Early and accurate detection of cholangiocarcinoma in patients with primary sclerosing cholangitis by methylation markers in bile

Background and Aims Primary sclerosing cholangitis (PSC) is associated with increased risk of cholangiocarcinoma (CCA). Early and accurate CCA detection represents an unmet clinical need as the majority of patients with PSC are diagnosed at an advanced stage of malignancy. In the present study, we aimed at establishing robust DNA methylation biomarkers in bile for early and accurate diagnosis of CCA in PSC. Approach and Results Droplet digital PCR (ddPCR) was used to analyze 344 bile samples from 273 patients with sporadic and PSC-associated CCA, PSC, and other nonmalignant liver diseases for promoter methylation of cysteine dioxygenase type 1, cannabinoid receptor interacting protein 1, septin 9, and vimentin. Receiver operating characteristic (ROC) curve analyses revealed high AUCs for all four markers (0.77-0.87) for CCA detection among patients with PSC. Including only samples from patients with PSC diagnosed with CCA 36 months) as controls, and remained high (83%) when only including patients with PSC and dysplasia as controls (n = 23). Importantly, the bile samples from the CCA-PSCPeer reviewe

Motorized spiral enteroscopy: results of an international multicenter prospective observational clinical study in patients with normal and altered gastrointestinal anatomy

BACKGROUND : Motorized spiral enteroscopy (MSE) has been shown to be safe and effective for deep enteroscopy in studies performed at expert centers with limited numbers of patients without previous abdominal surgery. This study aimed to investigate the safety, efficacy, and learning curve associated with MSE in a real-life scenario, with the inclusion of patients after abdominal surgery and with altered anatomy. METHODS : Patients with indications for deep enteroscopy were enrolled in a prospective observational multicenter study. The primary objective was the serious adverse event (SAE) rate; secondary objectives were the diagnostic and therapeutic yield, procedural success, time, and insertion depth. Data analysis was subdivided into training and core (post-training) study phases at centers with different levels of MSE experience. RESULTS : 298 patients (120 women; median age 68, range 19-92) were enrolled. In the post-training phase, 21.5 % (n = 54) had previous abdominal surgery, 10.0 % (n = 25) had surgically altered anatomy. Overall, SAEs occurred in 2.3 % (7/298; 95 %CI 0.9 %-4.8 %). The SAE rate was 2.0 % (5/251) in the core group and 4.3 % (2/47) in the training group, and was not increased after abdominal surgery (1.9 %). Total enteroscopy was achieved in half of the patients (n = 42) undergoing planned total enteroscopy. In 295/337 procedures (87.5 %), the anatomical region of interest could be reached. CONCLUSIONS : This prospective multicenter study showed that MSE was feasible and safe in a large cohort of patients in a real-life setting, after a short learning curve. MSE was shown to be feasible in postsurgical patients, including those with altered anatomy, without an increase in the SAE rate. Trial registration: ClinicalTrials.gov NCT03955081

Mortality and microbial diversity after allogenic hematopoietic stem cell transplantation: secondary analysis of a randomized nutritional intervention trial

Gut mucosal barrier injury is common following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and associated with poor clinical outcomes. Diet is critical for microbial diversity, but whether nutritional support affects microbiota and outcome after allo-HSCT is unknown. We present a secondary analysis of a randomized controlled nutritional intervention trial during allo-HSCT. We investigated if the intervention influenced gut microbiota, short-chain fatty acids (SCFAs), and markers of gut barrier functions, and if these parameters were associated with clinical outcomes. Fecal specimens were available from 47 recipients, and subjected to 16S rRNA gene sequencing. We found no significant differences between the intervention group and controls in investigated parameters. We observed a major depletion of microbiota, SCFAs, and altered markers of gut barrier function from baseline to 3 weeks post-transplant. One-year mortality was significantly higher in patients with lower diversity at 3 weeks post-HSCT, but not related to diversity at baseline. The relative abundance of Blautia genus at 3 weeks was higher in survivors. Fecal propionic acid was associated with survival. Markers of gut barrier functions were less strongly associated with clinical outcomes. Possibly, other strategies than dietary intervention are needed to prevent negative effects of gut microbiota and clinical outcomes after allo-HSCT

No Superiority of Stents vs Balloon Dilatation for Dominant Strictures in Patients With Primary Sclerosing Cholangitis

BACKGROUND & AIMS: Dominant strictures occur in approximately 50% of patients with primary sclerosing cholangitis (PSC). Short-term stents have been reported to produce longer resolution of dominant strictures than single-balloon dilatation. We performed a prospective study to compare the efficacy and safety of balloon dilatation vs short-term stents in patients with non-end-stage PSC. METHODS: We performed an open-label trial of patients with PSC undergoing therapeutic endoscopic retrograde cholangiopancreatography (ERCP) at 9 tertiary-care centers in Europe, from July 2011 through April 2016. Patients found to have a dominant stricture during ERCP were randomly assigned to groups that underwent balloon dilatation (n = 31) or stent placement for a maximum of 2 weeks (n = 34); patients were followed for 24 months. The primary outcome was the cumulative recurrence-free patency of the primary dominant strictures. RESULTS: Study recruitment was terminated after a planned interim analysis because of futility and differences in treatment-related serious adverse events (SAEs) between groups. The cumulative recurrence-free rate did not differ significantly between groups (0.34 for the stent group and 0.30 for the balloon dilatation group at 24 months; P = 1.0). Most patients in both groups had reductions in symptoms at 3 months after the procedure. There were 17 treatment related SAEs: post-ERCP pancreatitis in 9 patients and bacterial cholangitis in 4 patients. SAEs occurred in 15 patients in the stent group (45%) and in only 2 patients in the balloon dilatation group (6.7%) (odds ratio, 11.7; 95% confidence interval, 2.4-57.2; P =.001). CONCLUSIONS: In a multicenter randomized trial of patients with PSC and a dominant stricture, shortterm stents were not superior to balloon dilatation and were associated with a significantly higher occurrence of treatment related SAEs. Balloon dilatation should be the initial treatment of choice for dominant strictures in patients with PSC. This may be particularly relevant to patients with an intact papilla.Peer reviewe

Per-oral cholangioscopy in patients with primary sclerosing cholangitis: a 12-month follow-up study

Background & Aims: Patients with primary sclerosing cholangitis (PSC) have a 9%-20% lifetime incidence of cholangiocarcinoma (CCA). Per-oral cholangioscopy (POCS) added to endoscopic retrograde cholangiography (ERC) could potentially improve detection of CCA occurrence. We prospectively assessed POCS identification of 12-month CCA incidence in PSC patients undergoing ERC. Methods: Consecutive patients with PSC, an indication for ERC, and no prior liver transplantation were enrolled. During the index procedure, POCS preceded planned therapeutic maneuvers. The primary endpoint was ability of POCS visualization with POCS-guided biopsy to identify CCA during 12-month follow-up. Secondary endpoints included ability of ERC/cytology to identify CCA, repeat ERC, liver transplantation, and serious adverse events (SAEs). Results: Of 42 patients enrolled, 36 with successful cholangioscope advancement were analyzed. Patients had mean age 43.5±15.6 years, and 61% were male. Three patients diagnosed with CCA had POCS visualization impressions of benign/suspicious/suspicious, and respective POCS-guided biopsy findings of suspicious/positive/suspicious for malignancy at the index procedure. The 3 CCA cases had ERC visualization impressions of benign/benign/suspicious, and respective cytology findings of atypical/atypical/suspicious for malignancy. No additional patients were diagnosed with CCA during median 11.5-month follow-up. Twenty-three repeat ERCs (5 including POCS) were performed in 14 patients. Five patients had liver transplantation, one after CCA diagnosis and 4 after benign cytology at the index procedure. Three patients (7.1%) had post-ERC pancreatitis. No SAEs were POCS-related. Conclusion: In PSC patients, POCS visualization/biopsy and ERC/cytology each identified 3 cases of CCA. Some patients had a repeat procedure and none experienced POCS-related SAEs. (ClinicalTrials.gov number, NCT03766035)

Allogeneic bone marrow transplantation for patients with treatment-refractory Crohn's Disease

Background & aims: Durable remissions of Crohn's Disease (CD) have followed myeloablative conditioning therapy and allogeneic marrow transplantation. For patients with treatment-refractory disease, we used reduced-intensity conditioning to minimize toxicity, marrow from donors with low Polygenic Risk Scores for CD as cell sources, and protracted immune suppression to lower the risk of graft-versus-host disease (GVHD). Our aim was to achieve durable CD remissions while minimizing transplant-related complications. Methods: DNA from patients and their HLA-matched unrelated donors was genotyped and Polygenic Risk Scores calculated. Donor marrow was infused following non-myeloablative conditioning. Patient symptoms and endoscopic findings were documented at intervals after transplant. Results: We screened 807 patients, 143 of whom met eligibility criteria; 2 patients received allografts. Patient 1 had multiple complications and died at day 332 from respiratory failure. Patient 2 had resolution of CD symptoms until day 178 when CD recurred, associated with persistent host chimerism in both peripheral blood and intestinal mucosa. Withdrawal of immune suppression was followed by dominant donor immune chimerism in peripheral blood and resolution of CD findings. Over time, mucosal T-cells became donor-dominant. At 5 years after allografting, Patient 2 remained off all medications but had mild symptoms related to a jejunal stricture that required stricturoplasty at 6 years. At 8 years, she remains stable off medications. Conclusions: The kinetics of immunologic chimerism after allogeneic marrow transplantation for CD patients depends on the intensity of the conditioning regimen and the magnitude of immune suppression. One patient achieved durable improvement of her previously refractory CD only after establishing donor immunologic chimerism in intestinal mucosa. Her course provides proof-of-principal for allografting as a potential treatment for refractory CD, but an immunoablative conditioning regimen should be considered for future studies.(ClinicalTrials.gov, NCT01570348

Impact of artificial intelligence on colorectal polyp detection for early-career endoscopists: an international comparative study

Background Artificial intelligence (AI) for polyp detection is being introduced to colonoscopy, but there is uncertainty how this affects endoscopists’ ability to detect polyps and neoplasms. We performed a video-based study to address whether AI improved the endoscopists’ performance to detect polyps. Methods We established a dataset of 200 colonoscopy videos (length 5 s; 100 without polyps and 100 with one polyp). About 33 early-career endoscopists (50–400 colonoscopies performed) from 10 European countries classified each video as either ‘polyp present’ or ‘polyp not present’. The video assessment was performed twice with a four-week interval. The first assessment was performed without any AI tool, whereas the second was performed with an AI tool for polyp detection. The primary endpoint was early-career endoscopists’ sensitivity to detect polyps. Gold standard for presence and histology of polyps were confirmed by two expert endoscopists and pathologists, respectively. McNemar’s test was used for statistical significance. Results There were 86 neoplastic and 14 non-neoplastic polyps (mean size 5.6 mm) in the 100 videos with polyps. Early-career endoscopists’ sensitivity to detect polyps increased from 86.3% (95% confidence interval [CI]: 85.1–87.5%) to 91.7% (95%CI: 90.7–92.6%) with the AI aid (p < .0001). Their sensitivity to detect neoplastic polyps increased from 85.4% (95% CI: 84.0–86.7%) to 92.1% (95%CI: 91.1–93.1%) with the AI aid (p < .0001). Conclusion The polyp detection AI tool helped early-career endoscopists to increase their sensitivity to identify all polyps and neoplastic polyps during colonoscopy

Antibody-secreting plasma cells persist for decades in human intestine

Plasma cells (PCs) produce antibodies that mediate immunity after infection or vaccination. In contrast to PCs in the bone marrow, PCs in the gut have been considered short lived. In this study, we studied PC dynamics in the human small intestine by cell-turnover analysis in organ transplants and by retrospective cell birth dating measuring carbon-14 in genomic DNA. We identified three distinct PC subsets: a CD19+ PC subset was dynamically exchanged, whereas of two CD19− PC subsets, CD45+ PCs exhibited little and CD45− PCs no replacement and had a median age of 11 and 22 yr, respectively. Accumulation of CD45− PCs during ageing and the presence of rotavirus-specific clones entirely within the CD19− PC subsets support selection and maintenance of protective PCs for life in human intestine

Resident memory CD8 T cells persist for years in human small intestine

Resident memory CD8 T (Trm) cells have been shown to provide effective protective responses in the small intestine (SI) in mice. A better understanding of the generation and persistence of SI CD8 Trm cells in humans may have implications for intestinal immune-mediated diseases and vaccine development. Analyzing normal and transplanted human SI, we demonstrated that the majority of SI CD8 T cells were bona fide CD8 Trm cells that survived for &amp;gt;1 yr in the graft. Intraepithelial and lamina propria CD8 Trm cells showed a high clonal overlap and a repertoire dominated by expanded clones, conserved both spatially in the intestine and over time. Functionally, lamina propria CD8 Trm cells were potent cytokine producers, exhibiting a polyfunctional (IFN-γ+ IL-2+ TNF-α+) profile, and efficiently expressed cytotoxic mediators after stimulation. These results suggest that SI CD8 Trm cells could be relevant targets for future oral vaccines and therapeutic strategies for gut disorders

No Superiority of Stents vs Balloon Dilatation for Dominant Strictures in Patients With Primary Sclerosing Cholangitis

BACKGROUND & AIMS: Dominant strictures occur in approximately 50% of patients with primary sclerosing cholangitis (PSC). Short-term stents have been reported to produce longer resolution of dominant strictures than single-balloon dilatation. We performed a prospective study to compare the efficacy and safety of balloon dilatation vs short-term stents in patients with non-end-stage PSC. METHODS: We performed an open-label trial of patients with PSC undergoing therapeutic endoscopic retrograde cholangiopancreatography (ERCP) at 9 tertiary-care centers in Europe, from July 2011 through April 2016. Patients found to have a dominant stricture during ERCP were randomly assigned to groups that underwent balloon dilatation (n = 31) or stent placement for a maximum of 2 weeks (n = 34); patients were followed for 24 months. The primary outcome was the cumulative recurrence-free patency of the primary dominant strictures. RESULTS: Study recruitment was terminated after a planned interim analysis because of futility and differences in treatment-related serious adverse events (SAEs) between groups. The cumulative recurrence-free rate did not differ significantly between groups (0.34 for the stent group and 0.30 for the balloon dilatation group at 24 months; P = 1.0). Most patients in both groups had reductions in symptoms at 3 months after the procedure. There were 17 treatment-related SAEs: post-ERCP pancreatitis in 9 patients and bacterial cholangitis in 4 patients. SAEs occurred in 15 patients in the stent group (45%) and in only 2 patients in the balloon dilatation group (6.7%) (odds ratio, 11.7; 95% confidence interval, 2.4-57.2; P = .001). CONCLUSIONS: In a multicenter randomized trial of patients with PSC and a dominant stricture, short-term stents were not superior to balloon dilatation and were associated with a significantly higher occurrence of treatment-related SAEs. Balloon dilatation should be the initial treatment of choice for dominant strictures in patients with PSC. This may be particularly relevant to patients with an intact papilla. ClinicalTrials.gov no. NCT01398917.status: publishe