Location and appearance of dysplastic Barrett's esophagus recurrence after endoscopic eradication therapy: no additional yield from random biopsy sampling neosquamous mucosa.

BACKGROUND AND AIMS: Surveillance after complete remission of intestinal metaplasia (CRIM) is essential. Current recommendations are to sample visible lesions first, followed by random 4-quadrant biopsy sampling of the original Barrett's esophagus (BE) length. To inform post-CRIM surveillance protocols, we aimed to identify the anatomic location, appearance, and histology of BE recurrences. METHODS: We performed an analysis of 216 patients who achieved CRIM after endoscopic eradication therapy for dysplastic BE at a Barrett's Referral Unit between 2008 and 2021. The anatomic location, recurrence histology, and endoscopic appearance of dysplastic recurrences were evaluated. RESULTS: After a median of 5.5 years (interquartile range, 2.9-7.2) of follow-up after CRIM, 57 patients (26.4%) developed nondysplastic BE (NDBE) recurrence and 18 patients (8.3%) developed dysplastic recurrence. From 8158 routine surveillance biopsy samplings of normal-appearing tubular esophageal neosquamous epithelium, the yield for recurrent NDBE or dysplasia was 0%. One hundred percent of dysplastic tubular esophageal recurrences were visible and in BE islands, whereas 77.8% of gastroesophageal junction dysplastic recurrences were nonvisible. Four distinct endoscopic features suspicious for recurrent advanced dysplasia or neoplasia were identified: buried or subsquamous BE, irregular mucosal pattern, loss of vascular pattern, and nodularity or depression. CONCLUSIONS: The yield of routine surveillance biopsy sampling of normal-appearing tubular esophageal neosquamous epithelium was zero. BE islands with indistinct mucosal or loss of vascular pattern, nodularity or depression, and/or signs of buried BE should raise clinician suspicion for advanced dysplasia or neoplasia recurrence. We suggest a new surveillance biopsy sampling protocol with a focus on meticulous inspection, followed by targeted biopsy sampling of visible lesions and random 4-quadrant biopsy sampling of the gastroesophageal junction.

Direct percutaneous endoscopic gastrostomy for nutritional support in patients with aerodigestive tract cancers.

BACKGROUND: Conventional pull-through percutaneous endoscopic gastrostomy (PEG) risks infection and tumour implantation in head and neck cancers. Endoscopically inserted direct gastrostomy has lower rates of complications but is underutilised. AIMS: To describe the endoscopic steps for direct gastrostomy insertion and review our single-centre experience to assess the technical feasibility and safety. METHODS: Patients who underwent endoscopic direct gastrostomy insertion between December 2016 and June 2021 were included. A 24Fr introducer kit for gastrostomy feeding tube (Avanos Healthcare, Australia) was used. Patient and tumour characteristics, procedural data and 30-day outcomes were recorded. RESULTS: Thirty patients underwent direct PEG insertion (mean age 64 years and 24 male). All were planned for or currently undergoing radiotherapy. Twenty-six (87%) of 30 cases were performed under conscious sedation over a median procedure time of 21 min (interquartile range 11 min). No tumour seeding was seen, and one case of PEG-site infection was observed. CONCLUSIONS: Direct PEG is safe and effective and should be considered for patients with aerodigestive tract cancer in need of nutritional support.

Hepatitis B Virus Flares After Nucleot(s)ide Analogue Cessation Are Associated With Activation of Toll-Like Receptor Signaling Pathways.

BACKGROUND: We evaluated the patterns of peripheral Toll-like receptor (TLR) signaling activity and the expression of TLRs and natural killer (NK) cell activation in a cohort of patients experiencing severe hepatitis flares after stopping nucleot(s)ide analogues (NAs) therapy. METHODS: Samples were collected longitudinally from patients with chronic hepatitis B who were enrolled in a prospective study of NA discontinuation. Patients experiencing hepatitis flares were compared with patients with normal alanine aminotransferase. Peripheral blood mononuclear cells (PBMCs) were stimulated with TLR ligands and cytokine secretion in the cell culture supernatant measured. Expression of TLR2/4, NKG2D, NKp46, and triggering receptor expressed on myeloid cells 1 (TREM-1) on monocytes, NK, and NK-T cells was measured. RESULTS: Seventeen patients with severe reactivation hepatitis flares were compared to 12 nonflare patients. Hepatitis flares were associated with increased activity of TLR2-8 and TLR9 signaling in PBMCs at the time of peak flare compared to baseline. Hepatitis flares were also associated with (1) upregulation of TLR2 and (2) TREM-1 receptor expression on NK. There were no differences at baseline between flare patients and nonflare patients. CONCLUSIONS: Hepatitis flares off NA therapy have a significant innate inflammatory response with upregulation of TLR signaling on peripheral monocytes and TLR2 and TREM-1 expression on NK cells. This implicates the innate immune system in the immunopathogenesis of hepatitis B flares.

Quality of upper GI endoscopy: a prospective cohort study on impact of endoscopist education.

BACKGROUND AND AIMS: Guidelines on quality of upper GI (UGI) endoscopy have been proposed by the British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE). However, these guidelines have not been evaluated in clinical practice. We aimed to measure the impact of endoscopist education on the quality of gastroscopy based on these guidelines and the association between compliance with guidelines and the detection of clinically significant premalignant pathology such as Barrett's esophagus (BE), esophageal squamous dysplasia, gastric intestinal metaplasia (GIM), and Helicobacter pylori. METHODS: Endoscopists participated in a 1-hour education session on recommended performance measures and endoscopic detection of premalignant pathologies. A controlled before and after study was performed, measuring compliance with guidelines and rates of detection of pathology in control and intervention groups. RESULTS: Over 2 years, 2719 procedures were performed: 1412 in the control group and 1307 in the intervention group. The proportion of procedures complying with guidelines was higher in the intervention group. The use of biopsy sampling protocols (eg, management of precancerous conditions of the stomach, 52% vs 91%; P = .007) and standardized terminology (eg, Forrest classification, 24% vs 68%; P < .001) was significantly higher. Detection of H pylori was higher in the intervention group (5.5% vs 9.8%, P = .003). Minimum inspection time of 7 minutes was associated with detection of BE (7.4% vs 2.0%, P < .001). CONCLUSIONS: A simple endoscopist education session enhanced the quality of UGI endoscopy by improving compliance with BSG and ESGE recommendations and increasing the detection of clinically significant pathology. A minimum inspection time of 7 minutes was associated with increased diagnostic yield and may be a feasible quality indicator for clinical practice.

Barrett's esophagus with low-grade dysplasia: high rate of upstaging at Barrett's esophagus referral units suggests progression rates may be overestimated.

BACKGROUND AND AIMS: The reported progression rate from low-grade dysplasia (LGD) in Barrett's esophagus (BE) to high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) ranges from .4% to 13.4% per year. We hypothesize that some reported progression rates may be overestimated because of prevalent HGD or EAC that was not identified during endoscopic assessments performed in the community. Our aim is to determine the proportion of prevalent HGD or EAC detected by BE referral units (BERUs) in patients referred from the community with a recent diagnosis of LGD. METHODS: All patients referred from the community to 6 BERUs with a diagnosis of BE with LGD were identified. Patients with an assessment endoscopy performed at BERUs more than 6 months from their referral endoscopy in the community were excluded. Visible lesions and histology outcomes were compared between the community referral endoscopy and the assessment endoscopy performed at BERUs. RESULTS: The median time between BERU assessment and referral endoscopy was 79 days (interquartile range, 54-114). Of the 75 patients referred from the community with LGD, BERU assessment identified HGD or EAC in 20 patients (27%). BERU assessment identified more visible lesions than referral endoscopy performed in the community (39 [52%] vs 9 [12%], respectively; P = .029). CONCLUSIONS: BERU assessment endoscopy identified more visible lesions than community referral endoscopy and identified HGD or EAC in 27% of patients referred from the community with a recent diagnosis of LGD. Reported progression rates from LGD to HGD or EAC may be overestimated.

Quantifying early gastric cancer in Australia: What is the opportunity for gastric endoscopic submucosal dissection?

BACKGROUND AND AIMS: Endoscopic submucosal dissection (ESD) is the recommended treatment for early gastric cancer (EGC). However, there are challenges in attaining expertise in ESD in countries where the incidence of gastric cancer and proportion diagnosed at an early stage of disease are relatively low. This study aims to establish the proportion of gastric cancer meeting histological criteria for EGC, which may be suitable for ESD, in a Western population. METHODS: Gastric cancers reported to the Victorian Cancer Registry between January 2011 and December 2016 were analyzed. EGC was defined as tumor confined to mucosa (T1a) or submucosa (T1b). Histology reports were analyzed using Japanese and European guidelines to identify potential ESD candidates. Criteria for extended ESD were based on grade of differentiation, tumor depth, lymphovascular and perineural invasion, and ulceration. RESULTS: Twenty percent of 1217 gastric cancers was EGC (237 cases), with detailed histopathology reports suitable for evaluating ESD criteria recorded in 182 cases. Standard and extended ESD criteria were met in 46% (84/182) and 75% (132/182), respectively. Actual treatment of the 237 EGC was endoscopic in 14% (n = 33) and surgery in 86% (n = 204). Endoscopically treated EGCs were more likely to be stage T1a and located in the proximal stomach. CONCLUSIONS: EGCs represented 20% of reported gastric adenocarcinomas with the majority fulfilling criteria for ESD. ESD should be considered in the management algorithm and discussed at tumor board meetings involving interventional endoscopists. To increase utilization of ESD, systems need to be implemented to improve training, accreditation, and access to ESD.

Toll-like Receptor Expression and Signaling in Peripheral Blood Mononuclear Cells Correlate With Clinical Outcomes in Acute Hepatitis C Virus Infection.

BACKGROUND: Mechanisms by which spontaneous clearance of acute hepatitis C occurs are unclear. A critical role for the innate immune system and IFNL4 polymorphisms has been proposed. This study investigates whether Toll-like receptor (TLR) expression and signaling during acute hepatitis C correlates with clinical outcomes. METHODS: Participants identified from the Australian Trial in Acute Hepatitis C and the Networks study were followed longitudinally from the time of diagnosis of acute hepatitis C. Peripheral blood mononuclear cells (PBMCs) and plasma were collected at and 2 time points after diagnosis. At each time point, TLR2, TLR4, and CD86 expression on peripheral blood monocytes, natural killer (NK) cells, and NK T cells was measured, as well as the response of PBMCs to stimulation with TLR ligands. Cytokine and chemokine levels were measured in stimulated PBMCs and plasma. RESULTS: We identified 20 participants with acute hepatitis C (10 with hepatitis C virus [HCV] monoinfection and 10 with HCV and human immunodeficiency virus coinfection). Eleven participants (55%) spontaneously cleared HCV. Acute hepatitis C and spontaneous clearance was associated with lower TLR4 expression on monocytes (P = .009) and NK cells (P = .029). Acute hepatitis C and spontaneous clearance was also associated with a reduced interferon γ response to TLR4 (P = .038) and TLR7/8 stimulation (P = .035), a reduced interleukin 6 response to TLR7/8 stimulation (P = .037), and reduced IFN-γ-inducible protein 10 (IP-10) response to TLR2 stimulation (P = .042). Lower plasma IP-10 levels were associated with spontaneous clearance (P = .001). CONCLUSIONS: These findings implicate TLR4 signaling as playing a critical role in the outcome of acute hepatitis C.

Crohn's disease management after intestinal resection: a randomised trial.

BACKGROUND: Most patients with Crohn's disease need an intestinal resection, but a majority will subsequently experience disease recurrence and require further surgery. This study aimed to identify the optimal strategy to prevent postoperative disease recurrence. METHODS: In this randomised trial, consecutive patients from 17 centres in Australia and New Zealand undergoing intestinal resection of all macroscopic Crohn's disease, with an endoscopically accessible anastomosis, received 3 months of metronidazole therapy. Patients at high risk of recurrence also received a thiopurine, or adalimumab if they were intolerant to thiopurines. Patients were randomly assigned to parallel groups: colonoscopy at 6 months (active care) or no colonoscopy (standard care). We used computer-generated block randomisation to allocate patients in each centre to active or standard care in a 2:1 ratio. For endoscopic recurrence (Rutgeerts score ≥i2) at 6 months, patients stepped-up to thiopurine, fortnightly adalimumab with thiopurine, or weekly adalimumab. The primary endpoint was endoscopic recurrence at 18 months. Patients and treating physicians were aware of the patient's study group and treatment, but central reading of the endoscopic findings was undertaken blind to the study group and treatment. Analysis included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00989560. FINDINGS: Between Oct 13, 2009, and Sept 28, 2011, 174 (83% high risk across both active and standard care groups) patients were enrolled and received at least one dose of study drug. Of 122 patients in the active care group, 47 (39%) stepped-up treatment. At 18 months, endoscopic recurrence occurred in 60 (49%) patients in the active care group and 35 (67%) patients in the standard care group (p=0.03). Complete mucosal normality was maintained in 27 (22%) of 122 patients in the active care group versus four (8%) in the standard care group (p=0.03). In the active care arm, of those with 6 months recurrence who stepped up treatment, 18 (38%) of 47 patients were in remission 12 months later; conversely, of those in remission at 6 months who did not change therapy recurrence occurred in 31 (41%) of 75 patients 12 months later. Smoking (odds ratio [OR] 2.4, 95% CI 1.2-4.8, p=0.02) and the presence of two or more clinical risk factors including smoking (OR 2.8, 95% CI 1.01-7.7, p=0.05) increased the risk of endoscopic recurrence. The incidence and type of adverse and severe adverse events did not differ significantly between patients in the active care and standard care groups (100 [82%] of 122 vs 45 [87%] of 52; p=0.51) and (33 [27%] of 122 vs 18 [35%] of 52; p=0.36), respectively. INTERPRETATION: Treatment according to clinical risk of recurrence, with early colonoscopy and treatment step-up for recurrence, is better than conventional drug therapy alone for prevention of postoperative Crohn's disease recurrence. Selective immune suppression, adjusted for early recurrence, rather than routine use, leads to disease control in most patients. Clinical risk factors predict recurrence, but patients at low risk also need monitoring. Early remission does not preclude the need for ongoing monitoring. FUNDING: AbbVie, Gutsy Group, Gandel Philanthropy, Angior Foundation, Crohn's Colitis Australia, and the National Health and Medical Research Council.

Measurement of fecal calprotectin improves monitoring and detection of recurrence of Crohn's disease after surgery.

BACKGROUND & AIMS: Crohn's disease (CD) usually recurs after intestinal resection; postoperative endoscopic monitoring and tailored treatment can reduce the chance of recurrence. We investigated whether monitoring levels of fecal calprotectin (FC) can substitute for endoscopic analysis of the mucosa. METHODS: We analyzed data collected from 135 participants in a prospective, randomized, controlled trial, performed at 17 hospitals in Australia and 1 hospital in New Zealand, that assessed the ability of endoscopic evaluations and step-up treatment to prevent CD recurrence after surgery. Levels of FC, serum levels of C-reactive protein (CRP), and Crohn's disease activity index (CDAI) scores were measured before surgery and then at 6, 12, and 18 months after resection of all macroscopic Crohn's disease. Ileocolonoscopies were performed at 6 months after surgery in 90 patients and at 18 months after surgery in all patients. RESULTS: Levels of FC were measured in 319 samples from 135 patients. The median FC level decreased from 1347 µg/g before surgery to 166 µg/g at 6 months after surgery, but was higher in patients with disease recurrence (based on endoscopic analysis; Rutgeerts score, ≥i2) than in patients in remission (275 vs 72 µg/g, respectively; P < .001). Combined 6- and 18-month levels of FC correlated with the presence (r = 0.42; P < .001) and severity (r = 0.44; P < .001) of CD recurrence, but the CRP level and CDAI score did not. Levels of FC greater than 100 µg/g indicated endoscopic recurrence with 89% sensitivity and 58% specificity, and a negative predictive value (NPV) of 91%; this means that colonoscopy could have been avoided in 47% of patients. Six months after surgery, FC levels less than 51 µg/g in patients in endoscopic remission predicted maintenance of remission (NPV, 79%). In patients with endoscopic recurrence at 6 months who stepped-up treatment, FC levels decreased from 324 µg/g at 6 months to 180 µg/g at 12 months and 109 µg/g at 18 months. CONCLUSIONS: In this analysis of data from a prospective clinical trial, FC measurement has sufficient sensitivity and NPV values to monitor for CD recurrence after intestinal resection. Its predictive value might be used to identify patients most likely to relapse. After treatment for recurrence, the FC level can be used to monitor response to treatment. It predicts which patients will have disease recurrence with greater accuracy than CRP level or CDAI score.

Liver stiffness plus platelet count can be used to exclude high-risk oesophageal varices.

BACKGROUND/AIMS: Endoscopic screening for high-risk gastro-oesophageal varices (GOV) is recommended for compensated cirrhotic patients with transient elastography identifying increasing numbers of patients with cirrhosis without portal hypertension. Using liver stiffness measurement (LSM) ± platelet count, the aim was to develop a simple clinical rule to exclude the presence of high-risk GOV in patients with Child-Pugh A cirrhosis. METHODS: A retrospective analysis of 71 patients with Child-Pugh A cirrhosis diagnosed by transient elastography (LSM >13.6 kPa) who underwent screening gastroscopy was conducted. A predictive model using LSM ± platelet count was assessed to exclude the presence of high-risk GOV (diameter >5 mm and/or the presence of high-risk stigmata) and validated using a second cohort of 200 patients from two independent centres. RESULTS: High-risk GOV were present in 10 (15%) and 16 (8%) of the training and validation cohorts, respectively, which was associated with LSM and Pl count (P < 0.05). A combined model based on LSM and Pl count was more accurate for excluding the presence of high-risk GOV than either alone (training cohort AUROC: 0.87 [0.77-0.96] vs. 0.78 [0.65-0.92] for LSM and 0.71 [0.52-0.90] for platelets) with the combination of LSM ≤25 kPa and Pl ≥100 having a NPV of 100% in both the training and validation cohorts. A total of 107 (39%) patients meet this criterion. CONCLUSION: The combination of LSM ≤25 kPa and Pl ≥100 can be used in clinical practice to exclude the presence of high-risk GOV in patients with Child-Pugh A cirrhosis.

ITPA genotype protects against anemia during peginterferon and ribavirin therapy but does not influence virological response.

UNLABELLED: On-treatment anemia is associated with higher sustained virological response (SVR) rates during peginterferon plus ribavirin (RBV) therapy. Inosine triphosphatase (ITPA) variants causing ITPase deficiency have been shown to protect against RBV-induced anemia. However, ITPase activity has not been associated with SVR. To study this discrepancy, we examined the relationships between ITPase activity, on-treatment anemia, SVR, and RBV levels in hepatitis C virus genotype 1 (HCV-1) patients from the CHARIOT study. ITPA genotype (rs7270101, rs1127354) was used to define ITPase activity in 546 patients. Plasma RBV levels were measured using high-performance liquid chromatography (HPLC). Relationships between ITPase activity, on-treatment hemoglobin (Hb) levels, RBV levels, and SVR were tested using regression modeling, survival analysis, and locally weighted scatterplot smoothing (LOWESS) plot analysis. Hb decline was independently associated with SVR (P<0.0001). ITPase deficiency was present in 35%. ITPase deficiency strongly protected against Hb decline (P<0.0001), but was not associated with SVR (P=0.28). The probability of SVR increased with lower nadir Hb for both wild-type and deficient ITPase activity, but the association curve shifted to describe a parallel relationship at higher Hb levels in patients with ITPase deficiency. In a subset (n=203), we tested the hypothesis that the association between Hb decline and SVR reflected RBV levels rather than actual Hb level. RBV levels were associated with on-treatment Hb decline and SVR, but not ITPase activity. In regression models, adjustment for RBV levels attenuated the association between Hb decline and SVR. CONCLUSION: ITPase deficiency protects against RBV-induced anemia, but is not associated with SVR. Our data suggest that the relationship between Hb decline and SVR is not mechanistic, but is linked to RBV levels.

Detection and staging of esophageal cancers within Barrett's esophagus is improved by assessment in specialized Barrett's units.

BACKGROUND: Identification and resection of mucosal abnormalities are critical in managing dysplastic Barrett's esophagus (BE) because these areas may harbor esophageal adenocarcinoma (EAC). OBJECTIVES: To compare mucosal lesion and EAC detection rates in dysplastic BE in the community versus a BE unit and assess the impact of EMR on disease staging and management. DESIGN: Prospective cohort study. SETTING: Tertiary referral center. PATIENTS: Patients with dysplastic BE. INTERVENTIONS: Reassessment with high-definition white-light endoscopy (HD-WLE), narrow-band imaging (NBI), and Seattle protocol biopsies. EMR performed in lesions thought to harbor neoplasia. Review of referral histology and endoscopies. MAIN OUTCOME MEASUREMENTS: Mucosal lesion and EAC detection rates in a BE unit versus the community. Impact of EMR on management. RESULTS: Sixty-nine patients were referred (88% male; median age, 69 years). At referral, HD-WLE/NBI use was 57%/14%, and Seattle protocol adherence was 20%. Eighteen patients had intramucosal cancer. Lesions were detected in 65 patients in the BE unit versus 29 patients at referral (P < .001). EMR was performed in 47 patients. BE unit assessment confirmed EAC in all 18 patients and identified 10 additional patients (56% increased cancer detection, P = .036); all 10 had lesions identified in the BE unit (vs 3 identified at referral). EMR in these patients found submucosal cancer (n = 4) and intramucosal cancer (n = 6), resulting in esophagectomy (n = 4) and chemoradiotherapy (n = 1). LIMITATION: Academic center. CONCLUSION: BE assessment at a BE unit resulted in increased lesion and EAC detection. EMR of early cancers was critical in optimizing patient management. These data suggest that BE unit referral be considered in patients with dysplastic BE.

The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) affects up to 30% of the population and signifies increased risk of liver fibrosis and cirrhosis, type 2 diabetes, and cardiovascular disease. Therapies are limited. Weight loss is of benefit but is difficult to maintain. We aimed at examining the effect of the Mediterranean diet (MD), a diet high in monounsaturated fatty acids, on steatosis and insulin sensitivity, using gold standard techniques. METHODS: Twelve non-diabetic subjects (6 Females/6 Males) with biopsy-proven NAFLD were recruited for a randomised, cross-over 6-week dietary intervention study. All subjects undertook both the MD and a control diet, a low fat-high carbohydrate diet (LF/HCD), in random order with a 6-week wash-out period in- between. Insulin sensitivity was determined with a 3-h hyperinsulinemic-euglycemic clamp study and hepatic steatosis was assessed with localized magnetic resonance (1)H spectroscopy ((1)H-MRS). RESULTS: At baseline, subjects were abdominally obese with elevated fasting concentrations of glucose, insulin, triglycerides, ALT, and GGT. Insulin sensitivity at baseline was low (M=2.7 ± 1.0 mg/kg/min(-1)). Mean weight loss was not different between the two diets (p=0.22). There was a significant relative reduction in hepatic steatosis after the MD compared with the LF/HCD: 39 ± 4% versus 7 ± 3%, as measured by (1)H-MRS (p=0.012). Insulin sensitivity improved with the MD, whereas after the LF/HCD there was no change (p=0.03 between diets). CONCLUSIONS: Even without weight loss, MD reduces liver steatosis and improves insulin sensitivity in an insulin-resistant population with NAFLD, compared to current dietary advice. This diet should be further investigated in subjects with NAFLD.

Viral adaptation to host immune responses occurs in chronic hepatitis B virus (HBV) infection, and adaptation is greatest in HBV e antigen-negative disease.

Hepatitis B virus (HBV)-specific T-cell responses are important in the natural history of HBV infection. The number of known HBV-specific T-cell epitopes is limited, and it is not clear whether viral evolution occurs in chronic HBV infection. We aimed to identify novel HBV T-cell epitopes by examining the relationship between HBV sequence variation and the human leukocyte antigen (HLA) type in a large prospective clinic-based cohort of Asian patients with chronic HBV infection recruited in Australia and China (n = 119). High-resolution 4-digit HLA class I and II typing and full-length HBV sequencing were undertaken for treatment-naïve individuals (52% with genotype B, 48% with genotype C, 63% HBV e antigen [HBeAg] positive). Statistically significant associations between HLA types and HBV sequence variation were identified (n = 49) at 41 sites in the HBV genome. Using prediction programs, we determined scores for binding between peptides containing these polymorphisms and associated HLA types. Among the regions that could be tested, HLA binding was predicted for 14/18 (78%). We identified several HLA-associated polymorphisms involving likely known anchor residues that resulted in altered predicted binding scores. Some HLA-associated polymorphisms fell within known T-cell epitopes with matching HLA restriction. Enhanced viral adaptation (defined as the presence of the relevant HLA and the escaped amino acid) was independently associated with HBeAg-negative disease (P = 0.003). Thus, HBV appears to be under immune pressure in chronic HBV infection, particularly in HBeAg-negative disease.

IL28B genotype is not useful for predicting treatment outcome in Asian chronic hepatitis B patients treated with pegylated interferon-α.

BACKGROUND AND AIM: IL28B genotype predicts response to pegylated interferon (peg-IFN)-based therapy in chronic hepatitis C. However, the utility of IL28B genotyping in chronic hepatitis B (CHB) cohorts treated with peg-IFN is unclear. It was investigated whether IL28B genotype is associated with peg-IFN treatment outcomes in a predominantly Asian CHB cohort. METHODS: This was a retrospective analysis of CHB patients treated with 48 weeks of peg-IFN monotherapy. IL28B genotype (rs12979860) was determined (TaqMan allelic discrimination kit). Baseline hepatitis B virus (HBV)-DNA, alanine aminotransferase, and liver histology were available. The primary end-points were HBV e antigen (HBeAg) seroconversion with HBV-DNA < 2000 IU/mL 24 weeks post-therapy (HBeAg-positive patients) and HBV-DNA < 2000 IU/mL 24 weeks after peg-IFN (HBeAg-negative patients). The association between IL28B genotype and peg-IFN outcomes was analyzed. RESULTS: IL28B genotype was determined for 96 patients. Eighty-eight percent were Asian, 62% were HBeAg positive, and 13% were METAVIR stage F3-4. Median follow-up time was 39.3 months. The majority of patients carried the CC IL28B genotype (84%). IL28B genotype did not differ according to HBeAg status. The primary end-points were achieved in 27% of HBeAg-positive and 61% of HBeAg-negative patients. There was no association between IL28B genotype and the primary end-point in either group. Furthermore, there was no difference in HBeAg loss alone, HBV surface antigen, alanine aminotransferase normalization, or on-treatment HBV-DNA levels according to IL28B genotype. CONCLUSIONS: In the context of a small possible effect size and high frequency in Asian populations, IL28B genotyping is likely to have, at best, limited clinical utility for predicting peg-IFN treatment outcome for CHB patients in the Asia-Pacific region.

Baseline serum HBV RNA is associated with the risk of hepatitis flare after stopping nucleoside analog therapy in HBeAg-negative participants.

BACKGROUND AND AIMS: HBV RNA in peripheral blood reflects HBV cccDNA transcriptional activity and may predict clinical outcomes. The prospective Melbourne HBV-STOP trial studied nucleot(s)ide analog discontinuation in HBeAg-negative non-cirrhotic participants with long-term virological suppression. Ninety-six weeks after stopping treatment, the proportion of participants with virological relapse (HBV DNA > 2000 IU/mL), biochemical relapse (ALT > 2 × ULN and HBV DNA > 2000 IU/mL), or hepatitis flare (ALT > 5 × ULN and HBV DNA > 2000 IU/mL) was 89%, 58%, and 38%, respectively. We evaluated the ability of serum HBV RNA levels to predict these outcomes. APPROACH RESULTS: HBV RNA levels were measured using the Roche cobas 6800/8800 HBV RNA Investigational Assay. Sixty-five participants had baseline and longitudinal off-treatment specimens available for RNA testing. HBV RNA was detectable at baseline in 25% of participants and was associated with a higher risk of biochemical relapse (81% vs. 51%, p value 0.04) and hepatitis flare (63% vs. 31%, p value 0.04). Participants who had undetectable serum HBV RNA as well as HBsAg ≤ 100 IU/mL at baseline were less likely to experience virological relapse (4 of 9, 44%) than participants with detectable HBV RNA and HBsAg level > 100 IU/mL (15/15, 100%; p value 0.0009). Off-treatment levels of HBV RNA were correlated with HBV DNA and were associated with the risk of hepatitis flare. CONCLUSIONS: Serum HBV RNA may be a useful biomarker for guiding clinical decision-making before stopping nucleot(s)ide analog therapy. Baseline HBV RNA and HBsAg levels are associated with the risk of clinical relapse, hepatitis flare, and disease remission off-treatment.

SINGLE-01: a randomized, controlled trial comparing the efficacy and depth of insertion of single- and double-balloon enteroscopy by using a novel method to determine insertion depth.

BACKGROUND: Single-balloon enteroscopy (SBE) was introduced as an alternative to double-balloon enteroscopy (DBE) for the investigation and management of small-bowel conditions. To date, there is only 1 randomized, controlled trial comparing SBE and DBE in a Western population. OBJECTIVE: To compare the 2 instruments in a Western population to assess for differences in clinical outcomes and insertion depth (ID). A novel method to determine ID by counting folds on withdrawal was used. DESIGN: Multicenter, randomized, controlled trial. SETTING: University hospitals in Melbourne and Sydney, Australia. PATIENTS: Patients with suspected or proven small-bowel disease. INTERVENTIONS: SBE and DBE. MAIN OUTCOME MEASUREMENT: The primary endpoint was diagnostic yield (DY). Secondary endpoints were therapeutic yield (TY), procedure times, and ID. An intention-to-treat analysis was performed. RESULTS: A total of 116 patients were screened, and 107 patients were enrolled between July 2008 and June 2010, in whom 119 procedures were undertaken (53 SBEs and 66 DBEs). DY was 57% for SBE and 53% for DBE (P = .697). TY was 32% for SBE and 26% for DBE (P = .490). The median enteroscopy times were identical for SBE and DBE at 60 minutes. The mean ID by the fold-counting method for antegrade procedures was 201.1 folds for SBE and 258.6 folds for DBE (P = .046). After multiple comparisons adjustment, this difference did not reach statistical significance. Mean IDs by using the visual estimation method for SBE and DBE were, respectively, 72.1 cm and 75.2 cm (P = .835) for retrograde procedures and 203.8 cm and 234.1 cm (P = .176) for antegrade procedures. LIMITATIONS: Unable to reach target sample size, mostly single-center recruitment, novel method to determine ID, which requires further validation. CONCLUSIONS: SBE has DY, TY, and procedure times similar to those of DBE. There were no statistically significant differences in ID between SBE and DBE. By using the fold-counting method for antegrade procedures, the estimated IDs for SBE and DBE were 201.1 folds versus 258.6 folds (P = .046; P = not significant after adjustment for multiple comparisons). ( CLINICAL TRIAL REGISTRATION NUMBER: ACTRN12609000917235.).

Comparison of clinical characteristics and management of inflammatory bowel disease in Hong Kong versus Melbourne.

BACKGROUND AND AIM: Inflammatory bowel disease (IBD), common in Melbourne, was rare but is now increasing in incidence in Hong Kong (HK). To investigate whether these are the same diseases in the West and East, potential causes of changing incidence, and to plan resource needs, an appreciation of clinical characteristics in contrasting populations is essential. METHODS: Disease characteristics were collected from prospectively populated IBD databases in two specialist centers in Melbourne, Australia and HK. RESULTS: Of 795 patients (Crohn's disease [CD] : ulcerative colitis [UC] Melbourne 272:159 and HK 161:203), the age of diagnosis was higher, there were proportionally more male patients with CD but no UC sex difference, fewer patients were current or ex-smokers (CD 8% vs 50%; UC 17% vs 35%) and a family history of IBD was less common (2% vs 11%; P < 0.001) in HK compared to Melbourne. Stricturing and perianal CD were more common in HK (12% vs 6%; P < 0.001; and 29% vs 16%; P = 0.001, respectively). In HK for UC, more patients had extensive disease at diagnosis (42% vs 22%) but colectomy was less common (7% vs 20%; P < 0.001). In Melbourne there was greater steroid use at diagnosis and patients were more likely to receive an immunomodulator or anti-tumor necrosis factor agent. CONCLUSIONS: IBD in HK was diagnosed at an older age, and had more complicated disease behavior than in Melbourne. Medical therapy, however, was less intense in HK. These differences may relate to real differences in disease or delayed diagnosis due to late presentation and less disease recognition in HK.

Clinical application and diagnostic accuracy of artificial intelligence in colonoscopy for inflammatory bowel disease: systematic review.

Background and aims Artificial intelligence (AI) technology is being evaluated for its potential to improve colonoscopic assessment of inflammatory bowel disease (IBD), particularly with computer-aided image classifiers. This review evaluates the clinical application and diagnostic test accuracy (DTA) of AI algorithms in colonoscopy for IBD. Methods A systematic review was performed on studies evaluating AI in colonoscopy of adult patients with IBD. MEDLINE, Embase, Emcare, PsycINFO, CINAHL, Cochrane Library and Clinicaltrials.gov databases were searched on 28 th April 2021 for English language articles published between January 1, 2000 and April 28, 2021. Risk of bias and applicability were assessed with the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Diagnostic accuracy was presented as median (interquartile range). Results Of 1029 records screened, nine studies with 7813 patients were included for review. AI was used to predict endoscopic and histologic disease activity in ulcerative colitis, and differentiation of Crohn's disease from Behcet's disease and intestinal tuberculosis. DTA of AI algorithms ranged between 52-91 %. The sensitivity and specificity for AI algorithms predicting endoscopic severity of disease were 78 % (range 72-83, interquartile range 5.5) and 91 % (range 86-96, interquartile range 5), respectively. Conclusions AI has been primarily used to assess disease activity in ulcerative colitis. The diagnostic performance is promising and suggests potential for other clinical application of AI in IBD colonoscopy such as dysplasia detection. However, current evidence is limited by retrospective data and models trained on still images only. Future prospective multicenter studies with full-motion videos are needed to replicate the real-world clinical setting.

Stopping nucleot(s)ide analogues in non-cirrhotic HBeAg-negative chronic hepatitis B patients: HBsAg loss at 96 weeks is associated with low baseline HBsAg levels.

BACKGROUND AND AIMS: Current guidelines recommend long-term nucleot(s)ide analogue (NA) therapy for patients with HBeAg-negative chronic hepatitis B (CHB). However, disease remission has been described after stopping NA therapy, as well as HBsAg loss. METHODS: We performed a prospective multi-centre cohort study of stopping NA therapy. Inclusion criteria were HBeAg-negative CHB, the absence of cirrhosis and HBVDNA5× ULN occurred in 35 (32%); ALT flares were not associated with HBsAg loss. There were no unexpected safety issues. CONCLUSION: Virological reactivation was very common after stopping NA therapy and occurred earlier after stopping TDF versus ETV. The majority of patients had ALT <2× ULN at week 96, but only one-third achieved disease remission and HBsAg loss was rare. Very low HBsAg levels at baseline were uncommon but predicted for HBsAg loss and disease remission.