The targeted SMAC mimetic SW IV-134 augments platinum-based chemotherapy in pre-clinical models of ovarian cancer.

BACKGROUND: Ovarian cancer is initially responsive to frontline chemotherapy. Unfortunately, it often recurs and becomes resistant to available therapies and the survival rate for advanced and recurrent ovarian cancer is unacceptably low. We thus hypothesized that it would be possible to achieve more durable treatment responses by combining cisplatin chemotherapy with SW IV-134, a cancer-targeted peptide mimetic and inducer of cell death. SW IV-134 is a recently developed small molecule conjugate linking a sigma-2 ligand with a peptide analog (mimetic) of the intrinsic death pathway activator SMAC (second-mitochondria activator of caspases). The sigma-2 receptor is overexpressed in ovarian cancer and the sigma-2 ligand portion of the conjugate facilitates cancer selectivity. The effector portion of the conjugate is expected to synergize with cisplatin chemotherapy and the cancer selectivity is expected to reduce putative off-target toxicities. METHODS: Ovarian cancer cell lines were treated with cisplatin alone, SW IV-134 alone and a combination of the two drugs. Treatment efficacy was determined using luminescent cell viability assays. Caspase-3/7, - 8 and - 9 activities were measured as complementary indicators of death pathway activation. Syngeneic mouse models and patient-derived xenograft (PDX) models of human ovarian cancer were studied for response to SW IV-134 and cisplatin monotherapy as well as combination therapy. Efficacy of the therapy was measured by tumor growth rate and survival as the primary readouts. Potential drug related toxicities were assessed at necropsy. RESULTS: The combination treatment was consistently superior in multiple cell lines when compared to the single agents in vitro. The expected mechanism of tumor cell death, such as caspase activation, was confirmed using luminescent and flow cytometry-based assay systems. Combination therapy proved to be superior in both syngeneic and PDX-based murine models of ovarian cancer. Most notably, combination therapy resulted in a complete resolution of established tumors in all study animals in a patient-derived xenograft model of ovarian cancer. CONCLUSIONS: The addition of SW IV-134 in combination with cisplatin chemotherapy represents a promising treatment option that warrants further pre-clinical development and evaluation as a therapy for women with advanced ovarian cancer.

Modified frailty index is predictive of wound complications in obese patients undergoing gynecologic surgery via a midline vertical incision.

OBJECTIVES: There are limited methods to identify which obese patients will experience wound complications after undergoing gynecologic surgery. We sought to determine the association between frailty and postoperative wound complications and to develop a prediction model for wound complications in this patient population. METHODS: We reviewed prospectively collected data of obese patients undergoing laparotomy though midline vertical incisions from 7/2013-3/2016. Modified frailty index (mFI) was calculated using 11 comorbidities previously validated. The primary outcome was the composite rate of postoperative wound complication. Data was analyzed using Fisher exact test or Chi-square and t-tests or Kruskal-Wallis tests. Poisson regression models were used to generate relative risks. Prediction models were created with receiver-operator characteristic curve analysis. RESULTS: Of 163 patients included, 56 (34%) were considered frail. Wound complications occurred in 52 patients (31.9%): 28 (50%) frail and 24 (22.4%) non-frail patients (RR 2.23, 95%CI 1.29-3.85). Frail patients had significantly greater frequencies of wound breakdown (37.5% vs 15%, RR 2.51, 95%CI 1.31-4.81). After controlling for BMI, tobacco use, and maximum postoperative glucose, frailty remained an independent predictor of wound complication (aRR 1.88, 95%CI 1.04-3.40). The area under the curve for the predictive model incorporating frailty was 0.73 for wound complications. CONCLUSION: Frailty is associated with wound complications in obese patients undergoing gynecologic surgery via a midline vertical incision and is a useful tool in identifying the most high risk patients. Further prospective research is necessary to incorporate mFI into preoperative planning and counseling.

Is hormonal therapy after risk-reducing salpingo-oophorectomy associated with an increased risk of malignancy in pathogenic variant carriers?

OBJECTIVES: This study aimed to assess the association between hormone replacement therapy and the incidence of subsequent malignancies in patients who underwent risk-reducing salpingo-oophorectomy and had mutations predisposing them to Müllerian cancers. METHODS: This Institutional Review Board-approved retrospective study was performed at five academic institutions. Women were included if they were age 18-51 years, had one or more confirmed germline highly penetrant pathogenic variants, and underwent risk-reducing salpingo-oophorectomy. Patients with a prior malignancy were excluded. Clinicodemographic data were collected by chart review. Patients with no documented contact for one year prior to study termination were called to confirm duration of hormone use and occurrence of secondary outcomes. Hormone replacement therapy included any combination of estrogen or progesterone. RESULTS: Data were analyzed for 159 women, of which 82 received hormone replacement therapy and 77 did not. In both groups an average of 6 years since risk reduction had passed. The patients treated with hormone replacement therapy did not have a higher risk of subsequent malignancy than those not treated with hormone replacement therapy (6 out of 82 vs. 7 out of 77, P = .68). Patients who received hormone replacement therapy were younger than those who did not receive hormone replacement therapy (39.0 vs. 43.9 years, P < .01) and were more likely to have undergone other risk reductive procedures including mastectomy and/or hysterectomy, though this difference was not statistically significant (69.5% vs. 55.8%, P = .07). CONCLUSIONS: In this multi-institution retrospective study of data from patients with high-risk variant carriers who underwent risk-reducing salpingo-oophorectomy, there was no statistically significant difference in the incidence of malignancy between women who did and did not receive hormone replacement therapy.

Association between body mass index and surgical menopausal symptoms in patients with early stage endometrial cancer.

OBJECTIVES: Premenopausal women may undergo surgical menopause after staging for their endometrial cancer. Our aim was to determine the association between body mass index (BMI) and surgical menopausal symptoms. METHODS: We report a retrospective review of endometrial cancer patients whom underwent menopause secondary to their surgical staging procedure. Symptoms were classified as severe if treatment was prescribed, or mild if treatment was offered, but declined. Univariate analysis was performed with ANOVA and Chi-square tests as appropriate. Relative risks (RR) were generated from Poisson regression models. RESULTS: We identified 166 patients in whom the BMI (kg/m2) distribution was as follows: 33 (19.9%) had BMI <30, 49 (29.5%) had BMI 30-39.9, 50 (30.1%) had BMI 40-49.9, and 34 (20.5%) had BMI ≥50. There were no differences in race, age, or adjuvant treatment among the groups. Overall, 65 (39.2%) women reported symptoms of surgical menopause, including 19 (11.4%) mild and 46 (27.7%) severe. Symptom type did not differ by BMI; however, the prevalence of severe menopausal symptoms decreased with increasing BMI: <30 (45.5%), 30-39.9 (30.6%), 40-49.9 (22%), and ≥ 50 (14.7%); P = 0.002. Multivariate analysis confirmed that symptom prevalence decreased with increasing BMI. Compared to women with a BMI of <30, those with a BMI 40-49.9 (RR = 0.39, 95% CI: 0.17-0.87) or ≥ 50 (RR = 0.24, 95% CI: 0.08-0.70) were significantly less likely to experience menopausal symptoms. CONCLUSIONS: Women younger than 50 with BMI >40 and stage I endometrial cancer are significantly less likely than women with BMI <30 to experience menopausal symptoms after oophorectomy. This information may assist in peri-operative counseling.

Recurrence, death, and secondary malignancy after ovarian conservation for young women with early-stage low-grade endometrial cancer.

OBJECTIVE: To examine the association between ovarian conservation and oncologic outcome in surgically-treated young women with early-stage, low-grade endometrial cancer. METHODS: This multicenter retrospective study examined women aged <50 with stage I grade 1-2 endometrioid endometrial cancer who underwent primary surgery with hysterectomy from 2000 to 2014 (US cohort n = 1196, and Japan cohort n = 495). Recurrence patterns, survival, and the presence of a metachronous secondary malignancy were assessed based on ovarian conservation versus oophorectomy. RESULTS: During the study period, the ovarian conservation rate significantly increased in the US cohort from 5.4% to 16.4% (P = 0.020) whereas the rate was unchanged in the Japan cohort (6.3-8.7%, P = 0.787). In the US cohort, ovarian conservation was not associated with disease-free survival (hazard ratio [HR] 0.829, 95% confidence interval [CI] 0.188-3.663, P = 0.805), overall survival (HR not estimated, P = 0.981), or metachronous secondary malignancy (HR 1.787, 95% CI 0.603-5.295, P = 0.295). In the Japan cohort, ovarian conservation was associated with decreased disease-free survival (HR 5.214, 95% CI 1.557-17.464, P = 0.007) and an increased risk of a metachronous secondary malignancy, particularly ovarian cancer (HR 7.119, 95% CI 1.349-37.554, P = 0.021), but was not associated with overall survival (HR not estimated, P = 0.987). Ovarian recurrence or metachronous secondary ovarian cancer occurred after a median time of 5.9 years, and all cases were salvaged. CONCLUSION: Our study suggests that adoption of ovarian conservation in young women with early-stage low-grade endometrial cancer varies by population. Ovarian conservation for young women with early-stage, low-grade endometrial cancer may be potentially associated with increased risks of ovarian recurrence or metachronous secondary ovarian cancer in certain populations; nevertheless, ovarian conservation did not negatively impact overall survival.

Gynecologic Oncologists' Perceptions of Palliative Care and Associated Barriers: A Survey of the Society of Gynecologic Oncology.

OBJECTIVES: Gynecologic oncologists frequently care for patients at the end of life with the aid of palliative care (PC) specialists. Our primary objectives were to identify perceived barriers to integrating specialty PC into gynecologic cancer care. MATERIALS AND METHODS: Members of the Society of Gynecologic Oncology (SGO) were invited to participate in an anonymous online survey. A Likert scale captured perceptions regarding primary and specialty PC, frequent barriers to use of PC, and potential interventions. RESULTS: A total of 174 (16%) gynecologic oncologists completed the survey. The majority (75%) agreed or strongly agreed that PC should be integrated into cancer care at diagnosis of advanced or metastatic cancer. The most frequently perceived PC barriers included patients' unrealistic expectations (54%), limited access to specialty PC (25%), poor reimbursement (25%), time constraints (22%), and concern of reducing hope or trust (21%). The most agreed upon potential intervention was increased access to outpatient PC (80%). CONCLUSIONS: According to this cohort of SGO members, families' or patients' unrealistic expectations are the most frequent barriers to specialty PC. Understanding this communication breakdown is critically important.

National Cancer Database Report of Lymphadenectomy Trends in Endometrial Cancer.

OBJECTIVES: Lymph node involvement has a significant impact on prognosis that may direct adjuvant therapy. The role of routine lymph node staging (LNS) is controversial given conflicting results in multiple studies. Our aims are to describe treatment patterns of LNS, identify factors impacting LNS, and quantify the contemporary trends. METHODS/MATERIALS: The National Cancer Data Base was queried for patients undergoing hysterectomy for endometrioid and serous uterine carcinomas from 2003 to 2012. For endometrioid tumors, LNS was considered indicated if at least 1 of 4 criteria was met. Multivariate logistic regression and Cox proportional hazards model were used. RESULTS: A total of 161,683 patients were identified who received hysterectomy for 155,893 (96.4%) endometrioid and 5790 (3.6%) serous carcinomas. Receipt of LNS was significantly associated with greater than 50% myometrial invasion (odds ratio [OR], 1.63; 95% confidence interval [CI], 1.55-1.73), grades 3 to 4 (OR, 3.03; 95% CI, 2.83-3.25), and tumor size greater than 2 cm (OR, 1.17; 95% CI, 1.28-1.26). Of the 97,152 patients with endometrioid carcinoma who met criteria for comprehensive staging, 73,268 (75.4%) underwent LNS. Patients with endometrioid carcinoma meeting criteria for LNS were less likely to receive LNS if they were of African American race (OR, 0.92; 95% CI, 0.86-0.98), had Medicaid insurance status (OR, 0.75; 95% CI, 0.69-0.81), had Medicare insurance (OR, 0.82; 95% CI, 0.79-0.86), or received care at a community program (OR, 0.39; 95% CI, 0.33-0.46). CONCLUSIONS: Nationally, most patients with greater than 50% myometrial invasion, grades 3 to 4, and/or tumor size greater than 2 cm receive LNS, but this was significantly impacted by insurance status, demographic characteristics, and facility location/type.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for recurrent ovarian carcinoma: analysis of 30-day morbidity and mortality.

PURPOSE: The aim of this study was to evaluate morbidity and mortality associated with cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with ovarian, fallopian tube, and primary peritoneal cancer. METHODS: A retrospective review of patients undergoing cytoreductive surgery plus HIPEC from 1 January 2007 to 29 July 2013 at two academic medical centers was performed. Grade 3/4 complications (National Cancer Institute's Common Toxicity Criteria version 4.0) from day of surgery until 30 days postoperatively were recorded. RESULTS: Thirty-two patients were identified, with 27 cases of ovarian cancer, three primary peritoneal cancers, and two fallopian tube cancers. Indications included 24 at the time of cancer recurrence, six at interval surgical resection, and two in the consolidative setting. Hyperthermic chemotherapeutic regimens included carboplatin (n = 21), cisplatin (n = 4), oxaliplatin (n = 2), oxaliplatin + intravenous 5-fluorouracil (n = 1), doxorubicin (n = 1), and cisplatin + doxorubicin (n = 1). Infusion time ranged from 30 to 90 min, with a maximum temperature range of 41-43 °C. The combined grade 3/4 morbidity rate was 65.6 %, and the most frequent morbidities included grade 3 anemia (40.6 %), infection (15.6 %), and pleural effusion (12.5 %). Six patients required readmission (18.8 %), and two patients required reoperation (6.2 %). Full-thickness diaphragm resection/peritoneal stripping had a significant association with grade 3/4 pleural effusions (p = 0.0007). CONCLUSIONS: Cytoreductive surgery plus HIPEC is feasible in patients with ovarian cancer with 65.6 % grade 3/4 morbidity and no deaths. Balancing these complications with potential survival benefits is important in centers considering implementing HIPEC protocols.

Anti-angiogenesis therapy in gynecologic malignancies.

Anti-angiogenic agents are an important adjuvant treatment strategy in gynecologic cancer. Bevacizumab was recently approved for use in advanced cervical cancer and platinum-resistant ovarian cancer. The overall survival advantage bevacizumab confers in advanced cervical cancer prompted a paradigm shift in the standard of care for this disease. Because many other therapeutic options are available, and because of the heterogeneity of ovarian malignancies, the best combination of chemotherapeutics and bevacizumab has yet to be determined; studies are on-going. The utility of bevacizumab in uterine cancer has not been consistently demonstrated; current studies are limited to early-phase clinical trials. Other anti-angiogenic agents, including oral therapies for cervical and ovarian cancers, are under investigation; this therapeutic class of drugs appears promising.

Intraperitoneal chemotherapy from Armstrong to HIPEC: challenges and promise.

OPINION: The treatment of advanced stage ovarian, primary peritoneal and fallopian tube cancer represents a therapeutic challenge as evidenced by the 70 %-80 % recurrence rate. Our understanding of the synergy between surgical cytoreduction and effective systemic chemotherapy continues to evolve, with research supporting maximal cytoreductive effort followed by intraperitoneal chemotherapy. Specifically, analysis of phase III clinical trials has shown a median survival of 110 months in those treated with intraperitoneal chemotherapy, when surgery results in no visible residual disease. Additionally, incorporation of hyperthermic intraperitoneal chemotherapy at the time of surgical resection has gained attention as an alternate therapeutic option, in an attempt to obviate toxicities encountered with repetitive cycles of intraperitoneal chemotherapy. Currently, surgical cytoreduction in the hands of an experienced gynecologic oncologist, followed by intraperitoneal chemotherapy is thought to portend the greatest survival benefit in patients with advanced stage ovarian cancer spectrum cancers. Additional investigation regarding the oncologic outcomes and morbidity of hyperthermic intraperitoneal chemotherapy is warranted.

Palliative Care in Gynecologic Oncology.

The integration of palliative care and hospice into standard gynecologic oncology care is associated with cost-savings, longer survival, lower symptom burden, and better quality of life for patients and caregivers. Consequently, this comprehensive approach is formally recognized and endorsed by the Society of Gynecologic Oncology, the National Comprehensive Cancer Network, and the American Society of Clinical Oncology. This article reviews the background, benefits, barriers, and most practical delivery models of palliative care. It also discusses management of common symptoms experienced by gynecologic oncology patients.

Type II endometrial cancers with minimal, non-invasive residual disease on final pathology: What should we do next?

There are minimal data regarding the management of high risk endometrial cancer histologies lacking invasive disease on the final pathology specimen. This study examines a cohort of these patients and assesses outcomes including time to recurrence and risk of death after management with and without adjuvant therapies. Endometrial cancer patients with minimal or no remaining invasive disease on final pathologic specimen from 1995 to 2010 were included. Surgical procedure was at the discretion of the operating physician. Electronic medical records were used to abstract relevant clinicopathologic data and standard statistical methods were employed. 70 patients met inclusion criteria, of which 26 were high grade histologies. Adjuvant therapies were given in 12 of 26 patients. 6/26 patients recurred, of which 50% were salvaged with therapy at time of recurrence. Overall deaths occurred in 3 of 26 patients in the high risk cohort. Less than half of the high risk cohort received adjuvant therapies after surgical management. No histologic type was found to increase risk of recurrence, and treatment with initial adjuvant therapy did not significantly reduce recurrence risk. Large scale prospective trials are needed to aid in management of this unique endometrial cancer population.

Inpatient management of hypercalcemia portends a poor prognosis among gynecologic oncology patients: A trigger to initiate hospice care?

We aim to describe survival outcomes of gynecologic oncology inpatients treated with intravenous bisphosphonates for hypercalcemia and develop a risk stratification model that predicts decreased survival to aid with goals of care discussion. In a single-center, retrospective cohort study of gynecologic oncology patients admitted for bisphosphonate therapy for hypercalcemia. Survival from hypercalcemia to death was assessed by Kaplan-Meier method and log-rank test. Univariate log-rank test and Cox proportional hazards modeling were used to develop a risk stratification model. Sixty-five patients were evaluable with a median follow-up of 83.5 months. Mean age was 59.2 years, 64.6% had recurrent disease, and 30.8% had ≥2 previous lines of chemotherapy. Median survival was 38 days. Our analysis identified four risk factors (RFs) [brain metastasis, >1 site of metastasis, serum corrected peak calcium >12.4 (mg/dL), and peak ionized calcium >5.97 (mg/dL)] that predicted survival and were used to build a risk stratification score. Sum of RFs included 35 patients with 1 RF, 11 had 2 RFs, and 19 had ≥3 RF. Median survival for 1, 2, or ≥ 3 RFs was 53, 28, and 26 days respectively (p = .009). Survival at 6 months was 28.6%, 18.2%, and 5.3% for each group respectively. Hospice enrollment was 26.2%, and did not vary by group (p = .51). Among gynecologic oncology patients, inpatient management of hypercalcemia with bisphosphonates portends poor prognosis. Individualized risk stratification may help guide end-of-life discussions and identify patients who may benefit most from hospice care.

Sentinel lymph node mapping of a breast cancer of the vulva: Case report and literature review.

Ectopic breast tissue is rare and typically presents as an axillary mass. Previous reports have identified ectopic breast tissue in the vulva, but malignancy is exceedingly uncommon. We present a 62 years old with locally advanced breast carcinoma arising in the vulva demonstrates the utilization of sentinel lymph node mapping to identify metastatic lymph nodes previously unable to be identified via traditional surgical exploration. Our case supports the principles of adjuvant therapy for breast cancer to be applied to ectopic breast cancer arising in the vulva. A literature review highlights common key points in similar cases to guide management.