Epithelial ovarian cancer survival by race and ethnicity in an equal-access healthcare population.

BACKGROUND: Previous studies in the general population observed that compared with non-Hispanic White women, Pacific Islander and Black women have higher age-adjusted mortality rates from epithelial ovarian cancer (EOC), while Asian American patients have lower mortality. We investigated whether race and ethnicity is associated with differences in EOC survival in a United States Military population where patients have equal access to healthcare. METHODS: This retrospective study included women diagnosed with EOC between 2001 and 2018 among Department of Defense beneficiaries. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models adjusting for age and year of diagnosis, histology and stage. RESULTS: In our study population of 1230 invasive EOC cases (558 non-Hispanic White, 74 non-Hispanic Black, 73 Asian, 30 Pacific Islander and 36 Hispanic cases), 63% of the women died (all-cause death) after a mean = 4.8 years (SD = 4.1) of follow-up following diagnosis. Compared with non-Hispanic White cases, Asian cases had better overall survival, HR = 0.76 (95% CI = 0.58-0.98), whereas there were no differences in survival for other racial and ethnic groups. CONCLUSIONS: These findings highlight the need to investigate how differences in access to healthcare may influence observed racial and ethnic disparities for EOC.

Racial and ethnic differences in tumor characteristics among endometrial cancer patients in an equal-access healthcare population.

PURPOSE: There are racial and ethnic differences in endometrial cancer incidence and mortality rates; compared with Non-Hispanic White women, Black women have a similar incidence rate for endometrial cancer, but their mortality is higher. Pacific Islander women may also have worse outcomes compared to their White counterparts. We assessed tumor characteristics and adjuvant therapy by racial and ethnic group among endometrial cancer patients treated within the Military Health System, an equal access healthcare organization. METHODS: We retrospectively identified women diagnosed with invasive endometrial cancer among US Department of Defense beneficiaries reported in the Automated Central Tumor Registry database (year of diagnosis: 2001-2018). We compared tumor characteristics and receipt of adjuvant therapy across racial and ethnic groups using Chi-square or Fisher tests. Hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of all cause mortality were calculated using Cox proportional hazards regression models adjusting for age at diagnosis, adjuvant therapy, histology and stage. RESULTS: The study included 2574 endometrial cancer patients [1729 Non-Hispanic White, 318 Asian, 286 Black, 140 Pacific Islander and 101 Hispanic women]. Among all cases, a higher proportion of Black patients had non-endometrioid histology (46.5% versus ≤ 29.3% in other groups, P < 0.01) and grade 3-4 tumors (40.1% versus ≤ 29.3% in other groups, P < 0.01). In multivariable Cox models, compared with Non-Hispanic White cases, Black endometrial cancer patients had a higher mortality risk (HR 1.43, 95% CI, 1.13-1.83). There was no difference in mortality risk for other racial and ethnic groups. CONCLUSION: Black patients with endometrial cancer presented with more aggressive tumor features and they had worse overall survival compared with patients in other racial and ethnic groups. Further study is needed to better direct preventive and therapeutic efforts in order to correct endometrial cancer disparities in the future.

Underserved Pacific Islanders With Locally Advanced Cervical Cancer Receive Higher Rates of Standard-of-Care Radiation Treatment Through the Pacific Island Health Care Project and Military Health System Compared to the Average U.S. Population.

INTRODUCTION: Brachytherapy, with external beam radiation, increases survival in the treatment of locally advanced cervical cancer (LACC). In 2016, Robin et al. reported only 44% of patients received standard-of-care (SOC) brachytherapy in the USA. The Pacific Island Health Care Project has provided humanitarian medical care to women from the U.S. Associated Pacific Islands (USAPI) for three decades at Tripler Army Medical Center (TAMC), a military health care system (MHS) facility. We evaluated whether this underserved and understudied patient population received SOC treatment for LACC at TAMC. MATERIALS AND METHODS: The TAMC tumor registry was searched for all cervical cancer cases from 1997 to 2019. Subjects were excluded if they did not have stage IB2-IVA disease and were not from USAPI. The primary outcome was the overall utilization of brachytherapy, and statistical analysis was performed using the chi-square test. RESULTS: We identified 214 women with cervical cancer treated at TAMC, of which 67 met the study criteria. Ninety-two percent had squamous cell carcinoma on histology. Of the patients identified, 48 (71.6%, P < .001) were treated with brachytherapy. Fifteen (22.4%) patients received external radiation alone, and four (6.0%) received chemoradiation without brachytherapy. A post-hoc power analysis was conducted with a power of 91.3%. CONCLUSIONS: Women with cervical cancer from USAPI in the PIHCP program treated at TAMC received significantly higher rates of SOC radiation treatment than the U.S. population on average. This highlights the ability of PIHCP, through the MHS, to deliver SOC treatment for cervical cancer to an otherwise underserved patient population.

A rare case of metastatic uterine lymphoma in a renal transplant patient.

Primary and disseminated lymphoma of the female reproductive tract are rare types of lymphoma. However, in the setting of solid organ transplant, recipients have an approximately doubled risk of acquiring and dying from malignancy. Multiple treatment modalities are available for post-transplant lymphoproliferative diseases (PTLD), including chemotherapy, radiotherapy, surgery, and immunosuppression radiotherapy. We report a case of a 61-year-old female with multifocal nodal diffuse large B-cell lymphoma and a history of a renal transplant secondary to IgA nephropathy who developed metastatic diffuse large B-cell lymphoma to the uterus. While the baseline incidence of PTLD is elevated when compared with lymphoma in the general population, metastatic uterine lymphoma is rare. Awareness of reproductive organ involvement by lymphomas and increased malignancy risk in organ transplant patients are important considerations for diagnostic evaluation, including radiologic assessment.

Pineal gland metastasis from uterine serous carcinoma: A case report and review of the literature.

Uterine papillary serous carcinoma (UPSC) is a highly aggressive endometrial cancer histology with a propensity for distant metastasis. Despite the aggressive nature of UPSC, central nervous system metastasis is a rare occurrence with few cases reported in the literature. We present a case of a 58-year-old woman with a history of Stage IIIA UPSC who was diagnosed with recurrent, metastatic disease in the pineal gland more than 6 years after her initial diagnosis.

Matrix Drug Screen Identifies Synergistic Drug Combinations to Augment SMAC Mimetic Activity in Ovarian Cancer.

Inhibitor of apoptosis (IAP) proteins are frequently upregulated in ovarian cancer, resulting in the evasion of apoptosis and enhanced cellular survival. Birinapant, a synthetic second mitochondrial activator of caspases (SMAC) mimetic, suppresses the functions of IAP proteins in order to enhance apoptotic pathways and facilitate tumor death. Despite on-target activity, however, pre-clinical trials of single-agent birinapant have exhibited minimal activity in the recurrent ovarian cancer setting. To augment the therapeutic potential of birinapant, we utilized a high-throughput screening matrix to identify synergistic drug combinations. Of those combinations identified, birinapant plus docetaxel was selected for further evaluation, given its remarkable synergy both in vitro and in vivo. We showed that this synergy results from multiple convergent pathways to include increased caspase activation, docetaxel-mediated TNF-α upregulation, alternative NF-kB signaling, and birinapant-induced microtubule stabilization. These findings provide a rationale for the integration of birinapant and docetaxel in a phase 2 clinical trial for recurrent ovarian cancer where treatment options are often limited and minimally effective.

Characterization of ovarian cancer cell lines as in vivo models for preclinical studies.

OBJECTIVE: The value of cell lines for pre-clinical work lies in choosing those with similar characteristics. Selection of cell lines is typically based on patient history, histological subtype at diagnosis, mutation patterns, or signaling pathways. Although recent studies established consensus regarding molecular characteristics of ovarian cancer cell lines, data on in vivo tumorigenicity remains only sporadically available, impeding translation of in vitro work to xenograft models. METHODS: We introduced 18 ovarian cancer cell lines into athymic nude mice through subcutaneous, intraperitoneal, and ovary intrabursal routes, and observed tumor development over 6weeks. We also profiled cell line gene expression and identified differentially expressed gene sets based on their ability to form tumors in the subcutaneous or intraperitoneal locations. Representative cell lines were further subjected to proteomic analyses. RESULTS: Ovarian cancer cell lines showed variable ability to grow in mice when implanted subcutaneous, intraperitoneal, or intrabursal. While some cell lines grew well in both SC and IP locations, others showed a strong propensity to grow in one location only. Gene expression profiles suggested that cell lines showing preference for IP growth had gene expression patterns more similar to primary tumors. CONCLUSIONS: We report the tumorigenicity of 17 human ovarian cancer cell lines and one mouse cell line in three distinct anatomical locations, and associated gene networks. Growth patterns and histopathology, linked to molecular characteristics, provide a valuable resource to the research community, and better guide the choice of cell lines for in vitro studies to translate efficiently into xenograft testing.

Prolonged response to exemestane following multiple surgical resections and hormonal therapies in a patient with recurrent endometrial stromal sarcoma.

BACKGROUND: Endometrial stromal sarcomas (ESSs) are rare, indolent tumors with high recurrence rates. Management includes surgery and hormonal therapy given high estrogen and progesterone receptor (ER/PR) expression. CASE: A pre-menopausal patient with stage II ESSs (ER +/PR +) underwent primary surgery followed by adjuvant megestrol. Recurrence in the bladder/upper vagina (ER +/PR -) was diagnosed one year later and treated with anterior pelvic exenteration and adjuvant letrozole. Two years later she recurred and was treated with radical surgery and adjuvant exemestane therapy (tumor ER strongly +/PR +). The patient then had a five-year disease free interval before being diagnosed with her third recurrence (ER +). CONCLUSION: Exemestane treatment for ESSs can lead to a prolonged response, even in the setting of progression after prior aromatase inhibitor treatment.

Pharmacodynamic markers and clinical results from the phase 2 study of the SMAC mimetic birinapant in women with relapsed platinum-resistant or -refractory epithelial ovarian cancer.

BACKGROUND: Inhibitors of apoptosis proteins (IAPs) are key regulators of apoptosis and are frequently dysregulated in ovarian cancer. It was hypothesized that blocking IAPs with birinapant would increase tumor cell death and result in objective responses for women with platinum-refractory and -resistant ovarian cancer. METHODS: In this phase 2, Cancer Therapy Evaluation Program-sponsored study, patients received birinapant at 47 mg/m(2) on days 1, 8, and 15 of 28-day cycles. Pharmacokinetics were obtained during cycle 1. Plasma, peripheral blood mononuclear cells (PBMCs), and percutaneous tumor biopsy samples were collected before cycle 1 and after 6 weeks. The primary endpoint was an objective response or progression-free survival lasting greater than 6 months in a mini-max design. RESULTS: Eleven patients received birinapant; after this, accrual was terminated for lack of a clinical benefit. Birinapant was well tolerated, with predominantly grade 2 adverse events and 1 case of grade 3 lymphopenia. Pretreatment biopsy samples and PBMCs were collected; paired posttreatment biopsy samples and PBMCs were collected from 7 and 10 patients, respectively. There was consistent downregulation of cellular inhibitor of apoptosis protein 1 in tumors (P = .016) and PBMCs (P < .01). Procaspase 3 also decreased in tumors (P = .031) and PBMCs (P < .01); cleaved caspase 3 colocalized with H2A histone family member X (γ-H2AX) in tumors after birinapant exposure. Peripheral T and B cells decreased significantly after treatment, but natural killer cells did not (P = .04, P = .05, and P = .43, respectively). CONCLUSIONS: Birinapant shows consistent target suppression in vivo without single-agent antitumor activity in this small population. Single-agent pharmacodynamics are necessary to understand the drug's mechanism of action and set the stage for rational combination therapy. Preclinical studies are ongoing to identify optimal synergistic combinations for future clinical trials.

Menopausal hormone therapy and mortality among women diagnosed with ovarian cancer in the NIH-AARP Diet and Health Study.

BACKGROUND: Although menopausal hormone therapy (MHT) use has been linked with an increased risk of ovarian cancer, whether pre-diagnosis MHT use affects ovarian cancer-specific mortality is unknown. METHODS: Our analysis included 395 incident epithelial ovarian cancer patients with data on pre-diagnosis MHT use from the National Institutes of Health-AARP (NIH-AARP) Diet and Health Study. We used Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for MHT type and ovarian cancer-specific mortality, adjusted for tumor characteristics, treatment, and other risk factors. Effect modification by histology (serous vs. non-serous) was examined using likelihood ratio tests comparing models with and without interaction terms between MHT type and histology. RESULTS: Ovarian cancer-specific mortality was not associated with pre-diagnosis estrogen-only therapy (ET) (HR = 1.09, 95% CI = 0.70-1.68) or estrogen plus progestin-only therapy (EPT) (HR = 0.97, 95% CI = 0.68-1.38). Neither recency of use nor specific regimen of EPT-only (sequential vs. continuous) was related to mortality. In analyses stratified by histology, no significant association between MHT type and ovarian cancer-specific mortality was observed among serous or non-serous cases; however, a significant interaction between MHT type and histology was noted (p-heterogeneity = 0.01). CONCLUSION: Our results suggest that pre-diagnosis MHT use is not related to risk of ovarian cancer-specific death.

The role of reproductive hormones in epithelial ovarian carcinogenesis.

Epithelial ovarian cancer comprises ∼85% of all ovarian cancer cases. Despite acceptance regarding the influence of reproductive hormones on ovarian cancer risk and considerable advances in the understanding of epithelial ovarian carcinogenesis on a molecular level, complete understanding of the biologic processes underlying malignant transformation of ovarian surface epithelium is lacking. Various hypotheses have been proposed over the past several decades to explain the etiology of the disease. The role of reproductive hormones in epithelial ovarian carcinogenesis remains a key topic of research. Primary questions in the field of ovarian cancer biology center on its developmental cell of origin, the positive and negative effects of each class of hormones on ovarian cancer initiation and progression, and the role of the immune system in the ovarian cancer microenvironment. The development of the female reproductive tract is dictated by the hormonal milieu during embryogenesis. Intensive research efforts have revealed that ovarian cancer is a heterogenous disease that may develop from multiple extra-ovarian tissues, including both Müllerian (fallopian tubes, endometrium) and non-Müllerian structures (gastrointestinal tissue), contributing to its heterogeneity and distinct histologic subtypes. The mechanism underlying ovarian localization, however, remains unclear. Here, we discuss the role of reproductive hormones in influencing the immune system and tipping the balance against or in favor of developing ovarian cancer. We comment on animal models that are critical for experimentally validating existing hypotheses in key areas of endocrine research and useful for preclinical drug development. Finally, we address emerging therapeutic trends directed against ovarian cancer.

Survival advantage of marriage in uterine cancer patients contrasts poor outcome for widows: a Surveillance, Epidemiology and End Results study.

BACKGROUND: Marriage confers a survival advantage for many cancers but has yet to be evaluated in uterine cancer patients. We sought to determine whether uterine cancer survival varied by self-reported relationship status. METHODS: Data were downloaded from the Surveillance, Epidemiology, and End Results program for women diagnosed with uterine cancer (between 1991 and 2010 in nine geographic regions). Patients with complete clinical data for analysis were categorized as married, single, widowed or other (divorced or separated). Differences in distributions were evaluated using Chi-square, exact and/or Mantel-Haenszel test. Uterine cancer survival was analyzed by Kaplan-Meier method with log-rank test and multivariate Cox regression analysis. RESULTS: Of 47,420 eligible patients, 56% were married, 15% were single and 19% were widows. Married vs. non-married women had a higher likelihood of having low risk (grade 1/2 endometrioid) endometrial cancer and local disease (p<0.0001), and a reduced risk of cancer death (HR=0.8, 95% CI=0.77-0.84). Multivariate evaluation of uterine cancer survival by relationship type indicated that widows consistently had significantly worse uterine cancer survival than single, married and other women in all patients and subset analyses (p<0.0001). CONCLUSION: While marital status is associated with differential uterine cancer survival, evaluation of self-reported relationship by type indicated that the poor outcome observed in widows explained most of the benefit attributed to marriage. This report identifies widows as a new high-risk subpopulation with significantly inferior outcomes potentially benefiting from personalized care and social support.

An Uncommon Case of Bilateral Peroneal Nerve Palsy following Delivery: A Case Report and Review of the Literature.

Peroneal nerve palsy is an infrequent but potential complication of childbirth. Bilateral peroneal palsy is particularly rare following delivery with few reported cases. A 38-year-old gravida 1, para 0 underwent a prolonged second stage of labor, was diagnosed with an arrest of descent, and subsequently underwent an uncomplicated primary cesarean section. The patient was diagnosed with bilateral peroneal neuropathy four days after delivery. By two months postpartum, her foot drop had improved by 85% and the remainder of her symptoms resolved. Awareness of the risks of a peroneal neuropathy as well as implementation of preventive measures is important for members of the delivery team. Regional anesthesia during labor is a risk factor for the development of a peroneal neuropathy.

Fertility sparing treatment of a malignant uterine perivascular epithelioid cell tumor: A case report.

•Perivascular epithelioid cell tumors (PEComas) are a family of rare, poorly defined mesenchymal tumors of uncertain malignant potential.•Treatment for PEComas has most commonly involved excisional biopsy or surgical resection.•The use of mTOR inhibitors may provide the best medical treatment as well as a fertility-sparing treatment option.

Expression patterns of progesterone receptor membrane components 1 and 2 in endometria from women with and without endometriosis.

Endometriosis is a hormone-dependent inflammatory condition associated with pain and infertility. A growing body of evidence supports attenuated secretory-phase progesterone responsiveness in women with this disease. Herein, we compare the expression of progesterone receptor membrane components (PGRMC) 1 and 2 in eutopic endometrium from 11 women with laparoscopically and/or histologically proven stage III/IV endometriosis and 23 disease-free women. Menstrual cycle phase was determined using a combination of reported cycle day, serum hormone profile, and endometrial histologic dating. The PGRMC-1 (fold change -3.3; P < .05) and PGRMC-2 (fold-change -8.8; P < .05) gene expression were significantly downregulated in secretory phase, eutopic endometrium from women with endometriosis. Immunohistochemistry demonstrated decreased PGRMC-1 and PGRMC-2 protein expression in the secretory phase endometrial stroma cells of women with endometriosis. Consistent with the preclinical work of others, our results reflect downregulation of endometrial PGRMC-1 and PGRMC-2 expression in secretory phase endometrium from women with advanced stage endometriosis. Understanding the molecular mechanisms of attenuated progesterone action in endometriosis has important diagnostic and therapeutic implications.