Evaluation of Homologous Recombination Deficiency in Ovarian Cancer.

OPINION STATEMENT: Homologous recombination deficiency (HRD) is an important biomarker guiding selection of ovarian cancer patients who will derive the most benefit from poly(ADP-ribose) polymerase inhibitors (PARPi). HRD prevents cells from repairing double-stranded DNA damage with high fidelity, PARPis limit single-stranded repair, and together these deficits induce synthetic lethality. Germline or somatic BRCA mutations represent the narrowest definition of HRD, but do not reflect all patients who will have a durable PARPi response. HRD can also be defined by its downstream consequences, which are measured by different metrics depending on the test used. Ideally, all patients will undergo genetic counseling and germline testing shortly after diagnosis and have somatic testing sent once an adequate tumor sample is available. Should barriers to one test be higher, pursuing germline testing with reflex to somatic testing for BRCA wildtype patients or somatic testing first strategies are both evidence-based. Ultimately both tests offer complementary information, germline testing should be pursued for any patient with a history of ovarian cancer, and somatic testing is valuable at recurrence if not performed in the upfront setting. There is a paucity of data to suggest superiority of one germline or somatic assay; therefore, selection should optimize turnaround time, cost to patients, preferred result format, and logistical burden. Each clinic should implement a standard testing strategy for all ovarian cancer patients that ensures HRD status is known at the time of upfront chemotherapy completion to facilitate comprehensive counseling about anticipated maintenance PARPi benefit.

A randomized phase 2 study of sapanisertib in combination with paclitaxel versus paclitaxel alone in women with advanced, recurrent, or persistent endometrial cancer.

OBJECTIVE: This phase 2 study investigated sapanisertib (selective dual inhibitor of mTORC1/2) alone, or in combination with paclitaxel or TAK-117 (a selective small molecule inhibitor of PI3K), versus paclitaxel alone in advanced, recurrent, or persistent endometrial cancer. METHODS: Patients with histologic diagnosis of endometrial cancer (1-2 prior regimens) were randomized to 28-day cycles on four treatment arms: 1) weekly paclitaxel 80 mg/m2 (days 1, 8, and 15); 2) weekly paclitaxel 80 mg/m2 + oral sapanisertib 4 mg on days 2-4, 9-11, 16-18, and 23-25; 3) weekly sapanisertib 30 mg, or 4) sapanisertib 4 mg + TAK-117 200 mg on days 1-3, 8-10, 15-17, and 22-24. RESULTS: Of 241 patients randomized, 234 received treatment (paclitaxel, n = 87 [3 ongoing]; paclitaxel+sapanisertib, n = 86 [3 ongoing]; sapanisertib, n = 41; sapanisertib+TAK-117, n = 20). The sapanisertib and sapanisertib+TAK-117 arms were closed to enrollment after futility analyses. After a median follow-up of 14.4 (paclitaxel) versus 17.2 (paclitaxel+sapanisertib) months, median progression-free survival (PFS; primary endpoint) was 3.7 versus 5.6 months (hazard ratio [HR] 0.82; 95% confidence interval [CI] 0.58-1.15; p = 0.139); in patients with endometrioid histology (n = 116), median PFS was 3.3 versus 5.7 months (HR 0.66; 95% CI 0.43-1.03). Grade ≥ 3 treatment-emergent adverse event rates were 54.0% with paclitaxel versus 89.5% paclitaxel+sapanisertib. CONCLUSIONS: Our findings support inclusion of chemotherapy combinations with investigational agents for advanced or metastatic disease. The primary endpoint was not met and toxicity was manageable. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT02725268.

Entinostat, a selective HDAC1/2 inhibitor, potentiates the effects of olaparib in homologous recombination proficient ovarian cancer.

OBJECTIVE: Poly ADP ribose polymerase inhibitors (PARPi) are most effective in BRCA1/2 mutated ovarian tumors. Better treatments are needed for homologous recombination HR-proficient cancer, including CCNE1 amplified subtypes. We have shown that histone deacetylase inhibitors (HDACi) sensitize HR-proficient ovarian cancer to PARPi. In this study, we provide complementary preclinical data for an investigator-initiated phase 1/2 clinical trial of the combination of olaparib and entinostat in recurrent, HR-proficient ovarian cancer. METHODS: We assessed the in vitro effects of the combination of olaparib and entinostat in SKOV-3, OVCAR-3 and primary cells derived from CCNE1 amplified high grade serous ovarian cancer (HGSOC) patients. We then tested the combination in a SKOV-3 xenograft model and in a patient-derived xenograft (PDX) model. RESULTS: Entinostat potentiates the effect of olaparib in reducing cell viability and clonogenicity of HR-proficient ovarian cancer cells. The combination reduces peritoneal metastases in a SKOV-3 xenograft model and prolongs survival in a CCNE1 amplified HR-proficient PDX model. Entinostat also enhances olaparib-induced DNA damage. Further, entinostat decreases BRCA1, a key HR repair protein, associated with decreased Ki-67, a proliferation marker, and increased cleaved PARP, a marker of apoptosis. Finally, entinostat perturbs replication fork progression, which increases genome instability. CONCLUSION: Entinostat inhibits HR repair by reducing BRCA1 expression and stalling replication fork progression, leading to irreparable DNA damage and ultimate cell death. This work provides preclinical support for the clinical trial of the combination of olaparib and entinostat in HR-proficient ovarian cancer and suggests potential benefit even for CCNE1 amplified subtypes.

Undifferentiated Endometrial Carcinomas: Clinicopathologic Characteristics and Treatment Outcomes.

OBJECTIVE: Undifferentiated endometrial carcinoma (UEC) represents a recently recognized and rare diagnosis that is commonly misclassified on histopathologic evaluation. These cancers account for less than 10% of carefully reviewed series of endometrial cancers from academic medical centers. We reviewed a single-institutional experience with the management of UEC focusing on clinicopathologic characteristics and treatment outcomes. METHODS: The medical records of all patients treated for histologically proven endometrial carcinoma between 2007 through 2016 were reviewed. Analysis was limited to 24 consecutive patients with histologically proven endometrial carcinomas that had at least a component of undifferentiated carcinoma on central pathology review. All patients were initially treated by definitive surgical resection. Grade 3 endometrioid carcinomas treated over the same period were used as a control group. The Kaplan-Meier method was used to estimate survival outcomes. RESULTS: The median age at diagnosis was 66 years (range, 37-74 years). Ten patients presented with locally advanced or metastatic disease (42%). Fifteen patients (63%) received adjuvant chemotherapy with carboplatin and paclitaxel, 12 patients (50%) received adjuvant pelvic external beam radiation, and 10 patients (42%) received adjuvant vaginal cuff brachytherapy. With a median follow-up of 14 months (range, 0.5-115 months), 4 patients (21%) had developed disease recurrence and/or progression, 2 patients (11%) had died of disease, and 1 patient died of treatment complications. Twelve patients (63%) were alive with no evidence of disease at last contact. Outcomes were comparable to those with grade 3 endometrioid carcinoma. CONCLUSIONS: Our data are consistent with prior studies demonstrating that UEC represents a rare clinical entity characterized by high rates of locally advanced disease at presentation. However, survival outcomes appear to be comparable to other high-grade endometrial cancers. Further studies investigating optimal adjuvant therapy in these patients are warranted.

Selective targeting of IRAK1 attenuates low molecular weight hyaluronic acid-induced stemness and non-canonical STAT3 activation in epithelial ovarian cancer.

Advanced epithelial ovarian cancer (EOC) survival rates are dishearteningly low, with ~25% surviving beyond 5 years. Evidence suggests that cancer stem cells contribute to acquired chemoresistance and tumor recurrence. Here, we show that IRAK1 is upregulated in EOC tissues, and enhanced expression correlates with poorer overall survival. Moreover, low molecular weight hyaluronic acid, which is abundant in malignant ascites from patients with advanced EOC, induced IRAK1 phosphorylation leading to STAT3 activation and enhanced spheroid formation. Knockdown of IRAK1 impaired tumor growth in peritoneal disease models, and impaired HA-induced spheroid growth and STAT3 phosphorylation. Finally, we determined that TCS2210, a known inducer of neuronal differentiation in mesenchymal stem cells, is a selective inhibitor of IRAK1. TCS2210 significantly inhibited EOC growth in vitro and in vivo both as monotherapy, and in combination with cisplatin. Collectively, these data demonstrate IRAK1 as a druggable target for EOC.

Lineage specific extracellular vesicle-associated protein biomarkers for the early detection of high grade serous ovarian cancer.

High grade serous ovarian carcinoma (HGSOC) accounts for ~ 70% of ovarian cancer cases. Non-invasive, highly specific blood-based tests for pre-symptomatic screening in women are crucial to reducing the mortality associated with this disease. Since most HGSOCs typically arise from the fallopian tubes (FT), our biomarker search focused on proteins found on the surface of extracellular vesicles (EVs) released by both FT and HGSOC tissue explants and representative cell lines. Using mass spectrometry, 985 EV proteins (exo-proteins) were identified that comprised the FT/HGSOC EV core proteome. Transmembrane exo-proteins were prioritized because these could serve as antigens for capture and/or detection. With a nano-engineered microfluidic platform, six newly discovered exo-proteins (ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, MYOF) plus a known HGSOC associated protein, FOLR1 exhibited classification performance ranging from 85-98% in a case-control study using plasma samples representative of early (including stage IA/B) and late stage (stage III) HGSOCs. Furthermore, by linear combination of IGSF8 and ITGA5 based on logistic regression analysis, we achieved a sensitivity of 80% (99.8% specificity). These lineage-associated exo-biomarkers have potential to detect cancer while localized to the FT when patient outcomes are more favorable.

Lineage specific extracellular vesicle-associated protein biomarkers for the early detection of high grade serous ovarian cancer.

High grade serous ovarian carcinoma (HGSOC) accounts for ~ 70% of ovarian cancer cases. Non-invasive, highly specific blood-based tests for pre-symptomatic screening in women are crucial to reducing the mortality associated with this disease. Since most HGSOCs typically arise from the fallopian tubes (FT), our biomarker search focused on proteins found on the surface of extracellular vesicles (EVs) released by both FT and HGSOC tissue explants and representative cell lines. Using mass spectrometry, 985 EV proteins (exo-proteins) were identified that comprised the FT/HGSOC EV core proteome. Transmembrane exo-proteins were prioritized because these could serve as antigens for capture and/or detection. With a nano-engineered microfluidic platform, six newly discovered exo-proteins (ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, MYOF) plus a known HGSOC associated protein, FOLR1 exhibited classification performance ranging from 85 to 98% in a case-control study using plasma samples representative of early (including stage IA/B) and late stage (stage III) HGSOCs. Furthermore, by a linear combination of IGSF8 and ITGA5 based on logistic regression analysis, we achieved a sensitivity of 80% with 99.8% specificity and a positive predictive value of 13.8%. Importantly, these exo-proteins also can accurately discriminate between ovarian and 12 types of cancers commonly diagnosed in women. Our studies demonstrate that these lineage-associated exo-biomarkers can detect ovarian cancer with high specificity and sensitivity early and potentially while localized to the FT when patient outcomes are more favorable.

Higher baseline BMI and lower estimated median income associated with increasing BMI after endometrial cancer diagnosis.

Introduction: Endometrial cancer is often directly related to obesity and interventions for weight loss have mixed results. Risk factors for continued weight gain after diagnosis are not clearly defined in the literature. The objective of this study is to describe risk factors associated with increased body mass index (BMI) trajectory among endometrial cancer patients. Methods: Patients who were surgically treated for endometrial cancer at a single institution between 2010 and 2015 were identified. Demographics including age, race/ethnicity and estimated median income at diagnosis were obtained. BMI at five time points after diagnosis were calculated. BMI trajectories were estimated by latent class growth modeling using the PROC TRAJ procedure in SAS. Chi-squared tests and ANOVA were used to assess differences between trajectory groups. Statistical significance was set to a p-value < 0.05. Results: Of 695 patients included in the study, the average age at diagnosis was 62 years and over 70% of patients were obese at baseline. Patients experienced increasing, stable, or decreasing BMI over 2 years following diagnosis. Patients with younger age and lower estimated median income were most likely to be in the increasing BMI group. Among obese patients, those with Class I obesity (BMI 30 to 34.9 kg/m2) were most likely to experience decreasing BMI and those with Class III obesity (BMI > 40 kg/m2) were most likely to experience increasing BMI, p < 0.0001. Conclusion: A third of endometrial cancer survivors experience increasing BMI. Severity of obesity at diagnosis matters, patients with severe obesity (Class III) were most likely to experience weight gain.

Higher baseline BMI and lower estimated median income is associated with increasing BMI after endometrial cancer diagnosis.

Introduction: Endometrial cancer is often directly related to obesity and interventions for weight loss have mixed results. Risk factors for continued weight gain after diagnosis are not clearly defined in the literature. The objective of this study is to describe risk factors associated with increased body mass index (BMI) trajectory among endometrial cancer patients. Methods: Patients who were surgically treated for endometrial cancer at a single institution between 2010 and 2015 were identified. Demographics including age, race/ethnicity and estimated median income at diagnosis were obtained. BMI at five time points after diagnosis were calculated. BMI trajectories were estimated by latent class growth modeling using the PROC TRAJ procedure in SAS. Chi-squared tests and ANOVA were used to assess differences between trajectory groups. Statistical significance was set to a p-value < 0.05. Results: Of 695 patients included in the study, the average age at diagnosis was 62 years and over 70% of patients were obese at baseline. Patients experienced increasing, stable, or decreasing BMI over 2 years following diagnosis. Patients with younger age and lower estimated median income were most likely to be in the increasing BMI group. Among obese patients, those with Class I obesity (BMI 30 to 34.9 kg/m2) were most likely to experience decreasing BMI and those with Class III obesity (BMI > 40 kg/m2) were most likely to experience increasing BMI, p < 0.0001. Conclusion: A third of endometrial cancer survivors experience increasing BMI. Severity of obesity at diagnosis matters, patients with severe obesity (Class III) were most likely to experience weight gain.

Translational randomized phase II trial of cabozantinib in combination with nivolumab in advanced, recurrent, or metastatic endometrial cancer.

BACKGROUND: Combining immunotherapy and antiangiogenic agents is a promising treatment strategy in endometrial cancer. To date, no biomarkers for response have been identified and data on post-immunotherapy progression are lacking. We explored the combination of a checkpoint inhibitor (nivolumab) and an antiangiogenic agent (cabozantinib) in immunotherapy-naïve endometrial cancer and in patients whose disease progressed on previous immunotherapy with baseline biopsy for immune profiling. PATIENTS AND METHODS: In this phase II trial (ClinicalTrials.gov NCT03367741, registered December 11, 2017), women with recurrent endometrial cancer were randomized 2:1 to nivolumab with cabozantinib (Arm A) or nivolumab alone (Arm B). The primary endpoint was Response Evaluation Criteria in Solid Tumors-defined progression-free survival (PFS). Patients with carcinosarcoma or prior immune checkpoint inhibitor received combination treatment (Arm C). Baseline biopsy and serial peripheral blood mononuclear cell (PBMC) samples were analyzed and associations between patient outcome and immune data from cytometry by time of flight (CyTOF) and PBMCs were explored. RESULTS: Median PFS was 5.3 (90% CI 3.5 to 9.2) months in Arm A (n=36) and 1.9 (90% CI 1.6 to 3.4) months in Arm B (n=18) (HR=0.59, 90% CI 0.35 to 0.98; log-rank p=0.09, meeting the prespecified statistical significance criteria). The most common treatment-related adverse events in Arm A were diarrhea (50%) and elevated liver enzymes (aspartate aminotransferase 47%, alanine aminotransferase 42%). In-depth baseline CyTOF analysis across treatment arms (n=40) identified 35 immune-cell subsets. Among immunotherapy-pretreated patients in Arm C, non-progressors had significantly higher proportions of activated tissue-resident (CD103+CD69+) ɣδ T cells than progressors (adjusted p=0.009). CONCLUSIONS: Adding cabozantinib to nivolumab significantly improved outcomes in heavily pretreated endometrial cancer. A subgroup of immunotherapy-pretreated patients identified by baseline immune profile and potentially benefiting from combination with antiangiogenics requires further investigation.

Disparities in ovarian cancer survival at the only NCI-designated cancer center in Kansas.

BACKGROUND: This study examined the impact of geographic distance on survival outcomes for patients receiving treatment for ovarian cancer at the only NCI-designated cancer center (NCI-CC) in Kansas. METHODS: We identified ovarian cancer patients treated at the University of Kansas Cancer Center between 2010 and 2015. Demographic factors and clinical characteristics were abstracted. The main outcome measure was overall survival according to geographic distance from the institution. Kaplan Meier survival curves and Cox proportional hazard models were generated using SAS v9.4. RESULTS: 220 patients were identified. Survival analysis based on distance from the institution demonstrated that patients who lived ≤10 miles from the institution had worse overall survival (p = 0.0207) and were more likely to have suboptimal cytoreductive surgery (p = 0.0276). Lower estimated median income was also associated with a 1.54 increased risk of death, 95% CI (1.031-2.292), p = 0.0347. CONCLUSIONS: We determined that ovarian cancer survival disparities exist in our patient population. Lower rates of optimal cytoreductive surgery has been identified as a possible driver of poor prognosis for patients who lived in proximity to our institution.

Ascites-induced compression alters the peritoneal microenvironment and promotes metastatic success in ovarian cancer.

The majority of women with recurrent ovarian cancer (OvCa) develop malignant ascites with volumes that can reach > 2 L. The resulting elevation in intraperitoneal pressure (IPP), from normal values of 5 mmHg to as high as 22 mmHg, causes striking changes in the loading environment in the peritoneal cavity. The effect of ascites-induced changes in IPP on OvCa progression is largely unknown. Herein we model the functional consequences of ascites-induced compression on ovarian tumor cells and components of the peritoneal microenvironment using a panel of in vitro, ex vivo and in vivo assays. Results show that OvCa cell adhesion to the peritoneum was increased under compression. Moreover, compressive loads stimulated remodeling of peritoneal mesothelial cell surface ultrastructure via induction of tunneling nanotubes (TNT). TNT-mediated interaction between peritoneal mesothelial cells and OvCa cells was enhanced under compression and was accompanied by transport of mitochondria from mesothelial cells to OvCa cells. Additionally, peritoneal collagen fibers adopted a more linear anisotropic alignment under compression, a collagen signature commonly correlated with enhanced invasion in solid tumors. Collectively, these findings elucidate a new role for ascites-induced compression in promoting metastatic OvCa progression.

Heated Intraperitoneal Chemotherapy in the Management of Advanced Ovarian Cancer.

Heated intraperitoneal chemotherapy (HIPEC) has several potential benefits. Higher doses of chemotherapy can be used with HIPEC because the plasma-peritoneal barrier results in little absorption into the blood stream. HIPEC offers higher peritoneal penetration in comparison to an intravenous (IV) regimen and does not have the traditional normothermic intraperitoneal (IP) regimen limitation of post-operative adhesions. Hyperthermia itself has cytotoxic effects and can potentiate antineoplastic effects of chemotherapy in part by increasing the depth of tumor penetration by up to 3 mm. For the treatment of ovarian cancer, HIPEC has been evaluated in the recurrent setting with secondary cytoreduction. Recent studies, including a prospective trial, have evaluated its role in primary management of ovarian cancer. This review summarizes previous and ongoing studies regarding the use of HIPEC in the management of ovarian cancer.

Plastic Surgery for Women.

Plastic surgery is a broad field, including maxillofacial surgery, reconstruction after injuries, hand surgery, and skin flaps and grafts, but the most common procedures for women are liposuction and body contouring, breast surgery, and facial cosmetic procedures. Techniques of face and brow lifts, blepharoplasty, and rhinoplasty are discussed as well as botulinum toxin and filler injections, and laser and pulsed light techniques that may delay or eliminate the need for surgery. Comparison of the surgeries for breast reconstruction, reduction, augmentation, and mastopexy is discussed. New surgeries for enhancement of female genitalia are also examined.

Differential phosphorylation of connexin46 and connexin50 by H2O2 activation of protein kinase Cgamma.

PURPOSE: Fiber cell gap junction proteins connexin 46 (Cx46) and connexin 50 (Cx50) play distinct roles in the avascular lens. The purpose of this study was to determine how protein kinase Cgamma (PKCgamma) differentially regulates phosphorylation of Cx46 and Cx50 in oxidatively stressed lenses. METHODS: Sprague Dawley rats (six week old) were used in the experiments. PKCgamma enzyme activity was analyzed by use of the PepTag assay kit. Phosphorylation of caveolin-1, Cx46, and Cx50 was determined by immunoblotting. Lipid rafts were isolated by continuous sucrose gradient centrifugation. Lipid raft-localization of PKCgamma, Cx46, or Cx50 was demonstrated by immunoblotting. Association of caveolin-1 with PKCgamma, Cx46, or Cx50 was revealed by co-immunoprecipitation. RESULTS: H2O2 (100 microM) stimulated PKCgammaactivation in rat whole lens. Activated PKCgamma was recruited into caveolin-1 (Cav-1) containing lipid rafts and this activation enhanced the coimmunoprecipitation of Cav-1, Cx46, and Cx50 with PKCgamma. Both Cx50 and Cx46 were associated with Cav-1 in lipid rafts. H2O2 significantly induced threonine (Thr) phosphorylation of Cx46 and Cx50, and serine (Ser) phosphorylation of Cx50. However, There was only a small stimulation of Cx46 phosphorylation at Ser by H2O2, as Cx46 was already phosphorylated. CONCLUSIONS: Activation of PKCgamma by H2O2 stimulated differential Ser phosphorylation of Cx50 versus Cx46, within lipid rafts. This suggests that Cx50 and Cx46 may have different functions in lens.

Supporting the novice nurse to fly: a literature review.

The evolution from a newly graduated or novice nurse to a competent nurse can be challenging and difficult. This transition involves a tidal wave of emotions along with time needed to develop critical thinking skills, in order to apply their knowledge to patient situations, make decisions and respond with appropriate actions. The purpose of this paper was to explore the existing literature in the area of supports for novice nurses; by determining who is a novice nurse, what can plague a novice's transition, and how to support their successful transition. These results have been compared with the role of Clinical Nurse Expert at The Ottawa Hospital and overall, the findings suggest that a one year coaching program for novices is an effective strategy for supporting their transition, subsequently increasing their retention rates, as well as having a positive influence on the nursing profession, our patients and the healthcare system.