.

Authors
Kubo, A; Nakagawa, K; Varma, RK; Conrad, NK; Cheng, JQ; Lee, WC; Testa, JR; Johnson, BE; Kaye, FJ; Kelley, MJ
MLA Citation
Kubo, A, Nakagawa, K, Varma, RK, Conrad, NK, Cheng, JQ, Lee, WC, Testa, JR, Johnson, BE, Kaye, FJ, and Kelley, MJ. "The p16 status of tumor cell lines identifies small molecule inhibitors specific for cyclin-dependent kinase 4." Clin Cancer Res 5.12 (December 1999): 4279-4286.
PMID
10632371
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
5
Issue
12
Publish Date
1999
Start Page
4279
End Page
4286

The p16 status of tumor cell lines identifies small molecule inhibitors specific for cyclin dependent kinase (CDK) 4.

Authors
Kubo, A; Nakagawa, K; Varma, RK; Conrad, NK; Cheng, JQ; Lee, WC; Testa, JR; Johnson, BE; Kaye, FJ; Kelley, MJ
MLA Citation
Kubo, A, Nakagawa, K, Varma, RK, Conrad, NK, Cheng, JQ, Lee, WC, Testa, JR, Johnson, BE, Kaye, FJ, and Kelley, MJ. "The p16 status of tumor cell lines identifies small molecule inhibitors specific for cyclin dependent kinase (CDK) 4." CLINICAL CANCER RESEARCH 5 (November 1999): 3755S-3756S.
Source
wos-lite
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
5
Publish Date
1999
Start Page
3755S
End Page
3756S

Genomic screen for linkage of May-Hegglin anomaly.

Authors
Korczak, JF; Jawien, W; Lin, AY; Hoffmeister, K; Kelley, MJ
MLA Citation
Korczak, JF, Jawien, W, Lin, AY, Hoffmeister, K, and Kelley, MJ. "Genomic screen for linkage of May-Hegglin anomaly." AMERICAN JOURNAL OF HUMAN GENETICS 65.4 (October 1999): A258-A258.
Source
wos-lite
Published In
The American Journal of Human Genetics
Volume
65
Issue
4
Publish Date
1999
Start Page
A258
End Page
A258

Genomic structure of the EPHA1 receptor tyrosine kinase gene.

Some receptor tyrosine kinase genes are mutated in inherited and somatically acquired human cancers. To permit mutational analysis, the complete genomic structure of the human EPHA1 gene on chromosome 7q34 was determined and oligonucleotide pairs were designed to amplify coding regions. The gene contains 18 exons, two more than the related tyrosine kinase, EPHB2. Presumed sequencing errors in the published cDNA sequence of EPHA1 were identified in exons 10 and 11. Availability of this information will facilitate mutational analysis of EPHA1.

Authors
Owshalimpur, D; Kelley, MJ
MLA Citation
Owshalimpur, D, and Kelley, MJ. "Genomic structure of the EPHA1 receptor tyrosine kinase gene." Mol Cell Probes 13.3 (June 1999): 169-173.
PMID
10369740
Source
pubmed
Published In
Molecular and Cellular Probes
Volume
13
Issue
3
Publish Date
1999
Start Page
169
End Page
173
DOI
10.1006/mcpr.1999.0228

Phase I study of a five-day dose schedule of 4-Ipomeanol in patients with non-small cell lung cancer.

The mammalian pulmonary toxin 4-ipomeanol (IPO) is activated by the cytochrome P450 system in bronchial Clara cells in animals. The resulting metabolites bind rapidly to macromolecules, producing localized cytotoxicity. IPO has in vitro and in vivo antitumor activity in non-small cell lung cancer (NSCLC) and thus was proposed as a lung cancer-specific antitumor agent. We have completed a directed Phase I trial in patients with NSCLC. Forty-four patients (34 men and 10 women) with NSCLC were treated with IPO. All but two patients had an Eastern Cooperative Oncology Group performance status of 0 or 1. They received 91 courses of therapy with i.v. IPO; 82 courses were administered daily for five days, and 9 were single bolus doses. The dose-limiting toxicity of elevated serum transaminases was observed in three of seven patients at 922 mg/m2/day. The maximum tolerated dose was 693 mg/m2/day on 5 consecutive days every 3 weeks. One patient developed grade 4 pulmonary toxicity at 167 mg/m2/day. There was no significant hematological or renal toxicity. No objective antitumor responses were observed. Pharmacokinetic analysis of 39 patients from day 1 of IPO administration showed biexponential elimination with mean half-lives of 8.6 (alpha half-life) and 76 min (beta half-life). There was a linear relationship between the area under the plasma drug concentration-time curve and the dose of IPO. There was no significant difference between the pharmacokinetic parameters measured on day 1 and day 5. Using a 4-day in vitro cytotoxicity assay, two tumor cell lines established from patients treated at 693 mg/m2/day had IC50s of approximately 6 mM, a concentration more than 75-fold higher than the plasma levels measured in these patients. Thus, although the total amount of drug administered per cycle on a daily times five dose schedule is more than 2.5-fold higher than the recommended single daily dose, IPO is unlikely to be a useful drug for patients with lung cancer.

Authors
Kasturi, VK; Dearing, MP; Piscitelli, SC; Russell, EK; Sladek, GG; O'Neil, K; Turner, GA; Morton, TL; Christian, MC; Johnson, BE; Kelley, MJ
MLA Citation
Kasturi, VK, Dearing, MP, Piscitelli, SC, Russell, EK, Sladek, GG, O'Neil, K, Turner, GA, Morton, TL, Christian, MC, Johnson, BE, and Kelley, MJ. "Phase I study of a five-day dose schedule of 4-Ipomeanol in patients with non-small cell lung cancer." Clin Cancer Res 4.9 (September 1998): 2095-2102.
PMID
9748125
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
4
Issue
9
Publish Date
1998
Start Page
2095
End Page
2102

Correlation of expression of bombesin-like peptides and receptors with growth inhibition by an anti-bombesin antibody in small-cell lung cancer cell lines.

The murine anti-bombesin monoclonal antibody, 2A11, has been demonstrated to inhibit growth of some small-cell lung cancer (SCLC) cells in nude mice xenografts and in a clinical trial. To determine if the expression of bombesin-like peptides (BLP) and their receptors (GRP-R and NMB-R) correlate with an in vitro response to 2A11, we measured these parameters in seven SCLC cell lines. Gastrin releasing peptide (GRP) mRNA was detected in three of seven cell lines (NCI-H69, NCI-H345, NCI-H510) and neuromedin B (NMB) mRNA was detected in all seven lines using an RNase protection assay (RPA). Immunoreactive BLP was detected in the cell pellets of all lines (range 0.11-59.90 pmol/mg protein) by a solid phase GRP radioimmunoassay (RIA) using 125I-labeled 2A11. RPA detected GRP-receptor mRNA in two cell lines (NCI-H69 and NCI-H345) and NMB-receptor in three lines (NCI-H345, NCI-H510, and NCI-H660). Reverse transcriptase-PCR confirmed the presence of receptor mRNA in these lines and detected NMB-receptor in an additional three lines (NCI-H69, NCI-H82, and NCI-H187). Calcium mobilization in response to BLP stimulation was detected in the six cell lines expressing either GRP-R or NMB-R mRNA but not in NCI-N417, which had no detectable BLP-receptor. 2A11 (5 microg/ml) inhibited colony formation by 26-61% after 2 weeks in all cell lines except NCI-N417. Thus, growth inhibition by 2A11 requires the presence of at least one BLP-receptor. These findings may be useful in selecting patients with SCLC for treatment with 2A11.

Authors
Yang, HK; Scott, FM; Trepel, JB; Battey, JF; Johnson, BE; Kelley, MJ
MLA Citation
Yang, HK, Scott, FM, Trepel, JB, Battey, JF, Johnson, BE, and Kelley, MJ. "Correlation of expression of bombesin-like peptides and receptors with growth inhibition by an anti-bombesin antibody in small-cell lung cancer cell lines." Lung Cancer 21.3 (September 1998): 165-175.
PMID
9857994
Source
pubmed
Published In
Lung Cancer
Volume
21
Issue
3
Publish Date
1998
Start Page
165
End Page
175

Co-amplification of a novel cyclophilin-like gene (PPIE) with L-myc in small cell lung cancer cell lines.

Specific genetic alterations affecting proto-oncogenes of the myc gene family are frequently detected in human lung cancer. Among 11 SCLC cell lines with L-myc gene amplification, four were found to have alteration of the RLF gene by Southern blot and RT-PCR analyses. One cell line, NCI-H378, contained aberrantly-sized L-myc-hybridizing bands by Southern and Northern blot hybridization but had no alteration of RLF. Some L-myc-hybridizing cDNAs from NCI-H378 contained a novel sequence with close homology to the cyclophilins joined to antisense L-myc exon 2 sequence. Full length cDNAs isolated from human skeletal muscle containing only the novel sequence identify open reading frames of 301 and 296 amino acids and differ in the C-terminal region by 22 and 17 amino acids. This gene, tentatively named PPIE (peptidyl-prolyl cis-trans isomerase E), has 83% amino acid identity with the central conserved region of cyclophilin A, is evolutionarily conserved by Southern blot, and exhibits differential tissue expression with highest levels found in muscle and brain. Co-amplification of PPIE was observed in seven of eleven L-myc amplified cell lines. Analysis of radiation hybrids suggests that the gene order is RLF-PPIE-L-myc on chromosome 1p and pulse-field gel electrophoresis localizes all three genes to an 800 megabase Mlu I fragment. The prognostic and functional consequences of PPIE gene amplification in SCLC can now be determined.

Authors
Kim, JO; Nau, MM; Allikian, KA; Mäkelä, TP; Alitalo, K; Johnson, BE; Kelley, MJ
MLA Citation
Kim, JO, Nau, MM, Allikian, KA, Mäkelä, TP, Alitalo, K, Johnson, BE, and Kelley, MJ. "Co-amplification of a novel cyclophilin-like gene (PPIE) with L-myc in small cell lung cancer cell lines." Oncogene 17.8 (August 27, 1998): 1019-1026.
PMID
9747881
Source
pubmed
Published In
Oncogene: Including Oncogene Reviews
Volume
17
Issue
8
Publish Date
1998
Start Page
1019
End Page
1026
DOI
10.1038/sj.onc.1202006

Autocrine growth factors and neuroendocrine markers in the development of small-cell lung cancer.

Two different clinical trials using biological agents directed against an autocrine growth factor and a surface marker of neuroendocrine differentiation have been used for patients with relapsed small-cell lung cancer. In a phase II trial, an antibody (2A11) directed against the autocrine growth factor gastrin-releasing peptide has been used to treat patients with relapsed small-cell lung cancer. One of 12 evaluable patients treated with 2A11 250 mg/m2 three times weekly for 4 weeks achieved a complete response. An antibody directed against the neural cell adhesion molecule has been linked to a modified ricin molecule. This immunotoxin, N901-bR, has undergone phase I testing, and a recommended phase II dose of 30 micrograms/kg/day for 7 days by continuous infusion has been determined. In the phase I trial, one of 21 patients with relapsed or refractory small-cell lung cancer had a partial response to this treatment. Therefore, it appears that an antibody directed against an autocrine growth factor and an immunotoxin directed against a surface marker of neuroendocrine differentiation can inhibit the growth of small-cell lung cancer in vitro and in vivo; both produced some evidence of antitumor activity in patients. Further studies with agents directed against autocrine growth factors and surface markers of neuroendocrine differentiation appear warranted.

Authors
Johnson, BE; Kelley, MJ
MLA Citation
Johnson, BE, and Kelley, MJ. "Autocrine growth factors and neuroendocrine markers in the development of small-cell lung cancer." Oncology (Williston Park) 12.1 Suppl 2 (January 1998): 11-14.
PMID
9516605
Source
pubmed
Published In
Oncology
Volume
12
Issue
1 Suppl 2
Publish Date
1998
Start Page
11
End Page
14

Autocrine Growth Factors and Neuroendocrine Markers in the Development of Small-Cell Lung Cancer

Two different clinical trials using biological agents directed against an autocrine growth factor and a surface marker of neuroendocrine differentiation have been used for patients with relapsed small-cell lung cancer. In a phase II trial, an antibody (2A11) directed against the autocrine growth factor gastrin-releasing peptide has been used to treatpatients with relapsed small-cell lung cancer. One of 12 evaluable patients treated with 2A11 250 mg/m2 three times weekly for 4 weeks achieved a complete response. An antibody directed against the neural cell adhesion molecule has been linked to a modified ricin molecule. This immunotoxin, N901-bR, has undergone phase I testing, and a recommended phase II dose of 30 μg/kg/day for 7 days by continuous infusion has been determined. In the phase I trial, one of 21 patients with relapsed or refractory small-cell lung cancer had a partial response to this treatment. Therefore, it appears that an antibody directed against an autocrine growth factor and an immunotoxin directed against a surface marker of neuroendocrine differentiation can inhibit the growth of small-cell lung cancer in vitro and in vivo; both produced some evidence of antitumor activity in patients. Further studies with agents directed against autocrine growth factors and surface markers of neuroendocrine differentiation appear warranted.

Authors
Johnson, BE; Kelley, MJ
MLA Citation
Johnson, BE, and Kelley, MJ. "Autocrine Growth Factors and Neuroendocrine Markers in the Development of Small-Cell Lung Cancer." ONCOLOGY 12.1 SUPPL. 2 (1998): 11-14.
Source
scival
Published In
ONCOLOGY
Volume
12
Issue
1 SUPPL. 2
Publish Date
1998
Start Page
11
End Page
14

Fluorescence in situ hybridization analysis of keratinocyte growth factor gene amplification and dispersion in evolution of great apes and humans.

Keratinocyte growth factor (KGF) is a member of the fibroblast growth factor family. Portions of the gene encoding KGF were amplified during primate evolution and are present in multiple nonprocessed copies in the human genome. Nucleotide analysis of a representative sampling of these KGF-like sequences indicated that they were at least 95% identical to corresponding regions of the KGF gene. To localize these sequences to specific chromosomal sites in human and higher primates, we used fluorescence in situ hybridization. In human, using a cosmid probe encoding KGF exon 1, we assigned the location of the KGF gene to chromosome 15q15-21.1. In addition, copies of KGF-like sequences hybridizing only with a cosmid probe encoding exons 2 and 3 were localized to dispersed sites on chromosome 2q21, 9p11, 9q12-13, 18p11, 18q11, 21q11, and 21q21.1. The distribution of KGF-like sequences suggests a role for alphoid DNA in their amplification and dispersion. In chimpanzee, KGF-like sequences were observed at five chromosomal sites, which were each homologous to sites in human, while in gorilla, a subset of four of these homologous sites was identified; in orangutan two sites were identified, while gibbon exhibited only a single site. The chromosomal localization of KGF sequences in human and great ape genomes indicates that amplification and dispersion occurred in multiple discrete steps, with initial KGF gene duplication and dispersion taking place in gibbon and involving loci corresponding to human chromosomes 15 and 21. These findings support the concept of a closer evolutionary relationship of human and chimpanzee and a possible selective pressure for such dispersion during the evolution of higher primates.

Authors
Zimonjic, DB; Kelley, MJ; Rubin, JS; Aaronson, SA; Popescu, NC
MLA Citation
Zimonjic, DB, Kelley, MJ, Rubin, JS, Aaronson, SA, and Popescu, NC. "Fluorescence in situ hybridization analysis of keratinocyte growth factor gene amplification and dispersion in evolution of great apes and humans." Proc Natl Acad Sci U S A 94.21 (October 14, 1997): 11461-11465.
PMID
9326632
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
94
Issue
21
Publish Date
1997
Start Page
11461
End Page
11465

Oncogenic mutations in ras create HLA-A2.1 binding peptides but affect their extracellular antigen processing.

Point mutations in oncogene products such as ras may create neoantigenic determinants recognizable by T lymphocytes as tumor antigens, that could be marshalled to eliminate a tumor by inducing specific cytotoxic T lymphocytes (CTL) with an appropriate vaccine. Peptide-pulsed dendritic cells are a promising new approach to cancer vaccines. For such an approach to work, the determinant must be appropriately processed to the right size fragment and be presented by an appropriate HLA molecule. We have investigated both of these issues for a series of ras codon 12 and 13 point mutations that contain sequences predicted to bind to HLA-A2.1, the most common class I HLA molecule. We find that not only do the different mutations affect binding to HLA-A2.1, but also they affect extracellular antigen processing in two ways: by influencing the trimming of flanking residues from the longer sequence and by influencing the susceptibility of the optimal decamer to further proteolytic degradation. The influence of internal residues on cleavage of flanking residues downstream demonstrates the importance of distant interactions between separated amino acid side chains and/or conformational effects in determining antigen processing. These results may be important in designing an effective vaccine to induce mutant ras-specific tumor immunity.

Authors
Smith, MC; Pendleton, CD; Maher, VE; Kelley, MJ; Carbone, DP; Berzofsky, JA
MLA Citation
Smith, MC, Pendleton, CD, Maher, VE, Kelley, MJ, Carbone, DP, and Berzofsky, JA. "Oncogenic mutations in ras create HLA-A2.1 binding peptides but affect their extracellular antigen processing." Int Immunol 9.8 (August 1997): 1085-1093.
PMID
9263005
Source
pubmed
Published In
International Immunology
Volume
9
Issue
8
Publish Date
1997
Start Page
1085
End Page
1093

Antitumor activity of a monoclonal antibody directed against gastrin-releasing peptide in patients with small cell lung cancer.

BACKGROUND: Small cell lung cancer (SCLC) cells express and secrete gastrin-releasing peptide (GRP) which binds to receptors and stimulates growth of these cells. A murine monoclonal antibody, 2A11, which binds GRP with high affinity, decreased growth of SCLC cells in vitro and in athymic nude mice. A phase 1 trial and pharmacokinetic modeling in patients with lung cancer has defined the phase 2 dose of 2A11 but the antitumor activity in patients is unknown. METHODS: Thirteen patients with previously treated SCLC received 2A11 at 250 mg/m2 over 1 h three times per week for 4 weeks. Serum GRP, urine GRP, serum levels of 2A11, and human antimouse antibodies (HAMA) were determined. RESULTS: One of 12 (8%; 95% confidence interval, 0 to 38%) evaluable patients had complete resolution of radiographically detectable tumor lasting 4 months. Four patients (33%) had stable disease. No toxic reactions were observed. The pretreatment serum GRP level of the responding patient was 3.1 fmol/mL and the median of nine nonresponding patients was 7.3 fmol/mL (range, <1.0 to 29.0). The mean trough serum 2A11 level was 49+/-18 microg/mL in the responding patient and 32 to 487 mg/mL (median, 117) in 10 nonresponding patients. HAMA did not increase during 2A11 administration in any patient. CONCLUSIONS: Interruption of the GRP autocrine growth factor loop with 2A11 results in clinical antitumor activity in a minority of patients with previously treated SCLC. Further evaluation of the antitumor effects of 2A11 is warranted to define characteristics associated with response to 2A11.

Authors
Kelley, MJ; Linnoila, RI; Avis, IL; Georgiadis, MS; Cuttitta, F; Mulshine, JL; Johnson, BE
MLA Citation
Kelley, MJ, Linnoila, RI, Avis, IL, Georgiadis, MS, Cuttitta, F, Mulshine, JL, and Johnson, BE. "Antitumor activity of a monoclonal antibody directed against gastrin-releasing peptide in patients with small cell lung cancer." Chest 112.1 (July 1997): 256-261.
PMID
9228385
Source
pubmed
Published In
Chest
Volume
112
Issue
1
Publish Date
1997
Start Page
256
End Page
261

Purification and molecular cloning of a secreted, Frizzled-related antagonist of Wnt action.

Frizzled polypeptides are integral membrane proteins that recently were shown to function as receptors for Wnt signaling molecules. Here, we report the identification of a novel, secreted 36-kDa protein that contains a region homologous to a putative Wnt-binding domain of Frizzleds. This protein, called Frizzled-related protein (FRP), was first identified as a heparin-binding polypeptide that copurified with hepatocyte growth factor/scatter factor in conditioned medium from a human embryonic lung fibroblast line. Degenerate oligonucleotides, based on the NH2-terminal sequence of the purified protein, were used to isolate corresponding cDNA clones. These encoded a 313-amino acid polypeptide, containing a cysteine-rich domain of approximately 110 residues that was 30-40% identical to the putative ligand-binding domain of Frizzled proteins. A 4.4-kb transcript of the FRP gene is present in many organs, both in the adult and during embryogenesis, and homologs of the gene are detectable in DNA from several vertebrate species. In biosynthetic studies, FRP was secreted but, like Wnts, tended to remain associated with cells. When coexpressed with several Wnt family members in early Xenopus embryos, FRP antagonized Wnt-dependent duplication of the embryonic dorsal axis. These results indicate that FRP may function as an inhibitor of Wnt action during development and in the adult.

Authors
Finch, PW; He, X; Kelley, MJ; Uren, A; Schaudies, RP; Popescu, NC; Rudikoff, S; Aaronson, SA; Varmus, HE; Rubin, JS
MLA Citation
Finch, PW, He, X, Kelley, MJ, Uren, A, Schaudies, RP, Popescu, NC, Rudikoff, S, Aaronson, SA, Varmus, HE, and Rubin, JS. "Purification and molecular cloning of a secreted, Frizzled-related antagonist of Wnt action." Proc Natl Acad Sci U S A 94.13 (June 24, 1997): 6770-6775.
PMID
9192640
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
94
Issue
13
Publish Date
1997
Start Page
6770
End Page
6775

Paclitaxel by 96-hour continuous infusion in combination with cisplatin: a phase I trial in patients with advanced lung cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD) of paclitaxel administered by 96-hour continuous infusion in combination with cisplatin, to determine if the addition of granulocyte colony-stimulating factor (G-CSF) permits significant paclitaxel dose escalation, and to assess the toxicity and preliminary activity of this combination in patients with advanced lung cancer. PATIENTS AND METHODS: Fifty patients with untreated lung cancer were enrolled: 42 had advanced non-small-cell lung cancer (NSCLC) and eight had extensive-stage small-cell lung cancer (SCLC). Patients received paclitaxel doses of 100 to 180 mg/m2/96 hours and cisplatin doses of 60 to 80 mg/m2 as a single 30-minute bolus injection at the end of the paclitaxel infusion. RESULTS: Two of six patients experienced dose-limiting neutropenia at a dose of paclitaxel 140 mg/m2/96 hours and cisplatin 80 mg/m2. With G-CSF support, one of three patients experienced both dose-limiting mucositis and fatal neutropenic sepsis at a dose of paclitaxel 180 mg/m2/96 hours and cisplatin 80 mg/m2. Significant peripheral neuropathy developed in five patients and occurred after six or more cycles of therapy. Thirty-three of 42 patients with NSCLC had measurable disease; the objective response rate was 55%, with two complete responses and 16 partial responses. For all 42 patients with NSCLC, the median time to progression and median survival duration were 5 months and 10 months, respectively. The actuarial 1-year survival rate was 41%. Of eight SCLC patients, four responded to therapy, and the median survival duration for all SCLC patients was 11 months. CONCLUSION: The MTD without G-CSF is paclitaxel 120 mg/m2/96 hours and cisplatin 80 mg/m2, and the MTD with G-CSF is paclitaxel 160 mg/m2/96 hours and cisplatin 80 mg/m2. Infusional paclitaxel with cisplatin is well tolerated and active in patients with advanced NSCLC.

Authors
Georgiadis, MS; Schuler, BS; Brown, JE; Kieffer, LV; Steinberg, SM; Wilson, WH; Takimoto, CH; Kelley, MJ; Johnson, BE
MLA Citation
Georgiadis, MS, Schuler, BS, Brown, JE, Kieffer, LV, Steinberg, SM, Wilson, WH, Takimoto, CH, Kelley, MJ, and Johnson, BE. "Paclitaxel by 96-hour continuous infusion in combination with cisplatin: a phase I trial in patients with advanced lung cancer." J Clin Oncol 15.2 (February 1997): 735-743.
PMID
9053499
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
15
Issue
2
Publish Date
1997
Start Page
735
End Page
743
DOI
10.1200/JCO.1997.15.2.735

Purification and molecular cloning of a secreted, frizzled-related WNT antagonist

Frizzled polypeptides are integral membrane proteins that recently were shown to function as receptors for Wnt signaling molecules. Here, we report the identification of a novel, heparin-binding, 36 kDa Frizzled-related protein (FRP) that was purified from the conditioned medium of a human embryonic lung fibroblast line. Degenerate oligonucleotides, based on the amino-terminal sequence of the purified protein, were used to isolate corresponding cDNA clones. These encoded a 313-amino acid polypeptide, containing a cysteine-rich domain of ∼110 residues that was 30-40% identical to the putative ligand-binding domain of Frizzled proteins. A 4.4 kb transcript of the FRP gene is present in many organs, and homologs of the gene are detectable in DNA from several vertebrate species. In biosynthetic studies, FRP was secreted but, like Wnts, tended to remain associated with cells. When co-expressed with several Wnt family members in earlyXenopus embryos, FRP antagonized Wnt-dependent duplication of the embryonic dorsal axis. These results indicate that FRP may function as an inhibitor of Wnt action during development and in the adult.

Authors
Rubin, J; He, X; Kelley, M; Uren, A; Schaudies, P; Popescu, N; Rudikoff, S; Aaronson, S; Varmus, H; Finch, P
MLA Citation
Rubin, J, He, X, Kelley, M, Uren, A, Schaudies, P, Popescu, N, Rudikoff, S, Aaronson, S, Varmus, H, and Finch, P. "Purification and molecular cloning of a secreted, frizzled-related WNT antagonist." FASEB Journal 11.9 (1997): A1109-.
Source
scival
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
11
Issue
9
Publish Date
1997
Start Page
A1109

Pancreatic panniculitis

Authors
Skarin, A; Brown, R; Buckley, R; Kelley, M
MLA Citation
Skarin, A, Brown, R, Buckley, R, and Kelley, M. "Pancreatic panniculitis." Journal of Clinical Oncology 15.11 (1997): 3418-3419.
PMID
9363875
Source
scival
Published In
Journal of Clinical Oncology
Volume
15
Issue
11
Publish Date
1997
Start Page
3418
End Page
3419

Mutation of p53 gene in hepatocellular carcinoma cell lines with HBX DNA

It has been known that the incidence of p53 mutation is very rare in HBX-positive primary human hepatocellular carcinoma (HCC) tissues. The frequency of p53 mutation, however, in established cell lines with integrated HBV DNA and/or HBX has not been well studied. To know p53 mutational frequency, and to investigate whether the presence of HBX DNA sequence correlates with the absence of p53 mutation in the established HCC cell lines, we studied the p53 mutation and the presence of HBX sequence in 12 recently characterized HCC cell lines. As a result, all 12 (100%) lines showed mutation in the p53 gene. Three (25%) cell lines had transversion of codon 215 while no mutation of codon 249 was found. In contrast with previous reports, although HBX DNA was present in 11 cell lines, p53 mutation had occurred, indicating that the presence of HBX viral DNA does not correlate with a lack of p53 mutation in established HCC cell lines. Our results suggest that the frequency of p53 mutation is extremely high even in HBX DNA positive HCC cell lines.

Authors
Kang, MS; Lee, HJ; Lee, JH; Ku, JL; Lee, KP; Kelley, MJ; Won, YJ; Kim, ST; Park, JG
MLA Citation
Kang, MS, Lee, HJ, Lee, JH, Ku, JL, Lee, KP, Kelley, MJ, Won, YJ, Kim, ST, and Park, JG. "Mutation of p53 gene in hepatocellular carcinoma cell lines with HBX DNA." International Journal of Cancer 67.6 (October 30, 1996): 898-902.
Source
scopus
Published In
International Journal of Cancer
Volume
67
Issue
6
Publish Date
1996
Start Page
898
End Page
902
DOI
10.1002/(SICI)1097-0215(19960917)67:6<898::AID-IJC22>3.0.CO;2-X

Mutation of p53 gene in hepatocellular carcinoma cell lines with HBX DNA.

It has been known that the incidence of p53 mutation is very rare in HBX-positive primary human hepatocellular carcinoma (HCC) tissues. The frequency of p53 mutation, however, in established cell lines with integrated HBV DNA and/or HBX has not been well studied. To know p53 mutational frequency, and to investigate whether the presence of HBX DNA sequence correlates with the absence of p53 mutation in the established HCC cell lines, we studied the p53 mutation and the presence of HBX sequence in 12 recently characterized HCC cell lines. As a result, all 12 (100%) lines showed mutation in the p53 gene. Three (25%) cell lines had transversion of codon 215 while no mutation of codon 249 was found. In contrast with previous reports, although HBX DNA was present in 11 cell lines, p53 mutation had occurred, indicating that the presence of HBX viral DNA does not correlate with a lack of p53 mutation in established HCC cell lines. Our results suggest that the frequency of p53 mutation is extremely high even in HBX DNA positive HCC cell lines.

Authors
Kang, MS; Lee, HJ; Lee, JH; Ku, JL; Lee, KP; Kelley, MJ; Won, YJ; Kim, ST; Park, JG
MLA Citation
Kang, MS, Lee, HJ, Lee, JH, Ku, JL, Lee, KP, Kelley, MJ, Won, YJ, Kim, ST, and Park, JG. "Mutation of p53 gene in hepatocellular carcinoma cell lines with HBX DNA." Int J Cancer 67.6 (September 17, 1996): 898-902.
PMID
8824565
Source
pubmed
Published In
International Journal of Cancer
Volume
67
Issue
6
Publish Date
1996
Start Page
898
End Page
902
DOI
10.1002/(SICI)1097-0215(19960917)67:6<898::AID-IJC22>3.0.CO;2-X

Retreatment of patients surviving cancer-free 2 or more years after initial treatment of small cell lung cancer.

STUDY OBJECTIVE: To assess the outcome after retreatment of patients with small cell lung cancer (SCLC) who redevelop small cell cancer (SCC) 2 or more years after initial therapy. DESIGN: Retrospective analysis. SETTING: Single government institution: the National Cancer Institute. PATIENTS: Twenty patients who redeveloped SCC among 65 patients who survived 2 or more years after starting treatment for their initial cancer. MEASUREMENTS: The response rate of patients after retreatment, the survival duration from the time of redevelopment of SCC, and the toxicities of retreatment. RESULTS: Twenty patients redeveloped SCC: 18 with a relapse and 2 with a second primary cancer. Sixteen received treatment after they redeveloped SCLC while four did not. Eleven patients were retreated with chemotherapy alone, two patients received chemotherapy plus chest radiotherapy, one patient received radiotherapy alone, one patient underwent lobectomy, and one patient was treated with a monoclonal antibody followed by chemotherapy. Nine of 16 patients (56%) treated after they redeveloped SCLC had an objective response (3 complete and 6 partial). The median survival of all 20 patients after they redeveloped SCC was 3.9 months (range, 0 to 46 months). The median survival of the patients who were retreated was 6.5 months (range, 1 to 46 months). CONCLUSIONS: Patients who suffer relapses with SCLC 2 or more years from diagnosis are candidates for retreatment.

Authors
Chute, JP; Kelley, MJ; Venzon, D; Williams, J; Roberts, A; Johnson, BE
MLA Citation
Chute, JP, Kelley, MJ, Venzon, D, Williams, J, Roberts, A, and Johnson, BE. "Retreatment of patients surviving cancer-free 2 or more years after initial treatment of small cell lung cancer." Chest 110.1 (July 1996): 165-171.
PMID
8681622
Source
pubmed
Published In
Chest
Volume
110
Issue
1
Publish Date
1996
Start Page
165
End Page
171

Genetic analysis of second primary lung cancers in patients surviving small cell lung cancer.

We performed genetic analysis on 12 second primary non-small cell lung cancers in patients surviving small cell lung cancer to assess the potential contribution of smoking to the development of these tumors. Mutations of TP53 were found in three (25%) tumors, KRAS2 in three (25%) tumors, and CDKN2 in two (18%) tumors. Four (50%) mutations (one each in TP53 and CDKN2 and two in KRAS2) were G:C to T:A transversions on the coding strand, a mutation accounting for approximately one-third of mutations in smoking-related tumors but uncommonly found in lung cancers not associated with smoking. The genetic changes in these second lung cancers are more representative of smoking-associated malignancies than lung cancers arising in patients occupationally exposed to irradiation and atomic bomb survivors.

Authors
Kelley, MJ; Nakagawa, K; Conrad, NK; LeRiche, J; Murray, N; Lee, JS; Ro, JY; Shaw, EG; Tucker, MA; Johnson, BE
MLA Citation
Kelley, MJ, Nakagawa, K, Conrad, NK, LeRiche, J, Murray, N, Lee, JS, Ro, JY, Shaw, EG, Tucker, MA, and Johnson, BE. "Genetic analysis of second primary lung cancers in patients surviving small cell lung cancer." Clin Cancer Res 2.7 (July 1996): 1103-1105.
PMID
9816274
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
2
Issue
7
Publish Date
1996
Start Page
1103
End Page
1105

Biology and molecular genetics of lung cancer

The most extensively characterized autocrine growth loop in lung cancer involves the epidermal growth factor-like family and its receptors. The presence of one or more of the molecules in the tumor specimen is associated with shortened patient survival, monoclonal antibodies directed against ERB1 and ERB2 receptors inhibit the growth of lung cancer cells in vitro and in vivo, and antibodies directed against EBB1 are in clinical trials. The search for a lung cancer tumor suppressor gene on chromosome 3 is ongoing and candidate genes and chromosomal regions have been identified but the gene has not been discovered. The RB gene and CDKN2 participate in the same cell cycle pathway. One of these two genes is inactivated in nearly all lung cancers, Rb more commonly in SCLC and CDKN2 in NSCLC. These studies have provided insights into the genetic changes in lung cancer and a better understanding of the genetic differences between SCLC and NSCLC.

Authors
Johnson, BE; Kelley, MJ
MLA Citation
Johnson, BE, and Kelley, MJ. "Biology and molecular genetics of lung cancer." Seminars in Respiratory and Critical Care Medicine 17.4 (1996): 299-308.
Source
scival
Published In
Seminars in Respiratory and Critical Care Medicine
Volume
17
Issue
4
Publish Date
1996
Start Page
299
End Page
308

Candidate cancer vaccines: Oncogenic mutations in ras create hla-a2.1 binding peptides

Missense mutations in RAS facilitate neoplastic transformation in a variety of tissues. These mutant proteins are potential antigenic targets of tumor-specific, class I-restricted cytotoxic T lymphocyte responses. Such responses would require that peptides derived from the mutant protein bind to class I HLA molecules. RAS codons 12 and 13 lie within a sequence predicted to contain a binding motif for the most prevalent class I HLA allele, HLA-A2.1. We therefore synthesized RAS peptides (amino acids 4-20) corresponding to each of the common codon 12 missense mutations (V, D, A, C, R, S) or the wildtype (G) and a RAS peptide (amino acids 5-21) with an oncogenic codon 13 mutation, D (wildtype is G). These peptides were tested for their ability to bind to HLA-A2.1 in an MHC stabilization assay using the TAP-transporter deficient cell line, T2. The wildtype peptide along with peptides RAS12D, RAS12A, RAS12R, and RAS12S demonstrated little or no binding to HLA-A2.1. In contrast, both the RAS12C, and the RAS13D peptides stabilized HLA-A2.1 on T2 cells, indicating that they contain a segment that binds H1A-A2.1. Binding of RAS12V could not be assessed due to technical difficulties. These experimental results are consistent with the binding predictions of known motif data for these peptides. Thus, RAS12C and RAS13D peptides emerge as potential vaccine candidates for HLA.A2.1 positive individuals.

Authors
Smith, MC; Pendleton, CD; Kelley, MJ; Carbone, DP; Berzofsky, JA
MLA Citation
Smith, MC, Pendleton, CD, Kelley, MJ, Carbone, DP, and Berzofsky, JA. "Candidate cancer vaccines: Oncogenic mutations in ras create hla-a2.1 binding peptides." Journal of Investigative Medicine 44.3 (1996): 247a-.
Source
scival
Published In
Journal of Investigative Medicine
Volume
44
Issue
3
Publish Date
1996
Start Page
247a

Mechanism of inactivation of CDKN2 and MTS2 in non-small cell lung cancer and association with advanced stage

The CDKN2 tumor suppressor gene encodes an inhibitor of type D cyclin dependent kinases. CDKN2 is homozygously deleted in approximately 25% of non-small cell lung cancer (NSCLC) cell lines and these deletions are associated with advanced stage cancer. Conflicting reports of the frequency of CDKN2 alterations in NSCLC tumors prompted us to examine the relationship of these alterations and those of the related gene, MTS2, with patient stage and site of cancer. One hundred twenty-five NSCLC samples (71 cell lines and 54 tumors) were examined by PCR-SSCP. Twenty of 71 (28%) tumor cell lines had homozygous deletions, and six (8%) had point mutations compared to 4 (7%) with point mutations among 54 tumor samples. All mutations were observed in tumors or cell lines from patients with stage III or IV disease. Two patients with no mutations in their primary tumor had a CDKN2 point mutation detected in a metastatic tumor. Point mutations were G:C to T:A transversion on the coding strand in five of 10 and resulted in nonsense mutations in seven of 10. Undetectable CDKN2 mRNA, in the absence of detectable genetic alteration, was noted in a similar fraction of cell lines derived from patients with stage I or II disease [two of seven (29%)) and stage III or IV disease [15 of 49 (31%)]. Homozygous deletion of MTS2 was found in 17 of 20 cell lines with CDKN2 deletions; no point mutations of MTS2 were identified by SSCP in the 125 samples. Thus, CDKN2 is a frequent target of genetic alterations at 9p21 in NSCLC. Both deletions and point mutations of CDKN2 are closely associated with tumor dissemination.

Authors
Nakagawa, K; Conrad, NK; Williams, JP; Johnson, BE; Kelley, MJ
MLA Citation
Nakagawa, K, Conrad, NK, Williams, JP, Johnson, BE, and Kelley, MJ. "Mechanism of inactivation of CDKN2 and MTS2 in non-small cell lung cancer and association with advanced stage." Oncogene 11.9 (November 2, 1995): 1842-1851.
Source
scopus
Published In
Oncogene: Including Oncogene Reviews
Volume
11
Issue
9
Publish Date
1995
Start Page
1842
End Page
1851

Mechanism of inactivation of CDKN2 and MTS2 in non-small cell lung cancer and association with advanced stage.

The CDKN2 tumor suppressor gene encodes an inhibitor of type D cyclin dependent kinases. CDKN2 is homozygously deleted in approximately 25% of nonsmall cell lung cancer (NSCLC) cell lines and these deletions are associated with advanced stage cancer. Conflicting reports of the frequency of CDKN2 alterations in NSCLC tumors prompted us to examine the relationship of these alterations and those of the related gene, MTS2, with patient stage and site of cancer. One hundred twenty-five NSCLC samples (71 cell lines and 54 tumors) were examined by PCR-SSCP. Twenty of 71 (28%) tumor cell lines had homozygous deletions, and six (8%) had point mutations compared to 4 (7%) with point mutations among 54 tumor samples. All mutations were observed in tumors or cell lines from patients with stage III or IV disease. Two patients with no mutations in their primary tumor had a CDKN2 point mutation detected in a metastatic tumor. Point mutations were G:C to T:A transversion on the coding strand in five of 10 and resulted in nonsense mutations in seven of 10. Undetectable CDKN2 mRNA, in the absence of detectable genetic alteration, was noted in a similar fraction of cell lines derived from patients with stage I or II disease [two of seven (29%)] and stage III or IV disease [15 of 49 (31%)]. Homozygous deletion of MTS2 was found in 17 of 20 cell lines with CDKN2 deletions; no point mutations of MTS2 were identified by SSCP in the 125 samples. Thus, CDKN2 is a frequent target of genetic alterations at 9p21 in NSCLC. Both deletions and point mutations of CDKN2 are closely associated with tumor dissemination.

Authors
Nakagawa, K; Conrad, NK; Williams, JP; Johnson, BE; Kelley, MJ
MLA Citation
Nakagawa, K, Conrad, NK, Williams, JP, Johnson, BE, and Kelley, MJ. "Mechanism of inactivation of CDKN2 and MTS2 in non-small cell lung cancer and association with advanced stage." Oncogene 11.9 (November 2, 1995): 1843-1851.
PMID
7478613
Source
pubmed
Published In
Oncogene: Including Oncogene Reviews
Volume
11
Issue
9
Publish Date
1995
Start Page
1843
End Page
1851

CDKN2 in HPV-positive and HPV-negative cervical-carcinoma cell lines.

Human cervical cancers frequently contain retinoblastoma protein (Rb) that is inactivated by binding with human papilloma virus (HPV) E7 protein or through mutation. The CDKN2 gene encodes p16INK4 which inhibits cdk4-cyclin D phosphorylation of Rb, preventing the G1-S transition. To determine whether abnormalities of CDKN2 occur in cervical-cancer cells, II cervical cell lines, including 8 HPV-positive cell lines, 2 HPV-negative cell lines containing mutant Rb, and one tumorigenic cell line derived from normal cervical cells following transfection with HPV-16 and v-H-ras (CX16-2HR), were analyzed. No cell line had a homozygous deletion of exon 1 or 2 of CDKN2, and only one cell line, CX16-2HR, had an altered DNA sequence, which represents a common polymorphism at codon 148. To exclude the possibility of other subtle inactivating mutations, immunoblot analysis of protein lysates was performed using a polyclonal anti-p16INK4 rabbit anti-serum. Abundant levels of normal-sized p16INK4 were observed in all cell samples. Thus, no alterations of CDKN2 were detected in these cervical cell lines. These results confirm that mutational inactivation of p16INK4 is a rare event in tumor samples with compromised Rb activity.

Authors
Kelley, MJ; Otterson, GA; Kaye, FJ; Popescu, NC; Johnson, BE; Dipaolo, JA
MLA Citation
Kelley, MJ, Otterson, GA, Kaye, FJ, Popescu, NC, Johnson, BE, and Dipaolo, JA. "CDKN2 in HPV-positive and HPV-negative cervical-carcinoma cell lines." Int J Cancer 63.2 (October 9, 1995): 226-230.
PMID
7591209
Source
pubmed
Published In
International Journal of Cancer
Volume
63
Issue
2
Publish Date
1995
Start Page
226
End Page
230

TP53 and RAS mutations in metachronous tumors from patients with cancer of the upper aerodigestive tract.

Patients who initially develop an upper aerodigestive tract cancer have an increased risk of second primary cancers. We examined TP53 and RAS mutations and p53 protein in 21 tumors from 10 patients with upper aerodigestive tract cancer who developed a metachronous tumor, to assess the genetic changes that occur in multiple primary tumors from the same individual. Thirteen of 21 (62%) tumors were found to have mis-sense mutations of either TP53 or RAS. Six tumors had TP53 mutations in codons 5 to 8 and 10 tumors from 7 patients had mutations of codons 12 or 13 of K-RAS. Only one patient had concordance of a mutation in 2 tumors; this mutation occurred in K-RAS and was accompanied by discordance of TP53 mutation. Three patients had tumors discordant for both TP53 and RAS mutations. Smoking-related tumors had TP53 and RAS mutations which were transversions in 11 (9 G:C to T:A and 2 G:C to C:G) and transitions in 3 (2 G:C to A:T and 1 A:T to G:C). Tumors not associated with smoking contained only transitions (both G:C to A:T). p53 protein was detected by immunohistochemistry in 7 of 13 (54%) tumors and was concordant in the multiple tumors of 3 patients. Three of the 7 tumors staining for p53 also had TP53 mutations. Thus, genetic alterations are discordant in multiple primary cancers and the pattern of mutations is similar to that found in patients with a single primary tumor, supporting the concept that these cancers arise independently.

Authors
Yang, HK; Linnoila, RI; Conrad, NK; Krasna, MJ; Aisner, SC; Johnson, BE; Kelley, MJ
MLA Citation
Yang, HK, Linnoila, RI, Conrad, NK, Krasna, MJ, Aisner, SC, Johnson, BE, and Kelley, MJ. "TP53 and RAS mutations in metachronous tumors from patients with cancer of the upper aerodigestive tract." Int J Cancer 64.4 (August 22, 1995): 229-233.
PMID
7657384
Source
pubmed
Published In
International Journal of Cancer
Volume
64
Issue
4
Publish Date
1995
Start Page
229
End Page
233

Biology of small cell lung cancer.

The bombesin-like peptides can function as autocrine growth factors in lung cancer and candidate tumor suppressor genes on chromosomes 3 and 9 play important roles in lung cancer. Bombesin-like peptides can function as mitogens for normal bronchial epithelial cells and lung cancer cell lines. The monoclonal antibody directed against gastrin releasing peptide and bombesin, 2A11, can inhibit the growth of small cell lung cancer in vitro and in vivo and intravenous administration has induced a clinical remission in a patient with relapsed small cell lung cancer. The loss of a portion of one of the two short arms of chromosome 3 (3p) is identified in nearly 100% of tumor cell lines and tumors from patients with small cell lung cancer. Introduction of chromosome 3 into tumor cell lines suppresses their tumorigenicity in athymic nude mice, one of the characteristics of the cancer phenotype. Both copies of the candidate tumor suppressor gene on chromosome 9, CDKN2, are deleted in approximately one-fourth of lung cancer cell lines examined and the protein product of CDKN2, p16 is undetectable in one-third of the lung cancer cell lines studied. The CDKN2 gene is inactivated more commonly in non-small cell lung cancer than small cell lung cancer while the retinoblastoma gene is inactivated more commonly in small cell lung cancer than non-small cell lung cancer. It appears that a single defect in this cell cycle pathway is necessary for unregulated growth in lung cancer and current evidence suggests these defects differ between small cell and non-small cell lung cancer.

Authors
Johnson, BE; Kelley, MJ
MLA Citation
Johnson, BE, and Kelley, MJ. "Biology of small cell lung cancer." Lung Cancer 12 Suppl 3 (June 1995): S5-16. (Review)
PMID
7551956
Source
pubmed
Published In
Lung Cancer
Volume
12 Suppl 3
Publish Date
1995
Start Page
S5
End Page
16

Differential inactivation of CDKN2 and Rb protein in non-small-cell and small-cell lung cancer cell lines.

BACKGROUND: The CDKN2 gene encodes the human cyclin-dependent kinase 4 inhibitor. This inhibitor protein is believed to be a tumor suppressor that plays an essential role in cell cycle regulation. One half of all cancer cell lines and one fourth of lung cancer cell lines examined to date contain homozygous deletions (i.e., both alleles lost) of CDKN2. However, the relative frequency of homozygous CDKN2 deletions in non-small-cell lung cancers (NSCLC) and in small-cell lung cancers (SCLC) has not been determined. Inactivation or loss of another tumor suppressor encoded by the retinoblastoma gene (the Rb protein) is more common in SCLC than in NSCLC. PURPOSE: We measured the frequency of homozygous CDKN2 deletions in 77 NSCLC and in 93 SCLC tumor cell lines. In addition, possible associations were explored between CDKN2 gene loss, the presence or absence of Rb protein, and the clinical status of lung cancer patients. METHODS: DNA was isolated from each tumor cell line and from the primary tumor and normal tissue of one NSCLC patient. Sequences corresponding to exons 1 and 2 of the CDKN2 gene were amplified by use of the polymerase chain reaction, and the resulting amplification products were analyzed by agarose gel electrophoresis and DNA blotting. Genomic DNA blotting was also used to evaluate CDKN2 gene deletions. The frequency of homozygous CDKN2 loss and the presence or absence of functional Rb protein (reported previously) in the cell lines were compared. RESULTS: Homozygous deletion of CDKN2 was detected in 18 (23%) of 77 cell lines established from patients with NSCLC, compared with one (1%) of 93 cell lines established from patients with SCLC (P < .001). No CDKN2 gene loss was observed in the normal tissue of an NSCLC patient whose tumor cell line showed homozygous deletion of the gene; however, the primary tumor from this patient had evidence of CDKN2 loss. Homozygous CDKN2 deletion was detected in 13 (28%) of 46 tumor cell lines from patients with stage III or stage IV NSCLC, compared with zero of 10 tumor cell lines from patients with stage I or stage II NSCLC. Coincident loss of CDKN2 genes and functional Rb protein was rarely observed (in two of 135 cell lines). CONCLUSION: The frequency of homozygous CDKN2 gene deletion in NSCLC cell lines is greater than that observed for any other known, or candidate, tumor suppressor gene. IMPLICATION: Further study of the role of CDKN2 gene alteration in the pathogenesis of NSCLC is needed.

Authors
Kelley, MJ; Nakagawa, K; Steinberg, SM; Mulshine, JL; Kamb, A; Johnson, BE
MLA Citation
Kelley, MJ, Nakagawa, K, Steinberg, SM, Mulshine, JL, Kamb, A, and Johnson, BE. "Differential inactivation of CDKN2 and Rb protein in non-small-cell and small-cell lung cancer cell lines." J Natl Cancer Inst 87.10 (May 17, 1995): 756-761.
PMID
7563154
Source
pubmed
Published In
Journal of the National Cancer Institute
Volume
87
Issue
10
Publish Date
1995
Start Page
756
End Page
761

Anticancer antibodies for lung cancer.

Authors
Kelley, MJ; Mulshine, JL
MLA Citation
Kelley, MJ, and Mulshine, JL. "Anticancer antibodies for lung cancer." J Clin Oncol 12.11 (November 1994): 2519-2520. (Letter)
PMID
7818695
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
12
Issue
11
Publish Date
1994
Start Page
2519
End Page
2520
DOI
10.1200/JCO.1994.12.11.2519

Small cell lung carcinoma cell lines express mRNA for calcitonin and alpha- and beta-calcitonin gene related peptides.

Calcitonin (CT) and calcitonin gene related peptide (CGRP) are derived from preprohormones encoded by three mRNAs (CT, alpha-CGRP and beta-CGRP) from two genes (CALC1 and CALC2) on chromosome 11. Among 16 small cell lung cancer cell lines examined by RNase protection assay, 9 (56%) had detectable CT mRNA, 8 (50%) had alpha-CGRP mRNA, and 13 (81%) had beta-CGRP mRNA. At least one CALC1 transcript (CT or alpha-CGRP) was found in 11 (69%) cell lines with three having only CT mRNA, two having only alpha-CGRP mRNA, and six having both. beta-CGRP mRNA was detected in all of these 11 cell lines expressing a CALC1 transcript. Immunoreactive CT was detected by radioimmunoassay in eight of nine SCLC cell lines expressing CT mRNA, and immunoreactive CGRP was detected in 12 of 13 cell lines expressing a CGRP mRNA. The variety of expression of these three peptides in different cell lines of the same cell type should provide a useful system for further study of the control of expression of these peptides.

Authors
Kelley, MJ; Snider, RH; Becker, KL; Johnson, BE
MLA Citation
Kelley, MJ, Snider, RH, Becker, KL, and Johnson, BE. "Small cell lung carcinoma cell lines express mRNA for calcitonin and alpha- and beta-calcitonin gene related peptides." Cancer Lett 81.1 (June 15, 1994): 19-25.
PMID
8019984
Source
pubmed
Published In
Cancer Letters
Volume
81
Issue
1
Publish Date
1994
Start Page
19
End Page
25

Calcitonin elevation in small cell lung cancer without ectopic production.

To determine the relative contribution of ectopic calcitonin (CT) production versus nonectopic secretion of CT in patients with small cell lung cancer (SCLC), serum and urine immunoreactive CT (iCT) levels of 86 different subjects were measured by radioimmunoassay (RIA) using two polyclonal antisera (Ab3b and Ab4). The subjects included 49 previously untreated patients with SCLC, 17 smokers, and 20 nonsmokers. Serum and urine iCT values were highest in the patients with SCLC, intermediate in the smokers, and lowest in the nonsmokers (p < 0.0003). Sixteen of the 49 patients with SCLC had tumor cell lines available for determination of CT mRNA expression by RNase protection assay (RPA) and iCT production by RIA. CT mRNA was detected in nine of 16 subjects and iCT in eight of 16. The tumor cell lines of seven patients had undetectable CT by both RPA and RIA, and of these, five had elevated urine or serum iCT values compared with those of nonsmokers, and two had levels above all values in the smoker group. Immunohistochemical staining of formalin-fixed, paraffin-embedded tumor samples detected iCT in two of four tumors from patients whose tumor cell lines had CT mRNA by RPA and iCT by RIA, but in none of six whose tumor cell lines had undetectable CT mRNA. Thus, increased iCT values in some patients with SCLC are likely due to sources other than CT production by tumor cells.

Authors
Kelley, MJ; Becker, KL; Rushin, JM; Venzon, D; Phelps, R; Ihde, DC; Bliss, DP; Melby, K; Snider, RH; Johnson, BE
MLA Citation
Kelley, MJ, Becker, KL, Rushin, JM, Venzon, D, Phelps, R, Ihde, DC, Bliss, DP, Melby, K, Snider, RH, and Johnson, BE. "Calcitonin elevation in small cell lung cancer without ectopic production." Am J Respir Crit Care Med 149.1 (January 1994): 183-190.
PMID
8111580
Source
pubmed
Published In
American journal of respiratory and critical care medicine
Volume
149
Issue
1
Publish Date
1994
Start Page
183
End Page
190
DOI
10.1164/ajrccm.149.1.8111580

Genetic mechanisms of solid tumor oncogenesis.

The study of the genetic alterations of tumor suppressor genes and protooncogenes in solid tumors has greatly increased our understanding of cancer biology. These findings have extended epidemiologic associations of carcinogens with certain tumors. Further analysis of patterns of genetic changes may implicate carcinogenic substances in cases where epidemiology has not been able to do so. Identification of germline mutations in p53, APC, and NF1 has provided improved diagnosis and presymptomatic screening in cancer kindreds. The identification of additional alterations in tumor suppressor genes may further improve the ability to predict inherent cancer risk. Screening strategies based on detection of genetic abnormalities of preinvasive cancerous lesions, such as mutant ras in colonic polyps, may improve early diagnosis. Finally, strategies to replace lost tumor suppressor function may provide a future therapeutic modality.

Authors
Kelley, MJ; Johnson, BE
MLA Citation
Kelley, MJ, and Johnson, BE. "Genetic mechanisms of solid tumor oncogenesis." Adv Intern Med 39 (1994): 93-122. (Review)
PMID
8140969
Source
pubmed
Published In
Advances in internal medicine
Volume
39
Publish Date
1994
Start Page
93
End Page
122

Overview of genetic and molecular events in the pathogenesis of lung cancer.

Research on dominant oncogenes and tumor suppressor genes has characterized differences in genetic lesions between small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) and identified associations with clinical parameters. More than one half of all lung cancers contain a mutation of the p53 tumor suppressor gene. There does not appear to be an association between the presence of this mutation and survival. A ras family oncogene was found to be mutated in approximately 20 percent of tumors and tumor cell lines from patients with NSCLC in contrast to none of 45 tumors and tumor cell lines from patients with SCLC. The presence of a K-ras mutation was determined to be an adverse prognostic factor for survival in retrospective studies of patients with NSCLC. Mutations of K-ras are more common in tumors from smokers than nonsmokers and have not been detected in lung cancers resulting from occupational exposure to radon. Mutations in both the p53 gene and K-ras oncogene are most commonly G to T transversions in lung cancer vs G to A transitions in other cancers. Prospective studies of these mutations in resected tumor specimens taken from patients with accurate follow-up may continue to provide important clues about their potential clinical and biologic significance.

Authors
Johnson, BE; Kelley, MJ
MLA Citation
Johnson, BE, and Kelley, MJ. "Overview of genetic and molecular events in the pathogenesis of lung cancer." Chest 103.1 Suppl (January 1993): 1S-3S. (Review)
PMID
8380130
Source
pubmed
Published In
Chest
Volume
103
Issue
1 Suppl
Publish Date
1993
Start Page
1S
End Page
3S

Emergence of the keratinocyte growth factor multigene family during the great ape radiation.

The structural gene for human keratinocyte growth factor (KGF), a member of the fibroblast growth factor family, consists of three coding exons and two introns typical of other fibroblast growth factor loci. A portion of the KGF gene, located on chromosome 15, is amplified to approximately 16 copies in the human genome, and these highly related copies (which consist of exon 2, exon 3, the intron between them, and a 3' noncoding segment of the KGF transcript) are dispersed to multiple human chromosomes. The KGF-like sequences are transcriptionally active, differentially regulated in various tissues, and composed of three distinct classes of coding sequences that are 5% divergent from each other and from the authentic KGF sequence. Multiple copies of KGF-like genes were also discovered in the genomic DNAs of chimpanzee and gorilla but were not found in lesser apes (gibbon), Old World monkeys (African green monkey and macaques), mice, or chickens. The pattern of evolutionary occurrence suggests that a primordial KGF gene was amplified and chromosomally dispersed subsequent to the divergence of orangutan from African apes but before the trichotomous divergence of human, chimpanzee, and gorilla 5-8 million years ago. The appearance of a transcriptionally active and chromosomally dispersed multigene KGF family may have implications in the evolution of the great apes and humans.

Authors
Kelley, MJ; Pech, M; Seuanez, HN; Rubin, JS; O'Brien, SJ; Aaronson, SA
MLA Citation
Kelley, MJ, Pech, M, Seuanez, HN, Rubin, JS, O'Brien, SJ, and Aaronson, SA. "Emergence of the keratinocyte growth factor multigene family during the great ape radiation." Proc Natl Acad Sci U S A 89.19 (October 1, 1992): 9287-9291.
PMID
1409637
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
89
Issue
19
Publish Date
1992
Start Page
9287
End Page
9291

The surface envelope protein gene region of equine infectious anemia virus is not an important determinant of tropism in vitro.

Virulent, wild-type equine infectious anemia virus (EIAV) is restricted in one or more early steps in replication in equine skin fibroblast cells compared with cell culture-adapted virus, which is fully competent for replication in this cell type. We compared the sequences of wild-type EIAV and a full-length infectious proviral clone of the cell culture-adapted EIAV and found that the genomes were relatively well conserved with the exception of the envelope gene region, which showed extensive sequence differences. We therefore constructed several wild-type and cell culture-adapted virus chimeras to examine the role of the envelope gene in replication in different cell types in vitro. Unlike wild-type virus, which is restricted by an early event(s) for replication in equine dermis cells, the wild-type outer envelope gene chimeras are replication competent in this cell type. We conclude that even though there are extensive sequence differences between wild-type and cell culture-adapted viruses in the surface envelope gene region, this domain is not a determinant of the differing in vitro cell tropisms.

Authors
Perry, ST; Flaherty, MT; Kelley, MJ; Clabough, DL; Tronick, SR; Coggins, L; Whetter, L; Lengel, CR; Fuller, F
MLA Citation
Perry, ST, Flaherty, MT, Kelley, MJ, Clabough, DL, Tronick, SR, Coggins, L, Whetter, L, Lengel, CR, and Fuller, F. "The surface envelope protein gene region of equine infectious anemia virus is not an important determinant of tropism in vitro." J Virol 66.7 (July 1992): 4085-4097.
PMID
1318398
Source
pubmed
Published In
Journal of virology
Volume
66
Issue
7
Publish Date
1992
Start Page
4085
End Page
4097

Overview of genetic and molecular events in the pathogenesis of lung cancer

Research on dominant oncogenes and tumor suppressor genes has characterized differences in genetic lesions between small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) and identified associations with clinical parameters. More than one half of all lung cancers contain a mutation of the p53 tumor suppressor gene. There does not appear to be an association between the presence of this mutation and survival. A ras family oncogene was found to be mutated in approximately 20 percent of tumors and tumor cell lines from patients with NSCLC in contrast to none of 45 tumors and tumor cell lines from patients with SCLC. The presence of a K-ras mutation was determined to be an adverse prognostic factor for survival in retrospective studies of patients with NSCLC. Mutations of K-ras are more common in tumors from smokers than nonsmokers and have not been detected in lung cancers resulting from occupational exposure to radon. Mutations in both the p53 gene and K-ras oncogene are most commonly G to T transversions in lung cancer vs G to A transitions in other cancers. Prospective studies of these mutations in resected tumor specimens taken from patients with accurate follow-up may continue to provide important clues about their potential clinical and biologic significance.

Authors
Johnson, BE; Kelley, MJ
MLA Citation
Johnson, BE, and Kelley, MJ. "Overview of genetic and molecular events in the pathogenesis of lung cancer." Chest 103.1 SUPPL. (1992): 1S-3S.
Source
scival
Published In
Chest
Volume
103
Issue
1 SUPPL.
Publish Date
1992
Start Page
1S
End Page
3S
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