Predicting non-home discharge in epithelial ovarian cancer patients: External validation of a predictive model.

OBJECTIVE: To externally validate a model predicting non-home discharge in women undergoing primary cytoreductive surgery (CRS) for epithelial ovarian cancer (EOC). METHODS: Women undergoing primary CRS via laparotomy for EOC at three tertiary medical centers in an academic health system from January 2010 to December 2015 were included. Patients were excluded if they received neoadjuvant chemotherapy, had a non-epithelial malignancy, were not undergoing primary cytoreduction, or lacked documented model components. Non-home discharge included skilled nursing facility, acute rehabilitation facility, hospice, or inpatient death. The predicted probability of non-home discharge was calculated using age, pre-operative CA-125, American Society of Anesthesiologists (ASA) score and Eastern Cooperative Oncology Group (ECOG) performance status as described in the previously published predictive model. Model discrimination was calculated using a concordance index and calibration curves were plotted to characterize model performance across the cohort. RESULTS: A total of 204 admissions met inclusion criteria. The overall rate of non-home discharge was 12% (95% CI 8-18%). Mean age was 60.8 years (SD 11.0). Median length of stay (LOS) was significantly longer for patients with non-home discharge (8 vs. 5 days, P < 0.001). The predictive model had a concordance index of 0.86 (95% CI 0.76-0.93), which was similar to model performance in the original study (CI 0.88). The model provided accurate predictions across all probabilities (0 to 100%). CONCLUSIONS: Non-home discharge can be accurately predicted using preoperative clinical variables. Use of this validated non-home discharge predictive model may facilitate preoperative patient counseling, early discharge planning, and potentially decrease cost of care.

Intestinal Surgery in Gynecologic Oncology: Are We Training for the Future?

OBJECTIVE: The objective of this study was to assess the scope of intestinal surgery training across gynecologic oncology fellowships in the United States and identify factors associated with perceived preparedness to perform intestinal surgery independently. MATERIALS/METHODS: An institutional review board-approved survey was distributed to Society of Gynecologic Oncology fellows and candidate members within the first 3 years of practice. Questions addressed demographics, operative experience, preparedness and plans for performing intestinal surgery, and attitudes toward gynecologic oncologists (GOs) performing intestinal surgery. Responses were analyzed using descriptive statistics as well as univariate and multivariate analyses. RESULTS: Of 374 Society of Gynecologic Oncology members invited, 108 (29%) responded, including 38 fellows (35%) and 53 recent graduates (49%). Fifteen (14%) reported more than 3 years of practice and were excluded. Most participants (96%) received intestinal surgery training from GOs, and 64% reported that all faculty routinely performed intestinal surgery. Most participants (81%) believed GOs should perform intestinal procedures, whereas only 58% felt prepared and 59% planned to perform intestinal procedures independently. Fellows who performed more than 10 intestinal diversion procedures, participated directed in intestine-related intraoperative consultations, or reported that all faculty performed intestinal surgery were more likely to feel prepared to perform intestinal surgery independently. Sex, training region, intended practice environment, and fellowship curriculum were not associated with preparedness to perform intestinal surgery. CONCLUSIONS: Almost half of gynecologic oncology fellows and recent graduates in the United States do not feel prepared to perform intestinal procedures independently after fellowship. Increased volume and direct involvement of fellows in intestinal surgery may improve preparedness for performing intestinal surgery after fellowship.

Obesity risk awareness in women with endometrial cancer.

PURPOSE: To assess whether women with endometrial cancer could accurately classify their weight and identify the association between obesity and risk of endometrial, breast, and colon cancers. METHODS: This was an IRB-approved (Project No. 14-0075), survey-based cross-sectional study of women ages 18-80 years with a diagnosis of endometrial cancer. Patients were at least 6 months from hysterectomy and 3 months from chemotherapy or radiation. Statistical analysis was completed using Fisher's exact test, T test, ANOVA, Wilcoxon rank-sum test, or Kruskal-Wallis test. P values were two-tailed with P < 0.05 considered statistically significant. RESULTS: 140 women met inclusion criteria, and 133 questionnaires (95.0%) were completed. Mean age was 63.2 years (range 35-80), and mean BMI was 33.4 kg/m2 (range 17.6-72.2). Patients were primarily Caucasian (88.7%) and reported education beyond high school (67.8%). Among women with BMI 30.0-34.99 kg/m2, 12.9% perceived themselves as obese, compared to 32.0% of women with BMI 35.0-39.99 kg/m2, and 72.7% of women with BMI >40.0 kg/m2. Ability to correctly classify weight correlated significantly with education level (P = 0.02). Less than half of women identified obesity as a risk factor for breast (49.6%), colon (48.1%), and endometrial cancer (44.4%). 77% of all patients had discussed weight with their primary care doctor, and 38% had discussed weight with their oncologist (P < 0.001). CONCLUSIONS: The majority of obese women with endometrial cancer surveyed were unable to accurately classify their weight. Given the inconsistency between patient weight and perception of cancer risk, this represents an opportunity for gynecologic oncologists to educate their patients about weight control.

Effects of Repetition and Inactivity on Laparoscopic Skills Training.

STUDY OBJECTIVE: To describe the impact of task repetition and time between practice sessions on time to complete a surgical task using a high-fidelity laparoscopic simulator. DESIGN: An Institutional Review Board-approved retrospective cohort study of 33 obstetrics/gynecology residents with unlimited access to a high-fidelity laparoscopic simulator over a period of 12 months. Canadian Task Force design classification II-2. SETTING: Academic medical center and obstetrics/gynecology residency training program. PARTICIPANTS: Obstetrics/gynecology residents. INTERVENTIONS: Participation in a high-fidelity laparoscopic training exercise. MEASUREMENTS: Residents completed a standardized peg transfer exercise with data collected on the time to completion of the exercise, number of the attempt, and interval since the last day of practice. Data were analyzed using Spearman correlation coefficients and mixed-effects linear regression. MAIN RESULTS: A total of 33 residents participated during the 12-month period, completing 484 peg transfer exercises (mean, 16.2 per resident). Each repetition was correlated with a mean decrease in time to completion of 2.28 seconds (p < .0001). This correlation was most dramatic in the first 9 completed exercises, in which each repetition correlated with a decrease in time to complete of 7.98 seconds (p ≤ .0001). The lapse in practice preceding the exercise correlated with a negligible change in time to completion of 0.003 second (SD, 0.06; p = .90). CONCLUSION: The number of previous completed exercises was significantly correlated with decreased time to completion of this standardized exercise. Lapses in practice did not correlate with slower times to completion, suggesting that repetitive exposure to a simple surgical task has a greater impact on efficiency than lapse in practice.

Women 50 years or younger with endometrial cancer: the argument for universal mismatch repair screening and potential for targeted therapeutics.

OBJECTIVE: To identify young patients with endometrial cancer with potential Lynch-related DNA mismatch repair (MMR) protein expression defects and stathmin (STMN1) expression (part of the phosphoinositol 3-kinase pathway) and to correlate clinical data. METHODS: This retrospective study included women with endometrial cancer who were 50 years or younger at diagnosis. Clinical data were abstracted from chart review. Immunohistochemistry for MMR protein expression, STMN1, and pSTMN1 was performed and univariate analyses performed. RESULTS: The mean age of 111 patients was 43 years, and the mean body mass index was 39.6 kg/m². The majority of the endometrial cancers were endometrioid histology (87.4%), International Federation of Gynecology and Obstetrics stage I (73%) and grade 1 (58.6%). Loss of at least one MMR protein on immunohistochemistry was identified in 26% to 41% of patients depending on stringency. Women with loss of MMR protein expression were compared to women with intact tumor protein expression and were less likely to be stage I (58.6% vs 78.0%; P = 0.043), more likely to have grade 3 tumors (32.1% vs 13.9%; P = 0.034), had larger tumors (6.2 vs 3.7 cm; P < 0.001), had positive lymph nodes more often (24.1% vs 3.7%; P < 0.001), and more often reported a first-degree relative with colon cancer (17.2% vs 1.2%; P < 0.001). There were no significant differences in age, weight, body mass index, medical comorbidities, recurrence, or survival. Women with high STMN1 staining had significantly more grade 3 tumors (56.3% vs 15.8%; P = 0.001), more stage III/IV disease (37.5% vs 15.8%; P = 0.04), had higher mean percentage of myometrial invasion (38.9% vs 16.7%; P = 0.003), and more lymphovascular space invasion (43.8% vs 13.7%; P = 0.004). CONCLUSIONS: Clinical factors failed to differentiate between patients with intact or missing MMR protein expression, which supports universal screening for Lynch-associated protein defects in young women with endometrial cancer. Additionally, STMN1 staining may identify more aggressive tumors, which might benefit from more aggressive treatments or targeted treatment options.

Pretreatment with LCK inhibitors chemosensitizes cisplatin-resistant endometrioid ovarian tumors.

BACKGROUND: Ovarian cancer is the most fatal gynecologic malignancy in the United States. While chemotherapy is effective in the vast majority of ovarian cancer patients, recurrence and resistance to standard systemic therapy is nearly inevitable. We discovered that activation of the non-receptor tyrosine kinase Lymphocyte Cell-Specific Protein-Tyrosine Kinase (LCK) promoted cisplatin resistance. Here, we hypothesized that treating high grade, platinum resistant endometrioid cancer cells with an LCK inhibitor (LCKi) followed by co-treatment with cisplatin would lead to increased cisplatin efficacy. Our objective was to assess clinical outcomes associated with increased LCK expression, test our hypothesis of utilizing LCKi as pre-treatment followed by co-treatment with cisplatin in platinum resistant ovarian cancer in vitro, and evaluate our findings in vivo to assess LCKi applicability as a therapeutic agent. RESULTS: Kaplan-Meier (KM) plotter data indicated LCK expression is associated with significantly worse median progression-free survival (HR 3.19, p = 0.02), and a trend toward decreased overall survival in endometrioid ovarian tumors with elevated LCK expression (HR 2.45, p = 0.41). In vitro, cisplatin resistant ovarian endometrioid cells treated first with LCKi followed by combination LCKi-cisplatin treatment showed decreased cell viability and increased apoptosis. Immunoblot studies revealed LCKi led to increased expression of phosphorylated H2A histone family X ([Formula: see text]-H2AX), a marker for DNA damage. In vivo results demonstrate treatment with LCKi followed by LCKi-cisplatin led to significantly slowed tumor growth. CONCLUSIONS: We identified a strategy to therapeutically target cisplatin resistant endometrioid ovarian cancer leading to chemosensitization to platinum chemotherapy via treatment with LCKi followed by co-treatment with LCKi-cisplatin.

Thy-1 predicts poor prognosis and is associated with self-renewal in ovarian cancer.

BACKGROUND: Ovarian cancer is the leading cause of gynecologic cancer death in the United States despite effective first-line systemic chemotherapy. Cancer stem cells (CSCs) retain the ability to self-renew and proliferate and may be a means of harboring disease that evades standard treatment strategies. We previously performed a high-throughput screen to assess differential protein expression in ovarian CSCs compared to non-CSCs and observed that Thy-1 was more highly expressed in CSCs. Our primary aim was to validate Thy-1 (CD90) as a cancer stem cell (CSC) marker in epithelial ovarian cancer (EOC), correlate with clinical outcomes, and assess as a potential therapeutic target. RESULTS: Kaplan Meier (KM) Plotter data were correlated with survival outcomes. Quantitative real-time PCR, flow cytometry, and immunoblots assessed RNA and protein expression. Limiting dilution assays assessed self-renewal capacity and proliferation assays assessed proliferative capacity. RNA in-situ hybridization was performed on patient specimens to assess feasibility. Thy-1 (CD90) is more highly expressed in ovarian CSCs than non-CSCs, in EOC compared to benign ovarian epithelium (P < 0.001), and is highest in serous EOC (P < 0.05). Serous ovarian cancers with high Thy-1 expression have poorer outcomes (median PFS 15.8 vs. 18.3 months, P = 0 < 0.001; median OS 40.1 v. 45.8 months, P = 0.036). Endometrioid ovarian cancers with high Thy-1 have poorer PFS, but no difference in OS (upper quartile PFS 34 v. 11 months, P = 0.013; quartile OS not reached, P = 0.69). In vitro, Thy-1 expression is higher in CSCs versus non-CSCs. EOC cells with high Thy-1 expression demonstrate increased proliferation and self-renewal. Thy-1 knockdown in EOC cells decreases proliferative capacity and self-renewal capacity, and knockdown is associated with decreased expression of stem cell transcription factors NANOG and SOX2. RNA in situ hybridization is feasible in ovarian cancer tissue specimens. CONCLUSIONS: Thy-1 is a marker of ovarian CSCs. Increased expression of Thy-1 in EOC predicts poor prognosis and is associated with increased proliferative and self-renewal capacity. Thy-1 knockdown decreases proliferative and self-renewal capacity, and represents a potential therapeutic target.

Management Strategies for Recurrent Endometrial Cancer.

INTRODUCTION: Endometrial cancer is the most common gynecologic malignancy in the developed world, and its incidence is increasing. Mortality from this cancer has not improved in recent decades and is primarily driven by high-grade carcinomas that are more likely to present at an advanced stage and ultimately are more likely to recur. The prognosis for recurrent endometrial cancer is poor, especially for the 50% of these women that present with extrapelvic disease recurrence. As a standard of care, recurrent disease has been treated with platinum-based chemotherapy; however, new therapies are emerging as we identify drivers of proliferation and metastasis at the cellular and molecular levels. Areas Covered: We review currently available data for the management of recurrent endometrial cancer, with a focus on systemic treatment of recurrent disease. We discuss the available evidence for first-line, second-line, and subsequent systemic therapy and discuss emerging therapeutic targets including their biologic plausibility and early clinical data. Expert Commentary: Endometrial cancer, though prevalent, remains underfunded and understudied. Recurrent and metastatic disease remains difficult to treat, and prospective randomized data are limited. Our ability to reduce mortality due to this cancer is dependent on identifying new and effective therapeutic strategies for recurrent disease.