Severe methotrexate hypersensitivity during treatment for Gestational trophoblastic Neoplasia: Case Report and considerations for management.

•Methotrexate (MTX) hypersensitivity is rare and has not been widely reported in the setting of treatment of GTN.•Work up of hypersensitivity reactions may include consultation to an allergist, serum tryptase level, and possible skin testing.•In low-risk GTN, dactinomycin should be utilized after a hypersensitivity reaction to MTX.

Ovarian Masses: The Value of Acoustic Shadowing on Ultrasound Examination.

Adnexal lesions are a common finding in women and pose a clinical challenge since ovarian cancer is a highly lethal disease. However, most adnexal masses are benign, benefiting from a more conservative approach. In preoperative assessment, transvaginal ultrasound plays a key role in evaluating morphologic features that correlate with the risk of malignancy. The acoustic shadow is the loss of echo behind sound-absorbing components, such as calcifications or fibrous tissues, which are predominantly found in benign lesions. However, recognizing the acoustic shadow is a difficult skill to master, and its usefulness may be underappreciated.

Is hormonal therapy after risk-reducing salpingo-oophorectomy associated with an increased risk of malignancy in pathogenic variant carriers?

OBJECTIVES: This study aimed to assess the association between hormone replacement therapy and the incidence of subsequent malignancies in patients who underwent risk-reducing salpingo-oophorectomy and had mutations predisposing them to Müllerian cancers. METHODS: This Institutional Review Board-approved retrospective study was performed at five academic institutions. Women were included if they were age 18-51 years, had one or more confirmed germline highly penetrant pathogenic variants, and underwent risk-reducing salpingo-oophorectomy. Patients with a prior malignancy were excluded. Clinicodemographic data were collected by chart review. Patients with no documented contact for one year prior to study termination were called to confirm duration of hormone use and occurrence of secondary outcomes. Hormone replacement therapy included any combination of estrogen or progesterone. RESULTS: Data were analyzed for 159 women, of which 82 received hormone replacement therapy and 77 did not. In both groups an average of 6 years since risk reduction had passed. The patients treated with hormone replacement therapy did not have a higher risk of subsequent malignancy than those not treated with hormone replacement therapy (6 out of 82 vs. 7 out of 77, P = .68). Patients who received hormone replacement therapy were younger than those who did not receive hormone replacement therapy (39.0 vs. 43.9 years, P < .01) and were more likely to have undergone other risk reductive procedures including mastectomy and/or hysterectomy, though this difference was not statistically significant (69.5% vs. 55.8%, P = .07). CONCLUSIONS: In this multi-institution retrospective study of data from patients with high-risk variant carriers who underwent risk-reducing salpingo-oophorectomy, there was no statistically significant difference in the incidence of malignancy between women who did and did not receive hormone replacement therapy.

Type II endometrial cancers with minimal, non-invasive residual disease on final pathology: What should we do next?

There are minimal data regarding the management of high risk endometrial cancer histologies lacking invasive disease on the final pathology specimen. This study examines a cohort of these patients and assesses outcomes including time to recurrence and risk of death after management with and without adjuvant therapies. Endometrial cancer patients with minimal or no remaining invasive disease on final pathologic specimen from 1995 to 2010 were included. Surgical procedure was at the discretion of the operating physician. Electronic medical records were used to abstract relevant clinicopathologic data and standard statistical methods were employed. 70 patients met inclusion criteria, of which 26 were high grade histologies. Adjuvant therapies were given in 12 of 26 patients. 6/26 patients recurred, of which 50% were salvaged with therapy at time of recurrence. Overall deaths occurred in 3 of 26 patients in the high risk cohort. Less than half of the high risk cohort received adjuvant therapies after surgical management. No histologic type was found to increase risk of recurrence, and treatment with initial adjuvant therapy did not significantly reduce recurrence risk. Large scale prospective trials are needed to aid in management of this unique endometrial cancer population.

Do gynecologic oncology patients with severely diminished renal function and urinary tract obstruction benefit from ureteral stenting or percutaneous nephrostomy?

OBJECTIVE: To assess the renal outcomes of gynecologic oncology patients who present with hydronephrosis and acute kidney injury (AKI), have <20% renal function on diuretic renal scintigraphy, and undergo placement of a ureteral stent or percutaneous nephrostomy (PCN) tube. METHODS: This is a single-institution case series of gynecologic oncology patients who underwent diuretic renal scintigraphy from January 1, 2007, to June 1, 2017. Univariate and multivariate logistic analyses were used to assess predictors of <20% renal function. Recovery from AKI or elevated creatinine was reported for women with <20% renal function who received a unilateral ureteral stent or PCN tube on the same side as their more compromised kidney. RESULTS: Among 353 gynecologic oncology patients who underwent diuretic renal scintigraphy, 58 (16%) had renal function <20%. Mean age was 59.6 years, 17% had preexisting chronic kidney disease, and 44% had a diagnosis of cervical cancer. Renal atrophy on computed tomography scan (aOR 18.24, 95% CI 1.21-274.92) predicted renal function <20%. Of 10 women with <20% renal function who received a stent or PCN tube, 7 recovered from AKI or elevated creatinine. CONCLUSIONS: Gynecologic oncology patients with <20% renal function may recover from AKI after placement of a stent or PCN tube, indicating that a diuretic renal scintigraphy cutoff of <20% renal function may be overly conservative. Future studies are warranted to determine optimal renal function cutoffs for stent/PCN tube placement in gynecologic oncology patients.

p5RHH nanoparticle-mediated delivery of AXL siRNA inhibits metastasis of ovarian and uterine cancer cells in mouse xenografts.

Ovarian and uterine serous cancers are extremely lethal diseases that often present at an advanced stage. The late-stage diagnosis of these patients results in the metastasis of their cancers throughout the peritoneal cavity leading to death. Improving survival for these patients will require identifying therapeutic targets, strategies to target them, and means to deliver therapies to the tumors. One therapeutic target is the protein AXL, which has been shown to be involved in metastasis in both ovarian and uterine cancer. An effective way to target AXL is to silence its expression with small interfering RNA (siRNA). We investigate the ability of the novel siRNA delivery platform, p5RHH, to deliver anti-AXL siRNA (siAXL) to tumor cells both in vitro and in vivo as well as examine the phenotypic effects of this siRNA interference. First, we present in vitro assays showing p5RHH-siAXL treatment reduces invasion and migration ability of ovarian and uterine cancer cells. Second, we show p5RHH nanoparticles target to tumor cells in vivo. Finally, we demonstrate p5RHH-siAXL treatment reduces metastasis in a uterine cancer mouse xenograft model, without causing an obvious toxicity. Collectively, these findings suggest that this novel therapy shows promise in the treatment of ovarian and uterine cancer patients.

Association between body mass index and surgical menopausal symptoms in patients with early stage endometrial cancer.

OBJECTIVES: Premenopausal women may undergo surgical menopause after staging for their endometrial cancer. Our aim was to determine the association between body mass index (BMI) and surgical menopausal symptoms. METHODS: We report a retrospective review of endometrial cancer patients whom underwent menopause secondary to their surgical staging procedure. Symptoms were classified as severe if treatment was prescribed, or mild if treatment was offered, but declined. Univariate analysis was performed with ANOVA and Chi-square tests as appropriate. Relative risks (RR) were generated from Poisson regression models. RESULTS: We identified 166 patients in whom the BMI (kg/m2) distribution was as follows: 33 (19.9%) had BMI <30, 49 (29.5%) had BMI 30-39.9, 50 (30.1%) had BMI 40-49.9, and 34 (20.5%) had BMI ≥50. There were no differences in race, age, or adjuvant treatment among the groups. Overall, 65 (39.2%) women reported symptoms of surgical menopause, including 19 (11.4%) mild and 46 (27.7%) severe. Symptom type did not differ by BMI; however, the prevalence of severe menopausal symptoms decreased with increasing BMI: <30 (45.5%), 30-39.9 (30.6%), 40-49.9 (22%), and ≥ 50 (14.7%); P = 0.002. Multivariate analysis confirmed that symptom prevalence decreased with increasing BMI. Compared to women with a BMI of <30, those with a BMI 40-49.9 (RR = 0.39, 95% CI: 0.17-0.87) or ≥ 50 (RR = 0.24, 95% CI: 0.08-0.70) were significantly less likely to experience menopausal symptoms. CONCLUSIONS: Women younger than 50 with BMI >40 and stage I endometrial cancer are significantly less likely than women with BMI <30 to experience menopausal symptoms after oophorectomy. This information may assist in peri-operative counseling.

Participation in Regular Physical Activity After Total Knee or Hip Arthroplasty for Osteoarthritis: Prevalence, Associated Factors, and Type.

OBJECTIVE: To describe the rates of participation in regular physical activity presurgery and at 3 years follow-up after knee or hip arthroplasty, and to describe factors associated with participation postsurgery and types of activity undertaken. METHODS: A previously acquired multicenter, prospective cohort of knee or hip arthroplasty recipients was followed up for 3 years postsurgery. Regular participation in physical activity was defined as participation in physical activity ≥1 time/week, excluding incidental activities. Participants were interviewed about current participation as well as participation in the year presurgery. Joint-specific and health-related quality-of-life scores and information on experience of major complications were obtained. Information about comorbidity and body weight were updated. Factors associated with 3-year physical activity participation were determined using multivariable logistic regression modeling. RESULTS: In total, 73.4% of the eligible cohort (1,289 of 1,757) were followed up (718 patients with total knee arthroplasty, and 571 patients with total hip arthroplasty). Participation profiles were similar regardless of the joint replaced. Participation in physical activity increased postsurgery in the combined cohort (from 45.2% to 63.5%; P < 0.001). Participation at 3 years was associated with participation presurgery (P < 0.0001), better 3-year quality of life (P < 0.001), younger age (P = 0.002), better 3-year joint scores (P = 0.01), >1 lifetime arthroplasty (P = 0.02), and higher education level (P = 0.04). Low-impact and nonambulatory activities significantly increased postsurgery with no change in high-impact activities. CONCLUSION: Participation rates increased postsurgery when recovery was stable, but approximately one-third of arthroplasty recipients did not engage in physical activity at least once per week. Because participation is associated with habitual activity presurgery, a potential role for behavior change interventions is suggested. The increase in nonambulatory activities indicates that current devices measuring ambulatory activity alone are inadequate for capturing physical activity.

Gynecologic Oncologists' Perceptions of Palliative Care and Associated Barriers: A Survey of the Society of Gynecologic Oncology.

OBJECTIVES: Gynecologic oncologists frequently care for patients at the end of life with the aid of palliative care (PC) specialists. Our primary objectives were to identify perceived barriers to integrating specialty PC into gynecologic cancer care. MATERIALS AND METHODS: Members of the Society of Gynecologic Oncology (SGO) were invited to participate in an anonymous online survey. A Likert scale captured perceptions regarding primary and specialty PC, frequent barriers to use of PC, and potential interventions. RESULTS: A total of 174 (16%) gynecologic oncologists completed the survey. The majority (75%) agreed or strongly agreed that PC should be integrated into cancer care at diagnosis of advanced or metastatic cancer. The most frequently perceived PC barriers included patients' unrealistic expectations (54%), limited access to specialty PC (25%), poor reimbursement (25%), time constraints (22%), and concern of reducing hope or trust (21%). The most agreed upon potential intervention was increased access to outpatient PC (80%). CONCLUSIONS: According to this cohort of SGO members, families' or patients' unrealistic expectations are the most frequent barriers to specialty PC. Understanding this communication breakdown is critically important.

SQ1274, a novel microtubule inhibitor, inhibits ovarian and uterine cancer cell growth.

OBJECTIVE: Paclitaxel, a microtubule inhibitor, is subject to tumor resistance while treating high-grade serous ovarian and uterine cancer. This study aims to directly compare the effects of SQ1274, a novel microtubule inhibitor that binds to the colchicine-binding site on tubulin, and paclitaxel in high-grade serous ovarian and uterine cancer cell lines both in vitro and in vivo. METHODS: We assessed the sensitivity of ovarian (OVCAR8) and uterine (ARK1) cancer cell lines to SQ1274 and paclitaxel using XTT assays. We used western blot and quantitative real-time PCR to analyze changes in AXL RNA and protein expression by SQ1274 and paclitaxel. Differences in cell-cycle arrest and apoptosis were investigated using flow cytometry. Finally, we treated ovarian and uterine xenograft models with vehicle, paclitaxel, or SQ1274. RESULTS: First, we demonstrate that SQ1274 has a much lower IC50 than paclitaxel in both ARK1 (1.26 nM vs. 15.34 nM, respectively) and OVCAR8 (1.34 nM vs. 10.29 nM, respectively) cancer cell lines. Second, we show SQ1274 decreases both RNA and protein expression of AXL. Third, we show that SQ1274 causes increased cell-cycle arrest and apoptosis compared to paclitaxel. Finally, we report that SQ1274 more effectively inhibits tumor growth in vivo compared to paclitaxel. CONCLUSIONS: SQ1274 presents as a viable alternative to paclitaxel for treating ovarian and uterine cancer. This study supports the development of SQ1274 as a chemotherapeutic to treat ovarian and uterine cancer.

Meaningful Change Scores in the Knee Injury and Osteoarthritis Outcome Score in Patients Undergoing Anterior Cruciate Ligament Reconstruction.

BACKGROUND: Meaningful change scores in the Knee injury and Osteoarthritis Outcome Score (KOOS) in patients undergoing anterior cruciate ligament (ACL) reconstruction have not yet been established. PURPOSE: To define the minimal important change (MIC) for the KOOS after ACL reconstruction. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 2. METHODS: KOOS and anchor questions with 7-point scales ranging from "better, an important improvement" to "worse, an important worsening" were completed postoperatively by randomly chosen participants from the Norwegian Knee Ligament Registry. Presurgery KOOS scores were retrieved from the registry. The MIC for improvement was calculated with anchor-based approaches using the predictive modeling method adjusted for the proportion of improved patients, the mean change method, and the receiver operating characteristic (ROC) method. RESULTS: Complete data for at least one of the KOOS subscales were obtained from 542 (45.3%) participants. Predictive modeling MIC values were 12.1 for the KOOS subscales of Sport and Recreational Function and 18.3 for Knee-Related Quality of Life. These values aid in interpreting within-group improvement over time and can be used as responder criteria when comparing groups. The corresponding and much lower values for the subscales of Pain (2.5), Symptoms (-1.2), and Activities of Daily Living (2.4) are the results from patients reporting, on average, only mild problems with these domains preoperatively. Although 4% to 10% of patients reported subscale-specific worsening, MIC deterioration calculations were not possible. The ROC MIC values were associated with high degrees of misclassification. Values obtained by the mean change method were considered less reliable because these estimates are derived from subgroups of patients. Average KOOS change scores were approximately similar for patients reporting acceptable symptoms postoperatively and patients reporting important improvements on the anchor items after surgery. CONCLUSION: KOOS users should apply subscale-specific cutoffs for meaningful improvement. Our results confirm using the subscales of Sport and Recreational Function and Knee-Related Quality of Life as primary patient-reported outcomes after ACL reconstruction. The predictive modeling approach gave the most robust estimates of MIC values. Our data suggest that reporting acceptable symptoms postoperatively corresponds to reporting an important improvement after ACL reconstruction.

Venous Thromboembolism in Patients Receiving Extended Pharmacologic Prophylaxis After Robotic Surgery for Endometrial Cancer.

OBJECTIVE: This study aims to determine the rate of postoperative venous thromboembolism (VTE) in endometrial cancer patients undergoing robotic hysterectomy with or without extended pharmacologic VTE prophylaxis. METHODS/MATERIALS: A retrospective chart review of women undergoing robotic hysterectomy with or without other procedures for endometrial cancer from January 2010 to February 2015 was conducted at 2 institutions. Charts were manually abstracted, and rates of VTE within 30 and 60 days after surgery were determined. Patients were then stratified by those who did and did not receive extended VTE prophylaxis. RESULTS: A total of 403 patients were included, of which 367 patients (91%) received extended pharmacologic prophylaxis and 36 patients (9%) did not. Low molecular weight heparin prescriptions ranged from 7 to 30 days. Patients receiving extended prophylaxis (EP) were older (63 ± 11 vs 57 ± 12; P = 0.004), more frequently underwent lymphadenectomy (67% vs 34%; P < 0.001), and had higher-grade tumors compared with patients not receiving EP. Overall 30-day and 60-day VTE rates were 0.7% and 1.2%, respectively. There were no significant differences in 30-day and 60-day VTE rates among patients that did and did not receive EP, although a trend toward lower VTE rates in the EP group was observed (30-day rates 0.5% vs 2.8% respectively, P = 0.25; 60-day rates 0.8% vs 5.6%, P = 0.07). CONCLUSIONS: In this study, 30-day and 60-day VTE rates after minimally invasive surgery for endometrial cancer were low. Rates were also similar to those of previous reports in this setting in which the majority of patients did not receive extended VTE prophylaxis. Given the consistent finding that postoperative VTE in this population is rare regardless of prophylaxis use and the variability in practice patterns for VTE prophylaxis, the development of best practice guidelines for EP use specific to this setting is warranted.

Association of Metformin Use with Outcomes in Advanced Endometrial Cancer Treated with Chemotherapy.

There is increasing evidence that metformin, a commonly used treatment for diabetes, might have the potential to be repurposed as an economical and safe cancer therapeutic. The aim of this study was to determine whether stage III-IV or recurrent endometrial cancer patients who are using metformin during treatment with chemotherapy have improved survival. To test this we analyzed a retrospective cohort of subjects at two independent institutions who received chemotherapy for stage III-IV or recurrent endometrial cancer from 1992 to 2011. Diagnosis of diabetes, metformin use, demographics, endometrial cancer clinico-pathologic parameters, and survival duration were abstracted. The primary outcome was overall survival. The final cohort included 349 patients, 31 (8.9%) had diabetes and used metformin, 28 (8.0%) had diabetes but did not use metformin, and 291 (83.4%) did not have diabetes. The results demonstrate that the median overall survival was 45.6 months for patients with diabetes who used metformin compared to 12.5 months for patients with diabetes who did not use metformin and 28.5 months for patients without diabetes (log-rank test comparing the three groups P = 0.006). In a model adjusted for confounders, the difference in survival between the three groups remained statistically significant (P = 0.023). The improvement in survival among metformin users was not explained by better baseline health status or more aggressive use of chemotherapy. Overall, the findings in this retrospective cohort of endometrial cancer patients with stage III-IV or recurrent disease treated with chemotherapy indicate that patients with diabetes who were concurrently treated with metformin survived longer than patients with diabetes who did not use metformin.

Examining the Minimal Important Difference of Patient-reported Outcome Measures for Individuals with Knee Osteoarthritis: A Model Using the Knee Injury and Osteoarthritis Outcome Score.

OBJECTIVE: To examine the influence of different analytical methods, baseline covariates, followup periods, and anchor questions when establishing a minimal important difference (MID) for individuals with knee osteoarthritis (OA). Second, to propose MID for improving and worsening on the Knee injury and Osteoarthritis Outcome Score (KOOS). METHODS: Retrospective analysis of prospectively collected data from 272 patients with knee OA undergoing a multidisciplinary nonsurgical management strategy. The magnitude and rate of change as well as the influence of baseline covariates were examined for 5 KOOS subscales over 52 weeks. The MID for improving and worsening were investigated using 4 anchor-based methods. RESULTS: Waitlisted for joint replacement and exhibiting unilateral/bilateral symptoms influenced change in KOOS over time. Generally, low correlations between anchors and KOOS change scores limited calculations of MID; thus, they were only proposed for the pain, activities of daily living, and quality of life subscales. The method used to calculate the MID influenced the cutpoint; however, the type of anchor question only influenced the MID when analyzed with a particular mean change method. Depending on patient and clinical characteristics, the subscale, and the analytical approach used, the MID for KOOS improvement ranged from an absolute change of -1.5 to 20.6 points and worsening ranged from -19.17 to 8.5 points. CONCLUSION: MID vary with patient and clinical characteristics, KOOS subscale, and analytical approach. Provided the anchor question is relevant to the patient-reported outcome and baseline status is considered, the anchor does not appear to influence the MID for improvement or worsening when using some anchor-based methods.

Hyperglycemia-induced metabolic compensation inhibits metformin sensitivity in ovarian cancer.

Increasing interest in repurposing the diabetic medication metformin for cancer treatment has raised important questions about the translation of promising preclinical findings to therapeutic efficacy, especially in non-diabetic patients. A significant limitation of the findings to date is the use of supraphysiologic metformin doses and hyperglycemic conditions in vitro. Our goals were to determine the impact of hyperglycemia on metformin response and to address the applicability of metformin as a cancer therapeutic in non-diabetic patients. In normoglycemic conditions, lower concentrations of metformin were required to inhibit cell viability, while metformin treatment in hyperglycemic conditions resulted in increased glucose uptake and glycolytic flux, contributing to cell survival. Mechanistically, maintenance of c-Myc expression under conditions of hyperglycemia or via gene amplification facilitated metabolic escape from the effects of metformin. In vivo, treatment of an ovarian cancer mouse model with metformin resulted in greater tumor weight reduction in normoglycemic vs. hyperglycemic mice, with increased c-Myc expression observed in metformin-treated hyperglycemic mice. These findings indicate that hyperglycemia inhibits the anti-cancer effects of metformin in vitro and in vivo. Furthermore, our results suggest that metformin may elicit stronger responses in normoglycemic vs. hyperglycemic patients, highlighting the need for prospective clinical testing in patients without diabetes.

Characterization of membrane receptor binding activity for cortisol in the liver and kidney of the euryhaline teleost, Mozambique tilapia (Oreochromis mossambicus).

Glucocorticoids (GCs) regulate an array of physiological responses in vertebrates. Genomic GC actions mediated by nuclear steroid receptors require a lag time on the order of hours to days to generate an appreciable physiological response. Experimental evidence has accumulated that GCs, can also act rapidly through a nongenomic mechanism to modulate cellular physiology in vertebrates. Causal evidence in the Mozambique tilapia (Oreochromis mossambicus) suggests that the GC cortisol exerts rapid, nongenomic actions in the gills, liver, and pituitary of this euryhaline teleost, but the membrane receptor mediating these actions has not been characterized. Radioreceptor binding assays were conducted to identify a putative GC membrane receptor site in O. mossambicus. The tissue distribution, binding kinetics, and pharmacological signature of the GC membrane-binding activity were characterized. High affinity (Kd=9.527±0.001 nM), low-capacity (Bmax=1.008±0.116 fmol/mg protein) [(3)H] cortisol binding was identified on plasma membranes prepared from the livers and a lower affinity (Kd=30.08±2.373 nM), low capacity (Bmax=4.690±2.373 fmol/mg protein) binding was found in kidney membrane preparations. Competitors with high binding affinity for nuclear GC receptors, mifepristone (RU486), dexamethasone, and 11-deoxycorticosterone, displayed no affinity for the membrane GC receptor. The association and dissociation kinetics of [(3)H] cortisol binding to membranes were orders of magnitude faster (t1/2=1.7-2.6 min) than those for the intracellular (nuclear) GC receptor (t1/2=10.2h). Specific [(3)H] cortisol membrane binding was also detected in the gill and pituitary but not in brain tissue. This study represents the first characterization of a membrane GC receptor in fishes and one of only a few characterized in vertebrates.