Improving 30-day mortality after PEG tube placement in England from 2007 to 2019: a retrospective national cohort analysis of 87,862 patients.

BACKGROUND AND AIMS: PEG has been associated with poor case selection and high mortality. We examined indications, 30-day mortality, and 7-day adverse events in a national cohort undergoing PEG tube insertion. METHODS: Adult patients undergoing their first PEG tube insertion from 2007 to 2019 were identified in the Hospital Episode Statistics database. Indications and adverse events were identified using International Statistical Classification of Diseases and Related Health Problems, 10th Revision codes. Multivariable logistic regression modeling examined factors associated with mortality. RESULTS: Of 87,682 patients identified, 58% were men and median age was 69 years (interquartile range, 57-79). The number of patients with dementia or stroke as the indication for PEG fell from 2007 to 2019 (dementia, from 147 to 28 [P < .001]; stroke, from 2851 to 1781 [P < .001]). The median interval from stroke admission to PEG tube insertion increased from 21 (interquartile range, 12-36) to 28 (interquartile range, 13-45) days (P < .001). Aspiration pneumonia within 7 days of PEG fell from 10.2% to 8.6% (P = .04). Thirty-day mortality fell from 13.2% to 5.3% (P < .001), with associated factors of increasing age (≥82 years quintile odds ratio [OR], 4.44; 95% confidence interval [CI], 4.01-4.92), PEG tube insertion during emergency admission (OR, 2.10; 95% CI, 1.97-2.25), Charlson comorbidity score ≥5 (OR, 1.67; 95% CI, 1.53-1.82), and dementia (OR, 1.46; 95% CI, 1.26-1.71). Female sex (OR, .81; 95% CI, .77-.85), least-deprived quintile (OR, .88; 95% CI, .81-.95), and more recent years of PEG tube insertion (2019; OR, .44; 95% CI, .39-.51) were negatively associated with mortality. CONCLUSIONS: Thirty-day mortality after PEG tube insertion has fallen 60% over 13 years. Dementia or stroke as an indication for PEG fell, and the time interval from stroke to PEG tube insertion increased. These findings may be attributable to improved patient selection and timing for PEG tube insertion.

A prospective comparison of costs between robotics, laparoscopy, and laparotomy in endometrial cancer among women with Class III obesity or higher.

BACKGROUND AND OBJECTIVES: To compare the immediate operating room (OR), inpatient, and overall costs between three surgical modalities among women with endometrial cancer (EC) and Class III obesity or higher. METHODS: A multicentre prospective observational study examined outcomes of women, with early stage EC, treated surgically. Resource use was collected for OR costs including OR time, equipment, and inpatient costs. Median OR, inpatient, and overall costs across surgical modalities were analyzed using an Independent-Samples Kruskal-Wallis Test among patients with BMI ≥ 40. RESULTS: Out of 520 women, 103 had a BMI ≥ 40. Among women with BMI ≥ 40: median OR costs were $4197.02 for laparotomy, $5524.63 for non-robotic assisted laparoscopy, and $7225.16 for robotic-assisted laparoscopy (p < 0.001) and median inpatient costs were $5584.28 for laparotomy, $3042.07 for non-robotic assisted laparoscopy, and $1794.51 for robotic-assisted laparoscopy (p < 0.001). There were no statistically significant differences in the median overall costs: $10 291.50 for laparotomy, $8412.63 for non-robotic assisted laparoscopy, and $9002.48 for robotic-assisted laparoscopy (p = 0.185). CONCLUSION: There was no difference in overall costs between the three surgical modalities in patient with BMI ≥ 40. Given the similar costs, any form of minimally invasive surgery should be promoted in this population.

The impact of treatment with bile acid sequestrants on quality of life in patients with bile acid diarrhoea.

BACKGROUND: Bile acid diarrhoea (BAD) can be severely debilitating and negatively affect patients' quality of life (QoL). We carried out a multi-centre prospective study exploring QoL outcomes in patients with BAD after treatment with colesevelam. METHODS: Patients with or without a positive 23-seleno-25-homotaurocholic acid (SeHCAT) scan were recruited and categorised into four groups: SeHCAT negative control group (CG), idiopathic BAD, post-cholecystectomy (PC) and post-terminal ileal resection for Crohn's disease (CD). Patients with a positive SeHCAT were treated with colesevelam and dosing was titrated to symptomatic response. Patients were reviewed at 4- and 8-weekly intervals and QoL was evaluated by EQ-5D-3L, SF-36, IBDQ-32 at each visit (where relevant). Patients with a negative SeHCAT (CG cohort) completed one set of questionnaires before being discharged from the study. RESULTS: 47 patients (BAD = 24, PC = 12, CD = 11) completed paired QoL questionnaires before and after treatment and 30 CG patients completed a baseline questionnaire. There was a significant improvement in IBDQ-32 mean scores before and after treatment in CD patients [134.6 (95%CI 112.5-156.6) and 158.4 (136.1-180.6), respectively (p = 0.007). Following treatment, BAD patients had significantly improved mean SF-36 scores in the "Role limitation due to physical health" dimension (p = 0.02) and in the overall mental component summary (p = 0.03). Prior to starting treatment, BAD patients had the lowest scores in the 'activity' dimension of the EQ-5D-3L (p = 0.04), which improved significantly after treatment (p = 0.002). Overall, the BAD and CD cohort showed improved mean scores with treatment in all components of the SF-36 and EQ-5D-3L, while the PC cohort showed a general decline in mean scores after treatment. 55% of patients clinically responded to treatment of which 41.7%, 58.3% and 81.8% responded from the BAD, PC and CD groups respectively. Correlations between those deemed as responders with improvements on the SF-36 and EQ-5D dimensions were not statistically significant. CONCLUSION: Our results demonstrate improved QoL in the BAD and CD cohort with treatment. Further larger studies are recommended specifically investigating the PC cohort and whether patients may improve with newer treatments such as FXR agonists. Trial registration Ethical approval REC Ref: 16/LO/1325.

Improving the Rate of Same-day Discharge in Gynecologic Oncology Patients with Endometrial Cancer undergoing Minimally Invasive Robotic Surgery: A Quality Improvement Initiative.

STUDY OBJECTIVE/SETTING/PATIENTS: Same-day discharge (SDD) in patients with endometrial cancer undergoing minimally invasive surgery (MIS) is safe and feasible, with multiple patient and healthcare system benefits. Despite this, our local rate of SDD was only 29.4%. Several studies have suggested methods to improve rates of SDD but few have evaluated the application of such methods. The objectives of our quality improvement (QI) initiative were 2-fold: (1) to increase the rate of SDD in eligible patients with endometrial cancer undergoing MIS to 70% and (2) to evaluate the implementation of methods to improve rates of SDD. DESIGN/INTERVENTIONS/MEASUREMENTS: At our center, QI diagnostics were conducted, and root causes were identified. Four interventions were introduced: (1) setting SDD as the default discharge plan, (2) ensuring that a physician order for discharge was on the chart, (3) removing the Foley catheter in the operating room, and (4) introducing pre- and postoperative patient education documents. A time-series design was used; rate of SDD was tracked using baseline data and continuous post-intervention monitoring. Process measures (for each intervention) and balancing measures were defined and tracked. MAIN RESULTS: At the conclusion of our QI initiative, the average rate of SDD was 78.3%-exceeding our aim of 70%. This was achieved without compromising patient satisfaction (98.2%) or significantly impacting rates of readmission or presentations to the emergency department. CONCLUSIONS: Our initiative demonstrated the application of simple interventions that resulted in a substantial increase in our rate of SDD in the population of interest, without causing negative impacts on the defined balancing measures. These interventions were nonspecific to gynecologic oncology and could easily be applied across other surgical disciplines.

Clinical and pathological associations of PTEN expression in ovarian cancer: a multicentre study from the Ovarian Tumour Tissue Analysis Consortium.

BACKGROUND: PTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study. METHODS: Tumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran-Mantel-Haenszel tests. RESULTS: Downregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65-0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value < 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC (p value = 0.019) and associated with higher CD8 counts (p value = 0.0016). CONCLUSIONS: PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.

The Edmonton Obesity Staging System Predicts Mode of Delivery After Labour Induction.

OBJECTIVE: This study sought to evaluate the use of the Edmonton Obesity Staging System (EOSS) in predicting cesarean delivery among term, nulliparous, singleton pregnancies in women with overweight or obesity who are undergoing an induction of labour. METHODS: A prospective cohort study was performed in Edmonton, Alberta. Women undergoing an induction of labour at term were recruited to either a sample cohort, including women with a body mass index of ≥25 kg/m2 at first antenatal visit, or a control cohort with a body mass index of 18.5 to 24.9 kg/m2. Participating women provided a self-reported health history and consented to review of their medical records allowing allocation into EOSS categories. The primary outcome was the rate of cesarean delivery based on EOSS category. Secondary outcomes consisted of a summary score of adverse maternal, delivery, and neonatal events (Canadian Task Force Classification II-2). RESULTS: Overall, 345 women were recruited, with a participation rate of 93.7%. The sample cohort consisted of 276 women with overweight or obesity, whereas the control cohort included 69 normal-weight women. The overall rate of cesarean delivery was 30.4% for the control cohort and 35.8%, 29.9%, 43.2%, and 90.5% for women assigned an EOSS category 0, 1, 2, and 3, respectively (P < 0.001). A summary score was not indicative of overall rate of adverse maternal, delivery, and neonatal events (P = 0.22). CONCLUSION: The EOSS may help predict the chance of cesarean delivery in a high-risk group of nulliparous women with overweight or obesity who are undergoing an induction of labour at term.

Survey of nurses' knowledge and practice regarding medication administration using enteral tubes.

AIM AND OBJECTIVES: To identify the practice variation of the individual practitioners in medications' formulation modification for patients using enteral feeding tubing and to support health practitioners involved in this process. BACKGROUND: Blockage of enteral tubes is a common problem that can sometimes be resolved but may require replacement of the tube. Medications are a common culprit. DESIGN: A survey of 73 registered nurses' practices around medication administration via enteral feeding tubes. METHODS: A questionnaire study was undertaken within a district general hospital across a broad variety of wards to explore nurses' experiences of medication administration via enteral tubes. The study is reported in accordance with the squire 2.0 guidelines from the EQUATOR network. RESULTS: Seventy-three nurses responded. Twenty-six per cent reported never checking about drug modification for administration via a tube, 12% check every time and 61% when unsure about a new drug. The volume of fluid flushes administered after medication ranged from 7.5-150 ml. Seventy-one per cent of participants reported stopping feed when medications are required, varying from 1-60 min. Sixty per cent had experienced a blocked tube and 52% the tube being removed for these reasons. The clinical nurse specialist was the commonest first point of call to help. Staff named 15 medications as the most problematic to administer, lactulose and omeprazole were the top two. CONCLUSIONS: Practice varies significantly amongst nurses around medication administration. Theoretically, this may contribute to blocked tubes and excessive fluid administration to some patients. Barriers to medication administration were thematically grouped into: time, difficulty modifying medication, medication interactions and knowledge. Areas identified to support staff include training, devices to crush medications, medication suitability, multidisciplinary approach to streamline care and quick reference guides. RELEVANCE TO CLINICAL PRACTICE: Health professionals may use these results to reduce and ultimately avoid problems with administering medications through feeding tubes. Organisations may use these results to develop their local practice pathways for prescribing, dispensing and training around administration of medications through enteral tubes. In a community setting, this paper may improve the awareness of patients, caregivers and prescribers of the possible implications of tubing blockages.

A combination of the immunohistochemical markers CK7 and SATB2 is highly sensitive and specific for distinguishing primary ovarian mucinous tumors from colorectal and appendiceal metastases.

Primary ovarian mucinous tumors can be difficult to distinguish from metastatic gastrointestinal neoplasms by histology alone. The expected immunoprofile of a suspected metastatic lower gastrointestinal tumor is CK7-/CK20+/CDX2+/PAX8-. This study assesses the addition of a novel marker SATB2, to improve the diagnostic algorithm. A test cohort included 155 ovarian mucinous tumors (105 carcinomas and 50 borderline tumors) and 230 primary lower gastrointestinal neoplasms (123 colorectal adenocarcinomas and 107 appendiceal neoplasms). All cases were assessed for SATB2, PAX8 CK7, CK20, and CDX2 expression on tissue microarrays. Expression was scored in a 3-tier system as absent, focal (1-50% of tumor cells) and diffuse ( >50% of tumor cells) and then categorized into either absent/present or nondiffuse/diffuse. SATB2 and PAX8 expression was further evaluated in ovarian tumors from an international cohort of 2876 patients (expansion cohort, including 159 mucinous carcinomas and 46 borderline mucinous tumors). The highest accuracy of an individual marker in distinguishing lower gastrointestinal from ovarian mucinous tumors was CK7 (91.7%, nondiffuse/diffuse cut-off) followed by SATB2 (88.8%, present/absent cut-off). The most effective combination was CK7 and SATB2 with accuracy of 95.3% using the 3-tier interpretation, absent/focal/diffuse. This combination outperformed the standard clinical set of CK7, CK20 and CDX2 (87.5%). Re-evaluation of outlier cases confirmed ovarian origin for all but one case. The accuracy of SATB2 was confirmed in the expansion cohort (91.5%). SATB2 expression was also detected in 15% of ovarian endometrioid carcinoma but less than 5% of other ovarian histotypes. A simple two marker combination of CK7 and SATB2 can distinguish lower gastrointestinal from ovarian primary mucinous tumors with greater than 95% accuracy. PAX8 and CDX2 have value as second-line markers. The utility of CK20 in this setting is low and this warrants replacement of this marker with SATB2 in clinical practice.

Prospective cohort study comparing quality of life and sexual health outcomes between women undergoing robotic, laparoscopic and open surgery for endometrial cancer.

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.

Pharmacological Inhibition of p38 MAPK by SB203580 Increases Resistance to Carboplatin in A2780cp Cells and Promotes Growth in Primary Ovarian Cancer Cells.

Chemoresistance renders current chemotherapy regimens ineffective against advanced epithelial ovarian cancer (EOC). Carboplatin (the first-line chemotherapeutic agent to treat EOC) induces cell death by regulating multiple signaling pathways. The objective of this study is to identify the signaling pathways that contribute to carboplatin resistance in EOC. To this end, we performed a proteome profiler human phospho-kinase array experiment and compared the phosphorylation profiles between the cisplatin-sensitive A2780s versus its derivative cisplatin-resistant A2780cp cells. The phospho-kinase array revealed that A2780s and A2780cp cells displayed different profiles in basal and carboplatin-induced phosphorylation. Phosphorylation of p38 MAPK was increased by carboplatin more markedly in A2780s cells compared to A2780cp cells. Inhibition of p38 MAPK activity by its specific inhibitor SB203580 increased resistance to carboplatin in A2780cp cells, but not in A2780s cells or in ascites-derived high-grade serous EOC cells. Interestingly, SB203580 increased the number of viable cells in the primary EOC cells, which was concomitant with an increase in survivin expression. In conclusion, inhibition of p38 MAPK by SB203580 increases resistance to carboplatin in A2780cp cells and the number of viable cells in the primary EOC cells, suggesting that pharmacological inhibition of p38 MAPK might not be an effective therapeutic strategy for EOC.

Combined oral contraceptive use before the first birth and epithelial ovarian cancer risk.

BACKGROUND: Combined oral contraceptive (COC) use reduces epithelial ovarian cancer (EOC) risk. However, little is known about risk with COC use before the first full-term pregnancy (FFTP). METHODS: This Canadian population-based case-control study (2001-2012) included 854 invasive cases/2139 controls aged ⩾40 years who were parous and had information on COC use. We estimated odds ratios (aORs) and 95% confidence intervals (CI) adjusted for study site, age, parity, breastfeeding, age at FFTP, familial breast/ovarian cancer, tubal ligation, and body mass. RESULTS: Among parous women, per year of COC use exclusively before the FFTP was associated with a 9% risk reduction (95% CI=0.86-0.96). Results were similar for high-grade serous and endometrioid/clear cell EOC. In contrast, per year of use exclusively after the FFTP was not associated with risk (aOR=0.98, 95% CI=0.95-1.02). CONCLUSIONS: Combined oral contraceptive use before the FFTP may provide a risk reduction that remains for many years, informing possible prevention strategies.

Synchronous endometrial and ovarian carcinomas: predictors of risk and associations with survival and tumor expression profiles.

PURPOSE: Synchronous endometrial and ovarian tumors (SEOs) are diagnosed in 10% of ovarian cancer patients. We examined predictors of SEOs, evaluated associations of SEOs with survival and characterized ovarian tumor profiles using immunohistochemistry. METHODS: We included patients with endometrioid (n = 180) and clear cell (n = 165) ovarian carcinoma identified from the Alberta Cancer Registry between 1979 and 2010 for whom we abstracted medical records and constructed tumor tissue microarrays (TMAs). A concurrent diagnosis of endometrial cancer was obtained from the medical chart. We used unconditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) and Cox proportional hazards models to estimate hazard ratios (HRs) and 95% CIs. Protein expression in ovarian tumors of patients with and without SEOs was evaluated using Fisher's exact test. RESULTS: Comparing 52 patients with SEO tumors to 293 patients with endometrioid or clear cell ovarian carcinomas, endometriosis at the ovary (OR = 0.45, 95% CI = 0.23-0.87, p = 0.02) was the strongest predictor of decreased risk in multivariable models. Premenopausal status (OR = 2.17, 95% CI = 0.92-5.13, p = 0.08) and lower pre-treatment CA125 levels (OR = 0.17, 95% CI = 0.02-1.32, p = 0.09) showed weaker associations. There were no significant differences in survival between patients with or without SEO tumors. More patients with SEO tumors compared to endometrioid ovarian carcinoma were deficient in MLH1, PMS2 and PTEN (p ≤ 0.03). CONCLUSIONS: Endometriosis may not be the mechanism by which SEO cancers arise. Altered tumor oncoprotein expression between women with and without SEOs indicates important biological differences although this did not translate into prognostic differences.

Predictors of pretreatment CA125 at ovarian cancer diagnosis: a pooled analysis in the Ovarian Cancer Association Consortium.

PURPOSE: Cancer antigen 125 (CA125) is a glycoprotein expressed by epithelial cells of several normal tissue types and overexpressed by several epithelial cancers. Serum CA125 levels are mostly used as an aid in the diagnosis of ovarian cancer patients, to monitor response to treatment and detect cancer recurrence. Besides tumor characteristics, CA125 levels are also influenced by several epidemiologic factors, such as age, parity, and oral contraceptive use. Identifying factors that influence CA125 levels in ovarian cancer patients could aid in the interpretation of CA125 values for individuals. METHODS: We evaluated predictors of pretreatment CA125 in 13 studies participating in the Ovarian Cancer Association Consortium. This analysis included a total of 5,091 women with invasive epithelial ovarian cancer with pretreatment CA125 measurements. We used probit scores to account for variability in CA125 between studies and linear regression to estimate the association between epidemiologic factors and tumor characteristics and pretreatment CA125 levels. RESULTS: In age-adjusted models, older age, history of pregnancy, history of tubal ligation, family history of breast cancer, and family history of ovarian cancer were associated with higher CA125 levels while endometriosis was associated with lower CA125 levels. After adjusting for tumor-related characteristics (stage, histology, grade), body mass index (BMI) higher than 30 kg/m2 was associated with 10% (95% CI 2, 19%) higher CA125 levels, while race (non-white vs. white) was associated with 15% (95% CI 4, 27%) higher CA125 levels. CONCLUSION: Our results suggest that high BMI and race may influence CA125 levels independent of tumor characteristics. Validation is needed in studies that use a single assay for CA125 measurement and have a diverse study population.

History of hypertension, heart disease, and diabetes and ovarian cancer patient survival: evidence from the ovarian cancer association consortium.

PURPOSE: Survival following ovarian cancer diagnosis is generally low; understanding factors related to prognosis could be important to optimize treatment. The role of previously diagnosed comorbidities and use of medications for those conditions in relation to prognosis for ovarian cancer patients has not been studied extensively, particularly according to histological subtype. METHODS: Using pooled data from fifteen studies participating in the Ovarian Cancer Association Consortium, we examined the associations between history of hypertension, heart disease, diabetes, and medications taken for these conditions and overall survival (OS) and progression-free survival (PFS) among patients diagnosed with invasive epithelial ovarian carcinoma. We used Cox proportional hazards regression models adjusted for age and stage to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) overall and within strata of histological subtypes. RESULTS: History of diabetes was associated with increased risk of mortality (n = 7,674; HR = 1.12; 95% CI = 1.01-1.25). No significant mortality associations were observed for hypertension (n = 6,482; HR = 0.95; 95% CI = 0.88-1.02) or heart disease (n = 4,252; HR = 1.05; 95% CI = 0.87-1.27). No association of these comorbidities was found with PFS in the overall study population. However, among patients with endometrioid tumors, hypertension was associated with lower risk of progression (n = 339, HR = 0.54; 95% CI = 0.35-0.84). Comorbidity was not associated with OS or PFS for any of the other histological subtypes. Ever use of beta blockers, oral antidiabetic medications, and insulin was associated with increased mortality, HR = 1.20; 95% CI = 1.03-1.40, HR = 1.28; 95% CI = 1.05-1.55, and HR = 1.63; 95% CI = 1.20-2.20, respectively. Ever use of diuretics was inversely associated with mortality, HR = 0.71; 95% CI = 0.53-0.94. CONCLUSIONS: Histories of hypertension, diabetes, and use of diuretics, beta blockers, insulin, and oral antidiabetic medications may influence the survival of ovarian cancer patients. Understanding mechanisms for these observations could provide insight regarding treatment.

Association of Hormone Receptor Expression with Survival in Ovarian Endometrioid Carcinoma: Biological Validation and Clinical Implications.

This paper aims to validate whether hormone receptor expression is associated with longer survival among women diagnosed with ovarian endometrioid carcinoma (EC), and whether it identifies patients with stage IC/II tumors with excellent outcome that could be spared from toxic chemotherapy. Expression of estrogen receptor (ER) and progesterone receptor (PR) was assessed on 182 EC samples represented on tissue microarrays using the Alberta Ovarian Tumor Type (AOVT) cohort. Statistical analyses were performed to test for associations with ovarian cancer specific survival. ER or PR expression was present in 87.3% and 86.7% of cases, respectively, with co-expression present in 83.0%. Expression of each of the hormonal receptors was significantly higher in low-grade tumors and tumors with squamous differentiation. Expression of ER (Hazard Ratio (HR) = 0.18, 95% confidence interval 0.08-0.42, p = 0.0002) and of PR (HR = 0.22, 95% confidence interval 0.10-0.53, p = 0.0011) were significantly associated with longer ovarian cancer specific survival adjusted for age, grade, treatment center, stage, and residual disease. However, the five-year ovarian cancer specific survival among women with ER positive stage IC/II EC was 89.0% (standard error 3.3%) and for PR positive tumors 89.9% (standard error 3.2%), robustly below the 95% threshold where adjuvant therapy could be avoided. We validated the association of hormone receptor expression with ovarian cancer specific survival independent of standard predictors in an independent sample set of EC. The high ER/PR co-expression frequency and the survival difference support further testing of the efficacy of hormonal therapy in hormone receptor-positive ovarian EC. The clinical utility to identify a group of women diagnosed with EC at stage IC/II that could be spared from adjuvant therapy is limited.

Significant frequency of MSH2/MSH6 abnormality in ovarian endometrioid carcinoma supports histotype-specific Lynch syndrome screening in ovarian carcinomas.

AIMS: Lynch syndrome screening in ovarian carcinoma is controversial. The aim of this study was to assess the frequency of deficient mismatch repair (dMMR) protein in a retrospective cohort enriched for non-high-grade serous carcinomas and its association with outcome within histological types. METHODS AND RESULTS: Tissue microarrays representing 612 ovarian carcinomas were tested for mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) by immunohistochemistry. dMMR was detected in 13.8% of endometrioid and 2.4% of clear cell carcinomas, but not in other histological types. Within endometrioid carcinomas, 11 of 25 dMMR cases showed abnormal MLH1/PMS2, 10 cases showed abnormal MSH2/MSH6, and four cases showed only abnormal MSH6, indicating that at least 7.7% of endometrioid carcinomas have dMMR probably related to Lynch syndrome. The four dMMR clear cell carcinomas showed abnormal MSH2/MSH6 in three cases and only abnormal MSH6 in one case, all probably related to Lynch syndrome. Within endometrioid carcinomas, dMMR was significantly associated with age <50 years, synchronous endometrial endometrioid carcinoma, a higher CA125 level at diagnosis, higher FIGO grade, absence of ARID1A, and at least 20 CD8-positive intraepithelial lymphocytes per high-power field, but was not associated with cancer-specific death. Age <50 years, higher CA125 levels at diagnosis and at least 20 CD8-positive intraepithelial lymphocytes per high-power field remained significant after adjustment for multiple testing, but their sensitivity for identifying dMMR remained insufficient. CONCLUSION: Our data support the policy of histotype-specific Lynch syndrome screening in ovarian carcinoma confined to endometrioid and clear cell carcinomas.

Smoking may modify the association between neoadjuvant chemotherapy and survival from ovarian cancer.

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.

Adult lifetime alcohol consumption and invasive epithelial ovarian cancer risk in a population-based case-control study.

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.

Elevated ß-catenin activity contributes to carboplatin resistance in A2780cp ovarian cancer cells.

Ovarian cancer is the fifth leading cause of cancer-related mortalities in women. Epithelial ovarian cancer (EOC) represents approximately 90% of all ovarian malignancies. Most EOC patients are diagnosed at advanced stages and current chemotherapy regimens are ineffective against advanced EOC due to the development of chemoresistance. It is important to better understand the molecular mechanisms underlying acquired resistance to effectively manage this disease. In this study, we examined the expression of the Wnt/ß-catenin signaling components in the paired cisplatin-sensitive (A2780s) and cisplatin-resistant (A2780cp) EOC cell lines. Our results showed that several negative regulators of Wnt signaling are downregulated, whereas a few Wnt ligands and known Wnt/ß-catenin target genes are upregulated in A2780cp cells compared to A2780s cells, suggesting that Wnt/ß-catenin signaling is more active in A2780cp cells. Further analysis revealed nuclear localization of ß-catenin and higher ß-catenin transcriptional activity in A2780cp cells compared to A2780s cells. Finally, we demonstrated that chemical inhibition of ß-catenin transcriptional activity by its inhibitor CCT036477 sensitized A2780cp cells to carboplatin, supporting a role for ß-catenin in carboplatin resistance in A2780cp cells. In conclusion, our data suggest that increased Wnt/ß-catenin signaling activity contributes to carboplatin resistance in A2780cp cells.

RUNX3 contributes to carboplatin resistance in epithelial ovarian cancer cells.

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.