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Ovarian cancer is the fifth most common cause of cancer deaths among American women. Platinum and taxane combination chemotherapy represents the first-line approach for ovarian cancer, but treatment success is often limited by chemoresistance. Therefore, it is necessary to find new drugs to sensitize ovarian cancer cells to chemotherapy. Persistent activation of Signal Transducer and Activator of Transcription 3 (STAT3) signaling plays an important role in oncogenesis. Using a novel approach called advanced multiple ligand simultaneous docking (AMLSD), we developed a novel nonpeptide small molecule, LLL12B, which targets the STAT3 pathway. In this study, LLL12B inhibited STAT3 phosphorylation (tyrosine 705) and the expression of its downstream targets, which are associated with cancer cell proliferation and survival. We showed that LLL12B also inhibits cell viability, migration, and proliferation in human ovarian cancer cells. LLL12B combined with either paclitaxel or with cisplatin demonstrated synergistic inhibitory effects relative to monotherapy in inhibiting cell viability and LLL12B-paclitaxel or LLL12B-cisplatin combination exhibited greater inhibitory effects than cisplatin-paclitaxel combination in ovarian cancer cells. Furthermore, LLL12B-paclitaxel or LLL12B-cisplatin combination showed more significant in inhibiting cell migration and growth than monotherapy in ovarian cancer cells. In summary, our results support the novel small molecule LLL12B as a potent STAT3 inhibitor in human ovarian cancer cells and suggest that LLL12B in combination with the current front-line chemotherapeutic drugs cisplatin and paclitaxel may represent a promising approach for ovarian cancer therapy.

Ovarian cancer typically spreads throughout the peritoneal cavity, and despite standard of care treatments (surgical debulking and chemotherapy), the five-year relative survival rate remains below 50%. The use of antibody-photosensitizer conjugates (photoimmunotherapy) has emerged as a promising modality to achieve targeted photosensitizer delivery to ovarian cancer cells. In this study, we investigate epithelial growth factor (EGFR)-targeted PIT coupled with inhibition of prostaglandin E2 receptor 4 (EP4), a G-coupled-receptor that contributes to cancer progression and intracellularly transactivates EGFR. This potent triple combination significantly attenuates the metastatic behavior of ovarian cancer cells through simultaneously inducing photochemical damage and modulating protein expression.

Purpose/objective(s) Pelvic re-irradiation for patients with gynecologic cancers remains a challenge due to toxicity concerns. Given the dosimetric advantages of proton therapy, we aimed to assess oncologic and toxicity outcomes of patients treated with re-irradiation to the pelvis/abdomen with IMPT for gynecologic cancers. Materials/methods A single-institution retrospective IRB-approved analysis was conducted of all gynecologic cancer patients treated between 2015-2020 with IMPT re-irradiation with at least partial overlap with the treated volume of the prior treatment. Toxicities were graded according to CTCAE v5.0. The Kaplan-Meier (KM) method was used to estimate local control (LC), freedom from progression (FFP), overall survival (OS), and late toxicity with their 95% confidence interval (CI). Results A total of 29 patients received re-irradiation to the pelvis and/or abdomen with IMPT. One patient received a 2nd course of re-irradiation. Primary sites included endometrial (n = 15), cervical (n = 7), vaginal (n = 3), vulvar (n = 2) and ovarian cancer (n = 2). Twenty-five patients were treated for a recurrence of their gynecological cancer while 4 patients had re-irradiation for a new gynecological primary. Three patients were treated in the adjuvant setting, 6 patients received brachytherapy boost, and 3 patients received concurrent hyperthermia. Fifteen patients received systemic therapy associated with their course of re-irradiation, 11 of which was concurrent. The majority of patients received radiation (RT) to their pelvis only (n = 22), while 5 patients received RT to their pelvis + abdomen and 4 patients received RT to para-aortic field only. Median age at time of re-irradiation was 65 years (range 34-95). Median dose of prior RT was 45 Gy (range 30-59.4 Gy). Median time between initial RT and re-irradiation was 2 years (range 7 months - 39 years). Median re-irradiation dose was 49.2 Gy (range 30-61.6 Gy). Fractionation included conventional (n = 21), hyperfractionation (n = 7), and IMPT-SBRT (n = 2). Median follow-up was estimated at 17 months (range 1-34 months) using the inverse-Kaplan-Meier method; 11 patients had either local, regional, or distant progression. 12-month LC was 90% (95% CI 78%-100%), 12 month-OS was 62% (95% CI 42%-100%), and 12-month FFP was 57% (95% CI 35%-79%). Two patients developed acute grade 3+ toxicity (grade 3 diarrhea, grade 3 anemia). Two patients developed late grade 3+ toxicity (grade 3 sacral ulcer; 1 patient with grade 3 vulvar radiation necrosis and grade 3 radiation proctitis). 12-month freedom from toxicity was 96% (95% CI 88%-100%), and 24 month freedom from toxicity was 86% (95% CI 65%-100%). Conclusion This is the first series to report on clinical outcomes for re-irradiation with IMPT for gynecological malignancies. While extended long term follow-up is needed, our study demonstrates excellent local control with acceptable acute and late toxicity. Author disclosure A.E. Pollock: None. H. Risher: None. S.M. Bentzen: Travel Expenses; University of Copenhagen. D.M. Roque: None. G. Rao: None. E.M. Nichols: Arrange consortium meetings, help lead multi-institutional trials; GammaPod Research Consortium. Medical Director of University of Maryland Medical Center practice; University of Maryland School of Medicine. Oversee clinical operations of all UMSOM Radiation Oncology practices; University of Maryland School of Medicine. P. Mohindra: The Executive Committee shall recommend to the Board of Directors overall Alliance policy and direction, as well as Alliance priorities and activities. It shall approve, by majority vote, appointments of chairs for scientific and administrative committee; Alliance for Clinical Trials in Oncology. Participate in various activities of the f.

Ovarian cancer is the fifth most common cause of cancer deaths among American women. Platinum and taxane combination chemotherapy represents the first-line approach for ovarian cancer, but treatment success is often limited by chemoresistance. Therefore, it is necessary to find new drugs to sensitize ovarian cancer cells to chemotherapy. Persistent activation of Signal Transducer and Activator of Transcription 3 (STAT3) signaling plays an important role in oncogenesis. Using a novel approach called advanced multiple ligand simultaneous docking (AMLSD), we developed a novel nonpeptide small molecule, LLL12B, which targets the STAT3 pathway. In this study, LLL12B inhibited STAT3 phosphorylation (tyrosine 705) and the expression of its downstream targets, which are associated with cancer cell proliferation and survival. We showed that LLL12B also inhibits cell viability, migration, and proliferation in human ovarian cancer cells. LLL12B combined with either paclitaxel or with cisplatin demonstrated synergistic inhibitory effects relative to monotherapy in inhibiting cell viability and LLL12B-paclitaxel or LLL12B-cisplatin combination exhibited greater inhibitory effects than cisplatin- paclitaxel combination in ovarian cancer cells. Furthermore, LLL12B-paclitaxel or LLL12B-cisplatin combination showed more significant in inhibiting cell migration and growth than monotherapy in ovarian cancer cells. In summary, our results support the novel small molecule LLL12B as a potent STAT3 inhibitor in human ovarian cancer cellsand suggest that LLL12B in combination with the current front-line chemotherapeutic drugs cisplatin and paclitaxel may represent a promising approach for ovarian cancer therapy.

Purpose: Uterine-serous-carcinoma (USC) is an aggressive variant of endometrial cancer. On the basis of preliminary results of a multicenter, randomized phase II trial, trastuzumab (T), a humanized-mAb targeting Her2/Neu, in combination with carboplatin/paclitaxel (C/P), is recognized as an alternative in treating advanced/recurrent HER2/Neu-positive USC. We report the updated survival analysis of NCT01367002. Patients and Methods: Eligible patients had stage III to IV or recurrent disease. Participants were randomized 1:1 to receive C/P for six cycles ± T followed by maintenance T until progression or toxicity. Progression-free survival (PFS) was the primary endpoint; overall survival (OS) and toxicity were secondary endpoints. Results: Sixty-one patients were randomized. After a median-follow-up of 25.9 months, 43 progressions and 38 deaths occurred among 58 evaluable patients. Updated median-PFS continued to favor the T-arm, with medians of 8.0 months versus 12.9 months in the control and T-arms (HR = 0.46; 90% CI, 0.28–0.76; P = 0.005). Median-PFS was 9.3 months versus 17.7 months among 41 patients with stage III to IV disease undergoing primary treatment (HR = 0.44; 90% CI, 0.23–0.83; P = 0.015), and 7.0 months versus 9.2 months among 17 patients with recurrent disease (HR = 0.12; 90% CI, 0.03–0.48; P = 0.004). OS was higher in the T compared with the control arm, with medians of 29.6 months versus 24.4 months (HR = 0.58; 90% CI, 0.34–0.99; P = 0.046). The benefit was most notable in those with stage III to IV disease, with survival median not reached in the T-arm versus 24.4 months in the control arm (HR = 0.49; 90% CI, 0.25–0.97; P = 0.041). Toxicity was not different between arms. Conclusions: Addition of T to C/P increased PFS and OS in women with advanced/recurrent HER2/Neu-positive USC, with the greatest benefit seen for the treatment of stage III to IV disease.

Rare sex cord-stromal tumors of the ovary cannot be further subclassified and are therefore designated "sex cord-stromal tumor-not otherwise specified." These tumors have highly varied morphology, and the literature describing them is limited. Herein, we report the pathology and clinical course of a 46-yr-old woman diagnosed with sex cord-stromal tumor-not otherwise specified. The tumor was composed predominantly of juvenile granulosa cell tumor histology, with elements of thecoma, adult granulosa, Sertoli, as well as poorly differentiated epithelioid and sarcomatoid components. Next-generation sequencing revealed a FOXL2 C134W mutation, seen most commonly in adult granulosa cell tumors, as well as mutations in TP53 (V172F) and TERT promoter (-124C>T). The patient exhibited an aggressive clinical course involving rapid recurrence with distant metastases that responded to 4 cycles of cisplatin, bleomycin, and etoposide.

Highlights • Combination of olaparib and photodynamic therapy is effective in reducing the number and clonogenic survival of ovarian cancer cells. • Photodynamic therapy using a lipidated photosensitizer reduces the selective advantage of olaparib-resistant ovarian cancer cells. • Photodynamic therapy potentiates the DNA-damaging effects of olaparib., P-glycoprotein (P-gp) is an adenosine triphosphate (ATP)-dependent drug efflux protein commonly associated with multidrug resistance in cancer chemotherapy. In this report, we used a dual-fluorescent co-culture model to study the population dynamics of the drug sensitive human ovarian cancer cell line (OVCAR-8-DsRed2) and its resistant subline that overexpresses P-gp (NCI/ADR-RES-EGFP) during the course of a photodynamic therapy (PDT)-olaparib combination regimen. Without treatment, OVCAR-8-DsRed2 cells grew more rapidly than the NCI/ADR-RES-EGFP cells. Olaparib treatment reduced the total number of cancer cells by 70±4% but selected for the resistant NCI/ADR-RES-EGFP population since olaparib is an efflux substrate for the P-gp pump. This study used the FDA-approved benzoporphyrin derivative (BPD) photosensitizer or its lipidated formulation ((16:0)LysoPC-BPD) to kill OVCAR-8 cells and reduce the likelihood that olaparib-resistant cells would have selective advantage. Three cycles of PDT effectively reduced the total cell number by 66±3%, while stabilizing the population ratio of sensitive and resistant cells at approximately 1:1. The combination of olaparib treatment and PDT enhanced PARP cleavage and deoxyribonucleic acid (DNA) damage, further decreasing the total cancer cell number down to 10±2%. We also showed that the combination of olaparib and (16:0)LysoPC-BPD-based PDT is up to 18-fold more effective in mitigating the selection of resistant NCI/ADR-RES-EGFP cells, compared to using olaparib and BPD-based PDT. These studies suggest that PDT may improve the effectiveness of olaparib, and the use of a lipidated photosensitizer formulation holds promise in overcoming cancer drug resistance.

Simple Summary Accumulation of excess fluid in the abdomen typically indicates abnormal function or disease, such as cancer, in the underlying tissues. This accumulation of fluid, or ascites, occurs more frequently in patients with advanced-stage ovarian cancer than any other type of cancer. The presence of ascites indicates the poorest outcomes for patients with advanced stage ovarian cancer, but little is known about the reasons for these dismal outcomes. This review discusses the current understanding of ascites, starting with an overview of ovarian cancer and ascites, followed by a description of the tools used to analyze the components of ascites and how these components modulate ovarian cancer biology. A perspective on the mechanical effects of ascites and the impact of mechanical stress on treatment resistance is provided. Lastly, treatment options for ascites and opportunities to develop new therapeutic strategies to improve outcomes are discussed. Abstract Ascites refers to the abnormal accumulation of fluid in the peritoneum resulting from an underlying pathology, such as metastatic cancer. Among all cancers, advanced-stage epithelial ovarian cancer is most frequently associated with the production of malignant ascites and is the leading cause of death from gynecologic malignancies. Despite decades of evidence showing that the accumulation of peritoneal fluid portends the poorest outcomes for cancer patients, the role of malignant ascites in promoting metastasis and therapy resistance remains poorly understood. This review summarizes the current understanding of malignant ascites, with a focus on ovarian cancer. The first section provides an overview of heterogeneity in ovarian cancer and the pathophysiology of malignant ascites. Next, analytical methods used to characterize the cellular and acellular components of malignant ascites, as well the role of these components in modulating cell biology, are discussed. The review then provides a perspective on the pressures and forces that tumors are subjected to in the presence of malignant ascites and the impact of physical stress on therapy resistance. Treatment options for malignant ascites, including surgical, pharmacological and photochemical interventions are then discussed to highlight challenges and opportunities at the interface of drug discovery, device development and physical sciences in oncology.

Objectives: Ixabepilone is a microtubule-stabilizing agent that may retain activity in paclitaxel-treated patients. The goal of this multicenter randomized phase II study was to assess the activity and safety of ixabepilone with bevacizumab compared to ixabepilone alone in patients with platinum-resistant/refractory ovarian, fallopian tube, or primary peritoneal cancer. An exploratory objective was to examine the role of prior treatment with bevacizumab and tumor expression of class III s-tubulin (TUBB3) by immunohistochemistry as a predictive biomarker. Methods: Participants were randomly assigned to receive ixabepilone 20 mg/m2 days 1, 8, 15 with (IXA+BEV) or without (IXA) bevacizumab 10 mg/kg days 1, 15 every 28 days. Patients were stratified by receipt of prior BEV. The primary endpoint was progression-free survival (PFS). Overall survival (OS), safety, and response rates served as secondary endpoints. Download : Download high-res image (247KB) Download : Download full-size image Results: A total of 78 patients were randomized from March 2017-July 2020. Among 76 evaluable patients who received IXA+BEV (n=39) compared to IXA (n=37), the objective response rate was 33% (n=13) versus 8% (n=3) (P=0.004), with clinical benefit durable at 6 months in 37% (n=14) and 3% (n=1) (P Conclusions: IXA+BEV is a well-tolerated, effective combination for treatment of platinum/taxane-resistant/refractory ovarian cancer that extends both PFS/OS relative to IXA monotherapy. Prior receipt of BEV should not preclude use of IXA+BEV. TUBB3 is not a predictive biomarker for response to IXA+BEV.

The microtubule-stabilizing agent docetaxel in combination with gemcitabine represents one of the most effective regimens against the aggressive gynecologic tumor leiomyosarcoma (LMS). Upregulation of class III &beta, tubulin has previously been shown to confer taxane resistance in a variety of human cancers. Prostaglandin E2 receptor EP4 is linked to progression of a variety of human cancers and may represent a novel target for tumor inhibition in LMS. We evaluated the hypotheses that EP4 and class III &beta, tubulin have increased expression in LMS in comparison to normal myometrium or benign tumors and that expression of class III &beta, tubulin correlates with resistance to taxanes and poor clinical outcome. Gene expression was examined using TCGA data and correlated with clinicopathologic outcome which demonstrated that class III &beta, tubulin is more highly expressed in more aggressive sarcomas with EP4 being widely expressed in all subtypes of sarcoma. Immunohistochemistry for EP4 and class III &beta, tubulin was performed on patients with LMS, leiomyomatosis/STUMP, leiomyoma, and normal myometrium. Expression of EP4 and class III &beta, tubulin were characterized for cell lines SK-UT-1, SK-UT-1B, and PHM-41 and these cell lines were treated with docetaxel alone and in combination with EP4 inhibitors. In taxane-resistant cell lines that overexpress class III &beta, tubulin and EP4, treatment with EP4 inhibitor resulted in at least 2-fold sensitization to docetaxel. Expression of class III &beta, tubulin and EP4 in LMS may identify patients at risk of resistance to standard chemotherapies and candidates for augmentation of therapy through EP4 inhibition.

5523 Background: Microsatellite instability (MSI-H) is a biomarker for response to immune-checkpoint inhibitors (ICIs); however, these neoplasms are heterogenous including Lynch (germline), Lynch-like (somatic) and sporadic ( MLH1-methylated) tumors. Whether mechanisms underlying MSI alter responses to ICIs is unclear. We report data from a phase II pilot study (NCT02899793) of pembrolizumab in recurrent MSI-H endometrial cancer (EC) patients and potential mechanisms of primary/secondary ICI resistance. Methods: Patients with measurable, MSI-H EC confirmed by immunohistochemistry and polymerase chain reaction were evaluated by next-generation sequencing and received pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. The primary end point was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Results: Twenty-five patients (24 evaluable) were treated. Six (25%) patients harbored Lynch/Lynch-like tumors while 18 (75%) had sporadic EC. Tumor mutational burden (TMB) was higher in Lynch-like (median 2939, IQR:867-5108) versus sporadic tumors (median 604, IQR:411-798) ( P= 0.0076). Median follow-up was 25.8 months with an ORR of 58% (95% CI, 36.6-77.9%). ORR was 100% in Lynch/Lynch-like patients but only 44% in sporadic patients ( P= 0.024). The 3-year progression-free (PFS) and overall survival (OS) proportions were 100% versus 30% ( P= 0.017) and 100% versus 43% ( P= 0.043), respectively. Grade 3/4 treatment-related adverse events (6.8%) occurred in 12 patients. Defective antigen processing/presentation and deranged induction in interferon responses served as mechanisms of resistance in sporadic MSI-H EC. Conclusions: Our study demonstrated prognostic significance of Lynch-like versus sporadic MSI-H EC on ORR, PFS and OS when treated with pembrolizumab. Clinical studies evaluating separate subtypes of MSI-H EC treated with ICIs are warranted. Clinical trial information: NCT02899793.

Ovarian cancer has the highest mortality incidence of all gynecologic malignancies in the United States. The majority of ovarian cancer cases lead to recurrent disease that is often incurable and fatal due to innate or acquired chemoresistance; therefore, novel therapeutic interventions are desperately needed. Cyclooxygenases–COX-1 and COX-2–are enzymes that catalyze the production of prostaglandin E2 (PGE2), an important inflammatory lipid mediator that is functionally linked to progression of many cancers, including breast and ovarian cancer. PGE2 is exported from the cell via multidrug resistance-associated protein 4 (MRP4) where it acts in a paracrine and autocrine manner by activating a family of four G-protein coupled receptors (EP1-4) that are linked to different intracellular signaling pathways. EP2 and EP4 can activate PKA/cAMP, PI3K and ERK pathways. We hypothesize that the EP4 receptor has increased expression in ovarian cancer and that binding of its cognate ligand, PGE2, will drive ovarian cancer progression. We also hypothesize that alternation of the tumor microenvironment via MRP4 will also lead to inhibition of EP4-mediated signaling and affect phenotypes associated with ovarian cancer progression. In order to test this hypothesis, we analyzed the expression of the EP4 and MRP4 in a human ovarian cancer tissue microarray (TMA) as well as human ovarian cancer cell lines. Immunohistochemical analysis of EP4 on the TMA composed of varying histologies, including serous, endometrioid, and clear-cell, as well as normal ovarian tissue, revealed that EP4 was expressed in 38.7% of ovarian cancer tissues, whereas EP4 had no or low expression in 10 normal ovarian tissue samples. Immunohistochemistry of MRP4 also revealed increased expression in ovarian cancer histologies compared to normal ovarian tissue. Serous, endometrioid, and clear-cell subtypes presented with a majority of 4+ and 3+ staining intensities compared to normal ovarian tissue, which presented with mostly 2+ and 1+ staining, and none of the normal ovarian tissue presented with 4+ intensity. EP4 and MRP4 also has increased expression in multiple ovarian cancer cells lines including those representing low-grade serous, clear-cell, and high-grade serous ovarian cancer. Treatment of these cell lines with an EP4 antagonist resulted in decreased proliferation and migration compared to vehicle control. Consistent with the pharmacologic data, treatment of ovarian cancer cell lines with siRNA directed against the EP4 receptor led to decreased proliferation and migration. Inhibition of PGE2 export via MRP4 inhibitor Ceefourin and probenecid results in increased sensitization of ovarian cancer cell lines to treatment with paclitaxel. Based on these data, targeting of the PGE2 EP4 receptor and PGE2 export via MRP4 should be investigated further for the treatment of ovarian cancer. Citation Format: Jocelyn Reader, McMillan Ching, Cong (Ava) Fan, Sulan Wu, Paul Staats, Teklu Legesse, Olga Goloubeva, Ningbo Jian, Mark Carey, Amy Fulton, Dana Roque, Gautam Rao. Analysis of function and inhibition of PGE2 pathway members MRP4 and EP4 in treatment of ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B67.

The rise of immunotherapy is the greatest advance in oncology to occur over the last several years, but applications in gynecologic malignancies lag behind other tumors. The term "immunotherapy" envelops monoclonal antibodies as receptor mediators, including immune checkpoint inhibitors (ICPI), cancer vaccines, and adoptive immunotherapies alone or in combination with other therapeutic approaches. The purpose of this review is to summarize the status of immunotherapy trials in ovarian cancer and to specifically highlight data published in the last 1-2 years.

Purpose Uterine serous carcinoma is a rare, aggressive variant of endometrial cancer. Trastuzumab is a humanized monoclonal antibody that targets human epidermal growth factor receptor 2 (HER2)/neu, a receptor overexpressed in 30% of uterine serous carcinoma. This multicenter, randomized phase II trial compared carboplatin-paclitaxel with and without trastuzumab in patients with advanced or recurrent uterine serous carcinoma who overexpress HER2/neu. Methods Eligible patients had primary stage III or IV or recurrent HER2/neu-positive disease. Participants were randomly assigned to receive carboplatin-paclitaxel (control arm) for six cycles with or without intravenous trastuzumab (experimental arm) until progression or unacceptable toxicity. The primary end point was progression-free survival, which was assessed for differences between treatment arms via one-sided log-rank tests. Results From August 2011 to March 2017, 61 patients were randomly assigned. Forty progression-free survival–related events occurred among 58 evaluable participants. Among all patients, median progression-free survival was 8.0 months (control) versus 12.6 months (experimental; P = .005; hazard ratio [HR], 0.44; 90% CI, 0.26 to 0.76). Similarly, median progression-free survival was 9.3 (control) versus 17.9 (experimental) months among 41 patients with stage III or IV disease undergoing primary treatment ( P = .013; HR, 0.40; 90% CI, 0.20 to 0.80) and 6.0 (control) versus 9.2 months (experimental), respectively, among 17 patients with recurrent disease ( P = .003; HR, 0.14; 90% CI, 0.04 to 0.53). Toxicity was not different between treatment arms, and no unexpected safety signals emerged. Conclusion Addition of trastuzumab to carboplatin-paclitaxel was well tolerated and increased progression-free survival. These encouraging results deserve further investigation to determine their impact on overall survival in patients with advanced or recurrent uterine serous carcinoma who overexpress HER2/neu.

Minimally invasive surgical techniques compared with laparotomy offer the advantages of less intraoperative blood loss, shorter hospitalization, fewer wound complications and faster return to baseline activity for both hysterectomy and myomectomy. While morcellation allows for the laparoscopic removal of large specimens, it may result in intraperitoneal dissemination of benign disease or upstaging of occult malignancy leading to compromised survival. There has been heightened scrutiny over appropriate patient selection and preoperative assessment in light of recent warnings against power morcellation issued by the US FDA. This commentary therefore summarizes the magnitude of such risks associated with uterine morcellation, current national regulatory statements and potential merits of risk-reducing approaches such as contained morcellation. The importance of patient counseling is underscored.

Objective To describe the clinical outcome and tolerability of weekly ixabepilone (16–20 mg/m2 days 1, 8, 15 of a 28-day cycle) ± biweekly bevacizumab (10 mg/kg days 1 and 15) in patients with recurrent/persistent uterine or ovarian/primary peritoneal/fallopian tube cancers. Methods A single-institution retrospective review was performed inclusive of all patients who received ≥ 2 cycles from 01/2010 to 06/2014. Progression-free (PFS) and overall (OS) survival were determined using the Kaplan–Meier method. Toxicities were graded according to CTCAEv4.0. Best response was categorized using RECIST or by CA-125 criteria. Results A total of 60 patients (24 uterine and 36 ovarian cancers) were identified. Patients had received a median of 3.5 (range:1–10) prior lines of chemotherapy. Patients completed a mean of 4.7 ± 2.9 cycles of ixabepilone; 66.7% (16/24) and 91.7% (33/36) of patients with uterine and ovarian cancers received concurrent bevacizumab. For uterine cancers, objective response rate (ORR) was 41.7% (12.5% complete, 29.2% partial); median duration of response or stabilization was 7 months (range:2–30). Median PFS and OS were 5.2 and 9.6 months, respectively. PFS and OS were improved in the setting of concurrent bevacizumab (6.5 versus 3.0 months, p = 0.01, HR 0.2, 95% CI 0.05–0.77; 9.6 versus 4.2 months, p = 0.02, HR 0.58, 95% CI 0.04–0.74). Similar ORR was observed among ovarian cancers; median PFS/OS were not yet reached. Most toxicities were grade 1/2. Conclusions Weekly ixabepilone with or without biweekly bevacizumab has promising activity and acceptable toxicity in patients with platinum-/taxane-resistant endometrial and ovarian cancers. This combination warrants further prospective study in these populations.

Peripartum hemorrhage accounts for 8% of maternal deaths in the United States, and nearly 27% worldwide. A growing need exists for tactics to spare morbidity given a rise of abnormal placentation that contributes to excessive blood loss at the time of delivery. Approaches such as compression sutures, balloon tamponade, and pelvic artery embolization are not without side effects and potential implications for future fertility. The use of topical hemostatic agents has become widespread in gynecologic and obstetric surgery despite a paucity of distinct studies in the field, and may allow providers to increasingly avoid cesarean hysterectomy. A variety of topical hemostatic agents exist along a wide cost continuum, each characterized by specific efficacy, advantages, drawbacks, and often gaps in long-term data to support safety and impact on future fertility. Herein, we comprehensively review these agents and illustrate a non-traditional use of Monsel’s solution applied directly to the placental bed in a case of focal placenta accreta. This ultimately contributed to successful uterine preservation with no known adverse sequelae. Monsel’s solution may have a role in establishing hemostasis in the setting of abnormal placentation, and may be a particularly attractive alternative in resource-poor nations.

Background Mature cystic teratoma (MCT) is the most common germ cell tumor. It accounts for 10% to 20% of all ovarian masses. The likelihood of malignancy arising from within an MCT is low, and prognosis is poor. Methods A single-institution retrospective chart review was completed of all cases of MCT from 2004 to 2012. Multiple variables were examined including procedure performed, residual disease after surgery, surgical stage, histologic type, site of primary disease, date of recurrence, whether or not adjuvant chemotherapy was given, and whether or not there was death secondary to disease. Results During the study period, 1.2% of MCTs exhibited malignant transformation. The average age at presentation was 53.7 years. Mean follow-up time was 23 months. The most common presenting symptoms were bloating and abdominal pain. The average tumor size was 18 cm. Of note, 33% of cases were at least surgical stage IIIC at the time of presentation, whereas the remainder were stage IC or lower. Four (44.4%) of the 9 cases were identified as mucinous adenocarcinoma in addition to 1 case each of malignant melanoma, squamous cell carcinoma, and poorly differentiated adenocarcinoma. Only 1 patient experienced recurrence. One patient had a known MCT that was being managed expectantly and exhibited malignant transformation to a mucinous adenocarcinoma. Conclusions A large ovarian mass that is suspected to be a mature teratoma should be managed more aggressively in older patients. Our data suggest that although malignancy arising from mature teratomas is rare, it is more likely when patients are older than 40 years, the mass is greater than 18 cm, and there is any suspicion for a mucinous tumor. Like most ovarian tumors, these tumors most often present at later stages and, thus, can be difficult to treat. It is unclear what role chemotherapy or radiation plays in the management of these tumors.

Ovarian cancer is the leading cause of death from gynecologic malignancy in the US. Treatments have improved with conventional cytotoxic chemotherapy and advanced surgical techniques but disease recurrence is common and fatal in nearly all cases. Current evidence suggests that the immune system and its ability to recognize and eliminate microscopic disease is paramount in preventing recurrence. Ovarian cancer immunotherapy is targeting tumors through active, passive and adoptive approaches. The goal of immunotherapy is to balance the activation of the immune system against cancer while preventing the potential for tremendous toxicity elicited by immune modulation. In this paper we will review the different immunotherapies available for ovarian cancer as well as current ongoing studies and potential future directions.

INTRODUCTION AND HYPOTHESIS: Pelvic floor disorders (PFDs) negatively affect quality of life in the general population, and their prevalence in gynecologic cancer survivors has not been systematically described. This study aimed to determine the prevalence of PFDs in cancer survivors. We hypothesized that the prevalence of PFDs in the gynecologic cancer population would be higher than in the general female population. METHODS: We searched PubMed (1809 to present), EMBASE (1974 to present), and the Cochrane Central Register of Controlled Trials (CENTRAL) through May 2017. The search combined subject headings, title, and abstract words for gynecologic cancer, PFDs, and prevalence. Any studies evaluating the prevalence of PFDs in gynecologic malignancies were included. RESULTS: A total of 550 articles met the designated search criteria and 31 articles were included in this review. In cervical cancer survivors, before treatment the prevalences of stress urinary incontinence (SUI), urgency urinary incontinence (UUI) and fecal incontinence (FI) were 24–29%, 8–18% and 6%, respectively, and after treatment the prevalences of SUI, UUI, urinary retention, FI, fecal urge, dyspareunia and vaginal dryness were 4–76%, 4–59%, 0.4–39%, 2–34%, 3–49%, 12–58% and 15–47%, respectively. In uterine cancer survivors, before treatment the prevalences of SUI, UUI and FI were 29–36%, 15–25% and 3%, respectively, and after treatment the prevalences of urinary incontinence (UI) and dyspareunia were 2–44% and 7–39%, respectively. In vulvar cancer survivors, after treatment the prevalences of UI, SUI and FI were 4–32%, 6–20% and 1–20%, respectively. In ovarian cancer survivors, the prevalences of SUI, UUI, prolapse and sexual dysfunction were 32–42%, 15–39%, 17% and 62–75%, respectively. CONCLUSIONS: PFDs are prevalent in gynecologic cancer survivors and this is an important area of clinical concern and future research.

Background In 2017, there will be an estimated 12,820 women diagnosed with cervical cancer in the United States, causing an estimation of 4,210 deaths. Among U.S. women, there is a 33% greater incidence and 71% higher cervical cancer mortality in high-poverty counties when compared to low-income counties [1]. In those dispositioned to chemoradiation, treatment time of less than eight weeks is associated with compromised pelvic control. We sought to identify patient or disease characteristics and socioeconomic or psychosocial barriers that contribute to delays in treatment completion in order to formulate new policies to address these needs. ​​​​​​Methods Cervical cancer patients treated with primary chemoradiation through the University of Maryland from 2011-2016 were identified retrospectively. Patients were placed in one of two groups: those who completed radiation treatment within 56 days, and those who failed to complete treatment within 56 days. Time to completion of radiation therapy was evaluated in relation to patient and disease variables. ​​​​Results Forty-three patients with sufficient information for inclusion were identified. The median age was 51 years. Ten patients were stage I at diagnosis (23.3%), 16 were stage II (37.2%), 11 were stage III (25.5%) and six were stage IV (14%). Histopathology revealed squamous cell carcinoma in 37 patients (86%), adenocarcinoma in three patients (7%), mixed histology in two patients (4.7%), and neuroendocrine histology in one patient (2.3%). Twenty patients (46.5%) completed treatment within the recommended timeframe of 56 days while 23 patients (53.5%) did not. The most common reasons for a protracted treatment, or failure to complete the prescribed treatment were non-compliance/psychosocial factors (10 patients, 43.5%). Age, race, primary language, marital status, insurance, employment status, HIV status, mental health, substance abuse, tobacco use, stage at diagnosis, performance status at diagnosis, BMI (body mass index, kg/m2) at diagnosis, and income by zip code were not significantly associated with protracted treatment. The distance to treatment center was a significant factor (p=0.07); patients who lived closest to the treatment center were least likely to complete RT in the designated time frame. This is most likely due to the location of the treatment center, which is in the heart of an urban, low socioeconomic area. Conclusions More than half of all cervical cancer patients presenting to an urban tertiary care center do not complete chemoradiation therapy in the recommended timeframe. Underlying psychosocial factors are prominent. The role for patient navigation in this vulnerable population must be investigated.

The treatment of gynecological cancers continues to evolve with combination of different therapies. There has been a significant effort to induce stimulation of the immune system through treatment with interferons and interleukins in the past. More recently, the remarkable results of clinical trials demonstrating efficacy of checkpoint inhibitor immunotherapies in multiple cancer types has generated considerable interest within the gynecological community. Here, we review the findings of efforts to augment the humoral immune system and review the pre-clinical and clinical evidence for checkpoint inhibitors. The Abscopal effect, a phenomenon whereby localized radiation therapy results in immune mediated tumor regression in distant sites is currently also discussed in the context of gynecological cancers. The combination of various immunotherapies in gynecological cancer and emerging clinical evidence for the combinations may lead to improved treatment outcomes.

Uterine serous carcinoma (USC) is a highly aggressive variant of endometrial cancer. Although it only represents less than 10% of all cases, it accounts for a disproportionate number of deaths from endometrial cancer. Comprehensive surgical staging followed by carboplatin and paclitaxel chemotherapy represents the mainstay of USC therapy. Vaginal cuff brachytherapy is also of potential benefit in USC. Recent whole-exome sequencing studies have demonstrated gain of function of the HER2/NEU gene, as well as driver mutations in the PIK3CA/AKT/mTOR and cyclin E/FBXW7 oncogenic pathways in a large number of USCs. These results emphasize the relevance of these novel therapeutic targets for biologic therapy of chemotherapy-resistant recurrent USC.

Study Objective To evaluate the role of robotic simulation in training OBGYN residents by determining an optimal number of exercise repetitions prior to clinical debut; To assess whether clinical exposure accelerates proficiency by correlating laparoscopic/robotic experience with simulator skills acquisition Design Prospective cohort study Setting Urban academic center with active COEMIG designation Patients or Participants 2017-2018 Gynecology residents(PGY1-4) Interventions Voluntary participants were instructed to complete 10 repetitions of 5 exercises (pegboard-1, energy dissection-1, energy switching-1, ringr however, after one round, many trainees failed to attain the pre-determined passing score of 80%. Across all participants, mean scores by exercise were 82.5±15.6, 78.0±15.8, 72.6±17.9, 62.7±19.4, 60.1±22.1 (p Conclusion Robotic simulation may be useful for development/maintenance of robotic skills in Gynecology trainees. M-score® may be insufficiently sensitive; additional metrics should be explored. Robotic simulation is valued by trainees, however, not a milestone established by the ACGME. Protected time with incorporation into curricula would be needed to maximize utility.

BACKGROUND Uterine serous carcinoma (USC) is a subtype of endometrial cancer associated with chemoresistance and poor outcome. Overexpression of tubulin-β-III and p-glycoprotein has been linked to paclitaxel resistance in many cancers but has been undercharacterized among USCs. Epothilones have demonstrated activity in certain paclitaxel-resistant malignancies. In this study, relationships are clarified, in USCs relative to ovarian serous carcinomas (OSCs), between tubulin-β-III and p-glycoprotein expression, clinical outcome, and in vitro chemoresponsiveness to epothilone B, ixabepilone, and paclitaxel. METHODS Tubulin-β-III and p-glycoprotein were quantified by real-time polymerase chain reaction in 48 fresh-frozen tissue samples and 13 cell lines. Copy number was correlated with immunohistochemistry and overall survival. Median inhibitory concentration (IC50) was determined using viability and metabolic assays. Impact of tubulin-β-III knockdown on IC50 was assessed with small interfering RNAs. RESULTS USC overexpressed tubulin-β-III but not p-glycoprotein relative to OSC in both fresh-frozen tissues (552.9 ± 106.7 versus 202.0 ± 43.99, P = .01) and cell lines (1701.0 ± 376.4 versus 645.1 ± 157.9, P = .02). Tubulin-β-III immunohistochemistry reflected quantitative real-time polymerase chain reaction copy number and overexpression stratified patients by overall survival (copy number ≤ 400: 615 days; copy number > 400: 165 days, P = .049); p-glycoprotein did not predict clinical outcome. USCs remained exquisitely sensitive to patupilone in vitro despite tubulin-β-III overexpression (IC50,USC 0.245 ± 0.11 nM versus IC50,OSC 1.01 ± 0.13 nM, P = .006). CONCLUSIONS Tubulin-β-III overexpression in USCs discriminates poor prognosis, serves as a marker for sensitivity to epothilones, and may contribute to paclitaxel resistance. Immunohistochemistry reliably identifies tumors with overexpression of tubulin-β-III, and a subset of individuals likely to respond to patupilone and ixabepilone. Epothilones warrant clinical investigation for treatment of USCs. Cancer 2013;119:2582–2592. © 2013 American Cancer Society.

SUMMARY Type II endometrial cancers exhibit distinct histopathology, underlying pathogenesis and clinical behavior. These high-risk cancers are associated with an aggressive clinical course and a relatively poor prognosis that underscores the need for the development of novel rational therapeutic strategies that exploit their distinct underlying molecular pathway alterations. In this review, we describe the extent of disease burden and molecular characterization of type II endometrial cancers, summarize the historical development to support current standards of care and delineate the most recent preclinical and clinical advances in immunotherapy, cytotoxic agents and small-molecule inhibitors for this disease.

Ovarian cancer is the leading cause of death from gynecologic malignancy in the United States. Most cases of ovarian cancer present in late stages, leading to recurrent disease that is incurable and often fatal due to innate or acquired chemoresistance; therefore, new therapies are desperately needed. Cyclo-oygenases, COX-1 and COX-2, are enzymes that catalyze the production of the prostaglandin E2 (PGE2), a lipid mediator that is functionally linked to progression of many cancers including breast and ovarian cancer. PGE2 is exported from the cell via multidrug resistance-associated protein 4 (MRP4) where it acts in a paracrine and autocrine manner by activating a family of four G-protein coupled receptors (EP1-4) that are linked to different intracellular signaling pathways. EP2 and EP4 can activate PKA/cAMP, PI3K, and ERK pathways. COX-1 and COX-2 have been shown to be overexpressed in primary ovarian cancer as well as in many ovarian cancer cell lines. We hypothesized that the EP4 receptor is overexpressed in ovarian cancer; that binding of its cognate ligand, PGE2, will drive ovarian cancer progression; and that inhibition of the EP4-mediated signaling will lead to inhibition of ovarian cancer growth and metastasis. In order to test this hypothesis, we analyzed the expression of the EP4 receptor in a human ovarian cancer tissue microarray (TMA) as well as human ovarian cancer cell lines. Immunohistochemical analysis of EP4 on the TMA composed of varying histologies, including serous, endometrioid, and clear cell, as well as normal ovarian tissue revealed that EP4 was expressed in 38.7% of ovarian cancer patients, whereas EP4 was not expressed in the 10 normal ovarian tissue samples. Additionally, in comparison to immortalized human ovarian surface epithelial (HOSE) cells, EP4 is overexpressed in many of the cell lines analyzed, including OVCAR-3, COAV-3, SKOV3, and Kuramochi cells. Blockade of the EP4 receptor via antagonist or siRNA results in a decrease in proliferation, migration, and invasion in ovarian cancer cell lines. In addition to overexpression of EP4, MRP4 was also found to be overexpressed in ovarian cancer cell lines when compared to HOSE cells. Given the role of MRP4 in exporting PGE2 and affecting drug resistance/ sensitivity in breast cancer cell lines, we hypothesize that MRP4 will similarly play a role in modulating the amount of PGE2 in the microenvironment in ovarian cancer, thereby affecting signaling via of EP4 receptor. Functional testing of dual EP4/ MRP4 inhibition may provide much-needed new therapies for the treatment of ovarian cancer. Citation Format: Mc Millan Ching, Cong Fan, Dana Roque, Gautam Rao, Paul Staats, Amy Fulton, Jocelyn Reader. Functional analysis of PGE2 pathway members EP4 and MRP4 in ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A22.

Context.—In the era of targeted cancer therapy, there is growing interest in developing novel therapeutic strategies against endometrial carcinoma, especially its most biologically aggressive variant, serous adenocarcinoma. Several publications have demonstrated that a significant proportion of uterine serous carcinomas show HER2 overexpression and/or amplification, suggesting that HER2 may be a promising therapeutic target. Case reports have already shown clinical response to trastuzumab, a humanized monoclonal immunoglobulin (Ig) G1 antibody against HER2, and patients are currently being enrolled in a multi-institutional prospective randomized trial to evaluate the therapeutic efficacy of trastuzumab.Objective.—To review current data on HER2 testing and targeted therapy against HER2/neu in endometrial carcinoma.Data Sources.—Review of the literature and personal experience of the authors.Conclusions.—Parallel to the clinical studies, there is a need to develop standardized criteria for HER2 testing in endometrial carcinoma that reflect the unique biological and pathogenetic features of these tumors and correlate with clinical response to therapy. This article presents a comprehensive review of the current state of HER2-based therapy and HER2 testing in endometrial carcinoma.

The use of taxanes in the treatment of gynecologic malignancies has expanded tremendously over the past 30 years. Both paclitaxel and docetaxel have unique microtubule stabilizing, antiangiogenic and radiation sensitizing properties that endow them with remarkable activity as chemotherapeutic agents. As research into the appropriate dose, timing, treatment interval, and response rates have been studied, they have emerged as one of the most active agents available in the treatment of gynecologic cancer. The body of research on taxanes continues to expand especially with regard to the use of taxanes in alternative formulations and in combination with newer treatments or routes of treatment. This review focuses on the development of taxanes as an effective therapy in the treatment of gynecologic cancers and data currently available in the literature regarding their efficacy. Future directions of taxane-based chemotherapy with regards to ovarian, uterine, and cervical cancers are also addressed. There is little doubt that taxane-based chemotherapy will remain an integral part of the treatment of gynecologic cancer for the foreseeable future.

Critics have suggested that neoadjuvant chemotherapy (NACT) followed by interval debulking may select for resistant clones or cancer stem cells when compared to primary cytoreduction. β-tubulins are chemotherapeutic targets of taxanes and epothilones. Class III β-tubulin overexpression has been linked to chemoresistance and hypoxia. Herein, we describe changes in class III β-tubulin in patients with advanced ovarian carcinoma in response to NACT, in relationship to clinical outcome, and between patients who underwent NACT versus primary debulking; we characterize in vitro chemosensitivity to paclitaxel/patupilone of cell lines established from this patient population, and class III β-tubulin expression following repeated exposure to paclitaxel. Using immunohistochemistry, we observed among 22 paired specimens obtained before/after NACT decreased expression of class III β-tubulin following therapy within stroma (p=0.07), but not tumor (p=0.63). Poor median overall survival was predicted by high levels of class III β-tubulin in both tumor (HR 3.66 [1.11,12.05], p=0.03) and stroma (HR 4.53 [1.28,16.1], p=0.02). Class III β-tubulin expression by quantitative-real-time-polymerase-chain-reaction was higher among patients who received NACT (n=12) compared to primary cytoreduction (n=14) (mean±SD fold-change: 491.2±115.9 vs. 224.1±55.66, p=0.037). In vitro subculture with paclitaxel resulted in class III β-tubulin upregulation, however, cell lines that overexpressed class III β-tubulin remained sensitive to patupilone. Overexpression of class III β-tubulin in patients dispositioned to NACT may thus identify an intrinsically aggressive phenotype, and predict poor overall survival and paclitaxel resistance. Decreases in stromal expression may represent normalization of the tumor microenvironment following therapy. Epothilones warrant study for patients who have received neoadjuvant carboplatin and paclitaxel.

Purpose of review Uterine serous carcinoma (USC) is a highly aggressive variant of endometrial cancer with distinct molecular pathogenesis. This review summarizes the rationale behind current clinical approaches, as well as advances made in 2012 toward the elucidation of underlying pathway aberrations and development of targeted therapies that exploit these unique characteristics. Recent findings Within the last year, exome-wide analyses have highlighted key mutations to guide rational drug design. The PI3/AKT/mTOR pathway and regulators of cell cycle such as cyclin E/F-box proteins appear to be particularly important. Understanding the epithelial to mesenchymal transition may explain the aggressive pattern of spread frequently observed in this disease. There is heightened evidence for heritable syndromes in association with USC. Conflicting retrospective data continue to emerge regarding optimal therapy, especially for early-stage disease, although prospective studies are underway. Immunotherapies targeting Her2/Neu and vascular endothelial growth factor remain an area of active research. Upregulation of class III β-tubulin observed in paclitaxel-resistant disease may identify candidates for therapy with novel microtubule-stabilizing agents such as epothilones. Summary There is an expanding role for contemporary novel approaches in the treatment of USC. The results of clinical investigations using new target antigens, epothilones, and small molecule inhibitors are eagerly awaited.

To compare the in vitro sensitivity/resistance to patupilone versus paclitaxel in uterine and ovarian carcinosarcomas (CS).Five primary carcinosarcoma cell lines, two from uterine and three of ovarian origin, were evaluated for growth rate and tested for their in vitro sensitivity/resistance to patupilone versus paclitaxel by MTS assays. To identify potential mechanisms underlying the differential sensitivity/resistance to patupilone, expression levels of β-tubulin III (TUBB3) were determined with quantitative-real-time-polymerase-chain-reaction (q-RT-PCR) in primary uterine and ovarian CS cell lines and in 26 uterine and 9 ovarian CS fresh-frozen-tissues.No appreciable difference in sensitivity to patupilone versus paclitaxel was noted in ovarian CS cell lines, or when uterine and ovarian CS cell lines were compared in their response to paclitaxel. In contrast, uterine CS cell lines were found to be significantly more sensitive to patupilone than to paclitaxel (P0.002) and demostrated lower IC(50s) to patupilone (range 0.76-0.93nM) when compared to ovarian CS (range 1.9-3.4 nM, p0.05). Higher levels of TUBB3 were detected in uterine CS cell lines and fresh frozen tissues when compared to ovarian CS (P0.05).Uterine CS cell lines are significantly more sensitive than ovarian CS cell lines to patupilone versus paclitaxel. High expression of TUBB3 is associated with sensitivity to patupilone in primary CS cell lines and may act as a genetic marker to predict chemotherapy efficacy. Patupilone may represent a promising drug in the treatment of this subset of rare but highly aggressive gynecological tumors.

Proteomics embodies a diverse set of platforms devoted to the study of protein structure and function. Mass spectrometry and protein microarrays enable detailed analysis of a diverse set of proteins and their isoforms at the molecular level. These new, high-throughput, and comprehensive proteomic studies can be useful in advancing our understanding of disease processes and have wide potential for integration within clinical trials. Clinical trials incorporating proteomic-based endpoints are geared toward biomarker development, pathway discovery, and target validation. Screening the proteome has the potential to discover a protein biomarker or a signature of markers to predict disease presence, and we have initiated a multi-center clinical trial with the goal of defining a proteomic signature that can predict relapse of ovarian cancer. Serum and tissue proteomics reflect information from the tumor as well as from the tumor microenvironment, as demonstrated in our two recent clinical trials employing these analyses to evaluate effects of targeted agents. Proteomic techniques strengthen the link between bench and bedside by testing existing hypotheses about a disease state or treatment and validating them in the clinical setting. Defining signaling pathways and protein regulatory events in the clinical venue may thus lead to generation of new hypotheses and subsequently to novel treatment strategies.