Saketh R. Guntupalli

Nonsteroidal anti-inflammatory drugs and endometrial carcinoma mortality and recurrence

Background Recent data suggest that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) may be associated with reductions in endometrial cancer risk, yet very few have examined whether their use is related to prognosis among endometrial cancer patients. Methods Study subjects comprised 4374 participants of the NRG Oncology/Gynecology Oncology Group 210 Study with endometrial carcinoma who completed a presurgical questionnaire that assessed history of regular prediagnostic NSAID use and endometrial cancer risk factors. Recurrences, vital status, and causes of death were obtained from medical records and cancer registries. Fine-Gray semiproportional hazards regression estimated adjusted subhazard ratios (HRs) and 95% confidence intervals (CIs) for associations of NSAID use with endometrial carcinoma-specific mortality and recurrence. Models were stratified by endometrial carcinoma type (ie, type I [endometrioid] vs type II [serous, clear cell, or carcinosarcoma]) and histology. Results Five hundred fifty endometrial carcinoma-specific deaths and 737 recurrences occurred during a median of five years of follow-up. NSAID use was associated with 66% (HR = 1.66, 95% CI = 1.21 to 2.30) increased endometrial carcinoma-specific mortality among women with type I cancers. Associations were statistically significant for former and current users, and strongest among former users who used NSAIDs for 10 years or longer (HR = 2.23, 95% CI = 1.19 to 4.18, two-sided P trend = .01). NSAID use was not associated with recurrence or endometrial carcinoma-specific mortality among women with type II tumors. Conclusions In this study, use of NSAIDs was associated with increased endometrial carcinoma-specific mortality, especially in patients with type I tumors. Barring a clear biologic mechanism by which NSAIDs would increase the risk of cause-specific mortality, cautious interpretation is warranted.

High stathmin expression is a marker for poor clinical outcome in endometrial cancer: An NRG oncology group/gynecologic oncology group study

OBJECTIVE Gynecologic Oncology Group (GOG) 177 demonstrated that addition of paclitaxel to a backbone of adriamycin/cisplatin improves overall survival (OS) and progression-free survival (PFS) for patients with advanced or recurrent endometrial cancer. Using patient specimens from GOG-177, our objective was to identify potential mechanisms underlying the improved clinical response to taxanes. Stathmin (STMN1) is a recognized poor prognostic marker in endometrial cancer that functions as a microtubule depolymerizing protein, allowing cells to transit rapidly through mitosis. Therefore, we hypothesized that one possible mechanism underlying the beneficial effects of paclitaxel could be to counter the impact of stathmin. METHODS We analyzed the expression of stathmin by immunohistochemistry (IHC) in 69 specimens from patients enrolled on GOG-177. We also determined the correlation between stathmin mRNA expression and clinical outcomes in The Cancer Genome Atlas (TCGA) dataset for endometrial cancer. RESULTS We first established that stathmin expression was significantly associated with shorter PFS and OS for all analyzed cases in both GOG-177 and TCGA. However, subgroup analysis from GOG-177 revealed that high stathmin correlated with poor PFS and OS particularly in patients who received adriamycin/cisplatin only. In contrast, there was no statistically significant association between stathmin expression and OS or PFS in patients treated with paclitaxel/adriamycin/cisplatin. CONCLUSIONS Our findings demonstrate that high stathmin expression is a poor prognostic marker in endometrial cancer. Paclitaxel may help to negate the impact of stathmin overexpression when treating high risk endometrial cancer cases.

Surgical-pathological findings in type 1 and 2 endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study on GOG-210 protocol ☆

OBJECTIVE To report clinical and pathologic relationships with disease spread in endometrial cancer patients. METHODS Surgical candidates with uterine cancer (adenocarcinoma or carcinosarcoma) who were eligible to participate in a surgical pathological study to create a clinically annotated tissue biorepository to support translational and clinical research studies. All patients were to undergo a hysterectomy, bilateral salpingo-oophorectomy, and bilateral pelvic and para-aortic lymphadenectomy. From 2003-2007, open eligibility enrollment was conducted, and from 2007-2011, eligibility was restricted to enrich underrepresented patients or those at high risk. RESULTS This report details clinical pathological relationships associated with extra uterine disease spread of 5866 evaluable patients including those with endometrioid histology as well as papillary serous, clear cell and carcinosarcoma histologies. Review of unrestricted enrollment was constructed in an effort to capture a cross-section population representative of endometrial cancers seen by the GOG participating members. Evaluation of this group of patients suggested the more natural incidence of different surgical pathological findings as well as demographic information. The addition of 2151 patients enrolled during the restricted time interval allowed a total of 1630 poor histotype patients available for further analysis. As expected, endometrioid (E) cancers represented the largest enrollment and particularly E grade 1 and 2 (G1 and 2) were more frequently confined to the uterus. Grade 3 (G3) endometrioid cancers as well as the poor histotype (papillary serous, clear cell and carcinosarcoma) had a much greater propensity for extant disease. CONCLUSIONS This study confirms the previously reported surgical pathological findings for endometrioid cancers but in addition, using a large database of papillary serous, clear cell and carcinosarcoma, surgical pathological findings substantiate the categorization of poor histotypes for these cancers.

Preparedness of Ob/Gyn residents for fellowship training in gynecologic oncology

Residency training in obstetrics and gynecology is being challenged by increasingly stringent regulations and decreased operative experience. We sought to determine the perception of preparedness of incoming gynecologic oncology fellows for advanced surgical training in gynecologic oncology. An online survey was sent to gynecologic oncologists involved in fellowship training in the United States. They were asked to evaluate their most recent incoming clinical fellows in the domains of professionalism, level of independence/graduated responsibility, psychomotor ability, clinical evaluation and management, and academia and scholarship using a standard Likert-style scale. The response rate among attending physicians was 40% (n = 105/260) and 61% (n = 28/46) for program directors. Of those who participated, 49% reported that their incoming fellows could not independently perform a hysterectomy, 59% reported that they could not independently perform 30 min of a major procedure, 40% reported that they could not control bleeding, 40% reported that they could not recognize anatomy and tissue planes, and 58% reported that they could not dissect tissue planes. Fellows lacked an understanding of pathophysiology, treatment recommendations, and the ability to identify and treat critically ill patients. In the academic domain, respondents agreed that fellows were deficient in the areas of protocol design (54%), statistical analysis (54%), and manuscript writing (65%). These results suggest that general Ob/Gyn residency is ineffective in preparing fellows for advanced training in gynecologic oncology and should prompt a revision of the goals and objectives of resident education to correct these deficiencies.

Lymphovascular space invasion in robotic surgery for endometrial cancer.

Background: Minimally invasive surgery has become a standard treatment for endometrial cancer and offers significant benefits over abdominal approaches. There are discrepant data regarding lymphovascular space invasion (LVSI) and positive peritoneal cytology with the use of a uterine manipulator, with previous small-scale studies demonstrating an increased incidence of these prognostically important events. We sought to determine if there was a higher incidence of LVSI in patients who underwent robot-assisted surgery for endometrial cancer. Methods: We performed a single-institution review of medical records for patients who underwent open abdominal or robot-assisted hysterectomy for endometrial cancer over a 24-month period. The following data were abstracted: age, tumor grade and stage, size, depth of invasion, LVSI, and peritoneal cytology. For patients with LVSI, slides were reviewed by 2 pathologists for confirmation of LVSI. Results: Of 104 patients identified, LVSI was reported in 39 (37.5%) and positive peritoneal cytology in 6 (4.8%). Rates of peritoneal cytology were not significantly different between the 2 groups (odds ratio, 0.55; 95% confidence interval, 0.10–3.17; P = .50). LVSI was reported in significantly fewer robot-assisted hysterectomies than open procedures (odds ratio, 0.39; 95% confidence interval, 0.17–0.92; P = .03). In subgroup analyses restricted to early-stage disease (stage ≤ II), there was no significant difference in LVSI between open and robot-assisted hysterectomies (odds ratio, 0.64; 95% confidence interval, 0.22–1.85; P = .43). Conclusion: In this retrospective study, we found that use of a uterine manipulator in robot-assisted surgery did not increase the incidence of LVSI.

A phase II trial of a surgical protocol to decrease the incidence of wound complications in obese gynecologic oncology patients

OBJECTIVES Obese women have a high incidence of wound separation after gynecologic surgery. We explored the effect of a prospective care pathway on the incidence of wound complications. METHODS Women with a body mass index (BMI) ≥30 kg/m(2) undergoing a gynecologic procedure by a gynecologic oncologist via a vertical abdominal incision were eligible. The surgical protocol required: skin and subcutaneous tissues to be incised using a scalpel or cutting electrocautery, fascial closure using #1 polydioxanone suture, placement of a 7 mm Jackson-Pratt drain below Campers fascia, closure of Campers fascia with 3-0 plain catgut suture and skin closure with staples. Wound complication was defined as the presence of either a wound infection or any separation. Demographic and perioperative data were analyzed using contingency tables. Univariable and multivariable regression models were used to identify predictors of wound complications. Patients were compared using a multivariable model to a historical group of obese patients to assess the efficacy of the care pathway. RESULTS 105 women were enrolled with a median BMI of 38.1. Overall, 39 (37%) had a wound complication. Women with a BMI of 30-39.9 kg/m(2) had a significantly lower risk of wound complication as compared to those with a BMI >40 kg/m(2) (23% vs 59%, p<0.001). After controlling for factors associated with wound complications the prospective care pathway was associated with a significantly decreased wound complication rate in women with BMI <40 kg/m(2) (OR 0.40, 95% C.I.: 0.18-0.89). CONCLUSION This surgical protocol leads to a decreased rate of wound complications among women with a BMI of 30-39.9 kg/m(2).

Risk of metachronous ovarian cancer after ovarian conservation in young women with stage I cervical cancer

BACKGROUND: While there is an increasing trend of ovarian conservation at the time of surgical treatment for young women with stage I cervical cancer, the risk for subsequent ovarian cancer after ovarian conservation has not been well studied. OBJECTIVE: We sought to examine the incidence of and risk factors for metachronous ovarian cancer among young women with stage I cervical cancer who had ovarian conservation at the time of hysterectomy. STUDY DESIGN: The Surveillance, Epidemiology, and End Results Program was used to identify women aged <50 years who underwent hysterectomy with ovarian conservation for stage I cervical cancer from 1983 through 2013 (n = 4365). Time‐dependent analysis was performed for ovarian cancer risk after cervical cancer diagnosis. RESULTS: Mean age at cervical cancer diagnosis was 37 years, and the majority of patients had stage IA disease (68.2%) and squamous histology (72.9%). Median follow‐up time was 10.8 years, and there were 13 women who developed metachronous ovarian cancer. The 10‐ and 20‐year cumulative incidences of metachronous ovarian cancer were 0.2% (95% confidence interval, 0.1–0.4) and 0.5% (95% confidence interval, 0.2–0.8), respectively. Mean age at the time of diagnosis of metachronous ovarian cancer was 47.5 years, and stage III‐IV disease was seen in 55.6%. Age (≥45 vs <45 years, hazard ratio, 4.22; 95% confidence interval, 1.16–15.4; P = .018), ethnicity (non‐white vs white, hazard ratio, 4.29; 95% confidence interval, 1.31–14.0; P = .009), cervical cancer histology (adenocarcinoma or adenosquamous vs squamous, hazard ratio, 3.50; 95% confidence interval, 1.17–10.5; P = .028), and adjuvant radiotherapy use (yes vs no, hazard ratio, 3.69; 95% confidence interval, 1.01–13.4; P = .034) were significantly associated with metachronous ovarian cancer risk. The presence of multiple risk factors was associated with a significantly increased risk of metachronous ovarian cancer compared to the no risk factor group: 1 risk factor (hazard ratio range, 2.96‐8.43), 2 risk factors (hazard ratio range, 16.6‐31.0), and 3‐4 risk factors (hazard ratio range, 62.3‐109), respectively. CONCLUSION: Metachronous ovarian cancer risk after ovarian conservation for women with stage I cervical cancer is <1%. Older age, non‐white ethnicity, adenocarcinoma or adenosquamous histology, and adjuvant radiotherapy may be associated with an increased metachronous ovarian cancer risk.

Retrospective analysis of survival improvement by molecular biomarker-based personalized chemotherapy for recurrent ovarian cancer.

Aggressive tumors such as epithelial ovarian cancer (EOC) are highly heterogeneous in their therapeutic response, making it difficult to improve overall response by using drugs in unselected patients. The goal of this study was to retrospectively, but independently, examine whether biomarker-based personalized chemotherapy selection could improve survival of EOC patients. Using in vitro drug sensitivity and patient clinical outcome data, we have developed co-expression extrapolation (COXEN) biomarker models for predicting patient response to three standard chemotherapy drugs used to treat advanced EOC: paclitaxel, cyclophosphamide, and topotecan, for which sufficient patient data were available for our modeling and independent validation. Four different cohorts of 783 EOC patients were used in our study, including two cohorts of 499 patients for independent validation. The COXEN predictors for the three drugs independently showed high prediction both for patient short-term therapeutic response and long-term survival for recurrent EOC. We then examined the potential clinical benefit of the simultaneous use of the three drug predictors for a large diverse EOC cohort in a prospective manner, finding that the median overall survival was 21 months longer for recurrent EOC patients who were treated with the predicted most effective chemotherapies. Survival improvement was greater for platinum-sensitive patients if they were treated with the predicted most beneficial drugs. Following the FDA guidelines for diagnostic prediction analysis, our study has retrospectively, yet independently, showed a potential for biomarker-based personalized chemotherapy selection to significantly improve survival of patients in the heterogeneous EOC population when using standard chemotherapies.

Cost analysis of colposcopy for abnormal cytology in post-treatment surveillance for cervical cancer

OBJECTIVE The aim of this study was to estimate cost and outcomes associated with colposcopy following abnormal Pap for women with a history of cervical cancer. METHODS Decision models compared the costs and number of isolated local recurrences (ILR) detected using two strategies, colposcopy and no colposcopy, for women with a history of cervical cancer and low grade or high grade Pap. Clinical data for input were derived from a cohort of women with a history of cervical cancer undergoing surveillance Paps at 2 institutions. Costs were obtained using national reimbursement data. RESULTS Five hundred fifty-six patients underwent 2900 surveillance Paps. Twenty-seven of 50 women with a low grade Pap underwent colposcopy. One of 3 recurrences in the colposcopy group was an ILR diagnosed colposcopically. Colposcopy following low grade Pap costs

Sexual and Marital Dysfunction in Women With Gynecologic Cancer

354 more and resulted in a lower rate of diagnosis of ILR compared to no colposcopy (3.7% vs 8.6%). Sixty of 78 women with a high grade Pap underwent colposcopy. Three of 15 recurrences in the colposcopy group were ILR diagnosed colposcopically. Colposcopy following high grade Pap costs