Can we safely forgo hysterectomy in non-fertility-sparing surgery for borderline ovarian tumors?

Forgoing hysterectomy as part of borderline ovarian tumor (BOT) staging is considered appropriate for fertility preservation. We evaluated whether forgoing hysterectomy may also be acceptable in non-fertility-sparing surgery by evaluating the frequency of uterine involvement and the rate of recurrence involving the uterus. A review of all BOTs at one institution over ten years (2009-2019) was performed. Patients with hysterectomy prior to BOT diagnosis were excluded. Data were abstracted from electronic medical records. Bivariate statistics were used to compare groups. 129 patients with BOT on final pathology were identified. 67 cases included hysterectomy. Reasons for no hysterectomy (n = 62) included fertility preservation (40), benign intraoperative frozen pathology (4), patient preference (3), comorbidities (7), and unknown (8). Four of 67 (6.0%) uterine specimens had non-invasive serosal implants, of which two had grossly visible uterine involvement and all four had grossly visible extrauterine peritoneal disease. 12 of 129 (9.3%) patients had documented recurrence, of which all had uterine preservation at the time of initial surgery. Of the 12 recurrences with uterus in situ, none were documented to involve the uterus, and all were composed of non-invasive implants. In patients with BOT grossly confined to ovaries at the time of surgery, we found no cases of uterine involvement. We found no cases in which microscopic uterine serosal involvement changed stage and no cases of recurrence involving the uterus. Hysterectomy may be able to be safely excluded from non-fertility-sparing surgery for BOTs, particularly when disease is grossly confined to the ovaries.

Survival and clinical outcomes of patients with ovarian cancer who were treated on phase 1 clinical trials.

BACKGROUND: Patients with ovarian cancer who are enrolled on phase 1 trials typically have platinum-resistant and heavily pretreated disease, with a poor prognosis. In the current study, the authors assessed prognostic factors and survival in women with recurrent ovarian cancer who were treated on phase 1 clinical trials. METHODS: The authors performed a retrospective analysis of patients treated from 2008 through 2018 at the University of Colorado Cancer Center. Patient characteristics and treatment and toxicity-related survival data were assessed. Descriptive statistics and Cox proportional hazards models were used to identify risk factors associated with survival time. RESULTS: A total of 132 patients were treated on phase 1 clinical trials. Patients had a median age of 59 years (range, 33-88 years) with a median of 5.5 previous chemotherapy lines (range, 1-13 lines). Of the 132 patients, 53 (40%) were treated on multiple phase 1 trials with a median of 1 (range, 0-5) prior phase 1 trial. The overall response rate was 14.7%. The median overall survival was 11.3 months (95% CI, 9.1-13.4 months). Two patients died on trial due to progression of disease whereas no patients died of treatment-related toxicity. Independent risk factors found to be predictive of shorter survival were an elevated cancer antigen 125 (CA 125) level (hazard ratio [HR], 2.8; 95% CI, 1.6-5.2) and albumin <3.5 g/dL (HR, 2.5; 95% CI, 1.65-3.79). A body mass index >25 kg/m2 was predictive of longer survival (HR, 0.65; 95% CI, 0.44-0.96). CONCLUSIONS: In the current single-institution series, patients with heavily pretreated ovarian cancer who were treated on phase 1 clinical trials experienced a median overall survival of 11.3 months. When available, phase 1 clinical trials represent a reasonable treatment option for patients with heavily pretreated ovarian cancer with a preserved performance status.

Targeting Fatty Acid Oxidation to Promote Anoikis and Inhibit Ovarian Cancer Progression.

Epithelial-derived high-grade serous ovarian cancer (HGSOC) is the deadliest gynecologic malignancy. Roughly 80% of patients are diagnosed with late-stage disease, which is defined by wide-spread cancer dissemination throughout the pelvic and peritoneal cavities. HGSOC dissemination is dependent on tumor cells acquiring the ability to resist anoikis (apoptosis triggered by cell detachment). Epithelial cell detachment from the underlying basement membrane or extracellular matrix leads to cellular stress, including nutrient deprivation. In this report, we examined the contribution of fatty acid oxidation (FAO) in supporting anoikis resistance. We examined expression Carnitine Palmitoyltransferase 1A (CPT1A) in a panel of HGSOC cell lines cultured in adherent and suspension conditions. With CPT1A knockdown cells, we evaluated anoikis by caspase 3/7 activity, cleaved caspase 3 immunofluorescence, flow cytometry, and colony formation. We assessed CPT1A-dependent mitochondrial activity and tested the effect of exogenous oleic acid on anoikis and mitochondrial activity. In a patient-derived xenograft model, we administered etomoxir, an FAO inhibitor, and/or platinum-based chemotherapy. CPT1A is overexpressed in HGSOC, correlates with poor overall survival, and is upregulated in HGSOC cells cultured in suspension. CPT1A knockdown promoted anoikis and reduced viability of cells cultured in suspension. HGSOC cells in suspension culture are dependent on CPT1A for mitochondrial activity. In a patient-derived xenograft model of HGSOC, etomoxir significantly inhibited tumor progression. IMPLICATIONS: Targeting FAO in HGSOC to promote anoikis and attenuate dissemination is a potential approach to promote a more durable antitumor response and improve patient outcomes.

Multi-Omic Approaches Identify Metabolic and Autophagy Regulators Important in Ovarian Cancer Dissemination.

High-grade serous ovarian cancers (HGSOCs) arise from exfoliation of transformed cells from the fallopian tube, indicating that survival in suspension, and potentially escape from anoikis, is required for dissemination. We report here the results of a multi-omic study to identify drivers of anoikis escape, including transcriptomic analysis, global non-targeted metabolomics, and a genome-wide CRISPR/Cas9 knockout (GeCKO) screen of HGSOC cells cultured in adherent and suspension settings. Our combined approach identified known pathways, including NOTCH signaling, as well as novel regulators of anoikis escape. Newly identified genes include effectors of fatty acid metabolism, ACADVL and ECHDC2, and an autophagy regulator, ULK1. Knockdown of these genes significantly inhibited suspension growth of HGSOC cells, and the metabolic profile confirmed the role of fatty acid metabolism in survival in suspension. Integration of our datasets identified an anoikis-escape gene signature that predicts overall survival in many carcinomas.

Trocar site hernia development in patients undergoing robotically assisted or standard laparoscopic staging surgery for endometrial cancer.

OBJECTIVES: To compare the incidence and potential risk factors of trocar site hernia formation in women undergoing robotically assisted versus standard laparoscopic staging (RBT vs. LSC, respectively) for endometrial cancer. METHODS: We retrospectively identified all patients who underwent MIS staging for endometrial cancer at our institution from 01/09-12/12. Data collection involved the review of all operative notes, postoperative follow-up visit notes, and postoperative imaging reports. Appropriate statistical tests were used. RESULTS: We identified 760 eligible patients (LSC, 193; RBT, 567). The overall median age was 61years (range, 33-90). The median BMI was 28.5kg/m2 for LSC (range, 16.6-67.6) and 29.5kg/m2 for RBT (range, 17.9-66) patients (p=0.8). A trocar site hernia developed in 16 patients (2.1%)-5 (2.6%) of 193 LSC and 11 (1.9%) of 567 RBT patients (p=0.6). Median time to hernia diagnosis was 13months (range, 5-20.5) and 18months (range, 3-49), respectively (p=0.5). All hernias in the LSC cohort developed at the camera trocar site. In the RBT cohort, 10 developed at the camera trocar site and 1 at a lateral trocar site. Only BMI was associated with the development of hernias. A hernia was diagnosed in 7 (6.9%) of 101 patients with a BMI ≥40kg/m2 compared with 9 (1.4%) of 659 with a BMI <40kg/m2 (p=0.001). CONCLUSION: MIS for endometrial cancer is associated with a low rate of trocar site hernia formation, with similar rates associated with RBT and standard LSC. Higher BMI is associated with the development of postoperative trocar site hernias.

Extended left upper quadrant resection during primary cytoreductive surgery for Stage IV ovarian cancer.

OBJECTIVE: The completeness of primary cytoreductive surgery for Stage IV epithelial ovarian cancer is associated with greater progression free survival and overall survival Winter et al. (2008) [1]. Cytoreduction to no gross residual disease in patients with bulky upper abdominal disease presents significant surgical challenges, highlighting the importance of specialized and comprehensive surgical training in the treatment of advanced ovarian cancers Zivanovic et al. (2008) [2]. Extensive upper abdominal surgical procedures have shown to improve the ability to achieve cytoreduction to no gross residual disease Chi et al. (2004) [3]. This film displays an extended left upper quadrant resection in one of our recent patients. METHODS: The patient was a 62-year-old female with a CA-125 of 2,577U/mL, abdominal ascites, and a preoperative CT showing carcinomatosis with a left upper quadrant infiltration. Primary cytoreductive surgery was undertaken with exploratory laparotomy, type 2 radical oophorectomy (en bloc modified radical abdominal hysterectomy, bilateral salpingo-oophorectomy, pan-pelvic peritonectomy, distal colectomy, retosigmoid colectomy), with en bloc omentectomy, transverse colectomy, splenectomy, distal pancreatectomy, and diaphragm peritonectomy. RESULTS: Operative time was 337min with an estimated blood loss of 900mL. The patient was discharged home on post-operative day 10 after a standard prolongation in hospitalization required to meet milestones after extensive upper quadrant cytoreductive surgery. CONCLUSION: Bulky upper abdominal disease can present significant surgical challenges. This film illustrates obtaining cytoreduction to no gross residual disease is feasible. We show transection of the pancreas by reinforced linear staple closure due to its ease of use and surgeon preference, although controversy remains regarding the ideal technique.