Office-based sedation-free transnasal esophagogastroduodenoscopy with biopsies using single-use gastroscopes: A pediatric single-center experience.

Introduction: Unsedated transnasal endoscopy (TNE) as transnasal esophagoscopy (TN-Eso) has emerged as a promising alternative to esophagogastroduodenoscopy (EGD) under sedation to assess eosinophilic esophagitis (EoE). We report our center's experience using single-use gastroscopes to perform sedation-free transnasal EGD (TN-EGD) with biopsies in an office-based setting. Methods: A retrospective review was performed on patients with eosinophilic esophagitis who underwent office-based sedation-free TNE with topical analgesia and virtual reality (VR) procedural dissociation and distraction. A sterile, single-use, ultra-slim 3.5 mm outer diameter, 110 cm long gastroscope with 2 mm working channel (EvoEndo) was used to perform TNE with biopsies/brushings. Data including demographics, procedure success rate, total visit time, biopsy adequacy, procedure time, procedural preference, and complications were collected. Results: Office-based TNE was completed in 8 patients (six males, age range 11-20 years). The endoscope was advanced by an experienced transoral endoscopist successfully through the nares into stomach (transnasal esophagogastroscopy [TN-EG]) in all subjects (100%) and into the duodenum (TN-EGD) in seven subjects (87.5%). Biopsies were obtained from esophagus in all cases and from the stomach/duodenum in five cases. Histological assessment, esophageal brushing, disaccharidase enzyme analysis, or duodenal aspirate analysis were performed as indicated. EoE reevaluation was the primary indication to perform endoscopy in all patients. Visual and histologic findings were all adequate for assessment. There were no significant adverse events. Conclusion: Office-based TN-EGD with VR procedural distraction and dissociation using single-use gastroscopes was effective to monitor EoE, gastritis, and duodenitis in a pediatric practice.

Esophageal epithelial immunoglobulin G is an important marker for the diagnosis and management of pediatric eosinophilic esophagitis.

Background and Aim: Our primary aim was to describe the prevalence of immunoglobulin G (IgG) and its subclass IgG4 in immunohistochemistry staining in esophageal biopsy specimens of children with eosinophilic esophagitis (EoE) compared with that of specimens from children with gastroesophageal reflux disease (GERD). Methods: Esophageal biopsy specimens from children with EoE or GERD were stained prospectively for IgG and IgG4 antibodies. Subjects with EoE were divided into cohorts with either active EoE or EoE in remission. Active EoE cases were further divided into proton pump inhibitor responsive (PPI-r) and PPI-nonresponsive (PPI-nr) subgroups. Demographic, clinical, and histologic data were compared among groups, including quantified IgG and IgG4 staining, peak eosinophil count, eosinophil-derived neurotoxin levels, and EoE endoscopic reference score. Results: Seventy-nine children (aged 10.6 ± 5.6 years; 68% male) were enrolled. IgG-positive cell counts were significantly elevated in those with active EoE (n = 29, 3 [interquartile range, IQR: 2-6]/high-powered field [HPF]), compared with those having EoE remission (n = 25, 1 [IQR: 0-2]/HPF; P = 0.002) and those with GERD (n = 25, 0 [IQR: 0-0.25]/HPF, P = <0.0001). IgG-positive cell counts were significantly higher in the PPI-r (n = 15, 5 [IQR: 2.5-11]/HPF) subgroup, compared with the PPI-nr subgroup (n = 11, 3 [IQR: 1.5-3.5]/HPF; P = 0.041) at baseline endoscopy. Conclusion: Initial esophageal tissue biopsy specimens from pediatric subjects with active EoE showed a significant increase in IgG-positive staining compared with tissue from subjects in EoE remission or with GERD. There was higher positivity of IgG-stained cells in the PPI-r subgroup compared with the PPI-nr subgroup.

Histologic Outcomes With Vedolizumab Versus Adalimumab in Ulcerative Colitis: Results From An Efficacy and Safety Study of Vedolizumab Intravenous Compared to Adalimumab Subcutaneous in Participants With Ulcerative Colitis (VARSITY).

BACKGROUND AND AIMS: VARSITY (An Efficacy and Safety Study of Vedolizumab Intravenous [IV] Compared to Adalimumab Subcutaneous [SC] in Participants With Ulcerative Colitis) showed superior clinical remission and endoscopic improvement in ulcerative colitis with vedolizumab vs adalimumab. This analysis compared histologic outcomes. METHODS: Patients in VARSITY were randomized 1:1 to maintenance with vedolizumab IV 300 mg every 8 weeks or adalimumab SC 40 mg every 2 weeks (both following standard induction). Geboes Index and Robarts Histopathology Index (RHI) scores were used to assess prespecified histologic exploratory end points of histologic remission (Geboes <2 or RHI ≤2) and minimal histologic disease activity (Geboes ≤3.1 or RHI ≤4) at weeks 14 and 52. RESULTS: In total, 769 patients received vedolizumab (n = 383) or adalimumab (n = 386). Mean baseline histologic disease activity was similar between vedolizumab and adalimumab groups. Vedolizumab induced greater histologic remission than adalimumab at week 14 (Geboes: 16.7% vs 7.3%, Δ9.4% [95% confidence interval {CI}, 4.9%-13.9%], P < .0001; RHI: 25.6% vs 16.1%, Δ9.5% [95% CI, 3.8%-15.2%], P = .0011) and week 52 (Geboes: 29.2% vs 8.3%, Δ20.9% [95% CI, 15.6%-26.2%], P < .0001; RHI: 37.6% vs 19.9%, Δ17.6% [95% CI, 11.3%-23.8%], P < .0001) overall and in both anti-tumor necrosis factor (TNF)-naïve and -failure subgroups. Results were similar for minimal histologic disease activity. Histologic outcomes were generally better in anti-TNF-naïve vs -failure patients. At week 52, rates of mucosal healing (composite end point of histologic plus endoscopic improvement) were also higher with vedolizumab than adalimumab (Geboes: 25.6% vs 6.7%; RHI: 30.5% vs 14.5%). CONCLUSIONS: Higher rates of histologic remission, minimal histologic disease activity, and combined histologic plus endoscopic outcomes were observed with vedolizumab than with adalimumab in ulcerative colitis in both anti-TNF-naïve and -failure subgroups. REGISTRATION: ClinicalTrials.gov NCT02497469; EudraCT 2015-000939-33.

Using Eosinophil Biomarkers From Rectal Epithelial Samples to Diagnose Food Protein-induced Proctocolitis: A Pilot Study.

OBJECTIVES: The gold standard diagnostic procedure for food protein-induced proctocolitis (FPIP) requires flexible sigmoidoscopy (FS). To date there is no validated, noninvasive test to confirm FPIP diagnosis. Eosinophil-derived neurotoxin (EDN), a product of eosinophil (EOS) degranulation, has been shown to correlate with eosinophil infiltration in other tissues. Our objective was to compare EDN concentrations in rectal epithelial samples from infants with FPIP with those from a control population. METHODS: Children who underwent routine FS at Arnold Palmer Hospital for Children were enrolled in an IRB-approved, prospective, open-label pilot study between July 2017 and May 2019. We obtained rectal epithelial samples via: rectal swab, cytology brushing through FS, and rectal biopsy through FS. We then measured EDN levels in the samples and compared levels found in infants with FPIP against levels found in the control group. FPIP was defined as more than 60 EOS per 10 high-power fields (HPF) in rectal epithelial tissue obtained via rectosigmoid biopsy. RESULTS: Twenty-four patients were enrolled. The control group (n = 13) included patients with normal histopathology (84% boys, mean age 19 months, SD 6 months) and the FPIP group (n = 11) included patients with FPIP confirmed via biopsy (45% boys, mean age 6.9 months, SD 9 months). EDN concentration was significantly higher in the FPIP group than in the control group, for 2 sampling methods: rectal biopsy (183.6 ±â€Š114.6 vs 76.6 ±â€Š71.0 µg/mL; P = 0.010) and rectal swab (66.2 ±â€Š64.8 vs 20.4 ±â€Š22.2 µg/mL; P = 0.025). CONCLUSIONS: EDN concentrations measured from rectal swab and rectal biopsy samples is elevated and may be a useful tool to screen for FPIP in children.

Vedolizumab versus Adalimumab for Moderate-to-Severe Ulcerative Colitis.

BACKGROUND: Biologic therapies are widely used in patients with ulcerative colitis. Head-to-head trials of these therapies in patients with inflammatory bowel disease are lacking. METHODS: In a phase 3b, double-blind, double-dummy, randomized trial conducted at 245 centers in 34 countries, we compared vedolizumab with adalimumab in adults with moderately to severely active ulcerative colitis to determine whether vedolizumab was superior. Previous exposure to a tumor necrosis factor inhibitor other than adalimumab was allowed in up to 25% of patients. The patients were assigned to receive infusions of 300 mg of vedolizumab on day 1 and at weeks 2, 6, 14, 22, 30, 38, and 46 (plus injections of placebo) or subcutaneous injections of 40 mg of adalimumab, with a total dose of 160 mg at week 1, 80 mg at week 2, and 40 mg every 2 weeks thereafter until week 50 (plus infusions of placebo). Dose escalation was not permitted in either group. The primary outcome was clinical remission at week 52 (defined as a total score of ≤2 on the Mayo scale [range, 0 to 12, with higher scores indicating more severe disease] and no subscore >1 [range, 0 to 3] on any of the four Mayo scale components). To control for type I error, efficacy outcomes were analyzed with a hierarchical testing procedure, with the variables in the following order: clinical remission, endoscopic improvement (subscore of 0 to 1 on the Mayo endoscopic component), and corticosteroid-free remission at week 52. RESULTS: A total of 769 patients underwent randomization and received at least one dose of vedolizumab (383 patients) or adalimumab (386 patients). At week 52, clinical remission was observed in a higher percentage of patients in the vedolizumab group than in the adalimumab group (31.3% vs. 22.5%; difference, 8.8 percentage points; 95% confidence interval [CI], 2.5 to 15.0; P = 0.006), as was endoscopic improvement (39.7% vs. 27.7%; difference, 11.9 percentage points; 95% CI, 5.3 to 18.5; P<0.001). Corticosteroid-free clinical remission occurred in 12.6% of the patients in the vedolizumab group and in 21.8% in the adalimumab group (difference, -9.3 percentage points; 95% CI, -18.9 to 0.4). Exposure-adjusted incidence rates of infection were 23.4 and 34.6 events per 100 patient-years with vedolizumab and adalimumab, respectively, and the corresponding rates for serious infection were 1.6 and 2.2 events per 100 patient-years. CONCLUSIONS: In this trial involving patients with moderately to severely active ulcerative colitis, vedolizumab was superior to adalimumab with respect to achievement of clinical remission and endoscopic improvement, but not corticosteroid-free clinical remission. (Funded by Takeda; VARSITY ClinicalTrials.gov number, NCT02497469; EudraCT number, 2015-000939-33.).

Endoscopic, Radiologic, and Histologic Healing With Vedolizumab in Patients With Active Crohn's Disease.

BACKGROUND & AIMS: Vedolizumab is a gut-selective monoclonal antibody for the treatment of moderately to severely active Crohn's disease (CD). We performed a prospective study of endoscopic, radiologic, and histologic healing in patients with CD who received vedolizumab therapy. METHODS: We performed a phase 3b, open-label, single-group study of 101 patients with at least 3 months of active CD (a CD Activity Index [CDAI] score of 220-450, a simple endoscopic score for CD [SES-CD] of 7 or more, 1 or more mucosal ulcerations [identified by endoscopy], and failure of conventional therapy) from March 2015 through December 2017. Among the patients enrolled, 54.5% had previous failure of 1 or more tumor necrosis factor (TNF) antagonists and 44.6% had severe endoscopic disease activity (SES-CD scores above 15) at baseline. Participants received vedolizumab (300 mg intravenously) at weeks 0, 2, and 6, and then every 8 weeks thereafter, for 26 weeks (primary study) or 52 weeks (substudy, 56 patients). The primary endpoint at week 26 was endoscopic remission (SES-CD score of 4 or less); other endpoints included endoscopic response (50% reduction in SES-CD), radiologic remission (magnetic resonance index of activity score below 7), and histologic response (modified global histologic disease activity score of 4 or less). RESULTS: At week 26, 11.9% of patients were in endoscopic remission (95% confidence interval [CI] 6.3-9.8); at week 52, 17.9% of the patients were in endoscopic remission (95% CI 8.9-30.4). Higher proportions of patients naïve to TNF antagonists achieved endoscopic remission than patients with TNF-antagonist-failure at weeks 26 and 52. Higher proportion of patients with moderate CD (SES-CD scores, 7-15) achieved endoscopic remission at weeks 26 and 52 than patients with severe CD (SES-CD scores above 15). The proportion of patients with complete mucosal healing increased over time, with greater rates of healing in the colon than in the ileum. Remission was detected by magnetic resonance enterography in 21.9% of patients at week 26 (95% CI 9.3-40.0) and in 38.1% at week 52 (95% CI 18.1-61.6). At week 26, 24.4% of patients had a histologic response in the colon (95% CI 15.3-35.4) and 28.3% of patients had a histologic response in the ileum (95% CI 17.5-41.4). At week 52, 20.5% of patients had a histologic response in the colon (95% CI 9.8-35.3) and 34.3% of patients had a histologic response in the ileum (95% CI 19.1-52.2). There were no notable safety issues, including worsening of extraintestinal manifestations. CONCLUSIONS: In a phase 3b trial, we found that 26 and 52 weeks of treatment with vedolizumab (300 mg, at weeks 0, 2, and 6, and then every 8 weeks thereafter) induces endoscopic, radiologic, and histologic healing in patients with moderately to severely active CD. ClinicalTrials.gov no: NCT02425111.

Evaluation of APRI and FIB-4 scoring systems for non-invasive assessment of hepatic fibrosis in chronic hepatitis B patients.

BACKGROUND & AIMS: While the gold standard in the assessment of liver fibrosis remains liver biopsy, non-invasive methods have been increasingly used for chronic hepatitis B (CHB). This study aimed to evaluate the performance of two commonly used non-invasive scoring systems (aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis index based on four factors (FIB-4)) to predict fibrosis stage in CHB patients. METHODS: Demographic, histologic and clinical laboratory data from two trials investigating tenofovir disoproxil fumarate in CHB were analyzed. Predicted fibrosis stage, based on established scales and cut-off values for APRI and FIB-4 scores, was compared with Ishak scores obtained from liver biopsy at baseline and at 240 week follow-up. RESULTS: In the 575 patients with a baseline liver biopsy, APRI and FIB-4 scores correlated with Ishak stage (p<0.01); however extensive overlap in the distribution of both scores across Ishak stages prevented accurate determination of fibrosis. The majority (81-89%) of patients with advanced fibrosis or cirrhosis were missed by the scores. Similarly, 71% patients without fibrosis were misclassified as having clinically significant fibrosis. APRI and FIB-4 scores at week 240 tended to be low and underestimate fibrosis stage in the patients with liver biopsies after 240 weeks of therapy. APRI or FIB-4 reduction did not correlate with fibrosis regression after 240 weeks of antiviral therapy. CONCLUSIONS: APRI and FIB-4 scores are not suitable for use in clinical practice in CHB patients for assessment of hepatic fibrosis according to Ishak stage, especially in gauging improvements in liver fibrosis following therapy.

Long-term clinical outcomes in cirrhotic chronic hepatitis B patients treated with tenofovir disoproxil fumarate for up to 5 years.

BACKGROUND: Phase 3 clinical studies have shown that long-term treatment with tenofovir disoproxil fumarate (TDF) can suppress hepatitis B viral load and promote significant fibrosis regression and cirrhosis reversal in a majority of treated chronic hepatitis B (CHB) patients. This retrospective analysis investigated the impact of baseline cirrhosis status on virologic, serologic, and histologic outcomes in patients treated with TDF. METHODS: Patients enrolled in studies GS-US-174-0102 and GS-US-174-0103 who had baseline liver biopsy-diagnosed cirrhosis and entered the open-label phase of the studies were included in the virologic and serologic analyses. Patients (both HBeAg positive and negative) with paired liver biopsies at baseline and 5 years (N = 348) were included in a histologic analysis. RESULTS: After 5 years on study, comparing patients with and without baseline cirrhosis, respectively: 99.2 and 98.0% achieved virologic response (hepatitis B viral load < 69 IU/ml) (p = 0.686); 79.7 and 81.9% had normal serum levels of alanine aminotransferase (p = 0.586); 4.0 and 1.2% developed hepatocellular carcinoma (p = 0.044). In HBeAg-positive patients with and without baseline cirrhosis, HBsAg loss occurred in 14.4 and 8.3% of patients, respectively (p = 0.188). One HBeAg-negative patient had HBsAg loss. CONCLUSIONS: This represents the largest analyses to date of CHB patients with sequential liver biopsies demonstrating that treatment with TDF for up to 5 years is associated with favorable virologic, serologic, and histologic outcomes, regardless of baseline cirrhosis status. Notably, histologic improvement was observed in the majority of cirrhotic and noncirrhotic patients.

Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study.

BACKGROUND: Whether long-term suppression of replication of hepatitis B virus (HBV) has any beneficial effect on regression of advanced liver fibrosis associated with chronic HBV infection remains unclear. We aimed to assess the effects on fibrosis and cirrhosis of at least 5 years' treatment with tenofovir disoproxil fumarate (DF) in chronic HBV infection. METHODS: After 48 weeks of randomised double-blind comparison (trials NCT00117676 and NCT00116805) of tenofovir DF with adefovir dipivoxil, participants (positive or negative for HBeAg) were eligible to enter a 7-year study of open-label tenofovir DF treatment, with a pre-specified repeat liver biopsy at week 240. We assessed histological improvement (≥2 point reduction in Knodell necroinflammatory score with no worsening of fibrosis) and regression of fibrosis (≥1 unit decrease by Ishak scoring system). FINDINGS: Of 641 patients who received randomised treatment, 585 (91%) entered the open-label phase, and 489 (76%) completed 240 weeks. 348 patients (54%) had biopsy results at both baseline and week 240. 304 (87%) of the 348 had histological improvement, and 176 (51%) had regression of fibrosis at week 240 (p<0·0001). Of the 96 (28%) patients with cirrhosis (Ishak score 5 or 6) at baseline, 71 (74%) no longer had cirrhosis (≥1 unit decrease in score), whereas three of 252 patients without cirrhosis at baseline progressed to cirrhosis at year 5 (p<0·0001). Virological breakthrough occurred infrequently and was not due to resistance to tenofovir DF. The safety profile was favourable: 91 (16%) patients had adverse events but only nine patients had serious events related to the study drug. INTERPRETATION: In patients with chronic HBV infection, up to 5 years of treatment with tenofovir DF was safe and effective. Long-term suppression of HBV can lead to regression of fibrosis and cirrhosis. FUNDING: Gilead Sciences.

Natalizumab for the treatment of active Crohn's disease: results of the ENCORE Trial.

BACKGROUND & AIMS: A randomized placebo-controlled trial evaluated the efficacy of natalizumab induction therapy in patients with Crohn's disease. METHODS: Patients (N = 509) with moderately to severely active Crohn's disease and active inflammation characterized by elevated C-reactive protein concentrations were randomized (1:1) to receive natalizumab 300 mg or placebo intravenously at Weeks 0, 4, and 8. The primary end point was induction of response (> or =70-point decrease from baseline in the Crohn's Disease Activity Index score at Week 8 sustained through Week 12). Additional efficacy end points included the proportion of patients with sustained remission (Crohn's Disease Activity Index score <150 points) and response or remission over time. RESULTS: Response at Week 8 sustained through Week 12 occurred in 48% of natalizumab-treated patients and 32% of patients receiving placebo (P < .001). Sustained remission occurred in 26% of natalizumab-treated patients and 16% of patients receiving placebo (P = .002). Week 4 response rates were 51% for natalizumab and 37% for placebo (P = .001). Responses remained significantly higher at subsequent assessments (P < .001) in natalizumab-treated patients. Natalizumab-treated patients also had significantly higher remission rates at Weeks 4, 8, and 12 (P < or = .009). The frequency and types of adverse events were similar between treatment groups. CONCLUSIONS: Natalizumab induced response and remission at Week 8 that was sustained through Week 12. Response and remission rates for natalizumab were superior to those for placebo at Weeks 4, 8, and 12, demonstrating the early and sustained efficacy of natalizumab as induction therapy in patients with elevated C-reactive protein and active Crohn's disease. Natalizumab was well tolerated in this study.

Nonoperative imaging techniques in suspected biliary tract obstruction.

Evaluation of suspected biliary tract obstruction is a common clinical problem. Clinical data such as history, physical examination, and laboratory tests can accurately identify up to 90% of patients whose jaundice is caused by extrahepatic obstruction. However, complete assessment of extrahepatic obstruction often requires the use of various imaging modalities to confirm the presence, level, and cause of obstruction, and to aid in treatment plan. In the present summary, the literature on competing technologies including endoscopic retrograde cholangiopancreatography (ERCP), percutaneous transhepatic cholangiopancreatography (PTC), endoscopic ultrasound (EUS), intraductal ultrasonography (IDUS), magnetic resonance cholangiopancreatography (MRCP), helical CT (hCT) and helical CT cholangiography (hCTC) with regards to diagnostic performance characteristics, technical success, safety, and cost-effectiveness is reviewed. Patients with obstructive jaundice secondary to choledocholithiasis or pancreaticobiliary malignancies are the primary focus of this review. Algorithms for the management of suspected obstructive jaundice are put forward based on current evidence. Published data suggest an increasing role for EUS and other noninvasive imaging techniques such as MRCP, and hCT following an initial transabdominal ultrasound in the assessment of patients with suspected biliary obstruction to select candidates for surgery or therapeutic ERCP. The management of patients with a suspected pancreaticobiliary condition ultimately is dependent on local expertise, availability, cost, and the multidisciplinary collaboration between radiologists, surgeons, and gastroenterologists.

De-novo cholangiocarcinoma in the setting of recurrent primary sclerosing cholangitis following liver transplant.

Orthotopic liver transplantation is the only definitive therapeutic option in patients with primary sclerosing cholangitis (PSC) and end-stage liver disease. However, PSC recurs in up to 20% of patients transplanted for this indication. To date, no patient has been reported to develop cholangiocarcinoma (CCA) post-transplant, without biliary tract cancer having been present pretransplant. Here, we report recurrent PSC complicated by de-novo CCA in a 31-year-old man transplanted for PSC 8 years earlier. Cholangiocarcinoma was confirmed using a combination of computed tomography, cholangiography, positron emission tomography and histological examination of biliary cytology. He has since been successfully re-transplanted following preoperative chemo-radiotherapy. No viable tumor was identified in the explanted liver. This case establishes that long-term complications associated with PSC and biliary-enteric surgery such as CCA may become apparent in new grafts post-transplant.