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Featured researches published by Kouros Owzar.


The Lancet | 2009

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

Ronald P. DeMatteo; Karla V. Ballman; Cristina R. Antonescu; Robert G. Maki; Peter W.T. Pisters; George D. Demetri; Martin E. Blackstein; Charles D. Blanke; Margaret von Mehren; Murray F. Brennan; Shreyaskumar Patel; Martin D. McCarter; Jonathan Polikoff; Benjamin R. Tan; Kouros Owzar

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.


The New England Journal of Medicine | 2012

Lenalidomide after stem-cell transplantation for multiple myeloma

Philip L. McCarthy; Kouros Owzar; Craig C. Hofmeister; David D. Hurd; Hani Hassoun; Paul G. Richardson; Sergio Giralt; Edward A. Stadtmauer; Daniel J. Weisdorf; Ravi Vij; Jan S. Moreb; Natalie S. Callander; Koen van Besien; Teresa Gentile; Luis Isola; Richard T. Maziarz; Don A. Gabriel; Heather Landau; Thomas G. Martin; Muzaffar H. Qazilbash; Denise Levitan; Brian McClune; Robert Schlossman; Vera Hars; John Postiglione; Chen Jiang; Elizabeth Bennett; Susan Barry; Linda Bressler; Michael Kelly

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.).


Journal of Clinical Oncology | 2008

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

Michael C. Heinrich; Kouros Owzar; Christopher L. Corless; Donna Hollis; Ernest C. Borden; Christopher D. M. Fletcher; Christopher W. Ryan; Margaret von Mehren; Charles D. Blanke; Cathryn Rankin; Robert S. Benjamin; Vivien Bramwell; George D. Demetri; Monica M. Bertagnolli; Jonathan A. Fletcher

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.


AIDS | 2009

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

Olivier Lambotte; Guido Ferrari; Christiane Moog; Nicole L. Yates; Hua-Xin Liao; Robert Parks; Charles B. Hicks; Kouros Owzar; Georgia D. Tomaras; David C. Montefiori; Barton F. Haynes; Jean-François Delfraissy

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), FcγR-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) IFNγ 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 FcγR-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.


Journal of Clinical Oncology | 2010

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

Francisco Civantos; Robert P. Zitsch; David E. Schuller; Amit Agrawal; Russell B. Smith; Richard Nason; Guy Petruzelli; Christine G. Gourin; Richard J. Wong; Robert L. Ferris; Adel El Naggar; John A. Ridge; Randal C. Paniello; Kouros Owzar; Linda M. McCall; Douglas B. Chepeha; Wendell G. Yarbrough; Jeffrey N. Myers

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%).


Journal of Clinical Oncology | 2009

Phase I and Pharmacokinetic Study of Sorafenib in Patients With Hepatic or Renal Dysfunction: CALGB 60301

Antonius A. Miller; Daryl J. Murry; Kouros Owzar; Donna Hollis; Erin B. Kennedy; Ghassan K. Abou-Alfa; Apurva A. Desai; Jimmy Hwang; Miguel A. Villalona-Calero; E. Claire Dees; Lionel D. Lewis; Marwan Fakih; Martin J. Edelman; Fred Millard; Richard C. Frank; Raymond J. Hohl; Mark J. Ratain

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.


Cancer Epidemiology, Biomarkers & Prevention | 2008

Flaxseed Supplementation (Not Dietary Fat Restriction) Reduces Prostate Cancer Proliferation Rates in Men Presurgery

Wendy Demark-Wahnefried; Thomas J. Polascik; Stephen L. George; Boyd R. Switzer; John F. Madden; Mack T. Ruffin; Denise C. Snyder; Kouros Owzar; Vera Hars; David M. Albala; Philip J. Walther; Cary N. Robertson; Judd W. Moul; Barbara K. Dunn; Dean E. Brenner; Lori M. Minasian; Philip Stella; Robin T. Vollmer

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 (×100) 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. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3577–87)


Journal of Clinical Oncology | 2014

Pathologic and Molecular Features Correlate With Long-Term Outcome After Adjuvant Therapy of Resected Primary GI Stromal Tumor: The ACOSOG Z9001 Trial

Christopher L. Corless; Karla V. Ballman; Cristina R. Antonescu; Violetta Kolesnikova; Robert G. Maki; Peter W.T. Pisters; Martin E. Blackstein; Charles D. Blanke; George D. Demetri; Michael C. Heinrich; Margaret von Mehren; Shreyaskumar Patel; Martin D. McCarter; Kouros Owzar; Ronald P. DeMatteo

PURPOSE 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. PATIENTS AND METHODS 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. RESULTS 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. CONCLUSION 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.


Clinical Cancer Research | 2012

A Genome-Wide Association Study Identifies Novel Loci for Paclitaxel-Induced Sensory Peripheral Neuropathy in CALGB 40101

R. Michael Baldwin; Kouros Owzar; Hitoshi Zembutsu; Aparna Chhibber; Michiaki Kubo; Chen Jiang; Dorothy Watson; Rachel J. Eclov; Joel Mefford; Howard L. McLeod; Paula N. Friedman; Clifford A. Hudis; Eric Jorgenson; John S. Witte; Lawrence N. Shulman; Yusuke Nakamura; Mark J. Ratain; Deanna L. Kroetz

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. Clin Cancer Res; 18(18); 5099–109. ©2012 AACR.


Tuberculosis | 2011

Discriminating between latent and active tuberculosis with multiple biomarker responses

Marc A. Frahm; Neela D. Goswami; Kouros Owzar; Emily Hecker; Ann Mosher; Emily Cadogan; Payam Nahid; Guido Ferrari; Jason E. Stout

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.

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Howard L. McLeod

Washington University in St. Louis

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Federico Innocenti

University of North Carolina at Chapel Hill

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Alan P. Venook

University of California

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