Systematic review of self-assembling peptides as topical agents for treatment and prevention of gastrointestinal bleeding.

Background/Aims: Gastrointestinal bleeding is a significant and potentially lethal event. We aimed to review the efficiency and safety of self-assembling peptides for the treatment and prevention of gastrointestinal tract bleeding. Methods: We conducted a systematic search for studies describing the endoscopic use of self-assembling peptides for treatment or prevention of bleeding in the gastrointestinal tract in a parallel, independent fashion. The primary outcomes were rates of successful initial hemostasis, delayed bleeding, and rebleeding. The secondary outcomes were adverse events and ease and volume of gel used. Results: Seventeen studies were analyzed. Overall success rate of self-assembling peptides in gastrointestinal bleeding was 87.7% (38%-100%), regardless of etiology or associated treatments. Rebleeding rate ranged from 0% to 16.2%, with a mean of 4.7%, and overall delayed bleeding rate was 5% (range, 0%-15.9%). Only three adverse events were reported in a pooled number of 815 patients. The volume of gel used varied (0.43 to 3.7 mL) according to indication and type of bleeding. Conclusions: The limited available data on the use of self-assembling peptides in gastrointestinal endoscopy suggest a high efficiency and good safety profile.

Advances in the Pharmacological Management of Chronic Hepatitis B.

BACKGROUND: Hepatitis B, a vaccine-preventable liver infection, remains a global public health problem. Dedicated groups of experts and funding are focusing on achieving a functional cure to eradicate this disease by 2030. AREAS OF UNCERTAINTY: With more than 40 molecules available or under investigation as new treatments for hepatitis B virus (HBV) infection, none of them is curative so far. Available treatments are effective in suppressing HBV replication and in decreasing the risk of developing cirrhosis, liver failure, hepatocellular carcinoma, and death, but do not eliminate the virus, and the risk of hepatocellular carcinoma remains. Nucleoside/nucleotide analogs are recommended as first-line therapy for patients with chronic hepatitis B infection to inhibit viral replication and lower the HBV DNA values, but long-term therapy is usually needed to maintain suppression. Cessation of the therapy in accordance with clinical guidelines can result in virological and clinical relapse. DATA SOURCES: PubMed, Web of Science, clinicaltrials.gov , and gray literature sources were searched for articles discussing HBV management and new therapies. RESULTS: With current nucleoside/nucleotide analog therapies, fewer than 5% of patients lose hepatitis B surface antigen after 12 months, which underscores the need for new drugs that can achieve a functional cure. New therapies are being developed, including small interfering RNAs. Bepirovirsen, a modified antisense oligonucleotide, shows promising results and a good safety profile, but requires further exploration in larger number of patients to determine whether a functional cure is possible. CONCLUSIONS: Eradication of HBV infection with currently available therapies is not yet possible. Experts are developing innovative treatments, such as bepirovirsen, to achieve functional cure for this disease and to reduce morbidity and mortality associated with hepatic cirrhosis and hepatocellular carcinoma.

Markers of cardiac dysfunction associated with inflammation in a cohort of patients with acute decompensation of cirrhosis.

BACKGROUND AND AIMS: Inflammation underpinning acute decompensation (AD) of liver disease is an important driver for the development of acute-on-chronic liver failure or death. We aimed to investigate associations between inflammatory biomarkers and impaired cardiac function in patients admitted for AD of cirrhosis. METHODS: This is a retrospective analysis of a well-characterized prospective cohort of patients with AD of liver disease admitted to a tertiary referral center. All patients had echocardiographic assessment of cardiac function and serum samples at admission. We reclassified patients according to the CLIF-C AD score, measured inflammatory (IL-6, IL-8, TNF-ɑ, CD206) and cardiac-specific (NT-proBNP, troponin T) biomarkers and tested for associations with echocardiographic parameters of cardiac function. We explored the impact on outcome of these factors in multivariate analysis. RESULTS: We included 70 patients (58 ±â€…10 years, 28 women), with a mean CLIF-C AD score of 47 ±â€…7. Thirty-nine patients (56%) fulfilled the echocardiographic criteria for cardiac dysfunction. We found associations between parameters of diastolic dysfunction and serum concentrations of IL-6 and CD206. Echocardiographic parameters of cardiac function were not associated with markers of liver dysfunction such as the CLIF-C AD score. In multivariate analysis higher MELD, higher NT-proBNP, and IL-8 concentrations as well as the absence of echocardiographic criteria for cardiac dysfunction significantly associated with death during follow-up. CONCLUSION: We found evidence in favor of a clinically relevant link between serum biomarkers of inflammation (IL-6, CD206) and echocardiographic signals of cardiac dysfunction in patients with acutely decompensated cirrhosis.

Safety, Efficacy and Persistence of Advanced Therapies in Inflammatory Bowel Disease: Results from ORIGINS. A Retrospective Observational Study.

BACKGROUND AND AIMS: Real-world assessments of efficacy and safety of advanced therapies used for inflammatory bowel disease (IBD) patients are limited. We aimed to report safety, efficacy and treatment persistence of new molecules (infliximab, adalimumab, vedolizumab, tofacitinib, ustekinumab) in a retrospective multicentric national Romanian analysis. METHODS: We conducted a nationwide, retrospective observational multicentric study. Data were collected retrospectively from electronic and paper files. Patients who started on one of the five investigated molecules during December 2019-December 2021 were included. The main outcome measures were clinical remission, endoscopic healing, persistence on treatment and safety data. RESULTS: A total of 678 adult patients from 24 Romanian IBD centers with a diagnosis of ulcerative colitis or Crohn's disease were included. Participants had previously failure to one (268, 39.5%), two (108, 15%) or more treatment lines and only 38% (259) were biologic naïve. In the 24 months study period, most patients were started on vedolizumab (192, 28%), followed by adalimumab, infliximab, ustekinumab and tofacitinib. In biologic-naïve patients, most physicians (72%) preferred anti-TNF treatment as first line biologic (93 patients started on infliximab, 92 on adalimumab), followed by vedolizumab, ustekinumab and tofacitinib. During follow-up, 71% (470, p=0.05) of patients achieved clinical remission and 36% (134, p=0.03) achieved mucosal healing. The 6 months milestone for persistence was reached in 78% (530) of cases. Almost half of patients (47%, 316 patients) persisted on their current treatment for over 12 months. Overall, an adverse reaction was reported for 67 (10.4%) patients, with no lethal events. CONCLUSIONS: Population of biologic-experienced IBD patients in Romania is increasing and is becoming more difficult to achieve long-term disease control. Discontinuation rates for advanced therapies are high.

The perfect biliary plastic stent: the search goes on.

The introduction of biliary plastic stents has been a landmark achievement in the field of endoscopic retrograde cholangiopancreatography, ensuring minimally invasive and highly effective relief of the obstructed biliary system. Attempts to improve the patency and avoid complications after biliary plastic stenting have led to several innovations, but complications due to stent occlusion are still frequent. Because these complications are clinically relevant, and may guide stent choice and patient management, efforts have been made to elucidate the causes of and ways to prevent occlusion of indwelling stents. In this narrative review we focus on biliary plastic stents and discuss the mechanisms of stent occlusion, existing evidence on salient outcomes, as well as options to overcome existing limitations and prolong plastic stent patency.

Real-World Endoscopic and Histologic Outcomes in Ulcerative Colitis Patients: A Retrospective Cohort Study.

BACKGROUND: Histologic activity has emerged as an aspirational therapeutic goal in ulcerative colitis management. It is not yet a formal treatment target in ulcerative colitis. However, it could be used as an adjunct to mucosal healing to represent a deeper level of healing. We investigated mucosal and histologic remission rates and potential predictors of these outcomes in a cohort of UC patients. METHODS: We conducted a retrospective analysis of data collected from UC patients enrolled in an ongoing prospective cohort study. Mucosal healing was defined as Mayo endoscopic score = 0. RESULTS: A total of 131 patients with ulcerative colitis were enrolled in our study and were prospectively followed for a median length of 2 years (range 0-5 years), totaling 266 study visits. Mucosal healing was recorded for 27 patients at 70 (26%) different study visits. For patients with mucosal healing, histologic remission was achieved in 18/27 (66%) patients. On univariate analysis, sustained clinical remission, SIBDQ scores ≥ 5.5, CRP ≤ 5 mg/dL and absence of corticotherapy were associated with mucosal healing and SIBDQ scores ≥ 5.5 and CRP ≤ 5 mg/dL with histologic healing, respectively. After logistic regression analysis, none of the investigated factors were associated with mucosal and histologic healing. The number of CD8+ intraepithelial lymphocytes (IELs) was significantly greater than the number of CD4+ IELs in periods of disease activity, as well as during mucosal healing (p < 0.01 in both cases). CONCLUSIONS: Mucosal healing and histologic remission rates are low in real-life settings. The results of univariate analysis indicate that a good quality of life (SIBDQ score) and normal inflammatory markers (CRP) are associated with mucosal and histologic healing. However, frequently used patient- and disease-related factors, including mucosal healing, are not reliable predictors for histologic remission. Greater CD8+ lymphocyte involvement and higher CD8+/CD4+ distribution can have a meaningful impact on understanding the pathogenesis and natural history of ulcerative colitis, as well as future treatment options for lymphocyte-targeting medications.

EUS-guided fine needle biopsy is able to provide diagnosis in rare osteoclast-like giant cells undifferentiated carcinoma of the pancreas: report of two cases.

Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells (UC-OGC) is a rare subtype of pancreatic cancer, accounting for less than 1% of all pancreatic tumors. Preoperative diagnosis is cumbersome as cross-sectional imaging is often not capable to distinguish between UC-OGC and other pancreatic tumors such as pancreatic adenocarcinoma, mucinous carcinoma or neuroendocrine tumors and specific tumor markers seem to be lacking. Endoscopic ultrasound r `m(EUS) with tissue acquisition via fine-needle aspiration (FNA) or biopsy (FNB) with microscopic HE staining and immunohistochemistry allows for an accurate diagnosis, thus influencing further treatment. We present herein the cases of two patients with osteoclast-like giant cells tumors of the pancreas diagnosed by EUS-guided fine needle biopsy and perform a literature review on the role of EUS-guided biopsy for diagnosis.

A simple clinical score to stratify the risk of procedure-related adverse events in ERCP procedures with trainee involvement.

BACKGROUND : Optimal training strategies in endoscopic retrograde cholangiopancreatography (ERCP) remain controversial despite the shift toward competence-based training models, with limited data available on patient safety during training. We aimed to assess whether pre-procedural clinical predictors could identify patients at low risk of developing procedure-related adverse-events (AEs) in a training environment. METHODS : We performed a prospective, multicenter, cohort study in five training centers. A data collection system documenting indication, clinical data, trainee performance (assessed using a validated competence assessment tool), technical outcomes, and AEs over a 30-day follow-up was utilized. We developed a clinical risk score (Trainee Involvement in ERCP Risk Score [TIERS]) for patients undergoing ERCP and compared the rate of AEs in a training environment between low-risk and high-risk groups. The association between trainee performance and AE rate was also evaluated. RESULTS : 1283 ERCPs (409 [31.9 %, 95 %CI 29.3 %-34.4 %] with trainee involvement) performed by 11 trainers and 10 trainees were analyzed. AEs were more frequent in the high-risk compared with the low-risk group: 26.7 % (95 %CI 20.5 %-34.7 %) vs. 17.1 % (95 %CI 12.8 %-22.2 %). TIERS demonstrated a high negative predictive value for AEs (82.9 %, 95 %CI 79.4 %-85.8 %) and was the only predictor of AEs on multivariable analysis (odds ratio 1.38, 95 %CI 1.09-1.75). Suboptimal trainee performance was associated with an increase in AE rates. CONCLUSION : Simple, clinical-based predictive tools could improve ERCP training by selecting the most appropriate cases for hands-on training, with the aim of increasing patient safety.

Women's Sexual Dysfunctions Following Stem Cell Transplant and the Impact on Couple Relationship.

Stem cell transplant proved its efficacy in increasing the survival rate among young patients diagnosed with hematological malignancies. A transplant conditioning regimen is particularly destructive on the genital system, often determining premature ovarian failure, accompanied by vulvovaginal atrophy and sexual dysfunctions. The aims of the present study were, first, to evaluate sexual dysfunctions among transplanted women, using clinical examination and the female sexual function index (FSFI), and second, to determine their impact on a couple's relationship. A prospective observational comparative study was performed and included 38 patients who underwent allogenic stem cell transplant (SCT) procedures for different hematological malignancies and 38 healthy patients (control group). This study included baseline evaluation, one-year, and three-year follow-up visits. In addition to anamnesis and medically obtained information, FSFI was evaluated to determine the impact of gynecological damage in a subjective manner. In the study group, vulvovaginal atrophy was diagnosed in 76.32%, with subsequent sexual dysfunctions in 92.10% of patients, based on FSFI scoring. Even though the results improved throughout the study, at the last visit, mild vulvovaginal atrophy was diagnosed in 81.58% of patients, and the FSFI score was abnormal for 21.05%. When compared to the control group, both sexual dysfunctions and FSFI results were considerably impaired, with statistical significance. There is a confirmed negative impact of sexual dysfunctions and self-declared FSFI on couple/marital status and couple relationships, with statistical significance, at the last visit. In conclusion, anatomical, functional, and psychological difficulties are a reality of long-term survivors after a stem cell transplant. They should be addressed and assessed equally to other medical conditions, as they may determine serious consequences and impact the sexual quality of life and the couple's relationship.

Advances in the Diagnosis of Pancreatic Cystic Lesions.

Pancreatic cystic lesions (PCLs) are a heterogenous group of lesions ranging from benign to malignant. There has been an increase in PCLs prevalence in recent years, mostly due to advances in imaging techniques, increased awareness of their existence and population aging. Reliable discrimination between neoplastic and non-neoplastic cystic lesions is paramount to ensuring adequate treatment and follow-up. Although conventional diagnostic techniques such as ultrasound (US), magnetic resonance imaging (MRI) and computer tomography (CT) can easily identify these lesions, assessing the risk of malignancy is limited. Endoscopic ultrasound (EUS) is superior to cross-sectional imaging in identifying potentially malignant lesions due to its high resolution and better imaging characteristics, and the advantage of allowing for cyst fluid sampling via fine-needle aspiration (FNA). More complex testing, such as cytological and histopathological analysis and biochemical and molecular testing of the aspirated fluid, can ensure an accurate diagnosis.

Common bile duct size in malignant distal obstruction and lumen-apposing metal stents: a multicenter prospective study.

Background and study aims Feasibility of EUS-guided choledochoduodenostomy (EUS-CDS) using available lumen-apposing stents (LAMS) is limited by the size of the common bile duct (CBD) (≤ 12 mm, cut-off for experts; 15 mm, cut-off for non-experts). We aimed to assess the prevalence and predictive factors associated with CBD size ≥ 12 and 15 mm in naïve patients with malignant distal biliary obstruction (MDBO). Patients and methods This was a prospective cohort study involving 22 centers with assessment of CBD diameter and subjective feasibility of the EUS-CDS performance in naïve jaundiced patients undergoing EUS evaluation for MDBO. Results A total of 491 patients (mean age 69 ±â€Š12 years) with mean serum bilirubin of 12.7 ±â€Š6.6 mg/dL entered the final analysis. Dilation of the CBD ≥ 12 and 15 mm was detected in 78.8 % and 51.9 % of cases, respectively. Subjective feasibility of EUS-CDS was expressed by endosonographers in 91.2 % for a CBD ≥ 12 mm and in 96.5 % for a CBD ≥ 15 mm. On multivariate analysis, age ( P  < 0.01) and bilirubin level ( P  ≤ 0.001) were the only factors associated with both CBD dilation ≥ 12 and ≥ 15 mm. These variables were poorly associated with the extent of duct dilation; however, based on them a prediction model could be constructed that satisfactorily predicted CBD size ≥ 12 mm in patients at least 70 years and a bilirubin level ≥ 7 mg/dL. Conclusions Our study showed that at presentation in a large cohort of patients with MDBO, EUS-CDS can be potentially performed in three quarters to half of cases by expert and less experienced endosonographers, respectively. Dedicated stents or devices with different designs able to overcome the limitations of existing electrocautery-enhanced LAMS for EUS-CDS are needed.

Surrogate markers of mucosal healing in inflammatory bowel disease: A systematic review.

BACKGROUND: Mucosal healing (MH) has emerged as a key therapeutic target in inflammatory bowel disease (IBD), and achievement of this goal is documented by endoscopy with biopsy. However, colonoscopy is burdensome and invasive, and substitution with an accurate noninvasive biomarker is desirable. AIM: To summarize published data regarding the performance of noninvasive biomarkers in assessing MH in IBD patients. METHODS: We conducted a systematic review of studies that reported the performance of biomarkers in diagnosing MH in patients with IBD. The main outcome measure was to review the diagnostic accuracy of serum and fecal markers that showed promising utility in assessing MH. RESULTS: We screened 1301 articles, retrieved 46 manuscripts and included 23 articles for full-text analysis. The majority of the included manuscripts referred to fecal markers (12/23), followed by circulatory markers (8/23); only 3/23 of the included manuscripts investigated combined markers (serum and/or fecal markers). Fecal calprotectin (FC) was the most investigated fecal marker for assessing MH. In ulcerative colitis, for cutoff levels ranging between 58 mcg/g and 490 mcg/g, the sensitivity was 89.7%-100% and the specificity was 62%-93.3%. For Crohn's disease, the cutoff levels of FC ranged from 71 mcg/g to 918 mcg/g (sensitivity 50%-95.9% and specificity 52.3%-100%). The best performance for a serum marker was observed for the endoscopic healing index, which showed a comparable accuracy to the measurement of FC and a higher accuracy than the measurement of serum C-reactive protein. CONCLUSION: Several promising biomarkers of MH are emerging but cannot yet substitute for endoscopy with biopsy due to issues with reproducibility and standardization.

Motion training on a validated mechanical ERCP simulator improves novice endoscopist performance of selective cannulation: a multicenter trial.

Background and study aims Current data show that traditional training methods in endoscopic retrograde cholangiopancreatography (ERCP) fall short of producing competent trainees. We aimed to evaluate whether a novel approach to simulator-based training might improve the learning curve for novice endoscopists training in ERCP. Methods We conducted a multicenter, randomized controlled trial using a validated mechanical simulator (the Boskoski-Costamagna trainer). Trainees with no experience in ERCP received either standard cannulation training or motion training before undergoing standard cannulation training on the mechanical simulator. Trainees were timed and graded on their performance in selective cannulation of four different papilla configurations. Results Thirty-six trainees (16 in the motion training group, 20 in the standard group) performed 720 timed attempts at cannulating the bile duct on the simulator. Successful cannulation was achieved in 698 of 720 attempts (96.9 %), with no significant difference between the two study groups ( P  = 0.37). Trainees in the motion training group had significantly lower median cannulation times compared to the standard group (36 vs. 48 seconds, P  = 0.001) and better technical performance on the first papilla type ( P  = 0.013). Conclusions Our findings suggest that motion training could be an innovative method aimed at accelerating the learning curve of novice trainees in the early phase of their training. Future studies are needed to establish its role in ERCP training programs.

MLH1, BRAF and p53 - searching for significant markers to predict evolution towards adenocarcinoma in colonic sessile serrated lesions.

BACKGROUND AND AIM: Colonic serrated lesions are premalignant lesions, using an alternative malignization pathway, including multiple genetic and epigenetic alterations, as: mismatch repair deficiency due to MutL homolog 1 (MLH1) promoter methylation, tumor protein p53 (TP53) mutations, activating mutations of v-Raf murine sarcoma viral oncogene homolog B (BRAF) and Kirsten rat sarcoma viral oncogene homolog (KRAS). Our study aims to evaluate MLH1, BRAF and p53 immunohistochemical (IHC) status in sessile serrated lesions (SSLs), with and without dysplasia. MATERIALS AND METHODS: This is a retrospective case-control study including 20 SSLs with dysplasia and 20 SSLs without dysplasia (matching sex and age). IHC expression of MLH1, BRAF and p53 was evaluated as the percent of nuclear loss of MLH1, cytoplasmic positivity of BRAF and nuclear positivity of p53. Data concerning age, sex, localization of the lesion, dysplasia and IHC results were statistically processed using Microsoft Excel. RESULTS: We had very polymorphous patterns of IHC expression for BRAF, MLH1 and p53, especially in the dysplastic group. Thus, two patients were BRAF+∕MLH1-∕p53+, three were BRAF+∕MLH1-∕p53-, one was BRAF+∕MLH1+∕p53- and six were BRAF+∕MLH1+∕p53+. Dysplastic lesions without BRAF mutation exhibited the following phenotype: one case BRAF-∕MLH1-∕p53+, four BRAF-∕MLH1-∕p53- and three BRAF-∕MLH1+∕p53+. In the control group (SSLs without dysplasia), there was a more homogenous distribution of cases: eight cases BRAF+∕MLH1+∕p53-, seven BRAF-∕MLH1+∕p53-, one BRAF-∕MLH1-∕p53+, two BRAF-∕MLH1-∕p53- and two BRAF-∕MLH1+∕p53+. CONCLUSIONS: There are more routes on the serrated pathway, with different mutations and time of acquisition of each genetic or epigenetic lesion with the same morphological result. These lesions should be stratified according to their risk to poor outcome and their need to further surveillance.

Transient venous air embolism after ERCP: worrisome or not?

The paper describes the occurrence of a rare complication - portal and systemic venous air embolism - after endoscopic retrograde cholangiopancreatography, related to the endoscopic procedure. It can be associated with the more frequently encountered post-endoscopic retrograde cholangiopancreatography complications pancreatitis or cholangitis. However, it can also be noted with perforation. The presented case suggests that in the clinical context an early abdominal ultrasound examination confirming hepatic portal venous gas and/or systemic venous air embolism could be useful for the diagnosis of post-endoscopic retrograde cholangiopancreatography retroduodenal perforation, and thus highlights the need for a high index of suspicion should this occurrence be noted post-procedurally, in order to ensure the best care of patients.The paper describes the occurrence of a rare complication ­ portal and systemic venous air embolism ­ after endoscopic retrograde cholangiopancreatography, related to the endoscopic procedure. It can be associated with the more frequently encountered post-endoscopic retrograde cholangiopancreatography complications pancreatitis or cholangitis. However, it can also be noted with perforation. The presented case suggests that in the clinical context an early abdominal ultrasound examination confirming hepatic portal venous gas and/or systemic venous air embolism could be useful for the diagnosis of post-endoscopic retrograde cholangiopancreatography retroduodenal perforation, and thus highlights the need for a high index of suspicion should this occurrence be noted post-procedurally, in order to ensure the best care of patients.

Technical and clinical outcomes of endoscopic retrograde cholangiopancreatography (ERCP) procedures performed in patients with COVID-19.

BACKGROUND: The unprecedented situation caused by the coronavirus disease 2019 (COVID-19) pandemic has profoundly affected endoscopic practice in regard to access, volume, and workflow. We aimed to assess the potential changes in the technical outcomes of endoscopic retrograde cholangiopancreatography (ERCP) procedures carried out in patients with confirmed SARS-CoV-2 infection. METHODS: We conducted an international, multicenter, retrospective, matched case-control study of ERCP procedures carried out in patients with confirmed COVID-19. The main outcome was technical success of the procedure as assessed by the endoscopist, and the secondary outcome was the development of procedure-related adverse events. Each case was matched in a 1:4 ratio with controls extracted from each center's database in order to identify relevant changes in outcome measures compared with the pre-pandemic era. RESULTS: Eighteen procedures performed in 16 COVID-19 patients [14 men, 65 years (9-82)] and 67 controls were included in the final analysis. Technical success was achieved in 14/18 COVID-19 cases, which was significantly lower as compared with the control group (14/18 versus 64/67, p = 0.034), with an endoscopic reintervention required in 9/18 cases. However, the rate of procedure-related adverse events was low in both groups (1/18 versus 10/67, p = 0.44). On multivariable analysis, COVID-19 status remained the only risk factor for technical failure of the procedure [odds ratio of 19.9 (95% confidence interval 1.4-269.0)]. CONCLUSIONS: The COVID-19 pandemic has affected the volume and practice of ERCP, resulting in lower technical success rates without significantly impacting patient safety. Prioritizing cases and following recommendations on safety measures can ensure good outcome with minimal risk in dedicated centers.

Measuring trainee competence in performing endoscopic retrograde cholangiopancreatography: A systematic review of the literature.

Background: Current recommendations on training in endoscopic retrograde cholangiopancreatography are predicated on a performance-centred approach designed to ensure that trainees achieve appropriate skills. We aimed to analyse how competence in endoscopic retrograde cholangiopancreatography is defined in the literature and what proportion of trainees actually reach this threshold. Methods: We conducted a systematic MEDLINE search for studies reporting on endoscopic retrograde cholangiopancreatography training programmes in a clinical setting. The main outcome measure was threshold for achieving competence in endoscopic retrograde cholangiopancreatography; the secondary outcome measure was assessment of trainee performance. Quality was assessed using the Cochrane Risk of Bias tool and the Methodological Index for Non-Randomized Studies criteria. Results: Of 522 initially identified articles, 20 were included in the analysis; most studies showed a high risk of bias. Cannulation rate of the desired duct was the main marker of competence in all studies; however, only 8/20 studies reported on the performance of individual trainees, who achieved their respective standard of competence in only 25.6% of reported cases. Conclusions: Current literature identifies cannulation rate of a native papilla to be the most appropriate measure of endoscopic retrograde cholangiopancreatography competence; however, most trainees do not reach predefined competence thresholds. Furthermore, due to the limitations of available studies, the most appropriate competence measure remains subject for debate.

Efficacy and safety of biosimilar CT-P13 compared with originator infliximab in patients with active Crohn's disease: an international, randomised, double-blind, phase 3 non-inferiority study.

BACKGROUND: The infliximab biosimilar CT-P13 was approved for use in Crohn's disease after clinical comparison with originator infliximab in ankylosing spondylitis and rheumatoid arthritis; however, concerns about such indication extrapolation have been expressed. This study investigated whether CT-P13 is non-inferior to infliximab in patients with Crohn's disease who were naive to biological therapy. METHODS: In this randomised, multicentre, double-blind, phase 3 non-inferiority study, we enrolled patients with active Crohn's disease who had not responded to, or were intolerant to, non-biological treatments. Patients were randomly assigned (1:1:1:1) to receive CT-P13 then CT-P13, CT-P13 then infliximab, infliximab then infliximab, or infliximab then CT-P13, with switching occurring at week 30. Patients received 5 mg/kg CT-P13 or infliximab at weeks 0, 2, 6, and then every 8 weeks up to week 54. The primary endpoint was the proportion of patients with a decrease of 70 points or more in Crohn's Disease Activity Index (CDAI) from baseline to week 6. A non-inferiority margin of -20% was set (CT-P13 was non-inferior to infliximab if the lower limit of the two-sided 95% CI for the treatment difference was greater than -20). This trial is registered with ClinicalTrials.gov, number NCT02096861, and is completed. FINDINGS: Between Aug 20, 2014, and Feb 15, 2017, 308 patients were assessed for eligibility, and 220 patients were enrolled: 111 were randomly assigned to initiate CT-P13 (56 to the CT-P13-CT-P13 group and 55 to the CT-P13-infliximab group) and 109 to initiate infliximab (54 to the infliximab-infliximab group and 55 to the infliximab-CT-P13 group). CDAI-70 response rates at week 6 were similar for CT-P13 (77 [69·4%, 95% CI 59·9 to 77·8] of 111) and infliximab (81 [74·3%, 95% CI 65·1 to 82·2] of 109; difference -4·9% [95% CI -16·9 to 7·3]), thereby establishing non-inferiority. Over the total study period, 147 (67%) patients experienced at least one treatment-emergent adverse event (36 [64%] in the CT-P13-CT-P13 group, 34 [62%] in the CT-P13-infliximab group, 37 [69%] in the infliximab-infliximab group, and 40 [73%] in the infliximab-CT-P13 group). INTERPRETATION: This study showed non-inferiority of CT-P13 to infliximab in patients with active Crohn's disease. Biosimilar CT-P13 could be a new option for the treatment of active Crohn's disease. FUNDING: Celltrion, Pfizer.