Publications by authors named "Duncan McLeod"

46 Publications

Caucasian lean subjects with non-alcoholic fatty liver disease share long-term prognosis of non-lean: time for reappraisal of BMI-driven approach?

Gut 2021 Feb 4. Epub 2021 Feb 4.

Department of Medical Sciences, Division of Gastroenterology and Hepatology, A.O. Città della Salute e della Scienza di Torino, Università degli Studi di Torino, Torino, Italy

Objective: The full phenotypic expression of non-alcoholic fatty liver disease (NAFLD) in lean subjects is incompletely characterised. We aimed to investigate prevalence, characteristics and long-term prognosis of Caucasian lean subjects with NAFLD.

Design: The study cohort comprises 1339 biopsy-proven NAFLD subjects from four countries (Italy, UK, Spain and Australia), stratified into lean and non-lean (body mass index (BMI)
Results: Lean patients represented 14.4% of the cohort and were predominantly of Italian origin (89%). They had less severe histological disease (lean vs non-lean: non-alcoholic steatohepatitis 54.1% vs 71.2% p<0.001; advanced fibrosis 10.1% vs 25.2% p<0.001), lower prevalence of diabetes (9.2% vs 31.4%, p<0.001), but no significant differences in the prevalence of the I148M variant (p=0.57). During a median follow-up of 94 months (>10 483 person-years), 4.7% of lean vs 7.7% of non-lean patients reported liver-related events (p=0.37). No difference in survival was observed compared with non-lean NAFLD (p=0.069).

Conclusions: Caucasian lean subjects with NAFLD may progress to advanced liver disease, develop metabolic comorbidities and experience cardiovascular disease (CVD) as well as liver-related mortality, independent of longitudinal progression to obesity and genotype. These patients represent one end of a wide spectrum of phenotypic expression of NAFLD where the disease manifests at lower overall BMI thresholds.

Lay Summary: NAFLD may affect and progress in both obese and lean individuals. Lean subjects are predominantly males, have a younger age at diagnosis and are more prevalent in some geographic areas. During the follow-up, lean subjects can develop hepatic and extrahepatic disease, including metabolic comorbidities, in the absence of weight gain. These patients represent one end of a wide spectrum of phenotypic expression of NAFLD.
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http://dx.doi.org/10.1136/gutjnl-2020-322564DOI Listing
February 2021

Multifocal insulinoma secondary to insulinomatosis: persistent hypoglycaemia despite total pancreatectomy.

Endocrinol Diabetes Metab Case Rep 2020 Dec 24;2020. Epub 2020 Dec 24.

Department of Diabetes and Endocrinology, Westmead Hospital, Westmead, New South Wales, Australia.

Summary: Insulinomatosis is a rare cause of hyperinsulinaemic hypoglycaemia. The ideal management approach is not known. A 40-year-old woman with recurrent symptomatic hyperinsulinaemic hypoglycaemia was diagnosed with an insulinoma. A benign 12 mm pancreatic head insulinoma was resected but hypoglycaemia recurred 7 years later. A benign 10 mm pancreatic head insulinoma was then resected but hypoglycaemia recurred within 2 months. Octreotide injections were trialled but exacerbated hypoglycaemia. After a 2-year interval, she underwent total pancreatectomy. A benign 28 mm pancreatic head insulinoma was found alongside insulin-expressing monohormonal endocrine cell clusters (IMECCs) and islet cell hyperplasia, consistent with a diagnosis of insulinomatosis. Hypoglycaemia recurred within 6 weeks. There was no identifiable lesion on MRI pancreas, Ga-68 PET or FDG PET. Diazoxide and everolimus were not tolerated. MEN-1 testing was negative. Insulinomatosis should be suspected in insulinomas with early recurrence or multifocality. De novo lesions can arise throughout the pancreas. Extensive surgery will assist diagnosis but may not provide cure.

Learning Points: Insulinomas are usually benign and managed surgically. Insulinomatosis is characterised by multifocal benign insulinomas with a tendency to recur early. It is rare. Multifocal or recurrent insulinomas should raise suspicion of MEN-1 syndrome, or insulinomatosis. Insulinomatosis is distinguished histologically by insulin-expressing monohormonal endocrine cell clusters (IMECCs) and tumour staining only for insulin, whereas MEN-1 associated insulinomas stain for multiple hormones. The ideal treatment strategy is unknown. Total pancreatectomy may not offer cure.
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http://dx.doi.org/10.1530/EDM-20-0091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849475PMC
December 2020

Successful treatment of CMV, EBV, and adenovirus tissue infection following HLA-mismatched allogeneic stem cell transplant using infusion of third-party T cells from multiple donors in addition to antivirals, rituximab, and surgery.

Transpl Infect Dis 2020 Nov 24:e13528. Epub 2020 Nov 24.

Department of Haematology, Westmead Hospital, Sydney, NSW, Australia.

Viral infections, principally cytomegalovirus, Epstein Barr virus (EBV) and adenovirus, are a leading cause of morbidity and mortality after allogeneic stem cell transplantation. The use of systemic antivirals is limited by limited efficacy and organ toxicities. Inability to clear infection is exacerbated by transplant-related immunosuppression and prophylaxis or treatment of acute graft versus host disease. We report the first patient to clear three serious viral infections after stem cell transplant using third-party donor partially human leukocyte antigen (HLA) matched virus-specific cytotoxic T cells. The patient, a 53 year old female with transplanted for relapsed leukemia, with severe graft versus host disease received five T cell infusions from three separate donors that ultimately cleared serious systemic infections with cytomegalovirus and adenovirus, and an EBV-driven lymphoma. Systemic antivirals had resulted in failed clinical responses. Use of repeated infusions of partially HLA matched virus-specific T cells from banks containing cryopreserved cells should be strongly considered in transplant recipients with single or multiple refractory viral infections.
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http://dx.doi.org/10.1111/tid.13528DOI Listing
November 2020

Duodenal plasma cells correspond to serum IgA in common variable immunodeficiency.

Pathology 2020 Nov 17. Epub 2020 Nov 17.

Departments of Immunology and Immunopathology, Westmead Hospital, Sydney, NSW, Australia; The University of Sydney, Faculty of Medicine, Sydney, NSW, Australia; NSW Health Pathology, Sydney, NSW, Australia. Electronic address:

Common variable immunodeficiency (CVID) can be associated with a range of serum IgA concentrations, from absent, to variably reduced, and in some patients classified as 'possible CVID', even normal. The aim of this study was to assess the proportion of duodenal plasma cells in patients with CVID and determine whether there was an association with serum IgA concentration. Duodenal biopsies obtained at upper endoscopy from 35 patients with CVID were assessed for the presence of plasma cells and compared with serum IgA concentrations. A reduction or absence of duodenal plasma cells in 60% of patients with CVID and an association between the proportions of duodenal plasma cells and serum IgA concentrations was demonstrated. The presence of duodenal plasma cells associated with numbers of isotype switched memory B cells in the peripheral blood. A reduction in serum IgA over time was observed in 19% of CVID patients. The gastrointestinal tract provides a window into the immune system in CVID, and these results reinforce the association between gastrointestinal plasma cells and serum IgA concentrations. Preservation of gastrointestinal plasma cells and serum IgA in some patients with CVID, and the sequential decline of both in others, highlight the heterogeneity of this disorder.
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http://dx.doi.org/10.1016/j.pathol.2020.08.014DOI Listing
November 2020

Large prolapse-related lesions of the sigmoid colon.

Endoscopy 2020 Sep 22. Epub 2020 Sep 22.

Department of Gastroenterology and Hepatology, Westmead Hospital, Sydney, New South Wales, Australia.

Background:  Large prolapse-related lesions (LPRL) of the sigmoid colon have been documented histologically but may not be readily recognized endoscopically.

Methods:  Colonic lesions referred for endoscopic mucosal resection (EMR) were enrolled prospectively. Endoscopic features were carefully documented prior to resection. Final diagnosis was made based on established histologic criteria, including vascular congestion, hemosiderin deposition, fibromuscular hyperplasia, and crypt distortion.

Results:  Of 134 large ( ≥ 20 mm) sigmoid lesions, 12 (9.0 %) had histologic features consistent with mucosal prolapse. Distinct endoscopic features were: broad-based morphology; vascular pattern obscured by dusky hyperemia; blurred crypts of varying size and shape; and irregular spacing of sparse crypts. Focal histologic dysplasia was identified in 6 of 12 lesions (50.0 %).

Conclusions:  LPRL of the sigmoid colon exhibit a distinct endoscopic profile. Although generally non-neoplastic, dysplasia may be present, warranting consideration of EMR.
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http://dx.doi.org/10.1055/a-1248-2175DOI Listing
September 2020

Correction to: Pathological assessment of endoscopic resections of the gastrointestinal tract: a comprehensive clinicopathologic review.

Mod Pathol 2020 06;33(6):1236

H. Lee Moffitt Cancer Center & Research Institute and Departments of Pathology & Cell Biology and Oncologic Sciences, University of South Florida, Tampa, FL, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41379-020-0460-0DOI Listing
June 2020

Pathological assessment of endoscopic resections of the gastrointestinal tract: a comprehensive clinicopathologic review.

Mod Pathol 2020 06 6;33(6):986-1006. Epub 2020 Jan 6.

H. Lee Moffitt Cancer Center & Research Institute and Departments of Pathology & Cell Biology and Oncologic Sciences, University of South Florida, Tampa, FL, USA.

Endoscopic resection (ER) allows optimal staging with potential cure of early-stage luminal malignancies while maintaining organ preservation. ER and surgery are non-competing but complementary therapeutic options. In addition, histological examination of ER specimens can either confirm or refine the pre-procedure diagnosis. ER is used for the treatment of Barrett's related early carcinomas and dysplasias, early-esophageal squamous cell carcinomas and dysplasias, early gastric carcinomas and dysplasia, as well as low-risk submucosal invasive carcinomas (LR-SMIC) and, large laterally spreading adenomas of the colon. For invasive lesions, histological risk factors predict risk of lymph node metastasis and residual disease at the ER site. Important pathological risk factors predictive of lymph node metastasis are depth of tumor invasion, poor differentiation, and lymphovascular invasion. Complete resection with negative margins is critical to avoid local recurrences. For non-invasive lesions, complete resection is curative. Therefore, a systematic approach for handling and assessing ER specimens is recommended to evaluate all above key prognostic features appropriately. Correct handling starts with pinning the specimen before fixation, meticulous macroscopic assessment with orientation of appropriate margins, systematic sectioning, and microscopic assessment of the entire specimen. Microscopic examination should be thorough for accurate assessment of all pathological risk factors and margin assessment. Site-specific issues such as duplication of muscularis mucosa of the esophagus, challenges of assessing ampullectomy specimens and site-specific differences of staging of early carcinomas throughout the gastrointestinal tract (GI) tract should be given special consideration. Finally, a standard, comprehensive pathology report that allows optimal staging with potential cure of early-stage malignancies or better stratification and guidance for additional treatment should be provided.
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http://dx.doi.org/10.1038/s41379-019-0443-1DOI Listing
June 2020

Endoscopic submucosal dissection for suspected early gastric cancer: absolute versus expanded criteria in a large Western cohort (with video).

Gastrointest Endosc 2019 09 8;90(3):467-479.e4. Epub 2019 May 8.

Department of Gastroenterology and Hepatology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Sydney, New South Wales, Australia; Westmead Clinical School, The University of Sydney, Sydney, New South Wales, Australia.

Background And Aims: Endoscopic submucosal dissection (ESD) is an effective, minimally invasive, surgery-sparing technique for the treatment of early gastric cancer (EGC). It is not well established whether EGC within the Japanese expanded criteria can be safely and effectively treated using ESD in the West. We describe the outcomes of ESD for endoscopically suspected, biopsy specimen-confirmed EGC and its adenomatous precursor lesions (pEGC) using the Vienna classification of dysplasia in a Western cohort.

Methods: Prospective data were collected on all pEGCs undergoing ESD at a single expert endoscopy center. Outcomes were compared among pEGC, satisfying the Japanese absolute and expanded criteria, those outside criteria, and those specimens that contained low-grade dysplasia (LGD) only. Specialist GI pathologists reviewed and classified all ESD specimens. Patients were followed up at 6 and 12 months.

Results: Over 71 months, 135 pEGCs in 121 patients (mean age, 72.0 years; 61.2% men) underwent ESD. Median pEGC size was 20 mm (interquartile range, 15-30), and 62 (45.9%) satisfied the expanded clinical criteria. Perforation occurred in 1.5% and postprocedural bleeding in 5.2%. Forty-two pEGCs (31.1%) contained LGD only. Rates of en bloc and R0 resection were 94.8% and 86.7%, respectively. One hundred seven pEGCs (79.2%) met the absolute or expanded criteria for endoscopic cure. Two pEGCs recurred during follow-up. Ten of 26 patients with pEGC (38.5%) outside criteria for cure underwent surgery after ESD with residual tumor detected in 3 specimens. Fifteen patients with outside criteria for pEGCs did not undergo surgery because of frailty or their expressed wish. Eleven of 15 patients have so far undergone first surveillance with 1 of 11 experiencing endoscopic and histologic recurrence.

Conclusions: ESD is a safe and effective treatment for pEGCs in a Western context. Patients who either decline or are too frail for surgery, with outside criteria resections, may benefit from ESD for local disease control. Large Western studies of ESD for pEGCs are required to define long-term patient outcomes and surveillance guidelines, particularly where pathology shows LGD or high-grade dysplasia only. (Clinical trial registration number: NCT02306707.).
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http://dx.doi.org/10.1016/j.gie.2019.04.242DOI Listing
September 2019

A variant in the MICA gene is associated with liver fibrosis progression in chronic hepatitis C through TGF-β1 dependent mechanisms.

Sci Rep 2019 02 5;9(1):1439. Epub 2019 Feb 5.

Storr Liver Centre, The Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, and Westmead Hospital NSW, Sydney, Australia.

Hepatocarcinogenesis is tightly linked to liver fibrosis. Recently, two GWAS variants, MICA rs2596542 and DEPDC5 rs1012068 were identified as being associated with the development of HCV-induced hepatocellular carcinoma (HCC) in Japanese patients. The role of these variants on hepatic inflammation and fibrosis that are closely associated with HCC development is not known, nor are the biological mechanisms underlying their impact on the liver. Here, we demonstrate in 1689 patients with chronic hepatitis C (CHC) (1,501 with CHC and 188 with HCV-related HCC), that the MICA (T) allele, despite not being associated with HCC susceptibility, is associated with increased fibrosis stage (OR: 1.47, 95% CI: 1.05-2.06, p = 0.02) and fibrosis progression rate (hazards ratio: 1.41, 95% CI: 1.04-1.90, p = 0.02). The DEPDC5 variant was not associated with any of these phenotypes. MICA expression was down-regulated in advanced fibrosis stages. Further, (T) allele carriage was associated with lower MICA expression in liver and serum. Transforming growth factor-β1 (TGF-β1) expression suppresses MICA expression in hepatic stellate cells. Our findings suggest a novel mechanism linking susceptibility to advanced fibrosis and subsequently indirectly to HCC, to the level of MICA expression through TGF-β1-dependent mechanisms.
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http://dx.doi.org/10.1038/s41598-018-35736-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363805PMC
February 2019

Gastric Cancer Screening in Common Variable Immunodeficiency.

J Clin Immunol 2018 10 15;38(7):768-777. Epub 2018 Sep 15.

Faculty of Medicine, The University of Sydney, Sydney, NSW, Australia.

Individuals with common variable immunodeficiency (CVID) have an increased risk of gastric cancer, and gastrointestinal lymphoma, yet screening for premalignant gastric lesions is rarely offered routinely to these patients. Proposed screening protocols are not widely accepted and are based on gastric cancer risk factors that are not applicable to all CVID patients. Fifty-two CVID patients were recruited for screening gastroscopy irrespective of symptoms or blood results and were compared to 40 controls presenting for gastroscopy for other clinical indications. Overall, 34% of CVID patients had intestinal metaplasia (IM), atrophic gastritis or moderate to severe non-atrophic gastritis, which can increase the risk of gastric cancer, compared to 7.5% of controls (p < 0.01). Focal nodular lymphoid hyperplasia, a precursor lesion for gastrointestinal lymphoma, was seen in eight CVID patients (16%), one of whom was diagnosed with gastrointestinal lymphoma on the same endoscopy. High-risk gastric pathology was associated with increased time since diagnosis of CVID, smoking, Helicobacter pylori, a low-serum pepsinogen I concentration, and diarrhea, but not pepsinogen I/II ratio, iron studies, vitamin B12 levels or upper gastrointestinal symptoms. There was a lower rate of detection of IM when fewer biopsies were taken, and IM and gastric atrophy were rarely predicted by the endoscopist macroscopically, highlighting the need for standardized biopsy protocols. The prevalence of premalignant gastric lesions in patients with CVID highlights the need for routine gastric screening. We propose a novel gastric screening protocol to detect early premalignant lesions and reduce the risk of gastric cancer and gastric lymphoma in these patients.
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http://dx.doi.org/10.1007/s10875-018-0546-3DOI Listing
October 2018

ADAPT: An Algorithm Incorporating PRO-C3 Accurately Identifies Patients With NAFLD and Advanced Fibrosis.

Hepatology 2019 03;69(3):1075-1086

Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney and Westmead Hospital, Westmead, Australia.

Given the high global prevalence of nonalcoholic fatty liver disease (NAFLD), the need for relevant noninvasive biomarkers and algorithms to accurately stage disease severity is a critical unmet medical need. Identifying those with advanced fibrosis (≥ F3) is the most crucial, as these individuals have the greatest risk of adverse, long-term, liver-related outcomes. We aimed to investigate the role of PRO-C3 (a marker of type III collagen formation) as a biomarker for advanced fibrosis in NAFLD. We measured PRO-C3 by enzyme-linked immunosorbent assay in two large independent cohorts with extensive clinical phenotyping and liver biopsy: 150 in the derivation and 281 in the validation cohort. A PRO-C3-based fibrosis algorithm that included age, presence of diabetes, PRO-C3, and platelet count (ADAPT) was developed. PRO-C3 increased with fibrosis stage (Rho 0.50; P < 0.0001) and was independently associated with advanced fibrosis (odds ratio = 1.05; 95% confidence interval [CI] 1.02-1.08; P = 0.003). ADAPT showed areas under the receiver operating characteristics curve of 0.86 (95% CI 0.79-0.91) in the derivation and 0.87 in the validation cohort (95% CI 0.83-0.91) for advanced fibrosis. This was superior to the existing fibrosis scores, aspartate aminotransferase to platelet ratio index (APRI), FIB-4, and NAFLD fibrosis score (NFS) in most comparisons. Conclusion: PRO-C3 is an independent predictor of fibrosis stage in NAFLD. A PRO-C3-based score (ADAPT) accurately identifies patients with NAFLD and advanced fibrosis and is superior to APRI, FIB-4, and NFS.
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http://dx.doi.org/10.1002/hep.30163DOI Listing
March 2019

The clinical significance and synchronous polyp burden of large (≥ 20 mm) sessile serrated polyps in patients without serrated polyposis syndrome.

Endoscopy 2018 11 8;50(11):1080-1088. Epub 2018 May 8.

Department of Gastroenterology and Hepatology, Westmead Hospital, Sydney, Australia.

Background: Sessile serrated polyps (SSPs) are important precursors of colorectal carcinoma and interval cancer. Large SSPs (≥ 20 mm) outside the definition of serrated polyposis syndrome (SPS) have not been studied in comparison with SPS. We aimed to describe the characteristics of patients with large SSPs in this context.

Methods: Patients with at least one SSP (≥ 20 mm) were eligible. Data from three consecutive colonoscopies were used to compare clinical and endoscopic characteristics in three patient groups: SPS, a solitary large SSP, and patients with at least two SSPs without fulfilling the criteria for SPS (oligo-SSP). Data on the diagnostic colonoscopy were collected retrospectively, whereas the remaining data was collected prospectively.

Results: 67/146 patients (45.9 %) had SPS, 53/146 (36.3 %) had a solitary SSP, and 26/146 (17.8 %) were categorized as oligo-SSP. Personal (16.4 %, 9.4 %, and 11.5 %, respectively) and family (17.9 %, 17.0 %, and 23.1 %, respectively) history of colorectal carcinoma did not differ significantly between groups. Polyp burden was greater in SPS compared with solitary SSP but was not different from oligo-SSP (advanced adenomas: SPS 32.8 % vs. solitary SSP 9.4 % [ = 0.002] vs. oligo-SSP 34.6 % [ = 0.87]; ≥ 10 conventional adenomas: 11.9 % vs. 0 % [ = 0.01] vs. 3.8 % [ = 0.44], respectively). Dysplasia in large SSPs was frequent in all groups (41.1 % overall). SPS was recognized by referring endoscopists in only 9.0 % of cases.

Conclusion: Patients with oligo-SSPs have similar synchronous polyp burden and clinical characteristics as patients with SPS and may require similar surveillance. Modification of the criteria for the diagnosis of SPS to include this group seems warranted. Patients with a solitary SSP have a lower risk of synchronous polyps, including advanced adenomas. Larger studies are warranted to determine whether these patients may return to standard surveillance following complete examination and clearance of the colon.
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http://dx.doi.org/10.1055/a-0596-7231DOI Listing
November 2018

Fibrosis Severity as a Determinant of Cause-Specific Mortality in Patients With Advanced Nonalcoholic Fatty Liver Disease: A Multi-National Cohort Study.

Gastroenterology 2018 08 5;155(2):443-457.e17. Epub 2018 May 5.

Unit for the Clinical Management of Digestive Diseases. Centro para la Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas, Virgen del Rocio University Hospital, University of Seville, Seville, Spain.

Background & Aims: Little is known about the natural course of nonalcoholic fatty liver disease (NAFLD) with advanced fibrosis. We describe long-term outcomes and evaluate the effects of clinical and histologic parameters on disease progression in patients with advanced NAFLD.

Methods: We conducted a multi-national study of 458 patients with biopsy-confirmed NAFLD with bridging fibrosis (F3, n = 159) or compensated cirrhosis (222 patients with Child-Turcotte-Pugh scores of A5 and 77 patients with scores of A6), evaluated from April 1995 through November 2013 and followed until December 2016, death, or liver transplantation at hepatology centers in Spain, Australia, Hong Kong, and Cuba. Biopsies were re-evaluated and scored; demographic, clinical, laboratory, and pathology data for each patient were collected from the time of liver biopsy collection. Cox proportional and competing risk models were used to estimate rates of transplantation-free survival and major clinical events and to identify factors associated with outcomes.

Results: During a mean follow-up time of 5.5 years (range, 2.7-8.2 years), 37 patients died, 37 received liver transplants, 88 had initial hepatic decompensation events, 41 developed hepatocellular carcinoma, 14 had vascular events, and 30 developed nonhepatic cancers. A higher proportion of patients with F3 fibrosis survived transplantation-free for 10 years (94%; 95% confidence interval [CI], 86%-99%) than of patients with cirrhosis and Child-Turcotte-Pugh A5 (74%; 95% CI, 61%-89%) or Child-Turcotte-Pugh A6 (17%; 95% CI, 6%-29%). Patients with cirrhosis were more likely than patients with F3 fibrosis to have hepatic decompensation (44%; 95% CI, 32%-60% vs 6%, 95% CI, 2%-13%) or hepatocellular carcinoma (17%; 95% CI, 8%-31% vs 2.3%, 95% CI, 1%-12%). The cumulative incidence of vascular events was higher in patients with F3 fibrosis (7%; 95% CI, 3%-18%) than cirrhosis (2%; 95% CI, 0%-6%). The cumulative incidence of nonhepatic malignancies was higher in patients with F3 fibrosis (14%; 95% CI, 7%-23%) than cirrhosis (6%; 95% CI, 2%-15%). Death or transplantation, decompensation, and hepatocellular carcinoma were independently associated with baseline cirrhosis and mild (<33%) steatosis, whereas moderate alcohol consumption was associated with these outcomes only in patients with cirrhosis.

Conclusions: Patients with NAFLD cirrhosis have predominantly liver-related events, whereas those with bridging fibrosis have predominantly nonhepatic cancers and vascular events.
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http://dx.doi.org/10.1053/j.gastro.2018.04.034DOI Listing
August 2018

Wide-field endoscopic mucosal resection versus endoscopic submucosal dissection for laterally spreading colorectal lesions: a cost-effectiveness analysis.

Gut 2018 11 7;67(11):1965-1973. Epub 2017 Oct 7.

Department of Gastroenterology and Hepatology, Westmead Hospital, Sydney, New South Wales, Australia.

Objective: To compare the cost-effectiveness of endoscopic submucosal dissection (ESD) and wide-field endoscopic mucosal resection (WF-EMR) for removing large sessile and laterally spreading colorectal lesions (LSLs) >20 mm.

Design: An incremental cost-effectiveness analysis using a decision tree model was performed over an 18-month time horizon. The following strategies were compared: WF-EMR, universal ESD (U-ESD) and selective ESD (S-ESD) for lesions highly suspicious for containing submucosal invasive cancer (SMIC), with WF-EMR used for the remainder. Data from a large Western cohort and the literature were used to inform the model. Effectiveness was defined as the number of surgeries avoided per 1000 cases. Incremental costs per surgery avoided are presented. Sensitivity and scenario analyses were performed.

Results: 1723 lesions among 1765 patients were analysed. The prevalence of SMIC and low-risk-SMIC was 8.2% and 3.1%, respectively. Endoscopic lesion assessment for SMIC had a sensitivity and specificity of 34.9% and 98.4%, respectively. S-ESD was the least expensive strategy and was also more effective than WF-EMR by preventing 19 additional surgeries per 1000 cases. 43 ESD procedures would be required in an S-ESD strategy. U-ESD would prevent another 13 surgeries compared with S-ESD, at an incremental cost per surgery avoided of US$210 112. U-ESD was only cost-effective among higher risk rectal lesions.

Conclusion: S-ESD is the preferred treatment strategy. However, only 43 ESDs are required per 1000 LSLs. U-ESD cannot be justified beyond high-risk rectal lesions. WF-EMR remains an effective and safe treatment option for most LSLs.

Trial Registration Number: NCT02000141.
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http://dx.doi.org/10.1136/gutjnl-2017-313823DOI Listing
November 2018

A standardized imaging protocol for the endoscopic prediction of dysplasia within sessile serrated polyps (with video).

Gastrointest Endosc 2018 Jan 13;87(1):222-231.e2. Epub 2017 Jul 13.

Westmead Hospital, Department of Gastroenterology and Hepatology, Sydney, New South Wales, Australia; Westmead Clinical School, University of Sydney, Sydney, New South Wales, Australia.

Background And Aims: Dysplasia within sessile serrated polyps (SSPs) is difficult to detect and may be mistaken for an adenoma, risking incomplete resection of the background serrated tissue, and is strongly implicated in interval cancer after colonoscopy. The use of endoscopic imaging to detect dysplasia within SSPs has not been systematically studied.

Methods: Consecutively detected SSPs ≥8 mm in size were evaluated by using a standardized imaging protocol at a tertiary-care endoscopy center over 3 years. Lesions suspected as SSPs were analyzed with high-definition white light then narrow-band imaging. A demarcated area with a neoplastic pit pattern (Kudo type III/IV, NICE type II) was sought among the serrated tissue. If this was detected, the lesion was labeled dysplastic (sessile serrated polyp with dysplasia); if not, it was labeled non-dysplastic (sessile serrated polyp without dysplasia). Histopathology was reviewed by 2 blinded specialist GI pathologists.

Results: A total of 141 SSPs were assessed in 83 patients. Median lesion size was 15.0 mm (interquartile range 10-20), and 54.6% were in the right side of the colon. Endoscopic evidence of dysplasia was detected in 36 of 141 (25.5%) SSPs; of these, 5 of 36 (13.9%) lacked dysplasia at histopathology. Two of 105 (1.9%) endoscopically designated non-dysplastic SSPs had dysplasia at histopathology. Endoscopic imaging, therefore, had an accuracy of 95.0% (95% confidence interval [CI], 90.1%-97.6%) and a negative predictive value of 98.1% (95% CI, 92.6%-99.7%) for detection of dysplasia within SSPs.

Conclusions: Dysplasia within SSPs can be detected accurately by using a simple, broadly applicable endoscopic imaging protocol that allows complete resection. Independent validation of this protocol and its dissemination to the wider endoscopic community may have a significant impact on rates of interval cancer. (Clinical trial registration number: NCT03100552.).
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http://dx.doi.org/10.1016/j.gie.2017.06.031DOI Listing
January 2018

Risk Stratification for Covert Invasive Cancer Among Patients Referred for Colonic Endoscopic Mucosal Resection: A Large Multicenter Cohort.

Gastroenterology 2017 09 2;153(3):732-742.e1. Epub 2017 Jun 2.

Department of Gastroenterology and Hepatology, Westmead Hospital, Sydney, New South Wales, Australia; Westmead Clinical School, University of Sydney, School of Medicine, Sydney, New South Wales, Australia. Electronic address:

Background & Aims: Among patients with large colorectal sessile polyps or laterally spreading lesions, it is important to identify those at risk for submucosal invasive cancer (SMIC). Lesions with overt endoscopic evidence of SMIC are referred for surgery, although those without these features might still contain SMIC that is not visible on endoscopic inspection (covert SMIC). Lesions with a high covert SMIC risk might be better suited for endoscopic submucosal dissection than for endoscopic mucosal resection (EMR). We analyzed a group of patients with large colon lesions to identify factors associated with SMIC, and examined lesions without overt endoscopic high-risk signs to determine factors associated with covert SMIC.

Methods: We performed a prospective cohort study of consecutive patients referred for EMR of large sessile or flat colorectal polyps or laterally spreading lesions (≥20 mm) at academic hospitals in Australia from September 2008 through September 2016. We collected data on patient and lesion characteristics, outcomes of procedures, and histology findings. We excluded serrated lesions from the analysis of covert SMIC due to their distinct phenotype and biologic features.

Results: We analyzed 2277 lesions (mean size, 36.9 mm) from 2106 patients (mean age, 67.7 years; 53.2% male). SMIC was evident in 171 lesions (7.6%). Factors associated with SMIC included Kudo pit pattern V, a depressed component (0-IIc), rectosigmoid location, 0-Is or 0-IIa+Is Paris classification, non-granular surface morphology, and increasing size. After exclusion of lesions that were obviously SMIC or serrated, factors associated with covert SMIC were rectosigmoid location (odds ratio, 1.87; P = .01), combined Paris classification, surface morphology (odds ratios, 3.96-22.5), and increasing size (odds ratio, 1.16/10 mm; P = .012).

Conclusions: In a prospective study of 2106 patients who underwent EMR for large sessile or flat colorectal polyps or laterally spreading lesions, we associated rectosigmoid location, combined Paris classification and surface morphology, and increasing size with increased risk for covert malignancy. Rectosigmoid 0-Is and 0-IIa+Is non-granular lesions have a high risk for malignancy, whereas proximally located 0-Is or 0-IIa granular lesions have a low risk. These findings can be used to inform decisions on which patients should undergo endoscopic submucosal dissection, EMR, or surgery. ClinicalTrials.gov, Number: NCT02000141.
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http://dx.doi.org/10.1053/j.gastro.2017.05.047DOI Listing
September 2017

IFN-λ3, not IFN-λ4, likely mediates IFNL3-IFNL4 haplotype-dependent hepatic inflammation and fibrosis.

Nat Genet 2017 May 10;49(5):795-800. Epub 2017 Apr 10.

Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, New South Wales, Australia.

Genetic variation in the IFNL3-IFNL4 (interferon-λ3-interferon-λ4) region is associated with hepatic inflammation and fibrosis. Whether IFN-λ3 or IFN-λ4 protein drives this association is not known. We demonstrate that hepatic inflammation, fibrosis stage, fibrosis progression rate, hepatic infiltration of immune cells, IFN-λ3 expression, and serum sCD163 levels (a marker of activated macrophages) are greater in individuals with the IFNL3-IFNL4 risk haplotype that does not produce IFN-λ4, but produces IFN-λ3. No difference in these features was observed according to genotype at rs117648444, which encodes a substitution at position 70 of the IFN-λ4 protein and reduces IFN-λ4 activity, or between patients encoding functionally defective IFN-λ4 (IFN-λ4-Ser70) and those encoding fully active IFN-λ4-Pro70. The two proposed functional variants (rs368234815 and rs4803217) were not superior to the discovery SNP rs12979860 with respect to liver inflammation or fibrosis phenotype. IFN-λ3 rather than IFN-λ4 likely mediates IFNL3-IFNL4 haplotype-dependent hepatic inflammation and fibrosis.
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http://dx.doi.org/10.1038/ng.3836DOI Listing
May 2017

MBOAT7 rs641738 increases risk of liver inflammation and transition to fibrosis in chronic hepatitis C.

Nat Commun 2016 09 15;7:12757. Epub 2016 Sep 15.

Storr Liver Centre, Westmead Institute for Medical Research and Westmead Hospital, University of Sydney, Sydney, New South Wales 2145, Australia.

Cirrhosis likely shares common pathophysiological pathways despite arising from a variety of liver diseases. A recent GWAS identified rs641738, a polymorphism in the MBOAT7 locus, as being associated with the development of alcoholic cirrhosis. Here we explore the role of this variant on liver inflammation and fibrosis in two cohorts of patients with chronic hepatitis C. In 2,051 patients, rs641738 associated with severe hepatic inflammation and increased risk of fibrosis, as well as fast fibrosis progression. At functional level, rs641738 associated with MBOAT7 transcript and protein levels in liver and blood, and with serum inflammatory, oxidative stress and macrophage activation markers. MBOAT7 was expressed in immune cell subsets, implying a role in hepatic inflammation. We conclude that the MBOAT7 rs641738 polymorphism is a novel risk variant for liver inflammation in hepatitis C, and thereby for liver fibrosis.
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http://dx.doi.org/10.1038/ncomms12757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5027609PMC
September 2016

Deep mural injury and perforation after colonic endoscopic mucosal resection: a new classification and analysis of risk factors.

Gut 2017 10 27;66(10):1779-1789. Epub 2016 Jul 27.

Department of Gastroenterology and Hepatology, Westmead Hospital, Sydney, New South Wales, Australia.

Objectives: Perforation is the most serious complication associated with endoscopic mucosal resection (EMR). We propose a new classification for the appearance and integrity of the muscularis propria (MP) after EMR including various extents of deep mural injury (DMI). Risk factors for these injuries were analysed.

Design: Endoscopic images and histological specimens of consecutive patients undergoing EMR of colonic laterally spreading lesions ≥20 mm at a large Australian tertiary referral endoscopy unit were retrospectively analysed using our new DMI classification system. DMI was graded according to MP injury (I/II intact MP without/with fibrosis, III target sign, IV/V obvious transmural perforation without/with contamination). Histological specimens were examined for included MP and patient outcomes were recorded. All type III-V DMI signs were clipped if possible, types I and II DMI were clipped at the endoscopists' discretion.

Results: EMR was performed in 911 lesions (mean size 37 mm) in 802 patients (male sex 51.4%, mean age 67 years). DMI signs were identified in 83 patients (10.3%). Type III-V DMI was identified in 24 patients (3.0%); clipping was successfully performed in all patients. A clinically significant perforation occurred in two patients (0.2%). Only one of the 59 type I/II cases experienced a delayed perforation. 85.5% of patients with DMI were discharged on the same day, all without sequelae. On multivariable analysis, type III-V DMI was associated with transverse colon location (OR 3.55, p=0.028), en bloc resection (OR 3.84, p=0.005) and high-grade dysplasia or submucosal invasive cancer (OR 2.97, p 0.014).

Conclusions: In this retrospective analysis, use of the new classification and management with clips appeared to be a safe approach. Advanced DMI types (III-V) occurred in 3.0% of patients and were associated with identifiable risk factors. Further prospective clinical studies should use this new classification.

Trial Registration Number: NCT01368289; results.
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http://dx.doi.org/10.1136/gutjnl-2015-309848DOI Listing
October 2017

A standardized imaging protocol is accurate in detecting recurrence after EMR.

Gastrointest Endosc 2017 Mar 22;85(3):518-526. Epub 2016 Jun 22.

Department of Gastroenterology and Hepatology, Westmead Hospital, Sydney, New South Wales, Australia; Westmead Clinical School, University of Sydney, Sydney, New South Wales, Australia.

Background And Aims: EMR of large laterally spreading lesions (LSL) in the colon is a safe and effective alternative to surgery. Post-EMR scar assessment currently involves taking biopsy specimens of the scar to detect residual or recurrent adenoma (RRA). The accuracy of endoscopic imaging of the post-EMR scar is unknown. We aimed to determine the accuracy of a standardized imaging protocol in post-EMR scar assessment.

Methods: Prospective, single-center data from the Australian Colonic EMR study were analyzed. Consecutive patients undergoing first surveillance colonoscopy (SC1) after EMR of a large LSL were eligible. All scars were sequentially examined with high-definition white light (HD-WL) and narrow-band imaging (NBI) in a standardized fashion and then biopsies were performed. Endoscopic recurrence (recurrence at the post-EMR scar detected by systematic endoscopic assessment) was compared with the histologic findings.

Results: One hundred eighty-three post-EMR scars were included. Thirty of 183 (16.4%) were confirmed to have RRA histologically at SC1. Thirty-seven of 183 (20.2%) post-EMR scars demonstrated RRA endoscopically. The sensitivity and specificity of endoscopic RRA detection were 93.3% (95% confidence interval [CI], 77.9%-99.2%) and 94.1% (95% CI, 89.1%-97.3%), respectively. The positive predictive value was 75.7% (95% CI, 58.8%-88.2%) and the negative predictive value was 98.6% (95% CI, 95.1%-99.8%). The diagnostic accuracy was 94.0%. Sensitivity was higher for the combination of HD-WL and NBI as opposed to HD-WL alone (93.3% vs 66.7%). The specificity was high for both HD-WL and HD-WL + NBI (96.1% and 94.1%, respectively). Flat morphology of RRA was better seen with NBI (P = .002).

Conclusions: Endoscopic detection of RRA in the post-EMR scar is highly accurate using a standardized imaging protocol with HD-WL and NBI. This allows real-time, accurate detection of recurrence and its concurrent treatment, and raises the possibility that routine biopsy of the post-EMR scar may not be necessary.
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http://dx.doi.org/10.1016/j.gie.2016.06.031DOI Listing
March 2017

Traditional Serrated Adenomas: Not All Serrations Are the Same.

Am J Gastroenterol 2016 05;111(5):745-6

Department of Gastroenterology and Hepatology, Westmead Hospital, Sydney, New South Wales, Australia.

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http://dx.doi.org/10.1038/ajg.2016.63DOI Listing
May 2016

The macrophage activation marker sCD163 is associated with morphological disease stages in patients with non-alcoholic fatty liver disease.

Liver Int 2016 10 12;36(10):1549-57. Epub 2016 May 12.

Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.

Background & Aims: Macrophage activation plays a key pathogenic role in experimental non-alcoholic fatty liver disease (NAFLD) and contributes to the progression of steatohepatitis (NASH) and fibrosis. We studied macrophage activation in human NAFLD by measuring soluble (s)CD163, a specific macrophage activation marker, hypothesizing that sCD163 would be associated with the patients' morphological disease grade. Furthermore, we investigated an association between sCD163 and the apoptosis marker cytokeratin-18 (CK-18) to explore a link between macrophage activation and apoptosis.

Methods: sCD163 associations with biochemical and histological measures of NAFLD were investigated in two independent cohorts of 157 Australian and 174 Italian NAFLD patients, with liver biopsies graded for NAFLD severity, steatosis and fibrosis. sCD163 and CK-18 were measured by enzyme-linked immunosorbent assay.

Results: In both cohorts sCD163 increased in parallel with the patients' morphological disease grading, being independently associated with the Kleiner fibrosis score (P < 0.001). A high sCD163 predicted advanced fibrosis {F ≥ 3; Australian cohort: area under receiver-operating characteristics curve 0.77 [95% confidence interval (CI): 0.76-0.87], Italian cohort: 0.80 (95% CI: 0.72-0.88)}. In both groups, sCD163 was independently associated with CK-18 (P < 0.001).

Conclusion: Soluble CD163 reflecting macrophage activation is associated with morphological features of NAFLD suggesting their involvement in the pathogenesis of NAFLD, NASH and particularly fibrosis. An independent association between sCD163 and cytokeratin-18 suggests that apoptosis may contribute to macrophage activation in NAFLD/NASH.
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http://dx.doi.org/10.1111/liv.13150DOI Listing
October 2016

Diverse impacts of the rs58542926 E167K variant in TM6SF2 on viral and metabolic liver disease phenotypes.

Hepatology 2016 07 30;64(1):34-46. Epub 2016 Mar 30.

Storr Liver Centre, Westmead Millennium Institute and Westmead Hospital, University of Sydney, NSW, Australia.

Unlabelled: A genome-wide exome association study has identified the transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 variant encoding an E167K substitution as a genetic determinant of hepatic steatosis in nonalcoholic fatty liver disease (NAFLD). The roles of this variant across a spectrum of liver diseases and pathologies and on serum lipids comparing viral hepatitis to NAFLD and viral load in chronic viral hepatitis, as well as its intrahepatic molecular signature, have not been well characterized. We undertook detailed analyses in 3260 subjects with viral and nonviral liver diseases and in healthy controls. Serum inflammatory markers and hepatic expression of TM6SF2 and genes regulating lipid metabolism were assessed in a subset with chronic hepatitis C (CHC). The rs58542926 T allele was more prevalent in 502 NAFLD patients than controls (P = 0.02) but not different in cohorts with CHC (n = 2023) and chronic hepatitis B (n = 507). The T allele was associated with alterations in serum lipids and hepatic steatosis in all diseases and with reduced hepatic TM6SF2 and microsomal triglyceride transfer protein expression. Interestingly, the substitution was associated with reduced CHC viral load but increased hepatitis B virus DNA. The rs58542926 T allele had no effect on inflammation, impacted ≥F2 fibrosis in CHC and NAFLD assessed cross-sectionally (odds ratio = 1.39, 95% confidence interval 1.04-1.87, and odds ratio = 1.62, 95% confidence interval 1.03-2.52, respectively; P < 0.03 for both), but had no effect on fibrosis progression in 1174 patients with CHC and a known duration of infection.

Conclusion: The TM6SF2 E167K substitution promotes steatosis and lipid abnormalities in part by altering TM6SF2 and microsomal triglyceride transfer protein expression and differentially impacts CHC and chronic hepatitis B viral load, while effects on fibrosis are marginal. (Hepatology 2016;64:34-46).
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http://dx.doi.org/10.1002/hep.28475DOI Listing
July 2016

Endoscopic mucosal resection for large serrated lesions in comparison with adenomas: a prospective multicentre study of 2000 lesions.

Gut 2017 04 19;66(4):644-653. Epub 2016 Jan 19.

Departments of Gastroenterology and Hepatology, Westmead Hospital, Sydney, New South Wales, Australia.

Objective: Endoscopic mucosal resection (EMR) is effective for large laterally spreading flat and sessile lesions (LSLs). Sessile serrated adenomas/polyps (SSA/Ps) are linked to the relative failure of colonoscopy to prevent proximal colorectal cancer. We aimed to examine the technical success, adverse events and recurrence following EMR for large SSA/Ps in comparison with large conventional adenomas.

Design: Over 74 months till August 2014, prospective multicentre data of LSLs ≥20 mm were analysed. A standardised dye-based conventional EMR technique followed by scheduled surveillance colonoscopy was used.

Results: From a total of 2000 lesions, 323 SSA/Ps in 246 patients and 1527 adenomas in 1425 patients were included for analysis. Technical success for EMR was superior in SSA/Ps compared with adenomas (99.1% vs 94.5%, p<0.001). Significant bleeding and perforation were similar in both cohorts. The cumulative recurrence rates for adenomas after 6, 12, 18 and 24 months were 16.1%, 20.4%, 23.4% and 28.4%, respectively. For SSA/Ps, they were 6.3% at 6 months and 7.0% from 12 months onwards (p<0.001). Following multivariable adjustment, the HR of recurrence for adenomas versus SSA/Ps was 1.7 (95% CI 0.9 to 3.0, p=0.097). Subgroup analysis by lesion size revealed an eightfold increased risk of recurrence for 20-25 mm adenomas versus SSA/Ps, but no significantly different risk between lesion types in larger lesion groups.

Conclusion: Recurrence after EMR of 20-25 mm LSLs is significantly less frequent in SSA/Ps compared with adenomatous lesions. SSA/Ps can be more effectively removed than adenomatous LSLs with equivalent safety. Ensuring complete initial resection is imperative for avoiding recurrence.

Trial Registration Number: ClinicalTrials.gov NCT01368289.
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http://dx.doi.org/10.1136/gutjnl-2015-310249DOI Listing
April 2017

FibroGENE: A gene-based model for staging liver fibrosis.

J Hepatol 2016 Feb 1;64(2):390-398. Epub 2015 Dec 1.

Storr Liver Centre, The Westmead Millennium Institute for Medical Research and Westmead Hospital, The University of Sydney, NSW, Australia. Electronic address:

Background & Aims: The extent of liver fibrosis predicts long-term outcomes, and hence impacts management and therapy. We developed a non-invasive algorithm to stage fibrosis using non-parametric, machine learning methods designed for predictive modeling, and incorporated an invariant genetic marker of liver fibrosis risk.

Methods: Of 4277 patients with chronic liver disease, 1992 with chronic hepatitis C (derivation cohort) were analyzed to develop the model, and subsequently validated in an independent cohort of 1242 patients. The model was assessed in cohorts with chronic hepatitis B (CHB) (n=555) and non-alcoholic fatty liver disease (NAFLD) (n=488). Model performance was compared to FIB-4 and APRI, and also to the NAFLD fibrosis score (NFS) and Forns' index, in those with NAFLD.

Results: Significant fibrosis (⩾F2) was similar in the derivation (48.4%) and validation (47.4%) cohorts. The FibroGENE-DT yielded the area under the receiver operating characteristic curve (AUROCs) of 0.87, 0.85 and 0.804 for the prediction of fast fibrosis progression, cirrhosis and significant fibrosis risk, respectively, with comparable results in the validation cohort. The model performed well in NAFLD and CHB with AUROCs of 0.791, and 0.726, respectively. The negative predictive value to exclude cirrhosis was>0.96 in all three liver diseases. The AUROC of the FibroGENE-DT performed better than FIB-4, APRI, and NFS and Forns' index in most comparisons.

Conclusion: A non-invasive decision tree model can predict liver fibrosis risk and aid decision making.
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http://dx.doi.org/10.1016/j.jhep.2015.11.008DOI Listing
February 2016

Comparison of the histopathological effects of two electrosurgical currents in an in vivo porcine model of esophageal endoscopic mucosal resection.

Endoscopy 2016 Feb 4;48(2):117-22. Epub 2015 Nov 4.

Department of Gastroenterology and Hepatology, Westmead Hospital, Sydney, New South Wales, Australia.

Background And Study Aims: Stricture formation is the main limitation of endoscopic resection in the esophagus. The optimal electrosurgical current (ESC) for endoscopic resection in the esophagus and other gastrointestinal sites is unknown. There may be a relationship between the type of ESC used and the development of post-procedure esophageal stricture. Unlike the low power coagulating current (LPCC), the microprocessor-controlled current (MCC), which alternates between short pulse cutting and coagulation, avoids high peak voltages that are thought to result in deep thermal injury. The aim of this study was to determine the histopathological variables associated with these two commonly employed ESCs used for esophageal endoscopic resection.

Methods: Standardized endoscopic resection of normal mucosa by band mucosectomy was performed by a single endoscopist in 12 adult pigs. The procedures were randomized 1 : 1 to either LPCC (ERBE 100 C at 25 W) or MCC (ERBE Endocut Q, Effect 3). Necropsy and esophagectomy were performed at 72 hours after the procedure. Two histopathologists, who were blinded to the ESC allocation, independently assessed the presence and depth of ulceration, necrosis and inflammation.

Results: A total of 45 resections were analyzed. In the LPCC and MCC groups, ulceration extending into the muscularis propria was present in 9/24 (37.5 %) and 1/21 (4.8 %) resected specimens, respectively (P = 0.04). Necrosis extending into the muscularis propria was present in 13/24 (54.1 %) and 1/21 (4.8 %) resected specimens, respectively (P = 0.002). One case of microperforation with muscularis propria injury was noted in the LPCC group compared with none in the MCC group. The quantified mean depth of ulceration, necrosis, and acute inflammation was significantly greater in the LPCC group. 

Conclusions: In an in vivo porcine survival model of esophageal endoscopic mucosal resection, the use of MCC resulted in significantly less deep thermal ulceration, necrosis, and acute inflammation compared with LPCC. MCC should be used in preference over LPCC for esophageal endoscopic resection.
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http://dx.doi.org/10.1055/s-0034-1393303DOI Listing
February 2016

Markers of Collagen Remodeling Detect Clinically Significant Fibrosis in Chronic Hepatitis C Patients.

PLoS One 2015 25;10(9):e0137302. Epub 2015 Sep 25.

Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.

Background And Aim: Detection of advanced fibrosis (Metavir F≥3) is important to identify patients with a high urgency of antiviral treatments vs. those whose treatment could be deferred (F≤2). The aim was to assess the diagnostic value of novel serological extracellular matrix protein fragments as potential biomarkers for clinically significant and advanced fibrosis.

Methods: Specific protein fragments of matrix metalloprotease degraded type I, III, IV and VI collagen (C1M, C3M, C4M, C6M) and type III and IV collagen formation (Pro-C3 and P4NP7S) were assessed in plasma from 403 chronic hepatitis C patients by specific ELISAs. Patients were stratified according to Metavir Fibrosis stage; F0 (n = 46), F1 (n = 161), F2 (n = 95), F3 (n = 44) and F4 (n = 33) based on liver biopsy.

Results: Pro-C3 was significantly elevated in patients with significant fibrosis (≥F2) compared to F0-F1 (p<0.05), while the markers C3M, C4M, C6M and P4NP7S were significantly elevated in patients with advanced fibrosis (≥F3) compared to F0-F2 (p<0.05). C1M showed no difference between fibrosis stages. Using Receiver Operating Characteristics analysis, the best marker for detecting ≥F2 and ≥F3 was Pro-C3 with AUC = 0.75 and AUC = 0.86. Combination of Pro-C3 and C4M with age, BMI and gender in a multiple ordered logistic regression model improved the diagnostic value for detecting ≥F2 and ≥F3 with AUC = 0.80 and AUC = 0.88.

Conclusion: The Pro-C3 protein fragment provided clinically relevant diagnostic accuracy as a single marker of liver fibrosis. A model combining Pro-C3 and C4M along with patient's age, body mass index and gender increased the diagnostic power for identifying clinically significant fibrosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0137302PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4583995PMC
May 2016

The influence of clips on scars after EMR: clip artifact.

Gastrointest Endosc 2016 Mar 10;83(3):608-16. Epub 2015 Sep 10.

Department of Gastroenterology and Hepatology, Westmead Hospital, New South Wales, Australia; Westmead Clinical School, University of Sydney, New South Wales, Australia.

Background And Aims: Laterally spreading lesions ≥20 mm are conventionally removed by EMR. Endoscopic clips are increasingly used to mitigate the risk of delayed bleeding. Clips may alter the endoscopic appearance of the scar after EMR, interfering with the assessment of adenoma recurrence. We aimed to evaluate this.

Methods: Prospective, single-center data from the Australian Colonic Endoscopic resection study (January 2011-May 2015) were analyzed. Patients undergoing EMR of laterally spreading lesions with endoscopic clips used at the EMR defect were eligible. Data included patient and lesion characteristics and procedural, clinical, and histologic outcomes.

Results: Clips were used in 111 of 885 lesions (12.5%). A total of 62 of 111 clipped lesions had standardized, high-definition, white light, and narrow-band images of the scars after EMR at first surveillance colonoscopy, and the patients were enrolled. Analysis of the images showed 4 situations: a bland scar (N = 27), residual adenoma (N = 6), mucosal elevation with normal pit pattern (N = 14), or granulation tissue related to the presence of residual clips (N = 15). The latter 2 entities were termed post-EMR scar clip artifact (ESCA). Overall, 29 of 62 previously clipped EMR sites (46.8%) had ESCA at a median follow-up of 5.2 months. Twenty scars had residual clips, and 15 of 20 (75.0%) showed ESCA (P = .002). Lesions clipped for prophylaxis of bleeding were more likely to show ESCA than those clipped for deep mural injury or intraprocedural bleeding (65.5% vs 41.7%; P = .006). ESCA was associated with female sex (P = .010) and greater age (P = .011).

Conclusions: ESCA is characterized by a nodular elevation of the mucosa with a normal pit pattern and can occur with or without residual clips. Prophylactic clip closure and the presence of residual clips are associated with ESCA. (

Clinical Trial Registration Number: NCT01368289.).
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http://dx.doi.org/10.1016/j.gie.2015.08.071DOI Listing
March 2016

Characterization and significance of protrusions in the mucosal defect after cold snare polypectomy.

Gastrointest Endosc 2015 Sep 22;82(3):523-8. Epub 2015 Apr 22.

Department of Gastroenterology and Hepatology, Westmead Hospital, Sydney, New South Wales, Australia; University of Sydney, Sydney, New South Wales, Australia.

Background: Cold snare polypectomy (CSP) is widely practiced; however, the endoscopic features of the CSP mucosal defect have not been studied. In particular, protrusions within the cold snare defect (CSDPs) may create concern for residual polyp. The frequency and constituents of this phenomenon are unknown.

Objective: To describe the frequency, predictors, and histologic constituents of CSDPs.

Design: Prospective observational study.

Setting: Tertiary-care hospital endoscopy unit.

Patients: Eighty-eight consecutive patients undergoing CSP for a polyp ≤ 10 mm in size.

Intervention: Inspection of the cold snare mucosal defect with high-definition white light and biopsy sampling of CSDPs for separate histologic assessment, when present.

Main Outcome Measurement: Frequency and constituents of CSDPs.

Results: Two hundred fifty-seven consecutive polyps ≤ 10 mm in size were removed in 88 patients (50 men [57%], mean age 63 years). Polyps were predominately adenomatous (162, 63%), located in the proximal colon (159, 62%) and flat (200, 78%). Mean lesion size was 5.5 mm (range, 2-10 mm). High-grade dysplasia was present in a single polyp for which the defect was bland. CSDPs occurred in 36 polypectomies (14%). CSDPs were associated with polyp size ≥ 6 mm (odds ratio, 3.7; P < .001 multivariable analysis) but not age, sex, lesion, histopathology, morphology, or location. Histopathologic examination of CSDPs revealed submucosa in 34 (94%) and muscularis mucosa in 29 (80%). No residual adenomatous or serrated polyp tissue was detected.

Limitations: Single-center study. Small number of polyps with high-grade dysplasia.

Conclusion: Protrusions are common within the CSP mucosal defect and are associated with polyp size ≥ 6 mm. CSDPs do not represent vascular structures, do not contain residual polyp, and are not associated with adverse outcomes in short-term follow-up. However, CSDPs represent incomplete mucosal layer resection.
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http://dx.doi.org/10.1016/j.gie.2015.01.051DOI Listing
September 2015

Interferon-λ rs12979860 genotype and liver fibrosis in viral and non-viral chronic liver disease.

Nat Commun 2015 Mar 5;6:6422. Epub 2015 Mar 5.

Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Sydney, New South Wales 2145, Australia.

Tissue fibrosis is a core pathologic process that contributes to mortality in ~45% of the population and is likely to be influenced by the host genetic architecture. Here we demonstrate, using liver disease as a model, that a single-nucleotide polymorphism (rs12979860) in the intronic region of interferon-λ4 (IFNL4) is a strong predictor of fibrosis in an aetiology-independent manner. In a cohort of 4,172 patients, including 3,129 with chronic hepatitis C (CHC), 555 with chronic hepatitis B (CHB) and 488 with non-alcoholic fatty liver disease (NAFLD), those with rs12979860CC have greater hepatic inflammation and fibrosis. In CHC, those with rs12979860CC also have greater stage-constant and stage-specific fibrosis progression rates (P<0.0001 for all). The impact of rs12979860 genotypes on fibrosis is maximal in young females, especially those with HCV genotype 3. These findings establish rs12979860 genotype as a strong aetiology-independent predictor of tissue inflammation and fibrosis.
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http://dx.doi.org/10.1038/ncomms7422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4366528PMC
March 2015