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Oklahoma City, OK, United States

Zighelboim I.,University of Washington | Zighelboim I.,Temple University | Ali S.,Roswell Park Cancer Institute | Lankes H.A.,Roswell Park Cancer Institute | And 10 more authors.
Gynecologic Oncology | Year: 2015

Objective We sought to validate the clinicopathologic implications and prognostic significance of ATR (ataxia telangiectasia mutated and Rad3-related) mutation in patients with endometrioid endometrial cancer and defective DNA mismatch repair enrolled in a cooperative group molecular staging study of endometrial cancer. Methods After pathology review, only endometrioid tumors with high neoplastic cellularity (≥ 70%) and high quality DNA for molecular analyses were included. MSI (microsatellite instability) typing was performed and the target sequence in exon 10 of ATR was evaluated by direct sequencing in all MSI-high tumors. Associations between ATR mutations and clinicopathologic variables were assessed using contingency table tests. Differences in overall survival (OS) and disease-free survival (DFS) were evaluated by univariate analyses and multivariable Cox proportional hazard models. Results A total of 475 eligible cases were identified. Of 368 MSI + cases, the sequence of interest could be successfully genotyped in 357 cases. ATR mutations were exclusively identified in 46 tumors with high level microsatellite instability (MSI +) (12.9%, p < 0.001) and were associated with higher tumor grade (p = 0.001). ATR mutations were not associated with OS (HR 1.16; 95% CI, 0.58-2.32; p = 0.68) or DFS (HR 0.61; 95% CI, 0.25-1.50; p = 0.28). Conclusion Truncating mutations in exon 10 of ATR occur exclusively in tumors with evidence of defective DNA mismatch repair. We were not able to confirm the prognostic value of these mutations in patients with endometrioid endometrial cancer. © 2015 Elsevier Inc. Source

Kizer N.T.,Washington University in St. Louis | Hatem H.,Simon Cancer Center | Nugent E.K.,Stephenson Oklahoma Cancer Center | Zhou G.,Washington University in St. Louis | And 4 more authors.
International Journal of Gynecological Cancer | Year: 2015

Objective This retrospective study evaluates the influence of serum platelet count on chemotherapy response rates among women with endometrial cancer. Methods From 3 separate cancer centers, a total of 318 patients with endometrial cancer who received postoperative chemotherapy between June 1999 and October 2009 were retrospectively identified. Endometrioid, serous, clear cell, and carcinosarcoma histologies were included. Patients were classified as having an elevated platelet count if their serum platelet count was greater than 400 × 109/L at the time of initial diagnosis. Primary outcome was chemotherapy response, classified as either complete or partial/refractory. Secondary outcomes were disease-free and disease-specific survival. χ2 Test and Student t test were performed as appropriate. Kaplan-Meier curves and Cox proportional hazards models were used to assess serum platelet effect on survival. Results There were 125 deaths, 76 recurrences, and 48 disease progressions. Of the total group, 53 (16.7%) were categorized as having an elevated platelet count. An elevated platelet count was associated with a lower chemotherapy response rate in univariate analysis (hazard ratio [HR], 2.8; 95% 95% confidence interval [CI], 1.46-5.38; P < 0.01). Multivariate analysis showed elevated platelets to be independently associated with decreased disease-free survival (HR, 2.24; 95% CI, 1.26-3.98; P < 0.01) but not disease-specific survival (HR, 1.03; 95% CI, 0.56-1.88, P = 0.93). Conclusions Patients with endometrial cancer who have an elevated serum platelet count greater than 400 × 109/L may have lower chemotherapy response rates and are at increased risk for recurrence when compared with patients with a count within the reference range. © 2015 by IGCS and ESGO. Source

Moore K.N.,Stephenson Oklahoma Cancer Center | Sill M.W.,Roswell Park Cancer Institute | Tenney M.E.,University of Chicago | Darus C.J.,Maine Medical Center | And 3 more authors.
Gynecologic Oncology | Year: 2015

Objectives Ang1 & 2 (angiopoietin-1; - 2) interact with Tie2 receptors on endothelial cells to mediate vascular remodeling in an angiogenesis signaling pathway distinct from the VEGF axis. Trebananib is a peptide Fc fusion protein that binds Ang1 and 2 and prevents interaction with Tie2. The efficacy of trebananib in recurrent/persistent endometrial cancer (EC) was studied. Methods The primary objective was to determine the frequency of patients with objective tumor responses (ORR) and event-free survival for ≥ 6 months (6-month EFS) and determine toxicity of trebananib at a dose and schedule of 15 mg/kg, IV QW. Recurrent/persistent EC, measurable disease, and ≤ 2 prior chemotherapy lines were required. Results Thirty-two patients were eligible and treated. The most common histologies were G1/2 endometrioid (31%), G3 endometrioid (28%) and serous (31.3%). 78% of patients had 1 prior regimen. Patients received 1-9 + cycles of trebananib; 24 patients (75%) received ≤ 2 cycles. One patient had a partial response (3.1%); 8 patients had stable disease (25%) and 5 patients (15.6%) had 6 month EFS. Median progression-free survival and overall-survival were 1.97 months (90% CI 1.77-2.1) and 6.6 months (90% CI 4.01-14.75), respectively. Most common adverse events (AEs) were fatigue, anemia, and GI issues. Grade 3 and 4 AEs were: GI 31 and 0%; vascular 22 and 0%; metabolism/nutrition 19 and 3%; and general (including edema) 16 and 0%. Conclusions Trebananib has insufficient single agent activity in recurrent EC to warrant further investigation at this dose/schedule. © 2015 Elsevier Inc. Source

Matthiesen C.,Stephenson Oklahoma Cancer Center | Herman T.D.L.F.,Stephenson Oklahoma Cancer Center | Singh H.,Stephenson Oklahoma Cancer Center | Mascia A.,Proton Therapy | And 9 more authors.
Journal of Medical Imaging and Radiation Oncology | Year: 2015

Background This study aims to compare dosimetrically and radiobiologically 3D conformal, intensity modulated radiation therapy (IMRT), RapidArc (RA) volumetric modulated arc therapy and proton therapy techniques for early-stage glottic cancer. Methods Ten patients were retrospectively selected. Photon treatment planning was performed using Eclipse External Beam Planning, and proton planning was performed using CMS Xio. The minimum, mean and maximum dose values for planning target volume (PTV), mean and maximum dose values for organ at risk, % of volume of PTV receiving at least 95% of the prescription dose, and D20, D50 and D90 of carotid arteries were compared. Biological response models of tumour control probabilities and normal tissue complication probabilities were calculated. Results IMRT, RA and proton plans versus three-dimensional conformal radiotherapy (3D-CRT) plans consistently provided superior PTV coverage and decreased mean dose to the thyroid and carotid arteries. Conclusion All these three modalities showed superiority with less variation among themselves compared with 3D-CRT plans. Clinical investigation is warranted to determine if these treatment approaches will translate into a reduction in radiation therapy-induced toxicities. © 2014 The Royal Australian and New Zealand College of Radiologists. Source

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