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.

A fellow-run clinic achieves similar patient outcomes as faculty clinics: A safe and feasible model for gynecologic oncology fellow education.

OBJECTIVES: Fellow involvement in patient care is important for education, but effect on patient care is unclear. Our aim was to compare patient outcomes in gynecologic oncology attending clinics versus a fellow training clinic at a large academic medical center. METHODS: A retrospective review of consecutive gynecologic oncology patients from six attending clinics and one faculty-supervised fellow clinic was used to analyze differences based on patient demographics, cancer characteristics, and practice patterns. Primary outcome was overall survival (OS); secondary outcomes included recurrence-free survival (RFS), postoperative complications and chemotherapy within the last 30 days of life. Survival analyses were performed using Kaplan-Meier curves with log-rank tests. RESULTS: Of 159 patients, 76 received care in the attending clinic and 83 in the fellow clinic. Patients in the fellow clinic were younger, less likely to be Caucasian, and more overweight, but cancer site and proportion of advanced stage disease were similar. Both clinics had similar rates of moderate to severe adverse events related to surgery (15% vs. 8%, p = .76), chemotherapy (21% vs. 23%, p = .40), and radiation (14% vs. 17%, p = .73). There was no difference in median RFS in the fellow compared to attending clinic (38 vs. 47 months, p = .78). OS on both univariate (49 months-fellow clinic, 60 months-attending clinic vs. p = .40) and multivariate analysis [hazard ratio 1.3 (0.57, 2.75), P = .58] was not significantly different between groups. CONCLUSIONS: A fellow-run gynecologic oncology clinic designed to provide learning opportunities does not compromise patient outcomes and is a safe and feasible option for fellow education.

Low rates of cascade genetic testing among families with hereditary gynecologic cancer: An opportunity to improve cancer prevention.

OBJECTIVE: Cascade genetic testing (CGT) of hereditary breast and ovarian cancer (HBOC) or Lynch Syndrome (LS) patients' relatives offers opportunities to prevent cancer, but CGT rates are not well described. We aimed to measure reported disclosure of genetic testing results and CGT rates in these families and evaluate patients' views of educational media. METHODS: Patients with HBOC or LS identified from germline genetic testing at an academic institution between 2011 and 2016 were surveyed regarding disclosure, testing among relatives, and perceptions of educational materials. Medical records and pedigrees provided numbers of total and first-degree relatives. RESULTS: Of 103 mutation carriers consented, 64 (63%) completed the survey an average of 38 months after receiving genetic testing results. Participants' mean age was 53 years, and thirty-one (48%) had a cancer diagnosis. The majority (86%) felt extremely or very comfortable sharing health information. Participants disclosed results to 87% of first-degree relatives, but reported that only 40% of first-degree relatives underwent testing. First-degree female relatives had significantly higher CGT rates than first-degree male relatives (59% versus 21%, P < 0.001). Participants with HBOC reported higher CGT rates than those with LS (49% versus 33%, P = 0.02). Participants did not identify any one educational medium as more helpful than the others for disclosing results. CONCLUSION: Disclosure rates are high among HBOC and LS mutation carriers, but reported CGT rates are low. Gender- and mutation-specific barriers prevent patients' family members from undergoing CGT. Future studies should implement materials to address these barriers and improve CGT rates.

Risk of cervical and vaginal dysplasia after surgery for vulvar intraepithelial neoplasia or cancer: A 6 year follow-up study.

OBJECTIVES: To estimate the frequency of abnormal surveillance cytology leading to high-grade dysplasia after surgical management for high-grade vulvar intraepithelial neoplasia (VIN) and vulvar cancer and to determine whether prior hysterectomy reduces this risk. METHODS: Women who underwent surgery for high-grade VIN or vulvar cancer between 2006 and 2014 were identified retrospectively. Patients who underwent prior hysterectomy for any indication were included. Univariate and multivariate logistic regression analyses were used to identify clinical correlates of abnormal cytology after surgical treatment for VIN and vulvar cancer. RESULTS: During a median follow-up for 72 months, 302 women underwent surveillance with cytologic screening after vulvar surgery including 99 (33%) women with prior hysterectomy. 75 (25%) women had abnormal cytology results. Of those, 47 (63%) were low-grade and 28 (37%) were high-grade, including 2 (3%) cases of invasive cancer. The rates of high-grade vaginal intraepithelial neoplasia (VAIN), cervical intraepithelial neoplasia (CIN), or cancer were not significantly different despite prior hysterectomy (9% VAIN 2+, 7% CIN 2+). Multivariate analysis showed that correlates of high-grade cytology following treatment for VIN or vulvar cancer included non-white race [odds radio (OR) 3.6, 95% confidence interval (CI) 1.7-7.8], prior abnormal cytology (OR 3.5, 95% CI 1.6-7.6), and immunodeficiency (OR 3.4, 95% CI 1.3-8.8). Prior hysterectomy did not significantly decrease risk of high-grade cytology (OR 0.87, 95% CI 0.5-1.6). CONCLUSIONS: Women treated surgically for VIN/vulvar cancer have an 8% risk of at least high-grade dysplasia from surveillance screening and prior hysterectomy does not mitigate the risk. Extrapolating from current guidelines, we recommend surveillance cytology screening at least 6-12 months after treatment.

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.

Why do we continue to overtreat stage Ia carcinoma of the cervix?

The current recommended treatment for stage Ia2 cervical cancer is a radical or modified radical hysterectomy. Although in the United States the incidence of cervical cancer is low and declining, almost 50% of the >4000 new cases will present in early stages. An estimated 2200 women each year will undergo radical hysterectomy and many will have both early- and late-onset complications. The purpose of this review is to examine if there is still a role for radical hysterectomy in the proper treatment of stage Ia2 cervical cancer given most recent data. Sufficient histological evidence suggests that although parametrial involvement and lymph node metastases can increase the risk for recurrence, they are relatively uncommon at early stages. Worldwide data that challenge radical hysterectomy as standard of care have shown that conservative management of stage Ia2 cervical cancer results in similar survival and recurrence rates. It is the recommendation based on all reviewed data that radical hysterectomy should no longer be considered standard of care in all cases of stage Ia2 cervical cancer.

Rates of human papillomavirus vaccine uptake amongst girls five years after introduction of statewide mandate in Virginia.

BACKGROUND: The Commonwealth of Virginia enacted statewide school-entry human papillomavirus vaccine mandate in 2008 requiring all girls to receive the vaccine before starting the 6th grade. The mandate, one of very few in the country, has been in effect for 5 years. This study assesses the impact that it has had on the rates of human papillomavirus uptake. OBJECTIVE: The purpose of this study was to evaluate the uptake of the human papillomavirus vaccine among girls seeking well-child care 5 years after the introduction of a statewide mandate in Virginia in October 2008. STUDY DESIGN: This prospective cohort study used the Clinical Data Repository at the University of Virginia to identify girls 11-12 years old who was seen for well-child care from January to December 2014. Billing and diagnosis codes were used to establish human papillomavirus vaccine administration. Those girls who were identified through the Clinical Data Repository were then contacted by advance letter followed by a representative from the University of Virginia Center for Survey Research who invited the responsible parent or guardian to complete a 50-item telephone questionnaire. Questionnaire results were used to inform objective findings and to assess parental attitudes that were related to human papillomavirus vaccination. Findings were compared against those of Pierce et al (2013), who evaluated human papillomavirus vaccination levels in a similar cohort of patients in 2008, before mandate enactment, to assess relative change attributable to vaccine mandate. RESULTS: Nine hundred eight girls were identified through the Clinical Data Repository; 50.9% of the girls received at least 1 dose of human papillomavirus vaccine. White race and private insurance coverage were found to be associated negatively with human papillomavirus vaccine uptake (relative risk, 0.74 and 0.71; 95% confidence interval, 0.64-0.85 and 0.62-0.81, respectively). Black race and public insurance coverage were found to be associated positively with vaccine uptake (relative risk, 1.35 and 1.39; 95% confidence interval, 1.17-1.55 and 1.22-1.58, respectively). In comparison with the previous study, there has been no change in human papillomavirus vaccine uptake or distribution of uptake after the introduction of the statewide mandate for human papillomavirus vaccination. CONCLUSION: The statewide human papillomavirus vaccine mandate has had no impact on the overall rate of human papillomavirus vaccination, nor has it diminished the previously described racial or payer disparities in vaccine uptake in school-aged girls being seen for well-child care in the state of Virginia.

Electric morcellation-related reoperations after laparoscopic myomectomy and nonmyomectomy procedures.

STUDY OBJECTIVE: To identify, collate, and summarize the most common causes and pathologies of electric morcellation-related reoperations after laparoscopic myomectomy and nonmyomectomy procedures. DESIGN: A systematic review of published medical literature from January 1990 to February 2014 reporting morcellation-related reoperations after laparoscopic myomectomy and nonmyomectomy procedures involving the use of intracorporeal electric tissue morcellators. Publications were included in this review if patients underwent a second surgical procedure because of the onset of new clinical symptoms after a primary surgical procedure that involved intracorporeal morcellation or if histopathology of the morcellated surgical specimen revealed malignancy (Canadian Task Force classification II-3). SETTING: All case reports and case series were reported from community and academic hospitals in the United States and the rest of the world. PATIENTS: We identified 66 patients from 32 publications. INTERVENTIONS: Reoperation after laparoscopic myomectomy and nonmyomectomy procedures involving intracorporeal electric tissue morcellation. MEASUREMENTS AND MAIN RESULTS: For patients who presented with new clinical symptoms requiring reoperation, we recorded the follow-up period, nature and duration of the new symptoms, details of the second surgical procedure, intraoperative findings during the second surgical procedure, and the final histopathologic diagnosis. When histopathology of the morcellated specimen revealed malignancy, we recorded the specific type of malignancy, the corresponding surgical treatment that the patient underwent, and the follow-up period. Percentages and 95% confidence intervals were calculated for all categoric variables. Twenty-four (36.4%) patients underwent laparoscopic myomectomies, of which 19 (79.2%) and 5 (20.8%) patients required a second surgical procedure because of new clinical symptoms and the diagnosis of malignancy in the morcellated surgical specimen, respectively. Forty-two (63.6%) patients underwent laparoscopic hysterectomies; of these, 25 (59.5%) patients required a second surgical procedure because of the onset of new clinical symptoms, whereas the remaining 17 (40.5%) patients underwent a second surgical procedure because of the diagnosis of malignancy in the morcellated surgical specimen. The most common benign pathology was parasitic leiomyomata (22 patients, 33.3%). The most common malignant pathology was leiomyosarcoma (16 patients, 24.2%). CONCLUSION: Dispersion of tissue fragments into the peritoneal cavity at the time of morcellation continues to be a concern. It was previously thought that morcellated tissue fragments are resorbed by the peritoneal cavity; however, there is some evidence highlighting the long-term sequelae related to the growth and propagation of these dispersed tissue fragments in the form of parasitic leiomyomata, iatrogenic endometriosis, and cancer progression. Yet, the majority of laparoscopic myomectomy and nonmyomectomy procedures involving the use of intracorporeal electric tissue morcellators are uncomplicated, and institutions having no women with endometriosis or cancer are very unlikely to report surgical outcomes of uneventful electric morcellation. Thus, prospective studies are still required to validate the role of electric intracorporeal tissue morcellation in the pathogenesis of parasitic leiomyomata, iatrogenic endometriosis, and cancer progression.

Case Report: Low-Risk HPV associated Verruco-Papillary squamous cell carcinoma of the cervix.

•Cervical cancer plays a large role in morbidity and mortality for gynecologic cancer.•Most cases are involved with high-risk HPV, rare cases of low-risk HPV associated cancer exists.•Low risk HPV associated cervical cancers have increased difficulty in diagnosis.•No distinction exists in treatment between low and high risk HPV associated cervical cancer.

Implementation of an enhanced recovery protocol in gynecologic oncology.

Enhanced Recovery after Surgery (ERAS) is an evidence-based approach that aims to reduce narcotic use and maintain anabolic balance to enable full functional recovery. Our primary aim was to determine the effect of ERAS on narcotic usage among patients who underwent exploratory laparotomy by gynecologic oncologists. We characterized its effect on length of stay, intraoperative blood transfusions, bowel function, 30-day readmissions, and postoperative complications. A retrospective cohort study was performed at Abington Hospital-Jefferson Health in gynecologic oncology. Women who underwent an exploratory laparotomy from 2011 to 2016 for both benign and malignant etiologies were included before and after implementation of our ERAS protocol. Patients who underwent a bowel resection were excluded. A total of 724 patients were included: 360 in the non-ERAS and 364 in the ERAS cohort. An overall reduction in narcotic usage, measured as oral morphine milliequivalents (MMEs) was observed in the ERAS relative to the non-ERAS group, during the entire hospital stay (MME 34 versus 68, p < 0.001 and within 72 h postoperatively (MME 34 versus 60, p < 0.005). A shorter length of stay and earlier return of bowel function were also observed in the ERAS group. No differences in 30-day readmissions (p = 0.967) or postoperative complications (p = 0.328) were observed. This study demonstrated the benefits of ERAS in Gynecologic Oncology. A significant reduction of postoperative narcotic use, earlier return of bowel function and a shorter postoperative hospital stay was seen in the ERAS compared to traditional perioperative care.

Squamous cell carcinoma of the vulva: a review of present management and future considerations.

INTRODUCTION: Although a relatively uncommon disease, the treatment of vulvar cancer has changed considerably over the years and has been under considerable focus due to its past overtreatment and apparent increase in incidence. The purpose of this review is to describe the recommended management of the most commonly encountered vulvar carcinomas based on the most recent available literature. Areas covered: The clinical environment of squamous cell vulvar cancers are illustrated in order to describe the potential pitfalls and limitations of treatment. Then, by examining published data on the treatment efficacy, find those that are best at limiting morbidity and maximizing patient outcomes. In addition, effective prevention of HPV-related disease will be included as its limitation of disease can be considered an aspect of treatment. The benefits and limitations of medical and surgical modalities as well as the evolving discussion surrounding lymph node sampling and the novel role of genomics will also be considered. Expert commentary: Great care should be taken by the gynecologic oncology community regarding prevention and continuing efforts of limiting surgical morbidity while providing quality care. Although sentinel lymph node dissection is a controversial topic, greater attention should be paid to clinical trials to delineate the data, but also to limit our own biases in counseling patients.

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.

Morbidity and mortality of vulvar and vaginal cancers: Impact of 2-, 4-, and 9-valent HPV vaccines.

Vaginal and vulvar cancers do not account for a large proportion of gynecologic malignancies but their impact is significant. Both vaginal and vulvar lesions have precursors and display levels of dysplasia before progression to invasive disease. Human Papillomavirus (HPV) is a known causative agent of such dysplasia and can be detected now more readily than ever with adequate recognition techniques and provider awareness. Although HPV vaccination is still lagging compared to other recommended childhood vaccinations, the impact on lower genital tract neoplasia is promising. The bivalent and quadrivalent vaccines have been shown to be efficacious and the newest nonavalent vaccine should add even more of impact on coverage of cancer-causing HPV types. Although it is still early to show true clinical and population-based disease reduction due to low disease incidence and relatively short time of vaccine availability, the potential is noteworthy.