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.

Relationships among Inflammatory Biomarkers and Objectively Assessed Physical Activity and Sleep during and after Chemotherapy for Gynecologic Malignancies.

Little is known regarding associations between inflammatory biomarkers and objectively measured physical activity and sleep during and after chemotherapy for gynecologic cancer; thus, we conducted a longitudinal study to address this gap. Women with gynecologic cancer (patients) and non-cancer controls (controls) completed assessments before chemotherapy cycles 1, 3, and 6 (controls assessed contemporaneously), as well as at 6- and 12-month follow-ups. Physical activity and sleep were measured using wrist-worn actigraphs and sleep diaries, and blood was drawn to quantify circulating levels of inflammatory markers. Linear and quadratic random-effects mixed models and random-effects fluctuation mixed models were used to examine physical activity and sleep over time, as well as the associations with inflammatory biomarkers. On average, patients (n = 97) and controls (n = 104) were 62 and 58 years old, respectively. Compared to controls, patients were less active, more sedentary, had more time awake after sleep onset, and had lower sleep efficiency (p-values < 0.05). Across groups, higher levels of TNF-α were associated with more sedentary time and less efficient sleep (p-values ≤ 0.05). Higher levels of IL-1ß, TNF-α, and IL-6 were associated with lower levels of light physical activity (p-values < 0.05). Associations between inflammatory biomarkers, physical activity, and sleep did not differ between patients and controls. Given these results, we speculate that inflammation may contribute to less physical activity and more sleep problems that persist even 12 months after completing chemotherapy.

Actionable spontaneous antibody responses antagonize malignant progression in ovarian carcinoma.

OBJECTIVE: To demonstrate that shared antibody responses in endometriosis and endometriosis-associated ovarian cancer spontaneously antagonize malignant progression and can be leveraged to develop future immunotherapies. METHODS: B cells from cyopreserved clear cell ovarian carcinoma (CCC, n = 2), endometrioid ovarian carcinoma (EC, n = 2), and endometriomas (n = 2) were isolated, activated, and EBV-immortalized. Antibodies were purified from B cell supernatants and used for screening arrays containing most of the human proteome. Targets were prioritized based on accessibility (transmembrane or secreted proteins), expression in endometriosis and cancer, and concurrent IgA and IgG responses. We focused on antibodies targeting tumor-promoting syndecan binding protein (SDCBP) to demonstrate anti-tumor activity. Immunoblots and qPCR were performed to assess SDCBP expression in ovarian cancer and endometriosis cell lines and tumor samples. Recombinant IgG4 was generated using the variable heavy and light chains of dominant B cell receptors (BCRs) reacting against the extracellular domain of SDCBP, and used in in vivo studies in human CCC- and high-grade serous ovarian carcinoma (HGSOC)-bearing immunodeficient mice. RESULTS: Nine accessible proteins detected by both IgA and IgG were identified in all samples - including SDCBP, which is expressed in ovarian carcinomas of multiple histologies. Administration of α-SDCBP IgG4 in OVCAR3 (HGSOC), TOV21G and RMG-I (CCC) tumor-bearing mice significantly decreased tumor volume compared to control irrelevant IgG4. CONCLUSIONS: Spontaneous antibody responses exert suboptimal but measurable immune pressure against malignant progression in ovarian carcinomas. Using tumor-derived antibodies for developing novel immunotherapeutics warrants further investigation.

Prognostic features of endometrial cancer metastasis to the central nervous system.

OBJECTIVES: Central nervous system metastases (CNSm) secondary to endometrial cancer (EC) are rare. As a result, prognostic factors for this patient population are not well described. METHODS: EC patients with CNSm were identified retrospectively from two academic centers. EC patients without CNSm (non-CNSm) were used as controls. Chi-square and Fisher's exact tests were used for analysis of categorial variables. Wilcoxon tests were used for quantitative measures. Overall survival (OS) was compared with Log-rank test. Cox proportional hazard models were used to estimate hazard ratios for OS. RESULTS: 22 EC patients with CNSm and 354 non-CNSm patients were included. Compared to non-CNSm EC, the CNSm cohort was younger (58.5 vs 62.0 years, p = 0.018) with lower BMI (27.7 vs. 33.7 kg/m2, p = 0.005), and had more advanced stages (p = ≤ 0.001), grade 3 tumors (81.8% CNSm vs 25.1% non CNSm, p≤0.001) and serous histology (22.7% vs 8.5%, p = 0.010). Median survival after CNSm diagnosis was 9 months (95% CI 4, NA). CNSm was a strong poor prognostic factor (HR death 4.96, p = 0.022). Improved OS was seen with CNS as the only disease site (83m CNSm only vs 30m additional sites, p = 0.007) and less than five CNSm (49m <5 vs. 23m ≥5, p = 0.004). Surgical resection of CNSm (OS 83m surgery vs 33m no surgery, p = 0.003) or multimodal therapy (83m multimodal vs 33m single therapy, p = 0.027) resulted in longer OS. CONCLUSIONS: CNSm is a poor prognostic factor in EC, however, low volume disease with aggressive treatment may result in more favorable survival outcomes.

Cumulative burden of symptomatology in patients with gynecologic malignancies undergoing chemotherapy.

OBJECTIVE: Patients with gynecologic malignancies commonly experience distressing symptoms during chemotherapy. This study sought to evaluate whether symptoms accumulated over the course of several chemotherapy cycles, which could provide essential information for planning supportive interventions. METHOD: Patients with gynecologic malignancies completed questionnaires about fatigue, depressive symptoms, sleep, and physical activity 1 week before and after chemotherapy cycles 1, 3, and 6. Multilevel models examined the effects of time (pre- and postchemotherapy), treatment cycle (1, 3, 6), and their interaction on symptoms. Logistic regression models examined the effects of time, treatment cycle, and their interaction on the proportion of participants exceeding thresholds for clinically meaningful symptomatology. RESULTS: Most participants (N = 140; Mage = 60.8 years, SD = 10.4) had ovarian cancer (49%) and Stage III disease (55%). Participants reported worse fatigue, depressive symptoms, sleep disturbance, and sleep efficiency from pre- to posttreatment at each cycle (ps < .001). With each successive cycle, participants reported worse pretreatment fatigue (p < .001) and depressive symptoms (p < .01) but better sleep efficiency (p = .02). Fatigue increases attenuated across cycles (p = .04). There were no changes in physical activity. Across time points, at least half of participants met clinical thresholds for fatigue, sleep disturbance, and low sleep efficiency and were minimally physically active. Postchemotherapy cycle 6, 23% of participants reported clinically meaningful depressive symptoms. CONCLUSIONS: Patients with gynecologic malignancies have high rates of clinically meaningful symptomatology during chemotherapy. Patients may experience a cumulative burden of symptomatology as treatment progresses, which could have therapeutic implications. Early implementation of supportive interventions should be considered to prevent or mitigate cumulative treatment burden. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Off-label use of paclitaxel and pembrolizumab in a case of platinum refractory epithelial ovarian cancer and extensive thromboembolism.

•Management of platinum refractory ovarian cancer is challenging.•Extensive venous thromboembolism precludes anti-angiogenic combination chemotherapy.•Weekly paclitaxel and immune-checkpoint inhibitor combination provides a durable tumor control option.

The impact of distance to closest negative margin on survival after pelvic exenteration.

OBJECTIVE: To determine the effect of distance to closest negative margin on survival after pelvic exenteration (PE). METHODS: In this retrospective analysis of PE at Moffitt Cancer Center from 2000 to 2019, baseline characteristics, clinical details, and outcomes were ascertained. Distance to closest negative margin was measured. Close and distant negative margins were defined as <3 mm and ≥3 mm from malignancy to nearest surgical margin, respectively. Overall survival (OS) and progression-free survival (PFS) were determined, and Kaplan-Meier curves were compared. Cox proportional hazards regression was used to examine the association of margin status with OS and PFS. RESULTS: Of 124 PEs with malignancy, 80 (64.5%) had negative margins. Median survival was 62 (95% confidence interval [CI] 27-70) months for negative and 21 (95% CI 15-29) months for positive margins. Of 76 with negative margins and documented margin length, 26 had close and 50 had distant margins. Median survival was 32 (95% CI 14-62) months for close and 111 (95% CI 42-166) months for distant margins. Distant margins were associated with improved OS (p = 0.0054) and PFS (p = 0.0099) compared to close margins. After adjusting for other prognostic factors, patients with distant margins had significantly decreased risk of all-cause mortality (HR 0.39, 95% CI 0.19-0.78; p = 0.008) and progression (HR 0.48, 95% CI 0.23-0.99; p = 0.04) compared to positive margins. No significant differences in OS or PFS were observed between close and positive margins. This survival benefit remained among those with cervical cancer. Median survival in this cohort was 34.1 (95% CI 2.0-69.8) months for close and 165.7 (95% CI 24.5-165.7) for distant margins. CONCLUSIONS: Distant margins following PE are associated with improved OS and PFS compared to close margins.

Intraoperative tumor spill during minimally invasive hysterectomy for endometrial cancer: A survey study on experience and practice.

OBJECTIVE: Tumor spill during surgical treatment is associated with adverse oncologic outcomes in many solid tumors. However, in minimally invasive hysterectomy for endometrial cancer, intraoperative tumor spill has not been well studied. This study examined surgeon experiences and practices related to intraoperative tumor spill during minimally invasive hysterectomy for endometrial cancer. METHODS: A cross-sectional survey was conducted to the Society of Gynecologic Oncology. Participants were 220 U.S. gynecologic oncologists practicing minimally invasive hysterectomy for endometrial cancer. Interventions were 20 questions regarding surgeon demographics, surgical practice patterns (fallopian tubal ablation/ligation, intra-uterine manipulator use, and colpotomy approach), and tumor spill experience (uterine perforation with intra-uterine manipulator and tumor exposure during colpotomy). RESULTS: Nearly half of the responding surgeons completed subspeciality training >10 years ago (50.5%), and 74.1% had annual surgical volume of >40 cases. The majority of surgeons used an intra-uterine manipulator during minimally invasive hysterectomies for endometrial cancer (90.1%), and 87.2% of the users have experienced uterine perforation with an intra-uterine manipulator. Almost all surgeons performed colpotomy laparoscopically (95.9%), and nearly 60% had experienced tumor spill while making colpotomy (59.8%). Nearly 10-15% of surgeons have changed their postoperative therapy as a result of intraoperative uterine perforation (11.8%) or tumor spill (14.5%). Surgeons infrequently ablated or ligated fallopian tubes prior to performing the hysterectomy (14.1%). CONCLUSION: Our survey study suggests that many surgeons experienced intraoperative tumor spillage during minimally invasive hysterectomy for endometrial cancer. These findings warrant further studies examining its incidence and impact on clinical outcomes.

Trends in ureteral surgery on an academic gynecologic oncology service.

OBJECTIVE: To describe the incidence, complications, and trends associated with ureteral surgeries on a gynecologic oncology service in the context of a fellowship training program over a 24-year period. METHODS: We conducted a retrospective cohort analysis of ureteral surgeries by gynecologic oncologists at either Moffitt Cancer Center or Tampa General Hospital from 1997 to 2020. Patient characteristics, predisposing factors, location and type of injury, repair method, postoperative management and complications were abstracted from the medical record. The recent cohort (2005-2020) was compared to our prior series (1997-2004). RESULTS: Eighty-eight cases were included. The average number of ureteral surgeries per year decreased from 5.75 (1997-2004) to 2.63 (2005-2020). Of 46 iatrogenic injuries, 45 were recognized and repaired intraoperatively. Ureteral transection was the most common type (85% [39 of 46]) and the distal 5 cm was the most common location of injury (63% [29 of 46]). Ureteroneocystostomy was the most common method of repair (83% [73 of 88]). Postoperative management, including stenting and imaging, has not changed significantly. Length of urinary catheter usage decreased in the recent cohort without associated complications. Five patients had major postoperative complications and 4 involved the urinary tract. Of those with follow-up, 96% (66 of 69) of ureteroneocystostomies and 75% (9 of 12) of ureteroureterostomies had radiologically normal urinary tracts. CONCLUSIONS: Ureteral surgery is necessary in the case of injury or involvement with invasive disease. There has been a decrease in number of procedures. Ureteroneocystostomy has remained the most common method of reconstruction for both injury and resection with acceptable postoperative complication rates.

Major vascular injury during gynecologic cancer surgery.

OBJECTIVE: Vascular injury during major gynecologic cancer surgery is a rare but potentially fatal complication. The purpose of this study was to review our experience with major vascular injury during gynecologic cancer surgery. METHODS: This was a retrospective chart review of women undergoing surgery by our gynecologic oncology department from 7/1/99 to 6/30/20 who had a major vascular injury. We identified women who sustained a vascular injury by a combination of CPT code and medical record searches, fellow case logs and a list maintained for an ongoing quality assurance program. Data were expressed as median and range for continuous variables and as frequency and percentage for categorical variables. Fisher's exact test was used to analyze differences in complication rates between groups. RESULTS: Major vascular injury was identified in 52 patients and procedures. The inferior vena cava was the most common site of injury, 32.7% (17/52), followed by the external iliac vein, 23.1% (12/52). Lymph node dissection was the most common time for a vascular injury to occur 51.9% (27/52). The majority of injuries required suture repair, 80.8% (42/52). Estimated blood loss in cases with vascular injury ranged from 100 mL to massive unquantifiable blood loss in the case of an aortic injury. Patients required a median of 2units of packed red blood cells. Postoperative complications included anemia requiring blood transfusion, 19.6% (9/46) and venous thromboembolism, 19.6% (9/46). CONCLUSIONS: Vascular injury remains a rare but potentially morbid complication of gynecologic oncologic surgery. Prompt recognition and management are imperative in minimizing persistent bleeding and complications.

Lagged Relationships Among Chemotherapy-Induced Peripheral Neuropathy, Sleep Quality, and Physical Activity During and After Chemotherapy.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is well-documented and can become chronic for up to a third of patients. CIPN management is hampered by limited pharmacological options. Thus, identifying modifiable behaviors that influence CIPN may help inform future interventions. PURPOSE: The purpose of the current study was to examine bidirectional relationships between sleep quality, physical activity, and CIPN during and after chemotherapy. METHODS: Participants were 138 women with gynecologic cancer (M age = 61, 94% white, 96% non-Hispanic), collected as part of an ongoing study. Assessments occurred at postcycle 1, postcycle 6, and 6- and 12-month postchemotherapy. CIPN (EORTC-CIPN20), sleep quality (PSQI), and physical activity (IPAQ) were assessed via self-report. Objective physical activity was assessed via wrist actigraphy. Latent change score models were used to examine lagged relationships between CIPN, sleep quality, and physical activity pairs. RESULTS: Over the study period, sleep quality was found to contribute to CIPN (p = .001), but not the reverse (p > .05). Bidirectional relationships were observed between CIPN and both objective and subjective walking (ps ≤ .001). Illustrations of these relationships showed that patients with less CIPN early in treatment demonstrate more substantial increases in walking over time, while those with higher CIPN demonstrate more consistent levels of walking during and after treatment. CONCLUSIONS: These findings suggest that worse sleep quality and lower walking levels may contribute to the course and maintenance of CIPN. Future investigation should evaluate the impact of early interventions aimed at improving sleep quality and encouraging physical activity in patients treated with chemotherapy.

Comparison of Definitive Cervical Cancer Management With Chemotherapy and Radiation Between Two Centers With Variable Resources and Opportunities for Improved Treatment.

PURPOSE: Cervical cancer remains a major health challenge in low- to middle-income countries. We present the experiences of two centers practicing in variable resource environments to determine predictors of improved radiochemotherapy treatment. METHODS AND MATERIALS: This comparative review describes cervical cancer presentation and treatment with concurrent chemoradiotherapy with high-dose-rate brachytherapy between 2014 and 2017 at the National Radiotherapy Oncology and Nuclear Medicine Center (NRONMC) in Korle-Bu Teaching Hospital, Accra, Ghana, and Moffitt Cancer Center (MCC), Tampa, FL. RESULTS: Median follow-up for this study was 16.9 months. NRONMC patients presented with predominantly stage III disease (42% v 16%; P = .002). MCC patients received para-aortic node irradiation (16%) and interstitial brachytherapy implants (19%). Median treatment duration was longer for NRONMC patients compared with MCC patients (59 v 52 days; P < .0001), and treatment duration ≥ 55 days predicted worse survival on multivariable analysis (MVA; P = .02). Stage ≥ III disease predicted poorer local control on MVA. There was a difference in local control among patients with stage III disease (58% v 91%; P = .03) but not in survival between MCC and NRONMC. No significant difference in local control was observed for stage IB, IIA, and IIB disease. CONCLUSION: Although there were significant differences in disease presentation between the two centers, treatment outcomes were similar for patients with early-stage disease. Longer treatment duration and stage ≥ III disease predicted poor outcomes.

High-dose intensity-modulated chemoradiotherapy in vulvar squamous cell carcinoma: Outcome and toxicity.

INTRODUCTION: To evaluate clinical outcomes, pattern of failure, and toxicity after high-dose intensity-modulated radiation therapy (IMRT) for advanced vulvar cancer. METHODS: In this IRB approved retrospective study, the charts of women with histologically confirmed, non-metastatic vulvar cancer consecutively treated at our institution from 2012 to 2018 were reviewed to identify patients that received high-dose IMRT with curative intent. The treatment compliance, toxicities, and patterns of failure were investigated. Actuarial local, regional and distant recurrence and survival were estimated using Kaplan-Meier method and compared using log rank test. RESULTS: Twenty-six patients were identified, 23 were unresectable, and 3 refused surgery. Fifteen patients (58%) had inguinal node metastases; 10(38%) had pelvic node metastases. Elective surgical staging of groins was performed in 9-patients. Median tumor dose was 65.4Gy. Concurrent platinum-based chemotherapy was administered in 22(84.6%) patients. Complete response (CR) was achieved in 21/26 (80.7%) patients. Five patients had persistent disease following treatment and one sustained recurrence 5-months following radiotherapy. All persistent or recurrent disease occurred inside the irradiated volume. Median follow-up was 19 months (3-52 months). Actuarial 1-year local, regional and distant controls were 72.4%, 85.4%, and 86%, respectively. One and 2-year overall survivals were 91% and 62%, respectively. Complete response at 3-months was a strong predictor for overall survival (1-yr OS 73% vs 27%, HR 7.1 (95% CI 1.2-44); p = 0.01). Lymph node metastases adversely affected overall survival (2-yr OS 49% vs. 83%, p = 0.09). Grade 3-4 late urinary and soft-tissue toxicity was seen in 5 patients. Tumor doses >66 Gy (p = 0.03) and prior pelvic radiotherapy (p = 0.002) predicted grade 3-4 toxicity. CONCLUSION: High-dose IMRT for vulvar cancer achieves high rates of local control with acceptable dose dependent long-term toxicity.

Recurrence, death, and secondary malignancy after ovarian conservation for young women with early-stage low-grade endometrial cancer.

OBJECTIVE: To examine the association between ovarian conservation and oncologic outcome in surgically-treated young women with early-stage, low-grade endometrial cancer. METHODS: This multicenter retrospective study examined women aged <50 with stage I grade 1-2 endometrioid endometrial cancer who underwent primary surgery with hysterectomy from 2000 to 2014 (US cohort n = 1196, and Japan cohort n = 495). Recurrence patterns, survival, and the presence of a metachronous secondary malignancy were assessed based on ovarian conservation versus oophorectomy. RESULTS: During the study period, the ovarian conservation rate significantly increased in the US cohort from 5.4% to 16.4% (P = 0.020) whereas the rate was unchanged in the Japan cohort (6.3-8.7%, P = 0.787). In the US cohort, ovarian conservation was not associated with disease-free survival (hazard ratio [HR] 0.829, 95% confidence interval [CI] 0.188-3.663, P = 0.805), overall survival (HR not estimated, P = 0.981), or metachronous secondary malignancy (HR 1.787, 95% CI 0.603-5.295, P = 0.295). In the Japan cohort, ovarian conservation was associated with decreased disease-free survival (HR 5.214, 95% CI 1.557-17.464, P = 0.007) and an increased risk of a metachronous secondary malignancy, particularly ovarian cancer (HR 7.119, 95% CI 1.349-37.554, P = 0.021), but was not associated with overall survival (HR not estimated, P = 0.987). Ovarian recurrence or metachronous secondary ovarian cancer occurred after a median time of 5.9 years, and all cases were salvaged. CONCLUSION: Our study suggests that adoption of ovarian conservation in young women with early-stage low-grade endometrial cancer varies by population. Ovarian conservation for young women with early-stage, low-grade endometrial cancer may be potentially associated with increased risks of ovarian recurrence or metachronous secondary ovarian cancer in certain populations; nevertheless, ovarian conservation did not negatively impact overall survival.