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Owzar, Kouros

Overview:

cancer pharmacogenomics
drug induced neuropathy, neutropenia and hypertension
statistical genetics
statistical methods for high-dimensional data
copulas
survival analysis
statistical computing

Positions:

Professor of Biostatistics and Bioinformatics

Biostatistics & Bioinformatics
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2002

Ph.D. — University of North Carolina at Chapel Hill

Grants:

A hands-on, integrative next-generation sequencing course: design, experiment, and analysis

Administered By
Biostatistics & Bioinformatics
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 22, 2016
End Date
June 30, 2019

Health Disparity in African Americans: A Meta-analysis of Six Phase III Trials in Metastatic Castration-Resistant Prosta

Administered By
Biostatistics & Bioinformatics
AwardedBy
Department of Defense
Role
Collaborator
Start Date
September 30, 2015
End Date
September 29, 2018

Nanoplasmonics-based molecular analysis tool for molecular biomarkers of cancer

Administered By
Biomedical Engineering
AwardedBy
National Institutes of Health
Role
Biostatistician
Start Date
September 08, 2015
End Date
July 31, 2018

Integration of CT imaging features with cell-free plasma DNA as biomarkers for early lung cancer detection in patients with indeterminate pulmonary nodules

Administered By
Radiology, Cardiothoracic Imaging
AwardedBy
Society of Thoracic Radiology
Role
Collaborator
Start Date
January 01, 2016
End Date
January 15, 2018

Identification of Genetic Determinates for Disparities in African American Patients with Non-Small Cell Lung Cancer

Administered By
Medicine, Medical Oncology
AwardedBy
V Foundation for Cancer Research
Role
Significant Contributor
Start Date
November 01, 2016
End Date
November 01, 2017

Immune signatures in metastatic colorectal cancer

Administered By
Medicine, Medical Oncology
AwardedBy
Genentech, Inc.
Role
Statistician
Start Date
February 23, 2017
End Date
October 31, 2017

Predictive value of the IL6 pathway to direct anti-angiogenic therapy in advanced ovarian cancer

Administered By
Obstetrics and Gynecology, Gynecologic Oncology
AwardedBy
American Association of Obstetricians and Gynecologists Foundation
Role
Collaborator
Start Date
July 27, 2017
End Date
July 29, 2017

Pharmacogenomics of Microtubule Targeting Agents

Administered By
Biostatistics & Bioinformatics
AwardedBy
University of California - San Francisco
Role
Principal Investigator
Start Date
July 01, 2016
End Date
June 30, 2017

(PQD5) A novel genetic strategy to predict efficacy of anti-CD20 antibodies

Administered By
Biostatistics & Bioinformatics
AwardedBy
Cornell University
Role
Principal Investigator
Start Date
September 11, 2015
End Date
April 30, 2017

Blood-based Angiome Profiling to Direct Bevacizumab Therapy in Ovarian Cancer

Administered By
Obstetrics and Gynecology, Gynecologic Oncology
AwardedBy
National Institutes of Health
Role
Statistician
Start Date
May 01, 2014
End Date
April 30, 2017

Administrative Core

Administered By
Biostatistics & Bioinformatics
AwardedBy
University of North Carolina - Chapel Hill
Role
Principal Investigator
Start Date
May 15, 2015
End Date
March 31, 2017

Computational Resources and Dissemination Core

Administered By
Biostatistics & Bioinformatics
AwardedBy
University of North Carolina - Chapel Hill
Role
Principal Investigator
Start Date
May 15, 2015
End Date
March 31, 2017

Statistical/Computational Methods for Pharmacogenomics and Individualized Therapy

Administered By
Biostatistics & Bioinformatics
AwardedBy
University of North Carolina - Chapel Hill
Role
Principal Investigator
Start Date
May 15, 2015
End Date
March 31, 2017

National Clinical Trials Network - Network Group Statistics and DMCs

Administered By
Duke Cancer Institute
AwardedBy
Mayo Clinic
Role
Statistician
Start Date
April 17, 2014
End Date
February 28, 2017

Pharmacogenomic Analysis of Alliance Breast Cancer Studies

Administered By
Duke Cancer Institute
AwardedBy
Alliance for Clinical Trials in Oncology Foundation
Role
Principal Investigator
Start Date
October 01, 2015
End Date
September 30, 2016

Preoperative Breast Radiotherapy: A Tool to Provide Individualized and Biologically-Based Radiation Therapy

Administered By
Radiation Oncology
AwardedBy
Gateway for Cancer Research
Role
Collaborator
Start Date
July 01, 2015
End Date
June 30, 2016

PAAR Pharmacogenomics of Anticancer Agents Research Group

Administered By
Biostatistics & Bioinformatics
AwardedBy
University of Chicago
Role
Principal Investigator
Start Date
July 01, 2010
End Date
December 31, 2015

(PQD5) A novel genetic strategy to predict efficacy of anti-CD20 antibodies

Administered By
Biostatistics & Bioinformatics
AwardedBy
University of North Carolina - Chapel Hill
Role
Principal Investigator
Start Date
May 13, 2014
End Date
April 30, 2015

Computational Resources and Dissemination Core

Administered By
Biostatistics & Bioinformatics
AwardedBy
University of North Carolina - Chapel Hill
Role
Principal Investigator
Start Date
April 01, 2010
End Date
March 31, 2015

Poly-functional analyses of vaccine-induced T cell responses

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Statistician
Start Date
September 01, 2001
End Date
July 31, 2012

Cancer and Leukemia Group B Statistical Center

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

mTOR Therapy in Prostate Cancer: Signatures of Response and Biology of Resistance

Administered By
Institutes and Centers
AwardedBy
National Institutes of Health
Role
Statistician
Start Date
September 25, 2007
End Date
July 31, 2010
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Publications:

Apoptotic capacity and risk of squamous cell carcinoma of the head and neck.

Tobacco smoke and alcohol drinking are the major risk factors for squamous cell carcinoma of the head and neck (SCCHN). Smoking and drinking cause DNA damage leading to apoptosis, and insufficient apoptotic capacity may favour development of cancer because of the dysfunction of removing damaged cells. In the present study, we investigated the association between camptothecin (CPT)-induced apoptotic capacity and risk of SCCHN in a North American population.In a case-control study of 708 SCCHN patients and 685 matched cancer-free controls, we measured apoptotic capacity in cultured peripheral blood lymphocytes in response to in vitro exposure to CPT by using the flow cytometry-based method.We found that the mean level of apoptotic capacity in the cases (45.9 ± 23.3%) was significantly lower than that in the controls (49.0 ± 23.1%) (P = 0.002). When we used the median level of apoptotic capacity in the controls as the cutoff value for calculating adjusted odds ratios, subjects with a reduced apoptotic capacity had an increased risk (adjusted odds ratio = 1.42, 95% confidence interval = 1.13-1.78, P = 0.002), especially for those who were age ≥57 (1.73, 1.25-2.38, 0.0009), men (1.76, 1.36-2.27, <0.0001) and ever drinkers (1.67, 1.27-2.21, 0.0003), and these variables significantly interacted with apoptotic capacity (Pinteraction = 0.015, 0.005 and 0.009, respectively). A further fitted prediction model suggested that the inclusion of apoptotic capacity significantly improved in the prediction of SCCHN risk.Individuals with a reduced CPT-induced apoptotic capacity may be at an increased risk of developing SCCHN, and apoptotic capacity may be a biomarker for susceptibility to SCCHN.

Authors
Liu, Z; Liu, H; Han, P; Gao, F; Dahlstrom, KR; Li, G; Owzar, K; Zevallos, JP; Sturgis, EM; Wei, Q
MLA Citation
Liu, Z, Liu, H, Han, P, Gao, F, Dahlstrom, KR, Li, G, Owzar, K, Zevallos, JP, Sturgis, EM, and Wei, Q. "Apoptotic capacity and risk of squamous cell carcinoma of the head and neck." European journal of cancer (Oxford, England : 1990) 72 (February 2017): 166-176.
PMID
28033527
Source
epmc
Published In
European Journal of Cancer
Volume
72
Publish Date
2017
Start Page
166
End Page
176
DOI
10.1016/j.ejca.2016.11.018

Targeted Exome Sequencing of the Cancer Genome in Patients with Very High-risk Bladder Cancer.

We completed targeted exome sequencing of the tumors of 50 patients with pTis-pT4b bladder cancer. Mutations were categorized by type, stratified against previously identified cancer loci in the Catalogue of Somatic Mutations in Cancer and The Cancer Genome Atlas databases, and evaluated in pathway analysis and comutation plots. We analyzed mutation associations with receipt of neoadjuvant chemotherapy, nodal involvement, metastatic disease development, and survival. Compared with The Cancer Genome Atlas, we found higher mutation rates in genes encoding products involved in epigenetic regulation and cell cycle regulation. Of the pathways examined, PI3K/mTOR and Cell Cycle/DNA Repair exhibited the greatest frequencies of mutation. RB1 and TP53, as well as NF1 and PIK3CA were frequently comutated. We identified no association between mutations in specific genes and key clinical outcomes of interest when corrected for multiple testing. Discovery phase analysis of the somatic mutations in 50 high-risk bladder cancer patients revealed novel mutations and mutational patterns, which may be useful for developing targeted therapy regimens or new biomarkers for patients at very high risk of disease metastasis and death.In this report we found known, as well as previously unreported, genetic mutations in the tumors of patients with high-risk bladder cancer. These mutations, if validated, may serve as actionable targets for new trials.

Authors
Longo, T; McGinley, KF; Freedman, JA; Etienne, W; Wu, Y; Sibley, A; Owzar, K; Gresham, J; Moy, C; Szabo, S; Greshock, J; Zhou, H; Bai, Y; Inman, BA
MLA Citation
Longo, T, McGinley, KF, Freedman, JA, Etienne, W, Wu, Y, Sibley, A, Owzar, K, Gresham, J, Moy, C, Szabo, S, Greshock, J, Zhou, H, Bai, Y, and Inman, BA. "Targeted Exome Sequencing of the Cancer Genome in Patients with Very High-risk Bladder Cancer." European urology 70.5 (November 2016): 714-717.
PMID
27520487
Source
epmc
Published In
European Urology
Volume
70
Issue
5
Publish Date
2016
Start Page
714
End Page
717
DOI
10.1016/j.eururo.2016.07.049

SparkScore: Leveraging apache spark for distributed genomic inference

© 2016 IEEE.The method of the efficient score statistic is used extensively to conduct inference for high throughput genomic data due to its computational efficiency and abilityto accommodate simple and complex phenotypes. Inference based on these statistics can readily incorporate a priori knowledge from a vast collection of bioinformatics databases to further refine the analyses. The sampling distribution of the efficient score statistic is typically approximated using asymptotics. As this may be inappropriate in the context of small study size, or uncommon or rare variants, resampling methods are often used to approximate the exact sampling distribution. We propose SparkScore, a set of distributed computational algorithms implemented in Apache Spark, to leverage the embarrassingly parallel nature of genomic resampling inference on the basis of the efficient score statistics. We illustrate the application of this computational approachfor the analysis of data from genome-wide analysis studies(GWAS). This computational approach also harnesses thefault-tolerant features of Spark and can be readily extended to analysis of DNA and RNA sequencing data, including expression quantitative trait loci (eQTL) and phenotype association studies.

Authors
Bahmani, A; Sibley, AB; Parsian, M; Owzar, K; Mueller, F
MLA Citation
Bahmani, A, Sibley, AB, Parsian, M, Owzar, K, and Mueller, F. "SparkScore: Leveraging apache spark for distributed genomic inference." August 2, 2016.
Source
scopus
Published In
Proceedings - IEEE 28th International Parallel and Distributed Processing Symposium Workshops, IPDPSW 2014
Volume
2016-August
Publish Date
2016
Start Page
435
End Page
442
DOI
10.1109/IPDPSW.2016.6

Exploiting expression patterns across multiple tissues to map expression quantitative trait loci.

In order to better understand complex diseases, it is important to understand how genetic variation in the regulatory regions affects gene expression. Genetic variants found in these regulatory regions have been shown to activate transcription in a tissue-specific manner. Therefore, it is important to map the aforementioned expression quantitative trait loci (eQTL) using a statistically disciplined approach that jointly models all the tissues and makes use of all the information available to maximize the power of eQTL mapping. In this context, we are proposing a score test-based approach where we model tissue-specificity as a random effect and investigate an overall shift in the gene expression combined with tissue-specific effects due to genetic variants.Our approach has 1) a distinct computational edge, and 2) comparable performance in terms of statistical power over other currently existing joint modeling approaches such as MetaTissue eQTL and eQTL-BMA. Using simulations, we show that our method increases the power to detect eQTLs when compared to a tissue-by-tissue approach and can exceed the performance, in terms of computational speed, of MetaTissue eQTL and eQTL-BMA. We apply our method to two publicly available expression datasets from normal human brains, one comprised of four brain regions from 150 neuropathologically normal samples and another comprised of ten brain regions from 134 neuropathologically normal samples, and show that by using our method and jointly analyzing multiple brain regions, we identify eQTLs within more genes when compared to three often used existing methods.Since we employ a score test-based approach, there is no need for parameter estimation under the alternative hypothesis. As a result, model parameters only have to be estimated once per genome, significantly decreasing computation time. Our method also accommodates the analysis of next- generation sequencing data. As an example, by modeling gene transcripts in an analogous fashion to tissues in our current formulation one would be able to test for both a variant overall effect across all isoforms of a gene as well as transcript-specific effects. We implement our approach within the R package JAGUAR, which is now available at the Comprehensive R Archive Network repository.

Authors
Acharya, CR; McCarthy, JM; Owzar, K; Allen, AS
MLA Citation
Acharya, CR, McCarthy, JM, Owzar, K, and Allen, AS. "Exploiting expression patterns across multiple tissues to map expression quantitative trait loci." BMC bioinformatics 17 (June 24, 2016): 257-.
PMID
27341818
Source
epmc
Published In
BMC Bioinformatics
Volume
17
Publish Date
2016
Start Page
257
DOI
10.1186/s12859-016-1123-5

Fitting Cox Models with Doubly Censored Data Using Spline-Based Sieve Marginal Likelihood

Authors
Li, Z; Owzar, K
MLA Citation
Li, Z, and Owzar, K. "Fitting Cox Models with Doubly Censored Data Using Spline-Based Sieve Marginal Likelihood." Scandinavian Journal of Statistics 43.2 (2016): 476-486.
PMID
27239090
Source
manual
Published In
Scandinavian Journal of Statistics
Volume
43
Issue
2
Publish Date
2016
Start Page
476
End Page
486
DOI
10.1111/sjos.12186

Phase II Study of Allogeneic Transplantation for Older Patients With Acute Myeloid Leukemia in First Complete Remission Using a Reduced-Intensity Conditioning Regimen: Results From Cancer and Leukemia Group B 100103 (Alliance for Clinical Trials in Oncology)/Blood and Marrow Transplant Clinical Trial Network 0502.

Long-term survival rates for older patients with newly diagnosed acute myeloid leukemia (AML) are extremely low. Previous observational studies suggest that allogeneic hematopoietic stem-cell transplantation (HSCT) may improve overall survival (OS) because of lower rates of relapse. We sought to prospectively determine the value of HSCT for older patients with AML in first complete remission.We conducted a prospective multicenter phase II study to assess the efficacy of reduced-intensity conditioning HSCT for patients between the ages of 60 and 74 years with AML in first complete remission. The primary end point was disease-free survival at 2 years after HSCT. Secondary end points included nonrelapse mortality (NRM), graft-versus-host disease (GVHD), relapse, and OS.In all, 114 patients with a median age of 65 years received transplantations. The majority (52%) received transplantations from unrelated donors and were given antithymocyte globulin for GVHD prophylaxis. Disease-free survival and OS at 2 years after transplantation were 42% (95% CI, 33% to 52%) and 48% (95% CI, 39% to 58%), respectively, for the entire group and 40% (95% CI, 29% to 55%) and 50% (95% CI, 38% to 64%) for the unrelated donor group. NRM at 2 years was 15% (95% CI, 8% to 21%). Grade 2 to 4 acute GVHD occurred in 9.6% (95% CI, 4% to 15%) of patients, and chronic GVHD occurred in 28% (95% CI, 19% to 36%) of patients. The cumulative incidence of relapse at 2 years was 44% (95% CI, 35% to 53%).Reduced-intensity conditioning HSCT to maintain remission in selected older patients with AML is relatively well tolerated and appears to provide superior outcomes when compared with historical patients treated without HSCT. GVHD and NRM rates were lower than expected. Future transplantation studies in these patients should focus on further reducing the risk of relapse.

Authors
Devine, SM; Owzar, K; Blum, W; Mulkey, F; Stone, RM; Hsu, JW; Champlin, RE; Chen, Y-B; Vij, R; Slack, J; Soiffer, RJ; Larson, RA; Shea, TC; Hars, V; Sibley, AB; Giralt, S; Carter, S; Horowitz, MM; Linker, C; Alyea, EP
MLA Citation
Devine, SM, Owzar, K, Blum, W, Mulkey, F, Stone, RM, Hsu, JW, Champlin, RE, Chen, Y-B, Vij, R, Slack, J, Soiffer, RJ, Larson, RA, Shea, TC, Hars, V, Sibley, AB, Giralt, S, Carter, S, Horowitz, MM, Linker, C, and Alyea, EP. "Phase II Study of Allogeneic Transplantation for Older Patients With Acute Myeloid Leukemia in First Complete Remission Using a Reduced-Intensity Conditioning Regimen: Results From Cancer and Leukemia Group B 100103 (Alliance for Clinical Trials in Oncology)/Blood and Marrow Transplant Clinical Trial Network 0502." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 33.35 (December 2015): 4167-4175.
PMID
26527780
Source
epmc
Published In
Journal of Clinical Oncology
Volume
33
Issue
35
Publish Date
2015
Start Page
4167
End Page
4175
DOI
10.1200/jco.2015.62.7273

Prognostic significance of differential expression of angiogenic genes in women with high-grade serous ovarian carcinoma.

To identify angiogenic biomarkers associated with tumor angiogenesis and clinical outcome in high-grade serous ovarian cancer (HGSC).51 HGSC samples were analyzed using Affymetrix HG-U133A microarray. Microvessel density (MVD) counts were determined using CD31 and CD105. Associations between mRNA expression levels and overall survival were assessed using rank score statistic. Effect size was estimated as a hazard ratio (HR) under a proportional hazard model. The Storey q-value method was used to account for multiple testing within the false-discovery rate (FDR) framework. Publicly available databases including TCGA and GSE were used for external confirmation.Thirty-one angiogenic-related genes were significantly associated with survival (q≤0.05). Of these 31 genes, 4 were also associated with outcome in the TCGA data: AKT1 (q=0.02; TCGA p=0.01, HR=0.8), CD44 (q=0.003; TCGA p=0.05, HR=0.9), EPHB2 (q=0.01; TCGA p=0.05, HR=1.2), and ERBB2 (q=0.02; TCGA p=0.05, HR=1.2). While 5 were associated with outcome in the GSE database: FLT1 (q=0.03; GSE26712 p=0.01, HR=3.1); PF4 (q=0.02; GSE26712 p=0.01, HR=3.0); NRP1 (q=0.02; GSE26712 p<0.04, HR>1.4); COL4A3 (q=0.04; GSE26712 p=0.03, HR=1.3); and ANGPTL3 (q=0.02; GSE14764 p=0.02, HR=1.5). High AKT1 and CD44 were associated with longer survival. In contrast, high expression of EPHB2, ERBB2, FLT1; PF4, NRP1, COL4A3, and ANGPTL3 were associated with shorter survival. CD105-MVD and CD31-MVD were not significantly associated with angiogenic gene expression.Thirty-one angiogenic-related genes were associated with survival in advanced HGSC and nine of these genes were confirmed in independent publicly available databases.

Authors
Siamakpour-Reihani, S; Owzar, K; Jiang, C; Turner, T; Deng, Y; Bean, SM; Horton, JK; Berchuck, A; Marks, JR; Dewhirst, MW; Alvarez Secord, A
MLA Citation
Siamakpour-Reihani, S, Owzar, K, Jiang, C, Turner, T, Deng, Y, Bean, SM, Horton, JK, Berchuck, A, Marks, JR, Dewhirst, MW, and Alvarez Secord, A. "Prognostic significance of differential expression of angiogenic genes in women with high-grade serous ovarian carcinoma." Gynecologic oncology 139.1 (October 2015): 23-29.
PMID
26260910
Source
epmc
Published In
Gynecologic Oncology
Volume
139
Issue
1
Publish Date
2015
Start Page
23
End Page
29
DOI
10.1016/j.ygyno.2015.08.001

Participation in Cancer Pharmacogenomic Studies: A Study of 8456 Patients Registered to Clinical Trials in the Cancer and Leukemia Group B (Alliance).

Clinically annotated specimens from cancer clinical trial participants offer an opportunity for discovery and validation of pharmacogenomic findings. The purpose of this observational study is to better understand patient/institution factors that may contribute to participation in the pharmacogenomic component of prospective cancer clinical trials.Patient demographic information (age, sex, self-reported race) and institutional characteristics (CALGB/CTSU site, "diversity," and accrual) were evaluated for 8456 patients enrolled in seven CALGB phase III studies with a pharmacogenomic component. All statistical tests were two-sided.The majority of patients (81%) consented to participate in the pharmacogenomic component. However, in a multivariable analysis, site (CALGB vs CTSU) and "institutional diversity" (percent minority cancer patients on national trials) were statistically significantly associated with participation. For both whites and nonwhites, patients from CALGB sites were more likely to participate compared with patients from CTSU sites (whites: odds ratio [OR] = 2.26, 95% confidence interval [CI] = 1.68 to 3.04, P < .001; nonwhites: OR = 1.79, 95% CI = 1.52 to 2.11, P < .001). However, as "institutional diversity" increased, the likelihood of participation in the pharmacogenomics component decreased for both white (OR = 0.94, 95% CI = 0.91 to 0.97, P < .001) and nonwhite patients (OR = 0.90, 95% CI = 0.81 to 1.00, P = .05).Most clinical trial cancer patients across geographical, racial, and practice settings are willing to participate in pharmacogenomic studies. However, to promote equitable benefit to the larger cancer community, optimization of both patient and institutional participation are needed. Institutional factors may be even more compelling than patient demographics. Prospective studies are needed to identify and address barriers/incentives to participation in pharmacogenomic research at the patient, clinician, and institutional levels.

Authors
Dressler, LG; Deal, AM; Owzar, K; Watson, D; Donahue, K; Friedman, PN; Ratain, MJ; McLeod, HL
MLA Citation
Dressler, LG, Deal, AM, Owzar, K, Watson, D, Donahue, K, Friedman, PN, Ratain, MJ, and McLeod, HL. "Participation in Cancer Pharmacogenomic Studies: A Study of 8456 Patients Registered to Clinical Trials in the Cancer and Leukemia Group B (Alliance)." Journal of the National Cancer Institute 107.10 (October 2015).
PMID
26160883
Source
epmc
Published In
Journal of the National Cancer Institute
Volume
107
Issue
10
Publish Date
2015
DOI
10.1093/jnci/djv188

Incorporating Functional Information in Tests of Excess De Novo Mutational Load

© 2015 The American Society of Human Genetics.A number of recent studies have investigated the role of de novo mutations in various neurodevelopmental and neuropsychiatric disorders. These studies attempt to implicate causal genes by looking for an excess load of de novo mutations within those genes. Current statistical methods for assessing this excess are based on the implicit assumption that all qualifying mutations in a gene contribute equally to disease. However, it is well established that different mutations can have radically different effects on the ultimate protein product and, as a result, on disease risk. Here, we propose a method, fitDNM, that incorporates functional information in a test of excess de novo mutational load. Specifically, we derive score statistics from a retrospective likelihood that incorporates the probability of a mutation being damaging to gene function. We show that, under the null, the resulting test statistic is distributed as a weighted sum of Poisson random variables and we implement a saddlepoint approximation of this distribution to obtain accurate p values. Using simulation, we have shown that our method outperforms current methods in terms of statistical power while maintaining validity. We have applied this approach to four de novo mutation datasets of neurodevelopmental and neuropsychiatric disorders: autism spectrum disorder, epileptic encephalopathy, schizophrenia, and severe intellectual disability. Our approach also implicates genes that have been implicated by existing methods. Furthermore, our approach provides strong statistical evidence supporting two potentially causal genes: SUV420H1 in autism spectrum disorder and TRIO in a combined analysis of the four neurodevelopmental and neuropsychiatric disorders investigated here.

Authors
Jiang, Y; Han, Y; Petrovski, S; Owzar, K; Goldstein, DB; Allen, AS
MLA Citation
Jiang, Y, Han, Y, Petrovski, S, Owzar, K, Goldstein, DB, and Allen, AS. "Incorporating Functional Information in Tests of Excess De Novo Mutational Load." American Journal of Human Genetics 97.2 (August 6, 2015): 272-283.
Source
scopus
Published In
The American Journal of Human Genetics
Volume
97
Issue
2
Publish Date
2015
Start Page
272
End Page
283
DOI
10.1016/j.ajhg.2015.06.013

Incorporating Functional Information in Tests of Excess De Novo Mutational Load.

A number of recent studies have investigated the role of de novo mutations in various neurodevelopmental and neuropsychiatric disorders. These studies attempt to implicate causal genes by looking for an excess load of de novo mutations within those genes. Current statistical methods for assessing this excess are based on the implicit assumption that all qualifying mutations in a gene contribute equally to disease. However, it is well established that different mutations can have radically different effects on the ultimate protein product and, as a result, on disease risk. Here, we propose a method, fitDNM, that incorporates functional information in a test of excess de novo mutational load. Specifically, we derive score statistics from a retrospective likelihood that incorporates the probability of a mutation being damaging to gene function. We show that, under the null, the resulting test statistic is distributed as a weighted sum of Poisson random variables and we implement a saddlepoint approximation of this distribution to obtain accurate p values. Using simulation, we have shown that our method outperforms current methods in terms of statistical power while maintaining validity. We have applied this approach to four de novo mutation datasets of neurodevelopmental and neuropsychiatric disorders: autism spectrum disorder, epileptic encephalopathy, schizophrenia, and severe intellectual disability. Our approach also implicates genes that have been implicated by existing methods. Furthermore, our approach provides strong statistical evidence supporting two potentially causal genes: SUV420H1 in autism spectrum disorder and TRIO in a combined analysis of the four neurodevelopmental and neuropsychiatric disorders investigated here.

Authors
Jiang, Y; Han, Y; Petrovski, S; Owzar, K; Goldstein, DB; Allen, AS
MLA Citation
Jiang, Y, Han, Y, Petrovski, S, Owzar, K, Goldstein, DB, and Allen, AS. "Incorporating Functional Information in Tests of Excess De Novo Mutational Load." American journal of human genetics 97.2 (August 2015): 272-283.
PMID
26235986
Source
epmc
Published In
The American Journal of Human Genetics
Volume
97
Issue
2
Publish Date
2015
Start Page
272
End Page
283
DOI
10.1016/j.ajhg.2015.06.013

Functional FLT1 Genetic Variation is a Prognostic Factor for Recurrence in Stage I-III Non-Small-Cell Lung Cancer.

We propose that single-nucleotide polymorphisms (SNPs) in genes of the vascular endothelial growth factor pathway of angiogenesis will associate with survival in non-small-cell lung cancer (NSCLC) patients.Fifty-three SNPs in vascular endothelial growth factor-pathway genes were genotyped in 150 European stage I-III NSCLC patients and tested for associations with patient survival. Replication was performed in an independent cohort of 142 European stage I-III patients. Reporter gene assays were used to assess the effects of SNPs on transcriptional activity.In the initial cohort, five SNPs associated (q < 0.05) with relapse-free survival (RFS). The minor alleles of intronic FLT1 SNPs, rs7996030 and rs9582036, associated with reduced RFS (hazard ratio [HR] = 1.67 [95% confidence interval, CI, 1.22-2.29] and HR = 1.51 [95% CI, 1.14-2.01], respectively) and reduced transcriptional activity. The minor alleles of intronic KRAS SNPs, rs12813551 and rs10505980, associated with increased RFS (HR = 0.64 [0.46-0.87] and HR = 0.64 [0.47-0.87], respectively), and the minor allelic variant of rs12813551 also reduced transcriptional activity. Lastly, the minor allele of the intronic KRAS SNP rs10842513 associated with reduced RFS (HR = 1.65 [95% CI, 1.16-2.37]). Analysis of the functional variants suggests they are located in transcriptional enhancer elements. The negative effect of rs9582036 on RFS was confirmed in the replication cohort (HR = 1.69 [0.99-2.89], p = 0.028), and the association was significant in pooled analysis of both cohorts (HR = 1.67 [1.21-2.30], p = 0.0001).The functional FLT1 variant rs9582036 is a prognostic determinant of recurrence in stage I-III NSCLC. Its predictive value should be tested in the adjuvant setting of stage I-III NSCLC.

Authors
Glubb, DM; Paré-Brunet, L; Jantus-Lewintre, E; Jiang, C; Crona, D; Etheridge, AS; Mirza, O; Zhang, W; Seiser, EL; Rzyman, W; Jassem, J; Auman, T; Hirsch, FR; Owzar, K; Camps, C; Dziadziuszko, R; Innocenti, F
MLA Citation
Glubb, DM, Paré-Brunet, L, Jantus-Lewintre, E, Jiang, C, Crona, D, Etheridge, AS, Mirza, O, Zhang, W, Seiser, EL, Rzyman, W, Jassem, J, Auman, T, Hirsch, FR, Owzar, K, Camps, C, Dziadziuszko, R, and Innocenti, F. "Functional FLT1 Genetic Variation is a Prognostic Factor for Recurrence in Stage I-III Non-Small-Cell Lung Cancer." Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 10.7 (July 2015): 1067-1075.
PMID
26134224
Source
epmc
Published In
Journal of Thoracic Oncology
Volume
10
Issue
7
Publish Date
2015
Start Page
1067
End Page
1075
DOI
10.1097/jto.0000000000000549

Molecular and cellular profiling of acute responses to total body radiation exposure in ovariectomized female cynomolgus macaques.

The threat of radiation exposure requires a mechanistic understanding of radiation-induced immune injury and recovery. The study objective was to evaluate responses to ionizing radiation in ovariectomized (surgically post-menopausal) female cynomolgus macaques.Animals received a single total-body irradiation (TBI) exposure at doses of 0, 2 or 5 Gy with scheduled necropsies at 5 days, 8 weeks and 24 weeks post-exposure. Blood and lymphoid tissues were evaluated for morphologic, cellular, and molecular responses.Irradiated animals developed symptoms of acute hematopoietic syndrome, and reductions in thymus weight, thymopoiesis, and bone marrow cellularity. Acute, transient increases in plasma monocyte chemoattractant protein 1 (MCP-1) were observed in 5 Gy animals along with dose-dependent alterations in messenger ribonucleic acid (mRNA) signatures in thymus, spleen, and lymph node. Expression of T cell markers was lower in thymus and spleen, while expression of macrophage marker CD68 (cluster of differentiation 68) was relatively elevated in lymphoid tissues from irradiated animals.Ovariectomized female macaques exposed to moderate doses of radiation experienced increased morbidity, including acute, dose-dependent alterations in systemic and tissue-specific biomarkers, and increased macrophage/T cell ratios. The effects on mortality exceeded expectations based on previous studies in males, warranting further investigation.

Authors
DeBo, RJ; Register, TC; Caudell, DL; Sempowski, GD; Dugan, G; Gray, S; Owzar, K; Jiang, C; Bourland, JD; Chao, NJ; Cline, JM
MLA Citation
DeBo, RJ, Register, TC, Caudell, DL, Sempowski, GD, Dugan, G, Gray, S, Owzar, K, Jiang, C, Bourland, JD, Chao, NJ, and Cline, JM. "Molecular and cellular profiling of acute responses to total body radiation exposure in ovariectomized female cynomolgus macaques." International journal of radiation biology 91.6 (June 2015): 510-518.
PMID
25786585
Source
epmc
Published In
International Journal of Radiation Biology (Informa)
Volume
91
Issue
6
Publish Date
2015
Start Page
510
End Page
518
DOI
10.3109/09553002.2015.1028597

Genomic profiling in locally advanced and inflammatory breast cancer and its link to DCE-MRI and overall survival.

We have previously reported that dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) perfusion patterns obtained from locally advanced breast cancer (LABC) patients prior to neoadjuvant therapy predicted pathologic clinical response. Genomic analyses were also independently conducted on the same patient population. This retrospective study was performed to test two hypotheses: (1) gene expression profiles are associated with DCE-MRI perfusion patterns, and (2) association between long-term overall survival data and gene expression profiles can lead to the identification of novel predictive biomarkers.We utilised RNA microarray and DCE-MRI data from 47 LABC patients, including 13 inflammatory breast cancer (IBC) patients. Association between gene expression profile and DCE-MRI perfusion patterns (centrifugal and centripetal) was determined by Wilcoxon rank sum test. Association between gene expression level and survival was assessed using a Cox rank score test. Additional genomic analysis of the IBC subset was conducted, with a period of follow-up of up to 11 years. Associations between gene expression and overall survival were further assessed in The Cancer Genome Atlas Data Portal.Differences in gene expression profiles were seen between centrifugal and centripetal perfusion patterns in the sulphotransferase family, cytosolic, 1 A, phenol-preferring, members 1 and 2 (SULT1A1, SULT1A2), poly (ADP-ribose) polymerase, member 6 (PARP6), and metastasis tumour antigen1 (MTA1). In the IBC subset our analyses demonstrated that differential expression of 45 genes was associated with long-term survival.Here we have demonstrated an association between DCE-MRI perfusion patterns and gene expression profiles. In addition we have reported on candidate prognostic biomarkers in IBC patients, with some of the genes being significantly associated with survival in IBC and LABC.

Authors
Siamakpour-Reihani, S; Owzar, K; Jiang, C; Scarbrough, PM; Craciunescu, OI; Horton, JK; Dressman, HK; Blackwell, KL; Dewhirst, MW
MLA Citation
Siamakpour-Reihani, S, Owzar, K, Jiang, C, Scarbrough, PM, Craciunescu, OI, Horton, JK, Dressman, HK, Blackwell, KL, and Dewhirst, MW. "Genomic profiling in locally advanced and inflammatory breast cancer and its link to DCE-MRI and overall survival." International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group 31.4 (June 2015): 386-395.
PMID
25811737
Source
epmc
Published In
International Journal of Hyperthermia (Informa)
Volume
31
Issue
4
Publish Date
2015
Start Page
386
End Page
395
DOI
10.3109/02656736.2015.1016557

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

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

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

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

Prognostic significance of differential expression of angiogenic genes in women with high-grade serous ovarian carcinoma

© 2015 Elsevier Inc. All rights reserved.Objectives To identify angiogenic biomarkers associated with tumor angiogenesis and clinical outcome in high-grade serous ovarian cancer (HGSC). Methods 51 HGSC samples were analyzed using Affymetrix HG-U133A microarray. Microvessel density (MVD) counts were determined using CD31 and CD105. Associations between mRNA expression levels and overall survival were assessed using rank score statistic. Effect size was estimated as a hazard ratio (HR) under a proportional hazard model. The Storey q-value method was used to account for multiple testing within the false-discovery rate (FDR) framework. Publicly available databases including TCGA and GSE were used for external confirmation. Results Thirty-one angiogenic-related genes were significantly associated with survival (q 0.05). Of these 31 genes, 4 were also associated with outcome in the TCGA data: AKT1 (q = 0.02; TCGA p = 0.01, HR = 0.8), CD44 (q = 0.003; TCGA p = 0.05, HR = 0.9), EPHB2 (q = 0.01; TCGA p = 0.05, HR = 1.2), and ERBB2 (q = 0.02; TCGA p = 0.05, HR = 1.2). While 5 were associated with outcome in the GSE database: FLT1 (q = 0.03; GSE26712 p = 0.01, HR = 3.1); PF4 (q = 0.02; GSE26712 p = 0.01, HR = 3.0); NRP1 (q = 0.02; GSE26712 p 0.04, HR 1.4); COL4A3 (q = 0.04; GSE26712 p = 0.03, HR = 1.3); and ANGPTL3 (q = 0.02; GSE14764 p = 0.02, HR = 1.5). High AKT1 and CD44 were associated with longer survival. In contrast, high expression of EPHB2, ERBB2, FLT1; PF4, NRP1, COL4A3, and ANGPTL3 were associated with shorter survival. CD105-MVD and CD31-MVD were not significantly associated with angiogenic gene expression. Conclusions Thirty-one angiogenic-related genes were associated with survival in advanced HGSC and nine of these genes were confirmed in independent publicly available databases.

Authors
Siamakpour-Reihani, S; Owzar, K; Jiang, C; Turner, T; Deng, Y; Bean, SM; Horton, JK; Berchuck, A; Marks, JR; Dewhirst, MW; Secord, AA
MLA Citation
Siamakpour-Reihani, S, Owzar, K, Jiang, C, Turner, T, Deng, Y, Bean, SM, Horton, JK, Berchuck, A, Marks, JR, Dewhirst, MW, and Secord, AA. "Prognostic significance of differential expression of angiogenic genes in women with high-grade serous ovarian carcinoma." Gynecologic Oncology 139.1 (2015): 23-29.
Source
scival
Published In
Gynecologic Oncology
Volume
139
Issue
1
Publish Date
2015
Start Page
23
End Page
29
DOI
10.1016/j.ygyno.2015.08.001

Effect of age on the pharmacokinetics of busulfan in patients undergoing hematopoietic cell transplantation; an alliance study (CALGB 10503, 19808, and 100103).

Older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome have often been excluded from myeloablative-conditioning regimens containing busulfan because of non-disease-related morbidity and mortality. We hypothesized that busulfan clearance (BuCL) in older patients (>60 years) would be reduced compared to that in younger patients, potentially explaining observed differences in busulfan tolerability.AML patients in three CALGB hematopoietic cell transplantation studies were treated with a conditioning regimen using IV busulfan, dosed at 0.8 mg/kg. Plasma busulfan concentrations were determined by LC-MS and analyzed by non-compartmental methods. BuCL was normalized to actual (ABW), ideal (IBW), or corrected (CBW) body weight (kg). Differences in BuCL between age groups were examined using the Wilcoxon rank sum test.One hundred and eighty-five patients were accrued; 174 provided useable pharmacokinetic data. Twenty-nine patients ≥ 60 years old (median 66; range 60-74) had a significantly higher BuCL versus those <60 years old (median 50; range 18-60): BuCL 236 versus 168 mL/min, p = 0.0002; BuCL/ABW 3.0 versus 2.1 mL/min/kg, p = 0.0001; BuCL/IBW 3.8 versus 2.6 mL/min/kg, p = 0.0035; BuCL/CBW 3.4 versus 2.6 mL/min/kg, p = 0.0005. Inter-patient variability in clearance (CV %) was up to 48 % in both age groups. Phenytoin administration, a potential confounder, did not affect BuCL, regardless of weight normalization (p > 0.34).Contrary to our hypothesis, BuCL was significantly higher in older patients compared to younger patients in these studies and does not explain the previously reported increase in busulfan toxicity observed in older patients.

Authors
Beumer, JH; Owzar, K; Lewis, LD; Jiang, C; Holleran, JL; Christner, SM; Blum, W; Devine, S; Kolitz, JE; Linker, C; Vij, R; Alyea, EP; Larson, RA; Ratain, MJ; Egorin, MJ
MLA Citation
Beumer, JH, Owzar, K, Lewis, LD, Jiang, C, Holleran, JL, Christner, SM, Blum, W, Devine, S, Kolitz, JE, Linker, C, Vij, R, Alyea, EP, Larson, RA, Ratain, MJ, and Egorin, MJ. "Effect of age on the pharmacokinetics of busulfan in patients undergoing hematopoietic cell transplantation; an alliance study (CALGB 10503, 19808, and 100103)." Cancer chemotherapy and pharmacology 74.5 (November 2014): 927-938.
PMID
25163570
Source
epmc
Published In
Cancer Chemotherapy and Pharmacology
Volume
74
Issue
5
Publish Date
2014
Start Page
927
End Page
938
DOI
10.1007/s00280-014-2571-0

Vatalanib population pharmacokinetics in patients with myelodysplastic syndrome: CALGB 10105 (Alliance)

Authors
Wang, X; Owzar, K; Gupta, P; Larson, RA; Mulkey, F; Miller, AA; Lewis, LD; Hurd, D; Vij, R; Ratain, MJ; Murry, DJ; Oncology, ACT
MLA Citation
Wang, X, Owzar, K, Gupta, P, Larson, RA, Mulkey, F, Miller, AA, Lewis, LD, Hurd, D, Vij, R, Ratain, MJ, Murry, DJ, and Oncology, ACT. "Vatalanib population pharmacokinetics in patients with myelodysplastic syndrome: CALGB 10105 (Alliance)." BRITISH JOURNAL OF CLINICAL PHARMACOLOGY 78.5 (November 2014): 1005-1013.
Source
wos-lite
Published In
British Journal of Clinical Pharmacology
Volume
78
Issue
5
Publish Date
2014
Start Page
1005
End Page
1013
DOI
10.1111/bcp.12427

Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer.

We performed a multistage genome-wide association study including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT, per-allele odds ratio (OR) = 0.79, 95% confidence interval (CI) 0.74-0.84, P = 3.0 × 10(-12)), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2, OR = 1.46, 95% CI 1.30-1.65, P = 1.1 × 10(-10)), rs9581943 at 13q12.2 (PDX1, OR = 1.15, 95% CI 1.10-1.20, P = 2.4 × 10(-9)) and rs16986825 at 22q12.1 (ZNRF3, OR = 1.18, 95% CI 1.12-1.25, P = 1.2 × 10(-8)). We identified an independent signal in exon 2 of TERT at the established region 5p15.33 (rs2736098, OR = 0.80, 95% CI 0.76-0.85, P = 9.8 × 10(-14)). We also identified a locus at 8q24.21 (rs1561927, P = 1.3 × 10(-7)) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study identified multiple new susceptibility alleles for pancreatic cancer that are worthy of follow-up studies.

Authors
Wolpin, BM; Rizzato, C; Kraft, P; Kooperberg, C; Petersen, GM; Wang, Z; Arslan, AA; Beane-Freeman, L; Bracci, PM; Buring, J; Canzian, F; Duell, EJ; Gallinger, S; Giles, GG; Goodman, GE; Goodman, PJ; Jacobs, EJ; Kamineni, A; Klein, AP; Kolonel, LN; Kulke, MH; Li, D; Malats, N; Olson, SH; Risch, HA; Sesso, HD; Visvanathan, K; White, E; Zheng, W; Abnet, CC; Albanes, D; Andreotti, G; Austin, MA; Barfield, R; Basso, D; Berndt, SI; Boutron-Ruault, MC; Brotzman, M; Büchler, MW; Bueno-de-Mesquita, HB et al.
MLA Citation
Wolpin, BM, Rizzato, C, Kraft, P, Kooperberg, C, Petersen, GM, Wang, Z, Arslan, AA, Beane-Freeman, L, Bracci, PM, Buring, J, Canzian, F, Duell, EJ, Gallinger, S, Giles, GG, Goodman, GE, Goodman, PJ, Jacobs, EJ, Kamineni, A, Klein, AP, Kolonel, LN, Kulke, MH, Li, D, Malats, N, Olson, SH, Risch, HA, Sesso, HD, Visvanathan, K, White, E, Zheng, W, Abnet, CC, Albanes, D, Andreotti, G, Austin, MA, Barfield, R, Basso, D, Berndt, SI, Boutron-Ruault, MC, Brotzman, M, Büchler, MW, and Bueno-de-Mesquita, HB et al. "Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer." Nature genetics 46.9 (September 2014): 994-1000.
PMID
25086665
Source
epmc
Published In
Nature Genetics
Volume
46
Issue
9
Publish Date
2014
Start Page
994
End Page
1000
DOI
10.1038/ng.3052

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

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

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

Polygenic inheritance of paclitaxel-induced sensory peripheral neuropathy driven by axon outgrowth gene sets in CALGB 40101 (Alliance).

Peripheral neuropathy is a common dose-limiting toxicity for patients treated with paclitaxel. For most individuals, there are no known risk factors that predispose patients to the adverse event, and pathogenesis for paclitaxel-induced peripheral neuropathy is unknown. Determining whether there is a heritable component to paclitaxel-induced peripheral neuropathy would be valuable in guiding clinical decisions and may provide insight into treatment of and mechanisms for the toxicity. Using genotype and patient information from the paclitaxel arm of CALGB 40101 (Alliance), a phase III clinical trial evaluating adjuvant therapies for breast cancer in women, we estimated the variance in maximum grade and dose at first instance of sensory peripheral neuropathy. Our results suggest that paclitaxel-induced neuropathy has a heritable component, driven in part by genes involved in axon outgrowth. Disruption of axon outgrowth may be one of the mechanisms by which paclitaxel treatment results in sensory peripheral neuropathy in susceptible patients.

Authors
Chhibber, A; Mefford, J; Stahl, EA; Pendergrass, SA; Baldwin, RM; Owzar, K; Li, M; Winer, EP; Hudis, CA; Zembutsu, H; Kubo, M; Nakamura, Y; McLeod, HL; Ratain, MJ; Shulman, LN; Ritchie, MD; Plenge, RM; Witte, JS; Kroetz, DL
MLA Citation
Chhibber, A, Mefford, J, Stahl, EA, Pendergrass, SA, Baldwin, RM, Owzar, K, Li, M, Winer, EP, Hudis, CA, Zembutsu, H, Kubo, M, Nakamura, Y, McLeod, HL, Ratain, MJ, Shulman, LN, Ritchie, MD, Plenge, RM, Witte, JS, and Kroetz, DL. "Polygenic inheritance of paclitaxel-induced sensory peripheral neuropathy driven by axon outgrowth gene sets in CALGB 40101 (Alliance)." The pharmacogenomics journal 14.4 (August 2014): 336-342.
PMID
24513692
Source
epmc
Published In
The Pharmacogenomics Journal
Volume
14
Issue
4
Publish Date
2014
Start Page
336
End Page
342
DOI
10.1038/tpj.2014.2

Pathologic and molecular features correlate with long-term outcome after adjuvant therapy of resected primary GI stromal tumor: the ACOSOG Z9001 trial.

The ACOSOG (American College of Surgeons Oncology Group) Z9001 (Alliance) study, a randomized, placebo-controlled trial, demonstrated that 1 year of adjuvant imatinib prolonged recurrence-free survival (RFS) after resection of primary GI stromal tumor (GIST). We sought to determine the pathologic and molecular factors associated with patient outcome.There were 328 patients assigned to the placebo arm and 317 to the imatinib arm. Median patient follow-up was 74 months. There were 645 tumor specimens available for mitotic rate or mutation analysis.RFS remained superior in the imatinib arm (hazard ratio, 0.6; 95% CI, 0.43 to 0.75; Cox model-adjusted P < .001). On multivariable analysis of patients in the placebo arm, large tumor size, small bowel location, and high mitotic rate were associated with lower RFS, whereas tumor genotype was not significantly associated with RFS. Multivariable analysis of patients in the imatinib arm yielded similar findings. When comparing the two arms, imatinib therapy was associated with higher RFS in patients with a KIT exon 11 deletion of any type, but not a KIT exon 11 insertion or point mutation, KIT exon 9 mutation, PDGFRA mutation, or wild-type tumor, although some of these patient groups were small. Adjuvant imatinib did not seem to alter overall survival.Our findings show that tumor size, location, and mitotic rate, but not tumor genotype, are associated with the natural history of GIST. Patients with KIT exon 11 deletions assigned to 1 year of adjuvant imatinib had a longer RFS.

Authors
Corless, CL; Ballman, KV; Antonescu, CR; Kolesnikova, V; Maki, RG; Pisters, PW; Blackstein, ME; Blanke, CD; Demetri, GD; Heinrich, MC; von Mehren, M; Patel, S; McCarter, MD; Owzar, K; DeMatteo, RP
MLA Citation
Corless, CL, Ballman, KV, Antonescu, CR, Kolesnikova, V, Maki, RG, Pisters, PW, Blackstein, ME, Blanke, CD, Demetri, GD, Heinrich, MC, von Mehren, M, Patel, S, McCarter, MD, Owzar, K, and DeMatteo, RP. "Pathologic and molecular features correlate with long-term outcome after adjuvant therapy of resected primary GI stromal tumor: the ACOSOG Z9001 trial." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 32.15 (May 2014): 1563-1570.
PMID
24638003
Source
epmc
Published In
Journal of Clinical Oncology
Volume
32
Issue
15
Publish Date
2014
Start Page
1563
End Page
1570
DOI
10.1200/jco.2013.51.2046

Loss of β-catenin triggers oxidative stress and impairs hematopoietic regeneration.

Accidental or deliberate ionizing radiation exposure can be fatal due to widespread hematopoietic destruction. However, little is known about either the course of injury or the molecular pathways that regulate the subsequent regenerative response. Here we show that the Wnt signaling pathway is critically important for regeneration after radiation-induced injury. Using Wnt reporter mice, we show that radiation triggers activation of Wnt signaling in hematopoietic stem and progenitor cells. β-Catenin-deficient mice, which lack the ability to activate canonical Wnt signaling, exhibited impaired hematopoietic stem cell regeneration and bone marrow recovery after radiation. We found that, as part of the mechanism, hematopoietic stem cells lacking β-catenin fail to suppress the generation of reactive oxygen species and cannot resolve DNA double-strand breaks after radiation. Consistent with the impaired response to radiation, β-catenin-deficient mice are also unable to recover effectively after chemotherapy. Collectively, these data indicate that regenerative responses to distinct hematopoietic injuries share a genetic dependence on β-catenin and raise the possibility that modulation of Wnt signaling may be a path to improving bone marrow recovery after damage.

Authors
Lento, W; Ito, T; Zhao, C; Harris, JR; Huang, W; Jiang, C; Owzar, K; Piryani, S; Racioppi, L; Chao, N; Reya, T
MLA Citation
Lento, W, Ito, T, Zhao, C, Harris, JR, Huang, W, Jiang, C, Owzar, K, Piryani, S, Racioppi, L, Chao, N, and Reya, T. "Loss of β-catenin triggers oxidative stress and impairs hematopoietic regeneration." Genes & development 28.9 (May 2014): 995-1004.
PMID
24788518
Source
epmc
Published In
Genes & development
Volume
28
Issue
9
Publish Date
2014
Start Page
995
End Page
1004
DOI
10.1101/gad.231944.113

Robust rat pulmonary radioprotection by a lipophilic Mn N-alkylpyridylporphyrin, MnTnHex-2-PyP5+

With the goal to enhance the distribution of cationic Mn porphyrins within mitochondria, the lipophilic Mn(III)meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin, MnTnHex-2-PyP5+ has been synthesized and tested in several different model of diseases, where it shows remarkable efficacy at as low as 50μg/kg single or multiple doses. Yet, in a rat lung radioprotection study, at higher 0.6-1mg/kg doses, due to its high accumulation and micellar character, it became toxic. To avoid the toxicity, herein the pulmonary radioprotection of MnTnHex-2-PyP5+ was assessed at 50μg/kg. Fischer rats were irradiated to their right hemithorax (28Gy) and treated with 0.05mg/kg/day of MnTnHex-2-PyP5+ for 2 weeks by subcutaneously-implanted osmotic pumps, starting at 2h post-radiation. The body weights and breathing frequencies were followed for 10 weeks post-radiation, when the histopathology and immunohistochemistry were assessed. Impact of MnTnHex-2-PyP5+ on macrophage recruitment (ED-1), DNA oxidative damage (8-OHdG), TGF-β1, VEGF(A) and HIF-1α were measured. MnTnHex-2-PyP5+ significantly decreased radiation-induced lung histopathological (H&E staining) and functional damage (breathing frequencies), suppressed oxidative stress directly (8-OHdG), or indirectly, affecting TGF-β1, VEGF (A) and HIF-1α pathways. The magnitude of the therapeutic effects is similar to the effects demonstrated under same experimental conditions with 120-fold higher dose of ~5000-fold less lipophilic Mn(III)meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin, MnTE-2-PyP5+. © 2014 The Authors.

Authors
Gauter-Fleckenstein, B; Reboucas, JS; Fleckenstein, K; Tovmasyan, A; Owzar, K; Jiang, C; Batinic-Haberle, I; Vujaskovic, Z
MLA Citation
Gauter-Fleckenstein, B, Reboucas, JS, Fleckenstein, K, Tovmasyan, A, Owzar, K, Jiang, C, Batinic-Haberle, I, and Vujaskovic, Z. "Robust rat pulmonary radioprotection by a lipophilic Mn N-alkylpyridylporphyrin, MnTnHex-2-PyP5+." Redox Biology 2.1 (February 27, 2014): 400-410.
Source
scopus
Published In
Redox Biology
Volume
2
Issue
1
Publish Date
2014
Start Page
400
End Page
410
DOI
10.1016/j.redox.2013.12.017

A pharmacogenetic study of aldehyde oxidase I in patients treated with XK469

XK469 (NSC 697887) is a selective topoisomerase II β inhibitor eliminated mainly by aldehyde oxidase I (AOX1). We performed a candidate gene study to investigate whether AOX1 genetic variation contributes to interindividual variability in XK469 clearance. Forty-one AOX1 single nucleotide polymorphisms (SNPs) and seven liver expression quantitative trait loci were genotyped in White patients with advanced refractory solid tumors (n=59) and leukemia (n=33). We found a significant decrease in clearance (τ=-0.32, P=0.003) in solid tumor patients with rs10931910, although it failed to replicate in the leukemia cohort (τ=0.18, P=0.20). Four other AOX1 SNPs were associated with clearance (P=0.01-0.02) in only one of the two cohorts. Our study provides a starting point for future investigations on the functionality of AOX1 SNPs. However, variability in XK469 clearance cannot be attributed to polymorphisms in AOX1. © 2014 Wolters Kluwer Health Lippincott Williams & Wilkins.

Authors
Ramírez, J; Kim, TW; Liu, W; Myers, JL; Mirkov, S; Owzar, K; Watson, D; Mulkey, F; Gamazon, ER; Stock, W; Undevia, S; Innocenti, F; Ratain, MJ
MLA Citation
Ramírez, J, Kim, TW, Liu, W, Myers, JL, Mirkov, S, Owzar, K, Watson, D, Mulkey, F, Gamazon, ER, Stock, W, Undevia, S, Innocenti, F, and Ratain, MJ. "A pharmacogenetic study of aldehyde oxidase I in patients treated with XK469." Pharmacogenetics and Genomics 24.2 (February 1, 2014): 129-132.
Source
scopus
Published In
Pharmacogenetics and Genomics
Volume
24
Issue
2
Publish Date
2014
Start Page
129
End Page
132
DOI
10.1097/FPC.0000000000000023

A pharmacogenetic study of aldehyde oxidase I in patients treated with XK469.

XK469 (NSC 697887) is a selective topoisomerase II β inhibitor eliminated mainly by aldehyde oxidase I (AOX1). We performed a candidate gene study to investigate whether AOX1 genetic variation contributes to interindividual variability in XK469 clearance. Forty-one AOX1 single nucleotide polymorphisms (SNPs) and seven liver expression quantitative trait loci were genotyped in White patients with advanced refractory solid tumors (n=59) and leukemia (n=33). We found a significant decrease in clearance (τ=-0.32, P=0.003) in solid tumor patients with rs10931910, although it failed to replicate in the leukemia cohort (τ=0.18, P=0.20). Four other AOX1 SNPs were associated with clearance (P=0.01-0.02) in only one of the two cohorts. Our study provides a starting point for future investigations on the functionality of AOX1 SNPs. However, variability in XK469 clearance cannot be attributed to polymorphisms in AOX1.

Authors
Ramírez, J; Kim, TW; Liu, W; Myers, JL; Mirkov, S; Owzar, K; Watson, D; Mulkey, F; Gamazon, ER; Stock, W; Undevia, S; Innocenti, F; Ratain, MJ
MLA Citation
Ramírez, J, Kim, TW, Liu, W, Myers, JL, Mirkov, S, Owzar, K, Watson, D, Mulkey, F, Gamazon, ER, Stock, W, Undevia, S, Innocenti, F, and Ratain, MJ. "A pharmacogenetic study of aldehyde oxidase I in patients treated with XK469." Pharmacogenet Genomics 24.2 (February 2014): 129-132.
PMID
24300566
Source
pubmed
Published In
Pharmacogenetics and Genomics
Volume
24
Issue
2
Publish Date
2014
Start Page
129
End Page
132
DOI
10.1097/FPC.0000000000000023

Robust rat pulmonary radioprotection by a lipophilic Mn N-alkylpyridylporphyrin, MnTnHex-2-PyP(5+).

With the goal to enhance the distribution of cationic Mn porphyrins within mitochondria, the lipophilic Mn(III)meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin, MnTnHex-2-PyP(5+) has been synthesized and tested in several different model of diseases, where it shows remarkable efficacy at as low as 50 µg/kg single or multiple doses. Yet, in a rat lung radioprotection study, at higher 0.6-1 mg/kg doses, due to its high accumulation and micellar character, it became toxic. To avoid the toxicity, herein the pulmonary radioprotection of MnTnHex-2-PyP(5+) was assessed at 50 µg/kg. Fischer rats were irradiated to their right hemithorax (28 Gy) and treated with 0.05 mg/kg/day of MnTnHex-2-PyP(5+) for 2 weeks by subcutaneously-implanted osmotic pumps, starting at 2 h post-radiation. The body weights and breathing frequencies were followed for 10 weeks post-radiation, when the histopathology and immunohistochemistry were assessed. Impact of MnTnHex-2-PyP(5+) on macrophage recruitment (ED-1), DNA oxidative damage (8-OHdG), TGF-β1, VEGF(A) and HIF-1α were measured. MnTnHex-2-PyP(5+) significantly decreased radiation-induced lung histopathological (H&E staining) and functional damage (breathing frequencies), suppressed oxidative stress directly (8-OHdG), or indirectly, affecting TGF-β1, VEGF (A) and HIF-1α pathways. The magnitude of the therapeutic effects is similar to the effects demonstrated under same experimental conditions with 120-fold higher dose of ~5000-fold less lipophilic Mn(III)meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin, MnTE-2-PyP(5+).

Authors
Gauter-Fleckenstein, B; Reboucas, JS; Fleckenstein, K; Tovmasyan, A; Owzar, K; Jiang, C; Batinic-Haberle, I; Vujaskovic, Z
MLA Citation
Gauter-Fleckenstein, B, Reboucas, JS, Fleckenstein, K, Tovmasyan, A, Owzar, K, Jiang, C, Batinic-Haberle, I, and Vujaskovic, Z. "Robust rat pulmonary radioprotection by a lipophilic Mn N-alkylpyridylporphyrin, MnTnHex-2-PyP(5+)." Redox biology 2 (January 9, 2014): 400-410.
PMID
24624330
Source
epmc
Published In
Redox Biology
Volume
2
Publish Date
2014
Start Page
400
End Page
410
DOI
10.1016/j.redox.2013.12.017

Polygenic inheritance of paclitaxel-induced sensory peripheral neuropathy driven by axon outgrowth gene sets in CALGB 40101 (Alliance)

Peripheral neuropathy is a common dose-limiting toxicity for patients treated with paclitaxel. For most individuals, there are no known risk factors that predispose patients to the adverse event, and pathogenesis for paclitaxel-induced peripheral neuropathy is unknown. Determining whether there is a heritable component to paclitaxel-induced peripheral neuropathy would be valuable in guiding clinical decisions and may provide insight into treatment of and mechanisms for the toxicity. Using genotype and patient information from the paclitaxel arm of CALGB 40101 (Alliance), a phase III clinical trial evaluating adjuvant therapies for breast cancer in women, we estimated the variance in maximum grade and dose at first instance of sensory peripheral neuropathy. Our results suggest that paclitaxel-induced neuropathy has a heritable component, driven in part by genes involved in axon outgrowth. Disruption of axon outgrowth may be one of the mechanisms by which paclitaxel treatment results in sensory peripheral neuropathy in susceptible patients. © 2014 Macmillan Publishers Limited All rights reserved.

Authors
Chhibber, A; Mefford, J; Stahl, EA; Pendergrass, SA; Baldwin, RM; Owzar, K; Li, M; Winer, EP; Hudis, CA; Zembutsu, H; Kubo, M; Nakamura, Y; McLeod, HL; Ratain, MJ; Shulman, LN; Ritchie, MD; Plenge, RM; Witte, JS; Kroetz, DL
MLA Citation
Chhibber, A, Mefford, J, Stahl, EA, Pendergrass, SA, Baldwin, RM, Owzar, K, Li, M, Winer, EP, Hudis, CA, Zembutsu, H, Kubo, M, Nakamura, Y, McLeod, HL, Ratain, MJ, Shulman, LN, Ritchie, MD, Plenge, RM, Witte, JS, and Kroetz, DL. "Polygenic inheritance of paclitaxel-induced sensory peripheral neuropathy driven by axon outgrowth gene sets in CALGB 40101 (Alliance)." Pharmacogenomics Journal 14.4 (January 1, 2014): 336-342.
Source
scopus
Published In
The Pharmacogenomics Journal
Volume
14
Issue
4
Publish Date
2014
Start Page
336
End Page
342
DOI
10.1038/tpj.2014.2

Effect of age on the pharmacokinetics of busulfan in patients undergoing hematopoietic cell transplantation; An alliance study (CALGB 10503, 19808, and 100103)

© Springer-Verlag 2014.Purpose: Older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome have often been excluded from myeloablative-conditioning regimens containing busulfan because of non-disease-related morbidity and mortality. We hypothesized that busulfan clearance (BuCL) in older patients (>60 years) would be reduced compared to that in younger patients, potentially explaining observed differences in busulfan tolerability. Methods: AML patients in three CALGB hematopoietic cell transplantation studies were treated with a conditioning regimen using IV busulfan, dosed at 0.8 mg/kg. Plasma busulfan concentrations were determined by LC-MS and analyzed by non-compartmental methods. BuCL was normalized to actual (ABW), ideal (IBW), or corrected (CBW) body weight (kg). Differences in BuCL between age groups were examined using the Wilcoxon rank sum test. Results: One hundred and eighty-five patients were accrued; 174 provided useable pharmacokinetic data. Twenty-nine patients ≥60 years old (median 66; range 60-74) had a significantly higher BuCL versus those <60 years old (median 50; range 18-60): BuCL 236 versus 168 mL/min, p = 0.0002; BuCL/ABW 3.0 versus 2.1 mL/min/kg, p = 0.0001; BuCL/IBW 3.8 versus 2.6 mL/min/kg, p = 0.0035; BuCL/CBW 3.4 versus 2.6 mL/min/kg, p = 0.0005. Inter-patient variability in clearance (CV %) was up to 48 % in both age groups. Phenytoin administration, a potential confounder, did not affect BuCL, regardless of weight normalization (p > 0.34). Conclusions: Contrary to our hypothesis, BuCL was significantly higher in older patients compared to younger patients in these studies and does not explain the previously reported increase in busulfan toxicity observed in older patients.

Authors
Beumer, JH; Owzar, K; Lewis, LD; Jiang, C; Holleran, JL; Christner, SM; Blum, W; Devine, S; Kolitz, JE; Linker, C; Vij, R; Alyea, EP; Larson, RA; Ratain, MJ; Egorin, MJ
MLA Citation
Beumer, JH, Owzar, K, Lewis, LD, Jiang, C, Holleran, JL, Christner, SM, Blum, W, Devine, S, Kolitz, JE, Linker, C, Vij, R, Alyea, EP, Larson, RA, Ratain, MJ, and Egorin, MJ. "Effect of age on the pharmacokinetics of busulfan in patients undergoing hematopoietic cell transplantation; An alliance study (CALGB 10503, 19808, and 100103)." Cancer Chemotherapy and Pharmacology 74.5 (January 1, 2014): 927-938.
Source
scopus
Published In
Cancer Chemotherapy and Pharmacology
Volume
74
Issue
5
Publish Date
2014
Start Page
927
End Page
938
DOI
10.1007/s00280-014-2571-0

Differential Angiogenic Gene Expression in TP53 Wild-Type and Mutant Ovarian Cancer Cell Lines.

Underlying mechanisms regulating angiogenesis in ovarian cancer have not been completely elucidated. Evidence suggests that the TP53 tumor suppressor pathway and tumor microenvironment play integral roles. We utilized microarray technology to study the interaction between TP53 mutational status and hypoxia on angiogenic gene expression.Affymetrix U133A arrays were analyzed for angiogenic gene expression in 19 ovarian cancer cell lines stratified both by TP53 mutation status and A2780 wild-type (wt) TP53 vs. mutated (m) TP53 cell lines after treatment under hypoxic conditions or with ionizing radiation.Twenty-eight differentially expressed angiogenic genes were identified in the mTP53 cell lines compared to wtTP53 lines. Five genes were upregulated in mTP53 cells: 40% involved in extracellular matrix (ECM) degradation [matrix metalloproteinase 10 (MMP10)/15] and 60% in angiogenesis (fibroblast growth factor receptor 3/VEGFA/ephrin receptor-B4). Twenty-three genes were upregulated in wtTP53: nearly 22% were ECM constituents or involved in ECM degradation; over 40% were growth factors or mediators of angiogenesis. Five genes were upregulated in the A2780mTP53 cells: 40% involved in ECM remodeling (MMP10, ADAMTS1), 40% with pro-angiogenic activity (EFNB2, factor 2 receptor), and 20% with anti-angiogenic properties (ADAMTS1). Three genes were upregulated in hypoxia treated cells compared to controls: one with anti-angiogenic activity (angiopoietin-like 4) and two with pro-angiogenic activity (VEGFA, EFNA3). No significant gene fold changes were noted after exposure to radiation. Four genes continued to demonstrate significant differential expression (p ≤ 0.05) after adjusting for multiple comparisons. These genes included endoglin upregulation in wt lines (pro-angiogenesis) and upregulation of FGF20 (growth factor), ADAMTS1 (anti-angiogenesis) and MMP10 (ECM degradation) in mTP53 cell lines.Our exploratory findings indicate that non-overlapping angiogenic pathways may be altered by TP53 mutations and hypoxic conditions in the tumor microenvironment. Further evaluation is needed for confirmation.

Authors
Davidson, BA; Rubatt, JM; Corcoran, DL; Teoh, DK; Bernardini, MQ; Grace, LA; Soper, WJ; Berchuck, A; Siamakpour-Reihani, S; Chen, W; Owzar, K; Murphy, SK; Secord, AA
MLA Citation
Davidson, BA, Rubatt, JM, Corcoran, DL, Teoh, DK, Bernardini, MQ, Grace, LA, Soper, WJ, Berchuck, A, Siamakpour-Reihani, S, Chen, W, Owzar, K, Murphy, SK, and Secord, AA. "Differential Angiogenic Gene Expression in TP53 Wild-Type and Mutant Ovarian Cancer Cell Lines." Frontiers in oncology 4 (January 2014): 163-.
PMID
24999452
Source
epmc
Published In
Frontiers in Oncology
Volume
4
Publish Date
2014
Start Page
163
DOI
10.3389/fonc.2014.00163

MicroRNA expression differentiates squamous epithelium from barrett's esophagus and esophageal cancer

Background: Current strategies fail to identify most patients with esophageal adenocarcinoma (EAC) before the disease becomes advanced and incurable. Given the dismal prognosis associated with EAC, improvements in detection of early-stage esophageal neoplasia are needed. Aim: We sought to assess whether differential expression of microRNAs could discriminate between squamous epithelium, Barrett's esophagus (BE), and EAC. Methods: We analyzed microRNA expression in a discovery cohort of human endoscopic biopsy samples from 36 patients representing normal squamous esophagus (n = 11), BE (n = 14), and high-grade dysplasia/EAC (n = 11). RNA was assessed using microarrays representing 847 human microRNAs followed by quantitative real-time polymerase chain reaction (qRT-PCR) verification of nine microRNAs. In a second cohort (n = 18), qRT-PCR validation of five miRNAs was performed. Expression of 59 microRNAs associated with BE/EAC in the literature was assessed in our training cohort. Known esophageal cell lines were used to compare miRNA expression to tissue miRNAs. Results: After controlling for multiple comparisons, we found 34 miRNAs differentially expressed between squamous esophagus and BE/EAC by microarray analysis. However, miRNA expression did not reliably differentiate non-dysplastic BE from EAC. In the validation cohort, all five microRNAs selected for qRT-PCR validation differentiated between squamous samples and BE/EAC. Microarray results supported 14 of the previously reported microRNAs associated with BE/EAC in the literature. Cell lines did not generally reflect miRNA expression found in vivo. Conclusions: These data indicate that miRNAs differ between squamous esophageal epithelium and BE/EAC, but do not distinguish between BE and EAC. We suggest prospective evaluation of miRNAs in patients at high risk for EAC. © 2013 Springer Science+Business Media New York.

Authors
Garman, KS; Owzar, K; Hauser, ER; Westfall, K; Anderson, BR; Souza, RF; Diehl, AM; Provenzale, D; Shaheen, NJ
MLA Citation
Garman, KS, Owzar, K, Hauser, ER, Westfall, K, Anderson, BR, Souza, RF, Diehl, AM, Provenzale, D, and Shaheen, NJ. "MicroRNA expression differentiates squamous epithelium from barrett's esophagus and esophageal cancer." Digestive Diseases and Sciences 58.11 (November 1, 2013): 3178-3188.
Source
scopus
Published In
Digestive Diseases and Sciences
Volume
58
Issue
11
Publish Date
2013
Start Page
3178
End Page
3188
DOI
10.1007/s10620-013-2806-7

MicroRNA expression differentiates squamous epithelium from Barrett's esophagus and esophageal cancer.

BACKGROUND: Current strategies fail to identify most patients with esophageal adenocarcinoma (EAC) before the disease becomes advanced and incurable. Given the dismal prognosis associated with EAC, improvements in detection of early-stage esophageal neoplasia are needed. AIM: We sought to assess whether differential expression of microRNAs could discriminate between squamous epithelium, Barrett's esophagus (BE), and EAC. METHODS: We analyzed microRNA expression in a discovery cohort of human endoscopic biopsy samples from 36 patients representing normal squamous esophagus (n = 11), BE (n = 14), and high-grade dysplasia/EAC (n = 11). RNA was assessed using microarrays representing 847 human microRNAs followed by quantitative real-time polymerase chain reaction (qRT-PCR) verification of nine microRNAs. In a second cohort (n = 18), qRT-PCR validation of five miRNAs was performed. Expression of 59 microRNAs associated with BE/EAC in the literature was assessed in our training cohort. Known esophageal cell lines were used to compare miRNA expression to tissue miRNAs. RESULTS: After controlling for multiple comparisons, we found 34 miRNAs differentially expressed between squamous esophagus and BE/EAC by microarray analysis. However, miRNA expression did not reliably differentiate non-dysplastic BE from EAC. In the validation cohort, all five microRNAs selected for qRT-PCR validation differentiated between squamous samples and BE/EAC. Microarray results supported 14 of the previously reported microRNAs associated with BE/EAC in the literature. Cell lines did not generally reflect miRNA expression found in vivo. CONCLUSIONS: These data indicate that miRNAs differ between squamous esophageal epithelium and BE/EAC, but do not distinguish between BE and EAC. We suggest prospective evaluation of miRNAs in patients at high risk for EAC.

Authors
Garman, KS; Owzar, K; Hauser, ER; Westfall, K; Anderson, BR; Souza, RF; Diehl, AM; Provenzale, D; Shaheen, NJ
MLA Citation
Garman, KS, Owzar, K, Hauser, ER, Westfall, K, Anderson, BR, Souza, RF, Diehl, AM, Provenzale, D, and Shaheen, NJ. "MicroRNA expression differentiates squamous epithelium from Barrett's esophagus and esophageal cancer." Dig Dis Sci 58.11 (November 2013): 3178-3188.
PMID
23925817
Source
pubmed
Published In
Digestive Diseases and Sciences
Volume
58
Issue
11
Publish Date
2013
Start Page
3178
End Page
3188
DOI
10.1007/s10620-013-2806-7

Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis.

Authors
Fingerlin, TE; Murphy, E; Zhang, W; Peljto, AL; Brown, KK; Steele, MP; Loyd, JE; Cosgrove, GP; Lynch, D; Groshong, S; Collard, HR; Wolters, PJ; Bradford, WZ; Kossen, K; Seiwert, SD; du Bois, RM; Garcia, CK; Devine, MS; Gudmundsson, G; Isaksson, HJ; Kaminski, N; Zhang, Y; Gibson, KF; Lancaster, LH; Cogan, JD; Mason, WR; Maher, TM; Molyneaux, PL; Wells, AU; Moffatt, MF; Selman, M; Pardo, A; Kim, DS; Crapo, JD; Make, BJ; Regan, EA; Walek, DS; Daniel, JJ; Kamatani, Y; Zelenika, D; Smith, K et al.
MLA Citation
Fingerlin, TE, Murphy, E, Zhang, W, Peljto, AL, Brown, KK, Steele, MP, Loyd, JE, Cosgrove, GP, Lynch, D, Groshong, S, Collard, HR, Wolters, PJ, Bradford, WZ, Kossen, K, Seiwert, SD, du Bois, RM, Garcia, CK, Devine, MS, Gudmundsson, G, Isaksson, HJ, Kaminski, N, Zhang, Y, Gibson, KF, Lancaster, LH, Cogan, JD, Mason, WR, Maher, TM, Molyneaux, PL, Wells, AU, Moffatt, MF, Selman, M, Pardo, A, Kim, DS, Crapo, JD, Make, BJ, Regan, EA, Walek, DS, Daniel, JJ, Kamatani, Y, Zelenika, D, and Smith, K et al. "Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis." Nat Genet 45.11 (November 2013): 1409-.
PMID
24165735
Source
pubmed
Published In
Nature Genetics
Volume
45
Issue
11
Publish Date
2013
Start Page
1409
DOI
10.1038/ng1113-1409a

A phase II study of the oral VEGF receptor tyrosine kinase inhibitor vatalanib (PTK787/ZK222584) in myelodysplastic syndrome: Cancer and Leukemia Group B study 10105 (Alliance).

BACKGROUND: Angiogenesis is implicated in the pathophysiology and progression of myelodysplastic syndromes (MDS). Vatalanib (PTK787/ZK222584; Novartis and Schering AG) inhibits receptor tyrosine kinases of vascular endothelial growth factor, platelet derived growth factor and c-Kit. We examined whether vatalanib induces hematological responses in MDS and/or delays progression to acute myeloid leukemia (AML) or death. METHODS: Two cohorts were studied. Vatalanib 1250 mg orally was given once daily (cohort 1) or 750-1250 mg once daily in an intra-patient dose escalating schedule (cohort 2) in 28-day cycles to 155 patients with MDS; 142 patients were evaluable for response and 153 for toxicity. RESULTS: The median age was 70.5 years; 51 % had low risk (International Prognostic Scoring System {IPSS} Low/Intermediate-1) and 32 % had high risk (IPSS Intermediate-2/High) MDS. Hematological improvement was achieved in 7/142 (5 %) patients; all 7 were among the 47 patients able to remain on vatalanib for at least 3 months (hematological improvement achieved in 15 % of these 47 patients). For patients with low risk and high risk MDS, respectively, median progression-free survivals were 15 and 6 months, median times to transformation to AML were 28 and 6 months, and median overall survivals were 36 and 10 months. The most frequent non-hematological adverse events grade ≥ 2 were fatigue, nausea or vomiting, dizziness, anorexia, ataxia, diarrhea, and pain. Two deaths (one intra-cerebral hemorrhage and one sudden death) were possibly related to vatalanib. CONCLUSIONS: Vatalanib induces improvement in blood counts in a small proportion of MDS patients. Clinical applicability is limited by side effects.

Authors
Gupta, P; Mulkey, F; Hasserjian, RP; Sanford, BL; Vij, R; Hurd, DD; Odenike, OM; Bloomfield, CD; Owzar, K; Stone, RM; Larson, RA; Alliance for Clinical Trials in Oncology,
MLA Citation
Gupta, P, Mulkey, F, Hasserjian, RP, Sanford, BL, Vij, R, Hurd, DD, Odenike, OM, Bloomfield, CD, Owzar, K, Stone, RM, Larson, RA, and Alliance for Clinical Trials in Oncology, . "A phase II study of the oral VEGF receptor tyrosine kinase inhibitor vatalanib (PTK787/ZK222584) in myelodysplastic syndrome: Cancer and Leukemia Group B study 10105 (Alliance)." Invest New Drugs 31.5 (October 2013): 1311-1320.
PMID
23700288
Source
pubmed
Published In
Investigational New Drugs
Volume
31
Issue
5
Publish Date
2013
Start Page
1311
End Page
1320
DOI
10.1007/s10637-013-9978-z

Long-term results of adjuvant imatinib mesylate in localized, high-risk, primary gastrointestinal stromal tumor: ACOSOG Z9000 (Alliance) intergroup phase 2 trial.

OBJECTIVE: To conduct the first adjuvant trial of imatinib mesylate for treatment of gastrointestinal stromal tumor (GIST). BACKGROUND: GIST is the most common sarcoma. Although surgical resection has been the mainstay of therapy for localized, primary GIST, postoperative tumor recurrence is common. The KIT protooncogene or, less frequently, platelet-derived growth factor receptor alpha is mutated in GIST; the gene products of both are inhibited by imatinib mesylate. METHODS: This was a phase II, intergroup trial led by the American College of Surgeons Oncology Group, registered at ClinicalTrials.gov as NCT00025246. From September 2001 to September 2003, we accrued 106 patients who had undergone complete gross tumor removal but were deemed at high risk for recurrence. Patients were prescribed imatinib 400 mg per day for 1 year and followed with serial radiologic evaluation. The primary endpoint was overall survival (OS). RESULTS: After a median follow-up of 7.7 years, the 1-, 3-, and 5-year OS rates were 99%, 97%, and 83%, which compared favorably with a historical 5-year OS rate of 35%. The 1-, 3-, and 5-year recurrence-free survival (RFS) rates were 96%, 60%, and 40%. On univariable analysis, age and mitotic rate were associated with OS. On multivariable analysis, the RFS rate was lower with increasing tumor size, small bowel site, KIT exon 9 mutation, high mitotic rate, and older age. CONCLUSIONS: Adjuvant imatinib in patients with primary GIST who are at high risk of recurrence prolongs OS compared with that of historical controls. Optimal duration of adjuvant therapy remains undefined. (NCT00025246).

Authors
DeMatteo, RP; Ballman, KV; Antonescu, CR; Corless, C; Kolesnikova, V; von Mehren, M; McCarter, MD; Norton, J; Maki, RG; Pisters, PW; Demetri, GD; Brennan, MF; Owzar, K; American College of Surgeons Oncology Group (ACOSOG) Intergroup Adjuvant GIST Study Team for the Alliance for Clinical Trials in Oncology,
MLA Citation
DeMatteo, RP, Ballman, KV, Antonescu, CR, Corless, C, Kolesnikova, V, von Mehren, M, McCarter, MD, Norton, J, Maki, RG, Pisters, PW, Demetri, GD, Brennan, MF, Owzar, K, and American College of Surgeons Oncology Group (ACOSOG) Intergroup Adjuvant GIST Study Team for the Alliance for Clinical Trials in Oncology, . "Long-term results of adjuvant imatinib mesylate in localized, high-risk, primary gastrointestinal stromal tumor: ACOSOG Z9000 (Alliance) intergroup phase 2 trial." Ann Surg 258.3 (September 2013): 422-429.
PMID
23860199
Source
pubmed
Published In
Annals of Surgery
Volume
258
Issue
3
Publish Date
2013
Start Page
422
End Page
429
DOI
10.1097/SLA.0b013e3182a15eb7

Gastric cancer pharmacogenetics: progress or old tripe?

Gastric cancer remains the second most frequent cause of cancer-related mortality. While surgery is traditionally the initial treatment for early-stage disease, the addition of chemotherapy has been shown to significantly increase overall survival and progression-free survival in advanced and metastatic stages of disease. However, despite the incorporation of newer chemotherapies and regimens into gastric cancer clinical trials, the response rate and median overall survival for treated patients has not significantly improved throughout the years; therefore, newer therapeutic approaches to improve upon the medication selection process are warranted. Treatment and dose selection based on patient factors, such as genetic variation, may provide a more rational and potentially more powerful means of personalizing chemotherapy. This review provides an update on the current status of pharmacogenetic studies regarding germline DNA mutations that may alter response to chemotherapeutic agents used to treat gastric cancer, including perspectives on clinical translation and future work.

Authors
Patel, JN; Fuchs, CS; Owzar, K; Chen, Z; McLeod, HL
MLA Citation
Patel, JN, Fuchs, CS, Owzar, K, Chen, Z, and McLeod, HL. "Gastric cancer pharmacogenetics: progress or old tripe?." Pharmacogenomics 14.9 (July 2013): 1053-1064. (Review)
PMID
23837480
Source
pubmed
Published In
Pharmacogenomics
Volume
14
Issue
9
Publish Date
2013
Start Page
1053
End Page
1064
DOI
10.2217/pgs.13.88

Analysis of single nucleotide polymorphisms and radiation sensitivity of the lung assessed with an objective radiologic endpoin.

BACKGROUND: The primary objective of this study was to evaluate the association between radiation sensitivity of the lungs and candidate single nucleotide polymorphisms (SNP) in genes implicated in radiation-induced toxicity. METHODS: Patients with lung cancer who received radiation therapy (RT) had pre-RT and serial post-RT single photon emission computed tomography (SPECT) lung perfusion scans. RT-induced changes in regional perfusion were related to regional dose, which generated patient-specific dose-response curves (DRC). The slope of the DRC is independent of total dose and the irradiated volume, and is taken as a reflection of the patient's inherent sensitivity to RT. DNA was extracted from blood samples obtained at baseline. SNPs were determined by using a combination of high-resolution melting, TaqMan assays, and direct sequencing. Genotypes from 33 SNPs in 22 genes were compared against the slope of the DRC by using the Kruskal-Wallis test for ordered alternatives. RESULTS: Thirty-nine self-reported Caucasian patients with pre-RT and ≥6 month post-RT SPECTs, and blood samples were identified. An association between genotype and increasing slope of the DRC was noted in G(1301) A in XRCC1 (rs25487) (P = .01) and G(3748) A in BRCA1 (rs16942) (P = .03). CONCLUSIONS: By using an objective radiologic assessment, polymorphisms within genes involved in repair of DNA damage (XRCC1 and BRCA1) were associated with radiation sensitivity of the lungs.

Authors
Kelsey, CR; Jackson, IL; Langdon, S; Owzar, K; Hubbs, J; Vujaskovic, Z; Das, S; Marks, LB
MLA Citation
Kelsey, CR, Jackson, IL, Langdon, S, Owzar, K, Hubbs, J, Vujaskovic, Z, Das, S, and Marks, LB. "Analysis of single nucleotide polymorphisms and radiation sensitivity of the lung assessed with an objective radiologic endpoin." Clin Lung Cancer 14.3 (May 2013): 267-274.
PMID
23313170
Source
pubmed
Published In
Clinical lung cancer
Volume
14
Issue
3
Publish Date
2013
Start Page
267
End Page
274
DOI
10.1016/j.cllc.2012.10.006

VATALANIB POPULATION PHARMACOKINETICS IN PATIENTS WITH MYELODYSPLASTIC SYNDROME: CALGB 10105 (ALLIANCE)

Authors
Wang, X; Owzar, K; Gupta, P; Larson, RA; Mulkey, F; Miller, AA; Lewis, LD; Hurd, D; Vij, R; Ratain, MJ; Murry, D
MLA Citation
Wang, X, Owzar, K, Gupta, P, Larson, RA, Mulkey, F, Miller, AA, Lewis, LD, Hurd, D, Vij, R, Ratain, MJ, and Murry, D. "VATALANIB POPULATION PHARMACOKINETICS IN PATIENTS WITH MYELODYSPLASTIC SYNDROME: CALGB 10105 (ALLIANCE)." February 2013.
PMID
24838014
Source
wos-lite
Published In
Clinical Pharmacology & Therapeutics (Nature)
Volume
93
Publish Date
2013
Start Page
S82
End Page
S82

Integration of cell line and clinical trial genome-wide analyses supports a polygenic architecture of Paclitaxel-induced sensory peripheral neuropathy.

PURPOSE: We sought to show the relevance of a lymphoblastoid cell line (LCL) model in the discovery of clinically relevant genetic variants affecting chemotherapeutic response by comparing LCL genome-wide association study (GWAS) results to clinical GWAS results. EXPERIMENTAL DESIGN: A GWAS of paclitaxel-induced cytotoxicity was conducted in 247 LCLs from the HapMap Project and compared with a GWAS of sensory peripheral neuropathy in patients with breast cancer (n = 855) treated with paclitaxel in the Cancer and Leukemia Group B (CALGB) 40101 trial. Significant enrichment was assessed by permutation resampling analysis. RESULTS: We observed an enrichment of LCL cytotoxicity-associated single-nucleotide polymorphisms (SNP) in the sensory peripheral neuropathy-associated SNPs from the clinical trial with concordant allelic directions of effect (empirical P = 0.007). Of the 24 SNPs that overlap between the clinical trial (P < 0.05) and the preclinical cytotoxicity study (P < 0.001), 19 of them are expression quantitative trait loci (eQTL), which is a significant enrichment of this functional class (empirical P = 0.0447). One of these eQTLs is located in RFX2, which encodes a member of the DNA-binding regulatory factor X family. Decreased expression of this gene by siRNA resulted in increased sensitivity of Neuroscreen-1(NS-1; rat pheochromocytoma) cells to paclitaxel as measured by reduced neurite outgrowth and increased cytotoxicity, functionally validating the involvement of RFX2 in nerve cell response to paclitaxel. CONCLUSIONS: The enrichment results and functional example imply that cellular models of chemotherapeutic toxicity may capture components of the underlying polygenic architecture of related traits in patients.

Authors
Wheeler, HE; Gamazon, ER; Wing, C; Njiaju, UO; Njoku, C; Baldwin, RM; Owzar, K; Jiang, C; Watson, D; Shterev, I; Kubo, M; Zembutsu, H; Winer, EP; Hudis, CA; Shulman, LN; Nakamura, Y; Ratain, MJ; Kroetz, DL; Cancer and Leukemia Group B, ; Cox, NJ; Dolan, ME
MLA Citation
Wheeler, HE, Gamazon, ER, Wing, C, Njiaju, UO, Njoku, C, Baldwin, RM, Owzar, K, Jiang, C, Watson, D, Shterev, I, Kubo, M, Zembutsu, H, Winer, EP, Hudis, CA, Shulman, LN, Nakamura, Y, Ratain, MJ, Kroetz, DL, Cancer and Leukemia Group B, , Cox, NJ, and Dolan, ME. "Integration of cell line and clinical trial genome-wide analyses supports a polygenic architecture of Paclitaxel-induced sensory peripheral neuropathy." Clin Cancer Res 19.2 (January 15, 2013): 491-499.
PMID
23204130
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
19
Issue
2
Publish Date
2013
Start Page
491
End Page
499
DOI
10.1158/1078-0432.CCR-12-2618

The relationship of polymorphisms in ABCC2 and SLCO1B3 with docetaxel pharmacokinetics and neutropenia: CALGB 60805 (Alliance).

Docetaxel-related neutropenia was associated with polymorphisms in the drug transporters ABCC2 and SLCO1B3 in Japanese cancer patients. We hypothesized that this association is because of reduced docetaxel clearance, associated with polymorphisms in those genes. We studied 64 US cancer patients who received a single cycle of 75 mg/m of docetaxel monotherapy. We found that the ABCC2 polymorphism at rs-12762549 trended to show a relationship with reduced docetaxel clearance (P=0.048), but not with neutropenia. There was no significant association of the SLCO1B3 polymorphisms with docetaxel clearance or neutropenia. We conclude that the relationship between docetaxel-associated neutropenia and polymorphisms in drug transporters identified in Japanese patients was not confirmed in this cohort of US cancer patients.

Authors
Lewis, LD; Miller, AA; Owzar, K; Bies, RR; Markova, S; Jiang, C; Kroetz, DL; Egorin, MJ; McLeod, HL; Ratain, MJ; Alliance for Clinical Trials in Oncology,
MLA Citation
Lewis, LD, Miller, AA, Owzar, K, Bies, RR, Markova, S, Jiang, C, Kroetz, DL, Egorin, MJ, McLeod, HL, Ratain, MJ, and Alliance for Clinical Trials in Oncology, . "The relationship of polymorphisms in ABCC2 and SLCO1B3 with docetaxel pharmacokinetics and neutropenia: CALGB 60805 (Alliance)." Pharmacogenet Genomics 23.1 (January 2013): 29-33.
PMID
23188068
Source
pubmed
Published In
Pharmacogenetics and Genomics
Volume
23
Issue
1
Publish Date
2013
Start Page
29
End Page
33
DOI
10.1097/FPC.0b013e32835b16d8

The relationship of polymorphisms in ABCC2 and SLCO1B3 with docetaxel pharmacokinetics and neutropenia: CALGB 60805 (Alliance)

Docetaxel-related neutropenia was associated with polymorphisms in the drug transporters ABCC2 and SLCO1B3 in Japanese cancer patients. We hypothesized that this association is because of reduced docetaxel clearance, associated with polymorphisms in those genes. We studied 64 US cancer patients who received a single cycle of 75 mg/m of docetaxel monotherapy. We found that the ABCC2 polymorphism at rs-12762549 trended to show a relationship with reduced docetaxel clearance (P=0.048), but not with neutropenia. There was no significant association of the SLCO1B3 polymorphisms with docetaxel clearance or neutropenia. We conclude that the relationship between docetaxel-associated neutropenia and polymorphisms in drug transporters identified in Japanese patients was not confirmed in this cohort of US cancer patients.© 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Authors
Lewis, LD; Miller, AA; Owzar, K; Bies, RR; Markova, S; Jiang, C; Kroetz, DL; Egorin, MJ; McLeod, HL; Ratain, MJ
MLA Citation
Lewis, LD, Miller, AA, Owzar, K, Bies, RR, Markova, S, Jiang, C, Kroetz, DL, Egorin, MJ, McLeod, HL, and Ratain, MJ. "The relationship of polymorphisms in ABCC2 and SLCO1B3 with docetaxel pharmacokinetics and neutropenia: CALGB 60805 (Alliance)." Pharmacogenetics and Genomics 23.1 (2013): 29-33.
Source
scival
Published In
Pharmacogenetics and Genomics
Volume
23
Issue
1
Publish Date
2013
Start Page
29
End Page
33
DOI
10.1097/FPC.0b013e32835b16d8

A phase II study of the oral VEGF receptor tyrosine kinase inhibitor vatalanib (PTK787/ZK222584) in myelodysplastic syndrome: Cancer and Leukemia Group B study 10105 (Alliance)

Background: Angiogenesis is implicated in the pathophysiology and progression of myelodysplastic syndromes (MDS). Vatalanib (PTK787/ZK222584; Novartis and Schering AG) inhibits receptor tyrosine kinases of vascular endothelial growth factor, platelet derived growth factor and c-Kit. We examined whether vatalanib induces hematological responses in MDS and/or delays progression to acute myeloid leukemia (AML) or death. Methods: Two cohorts were studied. Vatalanib 1250 mg orally was given once daily (cohort 1) or 750-1250 mg once daily in an intra-patient dose escalating schedule (cohort 2) in 28-day cycles to 155 patients with MDS; 142 patients were evaluable for response and 153 for toxicity. Results: The median age was 70.5 years; 51 % had low risk (International Prognostic Scoring System {IPSS} Low/Intermediate-1) and 32 % had high risk (IPSS Intermediate-2/High) MDS. Hematological improvement was achieved in 7/142 (5 %) patients; all 7 were among the 47 patients able to remain on vatalanib for at least 3 months (hematological improvement achieved in 15 % of these 47 patients). For patients with low risk and high risk MDS, respectively, median progression-free survivals were 15 and 6 months, median times to transformation to AML were 28 and 6 months, and median overall survivals were 36 and 10 months. The most frequent non-hematological adverse events grade ≥2 were fatigue, nausea or vomiting, dizziness, anorexia, ataxia, diarrhea, and pain. Two deaths (one intra-cerebral hemorrhage and one sudden death) were possibly related to vatalanib. Conclusions: Vatalanib induces improvement in blood counts in a small proportion of MDS patients. Clinical applicability is limited by side effects. © 2013 Springer Science+Business Media New York.

Authors
Gupta, P; Mulkey, F; Hasserjian, RP; Sanford, BL; Vij, R; Hurd, DD; Odenike, OM; Bloomfield, CD; Owzar, K; Stone, RM; Larson, RA
MLA Citation
Gupta, P, Mulkey, F, Hasserjian, RP, Sanford, BL, Vij, R, Hurd, DD, Odenike, OM, Bloomfield, CD, Owzar, K, Stone, RM, and Larson, RA. "A phase II study of the oral VEGF receptor tyrosine kinase inhibitor vatalanib (PTK787/ZK222584) in myelodysplastic syndrome: Cancer and Leukemia Group B study 10105 (Alliance)." Investigational New Drugs 31.5 (2013): 1311-1320.
Source
scival
Published In
Investigational New Drugs
Volume
31
Issue
5
Publish Date
2013
Start Page
1311
End Page
1320
DOI
10.1007/s10637-013-9978-z

Long-term results of adjuvant imatinib mesylate in localized, high-risk, primary gastrointestinal stromal tumor: ACOSOG Z9000 (Alliance) intergroup phase 2 trial

Objective: To conduct the first adjuvant trial of imatinib mesylate for treatment of gastrointestinal stromal tumor (GIST). Background: GIST is the most common sarcoma. Although surgical resection has been the mainstay of therapy for localized, primary GIST, postoperative tumor recurrence is common. The KIT protooncogene or, less frequently, platelet-derived growth factor receptor alpha is mutated in GIST; the gene products of both are inhibited by imatinib mesylate. Methods: This was a phase II, intergroup trial led by the American College of Surgeons Oncology Group, registered at ClinicalTrials.gov as NCT00025246. From September 2001 to September 2003, we accrued 106 patients who had undergone complete gross tumor removal but were deemed at high risk for recurrence. Patients were prescribed imatinib 400 mg per day for 1 year and followed with serial radiologic evaluation. The primary endpoint was overall survival (OS). Results: After a median follow-up of 7.7 years, the 1-, 3-, and 5-year OS rates were 99%, 97%, and 83%, which compared favorably with a historical 5-year OS rate of 35%. The 1-, 3-, and 5-year recurrence-free survival (RFS) rates were 96%, 60%, and 40%. On univariable analysis, age and mitotic rate were associated with OS. On multivariable analysis, the RFS rate was lower with increasing tumor size, small bowel site, KIT exon 9 mutation, high mitotic rate, and older age. Conclusions: Adjuvant imatinib in patients with primary GIST who are at high risk of recurrence prolongs OS compared with that of historical controls. Optimal duration of adjuvant therapy remains undefined. © 2013 Lippincott Williams & Wilkins.

Authors
DeMatteo, RP; Ballman, KV; Antonescu, CR; Corless, C; Kolesnikova, V; Mehren, MV; McCarter, MD; Norton, J; Maki, RG; Pisters, PWT; Demetri, GD; Brennan, MF; Owzar, K
MLA Citation
DeMatteo, RP, Ballman, KV, Antonescu, CR, Corless, C, Kolesnikova, V, Mehren, MV, McCarter, MD, Norton, J, Maki, RG, Pisters, PWT, Demetri, GD, Brennan, MF, and Owzar, K. "Long-term results of adjuvant imatinib mesylate in localized, high-risk, primary gastrointestinal stromal tumor: ACOSOG Z9000 (Alliance) intergroup phase 2 trial." Annals of Surgery 258.3 (2013): 422-428.
Source
scival
Published In
Annals of Surgery
Volume
258
Issue
3
Publish Date
2013
Start Page
422
End Page
428
DOI
10.1097/SLA.0b013e3182a15eb7

A genome-wide association study identifies novel loci for paclitaxel-induced sensory peripheral neuropathy in CALGB 40101.

PURPOSE: Sensory peripheral neuropathy is a common and sometimes debilitating toxicity associated with paclitaxel therapy. This study aims to identify genetic risk factors for the development of this toxicity. EXPERIMENTAL DESIGN: A prospective pharmacogenetic analysis of patients with primary breast cancer, randomized to the paclitaxel arm of CALGB 40101, was used to identify genetic predictors of the onset and severity of sensory peripheral neuropathy. A genome-wide association study in 855 subjects of European ancestry was conducted and findings were replicated in additional European (n = 154) and African American (n = 117) subjects. RESULTS: A single nucleotide polymorphism in FGD4 was associated with the onset of sensory peripheral neuropathy in the discovery cohort [rs10771973; HR, 1.57; 95% confidence interval (CI), 1.30-1.91; P = 2.6 × 10(-6)] and in a European (HR, 1.72; 95% CI, 1.06-2.80; P = 0.013) and African American (HR, 1.93; 95% CI, 1.13-3.28; P = 6.7 × 10(-3)) replication cohort. There is also evidence that markers in additional genes, including EPHA5 (rs7349683) and FZD3 (rs10771973), were associated with the onset or severity of paclitaxel-induced sensory peripheral neuropathy. CONCLUSIONS: A genome-wide association study has identified novel genetic markers of paclitaxel-induced sensory peripheral neuropathy, including a common polymorphism in FGD4, a congenital peripheral neuropathy gene. These findings suggest that genetic variation may contribute to variation in development of this toxicity. Validation of these findings may allow for the identification of patients at increased risk of peripheral neuropathy and inform the use of an alternative to paclitaxel and/or the clinical management of this toxicity.

Authors
Baldwin, RM; Owzar, K; Zembutsu, H; Chhibber, A; Kubo, M; Jiang, C; Watson, D; Eclov, RJ; Mefford, J; McLeod, HL; Friedman, PN; Hudis, CA; Winer, EP; Jorgenson, EM; Witte, JS; Shulman, LN; Nakamura, Y; Ratain, MJ; Kroetz, DL
MLA Citation
Baldwin, RM, Owzar, K, Zembutsu, H, Chhibber, A, Kubo, M, Jiang, C, Watson, D, Eclov, RJ, Mefford, J, McLeod, HL, Friedman, PN, Hudis, CA, Winer, EP, Jorgenson, EM, Witte, JS, Shulman, LN, Nakamura, Y, Ratain, MJ, and Kroetz, DL. "A genome-wide association study identifies novel loci for paclitaxel-induced sensory peripheral neuropathy in CALGB 40101." Clin Cancer Res 18.18 (September 15, 2012): 5099-5109.
PMID
22843789
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
18
Issue
18
Publish Date
2012
Start Page
5099
End Page
5109
DOI
10.1158/1078-0432.CCR-12-1590

Power and sample size calculations for SNP association studies with censored time-to-event outcomes.

For many clinical studies in cancer, germline DNA is prospectively collected for the purpose of discovering or validating single-nucleotide polymorphisms (SNPs) associated with clinical outcomes. The primary clinical endpoint for many of these studies are time-to-event outcomes such as time of death or disease progression which are subject to censoring mechanisms. The Cox score test can be readily employed to test the association between a SNP and the outcome of interest. In addition to the effect and sample size, and censoring distribution, the power of the test will depend on the underlying genetic risk model and the distribution of the risk allele. We propose a rigorous account for power and sample size calculations under a variety of genetic risk models without resorting to the commonly used contiguous alternative assumption. Practical advice along with an open-source software package to design SNP association studies with survival outcomes are provided.

Authors
Owzar, K; Li, Z; Cox, N; Jung, S-H
MLA Citation
Owzar, K, Li, Z, Cox, N, and Jung, S-H. "Power and sample size calculations for SNP association studies with censored time-to-event outcomes." Genet Epidemiol 36.6 (September 2012): 538-548.
PMID
22685040
Source
pubmed
Published In
Genetic Epidemiology
Volume
36
Issue
6
Publish Date
2012
Start Page
538
End Page
548
DOI
10.1002/gepi.21645

Lenalidomide after stem-cell transplantation for multiple myeloma.

BACKGROUND: Data are lacking on whether lenalidomide maintenance therapy prolongs the time to disease progression after autologous hematopoietic stem-cell transplantation in patients with multiple myeloma. METHODS: Between April 2005 and July 2009, we randomly assigned 460 patients who were younger than 71 years of age and had stable disease or a marginal, partial, or complete response 100 days after undergoing stem-cell transplantation to lenalidomide or placebo, which was administered until disease progression. The starting dose of lenalidomide was 10 mg per day (range, 5 to 15). RESULTS: The study-drug assignments were unblinded in 2009, when a planned interim analysis showed a significantly longer time to disease progression in the lenalidomide group. At unblinding, 20% of patients who received lenalidomide and 44% of patients who received placebo had progressive disease or had died (P<0.001); of the remaining 128 patients who received placebo and who did not have progressive disease, 86 crossed over to lenalidomide. At a median follow-up of 34 months, 86 of 231 patients who received lenalidomide (37%) and 132 of 229 patients who received placebo (58%) had disease progression or had died. The median time to progression was 46 months in the lenalidomide group and 27 months in the placebo group (P<0.001). A total of 35 patients who received lenalidomide (15%) and 53 patients who received placebo (23%) died (P=0.03). More grade 3 or 4 hematologic adverse events and grade 3 nonhematologic adverse events occurred in patients who received lenalidomide (P<0.001 for both comparisons). Second primary cancers occurred in 18 patients who received lenalidomide (8%) and 6 patients who received placebo (3%). CONCLUSIONS: Lenalidomide maintenance therapy, initiated at day 100 after hematopoietic stem-cell transplantation, was associated with more toxicity and second cancers but a significantly longer time to disease progression and significantly improved overall survival among patients with myeloma. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00114101.).

Authors
McCarthy, PL; Owzar, K; Hofmeister, CC; Hurd, DD; Hassoun, H; Richardson, PG; Giralt, S; Stadtmauer, EA; Weisdorf, DJ; Vij, R; Moreb, JS; Callander, NS; Van Besien, K; Gentile, T; Isola, L; Maziarz, RT; Gabriel, DA; Bashey, A; Landau, H; Martin, T; Qazilbash, MH; Levitan, D; McClune, B; Schlossman, R; Hars, V; Postiglione, J; Jiang, C; Bennett, E; Barry, S; Bressler, L; Kelly, M; Seiler, M; Rosenbaum, C; Hari, P; Pasquini, MC; Horowitz, MM; Shea, TC; Devine, SM; Anderson, KC; Linker, C
MLA Citation
McCarthy, PL, Owzar, K, Hofmeister, CC, Hurd, DD, Hassoun, H, Richardson, PG, Giralt, S, Stadtmauer, EA, Weisdorf, DJ, Vij, R, Moreb, JS, Callander, NS, Van Besien, K, Gentile, T, Isola, L, Maziarz, RT, Gabriel, DA, Bashey, A, Landau, H, Martin, T, Qazilbash, MH, Levitan, D, McClune, B, Schlossman, R, Hars, V, Postiglione, J, Jiang, C, Bennett, E, Barry, S, Bressler, L, Kelly, M, Seiler, M, Rosenbaum, C, Hari, P, Pasquini, MC, Horowitz, MM, Shea, TC, Devine, SM, Anderson, KC, and Linker, C. "Lenalidomide after stem-cell transplantation for multiple myeloma." N Engl J Med 366.19 (May 10, 2012): 1770-1781.
PMID
22571201
Source
pubmed
Published In
The New England journal of medicine
Volume
366
Issue
19
Publish Date
2012
Start Page
1770
End Page
1781
DOI
10.1056/NEJMoa1114083

A polymorphism within the promoter of the TGFβ1 gene is associated with radiation sensitivity using an objective radiologic endpoint.

PURPOSE: To evaluate whether single nucleotide polymorphisms (SNPs) in the transforming growth factor-β1 (TGFβ1) gene are associated with radiation sensitivity using an objective radiologic endpoint. METHODS AND MATERIALS: Preradiation therapy and serial postradiation therapy single photon emission computed tomography (SPECT) lung perfusion scans were obtained in patients undergoing treatment for lung cancer. Serial blood samples were obtained to measure circulating levels of TGFβ1. Changes in regional perfusion were related to regional radiation dose yielding a patient-specific dose-response curve, reflecting the patient's inherent sensitivity to radiation therapy. Six TGFβ1 SNPs (-988, -800, -509, 869, 941, and 1655) were assessed using high-resolution melting assays and DNA sequencing. The association between genotype and slope of the dose-response curve, and genotype and TGFβ1 ratio (4-week/preradiation therapy), was analyzed using the Kruskal-Wallis test. RESULTS: 39 white patients with preradiation therapy and ≥ 6-month postradiation therapy SPECT scans and blood samples were identified. Increasing slope of the dose-response curve was associated with the C(-509)T SNP (p = 0.035), but not the other analyzed SNPs. This SNP was also associated with higher TGFβ1 ratios. CONCLUSIONS: This study suggests that a polymorphism within the promoter of the TGFβ1 gene is associated with increased radiation sensitivity (defined objectively by dose-dependent changes in SPECT lung perfusion).

Authors
Kelsey, CR; Jackson, L; Langdon, S; Owzar, K; Hubbs, J; Vujaskovic, Z; Das, S; Marks, LB
MLA Citation
Kelsey, CR, Jackson, L, Langdon, S, Owzar, K, Hubbs, J, Vujaskovic, Z, Das, S, and Marks, LB. "A polymorphism within the promoter of the TGFβ1 gene is associated with radiation sensitivity using an objective radiologic endpoint." Int J Radiat Oncol Biol Phys 82.2 (February 1, 2012): e247-e255.
PMID
21605940
Source
pubmed
Published In
International Journal of Radiation: Oncology - Biology - Physics
Volume
82
Issue
2
Publish Date
2012
Start Page
e247
End Page
e255
DOI
10.1016/j.ijrobp.2011.02.064

Identification of potential prognostic biomarkers in patients with untreated, advanced pancreatic cancer from a phase 3 trial (Cancer and Leukemia Group B 80303).

BACKGROUND: Patients with advanced stage adenocarcinoma of the pancreas have a poor prognosis. The identification of prognostic and/or predictive biomarkers may help stratify patients so that therapy can be individualized. METHODS: Serum samples from patients enrolled in the Cancer and Leukemia Group B 80303 phase 3 trial, "Randomized Study of Gemcitabine With Versus Without Bevacizumab in Patients With Locally Advanced or Metastatic Adenocarcinoma of the Pancreas" were used to discover novel biomarkers. For the discovery phase, 40 sera were selected based on length of survival and type of therapy, and subjected to liquid chromatography coupled to tandem mass spectrometry analysis (LC-MS-MS). The top features (proteins) were then further selected for validation by enzyme-linked immunosorbent assay (ELISA). RESULTS: Quantification by nano-LC-MS-MS resulted in 1452 peptides mapping to 156 proteins across all 40 samples, 92 of which had 2 or more peptides. After curation of the data, the authors selected 1 putative prognostic protein, alpha 1-antichymotrypsin (AACT), and 2 putative predictive proteins, histidine-rich glycoprotein (HRG) and complement factor H (CFH), for validation by ELISA. AACT was found to be negatively correlated with overall survival (τ = -0.30 [-0.38, -0.22]; P < .00001). There was no evidence for interaction with bevacizumab and HRG, but there was some evidence for a weak positive correlation of HRG with overall survival (τ = 0.11 [0.03, 0.19]; P < .01). CFH was found to be neither a predictive nor a prognostic factor for overall survival. CONCLUSIONS: AACT may be a useful prognostic marker in patients with advanced stage pancreatic carcinoma, although additional validation studies are needed.

Authors
Roberts, AS; Campa, MJ; Gottlin, EB; Jiang, C; Owzar, K; Kindler, HL; Venook, AP; Goldberg, RM; O'Reilly, EM; Patz, EF
MLA Citation
Roberts, AS, Campa, MJ, Gottlin, EB, Jiang, C, Owzar, K, Kindler, HL, Venook, AP, Goldberg, RM, O'Reilly, EM, and Patz, EF. "Identification of potential prognostic biomarkers in patients with untreated, advanced pancreatic cancer from a phase 3 trial (Cancer and Leukemia Group B 80303)." Cancer 118.2 (January 15, 2012): 571-578.
PMID
21713765
Source
pubmed
Published In
Cancer
Volume
118
Issue
2
Publish Date
2012
Start Page
571
End Page
578
DOI
10.1002/cncr.26270

A genome-wide association study of overall survival in pancreatic cancer patients treated with gemcitabine in CALGB 80303.

BACKGROUND AND AIMS: Cancer and Leukemia Group B 80303 was a randomized, phase III study in patients with advanced pancreatic cancer treated with gemcitabine plus either bevacizumab or placebo. We prospectively collected germline DNA and conducted a genome-wide association study (GWAS) using overall survival (OS) as the endpoint. EXPERIMENTAL DESIGN: DNA from 351 patients was genotyped for more than 550,000 single-nucleotide polymorphisms (SNP). Associations between OS and SNPs were investigated using the log-linear 2-way multiplicative Cox proportional hazards model. The subset of 294 genetically European patients was used for the primary analysis. RESULTS: A nonsynonymous SNP in interleukin (IL)17F (rs763780, H161R) and an intronic SNP in strong linkage disequilibrium (rs7771466) were associated with OS using genome-wide criteria (P ≤ 10(-7)). Median OS was significantly shorter (P = 2.61 × 10(-8)) for the rs763780 heterozygotes [3.1 months; 95% confidence interval (CI), 2.3-4.3] than for the patients without this variant (6.8 months; 95% CI, 5.8-7.3). After adjustment by stratification factors, the P value for the association was 9.51 × 10(-7). CONCLUSIONS: The variant 161R form of IL-17F is a natural antagonist of the antiangiogenic effects of wild-type 161H IL-17F, and angiogenesis may play an important role in the metastatic spread of pancreatic cancer. In this preliminary study, we hypothesize that the angiogenetic potential of pancreatic cancers in patients with variant IL-17F is higher than that of tumors in patients with wild-type IL-17F, conferring worse prognosis. This exploratory GWAS may provide the foundation for testing the biology and clinical effects of novel genes and their heritable variants through mechanistic and confirmatory studies in pancreatic cancer.

Authors
Innocenti, F; Owzar, K; Cox, NL; Evans, P; Kubo, M; Zembutsu, H; Jiang, C; Hollis, D; Mushiroda, T; Li, L; Friedman, P; Wang, L; Glubb, D; Hurwitz, H; Giacomini, KM; McLeod, HL; Goldberg, RM; Schilsky, RL; Kindler, HL; Nakamura, Y; Ratain, MJ
MLA Citation
Innocenti, F, Owzar, K, Cox, NL, Evans, P, Kubo, M, Zembutsu, H, Jiang, C, Hollis, D, Mushiroda, T, Li, L, Friedman, P, Wang, L, Glubb, D, Hurwitz, H, Giacomini, KM, McLeod, HL, Goldberg, RM, Schilsky, RL, Kindler, HL, Nakamura, Y, and Ratain, MJ. "A genome-wide association study of overall survival in pancreatic cancer patients treated with gemcitabine in CALGB 80303." Clin Cancer Res 18.2 (January 15, 2012): 577-584.
PMID
22142827
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
18
Issue
2
Publish Date
2012
Start Page
577
End Page
584
DOI
10.1158/1078-0432.CCR-11-1387

Dr. McCarthy and colleagues reply

Authors
McCarthy, PL; Owzar, K; Anderson, KC
MLA Citation
McCarthy, PL, Owzar, K, and Anderson, KC. "Dr. McCarthy and colleagues reply." New England Journal of Medicine 367.6 (2012): 574-575.
Source
scival
Published In
The New England journal of medicine
Volume
367
Issue
6
Publish Date
2012
Start Page
574
End Page
575
DOI
10.1056/NEJMc1206734

Statistical considerations for analysis of microarray experiments.

Microarray technologies enable the simultaneous interrogation of expressions from thousands of genes from a biospecimen sample taken from a patient. This large set of expressions generates a genetic profile of the patient that may be used to identify potential prognostic or predictive genes or genetic models for clinical outcomes. The aim of this article is to provide a broad overview of some of the major statistical considerations for the design and analysis of microarrays experiments conducted as correlative science studies to clinical trials. An emphasis will be placed on how the lack of understanding and improper use of statistical concepts and methods will lead to noise discovery and misinterpretation of experimental results.

Authors
Owzar, K; Barry, WT; Jung, S-H
MLA Citation
Owzar, K, Barry, WT, and Jung, S-H. "Statistical considerations for analysis of microarray experiments." Clin Transl Sci 4.6 (December 2011): 466-477. (Review)
PMID
22212230
Source
pubmed
Published In
Clinical and Translational Science
Volume
4
Issue
6
Publish Date
2011
Start Page
466
End Page
477
DOI
10.1111/j.1752-8062.2011.00309.x

Whole blood gene expression analyses in patients with single versus recurrent venous thromboembolism.

INTRODUCTION: Venous thromboembolism may recur in up to 30% of patients with a spontaneous venous thromboembolism after a standard course of anticoagulation. Identification of patients at risk for recurrent venous thromboembolism would facilitate decisions concerning the duration of anticoagulant therapy. OBJECTIVES: In this exploratory study, we investigated whether whole blood gene expression data could distinguish subjects with single venous thromboembolism from subjects with recurrent venous thromboembolism. METHODS: 40 adults with venous thromboembolism (23 with single event and 17 with recurrent events) on warfarin were recruited. Individuals with antiphospholipid syndrome or cancer were excluded. Plasma and serum samples were collected for biomarker testing, and PAXgene tubes were used to collect whole blood RNA samples. RESULTS: D-dimer levels were significantly higher in patients with recurrent venous thromboembolism, but P-selectin and thrombin-antithrombin complex levels were similar in the two groups. Comparison of gene expression data from the two groups provided us with a 50 gene probe model that distinguished these two groups with good receiver operating curve characteristics (AUC 0.75). This model includes genes involved in mRNA splicing and platelet aggregation. Pathway analysis between subjects with single and recurrent venous thromboembolism revealed that the Akt pathway was up-regulated in the recurrent venous thromboembolism group compared to the single venous thromboembolism group. CONCLUSIONS: In this exploratory study, gene expression profiles of whole blood appear to be a useful strategy to distinguish subjects with single venous thromboembolism from those with recurrent venous thromboembolism. Prospective studies with additional patients are needed to validate these results.

Authors
Lewis, DA; Stashenko, GJ; Akay, OM; Price, LI; Owzar, K; Ginsburg, GS; Chi, J-T; Ortel, TL
MLA Citation
Lewis, DA, Stashenko, GJ, Akay, OM, Price, LI, Owzar, K, Ginsburg, GS, Chi, J-T, and Ortel, TL. "Whole blood gene expression analyses in patients with single versus recurrent venous thromboembolism." Thromb Res 128.6 (December 2011): 536-540.
PMID
21737128
Source
pubmed
Published In
Thrombosis Research
Volume
128
Issue
6
Publish Date
2011
Start Page
536
End Page
540
DOI
10.1016/j.thromres.2011.06.003

"Sowing dragon's teeth?" Myeloma and AML.

Authors
McCarthy, PL; Owzar, K; Anderson, K
MLA Citation
McCarthy, PL, Owzar, K, and Anderson, K. ""Sowing dragon's teeth?" Myeloma and AML." Blood 118.15 (October 13, 2011): 4008-4009.
PMID
21998330
Source
pubmed
Published In
Blood
Volume
118
Issue
15
Publish Date
2011
Start Page
4008
End Page
4009
DOI
10.1182/blood-2011-08-372243

Reduced-intensity allogeneic transplantation provides high event-free and overall survival in patients with advanced indolent B cell malignancies: CALGB 109901.

Cancer and Leukemia Group B conducted a phase II study to evaluate the safety and efficacy of a reduced-intensity conditioning regimen with allogeneic transplantation to treat patients with recurrent low-grade B cell malignancies. Patients over age 18 with a diagnosis of relapsed, chemotherapy-sensitive disease underwent transplantation with a matched sibling donor, and conditioning with cyclophosphamide (1 g/m(2)/day × 3) and fludarabine phosphate (25 mg/m(2)/day × 5). Graft-versus-host prophylaxis included cyclosporine or tacrolimus plus low-dose methotrexate. Forty-four evaluable patients with a median age of 53 and median of 2 prior regimens were accrued. Sixteen patients had follicular non-Hodgkin lymphoma and 28 had histologies including 7 indolent B cell lymphomas, 4 mantle cell, 15 chronic lymphocytic leukemia (CLL), and 2 prolymphocytic leukemia (PLL) patients. The 6-month treatment-related mortality (TRM) was 2.4% and 3-year TRM was 9%. Three-year event-free and overall survival were 0.75 and 0.81 for the follicular patients, 0.59 and 0.71 for the CLL/PLL patients, and 0.55 and 0.64 for the other histologies. The incidence of grade II-IV acute graft-versus-host disease (GVHD) was 29%, and extensive chronic GVHD was 18%. This report demonstrates that allogeneic sibling transplantation with a reduced-intensity conditioning regimen is safe and efficacious for patients with advanced indolent B cell malignancies enrolled on a Cooperative Group study.

Authors
Shea, T; Johnson, J; Westervelt, P; Farag, S; McCarty, J; Bashey, A; Isola, L; Baxter-Lowe, LA; Kelly, M; Owzar, K; Linker, C; Cancer and Leukemia Group B,
MLA Citation
Shea, T, Johnson, J, Westervelt, P, Farag, S, McCarty, J, Bashey, A, Isola, L, Baxter-Lowe, LA, Kelly, M, Owzar, K, Linker, C, and Cancer and Leukemia Group B, . "Reduced-intensity allogeneic transplantation provides high event-free and overall survival in patients with advanced indolent B cell malignancies: CALGB 109901." Biol Blood Marrow Transplant 17.9 (September 2011): 1395-1403.
PMID
21296675
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
17
Issue
9
Publish Date
2011
Start Page
1395
End Page
1403
DOI
10.1016/j.bbmt.2011.01.016

Hematopoietic cell infusion for the treatment of nuclear disaster victims: new data from the Chernobyl accident.

PURPOSE: To present previously unavailable data on the use of stem cell administration to aid recovery of victims of the Chernobyl disaster. On 26 April 1986, an accident at Unit 4 of the Chernobyl Nuclear Power Plant took place during the planned test of one of the safety systems. The diagnosis of acute radiation syndrome (ARS) was confirmed in 134 individuals exposed to high levels of radiation. There were nine patients heretofore unreported in the scientific literature who underwent intraosseous injections of allogeneic bone marrow cells in Kyiv. CONCLUSIONS: Transplantation was associated with significantly shortened time to recovery of granulocyte and platelet counts in these patients. While current guidelines would certainly include the use of cytokines, these data provide an indication of the effectiveness of stem cell transplant to treat victims of radiation exposure.

Authors
Klymenko, SV; Belyi, DA; Ross, JR; Owzar, K; Jiang, C; Li, Z; N Minchenko, J; N Kovalenko, A; Bebeshko, VG; J Chao, N
MLA Citation
Klymenko, SV, Belyi, DA, Ross, JR, Owzar, K, Jiang, C, Li, Z, N Minchenko, J, N Kovalenko, A, Bebeshko, VG, and J Chao, N. "Hematopoietic cell infusion for the treatment of nuclear disaster victims: new data from the Chernobyl accident." Int J Radiat Biol 87.8 (August 2011): 846-850.
PMID
21406047
Source
pubmed
Published In
International Journal of Radiation Biology (Informa)
Volume
87
Issue
8
Publish Date
2011
Start Page
846
End Page
850
DOI
10.3109/09553002.2011.560995

Multiple testing for gene sets from microarray experiments.

BACKGROUND: A key objective in many microarray association studies is the identification of individual genes associated with clinical outcome. It is often of additional interest to identify sets of genes, known a priori to have similar biologic function, associated with the outcome. RESULTS: In this paper, we propose a general permutation-based framework for gene set testing that controls the false discovery rate (FDR) while accounting for the dependency among the genes within and across each gene set. The application of the proposed method is demonstrated using three public microarray data sets. The performance of our proposed method is contrasted to two other existing Gene Set Enrichment Analysis (GSEA) and Gene Set Analysis (GSA) methods. CONCLUSIONS: Our simulations show that the proposed method controls the FDR at the desired level. Through simulations and case studies, we observe that our method performs better than GSEA and GSA, especially when the number of prognostic gene sets is large.

Authors
Sohn, I; Owzar, K; Lim, J; George, SL; Mackey Cushman, S; Jung, S-H
MLA Citation
Sohn, I, Owzar, K, Lim, J, George, SL, Mackey Cushman, S, and Jung, S-H. "Multiple testing for gene sets from microarray experiments. (Published online)" BMC Bioinformatics 12 (May 26, 2011): 209-.
Website
http://hdl.handle.net/10161/4639
PMID
21615889
Source
pubmed
Published In
BMC Bioinformatics
Volume
12
Publish Date
2011
Start Page
209
DOI
10.1186/1471-2105-12-209

Discriminating between latent and active tuberculosis with multiple biomarker responses.

We sought to identify biomarker responses to tuberculosis specific antigens which could 1) improve the diagnosis of tuberculosis infection and 2) allow the differentiation of active and latent infections. Seventy subjects with active tuberculosis (N = 12), latent tuberculosis (N = 32), or no evidence of tuberculosis infection (N = 26) were evaluated. We used the Luminex Multiplexed Bead Array platform to simultaneously evaluate 25 biomarkers in the supernatant of whole blood samples following overnight stimulation using the Quantiferon(®) Gold In-Tube kit. We defined the response to stimulation as the difference (within an individual patient) between the response to the pooled tuberculosis antigens and the negative control. IP-10 response was significantly higher in tuberculosis-infected (active or latent) subjects compared to the uninfected group (p < 0.0001). Among the 25 parameters, expression levels of IL-15 and MCP-1 were found to be significantly higher in the active tuberculosis group compared to the latent tuberculosis group (p = 0.0006 and 0.0030, respectively). When combined, IL-15 and MCP-1 accurately identified 83% of active and 88% of latent infections. The combination of IL-15 and MCP-1 responses was accurate in distinguishing persons with active tuberculosis from persons with latent tuberculosis in this study.

Authors
Frahm, M; Goswami, ND; Owzar, K; Hecker, E; Mosher, A; Cadogan, E; Nahid, P; Ferrari, G; Stout, JE
MLA Citation
Frahm, M, Goswami, ND, Owzar, K, Hecker, E, Mosher, A, Cadogan, E, Nahid, P, Ferrari, G, and Stout, JE. "Discriminating between latent and active tuberculosis with multiple biomarker responses." Tuberculosis (Edinb) 91.3 (May 2011): 250-256.
PMID
21393062
Source
pubmed
Published In
Tuberculosis
Volume
91
Issue
3
Publish Date
2011
Start Page
250
End Page
256
DOI
10.1016/j.tube.2011.02.006

Reduced-intensity conditioning allogeneic hematopoietic cell transplantation for patients with hematologic malignancies who relapse following autologous transplantation: a multi-institutional prospective study from the Cancer and Leukemia Group B (CALGB trial 100002).

We prospectively treated 80 patients with relapse of malignancy or secondary myelodysplasia after autologous hematopoietic cell transplantation (AHCT) with allogeneic HCT (allo-HCT) using a reduced-intensity conditioning regimen of fludarabine 150 mg/m(2) plus intravenous busulfan 6.4 mg/kg. Both matched sibling (MSD) and unrelated donors (MUD) were allowed. Patients transplanted from MUD donors received more intensive graft-versus-host disease (GVHD) prophylaxis, including rabbit antithymocyte globulin (ATG) 10 mg/kg, mycophenolate mofetil, and an extended schedule of tacrolimus. With a median follow-up of 3.1 years (0.9-5.8), treatment-related mortality (TRM) at 6 months and 2 years was 8% and 23%, respectively. Neither TRM nor the rates of acute GVHD (aGVHD) were different in those with sibling or MUD donors. Donor CD3 cell chimerism >90% at day +30 was achieved more often in patients with MUD than with matched sibling donors, 70% versus 23% (P < .0001). Median event-free suvival was higher in patients who achieved early full donor chimerism (14.2 versus 8 months, P = .0395). Allo-HCT using this reduced-intensity conditioning regimen can be performed with low TRM in patients who have received a prior AHCT. Efforts to improve early donor CD3 chimerism may improve event-free survival.

Authors
Bashey, A; Owzar, K; Johnson, JL; Edwards, PS; Kelly, M; Baxter-Lowe, LA; Devine, S; Farag, S; Hurd, D; Ball, E; McCarthy, P; Lister, J; Shea, TC; Linker, C
MLA Citation
Bashey, A, Owzar, K, Johnson, JL, Edwards, PS, Kelly, M, Baxter-Lowe, LA, Devine, S, Farag, S, Hurd, D, Ball, E, McCarthy, P, Lister, J, Shea, TC, and Linker, C. "Reduced-intensity conditioning allogeneic hematopoietic cell transplantation for patients with hematologic malignancies who relapse following autologous transplantation: a multi-institutional prospective study from the Cancer and Leukemia Group B (CALGB trial 100002)." Biol Blood Marrow Transplant 17.4 (April 2011): 558-565.
PMID
20674758
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
17
Issue
4
Publish Date
2011
Start Page
558
End Page
565
DOI
10.1016/j.bbmt.2010.07.015

SNPpy--database management for SNP data from genome wide association studies.

BACKGROUND: We describe SNPpy, a hybrid script database system using the Python SQLAlchemy library coupled with the PostgreSQL database to manage genotype data from Genome-Wide Association Studies (GWAS). This system makes it possible to merge study data with HapMap data and merge across studies for meta-analyses, including data filtering based on the values of phenotype and Single-Nucleotide Polymorphism (SNP) data. SNPpy and its dependencies are open source software. RESULTS: The current version of SNPpy offers utility functions to import genotype and annotation data from two commercial platforms. We use these to import data from two GWAS studies and the HapMap Project. We then export these individual datasets to standard data format files that can be imported into statistical software for downstream analyses. CONCLUSIONS: By leveraging the power of relational databases, SNPpy offers integrated management and manipulation of genotype and phenotype data from GWAS studies. The analysis of these studies requires merging across GWAS datasets as well as patient and marker selection. To this end, SNPpy enables the user to filter the data and output the results as standardized GWAS file formats. It does low level and flexible data validation, including validation of patient data. SNPpy is a practical and extensible solution for investigators who seek to deploy central management of their GWAS data.

Authors
Mitha, F; Herodotou, H; Borisov, N; Jiang, C; Yoder, J; Owzar, K
MLA Citation
Mitha, F, Herodotou, H, Borisov, N, Jiang, C, Yoder, J, and Owzar, K. "SNPpy--database management for SNP data from genome wide association studies." PLoS One 6.10 (2011): e24982-.
PMID
22039405
Source
pubmed
Published In
PloS one
Volume
6
Issue
10
Publish Date
2011
Start Page
e24982
DOI
10.1371/journal.pone.0024982

Robust test method for time-course microarray experiments.

BACKGROUND: In a time-course microarray experiment, the expression level for each gene is observed across a number of time-points in order to characterize the temporal trajectories of the gene-expression profiles. For many of these experiments, the scientific aim is the identification of genes for which the trajectories depend on an experimental or phenotypic factor. There is an extensive recent body of literature on statistical methodology for addressing this analytical problem. Most of the existing methods are based on estimating the time-course trajectories using parametric or non-parametric mean regression methods. The sensitivity of these regression methods to outliers, an issue that is well documented in the statistical literature, should be of concern when analyzing microarray data. RESULTS: In this paper, we propose a robust testing method for identifying genes whose expression time profiles depend on a factor. Furthermore, we propose a multiple testing procedure to adjust for multiplicity. CONCLUSIONS: Through an extensive simulation study, we will illustrate the performance of our method. Finally, we will report the results from applying our method to a case study and discussing potential extensions.

Authors
Sohn, I; Owzar, K; George, SL; Kim, S; Jung, S-H
MLA Citation
Sohn, I, Owzar, K, George, SL, Kim, S, and Jung, S-H. "Robust test method for time-course microarray experiments. (Published online)" BMC Bioinformatics 11 (July 22, 2010): 391-.
Website
http://hdl.handle.net/10161/4334
PMID
20649954
Source
pubmed
Published In
BMC Bioinformatics
Volume
11
Publish Date
2010
Start Page
391
DOI
10.1186/1471-2105-11-391

permGPU: Using graphics processing units in RNA microarray association studies.

BACKGROUND: Many analyses of microarray association studies involve permutation, bootstrap resampling and cross-validation, that are ideally formulated as embarrassingly parallel computing problems. Given that these analyses are computationally intensive, scalable approaches that can take advantage of multi-core processor systems need to be developed. RESULTS: We have developed a CUDA based implementation, permGPU, that employs graphics processing units in microarray association studies. We illustrate the performance and applicability of permGPU within the context of permutation resampling for a number of test statistics. An extensive simulation study demonstrates a dramatic increase in performance when using permGPU on an NVIDIA GTX 280 card compared to an optimized C/C++ solution running on a conventional Linux server. CONCLUSIONS: permGPU is available as an open-source stand-alone application and as an extension package for the R statistical environment. It provides a dramatic increase in performance for permutation resampling analysis in the context of microarray association studies. The current version offers six test statistics for carrying out permutation resampling analyses for binary, quantitative and censored time-to-event traits.

Authors
Shterev, ID; Jung, S-H; George, SL; Owzar, K
MLA Citation
Shterev, ID, Jung, S-H, George, SL, and Owzar, K. "permGPU: Using graphics processing units in RNA microarray association studies. (Published online)" BMC Bioinformatics 11 (June 16, 2010): 329-.
Website
http://hdl.handle.net/10161/4333
PMID
20553619
Source
pubmed
Published In
BMC Bioinformatics
Volume
11
Publish Date
2010
Start Page
329
DOI
10.1186/1471-2105-11-329

Growth hormone mitigates against lethal irradiation and enhances hematologic and immune recovery in mice and nonhuman primates.

Medications that can mitigate against radiation injury are limited. In this study, we investigated the ability of recombinant human growth hormone (rhGH) to mitigate against radiation injury in mice and nonhuman primates. BALB/c mice were irradiated with 7.5 Gy and treated post-irradiation with rhGH intravenously at a once daily dose of 20 microg/dose for 35 days. rhGH protected 17 out of 28 mice (60.7%) from lethal irradiation while only 3 out of 28 mice (10.7%) survived in the saline control group. A shorter course of 5 days of rhGH post-irradiation produced similar results. Compared with the saline control group, treatment with rhGH on irradiated BALB/c mice significantly accelerated overall hematopoietic recovery. Specifically, the recovery of total white cells, CD4 and CD8 T cell subsets, B cells, NK cells and especially platelets post radiation exposure were significantly accelerated in the rhGH-treated mice. Moreover, treatment with rhGH increased the frequency of hematopoietic stem/progenitor cells as measured by flow cytometry and colony forming unit assays in bone marrow harvested at day 14 after irradiation, suggesting the effects of rhGH are at the hematopoietic stem/progenitor level. rhGH mediated the hematopoietic effects primarily through their niches. Similar data with rhGH were also observed following 2 Gy sublethal irradiation of nonhuman primates. Our data demonstrate that rhGH promotes hematopoietic engraftment and immune recovery post the exposure of ionizing radiation and mitigates against the mortality from lethal irradiation even when administered after exposure.

Authors
Chen, BJ; Deoliveira, D; Spasojevic, I; Sempowski, GD; Jiang, C; Owzar, K; Wang, X; Gesty-Palmer, D; Cline, JM; Bourland, JD; Dugan, G; Meadows, SK; Daher, P; Muramoto, G; Chute, JP; Chao, NJ
MLA Citation
Chen, BJ, Deoliveira, D, Spasojevic, I, Sempowski, GD, Jiang, C, Owzar, K, Wang, X, Gesty-Palmer, D, Cline, JM, Bourland, JD, Dugan, G, Meadows, SK, Daher, P, Muramoto, G, Chute, JP, and Chao, NJ. "Growth hormone mitigates against lethal irradiation and enhances hematologic and immune recovery in mice and nonhuman primates. (Published online)" PLoS One 5.6 (June 16, 2010): e11056-.
Website
http://hdl.handle.net/10161/4547
PMID
20585403
Source
pubmed
Published In
PloS one
Volume
5
Issue
6
Publish Date
2010
Start Page
e11056
DOI
10.1371/journal.pone.0011056

Early and late administration of MnTE-2-PyP5+ in mitigation and treatment of radiation-induced lung damage.

Chronic production of reactive oxygen and nitrogen species is an underlying mechanism of irradiation (IR)-induced lung injury. The purpose of this study was to determine the optimum time of delivery of an antioxidant and redox-modulating Mn porphyrin, MnTE-2-PyP(5+), to mitigate and/or treat IR-induced lung damage. Female Fischer-344 rats were irradiated to their right hemithorax (28 Gy). Irradiated animals were treated with PBS or MnTE-2-PyP(5+) (6 mg /kg/24 h) delivered for 2 weeks by sc-implanted osmotic pumps (beginning after 2, 6, 12, 24, or 72 h or 8 weeks). Animals were sacrificed 10 weeks post-IR. Endpoints were body weight, breathing frequency, histopathology, and immunohistochemistry (8-OHdG, ED-1, TGF-beta, HIF-1alpha, VEGF A). A significant radioprotective effect on functional injury, measured by breathing frequency, was observed for all animals treated with MnTE-2-PyP(5+). Treatment with MnTE-2-PyP(5+) starting 2, 6, and 12 h but not after 24 or 72 h resulted in a significant decrease in immunostaining for 8-OHdG, HIF-1alpha, TGF-beta, and VEGF A. A significant decrease in HIF-1alpha, TGF-beta, and VEGF A, as well as an overall reduction in lung damage (histopathology), was observed in animals beginning treatment at the time of fully developed lung injury (8 weeks post-IR). The catalytic manganese porphyrin antioxidant and modulator of redox-based signaling pathways MnTE-2-PyP(5+) mitigates radiation-induced lung injury when given within the first 12 h after IR. More importantly, this is the first study to demonstrate that MnTE-2-PyP(5+) can reverse overall lung damage when started at the time of established lung injury 8 weeks post-IR. The radioprotective effects are presumably mediated through its ability both to suppress oxidative stress and to decrease activation of key transcription factors and proangiogenic and profibrogenic cytokines.

Authors
Gauter-Fleckenstein, B; Fleckenstein, K; Owzar, K; Jiang, C; Rebouças, JS; Batinic-Haberle, I; Vujaskovic, Z
MLA Citation
Gauter-Fleckenstein, B, Fleckenstein, K, Owzar, K, Jiang, C, Rebouças, JS, Batinic-Haberle, I, and Vujaskovic, Z. "Early and late administration of MnTE-2-PyP5+ in mitigation and treatment of radiation-induced lung damage." Free Radic Biol Med 48.8 (April 15, 2010): 1034-1043.
PMID
20096348
Source
pubmed
Published In
Free Radical Biology and Medicine
Volume
48
Issue
8
Publish Date
2010
Start Page
1034
End Page
1043
DOI
10.1016/j.freeradbiomed.2010.01.020

The importance of identifying and validating prognostic factors in oncology.

Prognosis plays a vital role in patient management and decision making. The assessment of prognostic factors, which relate baseline clinical and experimental covariables to outcomes, is one of the major objectives in clinical research. Historically, the impetus for the identification of prognostic factors has been the need to accurately estimate the effect of treatment adjusting for these variables. In oncology, the variability in outcome may be related to prognostic factors rather than to differences in treatments. In this article, we begin with a brief review of prognostic factors, and then subsequently offer a general discussion of their importance. Next, we describe the significance of study design before presenting various modeling approaches for identifying these factors and discussing the relative values of the different approaches. We illustrate the concepts within the framework of published and ongoing phase III trials in oncology.

Authors
Halabi, S; Owzar, K
MLA Citation
Halabi, S, and Owzar, K. "The importance of identifying and validating prognostic factors in oncology." Semin Oncol 37.2 (April 2010): e9-18. (Review)
PMID
20494694
Source
pubmed
Published In
Seminars in Oncology
Volume
37
Issue
2
Publish Date
2010
Start Page
e9
End Page
18
DOI
10.1053/j.seminoncol.2010.04.001

Sentinel lymph node biopsy accurately stages the regional lymph nodes for T1-T2 oral squamous cell carcinomas: results of a prospective multi-institutional trial.

PURPOSE: The validity of sentinel lymph node biopsy (SLNB) for T1 or T2, clinically N0, oral cancer was tested by correlation of sentinel node pathologic status with that of nodes within the completion neck dissection. METHODS: This prospective, cooperative group trial involved 25 institutions over a 3-year period. One hundred forty patients with invasive oral cancers, stage T1 and T2, N0 including 95 cancers of the tongue, 26 of the floor of mouth, and 19 other oral cancers were studied. The study excluded lesions with diameter smaller than 6 mm or minimal invasion. Imaging was used to exclude nonpalpable gross nodal disease. Patients underwent injection of the lesion with (99m)Tc-sulfur colloid, nuclear imaging, narrow-exposure SLNB, and completion selective neck dissection. The major end point was the negative-predictive value (NPV) of SLNB. RESULTS: In the 106 SLNBs, which were found to be pathologically and clinically node-negative by routine hematoxylin and eosin stain, 100 patients were found to have no other pathologically positive nodes, corresponding to a NPV of 94%. With additional sectioning and immunohistochemistry, NPV was improved to 96%. In the forty patients with proven cervical metastases, the true-positive rate was 90.2% and was superior for tongue tumors relative to floor of mouth. For T1 lesions, metastases were correctly identified in 100%. CONCLUSION: For T1 or T2 N0 oral squamous cell carcinoma, SLNB with step sectioning and immunohistochemistry, performed by surgeons of mixed experience levels, correctly predicted a pathologically negative neck in 96% of patients (NPV, 96%).

Authors
Civantos, FJ; Zitsch, RP; Schuller, DE; Agrawal, A; Smith, RB; Nason, R; Petruzelli, G; Gourin, CG; Wong, RJ; Ferris, RL; El Naggar, A; Ridge, JA; Paniello, RC; Owzar, K; McCall, L; Chepeha, DB; Yarbrough, WG; Myers, JN
MLA Citation
Civantos, FJ, Zitsch, RP, Schuller, DE, Agrawal, A, Smith, RB, Nason, R, Petruzelli, G, Gourin, CG, Wong, RJ, Ferris, RL, El Naggar, A, Ridge, JA, Paniello, RC, Owzar, K, McCall, L, Chepeha, DB, Yarbrough, WG, and Myers, JN. "Sentinel lymph node biopsy accurately stages the regional lymph nodes for T1-T2 oral squamous cell carcinomas: results of a prospective multi-institutional trial." J Clin Oncol 28.8 (March 10, 2010): 1395-1400.
PMID
20142602
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
28
Issue
8
Publish Date
2010
Start Page
1395
End Page
1400
DOI
10.1200/JCO.2008.20.8777

A permutation-based multiple testing method for time-course microarray experiments.

BACKGROUND: Time-course microarray experiments are widely used to study the temporal profiles of gene expression. Storey et al. (2005) developed a method for analyzing time-course microarray studies that can be applied to discovering genes whose expression trajectories change over time within a single biological group, or those that follow different time trajectories among multiple groups. They estimated the expression trajectories of each gene using natural cubic splines under the null (no time-course) and alternative (time-course) hypotheses, and used a goodness of fit test statistic to quantify the discrepancy. The null distribution of the statistic was approximated through a bootstrap method. Gene expression levels in microarray data are often complicatedly correlated. An accurate type I error control adjusting for multiple testing requires the joint null distribution of test statistics for a large number of genes. For this purpose, permutation methods have been widely used because of computational ease and their intuitive interpretation. RESULTS: In this paper, we propose a permutation-based multiple testing procedure based on the test statistic used by Storey et al. (2005). We also propose an efficient computation algorithm. Extensive simulations are conducted to investigate the performance of the permutation-based multiple testing procedure. The application of the proposed method is illustrated using the Caenorhabditis elegans dauer developmental data. CONCLUSION: Our method is computationally efficient and applicable for identifying genes whose expression levels are time-dependent in a single biological group and for identifying the genes for which the time-profile depends on the group in a multi-group setting.

Authors
Sohn, I; Owzar, K; George, SL; Kim, S; Jung, S-H
MLA Citation
Sohn, I, Owzar, K, George, SL, Kim, S, and Jung, S-H. "A permutation-based multiple testing method for time-course microarray experiments. (Published online)" BMC Bioinformatics 10 (October 15, 2009): 336-.
PMID
19832992
Source
pubmed
Published In
BMC Bioinformatics
Volume
10
Publish Date
2009
Start Page
336
DOI
10.1186/1471-2105-10-336

Auto-SCT for AML in second remission: CALGB study 9620.

We studied the feasibility and efficacy of a two-step approach to Auto-SCT for patients with AML in second remission. Step 1 consisted of consolidation chemotherapy using cytarabine 2000 mg/m(2) i.v. every 12 h for 4 days plus etoposide 40 mg/kg total dose by continuous i.v. infusion over the same 4 days. PBSC were collected after G-CSF stimulation during recovery from this chemotherapy. Step 2, auto-SCT, used a preparative regimen of oral BU 16 mg/kg over 4 days followed by etoposide 60 mg/kg i.v. Of the 50 patients entered on Step 1, two died from treatment complications, and seven failed to proceed to transplantation. A median CD34+ cell dose of 5.9 x 10(6)/kg was collected in a median of three collections. With a median follow-up of 8.2 years, 5-year disease-free survival (DFS) is 28%. The most important prognostic factor was cytogenetics, with acute promyelocytic leukemia (APL) patients having a 5-year DFS of 67% compared with 16% for others. We conclude that this two-step approach to autologous transplantation produces good CD34+ mobilization and that this approach has cured some patients. Results in patients with APL are especially promising.

Authors
Linker, CA; Owzar, K; Powell, B; Hurd, D; Damon, LE; Archer, LE; Larson, RA; Cancer and Leukemia Group B,
MLA Citation
Linker, CA, Owzar, K, Powell, B, Hurd, D, Damon, LE, Archer, LE, Larson, RA, and Cancer and Leukemia Group B, . "Auto-SCT for AML in second remission: CALGB study 9620." Bone Marrow Transplant 44.6 (September 2009): 353-359.
PMID
19289999
Source
pubmed
Published In
Bone Marrow Transplantation
Volume
44
Issue
6
Publish Date
2009
Start Page
353
End Page
359
DOI
10.1038/bmt.2009.36

Progression-free survival as a predictor of overall survival in men with castrate-resistant prostate cancer.

PURPOSE: To explore whether progression-free survival (PFS) or biochemical PFS can be used as a predictor of overall survival (OS) and to investigate the dependence between PFS and OS in men with castrate-resistant prostate cancer. PATIENTS AND METHODS: Data from nine Cancer and Leukemia Group B trials that enrolled 1,296 men from 1991 to 2004 were pooled. Men were eligible if they had prostate cancer that had progressed during androgen deprivation therapy and did not receive prior treatment with chemotherapy, immunotherapy, or other nonhormonal therapy. Landmark analyses of PFS at 3 and 6 months from randomization/registration were performed to minimize lead time bias. The proportional hazards model was used to assess the significance effect of PFS rate at 3 and at 6 months in predicting OS. In addition, biochemical progression using the definitions of Prostate-Specific Antigen Working Group (PSAW) Criteria PSAWG1 and PSAWG2 were analyzed as time-dependent covariates in predicting OS. RESULTS: The median survival time among men who experienced progression at 3 months was 9.2 months (95% CI, 8.0 to 10.0 months) compared with 17.8 months in men who did not experience progression at 3 months (95% CI, 16.2 to 20.4 months; P < .0001). Compared with men who did not progress at 3 and at 6 months, the adjusted hazard ratios for death were 2.0 (95% CI, 1.7 to 2.4; P < .001) and 1.9 (95% CI, 1.6 to 2.4; P < .001) for men who experienced progression at 3 and 6 months, respectively. In addition, biochemical progression at 3 months predicted OS. The association between PFS and OS was 0.30 (95% confidence limits = 0.26, 0.32). CONCLUSION: PFS at 3 and 6 months and biochemical progression at 3 months predict OS. These observations require prospective validation.

Authors
Halabi, S; Vogelzang, NJ; Ou, S-S; Owzar, K; Archer, L; Small, EJ
MLA Citation
Halabi, S, Vogelzang, NJ, Ou, S-S, Owzar, K, Archer, L, and Small, EJ. "Progression-free survival as a predictor of overall survival in men with castrate-resistant prostate cancer." J Clin Oncol 27.17 (June 10, 2009): 2766-2771.
PMID
19380448
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
27
Issue
17
Publish Date
2009
Start Page
2766
End Page
2771
DOI
10.1200/JCO.2008.18.9159

Heterogeneous neutralizing antibody and antibody-dependent cell cytotoxicity responses in HIV-1 elite controllers.

OBJECTIVE: To determine the spectrum of antiviral antibodies in HIV-1-infected individuals in whom viral replication is spontaneously undetectable, termed HIV controllers (HICs). DESIGN: Multicenter French trial ANRS EP36 studying the viral control in HICs. METHODS: Neutralizing Antibody (nAb) activities (neutralization assay, competition with broadly reactive monoclonal antibodies, and reactivity against the viral MPER gp41 region), FcgammaR-mediated antiviral activities, antibody-dependent cell cytotoxicity (ADCC), as well as autoantibody levels, were quantified in plasma from 22 controllers and from viremic individuals. The levels of these different antibody responses and HIV-specific CD8 T cell responses quantified by enzyme-linked immunosorbent spot (ELISPOT) IFNgamma assay were compared in each controller. RESULTS: The levels of antibody against the gp120 CD4 binding site, gp41, as well as Env epitopes near to the sites bound by broadly nAbs 2F5 and 1b12 were not different between HICs and viremic individuals. We did not find significant autoantibody levels in HICs. The magnitude and breadth of nAbs were heterogeneous in HICs but lower than in viremic individuals. The levels of nAbs using FcgammaR-mediated assay inhibition were similar in both groups. Regardless of the type of antibody tested, there was no correlation with HIV-specific CD8 T cell responses. ADCC was detectable in all controllers tested and was significantly higher than in viremic individuals (P < 0.0002). CONCLUSION: There was no single anti-HIV-1 antibody specificity that was a clear correlate of immunity in controllers. Rather, for most antibody types, controllers had the same or lower levels of nAbs than viremic individuals, with the possible exception of ADCC antibodies.

Authors
Lambotte, O; Ferrari, G; Moog, C; Yates, NL; Liao, H-X; Parks, RJ; Hicks, CB; Owzar, K; Tomaras, GD; Montefiori, DC; Haynes, BF; Delfraissy, J-F
MLA Citation
Lambotte, O, Ferrari, G, Moog, C, Yates, NL, Liao, H-X, Parks, RJ, Hicks, CB, Owzar, K, Tomaras, GD, Montefiori, DC, Haynes, BF, and Delfraissy, J-F. "Heterogeneous neutralizing antibody and antibody-dependent cell cytotoxicity responses in HIV-1 elite controllers." AIDS 23.8 (May 15, 2009): 897-906.
PMID
19414990
Source
pubmed
Published In
AIDS
Volume
23
Issue
8
Publish Date
2009
Start Page
897
End Page
906
DOI
10.1097/QAD.0b013e328329f97d

Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301.

PURPOSE: We sought to characterize the pharmacokinetics (PK) and determine a tolerable dose of oral sorafenib in patients with hepatic or renal dysfunction. PATIENTS AND METHODS: Patients were assigned to one of nine cohorts: cohort 1, bilirubin < or = upper limit of normal (ULN) and AST < or = ULN and creatinine clearance (CC) > or = 60 mL/min; cohort 2, bilirubin more than ULN but < or = 1.5x ULN and/or AST more than ULN; cohort 3, CC between 40 and 59 mL/min; cohort 4, bilirubin more than 1.5x ULN to < or = 3x ULN (any AST); cohort 5, CC between 20 and 39 mL/min; cohort 6, bilirubin more than 3x ULN to 10x ULN (any AST); cohort 7, CC less than 20 mL/min; cohort 8, albumin less than 2.5 mg/dL (any bilirubin/AST); and cohort 9, hemodialysis. Sorafenib was administered as a 400-mg dose on day 1 for PK, and continuous daily dosing started on day 8. RESULTS: Of 150 registered patients, 138 patients were treated. With the exception of cohorts 6 and 7, at least 12 patients per cohort were assessable, and the dose level with prospectively defined dose-limiting toxicity in less than one third of patients by day 29 was considered tolerable. No significant associations between the sorafenib PK and cohort were found. CONCLUSION: We recommend the following empiric sorafenib starting doses by cohort: cohort 1, 400 mg twice a day; cohort 2, 400 mg twice a day; cohort 3, 400 mg twice a day; cohort 4, 200 mg twice a day; cohort 5, 200 mg twice a day; cohort 6, not even 200 mg every third day tolerable; cohort 7, not defined; cohort 8, 200 mg each day; and cohort 9, 200 mg each day.

Authors
Miller, AA; Murry, DJ; Owzar, K; Hollis, DR; Kennedy, EB; Abou-Alfa, G; Desai, A; Hwang, J; Villalona-Calero, MA; Dees, EC; Lewis, LD; Fakih, MG; Edelman, MJ; Millard, F; Frank, RC; Hohl, RJ; Ratain, MJ
MLA Citation
Miller, AA, Murry, DJ, Owzar, K, Hollis, DR, Kennedy, EB, Abou-Alfa, G, Desai, A, Hwang, J, Villalona-Calero, MA, Dees, EC, Lewis, LD, Fakih, MG, Edelman, MJ, Millard, F, Frank, RC, Hohl, RJ, and Ratain, MJ. "Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301." J Clin Oncol 27.11 (April 10, 2009): 1800-1805.
PMID
19255312
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
27
Issue
11
Publish Date
2009
Start Page
1800
End Page
1805
DOI
10.1200/JCO.2008.20.0931

Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Gastrointestinal stromal tumour is the most common sarcoma of the intestinal tract. Imatinib mesylate is a small molecule that inhibits activation of the KIT and platelet-derived growth factor receptor alpha proteins, and is effective in first-line treatment of metastatic gastrointestinal stromal tumour. We postulated that adjuvant treatment with imatinib would improve recurrence-free survival compared with placebo after resection of localised, primary gastrointestinal stromal tumour. METHODS: We undertook a randomised phase III, double-blind, placebo-controlled, multicentre trial. Eligible patients had complete gross resection of a primary gastrointestinal stromal tumour at least 3 cm in size and positive for the KIT protein by immunohistochemistry. Patients were randomly assigned, by a stratified biased coin design, to imatinib 400 mg (n=359) or to placebo (n=354) daily for 1 year after surgical resection. Patients and investigators were blinded to the treatment group. Patients assigned to placebo were eligible to crossover to imatinib treatment in the event of tumour recurrence. The primary endpoint was recurrence-free survival, and analysis was by intention to treat. Accrual was stopped early because the trial results crossed the interim analysis efficacy boundary for recurrence-free survival. This study is registered with ClinicalTrials.gov, number NCT00041197. FINDINGS: All randomised patients were included in the analysis. At median follow-up of 19.7 months (minimum-maximum 0-56.4), 30 (8%) patients in the imatinib group and 70 (20%) in the placebo group had had tumour recurrence or had died. Imatinib significantly improved recurrence-free survival compared with placebo (98% [95% CI 96-100] vs 83% [78-88] at 1 year; hazard ratio [HR] 0.35 [0.22-0.53]; one-sided p<0.0001). Adjuvant imatinib was well tolerated, with the most common serious events being dermatitis (11 [3%] vs 0), abdominal pain (12 [3%] vs six [1%]), and diarrhoea (ten [2%] vs five [1%]) in the imatinib group and hyperglycaemia (two [<1%] vs seven [2%]) in the placebo group. INTERPRETATION: Adjuvant imatinib therapy is safe and seems to improve recurrence-free survival compared with placebo after the resection of primary gastrointestinal stromal tumour. FUNDING: US National Institutes of Health and Novartis Pharmaceuticals.

Authors
Dematteo, RP; Ballman, KV; Antonescu, CR; Maki, RG; Pisters, PW; Demetri, GD; Blackstein, ME; Blanke, CD; von Mehren, M; Brennan, MF; Patel, S; McCarter, MD; Polikoff, JA; Tan, BR; Owzar, K; American College of Surgeons Oncology Group (ACOSOG) Intergroup Adjuvant GIST Study Team,
MLA Citation
Dematteo, RP, Ballman, KV, Antonescu, CR, Maki, RG, Pisters, PW, Demetri, GD, Blackstein, ME, Blanke, CD, von Mehren, M, Brennan, MF, Patel, S, McCarter, MD, Polikoff, JA, Tan, BR, Owzar, K, and American College of Surgeons Oncology Group (ACOSOG) Intergroup Adjuvant GIST Study Team, . "Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial." Lancet 373.9669 (March 28, 2009): 1097-1104.
PMID
19303137
Source
pubmed
Published In
The Lancet
Volume
373
Issue
9669
Publish Date
2009
Start Page
1097
End Page
1104
DOI
10.1016/S0140-6736(09)60500-6

Flaxseed supplementation (not dietary fat restriction) reduces prostate cancer proliferation rates in men presurgery.

BACKGROUND: Prostate cancer affects one of six men during their lifetime. Dietary factors are postulated to influence the development and progression of prostate cancer. Low-fat diets and flaxseed supplementation may offer potentially protective strategies. METHODS: We undertook a multisite, randomized controlled trial to test the effects of low-fat and/or flaxseed-supplemented diets on the biology of the prostate and other biomarkers. Prostate cancer patients (n = 161) scheduled at least 21 days before prostatectomy were randomly assigned to one of the following arms: (a) control (usual diet), (b) flaxseed-supplemented diet (30 g/d), (c) low-fat diet (<20% total energy), or (d) flaxseed-supplemented, low-fat diet. Blood was drawn at baseline and before surgery and analyzed for prostate-specific antigen, sex hormone-binding globulin, testosterone, insulin-like growth factor-I and binding protein-3, C-reactive protein, and total and low-density lipoprotein cholesterol. Tumors were assessed for proliferation (Ki-67, the primary endpoint) and apoptosis. RESULTS: Men were on protocol an average of 30 days. Proliferation rates were significantly lower (P < 0.002) among men assigned to the flaxseed arms. Median Ki-67-positive cells/total nuclei ratios (x100) were 1.66 (flaxseed-supplemented diet) and 1.50 (flaxseed-supplemented, low-fat diet) versus 3.23 (control) and 2.56 (low-fat diet). No differences were observed between arms with regard to side effects, apoptosis, and most serologic endpoints; however, men on low-fat diets experienced significant decreases in serum cholesterol (P = 0.048). CONCLUSIONS: Findings suggest that flaxseed is safe and associated with biological alterations that may be protective for prostate cancer. Data also further support low-fat diets to manage serum cholesterol.

Authors
Demark-Wahnefried, W; Polascik, TJ; George, SL; Switzer, BR; Madden, JF; Ruffin, MT; Snyder, DC; Owzar, K; Hars, V; Albala, DM; Walther, PJ; Robertson, CN; Moul, JW; Dunn, BK; Brenner, D; Minasian, L; Stella, P; Vollmer, RT
MLA Citation
Demark-Wahnefried, W, Polascik, TJ, George, SL, Switzer, BR, Madden, JF, Ruffin, MT, Snyder, DC, Owzar, K, Hars, V, Albala, DM, Walther, PJ, Robertson, CN, Moul, JW, Dunn, BK, Brenner, D, Minasian, L, Stella, P, and Vollmer, RT. "Flaxseed supplementation (not dietary fat restriction) reduces prostate cancer proliferation rates in men presurgery." Cancer Epidemiol Biomarkers Prev 17.12 (December 2008): 3577-3587.
PMID
19064574
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
17
Issue
12
Publish Date
2008
Start Page
3577
End Page
3587
DOI
10.1158/1055-9965.EPI-08-0008

Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group.

PURPOSE: Imatinib mesylate is standard treatment for patients who have advanced gastrointestinal stromal tumor (GIST), but not all patients benefit equally. In previous studies, GIST genotype correlated with treatment outcome and optimal imatinib dosing. PATIENTS AND METHODS: We examined the relationship between kinase genotype and treatment outcome for 428 patients enrolled on the North American phase III study SWOG S0033/CALGB 150105 and treated with either 400 mg or 800 mg daily doses of imatinib. RESULTS: The presence of KIT exon 11-mutant genotype (n = 283) correlated with improved treatment outcome when compared with KIT exon 9-mutant (n = 32) and wild-type (WT; n = 67) genotypes for objective response (complete response [CR]/partial response [PR], 71.7% v 44.4% [P = .007]; and 44.6% [P = .0002], respectively); time to tumor progression (TTP; median 24.7 months v 16.7 and 12.8 months, respectively); and overall survival (OS; median 60.0 months v 38.4 and 49.0 months, respectively). The survival outcomes for patients with exon 9-mutant, exon 11-mutant or WT GIST were not affected by imatinib dose. However, there was evidence of improved response rates for patients with exon 9-mutant tumors treated with imatinib 800 mg versus 400 mg (CR/PR, 67% v 17%; P = .02). Patients who had CD117-negative GIST had similar TTP but inferior OS compared with patients who had CD117-positive disease, which suggests that patients who have CD117-negative GIST may benefit from imatinib treatment. In addition, we identified novel but rare mutations of the KIT extracellular domain (exons 8 and 9). CONCLUSION: We confirmed the favorable impact of KIT exon 11 genotype when compared with KIT exon 9 and wild-type genotype for patients with advanced GIST who are treated with imatinib.

Authors
Heinrich, MC; Owzar, K; Corless, CL; Hollis, D; Borden, EC; Fletcher, CD; Ryan, CW; von Mehren, M; Blanke, CD; Rankin, C; Benjamin, RS; Bramwell, VH; Demetri, GD; Bertagnolli, MM; Fletcher, JA
MLA Citation
Heinrich, MC, Owzar, K, Corless, CL, Hollis, D, Borden, EC, Fletcher, CD, Ryan, CW, von Mehren, M, Blanke, CD, Rankin, C, Benjamin, RS, Bramwell, VH, Demetri, GD, Bertagnolli, MM, and Fletcher, JA. "Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group." J Clin Oncol 26.33 (November 20, 2008): 5360-5367.
PMID
18955451
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
26
Issue
33
Publish Date
2008
Start Page
5360
End Page
5367
DOI
10.1200/JCO.2008.17.4284

Statistical challenges in preprocessing in microarray experiments in cancer.

Many clinical studies incorporate genomic experiments to investigate the potential associations between high-dimensional molecular data and clinical outcome. A critical first step in the statistical analyses of these experiments is that the molecular data are preprocessed. This article provides an overview of preprocessing methods, including summary algorithms and quality control metrics for microarrays. Some of the ramifications and effects that preprocessing methods have on the statistical results are illustrated. The discussions are centered around a microarray experiment based on lung cancer tumor samples with survival as the clinical outcome of interest. The procedures that are presented focus on the array platform used in this study. However, many of these issues are more general and are applicable to other instruments for genome-wide investigation. The discussions here will provide insight into the statistical challenges in preprocessing microarrays used in clinical studies of cancer. These challenges should not be viewed as inconsequential nuisances but rather as important issues that need to be addressed so that informed conclusions can be drawn.

Authors
Owzar, K; Barry, WT; Jung, S-H; Sohn, I; George, SL
MLA Citation
Owzar, K, Barry, WT, Jung, S-H, Sohn, I, and George, SL. "Statistical challenges in preprocessing in microarray experiments in cancer." Clin Cancer Res 14.19 (October 1, 2008): 5959-5966. (Review)
PMID
18829474
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
14
Issue
19
Publish Date
2008
Start Page
5959
End Page
5966
DOI
10.1158/1078-0432.CCR-07-4532

Alternate statistical tools and limitations in genetic marker association studies in single-arm drug cancer trials.

Authors
Owzar, K
MLA Citation
Owzar, K. "Alternate statistical tools and limitations in genetic marker association studies in single-arm drug cancer trials." J Clin Oncol 26.9 (March 20, 2008): 1400-1401.
PMID
18349389
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
26
Issue
9
Publish Date
2008
Start Page
1400
End Page
1401
DOI
10.1200/JCO.2007.14.7306

Comparison of two Mn porphyrin-based mimics of superoxide dismutase in pulmonary radioprotection.

Development of radiation therapy (RT)-induced lung injury is associated with chronic production of reactive oxygen and nitrogen species (ROS/RNS). MnTE-2-PyP5+ is a catalytic Mn porphyrin mimic of SOD, already shown to protect lungs from RT-induced injury by scavenging ROS/RNS. The purpose of this study was to compare MnTE-2-PyP5+ with a newly introduced analogue MnTnHex-2-PyP5+, which is expected to be a more effective radioprotector due to its lipophilic properties. This study shows that Fischer rats which were irradiated to their right hemithorax (28 Gy) have less pulmonary injury as measured using breathing frequencies when treated with daily subcutaneous injections of MnTE-2-PyP5+ (3 and 6 mg/kg) or MnTnHex-2-PyP5+ (0.3, 0.6, or 1.0 mg/kg) for 2 weeks after RT. However, at 16 weeks post-RT, only MnTE-2-PyP5+ at a dose of 6 mg/kg is able to ameliorate oxidative damage, block activation of HIF-1alpha and TGF-beta, and impair upregulation of CA-IX and VEGF. MnTnHex-2-PyP5+ at a dose of 0.3 mg/kg is effective only in reducing RT-induced TGF-beta and CA-IX expression. Significant loss of body weight was observed in animals receiving MnTnHex-2-PyP5+ (0.3 and 0.6 mg/kg). MnTnHex-2-PyP5+ has the ability to dissolve lipid membranes, causing local irritation/necrosis at injection sites if given at doses of 1 mg/kg or higher. In conclusion, both compounds show an ability to ameliorate lung damage as measured using breathing frequencies and histopathologic evaluation. However, MnTE-2-PyP5+ at 6 mg/kg proved to be more effective in reducing expression of key molecular factors known to play an important role in radiation-induced lung injury.

Authors
Gauter-Fleckenstein, B; Fleckenstein, K; Owzar, K; Jiang, C; Batinic-Haberle, I; Vujaskovic, Z
MLA Citation
Gauter-Fleckenstein, B, Fleckenstein, K, Owzar, K, Jiang, C, Batinic-Haberle, I, and Vujaskovic, Z. "Comparison of two Mn porphyrin-based mimics of superoxide dismutase in pulmonary radioprotection." Free Radic Biol Med 44.6 (March 15, 2008): 982-989.
PMID
18082148
Source
pubmed
Published In
Free Radical Biology & Medicine
Volume
44
Issue
6
Publish Date
2008
Start Page
982
End Page
989
DOI
10.1016/j.freeradbiomed.2007.10.058

Authors' response

Authors
Owzar, K; Jung, S-H
MLA Citation
Owzar, K, and Jung, S-H. "Authors' response." Clinical Trials 5.3 (2008): 223-224.
Source
scival
Published In
Clinical Trials
Volume
5
Issue
3
Publish Date
2008
Start Page
223
End Page
224
DOI
10.1177/17407745080050031102

Designing phase II studies in cancer with time-to-event endpoints.

BACKGROUND: The primary clinical endpoint in many phase II studies in cancer is a time-to-event outcome subject to potential censoring. The decision in favor of abandoning or continuing investigation of the protocol regimen is typically based on the amount of statistical evidence suggesting an improvement compared to a given historical control. The primary statistical endpoint would typically be the median of the time-to-event distribution of the clinical endpoint. For the purpose of sample size or power calculations, software implementing parametric and nonparametric median tests, is freely available. The main assumptions are those of Exponential survival and a Uniform right-censoring mechanism. PURPOSE: The performance of the parametric and nonparametric methods is compared to that of using a binomial endpoint based on dichotomizing the event time at a clinically relevant landmark. As sufficient details on the various methods and related designs for phase II clinical design with survival endpoints are provided, this article should also serve as a comparative reference on these three methods for designing phase II studies in cancer with time-to-event endpoints. METHODS: The statistical performance, by virtue of considering the type I and II error rates, of the three methods is compared by carrying out a comprehensive simulation study. RESULTS: The parametric method may fail to control the type I error rate if the underlying survival distribution is not Exponential, while the nonparametric method may fail to control the type I error rate as the sample sizes for phase II studies are typically small. Both of these methods may be sensitive to the distribution of the censoring variable. LIMITATIONS: The results provided in this article are mostly discussed in the framework of specific examples and by using specific implementations of the tests. As such the results may not be universally generalizable. The recommended method has some drawbacks if patients are censored before the landmark of interest. CONCLUSION: A method that should be considered for the purpose of the statistical design and decision rule for phase II studies in cancer is the employment of a binomial endpoint based on dichotomizing the event time at a clinically relevant landmark.

Authors
Owzar, K; Jung, S-H
MLA Citation
Owzar, K, and Jung, S-H. "Designing phase II studies in cancer with time-to-event endpoints." Clin Trials 5.3 (2008): 209-221.
PMID
18559409
Source
pubmed
Published In
Clinical Trials
Volume
5
Issue
3
Publish Date
2008
Start Page
209
End Page
221
DOI
10.1177/1740774508091748

A copula approach for detecting prognostic genes associated with survival outcome in microarray studies.

A challenging and crucial issue in clinical studies in cancer involving gene microarray experiments is the discovery, among a large number of genes, of a relatively small panel of genes whose elements are associated with a relevant clinical outcome variable such as time-to-death or time-to-recurrence of disease. A semiparametric approach, using dependence functions known as copulas, is considered to quantify and estimate the pairwise association between the outcome and each gene expression. These time-to-event type endpoints are typically subject to censoring as not all events are realized at the time of the analysis. Furthermore, given that the total number of genes is typically large, it is imperative to control a relevant error rate in any gene discovery procedure. The proposed method addresses the two aforementioned issues by direct incorporation of the censoring mechanism and by appropriate statistical adjustment for multiplicity. The performance of the proposed method is studied through simulation and illustrated with an application using a case study in lung cancer.

Authors
Owzar, K; Jung, S-H; Sen, PK
MLA Citation
Owzar, K, Jung, S-H, and Sen, PK. "A copula approach for detecting prognostic genes associated with survival outcome in microarray studies." Biometrics 63.4 (December 2007): 1089-1098.
PMID
17484778
Source
pubmed
Published In
Biometrics
Volume
63
Issue
4
Publish Date
2007
Start Page
1089
End Page
1098
DOI
10.1111/j.1541-0420.2007.00802.x

Phase I and pharmacokinetic study of erlotinib for solid tumors in patients with hepatic or renal dysfunction: CALGB 60101.

PURPOSE: We investigated dose and pharmacokinetics of erlotinib in patients with hepatic dysfunction or renal dysfunction. PATIENTS AND METHODS: Patients were assigned to one of three cohorts: cohort 1, AST > or = 3x upper limit of normal; cohort 2, direct bilirubin of 1 to 7 mg/dL; and cohort 3, creatinine of 1.6 to 5.0 mg/dL. Cohort 1a was amended for albumin less than 2.5 g/dL. Erlotinib was administered orally daily to groups of at least three assessable patients in escalating doses of 50, 75, 100, and 150 mg, starting with 50 mg in hepatic dysfunction patients and 75 mg in renal dysfunction patients. RESULTS: Between December 2001 and May 2005, 55 patients were accrued. The distribution of assessable patients was: two of three in cohort 1, three of three in cohort 1a, 16 of 30 in cohort 2, and 18 of 18 in cohort 3. Dose-limiting toxicity (DLT) consisted of elevation of both total and direct bilirubin 1.5x baseline in three patients (cohort 1: one of five patients at 50 mg; cohort 2: two of six patients at 100 mg). In cohort 2, one of seven patients had DLT at 75 mg. No DLT was encountered in cohort 3 with 12 patients at 150 mg. Apparent oral clearance (mean +/- standard deviation) was cohort dependent as follows: 1.9 +/- 0.2 L/h in cohort 1; 3.7 +/- 4.7 L/h in cohort 1a; 2.4 +/- 1.1 L/h in cohort 2; and 4.5 +/- 2.7 L/h in cohort 3 (Kruskal-Wallis, P < .017). CONCLUSION: Patients with renal dysfunction tolerate 150 mg of erlotinib daily and seem to have an erlotinib clearance similar to patients without organ dysfunction. Patients with hepatic dysfunction should be treated at a reduced dose (ie, 75 mg daily) consistent with their reduced clearance.

Authors
Miller, AA; Murry, DJ; Owzar, K; Hollis, DR; Lewis, LD; Kindler, HL; Marshall, JL; Villalona-Calero, MA; Edelman, MJ; Hohl, RJ; Lichtman, SM; Ratain, MJ
MLA Citation
Miller, AA, Murry, DJ, Owzar, K, Hollis, DR, Lewis, LD, Kindler, HL, Marshall, JL, Villalona-Calero, MA, Edelman, MJ, Hohl, RJ, Lichtman, SM, and Ratain, MJ. "Phase I and pharmacokinetic study of erlotinib for solid tumors in patients with hepatic or renal dysfunction: CALGB 60101." J Clin Oncol 25.21 (July 20, 2007): 3055-3060.
PMID
17634483
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
25
Issue
21
Publish Date
2007
Start Page
3055
End Page
3060
DOI
10.1200/JCO.2007.11.6210

Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis.

Hedgehog (Hh) pathway activation promotes tumors in several endodermally derived tissues, but its role in the pathogenesis of hepatocellular carcinoma (HCC) is unknown. Although normal hepatocytes lack Hh signaling, activation of the Hh pathway in endodermal progenitors is required for liver development. Thus, we hypothesized that hepatocarcinogenesis may involve regulation of Hh signaling. This pathway is activated when Hh ligand binds to its receptor, Patched (PTC). In an unoccupied state, PTC normally functions as a tumor suppressor that inhibits Smoothened (SMO), a proto-oncoprotein, from activating downstream components and transcription of target genes. Here we show that in HCCs, overexpression of the Smo proto-oncogene, as well as an increase in the stoichiometric ratio of Smo to Ptc mRNA levels, correlated with tumor size, a prognostic indicator in HCC biology. In one tumor we identified a novel Smo mutation in an evolutionarily conserved residue. We also demonstrated that HCC cell lines (HepG2 and Hep3B) expressed Hh pathway components and activated Hh transcriptional targets. In Hep3B cells, cyclopamine, an inhibitor of wild-type SMO, had no effect, but KAAD-cyclopamine, a blocker of oncogenic SMO, inhibited Hh signaling activity by 50%, decreased expression of the hepatocarcinogenic oncogene, c-myc, by 8-fold, and inhibited the growth rate of Hep3B cells by 94%. These data support our hypothesis that Hh signaling is dysregulated in human hepatocarcinogenesis. We demonstrate that overexpression and/or tumorigenic activation of the Smo proto-oncogene mediates c-myc overexpression which plays a critical role in hepatocarcinogenesis and suggests that Smo is a prognostic factor in HCC tumorigenesis.

Authors
Sicklick, JK; Li, Y-X; Jayaraman, A; Kannangai, R; Qi, Y; Vivekanandan, P; Ludlow, JW; Owzar, K; Chen, W; Torbenson, MS; Diehl, AM
MLA Citation
Sicklick, JK, Li, Y-X, Jayaraman, A, Kannangai, R, Qi, Y, Vivekanandan, P, Ludlow, JW, Owzar, K, Chen, W, Torbenson, MS, and Diehl, AM. "Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis." Carcinogenesis 27.4 (April 2006): 748-757.
PMID
16339184
Source
pubmed
Published In
Carcinogenesis
Volume
27
Issue
4
Publish Date
2006
Start Page
748
End Page
757
DOI
10.1093/carcin/bgi292

Unirhinal olfactory function in schizophrenia patients and first-degree relatives.

Previous studies report birhinal impairments in odor identification in patients with schizophrenia and their family members. The authors employed unirhinal odor identification and detection threshold sensitivity tests in schizophrenia patients, healthy first-degree family members, and healthy comparison subjects. Patients and family members showed deficits in odor identification performance in both nostrils. Odor detection thresholds differed only between patients and healthy comparison subjects. Comparable odor identification deficits in both patients and healthy family members suggest that odor identification measures may serve as a sensitive endophenotypic vulnerability marker and that unirhinal olfactory measures are as precise, if not more so, than birhinal performance measures.

Authors
Roalf, DR; Turetsky, BI; Owzar, K; Balderston, CC; Johnson, SC; Brensinger, CM; Gur, RE; Siegel, SJ; Moberg, PJ
MLA Citation
Roalf, DR, Turetsky, BI, Owzar, K, Balderston, CC, Johnson, SC, Brensinger, CM, Gur, RE, Siegel, SJ, and Moberg, PJ. "Unirhinal olfactory function in schizophrenia patients and first-degree relatives." J Neuropsychiatry Clin Neurosci 18.3 (2006): 389-396.
PMID
16963589
Source
pubmed
Published In
The Journal of neuropsychiatry and clinical neurosciences
Volume
18
Issue
3
Publish Date
2006
Start Page
389
End Page
396
DOI
10.1176/jnp.2006.18.3.389

P-value calculation for multistage phase II cancer clinical trials.

Due to ethical and practical issues, clinical trials are conducted in multiple stages, but the reported p-values often fail to reflect the design aspect of the trials. We investigate some approaches to p-value calculation in analyzing multi-stage Phase II clinical trials that have a binary variable, such as response, as the primary endpoint. The sample space consists of the paired outcomes of the stopping stage and the number of responses, which jointly define a complete and sufficient statistic for the true binomial proportion. Calculating a p-value requires an ordering of the paired outcomes so that outcomes more extreme than the observed can be identified. We consider the orderings based on the maximum likelihood estimator and the uniformly minimum variance unbiased estimator. We will compare, using some examples, the p-values based on these alternative orderings and the one ignoring the multistage design aspect of phase II trials.

Authors
Jung, S-H; Owzar, K; George, SL; Lee, T
MLA Citation
Jung, S-H, Owzar, K, George, SL, and Lee, T. "P-value calculation for multistage phase II cancer clinical trials." J Biopharm Stat 16.6 (2006): 765-775.
PMID
17146978
Source
pubmed
Published In
Journal of Biopharmaceutical Statistics
Volume
16
Issue
6
Publish Date
2006
Start Page
765
End Page
775
DOI
10.1080/10543400600825645

Rejoinder

Authors
Jung, SH; Owzar, K; George, SL; Lee, T
MLA Citation
Jung, SH, Owzar, K, George, SL, and Lee, T. "Rejoinder." Journal of Biopharmaceutical Statistics 16.6 (2006): 781-783.
Source
scival
Published In
Journal of Biopharmaceutical Statistics
Volume
16
Issue
6
Publish Date
2006
Start Page
781
End Page
783
DOI
10.1080/10543400600954452

A multiple testing procedure to associate gene expression levels with survival.

In many microarray studies the primary objective is to identify, from a large panel of genes, those which are prognostic markers of a censored survival endpoint such as time to disease recurrence or death. Often, these genes are considered prognostic in that their respective expressions are associated with the survival endpoint of interest. To assess this association requires specifying an appropriate measure of association, a suitable test statistic and, as the number of genes is large, proper handling of multiplicity issues. In this paper, we will address these issues by utilizing a general correlation measure, a non-parametric test statistic, and control of the family-wise error rate by employing permutation resampling. Comprehensive simulation studies are conducted to investigate the statistical properties of the proposed procedure. The proposed method is applied to a recently published data set on patients with lung cancer.

Authors
Jung, S-H; Owzar, K; George, SL
MLA Citation
Jung, S-H, Owzar, K, and George, SL. "A multiple testing procedure to associate gene expression levels with survival." Stat Med 24.20 (October 30, 2005): 3077-3088.
PMID
16189805
Source
pubmed
Published In
Statistics in Medicine
Volume
24
Issue
20
Publish Date
2005
Start Page
3077
End Page
3088
DOI
10.1002/sim.2179

Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A.

BACKGROUND: Medullary thyroid carcinoma is the most common cause of death in patients with multiple endocrine neoplasia (MEN) type 2A (MEN-2A) or type 2B or familial medullary thyroid carcinoma. We sought to determine whether total thyroidectomy in asymptomatic young members of kindreds with MEN-2A who had a mutated allele of the RET proto-oncogene could prevent or cure medullary thyroid carcinoma. METHODS: A total of 50 patients 19 years of age or younger who were consecutively identified through a genetic screening program as carriers of a RET mutation characteristic of MEN-2A underwent total thyroidectomy. Five to 10 years after the surgery, each patient was evaluated by physical examination and by determination of plasma calcitonin levels after stimulation with provocative agents. RESULTS: In 44 of the 50 patients, basal and stimulated plasma calcitonin levels were at or below the limits of detection of the assay (proportion, 0.88; 95 percent confidence interval, 0.76 to 0.95). Two patients had basal and stimulated plasma calcitonin levels above the normal range. Stimulated plasma calcitonin levels had increased but remained within the normal range in four patients. The data suggest that there was a lower incidence of persistent or recurrent disease in children who underwent total thyroidectomy before eight years of age and in children in whom there were no metastases to cervical lymph nodes. CONCLUSIONS: In this study, young patients identified by direct DNA analysis as carriers of a RET mutation characteristic of MEN-2A had no evidence of persistent or recurrent medullary thyroid carcinoma five or more years after total thyroidectomy. A longer period of evaluation will be necessary to confirm that they are cured.

Authors
Skinner, MA; Moley, JA; Dilley, WG; Owzar, K; Debenedetti, MK; Wells, SA
MLA Citation
Skinner, MA, Moley, JA, Dilley, WG, Owzar, K, Debenedetti, MK, and Wells, SA. "Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A." N Engl J Med 353.11 (September 15, 2005): 1105-1113.
PMID
16162881
Source
pubmed
Published In
The New England journal of medicine
Volume
353
Issue
11
Publish Date
2005
Start Page
1105
End Page
1113
DOI
10.1056/NEJMoa043999

Copulas: Concepts and novel applications

A bivariate copula can be statistically interpreted as a bivariate distribution function with uniform marginals. Sklar (1959) argues that for any bivariate distribution function, say H with marginals F and G, there exists a copula functional, say C, such that H[x, y] = C[F[x], G[y]] , for (x, y) T in the support of H. What is to presented is self-contained review, mainly from a statistical point of view, of the concept of copulas vis-a-vis multivariate distributions and dependence and to motivate their utility via a number of applications to the design of clinical trials, microarray studies with survival endpoints and the analysis of dependent Receiver Operator Curves (ROC).

Authors
Owzar, K; Sen, PK
MLA Citation
Owzar, K, and Sen, PK. "Copulas: Concepts and novel applications." Metron 61.3 (December 1, 2003): 323-353.
Source
scopus
Published In
Metron: international journal of statistics
Volume
61
Issue
3
Publish Date
2003
Start Page
323
End Page
353

Physiologic impairment of olfactory stimulus processing in schizophrenia.

BACKGROUND: Behavioral studies of olfaction have demonstrated impairments in the ability to detect and identify odors in patients with schizophrenia. These deficits appear to be independent of either symptom severity or other cognitive impairment. Only limited efforts have been made to investigate the neurophysiologic substrate of these olfactory abnormalities. This article reports the first examination of olfactory electrophysiologic responses in patients with schizophrenia. METHODS: Olfactory event-related potential responses to three different concentrations of hydrogen sulfide were recorded in a sample of 21 patients and 20 healthy control subjects. Odors were presented via an olfactometer to ensure there was no associated trigeminal nerve stimulation. RESULTS: Patients exhibited abnormalities in the amplitudes of the N1 and P2 components of the olfactory evoked potential, and delayed latency of the P2. The N1 abnormality, which denotes primary olfactory cortex activity, was related to impaired odor detection threshold sensitivity; the P2 abnormality was related to impaired odor identification. CONCLUSIONS: These data indicate the presence of a primary physiologic impairment in the olfactory cortex underlying behavioral olfactory deficits seen in patients with schizophrenia. This is consistent with postmortem and in vitro studies suggesting abnormalities in olfactory receptor neurons. Understanding the nature of these physiologic olfactory impairments could offer clues to the basic neuropathology of this disorder.

Authors
Turetsky, BI; Moberg, PJ; Owzar, K; Johnson, SC; Doty, RL; Gur, RE
MLA Citation
Turetsky, BI, Moberg, PJ, Owzar, K, Johnson, SC, Doty, RL, and Gur, RE. "Physiologic impairment of olfactory stimulus processing in schizophrenia." Biol Psychiatry 53.5 (March 1, 2003): 403-411.
PMID
12614993
Source
pubmed
Published In
Biological Psychiatry
Volume
53
Issue
5
Publish Date
2003
Start Page
403
End Page
411
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