Near universal detection of alterations in CTNNB1 and Wnt pathway regulators in desmoid‐type fibromatosis by whole‐exome sequencing and genomic analysis

CTNNB1 mutations or APC abnormalities have been observed in ～85% of desmoids examined by Sanger sequencing and are associated with Wnt/β‐catenin activation. We sought to identify molecular aberrations in “wild‐type” tumors (those without CTNNB1 or APC alteration) and to determine their prognostic relevance. CTNNB1 was examined by Sanger sequencing in 117 desmoids; a mutation was observed in 101 (86%) and 16 were wild type. Wild‐type status did not associate with tumor recurrence. Moreover, in unsupervised clustering based on U133A‐derived gene expression profiles, wild‐type and mutated tumors clustered together. Whole‐exome sequencing of eight of the wild‐type desmoids revealed that three had a CTNNB1 mutation that had been undetected by Sanger sequencing. The mutation was found in a mean 16% of reads (vs. 37% for mutations identified by Sanger). Of the other five wild‐type tumors sequenced, two had APC loss, two had chromosome 6 loss, and one had mutation of BMI1. The finding of low‐frequency CTNNB1 mutation or APC loss in wild‐type desmoids was validated in the remaining eight wild‐type desmoids; directed miSeq identified low‐frequency CTNNB1 mutation in four and comparative genomic hybridization identified APC loss in one. These results demonstrate that mutations affecting CTNNB1 or APC occur more frequently in desmoids than previously recognized (111 of 117; 95%), and designation of wild‐type genotype is largely determined by sensitivity of detection methods. Even true CTNNB1 wild‐type tumors (determined by next‐generation sequencing) may have genomic alterations associated with Wnt activation (chromosome 6 loss/BMI1 mutation), supporting Wnt/β‐catenin activation as the common pathway governing desmoid initiation. © 2015 Wiley Periodicals, Inc.     

Consistent copy number changes and recurrent PRKAR1A mutations distinguish Melanotic Schwannomas from Melanomas: SNP‐array and next generation sequencing analysis

Melanotic Schwannomas (MS) are rare tumors that share histological features with melanocytic tumors and schwannomas. However, their genetics are poorly understood. To elucidate the genetic characteristics of MS, we performed genome‐wide studies in a series of cases. Twelve MS cases were available for the study. Genomic DNAs extracted from formalin‐fixed paraffin embedded tumor tissues were subjected to copy number (CN) and allelic imbalance (AI) analysis by Single Nucleotide Polymorphism (SNP)‐array and screened for mutations in coding exons of 341 key cancer‐associated genes using a hybrid capture‐based next‐generation sequencing (NGS) assay. Sanger sequencing was used to further verify recurrent mutations detected by NGS study. SNP‐array analysis revealed remarkably stereotypic chromosomal abnormalities in MS. Hypodiploidy was common, typically involving monosomies of chromosomes 1, 2, and 17. All 12 samples showed mutations in PRKAR1A gene, including 2 cases with 2 mutations each. The 14 mutations were scattered across PRKAR1A, and most were inactivating mutations. AI on 17q, presenting as loss of heterozygosity with or without CN losses, combined with a PRKAR1A mutation was observed in 9/12 MS cases. The remaining 3 cases included the two samples harboring two mutations in PRKAR1A. MS exhibits a stereotypic pattern of chromosomal losses. In contrast, melanomas are typically characterized by the presence of multiple CN aberrations, without demonstrable differences in the frequency of losses and gains. Inactivation of both alleles of PRKAR1A by “two hits” observed in almost all cases underscores the central role of PRKAR1A in the pathogenesis of this neoplasm. © 2015 Wiley Periodicals, Inc.     

The Effect of a Low Fructose and Low Glycemic Index/Load (FRAGILE) Dietary Intervention on Indices of Liver Function,Cardiometabolic Risk Factors,and Body Composition in Children and Adolescents With Nonalcoholic Fatty Liver Disease (NAFLD)

Background: Nonalcoholic fatty liver disease (NAFLD) is a common liver disease in obese children. Diets high in added fructose (high fructose corn syrup; HFCS) and glycemic index (GI)/glycemic load (GL) are associated with increased risk of NAFLD. Lifestyle modification is the main treatment, but no guidelines regarding specific dietary interventions for childhood NAFLD exist. We hypothesized that reductions in dietary fructose (total, free, and HFCS)/GI/GL over 6 months would result in improvements in body composition and markers of liver dysfunction and cardiometabolic risk in childhood NAFLD. Methods: Children and adolescents with NAFLD (n = 12) and healthy controls (n = 14) 7–18 years were studied at baseline and 3 and 6 months post–dietary intervention. Plasma markers of liver dysfunction (ALT, AST, γGT), cardiometabolic risk (TG, total cholesterol, LDL‐HDL cholesterol, Apo‐B100, Apo‐B48, Apo‐CIII, insulin, homeostasis model of assessment of insulin resistance [HOMA‐IR]), inflammation (TNF‐α, IL‐6, IL‐10), anthropometric, and blood pressure (BP) were studied using validated methodologies. Results: Significant reductions in systolic BP (SBP), percentage body fat (BF), and plasma concentrations of ALT (P = .04), Apo‐B100 (P < .001), and HOMA‐IR were observed in children with NAFLD at 3 and 6 months (P < .05). Dietary reductions in total/free fructose/HFCS and GL were related to reductions in SBP (P = .01), ALT (P = .004), HOMA‐IR (P = .03), and percentage BF in children with NAFLD. Reductions in dietary GI were associated with reduced plasma Apo‐B100 (P = .02) in both groups. With the exception of Apo‐B100, no changes in laboratory variables were observed in the control group. Conclusion: Modest reductions in fructose (total/free, HFCS) and GI/GL intake result in improvements of plasma markers of liver dysfunction and cardiometabolic risk in childhood NAFLD.     

An unusual source of electromagnetic interference

A 62‐year‐old male presented to his treating cardiologist for routine interrogation of his implantable cardiac defibrillator on the background of severe ischemic cardiomyopathy and end‐stage kidney disease on hemodialysis. The device log revealed multiple paroxysms of atrial fibrillation; however, upon scrutinizing these episodes it was evident that they always corresponded to episodes of hemodialysis while dialyzing through a chronic dialysis catheter, but not while dialyzing via an arteriovenous fistula. We report the novel finding of inappropriate sensing of current leak from the catheter by a lead with a floating atrial dipole.     

A 14-Day Elemental Diet Is Highly Effective in Normalizing the Lactulose Breath Test

Treatment of small intestinal bacterial overgrowth is frustrated by the low efficacy of antibiotics. Elemental diets have been shown to reduce enteric flora. In this study, we evaluate the ability of an elemental diet to normalize the lactulose breath test (LBT) in IBS subjects with abnormal breath test findings. Consecutive subjects with IBS and abnormal LBT suggesting the presence of bacterial overgrowth underwent a 2-week exclusive elemental diet. The diet consisted of Vivonex Plus (Novartis Nutrition Corp., Minneapolis, MN) in a quantity based on individual caloric requirement. On day 15 (prior to solid food), subjects returned for a follow-up breath test and those with an abnormal LBT were continued on the diet for an additional 7 days. The ability of an elemental diet to normalize the LBT was determined for days 15 and 21. A chart review was then conducted to evaluate any clinical benefit 1 month later. Of the 93 subjects available for analysis, 74 (80%) had a normal LBT on day 15 of the elemental diet. When those who continued to day 21 were included, five additional patients normalized the breath test (85%). On chart review, subjects who successfully normalized their breath test had a 66.4 +/- 36.1% improvement in bowel symptoms, compared to 11.9 +/- 22.0% in those who failed to normalize (P < 0.001). An elemental diet is highly effective in normalizing an abnormal LBT in IBS subjects, with a concomitant improvement in clinical symptoms.     

The gastrointestinal tract in uremia

Gastrointestinal mucosal abnormalities ranging from edema to ulceration occur in two thirds of patients dying of uremia. Early studies suggested that uremic patients on maintenance dialysis treatment were at increased risk of peptic ulceration but more recent data indicate that this is not so. Other gastrointestinal problems reported for uremic subjects on maintenance dialysis treatment include bleeding from telangiectatic lesions, constipation, mucosal deposition of amyloid and acute pancreatitis. Nausea and vomiting are common in the uremic patient but gastric emptying studies have yielded conflicting results. Patients undergoing renal transplantation are at increased risk of development of esophagitis, complicated peptic ulcer, intestinal ulceration, and perforation as well as acute pancreatitis.