Palmitic Acid Exerts Anti-Tumorigenic Activities by Modulating Cellular Stress and Lipid Droplet Formation in Endometrial Cancer.

Epidemiological and clinical evidence have extensively documented the role of obesity in the development of endometrial cancer. However, the effect of fatty acids on cell growth in endometrial cancer has not been widely studied. Here, we reported that palmitic acid significantly inhibited cell proliferation of endometrial cancer cells and primary cultures of endometrial cancer and reduced tumor growth in a transgenic mouse model of endometrial cancer, in parallel with increased cellular stress and apoptosis and decreased cellular adhesion and invasion. Inhibition of cellular stress by N-acetyl-L-cysteine effectively reversed the effects of palmitic acid on cell proliferation, apoptosis, and invasive capacity in endometrial cancer cells. Palmitic acid increased the intracellular formation of lipid droplets in a time- and dose-dependent manner. Depletion of lipid droplets by blocking DGAT1 and DGAT2 effectively increased the ability of palmitic acid to inhibit cell proliferation and induce cleaved caspase 3 activity. Collectively, this study provides new insight into the effect of palmitic acid on cell proliferation and invasion and the formation of lipid droplets that may have potential clinical relevance in the treatment of obesity-driven endometrial cancer.

Ipatasertib exhibits anti­tumorigenic effects and enhances sensitivity to paclitaxel in endometrial cancer in vitro and in vivo.

Endometrial cancer is the most common gynecologic cancer and one of the only cancers for which incidence and mortality is steadily increasing. Although curable with surgery in the early stages, endometrial cancer presents a significant clinical challenge in the metastatic and recurrent setting with few novel treatment strategies emerging in the past fifty years. Ipatasertib (IPAT) is an orally bioavailable pan­AKT inhibitor, which targets all three AKT isoforms and has demonstrated anti­tumor activity in pre­clinical models, with clinical trials emerging for many cancer types. In the present study, the MTT assay was employed to evaluate the therapeutic efficacy of IPAT or IPAT in combination with paclitaxel (PTX) in endometrial cancer cell lines and primary cultures of endometrial cancer. The effect of IPAT and PTX on the growth of endometrial tumors was evaluated in a transgenic mouse model of endometrial cancer. Apoptosis was assessed using cleaved caspase assays and cellular stress was assessed using ROS, JC1 and tetramethylrhodamine ethyl ester assays. The protein expression levels of markers of apoptosis and cellular stress, and DNA damage were evaluated using western blotting and immunohistochemistry. IPAT significantly inhibited cell proliferation, caused cell cycle G1 phase arrest, and induced cellular stress and mitochondrial apoptosis in a dose dependent manner in human endometrial cancer cell lines. Combined treatment with low doses of IPAT and PTX led to synergistic inhibition of cell proliferation and induction of cleaved caspase 3 activity in the human endometrial cancer cell lines and the primary cultures. Furthermore, IPAT effectively reduced tumor growth, accompanied by decreased protein expression levels of Ki67 and phosphorylation of S6 in the Lkb1fl/flp53fl/fl mouse model of endometrioid endometrial cancer. The combination of IPAT and PTX resulted in increased expression of phosphorylated­H2AX and KIF14, markers of DNA damage and microtubule dysfunction respectively, as compared with IPAT alone, PTX alone or placebo­treated mice. The results of the present study provide a biological rationale to evaluate IPAT and the combination of IPAT and PTX in future clinical trials for endometrial cancer.

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.

Ipatasertib, an oral AKT inhibitor, inhibits cell proliferation and migration, and induces apoptosis in serous endometrial cancer.

Ipatasertib (IPAT) is an orally administered, selective protein kinase B (AKT) inhibitor with promising data in solid tumors in both pre-clinical studies and clinical trials. Given that the PI3K/AKT/mTOR pathway is frequently dysregulated in uterine serous carcinoma (USC), we aimed to explore the functional impact of IPAT on anti-tumorigenic activity in USC cell lines and primary cultures of USC. We found that IPAT significantly inhibited cell proliferation and colony formation in a dose-dependent manner in USC cells. Induction of cell cycle arrest and apoptosis was observed in IPAT-treated ARK1 and SPEC-2 cells. Treatment with IPAT resulted in reduced adhesion and invasion of both cell lines with a concomitant decrease in the expression of Snail, Slug, and N-Cadherin. Compared with single-drug treatment, the combination of IPAT and paclitaxel synergistically reduced cell proliferation and increased the activity of cleaved caspase 3 in both cell lines. Additionally, IPAT inhibited growth in four of five primary USC cultures, and three of five primary cultures also exhibited synergistic growth inhibition when paclitaxel and IPAT were combined. These results support that IPAT appears to be a promising targeted agent in the treatment of USC.

Risk factors for atypical hyperplasia and endometrial cancer in the infertility population: a case-control study.

OBJECTIVE: To estimate the incidence and identify risk factors for atypical endometrial hyperplasia (AH) and endometrial cancer (EC) in American women undergoing infertility evaluation. DESIGN: Case-control study. SETTING: Academic reproductive endocrinology and infertility practice. PATIENTS: Female patients (18-50 years) seeking infertility evaluation from January 1, 2009 to December 1, 2018. Patients with known genetic predisposition to cancer or prior cancer diagnosis were excluded. Cases were defined as patients diagnosed with AH or EC during infertility workup (n = 22). Controls without AH or EC were randomly selected in a 10:1 ratio (n = 220) from all women undergoing infertility evaluation in the same year. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Incidence of AH or EC and odds of AH or EC accounting for age, race, body mass index (BMI), and ovulatory dysfunction. RESULTS: Twenty-two cases of AH or EC were identified among 11,569 women undergoing infertility evaluation (incidence 2 per 1,000 women, 95% confidence interval [CI] 1.2-2.9 per 1,000). Of these women, 68% had a BMI ≥30 kg/m2 compared with 25% of controls. In multivariable analyses, women with a BMI ≥30 kg/m2 were 5.9 times more likely to be diagnosed with AH or EC (adjusted odds ratio 5.9, 95% CI 2.0-17.2). Women with ovulatory dysfunction were 3.4 times more likely to be diagnosed with AH or EC (adjusted odds ratio 3.4, 95% CI 1.1-10.1). CONCLUSIONS: The incidence of AH and EC in a population of women undergoing infertility evaluation is 10 times that in the general population of premenopausal women. Obesity is the strongest independent risk factor for AH and EC in women with infertility.

Uterine Cellular Blue Nevus Arising in Mullerian and Pelvic Dendritic Melanocytosis: Case Report of a Rare Phenomenon to Be Distinguished From Uterine Melanoma.

A 37-yr-old woman presented to the gynecology clinic with abnormal uterine bleeding in the setting of known, large uterine fibroids. Preoperative endometrial biopsy identified atypical melanocytic cells concerning for uterine melanoma. Care was transferred to the gynecologic oncology service for hysterectomy. Intraoperative findings included macular, blue-black pigmentation of the peritoneum of the bladder and cervix, which was resected and sent for frozen section, confirming melanocytic neoplasia. The hysterectomy revealed multiple tan leiomyomas up to 12 cm, and a distinct 3 cm black, incompletely circumscribed mass in the endomyometrium composed of bland spindled cells with delicate melanin granules. The tumor cells were positive for Sox-10, BAP1, and Mart-1 (Melan-A) and negative for PRAME, PD-L1, and BRAFV600E by immunostains. Microscopic elements of similar melanocytes and melanophages were found in the cervix and bladder peritoneum. Molecular analysis of the uterine tumor identified a GNA11 mutation but no TERT or BAP1 mutation. The uterine melanocytic tumor has characteristic findings of a cellular blue nevus arising in association with dendritic melanocytosis of Mullerian and pelvic tissues, a rarely seen benign phenomenon that should be distinguished from malignant melanoma of the upper genital tract.

Paraneoplastic cerebellar degeneration heralding recurrence of fallopian tube adenocarcinoma: A case report and literature review.

•Paraneoplastic cerebellar degeneration in recurrence of fallopian tube cancer.•Describes the initial symptoms of paraneoplastic cerebellar degeneration.•Identify a diagnosis that can lead to rapid irreversible deterioration.•Describe management and outcomes of paraneoplastic cerebellar degeneration.

Top Ten Tips Palliative Care Clinicians Should Know About Caring for Serious Illness in Pregnancy.

Palliative care (PC) teams are increasingly being called upon to provide care earlier and more remote from end of life. Because much of the field has grown out of hospice and geriatric care, most teams have little to no experience caring for pregnant women or their fetuses when serious or life-threatening illness strikes. This article, written by a team of oncologists (gynecologic, medical, and radiation) and PC providers, seeks to demystify the care of seriously ill pregnant women and their fetuses by exploring the diagnostic, treatment, prognostication, symptom management, and communication needs of these patients. Truly comprehensive PC extends throughout the life span, from conception to death, regardless of age. Accordingly, increased knowledge of the unique needs of these vulnerable groups will enhance our ability to provide care across this continuum.

Low rate of intraperitoneal port placement in ovarian cancer patients, a population-based assessment.

INTRODUCTION: The National Comprehensive Cancer Network (NCCN) guidelines recommend intraperitoneal chemotherapy in optimally debulked stage III ovarian cancer patients. The objective of this investigation was to determine the rate of intraperitoneal port placement in patients undergoing surgery for ovarian cancer in a national database maintained by the American College of Surgeons. METHOD: We identified ovarian cancer patients in the National Surgical Quality Improvement Program database from 2006 to 2012. Demographics, comorbidities, operative outcomes, and postoperative complications were abstracted. Descriptive analyses were conducted using Wilcoxon rank-sum and Chi square tests, and multivariate regression models were used to analyze pre-operative and post-operative variables associated with intraperitoneal port placement. RESULTS: We identified 2659 ovarian cancer patients who underwent primary surgical management. Of these patients, only 128 (4.8%) had an intraperitoneal port placed at the time of surgery. In multivariable analyses, intraperitoneal ports were associated with body mass index ≤25, disseminated cancer, later portion of the study period (2009-2012), and operative time >200 min. Intraperitoneal port placement was not associated with any difference in surgical site infection, wound disruption, major postoperative complication, readmission within 30 days, or death within 30 days. DISCUSSION: Recent investigation of practice at NCCN institutions between 2003 and 2012 found only 35% of eligible ovarian cancer patients received intraperitoneal chemotherapy. Using intraperitoneal port placement as a surrogate for intraperitoneal chemotherapy administration, our investigation suggests an even lower rate (4.8%) nationally.

Sexual function following hysterectomy for endometrial cancer: A five-year follow up investigation.

OBJECTIVES: We sought to determine a baseline and five-year follow up sexual function score in women undergoing hysterectomy for endometrial cancer. METHODS: A cross-section of endometrial cancer patients receiving care from 2006 to 2010 was identified. Patients were surveyed during academic year 2011 using the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ). Respondents were re-surveyed in 2016. The PISQ was also administered at a single time point to a control group of urogynecology patients. Statistical analyses were conducted using STATA software, version 13.1. RESULTS: 129 endometrial cancer and 63 matched urogynecology patients responded to an initial survey and sufficiently answered the PISQ. There was no statistical difference in BMI, race, diabetes, or smoking history between groups. In 2011, 62.5% of endometrial cancer patients versus 72.6% of urogynecology patients reported sexual activity (p = 0.166). Median PISQ score for these groups was 33 [IQR 29-38] and 32 [IQR 28-37] respectively (p = 0.472). Twenty-nine (22%) endometrial cancer patients sufficiently answered the initial and 5-year follow up PISQ to be included in follow up analysis. Median PISQ score at five years was not significantly different from baseline: 31 [IQR 27-39] versus 33 [IQR 31-38] (p = 0.299). With multivariable modeling, no demographic or clinical characteristics of endometrial cancer patients were independently associated with sexual function (p = NS). CONCLUSIONS: Sexual function for endometrial cancer patients was not significantly different from women treated for benign disease. Sexual function also remained stable for endometrial cancer patients regardless of time from initial treatment. Further prospective studies are needed to better characterize sexual function in endometrial cancer survivors.

Knee motion and muscle activation patterns are altered in hip osteoarthritis: The effect of severity on walking mechanics.

BACKGROUND: Knee function is impaired in individuals with moderate hip osteoarthritis. How this extends to those undergoing total hip arthroplasty is unknown despite the common requirement for knee arthroplasty in this population. The study purpose was to determine whether sagittal plane knee joint movements and quadriceps and hamstring activation patterns differ between individuals with either moderate or severe unilateral hip osteoarthritis, and between ipsilateral and contralateral knees. METHODS: 20 individuals with moderate osteoarthritis and 20 with severe osteoarthritis were recruited. Sagittal knee motion and surface electromyograms from the hamstrings and quadriceps were collected during treadmill walking at a self-selected speed. Principal component analysis captured amplitude and temporal sagittal plane motion and EMG waveform features. Student's t-tests and Analysis of Variance determined between group differences and within/between group leg differences. FINDINGS: The severe groups' contralateral knee was in greater flexion at initial contact and demonstrated a movement profile of a longer stance phase (p < 0.001). The severe group had reduced sagittal plane knee motion (p < 0.0001); more so in the ipsilateral knee (p < 0.0001). The severe group had greater hamstring (p = 0.009) and quadriceps activation (p < 0.001) overall, specifically mid-stance quadriceps bilaterally (p = 0.002). Ipsilateral sagittal plane knee motion was reduced in both groups. Compared with those with moderate osteoarthritis, individuals with severe osteoarthritis walk with reduced sagittal plane knee motion bilaterally, suggesting prolonged contralateral stance, and elevated mid-stance hamstring and quadriceps activation. INTERPRETATION: Altered kinematics and muscle activity could contribute to a greater mechanical demand on the contralateral knee in those with more severe hip osteoarthritis.

Going social: Success in online recruitment of men who have sex with men for prevention HIV vaccine research.

OBJECTIVE: To compare the use of four different social media sites to recruit men who have sex with men (MSM) and transgender women to a phase 2b HIV prevention vaccine trial, HVTN 505. DESIGN: Retrospective, observational study. METHODS: The University of Pennsylvania HIV Vaccine Trials Unit (Penn HVTU) employed street outreach and online recruitment methods to recruit participants for HVTN 505 using a combination of national recruitment images/messages with Philadelphia-specific language and imagery. We compared the efficiency (number of enrolled participants per number of completed phone screens) and effectiveness (number of enrolled participants per time interval employed) of each strategy, as well as the demographics and risk behaviors of the populations. RESULTS: Online recruitment strategies populated 37% (71/191) of trial participants at our site. Among the four social media strategies employed, 45.1% (32/71) were enrolled through Facebook, 16.9% (12/71) through Craigslist, 15.5% (11/71) through a web-based marketing company (WBMC), and 22.5% (16/71) via GRINDR. The number of participants enrolled per month of strategy and the months the strategy was employed were Facebook - 32(33months), Craigslist - 12(33months), WBMC - 11(6months), and GRINDR - 16(0.56months). In-person and online recruitment strategies yielded participants of similar demographics and levels of risk behavior. CONCLUSION: Use of several social media recruitment modalities produced large numbers of MSM engaging in high risk behavior and willing to participate in an HIV prevention vaccine trial. In comparison to other social media and online strategies, recruitment via GRINDR was the most effective.

Survival implications of time to surgical treatment of endometrial cancers.

BACKGROUND: Optimal care for women with endometrial cancers often involves transfer of care from diagnosing physicians (eg, obstetrician-gynecologists) to treating physicians (eg, gynecologic oncologists.) It is critical to determine the effect of time to treatment on cancer outcomes to set best practices guidelines for referral processes. OBJECTIVE: We sought to determine the impact of time from diagnosis of endometrial cancer to surgical treatment on mortality and to characterize those patients who may be at highest risk for worsened survival related to surgical timing. STUDY DESIGN: The National Cancer Database was queried for incident endometrial cancers in adults from 2003 through 2012. Cancers were classified as low risk (grade 1 or 2 endometrioid histologies) or high risk (nonendometrioid and grade 3 endometrioid histologies) and analyzed separately. Demographic, clinicopathologic, and health system factors were collected. Unadjusted and adjusted hazard ratios for mortality were calculated by interval between diagnosis and surgery. Linear regression of patient and health care system characteristics was performed on diagnosis-to-surgery interval. RESULTS: For low-risk cancers (N = 140,078), surgery in the first and second weeks after diagnosis was independently associated with mortality risk (hazard ratio, 1.4; 95% confidence interval, 1.3-1.5; and hazard ratio, 1.1; 95% confidence interval, 1.0-1.2, respectively). The 30-day postoperative mortality was significantly higher among patients undergoing surgery in the first or second week postdiagnosis, compared to patients treated in the third or fourth week postdiagnosis (0.7% vs 0.4%; P < .001). Mortality risk was also significantly higher than baseline when time between diagnosis and surgery was >8 weeks. Independent associations with added time to surgery of at least 1 week were seen with black race (1.1 weeks; 95% confidence interval, 0.9-1.4), uninsurance (1.3 weeks; 95% confidence interval, 1.1-1.5), Medicaid insurance (1.7 weeks; 95% confidence interval, 1.5-1.9), and Charlson-Deyo comorbidity score >1 (1.0 weeks; 95% confidence interval, 0.8-1.2). For high-risk cancers (N = 68,360), surgery in the first and second weeks after diagnosis was independently associated with mortality risk (hazard ratio, 1.5; 95% confidence interval, 1.3-1.6; and hazard ratio, 1.2; 95% confidence interval, 1.1-1.2, respectively). The 30-day postoperative mortality was significantly higher among patients undergoing surgery in the first or second week postdiagnosis, compared to patients treated in the third or fourth week postdiagnosis (2.5% vs 1.0%; P < .001). Surgery after the third week postdiagnosis was not associated with a statistically significant increase in the adjusted risk of mortality. Independent associations with added time to surgery of at least 1 week were seen with uninsurance (1.4 weeks; 95% confidence interval, 0.9-1.9) and Medicaid insurance (1.4 weeks; 95% confidence interval, 1.1-1.7). CONCLUSION: Surgery in the first 2 weeks after diagnosis of endometrial cancer was associated with worsened survival associated with elevated perioperative mortality and treatment in low-volume hospitals. Delay in surgical treatment was a risk factor for mortality in low-risk cancers only and was likely associated with poor access to specialty care. We suggest that the target interval between diagnosis and treatment of endometrial cancers be ≤8 weeks; however, referral to an experienced surgeon and adequate preoperative optimization should be prioritized over expedited surgery.