Prevalence of viral DNA in high-grade serous epithelial ovarian cancer and correlation with clinical outcomes.

INTRODUCTION: Currently 11 infectious agents are classified as carcinogenic but the role of infectious agents on outcomes of epithelial ovarian cancer is largely unknown. OBJECTIVE: To explore the association between infectious agents and ovarian cancer, we investigated the prevalence of viral DNA in primary ovarian cancer tumors and its association with clinical outcomes. METHODS: Archived tumors from 98 patients diagnosed with high-grade serous epithelial ovarian cancer were collected between 1/1/1994 and 12/31/2010. After DNA extraction, Luminex technology was utilized to identify polymerase chain reaction-amplified viral DNA for 113 specific viruses. Demographic data and disease characteristics were summarized using descriptive statistics. We used logistic regression and Cox proportional hazards model to assess associations between tumor viral status and disease outcome and between tumor viral presence and overall survival (OS), respectively. RESULTS: Forty-six cases (45.9%) contained at least one virus. Six highly prevalent viruses were associated with clinical outcomes and considered viruses of interest (VOI; Epstein-Barr virus 1, Merkel cell polyomavirus, human herpes virus 6b, and human papillomaviruses 4, 16, and 23). Factors independently associated with OS were presence of VOI (HR 4.11, P = 0.0001) and platinum sensitivity (HR 0.21, P<0.0001). Median OS was significantly decreased when tumors showed VOI versus not having these viruses (22 vs 44 months, P<0.0001). Women <70 year old with VOI in tumors had significantly lower median OS versus age-matched women without VOI (20 vs 57 months, P = 0.0006); however, among women ≥70 years old, there was no difference in OS by tumor virus status. CONCLUSIONS: The presence of a VOI was significantly associated with a lower OS. These findings may have implications for clinical management of ovarian cancer but require additional studies.

Feasibility and safety of planned early discharge following laparotomy in gynecologic oncology with enhanced recovery protocol including opioid-sparing anesthesia.

Objective: This study aims to evaluate the feasibility and safety of planned postoperative day 1 discharge (PPOD1) among patients who undergo laparotomy (XL) in the department of gynecology oncology utilizing a modified enhanced recovery after surgery (ERAS) protocol including opioid-sparing anesthesia (OSA) and defined discharge criteria. Methods: Patients undergoing XL and minimally invasive surgery (MIS) were enrolled in this prospective, observational cohort study after the departmental implementation of a modified ERAS protocol. The primary outcome was quality of life (QoL) using SF36, PROMIS GI, and ICIQ-FLUTS at baseline and 2- and 6-week postoperative visits. Statistical significance was assessed using the two-tailed Student's t-test and non-parametric Mann-Whitney two-sample test. Results: Of the 141 subjects, no significant demographic differences were observed between the XL group and the MIS group. The majority of subjects, 84.7% (61), in the XL group had gynecologic malignancy [vs. MIS group; 21 (29.2%), p < 0.001]. All patients tolerated OSA. The XL group required higher intraoperative opioids [7.1 ± 9.2 morphine milligram equivalents (MME) vs. 3.9 ± 6.9 MME, p = 0.02] and longer surgical time (114.2 ± 41 min vs. 96.8 ± 32.1 min, p = 0.006). No significant difference was noted in the opioid requirements at the immediate postoperative phase and the rest of the postoperative day (POD) 0 or POD 1. In the XL group, 69 patients (73.6%) were successfully discharged home on POD1. There was no increase in the PROMIS score at 2 and 6 weeks compared to the preoperative phase. The readmission rates within 30 days after surgery (XL 4.2% vs. MIS 1.4%, p = 0.62), rates of surgical site infection (XL 0% vs. MIS 2.8%, p = 0.24), and mean number of post-discharge phone calls (0 vs. 0, p = 0.41) were comparable between the two groups. Although QoL scores were significantly lower than baseline in four of the nine QoL domains at 2 weeks post-laparotomy, all except physical health recovered by the 6-week time point. Conclusions: PPOD1 is a safe and feasible strategy for XL performed in the gynecologic oncology department. PPOD1 did not increase opioid requirements, readmission rates compared to MIS, and patient-reported constipation and nausea/vomiting compared to the preoperative phase.

Association between intrauterine device use and endometrial, cervical, and ovarian cancer: an expert review.

The intrauterine device is one of the most effective forms of contraception. Use of the intrauterine device has increased in the United States over the last 2 decades. Two formulations are commercially available in the United States: the levonorgestrel-releasing intrauterine device and the copper intrauterine device. The levonorgestrel intrauterine device releases progestin, causing endometrial suppression and cervical mucus thickening, whereas the primary mechanism of action of the copper intrauterine device is to create a local inflammatory response to prevent fertilization. Whereas the protective effects of combined hormonal contraception against ovarian and endometrial cancer, and of tubal sterilization against ovarian cancer are generally accepted, less is known about the effects of modern intrauterine devices on the development of gynecologic malignancies. The best evidence for a protective effect of intrauterine device use against cancer incidence pertains to levonorgestrel intrauterine devices and endometrial cancer, although studies suggest that both copper intrauterine devices and levonorgestrel intrauterine devices reduce endometrial cancer risk. This is supported by the proposed dual mechanisms of action including both endometrial suppression and a local inflammatory response. Studies on the relationship between intrauterine device use and ovarian cancer risk show conflicting results, although most data suggest reduced risk of ovarian cancer in intrauterine device users. The proposed biological mechanisms of ovarian cancer reduction (foreign-body inflammatory response, increased pH, antiestrogenic effect, ovulation suppression) vary by type of intrauterine device. Whereas it has been well established that use of copper intrauterine devices confers a lower risk of cervical intraepithelial neoplasms, the effect of levonorgestrel intrauterine device use on cervical cancer remains unclear. Older studies have linked its use to a higher incidence of cervical dysplasia, but more recent literature has found a decrease in cervical cancer with intrauterine device use. Various mechanisms of protection are postulated, including device-related inflammatory response in the endocervical canal and prostaglandin-mediated immunosurveillance. Overall, the available evidence suggests that both levonorgestrel intrauterine devices and copper intrauterine devices reduce gynecologic cancer risk. Whereas there is support for the reduction of endometrial cancer risk with hormonal and copper intrauterine device use, and reduction of cervical cancer risk with copper intrauterine device use, evidence in support of risk reduction with levonorgestrel intrauterine device use for cervical and ovarian cancers is less consistent.

Lifestyle intervention in ovarian cancer enhanced survival (LIVES) study (NRG/GOG0225): Recruitment, retention and baseline characteristics of a randomized trial of diet and physical activity in ovarian cancer survivors.

OBJECTIVE: The Lifestyle Intervention for oVarian cancer Enhanced Survival (LIVES) is a national study of a combined diet and physical activity intervention for stage II-IV ovarian cancer survival, an under-represented cancer in lifestyle behavioral intervention research. Here, we present the data on recruitment, retention, and baseline demographic, clinical and lifestyle behavior characteristics of the LIVES study participants. METHODS: The LIVES study (NRG Oncology/GOG 0225) is a Phase III diet plus physical activity intervention trial testing the hypothesis that ovarian cancer survivors in the lifestyle intervention will demonstrate better progression-free survival than those in the control condition. Study interventions were delivered via centralized telephone-based health coaching. Baseline descriptive statistics were computed for demographic, clinical, and lifestyle behavior characteristics. RESULTS: The LIVES study exceeded its recruitment goals, enrolling 1205 ovarian cancer survivors from 195 NRG/NCORP-affiliated oncology practices across 49 states from 2012 to 2018. The mean age of enrollees was 59.6 years; the majority (69.4%) with stage III disease; 89% White, 5.5% Hispanic; 64% overweight/obese. Baseline self-reported diet showed a mean daily intake of 6.6 servings of fruit and vegetables, 62.7 fat grams, and 21.7 g of fiber. Physical activity averaged 13.0 MET-hours/week of moderate to vigorous physical activity; 50.9 h/week of sedentary time. Retention rates exceeded 88%. CONCLUSION: The LIVES study demonstrates efficiency in recruiting and retaining ovarian cancer survivors in a 24-month study of diet and physical activity intervention with a primary endpoint of progression free survival that will be reported. TRIAL REGISTRATION: ClinicalTrials.govNCT00719303.

Clinical and Biological Activity of Chemoimmunotherapy in Advanced Endometrial Adenocarcinoma: A Phase II Trial of the Big Ten Cancer Research Consortium.

Purpose: The objective of this study was to assess the efficacy and safety of pembrolizumab in combination with standard carboplatin/paclitaxel in patients with advanced endometrial cancer (EC). Patients and Methods: This single-arm, open-label, multi-center phase II study enrolled patients with RECIST measurable advanced EC. Patients could have received < 1 prior platinum-based regimen and < one non-platinum chemotherapy. The primary endpoint was objective response rate (ORR). Planned sample size of 46 subjects provided 80% power to detect 15% ORR improvement compared to historical control rate of 50%. Results: 46 patients were enrolled, and 43 were evaluable for ORR. Median age was 66 (range: 43-86). Thirty-four (73.9%) patients had recurrent and 12 (26.1%) primary metastatic EC. Patients received carboplatin AUC 6, paclitaxel 175mg/m2 and pembrolizumab 200mg IV every 3 weeks for up to 6 cycles. ORR was 74.4% (32/43), higher than historic controls (p = 0.001). Median PFS was 10.6 months (95% CI 8.3-13.9 months). The most common grade 1-2 treatment related adverse event (TRAEs) included anemia (56.5%), alopecia (47.8%), fatigue (47.8%) and neuropathy (13%), while the most common grade 3-4 TRAEs were lymphopenia, leukopenia, and anemia (19.6% each). High-dimensional spectral flow cytometry (CyTEK) identified enrichment in peripheral CD8+ and CD4+ T cell populations at baseline in responders. The CD8+ T cell compartment in responders exhibited greater expression levels of PD-1 and PD-L1 and higher abundance of effector memory CD8+ cells compared to non-responders. Conclusions: Addition of pembrolizumab to carboplatin and paclitaxel for advanced EC was tolerated and improved ORR compared to historical outcomes.

Impact of age, comorbidity, and treatment characteristics on survival in older women with advanced high grade epithelial ovarian cancer.

OBJECTIVES: Older women have a worse prognosis with advanced epithelial ovarian cancer (EOC) and comorbidities likely contribute to poor outcomes. We sought to identify comorbid conditions and treatment-related factors in older women. METHODS: A retrospective chart review identified 351 patients who underwent cytoreductive surgery (CRS). 100/351 (28.5%) were ≥ 70 years old. Demographic and clinicopathologic information was collected. Crude progression-free (PFS) and overall survival (OS) estimates were calculated using Kaplan-Meier method. Cox proportional hazards regression model was used to estimate hazard ratios and adjustments for confounders. RESULTS: Study subjects ≥70 years old had significantly: higher Cumulative Illness Rating Scale-Geriatric (CIRS-G) score (5.9 vs 4.3; p = 0.0001), less completion of adjuvant chemotherapy (24% vs 15.1%; p = 0.049), less intraperitoneal (IP) therapy (18.2% vs 35.5%; p = 0.002), less clinical trial participation (16% vs 26.3%; p = 0.040), decreased platinum sensitivity (60% vs 73.7%; p = 0.012) and lacked BRCA mutations (0% vs 12%; p = 0.0006). They were less likely to have optimal CRS (75% vs 86.9%; p = 0.007) with same surgical complexity (p = 0.89). Patients ≥70 had significantly worse PFS and OS. In a multivariate analysis, better OS was associated with younger age (<70 years old), any IP therapy, completion of adjuvant chemotherapy, and platinum sensitivity. CONCLUSION: The older cohort had worse CIRS-G scores (5.9 vs 4.3; p = 0.0001), but no strong associations between comorbidities and treatment characteristics, but less optimal CRS rates (75% vs 86.9%; p = 0.007) with similar surgical complexity and less platinum sensitivity. Our results show comorbid conditions in older patients with advanced EOC may have less impact than tumor biology.

A National Survey of Obstetrician/Gynecologists' Knowledge, Attitudes, and Beliefs Regarding Adult Human Papillomavirus Vaccination.

Background: Many women see an obstetrician/gynecologist (OB/GYN) annually and receive their primary care from an OB/GYN. Understanding OB/GYNs' human papillomavirus (HPV) vaccination practices, including knowledge of and barriers to vaccination, is essential to design effective interventions to increase vaccination. This study evaluated OB/GYN knowledge, attitudes, and beliefs regarding vaccinating both younger (18-26 years) and mid-adult (27-45 years) women. Materials and Methods: Data were collected from OB/GYN providers in October 2019 through a nationwide web-based survey. Items included the following: HPV-related vaccination practices, recommendation strength, knowledge (seven items), benefits (four items), and barriers (eight items). Results: The sample (n = 224) was majority were White (69%), men (56%), and practice in suburban clinics (55%). Most (84%) reported they usually or always recommend HPV vaccine to eligible patients, but estimated only about half (51%) of other OB/GYNs did the same. Recommendation strength varied by patient age with 84% strongly recommending it to patients ≤18 years, compared with 79% and 25% strongly recommending to younger and mid-adult patients, respectively (p < 0.01). Participants reported lower benefits (p = 0.007) and higher barriers (p < 0.001) for 27- to 45-year-old patients compared with younger patients. Cost was the most frequently reported barrier, regardless of patient age. Overall knowledge was high (m = 5.2/7) but 33% of participants did not know the vaccine was safe while breastfeeding. Conclusions: Although providers reported strongly and consistently recommending the HPV vaccination to their adult patients, there were gaps in knowledge and attitudinal barriers that need to be addressed. Provider performance feedback may be important in improving HPV vaccination awareness among providers.

Human Papillomavirus Vaccination Prevalence Among Adults Aged 19-45 Years: An Analysis of the 2017 National Health Interview Survey.

INTRODUCTION: In 2018, the U.S. Food and Drug Administration extended the licensure for human papillomavirus vaccination to include everyone aged 27-45 years. In 2019, the Advisory Committee on Immunization Practices issued a recommendation that adults aged 27-45 years and their providers engage in shared clinical decision making about human papillomavirus vaccination. In addition, in 2019, the Advisory Committee on Immunization Practices reiterated that all previously unvaccinated individuals receive catch-up vaccination through age 26 years. This study estimates the pre-recommendation prevalence of human papillomavirus vaccination and factors associated with vaccination in 2 age groups (19-26 years [young adults] and 27-45 years [mid-adults]), forming a baseline to monitor future coverage among U.S. adults. METHODS: The final sample included 9,744 individuals (2,522 young adults and 7,222 mid-adults) who participated in the 2017 National Health Interview Survey. The main outcomes were receipt of 1 or more human papillomavirus vaccination and whether the participant had been vaccinated as an adult. Demographic characteristics and healthcare factors were included as covariates in statistical analyses. RESULTS: Population estimate of receiving 1 or more human papillomavirus vaccine doses among young adults was 36.3% (female: 51.5%, male: 21.2%; p<0.001) and 9.7% for mid-adults (females: 15.8%, males: 3.2%; p<0.001). In the best-fit model, age was inversely associated with vaccination for mid-adults (female: OR=0.84, 95% CI=0.81, 0.86; male: OR=0.86; 95% CI=0.82, 0.90) and male young adults (OR=0.79, 95% CI=0.71, 0.88). Of the entire vaccinated sample aged 19-45 years, 26.6% had received their first vaccination as an adult (95% CI=23.9, 29.4). CONCLUSIONS: These data emphasize the continued need for vaccinating adolescents aged 11-12 years given that few adults were vaccinated against human papillomavirus.

The effect of distance from cancer facility on advanced clinical stage at diagnosis in patients with cervical cancer.

PURPOSE/OBJECTIVES: In the United States, cervical cancer remains a significant cause of morbidity and mortality. The effect of distance has a complicated relationship with disease characteristics and outcomes in other cancers. The purpose of this study is to investigate the relationship between distance from cancer facility on clinical stage at diagnosis in women with cervical cancer. MATERIALS/METHODS: Data were obtained from the National Cancer Database which include patient demographics, disease characteristics, and treatment details. Persons diagnosed with cervical cancer from 2004 to 2015 were included. Subjects were excluded if they had missing information, variant histology, or lived >1,000 miles from their facility resulting in 51,413 persons. Disease was classified as localized (stage 1a-2a) or advanced (stage 2b-4b). Univariate comparisons were performed using analysis of variance and chi-square test. Multivariable logistic regression was used to investigate the effect of distance quartiles on advanced stage while adjusting for other significant variables. RESULTS: Mean age was 51.0 years, 16.9% of women were black, 14.7% were Hispanic, 45.0% had private insurance, and 10.7% were uninsured. Overall, 50.9% of women presented with advanced disease. In multivariable analysis, greater distance demonstrated a stepwise risk reduction of advanced disease where those in the farthest quartile had odds ratio of 0.73 (p<0.001) relative to the closest. Additionally, age, race, income, and insurance status significantly affected risk of advanced disease. CONCLUSIONS: Distance from cancer facility resulted in lower risk of advanced stage disease at diagnosis. Additional research could elucidate the nuanced relationship between distance, disease characteristics and outcomes in cervical cancer.

Dual antibiotic prevention bundle is associated with decreased surgical site infections.

BACKGROUND: Gynecologic oncology surgery is associated with a wide variation in surgical site infection risk. The optimal method for infection prevention in this heterogeneous population remains uncertain. STUDY DESIGN: A retrospective cohort study was performed to compare surgical site infection rates for patients undergoing hysterectomy over a 1-year period surrounding the implementation of an institutional infection prevention bundle. The bundle comprised pre-operative, intra-operative, and post-operative interventions including a dual-agent antibiotic surgical prophylaxis with cefazolin and metronidazole. Cohorts consisted of patients undergoing surgery during the 6 months prior to this intervention (pre-bundle) versus those undergoing surgery during the 6 months following the intervention (post-bundle). Secondary outcomes included length of stay, readmission rates, compliance measures, and infection microbiology. Data were compared with pre-specified one-sided exact test, Chi-square test, Fisher's exact test, or Kruskal-Wallis test as appropriate. RESULTS: A total of 358 patients were included (178 PRE, 180 POST). Median age was 58 (range 23-90) years. The post-bundle cohort had a 58% reduction in surgical site infection rate, 3.3% POST vs 7.9% PRE (-4.5%, 95% CI -9.3% to -0.2%, p=0.049) as well as reductions in organ space infection, 0.6% POST vs 4.5% PRE (-3.9%, 95% CI -7.2% to -0.7%, p=0.019), and readmission rates, 2.2% POST vs 6.7% PRE (-4.5%, 95% CI -8.7% to -0.2%, p=0.04). Gram-positive, Gram-negative, and anaerobic bacteria were all prevalent in surgical site infection cultures. There were no monomicrobial infections in post-cohort cultures (0% POST vs 58% PRE, p=0.04). No infections contained methicillin-resistant Staphylococcus aureus. CONCLUSION: Implementation of a dual antibiotic infection prevention bundle was associated with a 58% reduction in surgical site infection rate after hysterectomy in a surgically diverse gynecologic oncology practice.

Expression of the BAD pathway is a marker of triple-negative status and poor outcome.

Triple-negative breast cancer (TNBC) has few therapeutic targets, making nonspecific chemotherapy the main treatment. Therapies enhancing cancer cell sensitivity to cytotoxic agents could significantly improve patient outcomes. A BCL2-associated agonist of cell death (BAD) pathway gene expression signature (BPGES) was derived using principal component analysis (PCA) and evaluated for associations with the TNBC phenotype and clinical outcomes. Immunohistochemistry was used to determine the relative expression levels of phospho-BAD isoforms in tumour samples. Cell survival assays evaluated the effects of BAD pathway inhibition on chemo-sensitivity. BPGES score was associated with TNBC status and overall survival (OS) in breast cancer samples of the Moffitt Total Cancer Care dataset and The Cancer Genome Atlas (TCGA). TNBC tumours were enriched for the expression of phospho-BAD isoforms. Further, the BPGES was associated with TNBC status in breast cancer cell lines of the Cancer Cell Line Encyclopedia (CCLE). Targeted inhibition of kinases known to phosphorylate BAD protein resulted in increased sensitivity to platinum agents in TNBC cell lines compared to non-TNBC cell lines. The BAD pathway is associated with triple-negative status and OS. TNBC tumours were enriched for the expression of phosphorylated BAD protein compared to non-TNBC tumours. These findings suggest that the BAD pathway it is an important determinant of TNBC clinical outcomes.

Impact of lympho-vascular space invasion on tumor characteristics and survival outcome of women with low-grade serous ovarian carcinoma.

BACKGROUND AND OBJECTIVES: To examine association of lympho-vascular space invasion (LVSI) with clinico-pathological factors and to evaluate survival of women with low-grade serous ovarian carcinoma containing areas of LVSI. METHODS: This is a multicenter retrospective study examining consecutive cases of surgically treated stage I-IV low-grade serous ovarian carcinoma (n = 178). Archived histopathology slides for the ovarian tumors were reviewed, and LVSI was scored as present or absent. LVSI status was correlated to clinico-pathological findings and survival outcome. RESULTS: LVSI was seen in 79 cases (44.4%, 95% confidence interval [CI] 37.1-51.7). LVSI was associated with increased risk of omental metastasis (87.0% vs 64.9%, odds ratio [OR] 3.62, P = 0.001), high pelvic lymph node ratio (median 12.9% vs 0%, P = 0.012), and malignant ascites (49.3% vs 32.6%, OR 2.01, P = 0.035). On multivariable analysis, controlling for age, stage, and cytoreductive status, presence of LVSI in the ovarian tumor remained an independent predictor for decreased progression-free survival (5-year rates 21.0% vs 35.7%, adjusted-hazard ratio 1.57, 95%CI 1.06-2.34, P = 0.026). LVSI was significantly associated with increased risk of recurrence in lymph nodes (OR 2.62, 95%CI 1.08-6.35, P = 0.047). CONCLUSION: LVSI in the ovarian tumor is associated with adverse clinico-pathological characteristics and decreased progression-free survival in women with low-grade serous ovarian carcinoma.

Metastatic uterine tumor resembling ovarian sex cord tumor: A case report and review of the literature.

Uterine tumors resembling ovarian sex cord tumors (UTROSCTs) are rare and commonly characterized as benign tumors, with infrequent reports of metastasis and recurrence. Treatment recommendations have not been well established, particularly for more advanced cases. We present the first reported death from a metastatic UTROSCT, summarize the available literature, and describe characteristics common to UTROSCTs with aggressive features. In this case, a 49-year-old woman presented with abdominal distension and pain; initial imaging and diagnostic workup suggested metastatic epithelial ovarian cancer to be the cause. The patient subsequently underwent neoadjuvant chemotherapy followed by optimal cytoreductive surgery and adjuvant chemotherapy. Final pathology revealed UTROSCT with omental and peritoneal metastases. She then underwent adjuvant chemotherapy with subsequent recurrence and died 15 months after her initial diagnosis. Our analysis of this case and the available literature led us to identify pathologic risk factors that may help predict aggressive UTROSCT behavior.