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Infertility affects one in eight women in the USA. In vitro fertilization (IVF) is an effective but costly treatment that lacks uniform insurance coverage. We evaluated the current insurance coverage landscape for IVF in America.We conducted a cross-sectional analysis of 58 insurance companies with the greatest state enrollment and market share, calculated to represent the majority of Americans with health insurance. Individual companies were evaluated for a publicly available policy on IVF services by web-based search, telephone interview, or email to the insurer. Coverage status, required criteria, qualifying risk factors, and contraindications to coverage were extracted from available policies.Fifty-one (88%) of the fifty-eight companies had a policy for IVF services. Thirty-five (69%) of these policies extended coverage. Case-by-case coverage was stated in seven policies (14%), while coverage was denied in the remaining nine (18%). The most common criterion to receive coverage was a documented diagnosis of infertility (n = 23, 66%), followed by care from a reproductive endocrinologist (n = 9, 26%). Twenty-three (45%) of the companies with a policy had at least one contraindication to coverage. Three companies (6%) limited the number of IVF cycles to be covered, capping payments after 3-4 lifetime cycles.Most Americans with health insurance are provided a public policy regarding IVF. However, there is great variation in coverage and requirements to receive coverage between insurers. Coupled with inconsistencies in state-level mandates and available choices for employer-sponsored plans, this may limit coverage of IVF services and, therefore, access to infertility treatment.

Objectives To describe risk factors/incidence of abnormal cervical/vaginal cytology/histology and cancer among women living with human immunodeficiency virus (WLHIV) ≥65 years compared to HIV-negative matched controls Study Design Retrospective cohort of patients who underwent Pap screening at the University of Maryland 01/2003-04/2019. Results WLHIV and HIV-negative controls ( n = 70 each) underwent 140/151 Pap tests, respectively. Among WLHIV, 29% exhibited abnormal results and were less likely than HIV-negative women with normal Paps to have had serially negative Pap tests prior to age 65 ( p = .03). In both groups, 1.4% developed cervical cancer. Abnormal Paps were more frequent in WLHIV than in HIV-negative women (31% vs 10%, p < .0001, RR:3.2, 95%CI1.9–5.4) as was HRHPV (high-risk human papillomavirus) status (43% vs 19%, p = .0233, RR:2.3, 95%CI1.2–4.6). The RR for an abnormal Pap was 2.6 (95% CI:1.1–4.2) for VL >1000 copies/mL and 0.4 (95% CI:0.2–0.7) for CD4 count of >200 cells/μL. No individual with an initially normal Pap experienced an abnormal result over a mean of 42.5 and 43.5 months in the HIV-positive and HIV-negative groups, respectively. Conclusions HIV status was associated with a higher rate of abnormal Pap/HRHPV; however, no significant difference in cervical/vaginal cancer. Elevated VL/low CD4 count were associated with greater risk for an abnormal Pap.

Uterine serous carcinoma (USC) is an aggressive variant of endometrial cancer with a poor prognosis. Approximately 30% of USC overexpress HER2/neu, a recognized target for trastuzumab in advanced/recurrent HER2/neu-positive USC. We evaluated the efficacy of the pan-c-erb inhibitor neratinib and the poly (ADP-ribose)-polymerase (PARP) inhibitor olaparib as single agents and in combination against USC cell lines and xenografts.In-vitro cell-viability assays with olaparib, neratinib, and olaparib/neratinib were assessed using flow-cytometry based assays against a panel of USC cell lines with high and low HER2/neu expression. Homologous recombination deficiency (HRD) signatures were evaluated as described by Alexandrov et al. (Nature;2020;578:94-101) while downstream signaling affected by neratinib/olaparib exposure was assessed with immunoblotting. Efficacy of single- versus dual-agent inhibition was evaluated in-vivo using two USC-xenografts with 3+ HER2/neu expression.Neratinib was more potent than olaparib in suppression of in-vitro growth of HER2/neu 3+ cell lines (ARK1: p = 0.0047; ARK2: p = 0.0428) while no difference was noted against HER2/neu 1+ tumors (ARK4). Importantly, the combination of olaparib with neratinib synergistically improved tumor suppression compared to either single-agent in vitro. USC cells exposed to olaparib upregulated HER2/neu expression, while neratinib treatment increased PARP activity (ARK1: p0.0001; ARK2: p0.0001). Single-agent neratinib transiently inhibited in vivo growth of USC xenografts harboring HER2/neu gene amplification (ARK1: p0.05; ARK2: p0.05). In contrast, the combination of the two inhibitors caused a stronger and durable growth inhibition in both USC xenografts (ARK1: p0.05; ARK2: p0.05).The combination of olaparib and neratinib is active and synergistic against primary HER2/neu + USC. This combination may represent a novel therapeutic option for USC patients with HER2/neu+, homologous recombination-proficient tumors resistant to chemotherapy.

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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.

Treatments for advanced and recurrent ovarian cancer remain a challenge due to a lack of potent, selective, and effective therapeutics. Here, we developed the basis for a transformative anticancer strategy based on anthrax toxin that has been engineered to be selectively activated by the catalytic power of zymogen-activating proteases on the surface of malignant tumor cells to induce cell death. Exposure to the engineered toxin is cytotoxic to ovarian tumor cell lines and ovarian tumor spheroids derived from patient ascites. Preclinical studies demonstrate that toxin treatment induces tumor regression in several in vivo ovarian cancer models, including patient-derived xenografts, without adverse side effects, supportive of progression toward clinical evaluation. These data lay the groundwork for developing therapeutics for treating women with late-stage and recurrent ovarian cancers, utilizing a mechanism distinct from current anticancer therapies.

Ovarian cancer is the most lethal gynecological cancer type in the United States. The success of current chemotherapies is limited by chemoresistance and side effects. Targeted therapy is a promising future direction for cancer therapy. In the present study, the efficacy of co‑targeting IL‑6 and IL‑8 in human ovarian cancer cells by bazedoxifene (Baze) + SCH527123 (SCH) treatment was examined. ELISA, cell viability, cell proliferation, cell migration, cell invasion, western blotting and peritoneal ovarian tumor mouse model analyses were performed to analyze the expression levels of IL‑6 and IL‑8, tumor growth, tumor migration and invasion, and the possible pathways of human ovarian cancer cell lines (SKOV3, CAOV3 and OVCAR3) and patient‑derived OV75 ovarian cancer cells. Each cell line was treated by monotherapy or combination therapy. The results demonstrated that IL‑6 and IL‑8 were secreted by human ovarian cancer cell lines. Compared with the DMSO control, the combination of IL‑6/glycoprotein 130 inhibitor Baze and IL‑8 inhibitor SCH synergistically inhibited cell viability in ovarian cancer cells. Baze + SCH also inhibited cell migration and invasion, suppressed ovarian tumor growth and inhibited STAT3 and AKT phosphorylation, as well as survivin expression. Therefore, co‑targeting the IL‑6 and IL‑8 signaling pathways may be an effective approach for ovarian cancer treatment.

Background: The development of chemoresistance to paclitaxel and carboplatin represents a major therapeutic challenge in ovarian cancer, a disease frequently characterized by malignant ascites and extrapelvic metastasis. Microtentacles (McTNs) are tubulin-based projections observed in detached breast cancer cells. In this study, we investigated whether ovarian cancers exhibit McTNs and characterized McTN biology. Methods: We used an established lipid-tethering mechanism to suspend and image individual cancer cells. We queried a panel of immortalized serous (OSC) and clear cell (OCCC) cell lines as well as freshly procured ascites and human ovarian surface epithelium (HOSE). We assessed by Western blot β-tubulin isotype, α-tubulin post-translational modifications and actin regulatory proteins in attached/detached states. We studied clustering in suspended conditions. Effects of treatment with microtubule depolymerizing and stabilizing drugs were described. Results: Among cell lines, up to 30% of cells expressed McTNs. Four McTN morphologies (absent, symmetric-short, symmetric-long, tufted) were observed in immortalized cultures as well as ascites. McTN number/length varied with histology according to metastatic potential. Most OCCC overexpressed class III ß-tubulin. OCCC/OSC cell lines exhibited a trend towards more microtubule-stabilizing post-translational modifications of α-tubulin relative to HOSE. Microtubule depolymerizing drugs decreased the number/length of McTNs, confirming that McTNs are composed of tubulin. Cells that failed to form McTNs demonstrated differential expression of α-tubulin- and actin-regulating proteins relative to cells that form McTNs. Cluster formation is more susceptible to microtubule targeting agents in cells that form McTNs, suggesting a role for McTNs in aggregation. Conclusions: McTNs likely participate in key aspects of ovarian cancer metastasis. McTNs represent a new therapeutic target for this disease that could refine therapies, including intraperitoneal drug delivery.

Simple Summary Microtubule-interfering drugs have been used alone or in combination in the treatment of epithelial ovarian cancer. Over the years and with increasing chemoresistance to taxanes, epothilones (i.e., ixabepilone) have become of interest as alternatives to taxanes. In this review, we discuss the role of microtubule-interfering chemotherapeutic agents in treatment of newly diagnosed and recurrent ovarian cancer, as well as common mechanisms of chemoresistance. We also discuss future directions for the use of microtubule-interfering agents in ovarian cancer. Abstract Taxanes and epothilones are chemotherapeutic agents that ultimately lead to cell death through inhibition of normal microtubular function. This review summarizes the literature demonstrating their current use and potential promise as therapeutic agents in the treatment of epithelial ovarian cancer (EOC), as well as putative mechanisms of resistance. Historically, taxanes have become the standard of care in the front-line and recurrent treatment of epithelial ovarian cancer. In the past few years, epothilones (i.e., ixabepilone) have become of interest as they may retain activity in taxane-treated patients since they harbor several features that may overcome mechanisms of taxane resistance. Clinical data now support the use of ixabepilone in the treatment of platinum-resistant or refractory ovarian cancer. Clinical data strongly support the use of microtubule-interfering drugs alone or in combination in the treatment of epithelial ovarian cancer. Ongoing clinical trials will shed further light into the potential of making these drugs part of current standard practice.

Simple Summary Photodynamic priming is an emerging strategy that leverages subtherapeutic photochemistry for therapeutic benefits, often used as part of combination regimens. Our study aimed to couple photodynamically priming with antagonism of the prostaglandin E receptor 4, a therapeutic target linked to cancer-associated migration, invasion, angiogenesis, and immune evasion. Photodynamic priming and antagonism of the prostaglandin E receptor 4 independently attenuated OVCAR-5 ovarian cancer cell migration in a gap closure model, though their combination induced the most significant reductions. More potent combination effects were revealed when invasiveness was characterized using a transwell invasion model with CAOV3 ovarian cancer cells. Immunoblotting identified the epithelial growth factor receptor, cAMP-response element binding protein, and extracellular signal-regulated kinase 1/2 as potential mediators of these combinational effects. This work provides new evidence of a novel and clinically relevant combination strategy to address metastatic behavior, a major challenge in the treatment of cancer. Abstract The combination of photodynamic agents and biological inhibitors is rapidly gaining attention for its promise and approval in treating advanced cancer. The activity of photodynamic treatment is mainly governed by the formation of reactive oxygen species upon light activation of photosensitizers. Exposure to reactive oxygen species above a threshold dose can induce cellular damage and cancer cell death, while the surviving cancer cells are “photodynamically primed”, or sensitized, to respond better to other drugs and biological treatments. Here, we report a new combination regimen of photodynamic priming (PDP) and prostaglandin E2 receptor 4 (EP4) inhibition that reduces the migration and invasion of two human ovarian cancer cell lines (OVCAR-5 and CAOV3) in vitro. PDP is achieved by red light activation of the FDA-approved photosensitizer, benzoporphyrin derivative (BPD), or a chemical conjugate composed of the BPD linked to cetuximab, an anti-epithelial growth factor receptor (EGFR) antibody. Immunoblotting data identify co-inhibition of EGFR, cAMP-response element binding protein (CREB), and extracellular signal-regulated kinase 1/2 (ERK1/2) as key in the signaling cascades modulated by the combination of EGFR-targeted PDP and EP4 inhibition. This study provides valuable insights into the development of a molecular-targeted photochemical strategy to improve the anti-metastatic effects of EP4 receptor antagonists.

Microsatellite instability-high (MSI-H)/mismatch repair deficiency (dMMR) is a biomarker for responses to immune checkpoint inhibitors (ICIs). Whether mechanisms underlying microsatellite instability alter responses to ICIs is unclear. This article reports data from a prospective phase 2 pilot study of pembrolizumab in patients with recurrent MSI-H endometrial cancer (EC) analyzed by whole exome sequencing (WES) and potential mechanisms of primary/secondary ICI resistance (NCT02899793).Patients with measurable MSI-H/dMMR EC confirmed by polymerase chain reaction/immunohistochemistry were evaluated by WES and received 200 mg of pembrolizumab every 3 weeks for ≤2 years. The primary end point was the objective response rate (ORR). Secondary end points included progression-free survival (PFS) and overall survival (OS).Twenty-five patients (24 evaluable) were treated. Six patients (25%) harbored Lynch/Lynch-like tumors, whereas 18 (75%) had sporadic EC. The tumor mutation burden was higher in Lynch-like tumors (median, 2939 mutations/megabase [Mut/Mb]; interquartile range [IQR], 867-5108 Mut/Mb) than sporadic tumors (median, 604 Mut/Mb; IQR, 411-798 Mut/Mb; P = .0076). The ORR was 100% in Lynch/Lynch-like patients but only 44% in sporadic patients (P = .024). The 3-year PFS and OS proportions were 100% versus 30% (P = .017) and 100% versus 43% (P = .043), respectively.This study suggests prognostic significance of Lynch-like cancers versus sporadic MSI-H/dMMR ECs for ORR, PFS, and OS when patients are treated with pembrolizumab. Larger confirmatory studies in ECs and other MSI-H/dMMR tumors are necessary. Defective antigen processing/presentation and deranged induction in interferon responses serve as mechanisms of resistance in sporadic MSI-H ECs. Oligoprogression in MSI-H/dMMR patients appears salvageable with surgical resection and/or local treatment and the continuation of pembrolizumab off study. Clinical studies evaluating separate MSI-H/dMMR EC subtypes treated with ICIs are warranted.

This multi-center RP2 study assessed activity/safety of ixabepilone + bevacizumab compared to ixabepilone in platinum-resistant/refractory ovarian/fallopian tube/primary peritoneal cancer. Additional objectives were to examine the role of prior bevacizumab and taxanes, and explore class III-ß-tubulin (TUBB3) as a predictive biomarker.Participants were randomised to receive ixabepilone 20 mg/mAmong 76 evaluable patients who received IXA + BEV (n = 39) compared to IXA (n = 37), the ORR was 33% (n = 13) versus 8% (n = 3)(P = 0.004), durable at 6 months in 37% (n = 14) and 3% (n = 1) (P 0.001). BEV significantly improved PFS (median:5.5 vs 2.2 months, HR = 0.33, 95%CI 0.19-0.55, P 0.001) and OS (median:10.0 vs 6.0 months, HR = 0.52, 95%CI 0.31-0.87, P = 0.006). Both regimens were well-tolerated. TUBB3 expression did not predict response. Subgroup analyses revealed minimal effect of prior BEV or taxane resistant/refractory status on response to IXA + BEV.IXA + BEV is a well-tolerated, effective combination for platinum/taxane-resistant ovarian cancer that extends PFS and likely OS relative to IXA monotherapy. Prior receipt of BEV should not preclude the use of IXA + BEV. TUBB3 is not a predictive biomarker.NCT3093155.

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.

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.

Ovarian carcinomas are categorized into five major histotypes, each characterized by distinct differences in grade at diagnosis, presentation with metastatic disease, and clinical responses to treatments. Microtentacles (McTNs), microtubule-based extensions of the plasma membrane, were initially described on cells of nongynecologic primaries with high metastatic potential but have not been extensively explored in ovarian carcinomas. In this study, we investigated whether ovarian cancer cells exhibit McTNs as well as the effect of microtubule-targeted drugs on ovarian cancer McTNs. We analyzed 3 immortalized ovarian surface epithelium cell lines (IOSE), 8 clear-cell (OCCC), 3 low-grade serous (LGS), and 6 high-grade serous (HGS) ovarian cancer cells for McTN phenotype, length, and number, using a novel tethering platform in which cells are suspended but stationary, allowing for analysis via confocal microscopy. Additionally, selected cell lines were also treated with microtubule-targeting agents, including paclitaxel, ixabepilone, vinblastine, and colchicine and the effects on McTN dynamics and functions were analyzed. Tubulin subtype expression and post-translational modifications (PTM) were characterized by Western blot. Unpaired t-tests were used to describe differences between McTN length and number. We observed 4 patterns of McTN expression: absent (A), symmetric-short (SS), symmetric-long (SL), and tufted (T). In some cases, multiple morphologies were observed within the same cell line. LGS and OCCC expressed fewer McTNs per cell than HSC. McTNs were shorter among OCCC compared to HGS; whereas LGS expressed a range of McTN lengths similar to those observed in HGS. We also observed differences in the expression of the PTM between the different ovarian cancer subtypes, including alterations in alpha tubulin-stabilizing modifications such as glu-tubulin and acetylated tubulin, as well as proteins involved in actin cortex stability. Increased acetylated tubulin was associated with increased McTN number and length in HGS cells. Microtubule-destabilizing drugs such as colchicine and vinblastine led to a decrease in McTN formation. Ovarian cancer metastasis typically occurs through shedding of the main tumor into the peritoneal space, and the spread of disease is the leading cause of mortality. Studying McTN function and response to chemotherapeutics allows us to improve our understanding of ovarian cancer metastasis and the effect of microtubule-targeting compounds on the spread of ovarian cancer. Citation Format: Cong (Ava) Fan, Sulan Wu, Jocelyn Reader, Eleanor Claire-Higgins Ory, Cornell Lee, McMillan Ching, Trevor Mathias, Julia Ju, Rachel Lee, Michele Vitolo, Stuart Martin, Christopher Jewell, Amy Fulton, Gautam Rao, Mark Carey, Dana M. Roque. Characterization of microtentacle phenotype and function in ovarian carcinomas [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 B68.

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.

Ovarian adenocarcinoma is typified by detection at late stages with dissemination of cancer cells into the peritoneal cavity and frequent acquisition of chemoresistance. A number of studies show the importance of the tumor microenvironment and innate immune recognition in tumor progression. Ovarian cancer cells can regulate the composition of their stroma to promote the formation of ascitic fluid rich in cytokines and bioactive lipids such as PGE2, and to stimulate the differentiation of stromal cells into a pro-tumoral phenotype. In response, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, tumor-associated macrophages, and other peritoneal cells can act through direct and indirect mechanisms to regulate tumor growth, chemoresistance via alteration of class III β‎ tubulin, angiogenesis and dissemination. This chapter deciphers the current knowledge about the role of stromal cells, associated secreted factors, and the immune system on tumor progression. This suggests that targeting the microenvironment holds great potential to improve the prognosis of patients with ovarian adenocarcinoma.

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.

Background: Uterine serous carcinomas (USCs) are an aggressive form of uterine cancer that may rely on HER2/neu amplification as a driver of proliferation. The objective of this paper is to assess the sensitivity of USC cell lines with and without HER2/neu gene amplification to afatinib, an irreversible ErbB tyrosine kinase inhibitor, and to test the efficacy of afatinib in the treatment of HER2-amplified USC xenografts. Methods: Eight of fifteen primary USC cell lines (four with HER2 amplification and four without) demonstrating similar in vitro growth rates were treated with scalar concentrations of afatinib. Effects on cell growth, signalling and cell cycle distribution were determined by flow cytometry assays. Mice harbouring xenografts of HER2/neu-amplified USC were treated with afatinib by gavage to determine the effect on tumour growth and overall survival. Results: Primary chemotherapy-resistant USC cell lines harbouring HER2/neu gene amplification were exquisitely sensitive to afatinib exposure (mean±s.e.m. IC50=0.0056±0.0006 μM) and significantly more sensitive than HER2/neu-non-amplified USC cell lines (mean±s.e.m. IC50=0.563±0.092 μM, P

BACKGROUND: Solitomab is a novel, bispecific, single-chain antibody that targets epithelial cell adhesion molecule (EpCAM) on tumor cells and also contains a cluster of differentiation 3 (CD3) (T-cell coreceptor) binding region. The authors evaluated the in vitro activity of solitomab against primary chemotherapy-resistant epithelial ovarian carcinoma cell lines as well as malignant cells in ascites. METHODS: EpCAM expression was evaluated by flow cytometry in 5 primary ovarian cancer cell lines and in 42 fresh ovarian tumor cell cultures in ascites from patients with mainly advanced or recurrent, chemotherapy-resistant disease. The potential activity of solitomab against EpCAM-positive tumor cells was evaluated by flow cytometry, proliferation, and 4-hour chromium-release, cellmediated cytotoxicity assays. RESULTS: EpCAM expression was detected by flow cytometry in approximately 80% of the fresh ovarian tumors and primary ovarian tumor cell lines tested. EpCAM-positive, chemotherapy-resistant cell lines were identified as resistant to natural killer cell-mediated or T-cell–mediated killing after exposure to peripheral blood lymphocytes in 4-hour chromium-release assays (mean6standard error of the mean, 3.6%60.7% of cells killed after incubation of EpCAM-positive cell lines with control bispecific antibody). In contrast, after incubation with solitomab, EpCAM-positive, chemotherapy-resistant cells became highly sensitive to T-cell cytotoxicity (mean6standard error of the mean, 28.2%62.05% of cells killed; P

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.