Citations

AbstractBackgroundWhile high resolution esophageal manometry combined with impedancometry has demonstrated that gastric pressurizations lead to rumination, the contribution of upper esophageal sphincter (UES) and esophagogastric junction (EGJ) function to rumination is unclear. Behavioral therapy with diaphragmatic breathing (DB) can reduce rumination. We aimed to evaluate the pressures in the stomach, EGJ and UES during rumination and the effects of DB augmented with biofeedback therapy.MethodsSixteen patients with rumination were studied with manometry and impedancometry before and after a meal. The postprandial assessment comprised three periods: before, during, and after DB augmented with biofeedback therapy.Key ResultsAll patients had postprandial rumination, which was associated (p < 0.001) with increased gastric pressure and reversal of the postprandial gastroesophageal pressure gradient from −4 (−43 to 18) before to 20 (7–79) mmHg during rumination. The EGJ pressure was lower (p < 0.001) during gastric pressurizations that were associated with rumination vs those that were not. The UES also relaxed, almost completely, during rumination. Patients had a median (range) of 5 (2–10) rumination episodes before, 1 (0–2) (p < 0.001) during, and 3 (1–5) after (p < 0.001 vs during) diaphragmatic breathing. During manometry and impedancometry, DB was well‐tolerated and learned within 5 min. Diaphragmatic breathing increased EGJ pressure (p < 0.001) and restored a negative gastroesophageal pressure gradient (−20 mmHg [−80 to 7]).Conclusions & InferencesDiaphragmatic breathing aided with high resolution esophageal manometry is well‐tolerated, effective and averts the gastroesophageal pressure disturbance that leads to rumination.

This article provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward.

Objective IBS shows genetic predisposition, but adequately powered gene-hunting efforts have been scarce so far. We sought to identify true IBS genetic risk factors by means of genome-wide association (GWA) and independent replication studies. Design We conducted a GWA study (GWAS) of IBS in a general population sample of 11 326 Swedish twins. IBS cases (N=534) and asymptomatic controls (N=4932) were identified based on questionnaire data. Suggestive association signals were followed-up in 3511 individuals from six case-control cohorts. We sought genotype-gene expression correlations through single nucleotide polymorphism (SNP)-expression quantitative trait loci interactions testing, and performed in silico prediction of gene function. We compared candidate gene expression by real-time qPCR in rectal mucosal biopsies of patients with IBS and controls. Results One locus at 7p22.1, which includes the genes KDELR2 (KDEL endoplasmic reticulum protein retention receptor 2) and GRID2IP (glutamate receptor, ionotropic, delta 2 (Grid2) interacting protein), showed consistent IBS risk effects in the index GWAS and all replication cohorts and reached p=9.31×10 −6 in a meta-analysis of all datasets. Several SNPs in this region are associated with cis effects on KDELR2 expression, and a trend for increased mucosal KDLER2 mRNA expression was observed in IBS cases compared with controls. Conclusions Our results demonstrate that general population-based studies combined with analyses of patient cohorts provide good opportunities for gene discovery in IBS. The 7p22.1 and other risk signals detected in this study constitute a good starting platform for hypothesis testing in future functional investigations.

Abstract Background: Mucinous ovarian carcinomas (MC) and mucinous borderline ovarian tumours (MBOT) are associated with ERBB2 amplification and KRAS activating mutations. These events occur in a near-mutually exclusive pattern, and KRAS mutations are more prevalent in MBOTs than MC's whereas ERBB2 amplification is more frequently seen in MCs. Frequencies of mutations in other oncogenes and tumour suppressor genes in MC are not well established though TP53, BRAF, NRAS, and CDKN2A mutations have all been reported. As these carcinomas are commonly chemo-resistant a definitive molecular categorization of this subtype is needed as treatment options are explored. Methods: We undertook review of pathology reports and after exclusion of potential gastric, appendiceal or pancreatic involvement over 100 mucinous ovarian tumours were identified. HPV testing was undertaken to exclude rare metastasis from endocervical primary site. All specimens were assayed for p53 expression via TMA and subject to sequencing of common cancer gene hotspots using Ion-Torrent or Illumina MiSeq. Previously derived data on ERBB2 status was combined in our analysis and, where available, samples showing heterogeneity of ERBB2 amplification and any other Ras-pathway activating mutation were microdissected with components evaluated independently for concurrent hotspot mutations. Results: All samples were consistent with mucinous tumours of ovarian origin and none were HPV positive. We detected mutations in KRAS, BRAF, CDKN2A, TP53, PTEN, PIK3CA as well as presumed somatic/detrimental, variants in APC that have not previously been reported in mucinous tumours. Despite some samples having enriched tumour content, lower than expected allelic frequencies of KRAS activating mutations suggested intra-tumoural heterogeneity. This was consistent with results observed previously with rare ERBB2 amplification coinciding KRAS mutations. Conclusions: The prevalence of Ras-pathway mutations, especially amongst borderline lesions, suggests these mutations are critical for tumour onset. However varying allelic frequencies of KRAS mutations suggest progression to carcinoma is strongly influenced by other molecular features. Citation Format: Michael S. Anglesio, Robertson Mackenzie, Stefan Kommoss, Boris J. Winterhoff, Benjamin Kipp, Jaoquin Garcia, Jesse S. Voss, Kevin Halling, Sarah Kerr, Janine Senz, Winnie Yang, Magnus von Knebel Doeberitz, Elena-Sophie Prigge, Miriam Reuschenbach, Anna V. Tinker, Blake Gilks, Jamie N. Bakkum-Gamez, David G. Huntsman, Jessica N. McAlpine. Defining ovarian mucinous tumors: Cancer genes and heterogeneity. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A18.

Abstract Background: HER2 overexpression or amplification, occuring in ∼15-20% of breast cancers (BC), is associated with a poor prognosis. Trastuzumab (T) and pertuzumab (P) are humanized monoclonal antibodies that bind to different HER2 epitopes, inhibiting HER2 signaling. It was previously shown that first-line (1L) treatment of patients (pts) with HER2-positive metastatic breast cancer (MBC) with vinorelbine (V)+T had similar efficacy to docetaxel+T, but with fewer adverse events (AEs) (HERNATA). In a recent study, P+T+docetaxel significantly improved progression-free survival (PFS) and overall survival (OS) compared with T+docetaxel in pts with HER2-positive 1L MBC (CLEOPATRA). The objective of the VELVET study is to investigate the efficacy and safety of P+T+V for 1L treatment of HER2-positive MBC. Methods: This is a multicenter, open-label, single-arm, two-cohort, Phase II study. The recruitment target is 105 pts per cohort. Pts in Cohort 1 receive P+T+V as separate infusions. Pts in Cohort 2 receive P+T from a single infusion bag followed by V. The initial dose of P is 840 mg, followed by 420 mg q3w; the initial dose of T is 8 mg/kg, followed by 6 mg/kg q3w; V is administered at 25 mg/m2 in Cycle 1, followed by 30-35 mg/m2, on Days 1 and 8 of each cycle, q3w. Pts must have HER2-positive MBC or locally advanced BC (LABC) and a baseline left ventricular ejection fraction (LVEF) of ≥55%. Previous treatment with systemic nonhormonal anticancer therapy in the metastatic setting is not allowed. The primary endpoint is independently assessed overall response rate. Secondary endpoints include PFS, OS, and safety. Results: Interim safety data are presented for Cohort 1; 106 pts were enrolled. Median age at screening was 56 years. Median interval between initial BC diagnosis and enrollment was 2.6 years. 33% of pts had Stage IV BC at initial BC diagnosis. At diagnosis of advanced disease, 13% and 87% of pts had LABC and MBC, respectively. 54% of pts had previously received chemotherapy, including taxane (38%) and anthracycline (36%). 41% had prior T exposure. A median of 6 cycles of P, T, and V was received at the time of this analysis. An AE overview is shown in the table. Pts, n(%)N = 106Any AE102(96)Grade 338(36)Grade 417(16)Grade 52(2)aAny serious AE25(24)Most frequent (≥4 pts) grade ≥3 AEs Neutropeniab21(20)Febrile neutropenia6(6)Leukopenia5(5)Asthenia4(4)Constipation4(4)Diarrhea4(4)a Myocardial infarction and septic shock; b Covers ‘neutropenia’ and ‘neutrophil count decreased’ Grade ≥3 neutropenia/febrile neutropenia was experienced by 8% of pts in Cycle 1 and by 14% of pts in Cycle 2; this proportion decreased during subsequent cycles. There was no overall decrease in mean LVEF from baseline. Conclusions: The combination of P+T+V was well tolerated; no new safety signals were observed. The incidences of grade ≥3 neutropenia, febrile neutropenia, and leukopenia were lower than those previously observed in pts with HER2-positive MBC treated with 1L P+T+docetaxel in CLEOPATRA or those treated with T+V in HERNATA; however, it should be noted that the treatment period in these two studies was longer. Efficacy data for Cohorts 1 and 2 will be reported at the end of the study. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-10.

AbstractBackgroundThe etiology of irritable bowel syndrome (IBS) is not been fully elucidated, but childhood trauma may disturb the brain–gut axis and therefore be important. Thus, we conducted a family based case–control study of IBS cases and their relatives with the aims to (i) determine the frequency of childhood trauma among IBS cases and controls as well as their relatives, and (ii) assess childhood trauma among IBS cases with affected relatives (familial IBS).MethodsOutpatients with IBS, matched controls, and their first‐degree relatives completed a self‐report version of Bremner' Early Trauma Inventory. Percent of cases and controls with a family history were compared and odds ratios were computed using chi‐squared test; recurrence risks to relatives were computed using logistic regression and generalized estimating equations.Key ResultsData were collected from 409 cases, 415 controls, 825 case relatives, and 921 control relatives. IBS cases had a median age of 50 and 83% were women. Of IBS cases, 74% had experienced any general trauma compared to 59% among controls, yielding an odds ratio of 1.56 (95% CI: 1.13–2.15, p < 0.008). There were no statistical differences between IBS relatives and control relatives with regards to lifetime trauma.Conclusions & InferencesIBS is associated with childhood trauma, and these traumas often occur prior to onset of IBS symptoms. This provides further insight into how traumatic childhood events are associated with development of adult IBS.

AbstractAlzheimer's disease is the public health crisis of the 21st century. There is a clear need for a widely available, inexpensive and reliable method to diagnosis Alzheimer's disease in the earliest stages, track disease progression, and accelerate clinical development of new therapeutics. One avenue of research being explored is blood based biomarkers. In April 2012, the Alzheimer's Association and the Alzheimer's Drug Discovery Foundation convened top scientists from around the world to discuss the state of blood based biomarker development. This manuscript summarizes the meeting and the resultant discussion, including potential next steps to move this area of research forward.

Abstract Objectives To evaluate the periprocedural characteristics and outcomes of patients supported with Impella 2.5 prior to percutaneous coronary intervention (pre‐PCI) versus those who received it after PCI (post‐PCI) in the setting of cardiogenic shock (CS) complicating an acute myocardial infarction (AMI). Background Early mechanical circulatory support may improve outcome in the setting of CS complicating an AMI. However, the optimal timing to initiate hemodynamic support has not been well characterized. Methods Data from 154 consecutive patients who underwent PCI and Impella 2.5 support from 38 US hospitals participating in the USpella Registry were included in our study. The primary end‐point was survival to discharge. Secondary end‐points included assessment of patients' hemodynamics and in‐hospital complications. A multivariate regression model was used to identify independent predictors for mortality. Results Both groups were comparable except for diabetes (P = 0.02), peripheral vascular disease (P = 0.008), chronic obstructive pulmonary disease (P = 0.05), and prior stroke (P = 0.04), all of which were more prevalent in the pre‐PCI group. Patients in the pre‐PCI group had more lesions (P = 0.006) and vessels (P = 0.01) treated. These patients had also significantly better survival to discharge compared to patients in the post‐PCI group (65.1% vs.40.7%, P = 0.003). Survival remained favorable for the pre‐PCI group after adjusting for potential confounding variables. Initiation of support prior to PCI with Impella 2.5 was an independent predictor of in‐hospital survival (Odds ratio 0.37, 95% confidence interval: 0.17–0.79, P = 0.01) in multivariate analysis. The incidence of in‐hospital complications included in the secondary end‐point was similar between the 2 groups. Conclusions The results of our study suggest that early initiation of hemodynamic support prior to PCI with Impella 2.5 is associated with more complete revascularization and improved survival in the setting of refractory CS complicating an AMI. (J Interven Cardiol 2014;27:1–11)