The MEMORY Study: MulticentEr study of Minimally invasive surgery versus Open Radical hYsterectomy in the management of early-stage cervical cancer: Survival outcomes.

OBJECTIVE: The Laparoscopic Approach to Cervical Cancer (LACC) trial found that minimally invasive radical hysterectomy compared to open radical hysterectomy compromised oncologic outcomes and was associated with worse progression-free survival (PFS) and overall survival (OS) in early-stage cervical carcinoma. We sought to assess oncologic outcomes at multiple centers between minimally invasive (MIS) radical hysterectomy and OPEN radical hysterectomy. METHODS: This is a multi-institutional, retrospective cohort study of patients with 2009 FIGO stage IA1 (with lymphovascular space invasion) to IB1 cervical carcinoma from 1/2007-12/2016. Patients who underwent preoperative therapy were excluded. Squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinomas were included. Appropriate statistical tests were used. RESULTS: We identified 1093 cases for analysis-715 MIS (558 robotic [78%]) and 378. OPEN procedures. The OPEN cohort had more patients with tumors >2 cm, residual disease in the hysterectomy specimen, and more likely to have had adjuvant therapy. Median follow-up for the MIS and OPEN cohorts were 38.5 months (range, 0.03-149.51) and 54.98 months (range, 0.03-145.20), respectively. Three-year PFS rates were 87.9% (95% CI: 84.9-90.4%) and 89% (95% CI: 84.9-92%), respectively (P = 0.6). On multivariate analysis, the adjusted HR for recurrence/death was 0.70 (95% CI: 0.47-1.03; P = 0.07). Three-year OS rates were 95.8% (95% CI: 93.6-97.2%) and 96.6% (95% CI: 93.8-98.2%), respectively (P = 0.8). On multivariate analysis, the adjusted HR for death was 0.81 (95% CI: 0.43-1.52; P = 0.5). CONCLUSION: This multi-institutional analysis showed that an MIS compared to OPEN radical hysterectomy for cervical cancer did not appear to compromise oncologic outcomes, with similar PFS and OS.

Comparative outcomes between robotic and abdominal radical hysterectomy for IB1 cervical cancer: Results from a single high volume institution.

OBJECTIVE: To compare the perioperative morbidity and survival between abdominal radical hysterectomy (ARH) and robotic radical hysterectomy (RRH). METHODS: A retrospective cohort of patients undergoing radical hysterectomy for cervical cancer from 2010 to 2016 was identified. Patients with stage IB1 cervical cancer were included and were grouped by ARH vs. RRH. Tumor characteristics, perioperative complications, recurrence rate, progression-free survival (PFS), and overall survival (OS) were compared between groups. RESULTS: 105 patients were identified; 56 underwent ARH and 49 underwent RRH. Those who had ARH were more likely to have lesions that were ≥2 cm (62% vs. 39%, p = 0.02) and that were higher grade (p = 0.048). Other tumor characteristics were similar between groups. There was no difference in perioperative complication rates between groups. Additionally, there were no differences in recurrence risk (RR) (14% vs. 24%, p = 0.22), progression-free survival (PFS) (p = 0.28), or overall survival (OS) (p = 0.16). However, in those with tumors ≥2 cm there was a higher risk of recurrence in the overall cohort (30% vs. 8%, p = 0.006), and a shorter PFS in the RRH group (HR 0.31, p = 0.04). On multivariate analysis patients that underwent ARH or had tumors < 2 cm had a lower likelihood of recurrence (HR 0.38, p = 0.04; HR 0.175, p = 0.002) and death (HR 0.21, p = 0.029; HR 0.15, p = 0.02). CONCLUSION: Perioperative morbidity was similar between those undergoing ARH vs. RRH for IB1 cervical cancer. Patients with tumors ≥ 2 cm undergoing RRH had a shorter PFS compared to ARH. On multivariate analysis, RRH and tumor size ≥ 2 cm were independently associated with recurrence and death in this population.

Extending the platinum-free interval: The impact of omitting 2nd line platinum chemotherapy in intermediate platinum-sensitive ovarian cancer.

OBJECTIVES: Patients with epithelial ovarian cancer (EOC) recurring between 6 and 12 months after primary platinum chemotherapy have worse prognosis than those recurring in >12 months. Artificially prolonging the platinum-free interval (PFI) with cytotoxic chemotherapy was tested in MITO-8 with poor outcomes. This study aimed to determine the impact of using non-platinum or targeted therapy in 2nd line treatment of EOC patients recurring 6-12 months after completion of primary platinum-based chemotherapy. METHODS: A multi-institutional retrospective review of 177 patients with recurrent EOC and PFI of 6-12 months following primary chemotherapy was performed comparing platinum versus non-platinum chemotherapy or targeted therapy for 2nd line treatment. PFI1 was defined as the date of last chemotherapy to date of recurrence. PFS2/3 were defined as start of 2nd or 3rd line chemotherapy to start of subsequent line. RESULTS: Of 177 patients, the majority of patients were Caucasian, had serous histology, and underwent primary cytoreductive surgery. Median PFI1 was 8.2 months (95% CI 8-9 months). Second line platinum was omitted in 28% of patients. Bevacizumab was used in 2nd line in 16% of patients; 19% received other targeted therapies. Median PFS2 for platinum chemotherapy was longer than non-platinum (7.1 vs 3 months, p = 0.0114). Median PFS2 was significantly longer for platinum vs. targeted therapy (7.1 vs. 3 months p = 0.0431). Median OS for platinum in 2nd line vs. no platinum was 43.6 vs. 37.6 months (p = 0.0174). CONCLUSIONS: Use of non-platinum chemotherapy and even targeted therapy to prolong PFI in patients with EOC recurring between 6 and 12 months leads to worse survival.

Neutrophilia and mortality in women with uterine carcinosarcoma.

OBJECTIVE: The objective of this study was to investigate the relationship between pre-treatment absolute neutrophil count and clinical outcomes in patients with uterine carcinosarcoma. METHODS: In an Institutional Review Board approved, retrospective cohort study of 103 patients with uterine carcinosarcoma, the pre-treatment absolute neutrophil count data were obtained from the medical records, along with clinical, pathologic, treatment, and outcome data. Kaplan-Meier survival estimates were calculated and compared by the log rank test. Univariable and multivariable Cox proportional hazard regression models were used to examine the relationship of pre-treatment absolute neutrophil count with progression-free survival and overall survival. RESULTS: Uterine carcinosarcoma patients in the highest quartile of pre-treatment absolute neutrophil count had significantly reduced progression-free survival (p<0.001, log rank test), and overall survival (p<0.001, log rank test), compared with patients in the lower absolute neutrophil count quartiles. On multivariable analysis, high absolute neutrophil count was an independent poor prognostic factor for disease recurrence, HR 2.97 (95% CI 1.35 to 6.53, p=0.007) for highest versus lowest quartile absolute neutrophil count, and for mortality, HR 4.43 (95% CI 1.64 to 12.00, p= 0.003). CONCLUSIONS: High pre-treatment absolute neutrophil count is an independent poor prognostic factor in patients with uterine carcinosarcoma and may be useful as a potential biomarker in clinical trials. The mechanistic relationship of neutrophilia and uterine carcinosarcoma progression merits further investigation.

Timing of robotic hysterectomy after cervical excisional procedure.

INTRODUCTION: While traditional teaching has been to wait 6 weeks between cervical excisional procedure and hysterectomy, studies have produced conflicting evidence, with data supporting a delay of anywhere between 48 hours to 6 weeks depending on surgical approach. Our study sought to evaluate if the time between cervical excisional procedure and robotic hysterectomy impacts peri-operative complication rates. METHODS: A retrospective cohort of patients who underwent robotic hysterectomy from August 2006 to December 2013 for cervical dysplasia or International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IA1-B1 cervical cancer at a single tertiary care center was performed. Patients were categorized into three groups: early surgical intervention (<6 weeks from excisional procedure), delayed surgical intervention (≥6 weeks from excisional procedure), and no excisional procedure. Secondary analysis was performed by hysterectomy type (simple vs radical). Peri-operative outcomes and complications were compared. Statistical analysis included Chi-square, Fisher's exact test, and Wilcoxon rank sum test. RESULTS: A total of 160 patients were identified. Of these, 32 (20.0%) had early surgical intervention, 52 (32.5%) had delayed surgical intervention, and 76 (47.5%) had no excisional procedure. There was no difference between groups in complication rates, including average estimated blood loss (82 vs 55 vs 71 mL; p=0.07), urologic injury (0% in all groups; p=1.0), anemia (3% vs 0% vs 1%; p=0.47), infection (0% vs 2% vs 3%; p=1.0), vaginal cuff separation (0% in all groups; p=1.0), or venous thromboembolism (0% vs 0% vs 1%; p=1.0). Additionally, there were no differences in length of stay (p=0.18) or 30-day readmission rates (p=1.0). Finally, there were no significant differences in peri-operative outcomes when stratified by radical versus simple hysterectomy. DISCUSSION: Waiting 6 weeks between cervical excisional procedure and robotic hysterectomy does not impact peri-operative complication rates. This suggests that the time from excisional procedure should not factor into surgical planning for those who undergo robotic hysterectomy.

Association Between Preoperative Chemotherapy and Postoperative Complications in Patients Undergoing Surgery for Ovarian Cancer.

BACKGROUND: This study sought to determine the association between preoperative chemotherapy and postoperative morbidity and mortality in ovarian cancer patients. METHODS: The American College of Surgeons National Surgical Quality Improvement Program was used to identify women who underwent surgery for ovarian cancer between 2005 and 2012. The women were divided into two groups based on whether they had received chemotherapy within 30 days before surgery or not. Preoperative variables, intraoperative measures, and postoperative morbidity and mortality were compared using χ(2) and Student's t test. Multivariable analyses using logistic regression modeling were used to correct for potential confounding variables. RESULTS: Of 1807 patients, 1612 (89.2%) underwent primary surgery, and 195 (10.8%) received preoperative chemotherapy. The chemotherapy group had a lower preoperative platelet count (317,640 vs 249,740 plt/µL; P < 0.001), hematocrit (36.9 vs 33.1%; P < 0.001), and white blood cell (WBC) count (7970 vs 6060 WBC/µL; P < 0.001). Postoperatively, the chemotherapy group had a higher rate of organ/space infection (2.2 vs 4.6%; P = 0.04; odds ratio [OR], 2.12; 95% confidence interval [CI], 1.01-4.47) and a higher blood transfusion rate (17.1 vs 32.3%; P < 0.001; OR, 2.31; 95% CI, 1.67-3.20). A subanalysis of only those with disseminated cancer showed myelosuppression and an increased blood transfusion rate in the chemotherapy group. In multivariable analyses, preoperative chemotherapy, hematocrit, and ascites were independent predictors of postoperative blood transfusion in the entire cohort, whereas preoperative chemotherapy was the only independent predictor of postoperative blood transfusion in the disseminated cancer group. CONCLUSIONS: Preoperative chemotherapy for the treatment of ovarian cancer is associated with myelosuppression and an increased risk of postoperative blood transfusion.

Lack of Agreement Between Endocervical Brush and Endocervical Curettage in Women Undergoing Repeat Endocervical Sampling.

OBJECTIVE: To evaluate agreement between an abnormal endocervical brush (ECB) collected at the time of colposcopy and subsequent endocervical curettage (ECC). METHODS: All women evaluated for lower genital tract disease at a single academic institution were prospectively entered into a database. The database was queried for those who had a colposcopic exam with ECB between April 1, 2013, and June 15, 2015, and who subsequently returned for an ECC to further evaluate eligibility for expectant management or ablative therapy. ECB and ECC results were divided into 2 groups: "low-grade" included low-grade squamous intraepithelial lesions (LSIL) or atypical squamous cells of undetermined significance, and "high-grade" included high-grade squamous intraepithelial lesions (HSIL) or atypical squamous cells-cannot exclude high-grade. Women with atypical glandular cells and unsatisfactory ECB results were excluded. Percent agreement between ECB and ECC was calculated based on these categories. RESULTS: Seventy-nine women were included: 54 (68%) had a low-grade ECB, and 25 (32%) had a high-grade ECB. Of those who had a low-grade ECB, 4 had a low-grade ECC, 3 had a high-grade ECC, and 47 were negative, resulting in an agreement of 7.4% (4/54). Of those who had a high-grade ECB, 1 had a low-grade ECC, 4 had a high-grade ECC, and 20 were negative, resulting in 16% (4/25) agreement. CONCLUSIONS: Our data suggest that there is poor agreement between ECC and ECB in our patient population.

Comparative Surgical Outcomes for Endometrial Cancer Patients 65 Years Old or Older Staged With Robotics or Laparotomy.

BACKGROUND: This study aimed to assess the safety of robotic surgery for older women undergoing surgery for endometrial cancer. METHODS: A retrospective chart review of women undergoing surgery for endometrial cancer between October 2010 and December 2012 was conducted at the authors' institution. This cohort was divided by age (≥65 vs <65 years) and surgical approach (laparotomy vs robotic surgery). Postoperative morbidity and mortality were compared using standard statistical analysis. RESULTS: Of 228 patients identified, 73 (32 %) were 65 years old or older, and 98 (43 %) had undergone robotic surgery. Among the robotic surgery patients, women 65 years old or older had a higher Charlson comorbidity score (7.6 vs 4.9; p < 0.01) and were more likely to undergo pelvic lymphadenectomy (73 vs 39 %; p < 0.01). The complication rates did not differ between the groups except for increased urinary retention in the older group (15 % vs 3 %; p = 0.04). Older patients had a longer hospital stay (2.2 vs 1.3 days; p < 0.01) and a similar rate of discharge home (100 vs 96 %; p = 0.09). For the patients 65 years old or older, robotic surgery was associated with less blood loss (131 vs 235 ml; p = 0.03), a lower rate of ileus (0 vs 15 %; p = 0.04), a lower perioperative surgical complication rate (4 vs 30 %; p = 0.01), a shorter hospital stay (2.2 vs 4.4 days; p < 0.01), and a similar rate of discharge home (96 vs 91 %; p = 0.45) compared with laparotomy. CONCLUSION: Robotic surgery appears to be associated with less postoperative morbidity than laparotomy for endometrial cancer staging in women 65 years old or older. The complication rates after robotic surgery were similar between the two age groups.

Predicting MSSA in Acute Hematogenous Osteomyelitis in a Setting With MRSA Prevalence.

BACKGROUND: Increased severity of illness in patient with acute hematogenous osteomyelitis (AHO) with methicillin-resistant Staphylococcus aureus (MRSA) necessitates prompt intervention, but overtreatment of methicillin-sensitive S. aureus (MSSA) may contribute to antibiotic resistance. Therefore, predicting methicillin sensitivity in suspected AHO is desirable. A previously published prediction algorithm has not performed well in settings with high prevalence of MRSA. We sought to develop a predictive equation using presenting factors to predict MRSA in our patient population with a predominance of MRSA. METHODS: A retrospective chart review was performed. Consecutive cases of AHO with positive blood or bone cultures were identified at a single children's hospital. Presenting features were recorded including duration of symptoms, weight-bearing, prior antibiotic use, vital signs, complete blood count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Univariate comparison was made between the groups with MRSA and MSSA. Continuous variables were compared with t tests and discrete variables were compared using the Fischer exact test. Logistic regression was performed using a forward stepwise regression to develop a model to predict MRSA. RESULTS: A total of 68 patients formed the study group, and 60% had MRSA (41 MRSA, 27 MSSA). Temperature, respiratory rate, heart rate, white blood cell count, absolute neutrophil count (ANC), ESR), and CRP were significantly higher in MRSA cases, whereas platelets were lower. Logistic regression resulted in a model utilizing temperature, ANC, and CRP. This model correctly predicted 87% of cases (92% of MRSA and 79% of MSSA) with an area under the curve of 0.919±0.035 with a 95% confidence interval of 0.851, 0.987. CONCLUSION: A logistic regression model incorporating temperature, ANC, and CRP correctly predicts methicillin resistance of S. aureus in 87% of cases. The model differs from one developed at an institution with a low rate of MRSA. Prediction of MRSA could help direct antibiotic management, whereas prediction of MSSA could help prevent overuse of antibiotics directed against MRSA. LEVEL OF EVIDENCE: Diagnostic study level IV.

Black race independently predicts worse survival in uterine carcinosarcoma.

OBJECTIVE: GOG 150 suggested that Black women had worse survival compared to White women with uterine carcinosarcoma. Our objective was to compare treatment and survival outcomes between Black and White women at a National Comprehensive Cancer Network (NCCN) cancer center serving a diverse racial population. METHODS: An IRB approved retrospective cohort study of uterine carcinosarcoma patients diagnosed between 2000 and 2012 was performed. Survival was compared by race and stratified by stage. Median progression free and overall survival (PFS and OS) were calculated using Kaplan-Meier estimates and compared with the log-rank test. Multivariate survival analysis was performed with Cox proportional hazards model. RESULTS: 158 women were included: 93 (59%) were Black and 65 (41%) were White. 95 (60%) had early stage disease and 63 (40%) had advanced stage disease. Black women had a shorter PFS (7.9 vs. 14.2 months, p<0.001) and OS (13.4 vs. 30.8 months, p<0.001). There was no difference in survival between Black and White women with advanced stage disease (OS 8.5 vs. 11.8, p=0.18). However, PFS and OS were worse in Black women compared to White women with early stage disease (PFS 13.6 vs. 77.4, p=0.001), (OS 25.4 vs. 94.7, p=0.003). On multivariate analysis accounting for age, stage, BMI, and adjuvant treatment, Black race remained independently associated with risk of death (HR 2.0; 95% CI 1.25-3.23). CONCLUSIONS: Black women with uterine carcinosarcoma have worse survival compared to White women despite similar patient and treatment characteristics. This difference is largely due to differences in survival in early stage disease.

Radical surgical cytoreduction in the treatment of ovarian carcinosarcoma.

OBJECTIVE: Carcinosarcomas are rare and aggressive ovarian malignancies. Treatment recommendations, which include surgical cytoreduction followed by platinum based chemotherapy, have been based on small amounts of retrospective data or extrapolated from experience with high-grade epithelial ovarian adenocarcinoma. Our objective was to determine the effects of radical primary cytoreduction on progression-free survival (PFS) and overall survival (OS). METHODS: Following IRB approval, records of women with ovarian carcinosarcomas diagnosed between 2000 and 2012 at our institution were reviewed. Demographics, tumor characteristics, treatments, PFS, and OS were collected. Patients were divided into three groups based on the amount of residual disease: >1cm of disease, ≤ 1 cm of disease, or no visible disease. Chi-square and student's t-test were used to compare variables among groups. Kaplan-Meier survival curves were generated and compared with the log-rank test. RESULTS: 51 patients with ovarian carcinosarcoma were identified and all underwent primary cytoreductive surgery. Following surgical cytoreduction, 18 patients (35%) had no visible disease, 20 (39%) had ≤ 1 cm of disease, and 13 (25%) had >1cm of residual disease. Median PFS varied significantly among groups: 29 vs. 21 vs. 2 months (p=0.036) as did median OS: 57 vs. 32 vs. 11 months (p=0.015). When patients with stage 3 disease were analyzed separately, median OS still varied significantly among groups: 57 versus 31 versus 3 months (p=0.009). CONCLUSION: Degree of surgical cytoreduction appears to correlate with PFS and OS. Radical surgery resulting in no visible disease is recommended for the upfront surgical treatment of ovarian carcinosarcoma.

Ewing sarcoma of the uterus: A case report.

A case is described of Ewing sarcoma of the uterus, an atypical presentation of an already rare cancer. A 55-year-old woman presented with abdominal pain, abnormal uterine bleeding and a uterine mass that measured 11 × 10 × 14.5 cm and demonstrated heterogeneous enhancement with possible areas of central necrosis, concerning for sarcoma. She had a complete surgical resection with total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, bilateral pelvic lymph node dissection, and excision of mesenteric tumor implants. Her final pathology showed primary Ewing sarcoma-primitive neuroectodermal tumor of the uterus with metastatic spread to the peritoneal cavity. She finished 14 cycles of vincristine-doxyrubicin-cyclophosphamide-ifosfamide, etoposide chemotherapy with no evidence of recurrent metastatic disease at 6-month follow-up. Ewing sarcoma is a rare cancer, predominantly seen in adolescents, that typically are of the bone, although in rare instances it can arise from soft tissue; even rarer are presentations in the female genital tract. Even with typical presentations of Ewing sarcoma of the bone, metastatic disease has an overall poor prognosis. The scarcity of cases of metastatic Ewing sarcoma-peripheral neuroendocrine tumors of the uterus makes the condition especially difficult to study. This report describes a case of Ewing sarcoma of the uterus treated by complete surgical resection and aggressive multimodal chemotherapy.

Assessment of Pre-operative Vaginal Preparation for Laparoscopic Hysterectomy.

Objective: Determine the difference in microbial growth from the vagina and uterine manipulator among patients undergoing laparoscopic hysterectomy after randomization to one of three vaginal preparation solutions (10% Povidone-iodine, 2% Chlorhexidine, or 4% Chlorhexidine). Method: This was a prospective randomized controlled trial in an academic community hospital. Patients were ≥ 18 years old and scheduled for laparoscopic hysterectomy for benign and malignant indications. Results: Fifty patients were identified and randomized into each arm. Prior to surgery, the surgical team prepared the vaginal field using 10% Povidone-iodine, 2% Chlorhexidine, or 4% Chlorhexidine, according to group assignment. Cultures were collected from the vagina after initial preparation, prior to the colpotomy, and on surfaces of the uterine manipulator. Bacterial count from the baseline vaginal fornix/cervical canal cultures did not differ significantly among the three groups. There was a difference in bacterial count among the second cervical canal/vaginal fornix cultures (p < 0.01), with the Povidone-iodine arm demonstrating the highest level of growth of cultures (93.8%), followed by 2% Chlorhexidine (47.4%), and 4% Chlorhexidine (20%). There was no difference in growth on the uterine manipulator handle and no difference in vaginal itching or burning was found across the three arms postoperatively. Conclusion: Bacterial growth prior to colpotomy was the lowest with 4% Chlorhexidine followed by 2% Chlorhexidine, the Povidone-iodine group exhibited the highest bacterial growth. There was no difference in moderate to severe vaginal itching or burning. This showed that 4% Chlorhexidine is superior in reducing bacterial growth when used in laparoscopic hysterectomy.

Incisional infiltration versus transversus abdominis plane block of liposomal bupivacaine after midline vertical laparotomy for suspected gynecologic malignancy: a pilot study.

Background: To evaluate whether incisional infiltration of liposomal bupivacaine would decrease opioid requirement and pain scores after midline vertical laparotomy for suspected or known gynecologic malignancy compared with transversus abdominis plane (TAP) block with liposomal bupivacaine. Methods: A prospective, single blind randomized controlled trial compared incisional infiltration of liposomal bupivacaine plus 0.5% bupivacaine versus TAP block with liposomal bupivacaine plus 0.5% bupivacaine. In the incisional infiltration group, patients received 266 mg free base liposomal bupivacaine with 150 mg bupivacaine hydrochloride. In the TAP block group, 266 mg free base bupivacaine with 150 mg bupivacaine hydrochloride was administered bilaterally. The primary outcome was total opioid use during the first 48-hour postoperative period. Secondary outcomes included pain scores at rest and with exertion at 2, 6, 12, 24 and 48 h after surgery. Results: Forty three patients were evaluated. After interim analysis, a three-fold higher sample size than originally calculated was required to detect a statistically significant difference. There was no clinical difference between the two arms in mean opioid requirement (morphine milligram equivalents) for the first 48 h after surgery (59.9 vs. 80.8, p = 0.13). There were no differences in pain scores at rest or with exertion between the two groups at pre-specified time intervals. Conclusion: In this pilot study, incisional infiltration of liposomal bupivacaine and TAP block with liposomal bupivacaine demonstrated clinically similar opioid requirement after gynecologic laparotomy for suspected or known gynecologic cancer. Given the underpowered study, these findings cannot support the superiority of either modality after open gynecologic surgery.

Inhibition of the Wnt/ß-catenin pathway enhances antitumor immunity in ovarian cancer.

BACKGROUND: The Wnt/ß-catenin pathway is linked to tumorigenesis in a variety of tumors and promotes T cell exclusion and resistance to checkpoint inhibitors. We sought to determine whether a small molecule inhibitor of this pathway, WNT974, would impair tumor growth, affect gene expression patterns, and improve the immune response in human and murine ovarian cancer models. METHODS: Human ovarian cancer cells were treated with WNT974 in vitro. RNAseq libraries were constructed and differences in gene expression patterns between responders and nonresponders were compared to The Cancer Genome Atlas (TCGA). Mice with subcutaneous or intraperitoneal ID8 ovarian cancer tumors were treated with WNT974, paclitaxel, combination, or control. Tumor growth and survival were measured. Flow cytometry and ß-TCR repertoire analysis were used to determine the immune response. RESULTS: Gene expression profiling revealed distinct signatures in responders and nonresponders, which strongly correlated with T cell infiltration patterns in the TCGA analysis of ovarian cancer. WNT974 inhibited tumor growth, prevented ascites formation, and prolonged survival in mouse models. WNT974 increased the ratio of CD8+ T cells to T regulatory cells (Tregs) in tumors and enhanced the effector functions of infiltrating CD4+ and CD8+ T cells. Treatment also decreased the expression of inhibitory receptors on CD8+ T cells. Combining WNT974 with paclitaxel further reduced tumor growth, prolonged survival, and expanded the T cell repertoire. CONCLUSIONS: These findings suggest that inhibiting the Wnt/ß-catenin pathway may have a potent immunomodulatory effect in the treatment of ovarian cancer, particularly when combined with paclitaxel.

Checkpoint inhibitors in ovarian cancer: A review of preclinical data.

Ovarian cancer is the deadliest gynecologic malignancy, and relapse after initial treatment is frequently fatal. Although ovarian cancer typically has an immunosuppressive tumor microenvironment, a strong intratumoral T cell presence is associated with an improved response to chemotherapy and better overall prognosis. Given the success of checkpoint inhibitors in the treatment of other malignancies, there has been an attempt to replicate these results in ovarian cancer clinical trials. Preclincal studies in ovarian cancer have also been conducted over the past decade, and most of the focus has been on the use of programmed cell death protein 1 (PD-1). Several other checkpoint inhibitors have also been investigated in various combinations with chemotherapy, oncolytic vaccines, co-stimulatory molecules, poly ADP ribose polymerase (PARP) inhibitors, and other checkpoint inhibitors. Unfortunately, these successes have yet to translate to the clinical realm. Whether this is because the drug class is truly ineffective in ovarian cancer, or simply because the research is lacking is unclear. Either way, it is evident that preclinical data on the use of checkpoint inhibitors is woefully deficient in ovarian cancer and more research is urgently needed to inform the translation of immune checkpoint blockade into successful clinical use. In this review, we discuss the results from preclinical studies using checkpoint inhibitors to treat ovarian cancer, with a focus on strategies that show potential for clinical use.

The perceptions of gynecologic oncology fellows on readiness for subspecialty training following OB/GYNRESIDENCY.

A recent survey of fellowship program directors (PD) within gynecologic oncology (GO) noted concerns regarding the abilities of incoming fellows. The objective of this study was to evaluate the perceptions of current and former fellows in gynecologic oncology of their readiness for fellowship training. A previously used survey was modified and distributed in 2016 to current and former fellows in GO. The survey explored domains of independent practice, psychomotor ability, clinical evaluation and scholarship. A standard Likert scale was employed and domains/responses were tailored to the subspecialty. A total of 150 current and recently former fellows responded to the survey, for a response rate of 38.7%. Nearly 70% of respondents reported being able to independently perform a hysterectomy when starting fellowship, and nearly 50% felt they could perform lysis of adhesions either without assistance. Although nearly 95% reported having had the opportunity to develop a plan of action for patients on labor and delivery, only 40.7% felt able to independently manage postoperative complications without assistance. Common themes that emerged in the open-ended responses pertained to self-perception of inadequate surgical skills and knowledge specific to gynecologic oncology. Although the majority of current and former fellows in gynecologic oncology report feeling prepared for fellowship, themes noted in the open-ended responses suggest a lack of confidence in surgical skills and clinical knowledge.

Fellow Perceptions of Residency Training in Obstetrics and Gynecology.

OBJECTIVE: To evaluate the perceptions of current and former fellows in obstetrics and gynecology (OBG) subspecialties of their readiness for fellowship training. METHODS: A previously used survey was modified and distributed in 2016 to current and former fellows in gynecologic oncology, maternal-fetal medicine, reproductive endocrinology-infertility, and female pelvic medicine and reconstructive surgery. The survey explored domains of professionalism, independent practice, psychomotor ability, clinical evaluation, and scholarship. A standard Likert scale was employed and domains/responses were tailored to each subspecialty. Standard statistical models were utilized. RESULTS: A total of 478 fellows responded to the survey. Nearly 75% of fellows from each specialty reported feeling prepared or very prepared for fellowship. More than 65% of fellows from each specialty reported feeling very prepared to perform core surgical procedures. More than 90% of respondents reported having opportunities during residency to independently develop a plan of action for patients on labor and delivery. Fewer respondents reported opportunities to independently manage postoperative complications-40.7% of gynecologic oncology and 44.7% of female pelvic medicine and reconstructive surgery reported having such opportunities, whereas 91.9% of maternal-fetal medicine respondents reported having had such opportunities. While 46.4% of respondents received education on scientific writing during residency, 80% reported writing a manuscript as a resident. CONCLUSIONS: The majority of current and former fellows in OBG subspecialties report feeling prepared for fellowship in terms of clinical and surgical skills. Their feedback reveals opportunities for improvement of independent practice in gynecologic scenarios, as well as formal education on scientific research, for OBG residencies.

Insulin-like growth factor 2: a poor prognostic biomarker linked to racial disparity in women with uterine carcinosarcoma.

The objective of this study was to investigate the relationship of insulin-like growth factor 2 (IGF2) expression and survival in women with uterine carcinosarcoma (UCS). Insulin-like growth factor 2 protein expression was determined by immunohistochemical staining of tumor tissues from 103 patients with UCS. The H-score (product of staining intensity and percentage positive cells) was quantified for the epithelial cytoplasmic (EC), epithelial nuclear (EN), and malignant stromal compartments. Multivariable Cox proportional hazard regression models were used to examine the relationship of IGF2 levels with progression-free survival (PFS) and overall survival (OS). Adjusting for stage, race, and adjuvant therapy, PFS and OS were reduced in patients with high IGF2 (H-score ≥ median) in the EC and EN compartments. Black race was independently associated with reduced PFS and OS in patients with early-stage disease, and IGF2 levels in the EC were higher in black than in white patients (P = 0.02, Wilcoxon test). In a race-stratified multivariable analysis, high IGF2 in the epithelial compartments more than doubled the risk of death in black women; HR = 2.43 (95% CI: 1.18-5.01, P = 0.02) for high IGF2 in the EC; and HR = 2.34 (95% CI: 1.25-4.39, P = 0.008) for high IGF2 in the EN. In conclusion, high tumor IGF2 expression is an independent risk factor for reduced PFS and OS in UCS. Black women have elevated tumor IGF2 compared with white women, and decreased survival associated with high IGF2. These findings identify IGF2 as a candidate biomarker for survival linked to racial disparity in women with UCS.