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Objective: Enhanced recovery pathways have been shown to reduce length of stay without increasing readmission or complications in numerous areas of surgery. Uptake of gynecologic oncology ERAS guidelines has been limited. We describe the effect of ERAS guideline implementation in gynecologic oncology on length of stay, patient outcomes, and economic impact for a province-wide single-payer system., Methods: We compared pre- and post-guideline implementation outcomes in consecutive staging and debulking patients at two centers that provide the majority of surgical gynecologic oncology care in Alberta, Canada between March 2016 and April 2017. Clinical outcomes and compliance were obtained using the ERAS Interactive Audit System. Patients were followed until 30 days after discharge. Negative binomial regression was employed to adjust for patient characteristics., Results: We assessed 152 pre-ERAS and 367 post-ERAS implementation patients. Mean compliance with ERAS care elements increased from 56% to 77.0% after implementation (p < 0.0001). Median length of stay for all surgeries decreased from 4.0 days to 3.0 days post-ERAS (p < 0.0001), which translated to an adjusted LOS decrease of 31.4% (95% CI = [21.7% - 39.9%], p < 0.0001). In medium/high complexity surgery median LOS was reduced by 2.0 days (p = 0.0005). Complications prior to discharge decreased from 53.3% to 36.2% post-ERAS (p = 0.0003). There was no significant difference in readmission (p = 0.6159), complications up to 30 days (p = 0.6274), or mortality (p = 0.3618) between the cohorts. The net cost savings per patient was $956 (95%CI: $162 to $1636)., Conclusions: Systematic implementation of ERAS gynecologic oncology guidelines across a healthcare system improves patient outcomes and saves resources., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To evaluate patient-reported outcomes (PROs) between women treated by laparoscopic, robotic and open approaches for endometrial cancer., Methods: Prospective cohort study comparing PRO at baseline, short- (1 and 3 weeks) and long-term (12 and 24 weeks) follow-up postoperatively. Quality of life (QOL) measures were the Functional Assessment of Cancer Therapy (FACT-G), EuroQol Five Dimensions (EQ-5D), and Brief Pain Inventory (BPI). Sexual health measures were the Female Sexual Function Index (FSFI) and the Sexual Adjustment and Body Image Scale for Gynecologic Cancer (SABIS-G)., Results: 468 eligible patients (laparotomy = 92, laparoscopy = 152, robotic = 224) were recruited. There were no significant differences between the laparoscopy and robotic groups for any PRO (P > 0.05). At short-term follow-up, patients who underwent minimally invasive surgery (robotic or laparoscopy) had significantly higher FACT-G (P < 0.0001) and EQ-5D (P < 0.0001) scores, with less pain (P = 0.02) and improved pain interference (P = 0.0008), than patients undergoing laparotomy. At long-term follow-up, there were sustained improvements in the FACT-G (P = 0.035) and the health state EQ-5D visual analogue scale (P = 0.022). Surgical approach had no impact on sexual health (P > 0.05); however the mean FSFI score for the entire cohort met clinical cut-offs for sexual dysfunction., Conclusion: Minimally invasive approaches result in improved QOL beyond the short-term postoperative period, with benefits noted up to 12 weeks after surgery. This prolonged QOL advantage provides further evidence that MIS should be the standard surgical approach for women with early stage endometrial cancer., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Meta-analyses report a null association between recent alcohol consumption and ovarian cancer risk. However, because few studies investigated different types of alcohol over adult ages, we investigated adult lifetime and type (beer, wine, spirits) of consumption and risk., Methods: Consumption after age 20years was ascertained in 1144 invasive epithelial ovarian cancer cases and 2513 controls in a population-based case-control study (Alberta and British Columbia, Canada, 2001-2012). Non-drinkers consumed any types of alcohol <12 times per year on average. Logistic regression was use to estimate adjusted odds ratios [aOR] and 95% confidence intervals [CIs]., Results: Wine consumption was associated with a risk reduction (aOR=0.67, 95% CI: 0.50-0.88) relative to non-drinkers, but not beer (aOR=1.06, 95% CI: 0.71-1.58) or spirits (aOR=0.98, 95% CI: 0.69-1.39). The reduced risk was stronger for exclusive red wine drinkers (aOR=0.44, 95% CI: 0.19-0.92) than white wine drinkers (aOR=0.79, 95% CI: 0.46-1.34), although most women drank both types of wine. Risk decreased with increasing cumulative consumption of any wine (P-trend<0.05) and was evident for the serous histotype. Wine consumption initiated prior to age 50 was associated with a risk reduction (e.g., at 40-49years, aOR=0.58, 95% CI: 0.42-0.78), but not drinking initiated after 50years of age. For any type, level, or age at initiation of alcohol consumption, we found no increased risks., Conclusions: For the moderate consumption in this study, higher levels of wine consumption were generally associated with risk reductions; reductions may be stronger for red wine. Our results suggest that alcohol consumption that is guideline concordant will not increase epithelial ovarian cancer risk., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Tobacco smoking by cancer patients is associated with increased mortality. Less is known of the impact of smoking on recurrence risk and interaction with chemotherapy treatment. We examined these associations in ovarian cancer., Methods: Patients were identified from the Alberta Cancer Registry between 1978 and 2010 and were oversampled for less-common histologic ovarian tumor types. Medical records were abstracted for 678 eligible patients on lifestyle, medical and cancer treatment, and review of pathology slides was performed for 605 patients. We estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazard models adjusted for age at diagnosis, race, stage and residual disease., Results: Among patients receiving adjuvant chemotherapy (N=432), current smoking was significantly associated with shorter duration of overall (OS; HR, 8.56; 95% CI, 1.50-48.7) and progression-free (PFS; HR, 5.74; 95% CI, 1.05-31.4) survival from mucinous ovarian cancer only. There was no significant association between neoadjuvant chemotherapy and survival. However, among patients receiving neoadjuvant chemotherapy (N=44), current smokers had shorter PFS (HR, 4.32; 95% CI, 1.36-13.8; N=32 progressed/9 censored events) compared to never smokers, but the HRs were not statistically different across smoking categories (P interaction=0.87)., Conclusions: Adverse associations were observed between smoking status and OS or PFS among patients with mucinous ovarian cancer receiving adjuvant chemotherapy. No significant effect was found from neoadjuvant chemotherapy on PFS overall; however, smoking may modify this association. Although needing replication, these findings suggest that patients may benefit from smoking cessation interventions prior to treatment with chemotherapy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Resistance to platinum-based therapeutic agents represents a major hurdle in the treatment of epithelial ovarian cancer (EOC). There is an urgent need to better understand the underlying mechanisms. Here, we investigated the role of RUNX3 in carboplatin resistance in EOC cells., Methods: Expression of RUNX3 was determined in human EOC cell line A2780s (cisplatin-sensitive) and A2780cp (cisplatin-resistant), human ovarian surface epithelium (OSE) and primary EOC cells. The effects of RUNX3 expression on sensitivity to carboplatin were determined in A2780s and A2780cp cells using neutral red uptake and clonogenic assays. Carboplatin-induced apoptosis was determined by measuring cleaved PARP using Western blotting. The expression of cellular inhibitor of apoptosis protein-2 (cIAP2) and its regulation by RUNX3 were assessed by quantitative RT-PCR and Western blotting., Results: The expression of RUNX3 was elevated in A2780cp cells compared to A2780s cells and in EOC tissues from chemoresistant patients compared to those from chemosensitive patients. Overexpression of RUNX3 rendered A2780s cells more resistant to carboplatin, whereas inhibition of RUNX3 increased sensitivity to carboplatin in A2780cp cells. Inhibition of RUNX3 potentiated carboplatin-induced apoptosis in A2780cp cells as demonstrated by more pronounced PARP cleavage. Interestingly, the expression of cIAP2 was elevated in A2780cp cells compared to A2780s cells. Overexpression of RUNX3 increased cIAP2 expression in A2780s cells, whereas inhibition of RUNX3 decreased cIAP2 expression and potentiated carboplatin-induced decrease of cIAP2 in A2780cp cells., Conclusions: RUNX3 contributes to carboplatin resistance in EOC cells and may hold promise as a therapeutic target to treat EOC and/or a biomarker to predict chemoresistance., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Notch3 is implicated in chemoresistance of ovarian cancer, yet the molecular mechanism underlying Notch3-mediated drug resistance remains to be elucidated. Here, we investigated the role of Notch3 in carboplatin-induced apoptosis in ovarian cancer cells., Methods: Ovarian cancer cell line OVCA429 cells were stably transduced with an empty vector or a retroviral vector expressing the Notch3 intracellular domain (NICD3, the constitutively active form of Notch3) to generate OVCA429/vector and OVCA429/NICD3 cells. Epithelial-mesenchymal transition (EMT) was determined by morphological change and expression of the EMT markers. Carboplatin-induced cytotoxicity was determined by the neutral red uptake assay. Apoptosis was determined by Annexin V staining and Western blotting. Carboplatin-induced phosphorylation of extracellular signal-regulated kinase (ERK) was identified by a phospho-kinase array and confirmed by Western blotting., Results: Activation of Notch3 in OVCA429 cells causes a spindle and fibroblast-like morphology, induces the expression of smooth muscle α-actin, Slug and Snail, but decreases the expression of E-cadherin, indicating that Notch3 activation induces EMT in OVCA429 cells. Furthermore, Notch3 activation renders OVCA429 cells more resistant to carboplatin-induced cytotoxicity and attenuates carboplatin-induced apoptosis in these cells. Our results indicate that phosphorylation of ERK is a positive regulator of carboplatin-induced apoptosis in OVCA429 cells. Interestingly, carboplatin-induced ERK phosphorylation is inhibited by Notch3 activation., Conclusions: Notch3 activation induces EMT and attenuates carboplatin-induced apoptosis in OVCA429 cells. ERK phosphorylation plays a pro-apoptotic role in carboplatin-induced apoptosis in OVCA429 cells. Interestingly, Notch3 activation attenuates carboplatin-induced ERK phosphorylation in these cells., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: The objective of this study is to examine the outcomes of combined chemotherapy using methotrexate and dactinomycin in the management of women with low-risk gestational trophoblastic neoplasia (GTN). The primary outcome is the total number of cycles of chemotherapy required to achieve a normal level of human chorionic gonadotropin (hCG). The secondary outcome is treatment-related toxicity., Methods: A retrospective chart review of all patients with GTN treated between 1996-2007 and 1991-2007 was performed at the Alberta Cross Cancer Institute and the British Columbia Cancer Agency, respectively. Patients with low-risk GTN, treated with 0.6 mg/m(2) dactinomycin (days 1 and 2) and methotrexate 100mg/m(2) were included. Toxicities were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events. The number of cycles to achieve normalization of hCG was determined, and multivariate analyses were performed to identify factors associated with treatment duration., Results: One hundred women were eligible. The average age was 29 years (range 15-46). The median number of cycles to achieve a normal hCG was 3 (range 1-11). Two patients required second-line treatment and one patient chose to proceed with hysterectomy. Ninety-eight percent of patients were primarily cured with this regimen, and 2 were cured with second line treatment. Grade 3 and 4 hematologic toxicities were experienced by 12% and 8% of patients, respectively. Grade 2 and 3 stomatitis or mucositis were noted in 44% and 3% of patients, respectively., Conclusions: Low-risk GTN is reliably and rapidly cured with combined methotrexate-dactinomycin. Toxicity is modest., (Copyright © 2011. Published by Elsevier Inc.)

Objectives: To estimate the prevalence of physical activity in ovarian cancer survivors and to determine if there is a dose-response relationship between physical activity and quality of life., Methods: Ovarian cancer survivors identified from a Canadian provincial cancer registry were mailed a questionnaire measuring self-reported leisure time physical activity (Godin Leisure Time Exercise Questionnaire), cancer-specific quality of life (Functional Assessment of Cancer Therapy-Ovarian), and standard demographic and medical variables., Results: Completed questionnaires were received from 359 (51.4%) participants. Analyses indicated that 31.1% were meeting public health physical activity guidelines (i.e., at least 60 min of strenuous or 150 min of moderate/strenuous physical activity per week). Comparisons using different volumes of physical activity showed support for the current guidelines. Specifically, participants meeting current physical activity guidelines reported significantly better quality of life than those not meeting guidelines [mean difference: 12.5; 95% CI: 9.1 to 16.0; p<0.001; d=0.75]. Disease status was the only variable to moderate this association. Adjusting for important demographic and medical variables did not alter the findings., Conclusions: Few ovarian cancer survivors are meeting public health physical activity guidelines, but those that are meeting guidelines report significantly and meaningfully better quality of life. Clinical trials investigating the causal effects of physical activity on quality of life in ovarian cancer survivors are warranted.

Objective: To determine the incidence of parametrial involvement in clinical stage IA and IB1 cervical cancer and whether pelvic lymph node status is a predictor of parametrial status., Methods: Retrospective review of 120 patients with FIGO stage IA/IB1 cervical carcinoma treated by class II radical abdominal hysterectomy between January 1997 and December 2001 was performed. The parametria were examined for microscopic involvement of parametrial lymph nodes and/or tissue. Continuous variables were compared using Wilcoxon rank sum test, and Fisher's exact test was used to categorical variables. Kaplan-Meier curves were constructed for overall survival (OS) and recurrence-free survival (RFS). Cox proportional hazards model was used to investigate prognostic factors., Results: One hundred ten patients were eligible. Five patients (5%) had positive parametria and 13 patients (12%) had positive pelvic lymph nodes. Four (80%) patients with positive parametria had positive pelvic lymph nodes. The groups did not differ significantly in terms of age (P = 0.92), histology (P = 0.15), or LVSI (P = 0.20). Positive parametria was associated with larger tumor size (3.0 vs. 2.0 cm, P < 0.05), greater depth of invasion (16 mm vs. 5 mm, P = 0.03), and pelvic lymph node metastases (80% vs. 10%, P = 0.001). The only variable that was significant in the proportional hazards model was lymph node status (P = 0.02). After median follow-up of 48 months, there was a significant difference in recurrence (40% vs. 4%, P = 0.03) and RFS (0.0003)., Conclusions: Acknowledging small sample size and retrospective study, positive parametrial involvement in stage IA and IB1 cervical cancer is infrequent. There is a significant association with lymph node status. Thus, there may be a role for less radical surgery combined with pelvic lymphadenectomy in this patient population.

Objectives: The aim of this study was to compare peri-operative morbidity and recurrence-free survival of early-stage cervical cancer patients treated by laparoscopic-assisted radical vaginal hysterectomy (LARVH) with time-matched radical abdominal hysterectomy (RAH) controls at our center., Methods: Since July 1984, all patients with FIGO stage IA/IB cervical cancer undergoing radical surgery by members of our division have been entered into a prospective database. Since November 1996, one surgeon at our center has performed LARVH on all surgically appropriate patients. Non-parametric tests were used. Differences between medians were compared using Wilcoxon Rank Sum test. Statistical analysis used the Kaplan-Meier method to calculate disease-free survival. Differences between survival curves were compared with the log rank test. Statistical significance was defined as P < 0.05., Results: Between November 1996 and December 2003, 71 and 205 patients have undergone LARVH and RAH, respectively, for FIGO stage IA/IB carcinoma of the cervix. Both groups were similar with respect to age and Quetelet index. There were no differences in tumor size, histology, grade, depth of invasion, lymph node metastases, or surgical margins. All laparoscopic procedures were completed successfully with no conversions to laparotomy. Intra-operative morbidity characteristics analyzed (LARVH vs. RAH) were blood loss 300 ml vs. 500 ml (P < 0.001), operative time 3.5 h vs. 2.5 h (P < 0.001), and intra-operative complications 13% vs. 4% (P < 0.03). Intra-operative complications in the LARVH group included: cystotomy (7), ureteric injury (1), and bowel injury (1). There was no difference in transfusion rates. There was no difference between post-operative infectious and non-infectious complications (LARVH vs. RAH), 9% vs. 5% and 5% vs. 2%, respectively. The median time to normal urine residual was 10 days vs. 5 days (P < 0.001), and the median length of hospital stay was 1 day vs. 5 days (P < 0.001). Twenty-two percent of patients received post-operative radiotherapy for high-risk features in both groups. After a median follow-up of 17 and 21 months, there have been 4 recurrences in the LARVH group and 13 in the RAH (P = NS). The overall 2-year recurrence-free survival was 94% and 94% in the LARVH and RAH groups, respectively (P = NS)., Conclusion: Our data demonstrate that early cervical cancer can be treated successfully with LARVH with similar efficacy and recurrence rates to RAH. The major benefits are less intra-operative blood loss and shorter hospital stay. It is a safe procedure with low overall morbidity and complication rates. However, at present, LARVH is associated with an increase in intra-operative complications, and patients may have an increased time to return to normal bladder function.