Linoleic acid exhibits anti-proliferative and anti-invasive activities in endometrial cancer cells and a transgenic model of endometrial cancer.

Emerging evidence has provided considerable insights into the integral function of reprogramming fatty acid metabolism in the carcinogenesis and progression of endometrial cancer. Linoleic acid, an essential fatty acid with the highest consumption in the Western diet regimen, has shown pro-tumorigenic or anti-tumorigenic effects on tumor cell growth and invasion in multiple types of cancer. However, the biological role of linoleic acid in endometrial cancer remains unclear. In the present study, we aimed to investigate the functional impact of linoleic acid on cell proliferation, invasion, and tumor growth in endometrial cancer cells and in a transgenic mouse model of endometrial cancer. The results showed that Linoleic acid significantly inhibited the proliferation of endometrial cancer cells in a dose-dependent manner. The treatment of HEC-1A and KLE cells with linoleic acid effectively increased intracellular reactive oxygen species (ROS) production, decreased mitochondrial membrane potential, caused cell cycle G1 arrest, and induced intrinsic and extrinsic apoptosis pathways. The anti-invasive ability of linoleic acid was found to be associated with the epithelial-mesenchymal transition process in both cell lines, including the decreased expression of N-cadherin, snail, and vimentin. Furthermore, treatment of Lkb1fl/flp53fl/fl transgenic mice with linoleic acid for four weeks significantly reduced the growth of endometrial tumors and decreased the expression of VEGF, vimentin, Ki67, and cyclin D1 in tumor tissues. Our findings demonstrate that linoleic acid exhibits anti-proliferative and anti-invasive activities in endometrial cancer cell lines and the Lkb1fl/flp53fl/fl mouse model of endometrial cancer, thus providing a pre-clinical basis for future dietary interventions with linoleic acid in endometrial cancer.

A novel dopamine receptor D2 antagonist (ONC206) potentiates the effects of olaparib in endometrial cancer.

Poly ADP-ribose polymerase (PARP) inhibitors are effective therapies for cancer patients with homologous recombination (HR) deficient tumors. The imipridone ONC206 is an orally bioavailable dopamine receptor D2 antagonist and mitochondrial protease ClpP agonist that has anti-tumorigenic effects in endometrial cancer via induction of apoptosis, activation of the integrated stress response and modulation of PI3K/AKT signaling. Both PARP inhibitors and imipridones are being evaluated in endometrial cancer clinical trials but have yet to be explored in combination. In this manuscript, we evaluated the effects of the PARP inhibitor olaparib in combination with ONC206 in human endometrioid endometrial cancer cell lines and in a genetically engineered mouse model of endometrial cancer. Our results showed that simultaneous exposure of endometrial cancer cells to olaparib and ONC206 resulted in synergistic anti-proliferative effects and increased cellular stress and apoptosis in both cell lines, compared to either drug alone. The combination treatment also decreased expression of the anti-apoptotic protein Bcl-2 and reduced phosphorylation of AKT and S6, with greater effects compared to either drug alone. In the transgenic model of endometrial cancer, the combination of olaparib and ONC206 resulted in a more significant reduction in tumor weight in obese and lean mice compared to ONC206 alone or olaparib alone, together with a considerably decreased Ki-67 and enhanced H2AX expression in obese and lean mice. These results suggest that this novel dual therapy may be worthy of further exploration in clinical trials.

Asparagus officinalis combined with paclitaxel exhibited synergistic anti-tumor activity in paclitaxel-sensitive and -resistant ovarian cancer cells.

PURPOSE: Although paclitaxel is a promising first-line chemotherapeutic drug for ovarian cancer, acquired resistance to paclitaxel is one of the leading causes of treatment failure, limiting its clinical application. Asparagus officinalis has been shown to have anti-tumorigenic effects on cell growth, apoptosis, cellular stress and invasion of various types of cancer cells and has also been shown to synergize with paclitaxel to inhibit cell proliferation in ovarian cancer. METHODS: Human ovarian cancer cell lines MES and its PTX-resistant counterpart MES-TP cell lines were used and were treated with Asparagus officinalis and paclitaxel alone as well as in combination. Cell proliferation, cellular stress, invasion and DMA damage were investigated and the synergistic effect of a combined therapy analyzed. RESULTS: In this study, we found that Asparagus officinalis combined with low-dose paclitaxel synergistically inhibited cell proliferation, induced cellular stress and apoptosis and reduced cell invasion in paclitaxel-sensitive and -resistant ovarian cancer cell lines. The combined treatment effects were dependent on DNA damage pathways and suppressing microtubule dynamics, and the AKT/mTOR pathway and microtubule-associated proteins regulated the inhibitory effect through different mechanisms in paclitaxel-sensitive and -resistant cells. CONCLUSION: These findings suggest that the combination of Asparagus officinalis and paclitaxel have potential clinical implications for development as a novel ovarian cancer treatment strategy.

Non-islet cell tumor hypoglycemia in a patient with uterine carcinosarcoma.

•Non-islet cell tumor hypoglycemia (NICTH) is a rare cause of hypoglycemia in patients with uterine carcinosarcoma.•Complete surgical resection is the first-line treatment for NICTH.•In patients with tumors not amenable to complete resection, partial resection can provide improvement in severe hypoglycemia.

Comparing Laparotomy with Robot-assisted Interval Debulking Surgery for Patients with Advanced Epithelial Ovarian Cancer Receiving Neoadjuvant Chemotherapy.

STUDY OBJECTIVE: Compare survival of patients with advanced epithelial ovarian cancer (EOC) undergoing interval debulking surgery (IDS) with either robot-assisted (R-IDS) or open (O-IDS) approach. Second, we assessed the impact of adjuvant and neoadjuvant chemotherapy (NACT) cycles as independent variables associated with survival in this patient population. DESIGN: Retrospective cohort study. SETTING: Single tertiary care center. PATIENTS: Total of 93 patients diagnosed with advanced EOC who underwent NACT before primary debulking surgery after consultation with a gynecologic oncologist. INTERVENTIONS: All patients underwent IDS after completion of NACT with either R-IDS or O-IDS between 2011 and 2018 at a single tertiary care center. Exclusion criteria included receiving fewer than 3 or more than 6 cycles of NACT or having concurrent diagnoses of other malignancies during the treatment period. MEASUREMENTS AND MAIN RESULTS: A total of 93 patients were identified (n = 43 R-IDS; n = 50 O-IDS). Median age (63.0 vs 66.2 years) did not differ between the 2 groups (p = .1). Of the total patients, 91% were optimally cytoreduced (57% R0 and 34% R1), and R0 rate was not influenced by surgical modality (52% O-IDS vs 63% R-IDS, p = .4). Progression-free survival (PFS) and overall survival (OS) did not differ between patients undergoing O-IDS and those undergoing R-IDS (PFS 15.4 vs 16.7 months, p = .7; OS 38.2 vs 35.6 months, p = .7). Cytoreduction to R0 improved both PFS and OS independent of surgical approach. Subgroup analysis showed that, specifically in patients undergoing R-IDS, receiving >6 total cycles of chemotherapy was independently associated with both decreased PFS (hazard ratio 3.85; 95% confidence interval, 1.52-9.73) and OS (hazard ratio 3.97; 95% confidence interval, 1.08-14.59). When analyzed separately, neither NACT nor adjuvant cycle numbers had any effect on survival. CONCLUSION: In this retrospective study of patients with advanced EOC undergoing IDS after NACT, the use of robot-assisted surgery did not affect debulking success or oncologic survival indices. Receiving >6 total cycles of chemotherapy before IDS was associated with a decrease in both PFS and OS in patients undergoing R-IDS in this cohort and warrants further investigation.

Bilateral Otorrhagia after Robotically Assisted Gynecologic Surgery in the Setting of a Reduced Trendelenburg Position and Low-Pressure Pneumoperitoneum: A Case Report and Review of the Literature.

Perioperative otorrhagia in association with nonotolaryngologic surgery is rare. The cause is typically attributed to the physiologic derangements associated with the Trendelenburg position and pneumoperitoneum during laparoscopic surgery. The most well-accepted etiology is an increase in arterial and venous pressures causing the rupture of subcutaneous capillaries, although the exact etiology remains unclear. We present the first reported case of bilateral spontaneous otorrhagia associated with robotically assisted laparoscopic surgery involving a reduced Trendelenburg position and low-pressure pneumoperitoneum. Perioperative hypertension, female gender, advanced age, and increased bleeding risk may contribute to the development of this rare complication.

Metastatic small cell neuroendocrine carcinoma of the cervix treated with the PD-1 inhibitor, nivolumab: a case report.

BACKGROUND: Nivolumab is an immune checkpoint inhibitor specific for the programmed death 1 (PD-1) receptor that has led to clinical responses in many cancer types. Identifying biomarkers predictive of response to PD-1 blockade is an area of active investigation. CASE PRESENTATION: We present a patient with recurrent, metastatic, PD-L1-negative small cell neuroendocrine carcinoma of the cervix (SCNEC) who experienced a complete response to nivolumab. Though nivolumab was discontinued over 4 months ago due to treatment-related adverse events, she continues to have no evidence of disease. CONCLUSIONS: Immune checkpoint inhibitors may be active in neuroendocrine cervical cancer, with potential for dramatic responses in a modest subset of patients.