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Purpose: Ovarian high-grade serous carcinoma (HGSC) is usually diagnosed at late stage. We investigated whether late-stage HGSC has unique genomic characteristics consistent with acquisition of evolutionary advantage compared with early-stage tumors. Experimental Design: We performed targeted next-generation sequencing and shallow whole-genome sequencing (sWGS) on pretreatment samples from 43 patients with FIGO stage I–IIA HGSC to investigate somatic mutations and copy-number (CN) alterations (SCNA). We compared results to pretreatment samples from 52 patients with stage IIIC/IV HGSC from the BriTROC-1 study. Results: Age of diagnosis did not differ between early-stage and late-stage patients (median 61.3 years vs. 62.3 years, respectively). TP53 mutations were near-universal in both cohorts (89% early-stage, 100% late-stage), and there were no significant differences in the rates of other somatic mutations, including BRCA1 and BRCA2. We also did not observe cohort-specific focal SCNA that could explain biological behavior. However, ploidy was higher in late-stage (median, 3.0) than early-stage (median, 1.9) samples. CN signature exposures were significantly different between cohorts, with greater relative signature 3 exposure in early-stage and greater signature 4 in late-stage. Unsupervised clustering based on CN signatures identified three clusters that were prognostic. Conclusions: Early-stage and late-stage HGSCs have highly similar patterns of mutation and focal SCNA. However, CN signature analysis showed that late-stage disease has distinct signature exposures consistent with whole-genome duplication. Further analyses will be required to ascertain whether these differences reflect genuine biological differences between early-stage and late-stage or simply time-related markers of evolutionary fitness. See related commentary by Yang et al., p. 2730

PurposeHigh grade serous carcinoma (HGSC) is the commonest type of ovarian cancer. Nearly all HGSC cases are diagnosed at late stage and it is not clear whether early stage HGSC has unique characteristics compared to late stage tumours.Experimental DesignWe analysed samples from 45 patients with FIGO stage I - IIA HGSC - 40 from the pathology archives of three large UK cancer centres and 5 from the BriTROC-1 study. We performed shallow whole genome sequencing (sWGS) and targeted next generation sequencing to investigate somatic mutations and copy number alterations. We compared results to 51 stage IIIC/IV HGSC patients from the BriTROC-1 study.ResultsThere was no difference in median age between the early stage (median 61.3 years, range 40-84) and late stage (median 62.3 years, range 34-76) patients at diagnosis. TP53 mutations were near-universal (92% early stage, 100% late stage samples) and there were no significant differences in the rates of other somatic mutations, including BRCA1 and BRCA2, or focal copy number alterations between early- and late-stage cohorts. There were also no unique amplifications or deletions in either cohort. However, median ploidy was greater in late stage (median 3.1) than early stage (median 2.0) samples. In addition, there were higher numbers of breakpoints per 10MB and per chromosome arm and higher absolute copy number in late stage than early stage cohorts; early stage samples had longer segment length. Overall copy number signature exposures were significantly different between early and late stage samples with greater signature 3 exposure in early stage and greater signature 4 in late stage. Both simplex plot and unsupervised hierarchical clustering suggested that a subset of late stage samples retain early stage appearances with high signature 3 and co-clustering with the early stage samplesConclusionsThese data suggest that there are no unique mutations or focal copy number alterations in early stage HGSC. However, whole genome duplication is significantly more common in late-stage disease, suggesting evolution during disease progression. However, a subset of late stage HGSC retains early-stage features, which are associated with improved overall survival.

Background and Aims: In recent years an increasing number of studies on Non-Celiac Gluten/Wheat Sensitivity (NCG/WS) have been published but no markers of this condition have as yet been found. Although the NCG/WS clinical presentation often overlaps with IBS, no previous study evacuate colon or rectal histology in NCG/WS patients. Patients and Methods: We performed a prospective study on 78 patients (66 females, 12 males, mean age 36. 4 years) diagnosed with NCG/WS by double-blind wheat challenge, presenting at two tertiary care centers in Italy from January 2015 through September 2016. Data were also collected from 55 control patients either with celiac disease (CD) or with self-reported NCG/WS who tested negative at the wheat challenge. Duodenal immunohistochemistry studies were performed to evaluate the number of intra-epithelial CD3+ lymphocytes (IEL), lamina propria CD45+ immunocytes, CD3+, CD4+ and CD8+ lymphocytes, mast cells, eosinophils, and presence and size of lymphoid nodules. Identical studies were performed on the rectal mucosa of NCWS patients and of self-reported NCG/WS with a negative wheat challenge. Results: In the duodenum, NCG/WS patients showed a significantly higher number of CD3+ IEL, lamina propria (LP) CD4S+ immunocytes and eosinophils than self-reported NCG/WS with a negative wheat challenge. NCG/WS patients with dyspepsia had a higher number of LP eosinophils than those not reporting upper digestive tract symptoms. In the rectal mucosa, NCG/WS patients showed enlarged lymphoid follicles more frequently than self-reported NCG/WS subjects with a negative wheat challenge, and a higher number of CD3+ intra-epithelial lymphocytes and LP CD45+ and eosinophils than control patients. The CD controls had the highest number of immunocytes (CD3+, CD45-P, eosinophils) of the 3 groups studied, both in the duodenum and in the rectum. Conclusions: Both the duodenal and rectal mucosa are inflammed in NCG/WS patients and eosinophils are increased in these districts. NCG/WS could be considered an inflammatory condition of the entire intestinal tract, mainly involving the rectum, and eosinophil infiltration a key candidate player in the pathogenesis of NCG/WS. The study was supported by the Italian Foundation for Celiac Disease (FC) Grant for Project 013/2014.

This article addresses the development of a computerized provider order entry (CPOE)-embedded solution for weight-based neonatal drug infusion developed during the transition from a legacy CPOE system to a customized application of a neonatal CPOE product during a hospital-wide information system transition. The importance of accurate fluid management in the neonate is reviewed. The process of tailoring the system that eventually resulted in the successful development of a computer application enabling weight-based medication infusion calculation for neonates within the CPOE information system is explored. In addition, the article provides guidelines on how to customize a vendor solution for hospitals with neonatal intensive care unit.

To analyze risk factors for type 2 diabetes among women attending menopause clinics in Italy for counselling about the menopause.Women attending a network of first-level outpatient menopause clinics in Italy for general counselling about menopause or treatment of menopausal symptoms.Cross-sectional study with no exclusion criteria. Type 2 diabetes was defined according to National Diabetes Data Groups Indications and the fasting blood glucose at an oral glucose tolerance test within the previous year.Out of the 44 694 considered in this analysis, 808 had a diagnosis of diabetes type 2 (1.8%). In comparison with women aged50 years, the multivariate odds ratios (OR) of type 2 diabetes were 1.31 (95% confidence interval (CI), 0.99-1.74) for women aged 50-52 years, 1.66 (95% CI, 1.27-2.17) at 53-56 years and 2.84 (95% CI, 2.20-3.67) in women agedor = 57 years. Type 2 diabetes was less frequently reported in more educated women (OR high school/university vs. primary school = 0.44 (95% CI, 0.36-0.55)). Being overweight was associated with an increased risk of type 2 diabetes. In comparison with women reporting a low level of physical activity, the multivariate OR of type 2 diabetes was 0.67 (95% CI, 0.54-0.84) for women reporting regular physical activity. In comparison with premenopausal women, the multivariate OR of type 2 diabetes was 1.38 (95% CI, 1.03-1.84) in women with natural menopause. This finding was present also after allowing for the potential confounding effect of age. The multivariate OR of diabetes for users of hormonal replacement therapy was 0.58 (95% CI, 0.46-0.73).This large cross-sectional study suggests that postmenopausal women are at higher risk of type 2 diabetes after allowance for the effect of age. Other main determinants of risk of type 2 diabetes in women around menopause were low socioeconomic status and being overweight. Diabetes was found less frequently in those taking hormone replacement therapy.