Citations

BackgroundOctogenarians (>80 years) have been underrepresented in clinical trials of cardiac resynchronization therapy (CRT).ObjectiveTo determine the benefit of CRT with or without a defibrillator in older elderly patients.MethodsWe retrospectively studied consecutive patients who received CRT at our institution from 2002 through 2008. New York Heart Association (NYHA) class and echocardiographic parameters were assessed before and after CRT. Thirty‐day complications after device implant were collected. Survival data were obtained from the national death and location database. Data were compared between those 80 years and younger and those older than 80 years.ResultsOf 728 patients identified, 90 (12.4%) were older than 80 years. After CRT, older and younger patients had similar improvements in NHYA class (P = 0.41), ejection fraction (P = 0.48), and mitral valve regurgitation (MR) severity (P = 0.42). In the older patients, defibrillator implantation was associated with comparable improvement in NYHA class, ejection fraction, and MR grade severity (P > 0.05), as in those without a defibrillator. Overall survival was worse in octogenarians than in the younger patients by Kaplan‐Meier estimates (P = 0.001). Multivariate analysis showed similar survival between the younger and older subjects (hazard ratio, 1.23; 95% confidence interval, 0.83–1.84; P = 0.31). The observed complication rate in all study subjects was 12.2%, with no difference between the two age groups.ConclusionOctogenarian patients who received CRT with or without a defibrillator for advanced heart failure had similar clinical benefits as younger patients. CRT should not be withheld from octogenarians meeting current selection guidelines.

Summary Background Coeliac disease, an autoimmune disorder triggered by gluten ingestion, is managed by a gluten‐free diet ( GFD ), which is difficult for many patients. Larazotide acetate is a first‐in‐class oral peptide that prevents tight junction opening, and may reduce gluten uptake and associated sequelae. Aim To evaluate the efficacy and tolerability of larazotide acetate during gluten challenge. Methods This exploratory, double‐blind, randomised, placebo‐controlled study included 184 patients maintaining a GFD before and during the study. After a GFD run‐in, patients were randomised to larazotide acetate (1, 4, or 8 mg three times daily) or placebo and received 2.7 grams of gluten daily for 6 weeks. Outcomes included an experimental biomarker of intestinal permeability, the lactulose‐to‐mannitol ( LAMA ) ratio and clinical symptoms assessed by Gastrointestinal Symptom Rating Scale ( GSRS ) and anti‐transglutaminase antibody levels. Results No significant differences in LAMA ratios were observed between larazotide acetate and placebo groups. Larazotide acetate 1‐mg limited gluten‐induced symptoms measured by GSRS ( P = 0.002 vs. placebo). Mean ratio of anti‐tissue transglutaminase IgA levels over baseline was 19.0 in the placebo group compared with 5.78 ( P = 0.010), 3.88 ( P = 0.005) and 7.72 ( P = 0.025) in the larazotide acetate 1‐, 4‐, and 8‐mg groups, respectively. Adverse event rates were similar between larazotide acetate and placebo groups. Conclusions Larazotide acetate reduced gluten‐induced immune reactivity and symptoms in patients with coeliac disease undergoing gluten challenge and was generally well tolerated; however, no significant difference in LAMA ratios between larazotide acetate and placebo was observed. Results and design of this exploratory study can inform the design of future studies of pharmacological interventions in patients with coeliac disease.

Object The goal of this study was to determine the risk of using antithrombotic agents in patients with established intracerebral cavernous malformations (ICMs). Methods From a previously described cohort of 292 patients with radiographically defined ICMs, 40 required an antithrombotic after the ICM was diagnosed. Patients underwent follow-up to determine the incidence of hemorrhage. Results The mean age of these 40 patients was 62.4 years; there were 21 male and 19 female patients. Five (12.5%) of the 40 patients initially presented with hemorrhage and 4 (10%) had multiple ICMs. Of these patients, 32 were placed on an antiplatelet agent alone, 6 on an anticoagulant alone, and 2 were placed on both. In patients necessitating any antithrombotic agent, 1 patient developed a prospective hemorrhage over the 258 person-years of follow-up (prospective hemorrhage rate 0.41% per person-year). Conclusions Antithrombotics likely do not precipitate hemorrhage in patients with known ICMs. However, caution should be exercised in the use of antithrombotics in patients with ICMs at high risk for hemorrhage. The risks and benefits of antithrombotics in each situation should be carefully weighed against the natural history of ICM.

Context .—Malignant mesothelioma (MM) is an uncommon tumor that can be difficult to diagnose. Objective .—To provide updated practical guidelines for the pathologic diagnosis of MM. Data Sources .—Pathologists involved in the International Mesothelioma Interest Group and others with an interest in the field contributed to this update. Reference material includes peer-reviewed publications and textbooks. Conclusions .—There was consensus opinion regarding (1) distinction of benign from malignant mesothelial proliferations (both epithelioid and spindle cell lesions), (2) cytologic diagnosis of MM, (3) key histologic features of pleural and peritoneal MM, (4) use of histochemical and immunohistochemical stains in the diagnosis and differential diagnosis of MM, (5) differentiation of epithelioid MM from various carcinomas (lung, breast, ovarian, and colonic adenocarcinomas, and squamous cell and renal cell carcinomas), (6) diagnosis of sarcomatoid mesothelioma, (7) use of molecular markers in the diagnosis of MM, (8) electron microscopy in the diagnosis of MM, and (9) some caveats and pitfalls in the diagnosis of MM. Immunohistochemical panels are integral to the diagnosis of MM, but the exact makeup of panels used is dependent on the differential diagnosis and on the antibodies available in a given laboratory. Immunohistochemical panels should contain both positive and negative markers. It is recommended that immunohistochemical markers have either sensitivity or specificity greater than 80% for the lesions in question. Interpretation of positivity generally should take into account the localization of the stain (eg, nuclear versus cytoplasmic) and the percentage of cells staining (>10% is suggested for cytoplasmic membranous markers). These guidelines are meant to be a practical reference for the pathologist.

Objective Eosinophil predominant inflammation characterises histological features of eosinophilic oesophagitis (EoE). Endoscopy with biopsy is currently the only method to assess oesophageal mucosal inflammation in EoE. We hypothesised that measurements of luminal eosinophil-derived proteins would correlate with oesophageal mucosal inflammation in children with EoE. Design The Enterotest diagnostic device was used to develop an oesophageal string test (EST) as a minimally invasive clinical device. EST samples and oesophageal mucosal biopsies were obtained from children undergoing upper endoscopy for clinically defined indications. Eosinophil-derived proteins including eosinophil secondary granule proteins (major basic protein-1, eosinophil-derived neurotoxin, eosinophil cationic protein, eosinophil peroxidase) and Charcot–Leyden crystal protein/galectin-10 were measured by ELISA in luminal effluents eluted from ESTs and extracts of mucosal biopsies. Results ESTs were performed in 41 children with active EoE (n=14), EoE in remission (n=8), gastro-oesophageal reflux disease (n=4) and controls with normal oesophagus (n=15). EST measurement of eosinophil-derived protein biomarkers significantly distinguished between children with active EoE, treated EoE in remission, gastro-oesophageal reflux disease and normal oesophagus. Levels of luminal eosinophil-derived proteins in EST samples significantly correlated with peak and mean oesophageal eosinophils/high power field (HPF), eosinophil peroxidase indices and levels of the same eosinophil-derived proteins in extracts of oesophageal biopsies. Conclusions The presence of eosinophil-derived proteins in luminal secretions is reflective of mucosal inflammation in children with EoE. The EST is a novel, minimally invasive device for measuring oesophageal eosinophilic inflammation in children with EoE.

Abstract Background: Estrogen receptors are over-expressed in around 70% of breast cancer cases. The genetic changes that occur during aromatase inhibitor (AI) treatment are not well understood and may differ depending upon the patient's response phenotype. Methods: We performed whole genome sequencing (WGS) of matched blood, pre-treatment, and post-treatment biopsy samples from 22 estrogen receptor positive breast cancer patients treated with neoadjuvant aromatase inhibitors. For 5 cases, we performed the whole genome sequencing (WGS) on patients’ matched normal, two pre AI-treatment, and two post AI-treatment DNA isolates from biopsy samples. We validated all putative coding and non-coding somatic mutations using deep sequencing. By comparing the validated somatic mutations from pre- and post- AI treatment biopsy samples, we were able to determine the alterations in the tumor genomes. In every case we defined the clonal architecture of each pair of pre-treatment and post-treatment biopsy samples by comparing the variant allele frequencies from thousands of validated somatic mutations. Results: Comparisons of the two pre AI-treatment biopsy samples from the same patient indicates that the variant allele frequencies of mutations showed high concordances in all 5 cases, 0.74 to 0.95 range of correlation coefficient. Only a small percentage of somatic mutations were detected in one pre-treatment sample and not the other (4.65% overall). In comparing the somatic variations between pre-treatment and matched post-treatment biopsy samples in 22 cases, we found that patients with good clinical response to AI treatment retained known driver mutations only in their pre-treatment tumors. Conversely, those patients with poor clinical response presented new driver mutations in their post-treatment samples. Furthermore, the variant allele frequency for most mutated genes decreased in post AI treatment samples for patients with good AI treatment response; on the contrary, the variant allele frequency increased for patients with poor clinical response. Conclusions: From WGS of matched normal, pre-treatment, and post-treatment biopsy samples, we identified new driver genes mutated in patients with poor clinical response, while patients with good clinical response had lost mutated driver genes in their post-treatment biopsy samples. The genetic landscape revealed by WGS of pre-treatment and post-treatment biopsy samples reveals mutational repertoires are remodeled by AI therapy. This finding suggests deep sequencing of AI treated samples will be necessary to reveal the complete complement of mutations present in a patient's tumor. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-423. doi:1538-7445.AM2012-LB-423

Abstract Background. Several recent studies have reported an inverse relationship between sun exposure and non-Hodgkin (NHL) risk. One hypothesis is that vitamin D mediates this effect. We evaluated the association of sun exposure at various ages and common variants in vitamin D related genes with risk of NHL and its major subtypes. Methods. Newly diagnosed NHL cases (N=1023) and frequency matched controls (N=1254) were enrolled in a clinic-based case-control study conducted at the Mayo Clinic. Thirty-eight single nucleotide polymorphisms (SNPs) from 5 candidate genes relevant to vitamin D metabolism and sun sensitivity (IRF4, RXR, VDR, CYP24A1, CYP27B1) were genotyped. Participants also completed a detailed questionnaire, including self-reported sun exposure at ages 13-21, 22-40, and 41+ years. Odds ratios (OR), 95% confidence intervals (CI), and tests for trend and effect modification were estimated using unconditional logistic regression adjusted for age and gender. ORs are reported for the highest vs. lowest exposure category or as the ordinal OR for SNPs. Results. The mean age of diagnosis/enrollment was 61 years for cases and 60 years for controls. The most common subtypes were chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; 34%), follicular (FL; 24%), and diffuse large B-cell (DLBCL; 18%) lymphomas. There was a significant decrease in NHL risk with increased sun exposure at ages 13-21 years (OR=0.66, 95% CI 0.44-1.00; ptrend=0.04), which attenuated with increasing age at exposure. Exploratory analysis by NHL subtype indicated a trend toward a protective effect of sun exposure at ages 13-21 years for each of the major subtypes, though these estimates did not reach statistical significance. Of the 38 SNPs evaluated, there was a significant association for 3 SNPs in VDR and 1 SNP in CYP24A1: rs3819545 (OR=1.24, 95% CI 1.10-1.40, p=0.0004), rs2239186 (OR=1.22, 95% CI 1.05-1.41, p=0.009), and rs886441 (OR=0.82, 95% CI 0.70-0.96, p=0.02) for VDR and rs2762939 (OR=0.85, 95% CI 0.75-0.98, p=0.02) for CYP24A1. Both the VDR and CYP24A1 associations were observed for CLL/SLL, FL, but were attenuated for DLBCL. There was no evidence of any significant effect modification of sun exposure at ages 13-21 years by genotype in these four SNPs for NHL overall, or for NHL subtypes. Conclusions. We observed an inverse association between the frequency of sun exposure at ages 13-21 years and NHL risk, which attenuated for sun exposure at older ages, suggesting that early life exposure may be more relevant. While genetic variation in VDR and CYP24A1 were associated with NHL risk, there was no evidence for an interaction of sun exposure with these genes, suggesting that a sun association may not act through the vitamin D metabolism pathway. This would be consistent with a lack of association of circulating vitamin D with NHL risk recently published from the Cohort Consortium pooling project. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1894. doi:10.1158/1538-7445.AM2011-1894

The penetrations of methicillin, oxacillin, and cephalothin into cortical bone and synovial tissues were studied 1 h after their intravenous administration in 105 patients having arthroplasty of the hip. Although the lowest serum levels were noted with cephalothin ( P < 0.01), more patients receiving cephalothin achieved osseous drug levels inhibitory to staphylococci ( P < 0.01). Differences in the penetration of the three agents into synovial tissues were not statistically significant.

Abstract Rare germline mutations in the breast and ovarian cancer predisposition genes BRCA1 and BRCA2 are present in roughly 5 percent of ovarian cancer patients. Both genes play key roles in DNA damage repair but appear to have distinct, although often complementary, functions. The risks of breast and ovarian cancer have been shown to differ between BRCA1 and BRCA2 carriers, and mutation-specific effects have also been suggested for both groups. Published reports comparing the survival of ovarian cancer patients with and without BRCA1/2 mutations generally show a survival advantage among mutation carriers. This is thought to be related to an improved response of carriers to platinum-based therapies. Since it is not known whether BRCA1 and BRCA2 carriers show similar survival patterns, we have performed a large, multicenter study to investigate the impact of germline BRCA1 and BRCA2 mutations on ovarian cancer survival. 3,531 invasive epithelial ovarian cancer cases (1,178 BRCA1, 367 BRCA2 and 1,986 BRCA-negative) with survival time data from twenty-four studies in the U.S.A, Europe, Israel and Asia were included. In our main analysis, we excluded patients who were known or who were likely to have not received platinum-based therapy. Compared to non-carriers, BRCA1 and BRCA2 carriers were more likely to present with advanced stage (BRCA1; p=2×10−4, BRCA2; p=4×10−6), high grade (BRCA1; p=4×10−9, BRCA2; p=1×10−4), serous disease (BRCA1; p=3×10−6, BRCA2; p=0.003). BRCA1 carriers were younger at diagnosis (p=2×10−9) and BRCA2 slightly older at diagnosis (p=0.002) than non-carriers. BRCA1 and BRCA2 carriers did not differ in terms of tumor stage, grade or histology but did show differences in the age at diagnosis (p=2×10−14). In an unadjusted analysis, neither BRCA1 nor BRCA2 carriers differed from non-carriers in overall survival (BRCA1: HR=1.02, p=0.77, BRCA2: HR=0.89, p=0.36). After adjusting for stage, grade, histology and age at diagnosis, BRCA1 carriers showed a modest, non-significant, survival advantage (HR=0.84, p=0.12) while BRCA2 carriers showed a marked improvement (HR=0.57, p=6×10−4) compared to non-carriers. This survival advantage was also seen when comparing BRCA2 carriers to BRCA1 carriers after adjustment for age at diagnosis (HR=0.69, p=5×10−4). Similar results were obtained when we restricted the analysis to high grade, advanced stage, serous cases. The survival differences we observed between BRCA1 and BRCA2 carriers could be related to differences in tumor biology or chemo-sensitivity. Additional analyses investigating the later will be presented in addition to mutation-specific effects within BRCA1 and BRCA2. In this study, we provide strong evidence for genetic heterogeneity of survival effects in ovarian cancer patients with BRCA mutations. This could be applied to both clinical prediction and to aid our understanding of the complex biology of BRCA mutations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2752. doi:10.1158/1538-7445.AM2011-2752