Phase 2 study of the Exportin 1 inhibitor selinexor in patients with recurrent gynecological malignancies.

BACKGROUND: Selinexor is an oral inhibitor of the nuclear export protein Exportin 1 (XPO1) with demonstrated antitumor activity in solid and hematological malignancies. We evaluated the efficacy and safety of selinexor in heavily pretreated, recurrent gynecological malignancies. METHODS: In this phase 2 trial, patients received selinexor (35 or 50 mg/m2 twice-weekly [BIW] or 50 mg/m2 once-weekly [QW]) in 4-week cycles. Primary endpoint was disease control rate (DCR) including complete response (CR), partial response (PR) or stable disease (SD) ≥12 weeks. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. RESULTS: 114 patients with ovarian (N = 66), endometrial (N = 23) or cervical (N = 25) cancer were enrolled. Median number of prior regimens for ovarian, endometrial and cervical cancer was 6 (1-11), 2 (1-5), and 3 (1-6) respectively. DCR was 30% (ovarian 30%; endometrial 35%; cervical 24%), which included confirmed PRs in 8%, 9%, and 4% of patients with ovarian, endometrial, and cervical cancer respectively. Median PFS and OS for patients with ovarian, endometrial and cervical cancer were 2.6, 2.8 and 1.4 months, and 7.3, 7.0, and 5.0 months, respectively. Common Grade 3/4 adverse events (AEs) were thrombocytopenia (17%), fatigue (14%), anemia (10%), nausea (9%) and hyponatremia (9%). Patients with ovarian cancer receiving 50 mg/m2 QW had fewer high-grade AEs with similar efficacy as BIW treatment. CONCLUSIONS: Selinexor demonstrated single-agent activity and disease control in patients with heavily pretreated ovarian and endometrial cancers. Side effects were a function of dose level and treatment frequency, similar to previous reports, reversible and mitigated with supportive care.

Inter-hospital variation in use of obstetrical blood transfusion: a population-based cohort study.

OBJECTIVE: To identify the extent of hospital-to-hospital variation in use of obstetrical blood transfusion. DESIGN: Population-based cohort study linking provincial perinatal and blood transfusion registries. SETTING: British Columbia, Canada, 2004-2015. POPULATION: All pregnant women delivering at or beyond 20 weeks' gestation at any British Columbia hospital. METHODS: Mixed-effects regression models were used to estimate hospital-specific transfusion rates after sequentially accounting for (1) the role of random variation, (2) maternal medical and obstetrical characteristics (i.e. patient case mix) and (3) institutional and delivery factors (such as use of instrumental or caesarean delivery). MAIN OUTCOME MEASURES: Hospital-specific use of obstetrical red blood cell transfusion. RESULTS: Among 44 hospitals, crude institutional transfusion rates across the study period ranged from 3.7 to 23.6 per 1000, with an average of 8.3 per 1000. After adjusting for maternal characteristics, institution and delivery risk factors, a nearly three-fold difference in rates between the 10th and 90th percentile remained (5.4-14.5 per 1000). Twelve sites had rates significantly higher or lower than the provincial average. Women residing in remote areas were 2.5-fold (95% CI 1.8-3.5] more likely to receive a blood transfusion than were women residing in metropolitan areas. CONCLUSIONS: Meaningful variation between hospitals in use of blood transfusion during pregnancy was not explained by differences in patient case-mix or institutional factors, suggesting that over- or under-utilisation of this resource may be occurring in obstetrical care. TWEETABLE ABSTRACT: Use of blood transfusion in pregnant women varied broadly between hospitals in British Columbia, Canada.

Employment, work hours and weight gain among middle-aged women.

OBJECTIVE: To investigate the influence of employment and work hours on weight gain and weight loss among middle-aged women. DESIGN: Quantile regression techniques were used to estimate the influence of employment and hours worked on percentage weight change over 2 years across the entire distribution of weight change in a cohort of middle-aged women. A range of controls was included in the models to isolate the effect of work status. SUBJECTS: A total of 9276 women aged 45-50 years at baseline who were present in both the 1996 and 1998 surveys of the Australian Longitudinal Study of Women's Health. The women were a representative sample of the Australian population. RESULTS: Being out of the labour force or unemployed was associated with lower weight gain and higher weight loss than being employed. The association was stronger at low to moderate levels of weight gain. Among employed women, working regular (35-40), long (41-48) or very long (49+) hours was associated with increasingly higher levels of weight gain compared with working part-time hours. The association was stronger for women with greater weight gain overall. The association between unemployment and weight change became insignificant when health status was controlled for. CONCLUSIONS: Employment was associated with more weight gain and less weight loss. Among the employed, working longer hours was associated with more weight gain, especially at the higher levels of weight gain where the health consequences are more serious. These findings suggest that as women work longer hours they are more likely to make lifestyle choices that are associated with weight gain.

P63 expression in lung carcinoma: a tissue microarray study of 408 cases.

p63 is a recently discovered member of the p53 family that has been shown to be important in the development of epithelial tissues. p63 may also play a role in squamous cell carcinomas of the lung, head and neck, and cervix, and its expression is increased in these tumors. The purpose of this study was to investigate the expression of p63 in a broad spectrum of histologic types of lung tumors. A total of 441 cases of primary lung tumors with follow-up data were identified, and the paraffin-embedded tissue blocks were used to construct a duplicate core tissue microarray. After review of the tissue cores, 408 cases, consisting of 123 squamous cell carcinomas, 93 adenocarcinomas, 68 large cell carcinomas, 68 classic carcinoids, 31 atypical carcinoids, 11 large cell neuroendocrine carcinomas, and 14 small cell carcinomas, were adequate for analysis. Immunohistochemistry was performed at 2 different laboratories using monoclonal antibody 4A4 to detect the expression of p63, using different staining protocols. p53 expression was also studied with immunohistochemistry using monoclonal antibody DO-7. Kaplan-Meier curves were plotted to compare the survival of p63-expressing versus nonexpressing tumors. A large proportion of squamous cell carcinomas expressed p63 (96.9%), most showing strong positive nuclear immunoreactivity. Expression in other nonsmall cell lung cancers was also present. Thirty percent of adenocarcinomas and 37% of large cell carcinomas showed p63 expression. In the neuroendocrine tumors, an increasing proportion of tumors stained for p63 as tumor grade increased; 1.9% of classic carcinoids, 30.8% of atypical carcinoids, 50% of large cell neuroendocrine carcinomas, and 76.9% of small cell carcinomas were positive. Approximately half of the positively staining neuroendocrine cases showed strong staining. Expression of p63 was of prognostic significance in neuroendocrine tumors (P < 0.0001), with higher-grade tumors more likely to express p63. Correlation between p63 and p53 expression was not observed (P = 0.18) in nonsmall cell lung cancer; however, a significant correlation between the 2 markers was found in neuroendocrine tumors (P < 0.0001). p63 staining was repeated with a different staining protocol, yielding similar results overall but a lower percentage of positive cases (34.2% vs. 48.4% of tumors positive). In conclusion, p63 expression is consistently expressed in squamous cell carcinoma in the lung, but is also expressed in a subset of adenocarcinomas and large cell carcinomas. Pulmonary neuroendocrine tumors also show p63 staining in some instances, particularly in higher-grade tumors, and the majority of small cell carcinomas are p63-positive. These results suggest that p63 may be involved in oncogenesis in a broader range of tumors than was previously thought.

The cost-effectiveness of shopping to a predetermined grocery list to reduce overweight and obesity.

BACKGROUND: Pre-commitment strategies can encourage participants to commit to a healthy food plan and have been suggested as a potential strategy for weight loss. However, it is unclear whether such strategies are cost-effective. OBJECTIVE: To analyse whether pre-commitment interventions that facilitate healthier diets are a cost-effective approach to tackle obesity. METHODS: Effectiveness evidence was obtained from a systematic review of the literature. For interventions demonstrating a clinically significant change in weight, a Markov model was employed to simulate the long-term health and economic consequences. The review supported modelling just one intervention: grocery shopping to a predetermined list combined with standard behavioural therapy (SBT). SBT alone and do nothing were used as comparators. The target population was overweight or obese adult women. A lifetime horizon for health effects (expressed as quality-adjusted life years (QALYs)) and costs from the perspective of the UK health sector were used to calculate incremental cost-effectiveness ratios (ICERs). RESULTS: In the base case analysis, the pre-commitment strategy of shopping to a list was found to be more effective and cost saving when compared against SBT, and cost-effective when compared against 'do nothing' (ICER=£166 per QALY gained). A sensitivity analysis indicated that shopping to a list remained dominant or cost-effective under various scenarios. CONCLUSION: Our findings suggest grocery shopping to a predetermined list combined with SBT is a cost-effective means for reducing obesity and its related health conditions.

Warfarin-amiodarone drug-drug interactions: determination of [I](u)/K(I,u) for amiodarone and its plasma metabolites.

A retrospective clinical evaluation in a cohort of 73 patients receiving stable anticoagulation therapy showed that the addition/elimination of amiodarone resulted in a 6-65% change in warfarin dose requirement. To evaluate the roles of amiodarone and its circulating metabolites in this highly variable inhibitory drug interaction, a liquid chromatography-electrospray ionization-tandem mass spectrometry assay was developed for the quantitation of low concentrations of these compounds in human plasma, using newly synthesized deuterated analogs as internal standards. Inhibition constant (K(I)) values were determined for the inhibition of (S)-warfarin 7-hydroxylation in human liver microsomes by the parent drug and its metabolites, and the unbound drug fractions (f(u)) were measured in order to calculate the ratio of unbound plasma concentration to the microsomal K(I) for the unbound drug ([I](u)/K(I,u)). From these ratios, we predict that a minor metabolite of amiodarone, namely, N,N-didesethylamiodarone (DDEA), is a major contributor to the interaction between warfarin and amiodarone.

Impact of the CYP4F2 p.V433M polymorphism on coumarin dose requirement: systematic review and meta-analysis.

A systematic review and a meta-analysis were performed to quantify the accumulated information from genetic association studies investigating the impact of the CYP4F2 rs2108622 (p.V433M) polymorphism on coumarin dose requirement. An additional aim was to explore the contribution of the CYP4F2 variant in comparison with, as well as after stratification for, the VKORC1 and CYP2C9 variants. Thirty studies involving 9,470 participants met prespecified inclusion criteria. As compared with CC-homozygotes, T-allele carriers required an 8.3% (95% confidence interval (CI): 5.6-11.1%; P < 0.0001) higher mean daily coumarin dose than CC homozygotes to reach a stable international normalized ratio (INR). There was no evidence of publication bias. Heterogeneity among studies was present (I(2) = 43%). Our results show that the CYP4F2 p.V433M polymorphism is associated with interindividual variability in response to coumarin drugs, but with a low effect size that is confirmed to be lower than those contributed by VKORC1 and CYP2C9 polymorphisms.

Evaluation of immunohistochemical markers in non-small cell lung cancer by unsupervised hierarchical clustering analysis: a tissue microarray study of 284 cases and 18 markers.

This study has investigated a panel of immunomarkers in non-small cell lung carcinoma (NSCLC). Unsupervised hierarchical clustering analysis was used to investigate the possibility of identifying different subgroups in NSCLC based on their molecular expression profile rather than morphological features. A tissue microarray consisting of 284 cases of NSCLC was constructed. Immunohistochemistry was used to detect the presence of 18 biomarkers including synaptophysin, chromogranin, bombesin, NSE, GFI1, ASH-1, p53, p63, p21, p27, E2F-1, cyclin D1, Bcl-2, TTF-1, CEA, HER2/neu, cytokeratin 5/6, and pancytokeratin. Univariate analysis of all 18 markers for prognostic significance was performed. Immunohistochemical scoring data for NSCLC were analysed by unsupervised hierarchical clustering analysis. Kaplan-Meier survival curves were plotted for the different cluster groups of lung tumours identified by this method. Analysis of the three different World Health Organization (WHO) subtypes (adenocarcinoma, squamous cell carcinoma, large cell carcinoma) of NSCLC individually showed that different markers were significant in different subtypes. For example, p53 and p63 were significant for squamous cell carcinoma (p = 0.007 and p = 0.03, respectively), whereas cyclin D1 and HER2/neu were significant prognostic markers for adenocarcinoma (p = 0.025 and p = 0.015, respectively). These markers were not significant prognostic predictors for NSCLC as a group. Hierarchical clustering analysis of NSCLC produced four separate cluster groups, although the vast majority of cases were found in two cluster groups, one dominated by squamous cell carcinoma and the other by adenocarcinoma. The clinical outcomes of cases from the four cluster groups were not significantly different. Prognostic indicators vary between different morphological subtypes of NSCLC. Unsupervised hierarchical clustering analysis, based on an extended immunoprofile, identifies two main cluster groups corresponding to adenocarcinoma and squamous cell carcinoma; cases of large cell carcinomas are assigned to one of these two groups based on their molecular phenotype.