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Background Recently, comparative trials among biologics in ulcerative colitis (UC) provided conflicting results on their reciprocal superiority or equivalence. Therefore, in patients naive to biologics, the first-choice biological drug is uncertain. Methods In a retrospective, real-life, multicentre inception cohort study involving 11 Italian IBD tertiary centres, all consecutive patients, naive to biologics, treated with adalimumab (ADA), infliximab biosimilar (CTP-13), golimumab (GOL) or vedolizumab (VDZ) after their postmarketing approval (2014–2018) for moderate–severe active UC, were followed up for 1 year or until relapse. All drugs were compared with each other and to naive patients treated with IFX-originator (IFX-O, Remicade) in 2013–2014 as a reference group. A propensity score analysis was performed. The primary endpoint was the 1 year relapse-free, optimisation-free, steroid-free remission, defined as Mayo score ≤2, with bleeding subscore = 0, no relapse after first clinical remission and no optimisation with dose intensification or steroids courses. Multiple further secondary endpoints were analysed (Table 1). Results Two hundred ninety-six naive patients (ADA = 56, CTP-13 = 73, GOL = 60, VDZ = 34, IFX-O = 73) were included. The primary end-point was achieved in similar percentages in all groups, irrespective of optimisation. IFX-O and ADA had similar rates of clinical remission achieved once during the follow-up but higher rates than GOL and VDZ. The 1-year relapse rate, however, was lower with VDZ than ADA, GOL and IFX-O. Treatment failure for primary/secondary no response was higher with GOL than IFX-O and ADA. Treatment failures for intolerance were similar among all drugs. CTP-13 performed differently than the originator for some secondary end-points. Conclusion Based on a strict definition of clinical remission, all biologics appear equally effective at 1 year in patients naive to these drugs. IFX originator and ADA appear more effective in the induction phase, while patients responders to VDZ had more prolonged clinical remission. Some differences on secondary questionable outcomes between IFX biosimilar and originator have been observed.

Background Until 2014, infliximab originator (Remicade, IFX-O) was the only biological treatment approved in Italy for ulcerative colitis (UC), followed by the sequential approval of adalimumab (ADA), infliximab biosimilar (CTP-13), golimumab (GOL) and vedolizumab (VDZ). Recently, comparative trials among these drugs provided conflicting results on their reciprocal superiority or equivalence. Methods In a retrospective, real-life, multicenter inception cohort study involving 11 Italian IBD tertiary centres, all consecutive patients with moderate-to-severe active UC, treated with ADA, CTP-13, GOL or VDZ after their post-marketing approval (2014–2018) were followed-up for 1 year or until relapse. All drugs were compared with each other and to patients treated with Remicade in 2013–2014 (reference group). The 80% power calculation of the study required at least 75 patients in each arm. A propensity score analysis was performed. The primary endpoint was the 1 year relapse-free, optimisation-free, steroid-free remission, defined as Mayo partial score ≤2, with bleeding subscore = 0, no relapse after first clinical remission and no optimisation with dose intensification or steroids courses. Multiple further secondary endpoints were analysed (Table 1). Results 492 patients (ADA=90, CTP-13=105, GOL=79, VDZ=142, IFX-O=76) were included. Overall, 65% achieved clinical remission once during the follow-up, with IFX-O performing better than GOL and VDZ. The relapse rate was 24%, with the lowest rates with VDZ. The primary end-point was achieved in similar percentages in all groups, except for lower rates with GOL than IFX-O. IFX-O performed better than each other drug for other clinical outcomes (Table 1). Discontinuation for intolerance was similar among the drugs, but CTP-13 had more frequent adverse events (mainly infusion reactions) than ADA, VDZ and IFX-O. Conclusion Based on a strict definition of clinical remission, all biologics appear equally effective at 1 year, except for GOL vs. IFX originator. IFX-O appears more effective in multiple questionable clinical outcomes. IFX biosimilar had more adverse events than the other drugs. IFX originator should be used as the reference drug in head to head, controlled, comparison trials for current and future biologics in UC.

Background Magnetic resonance cholangio-pancreatography (MRCP), endoscopic ultrasonography (EUS), and endoscopic cholangio-pancreatography (ERCP) are the most frequently employed second-step procedures to detect biliary and pancreatic abnormalities in patients with acute recurrent pancreatitis (ARP) of unknown aetiology. MRCP and EUS both give a better view of the bilio-pancreatic ductal system after secretin stimulation (MRCP-S, EUS-S). EUS also serves to identify changes in the pancreatic parenchyma consistent with chronic pancreatitis, at an early stage. However, no studies have compared MRCP-S, EUS-S, and ERCP in the diagnosis of recurrent pancreatitis. Aim To prospectively compare the diagnostic yield of MRCP-S, EUS-S, and ERCP in the evaluation of patients with acute recurrent pancreatitis with non-dilated ducts, of unknown aetiology. Methods Forty-four consecutive patients with ARP were prospectively scheduled to undergo MRCP-S, EUS-S and ERCP, in accordance with a standard protocol approved by the institutional review board. Diagnoses such as biliary microlithiasis, congenital variants of the pancreatic ducts, chronic pancreatitis and sphincter of Oddi dysfunction were compared between the three procedures. The diagnosis of chronic pancreatitis was established according to ductal morphology by MRCP-S and ERCP, ductal and parenchymal morphology by EUS-S. Results The three procedures combined achieved a diagnosis that could have explained the recurrence of pancreatitis in 28/44 patients (63.6%). EUS-S recognized ductal and/or parenchymal abnormalities with the highest frequency (35/44 patients, 79.5%). Both MRCP-S and EUS-S were superior to ERCP for detecting pancreatic ductal abnormalities. EUS-S showed up pancreatic parenchymal changes in more than half the cases. Both EUS and MRCP secretin kinetics were concordant in identifying two cases with sphincter of Oddi dysfunction. Conclusions The diagnostic yield of EUS-S in recurrent pancreatitis with non-dilated ducts and unknown aetiology was 13.6% and 16.7% higher than MRCP-S and ERCP respectively (although not significant), which both gave substantially similar diagnostic yields. In no case did ERCP alone find a diagnosis missed by the other two procedures. MRCP-S and EUS-S should both be used in the diagnostic work-up of idiopathic recurrent pancreatitis as complementary, first-line, techniques, instead of ERCP.

Background and aim Celiac disease is a common condition with many atypical manifestations, where histology serves as the “gold standard” for diagnosis. A useful new technique, optical coherence tomography, can depict villous morphology in detail, using light waves. This study examined the correlation between the sensitivity and specificity of optical coherence tomography in pediatric patients undergoing esophago-gastro-duodenoscopy for the diagnosis of celiac disease. Materials and methods A total of 134 children were prospectively enrolled, 67 with a serological suspicion of celiac disease (group 1) and 67 with negative histology for celiac disease (group 2). During a diagnostic esophago-gastro-duodenoscopy we acquired multiple images and films in the four quadrants of the second part of the duodenum, and biopsies were taken in the area where optical coherence tomography had been done. Three patterns of villous morphology were considered: pattern 1 = no atrophy (types 0, 1 or 2 of the Marsh classification); pattern 2 = mild atrophy (type 3a or 3b); pattern 3 = marked atrophy (type 3c). Results The diagnosis of celiac disease was histologically confirmed in all 67 children with positive antiendomysium and/or antitransglutaminase antibodies. Optical coherence tomography correlated with pattern 1 histology in 11/11 cases, pattern 2 in 30/32 (93.8%) and pattern 3 in 22/24 (91.6%). Sensitivity and specificity were 82% and 100%. In the control group there was 100% concordance between optical coherence tomography and histology. The overall concordance between optical coherence tomography and histology in determining patchy lesions was 75%. Conclusion Optical coherence tomography could be a helpful diagnostic tool in children with mild or marked villous atrophy for diagnosing celiac disease during upper gastrointestinal (GI) endoscopy, avoiding biopsies. However, duodenal biopsies are mandatory if the optical coherence tomography shows normal villous morphology in patients with positive antibodies.

BACKGROUND AND STUDY AIMS: In a previous study, a new flexible bipolar hybrid cryotherm probe was applied with success to the pancreas of a living pig. Here we evaluated feasibility, efficacy, and safety of its application to the porcine liver and spleen. MATERIAL AND METHODS: Ten applications to the liver and nine to the spleen were performed in 19 pigs. Power input (16 - 18 W) and simultaneous cooling with CO 2 (standardized pressure: 675psi) as the cryogenic agent were investigated. Application time varied from 120 seconds to 900 seconds. The ablation area was measured by endoscopic ultrasound (EUS) after ablation (T0), and before euthanasia (T1). Gross pathology (T2) and histology after necropsy represented the gold standard. The interval from treatment to euthanasia was 1 or 2 weeks. RESULTS: For both organs the correlation between EUS and gross pathology was good (correlation coefficient R liver = 0.71; R spleen = 0.73). EUS tended to overestimate the area of the ablated zone. EUS observed a time-dependent ablation area: we demonstrated a positive trend of lesion size (T1) over time in liver tissue (R = 0.51 ( P = 0.1)). In the spleen we found a clear correlation of lesion area T2 and application time (R = 0.75, P = 0.01). There were no complications. CONCLUSIONS: Selective EUS-guided transgastric cryotherm ablation of the liver and spleen in a pig model is feasible and safe. The new bipolar probe creates a time-dependent ablation area without any complications, and opens a field of new potential indications of RF-ablative therapies.

Background It has been speculated that midazolam may be effective in reducing the required dose of propofol during sedation. Aim To evaluate the sparing effect of midazolam during target-controlled propofol infusion. Methods Two hundred-seventy patients undergoing upper endoscopic ultrasound were randomised to receive sedation with propofol plus placebo (group A) or plus midazolam (group B). Outcome parameters were the procedure duration, the discharge time and the satisfaction of patients, operator and nurse about the quality of sedation. Results The mean propofol dose administered was 364 ± 207 mg in group A and 394 ± 204 mg in group B. Mean procedure duration (group A: 32 ± 17 min, group B: 35 ± 22 min) and discharge time (group A: 39 ± 30 min, group B: 38 ± 24 min) were similar in both groups. No severe complications were observed. The quality of sedation was judged satisfactory for all patients by both the endoscopist and the nurse assistant without any difference between the two groups. No patient remembered the procedure or reported it as unpleasant. Conclusions Target-controlled propofol infusion provides safe and effective sedation; premedication with low dose of midazolam does not reduce the total amount of propofol administered. Further studies are needed to compare propofol alone with propofol co-administered with opioid.

Background and aim: Pancreatic NeuroEndocrine Tumors (P-NETs) are a heterogeneous group of neoplasms with highly variable clinical behavior.In the attempt to assess a better prognostic description, the European Neuroendocrine Tumors Society (ENETS) proposed a new grading and TNM-based staging system. Aims of this study were to compare pre-operative and postoperative Staging and Grading in P-NETs and their prognostic significance; to determine if a new cut-off value of Ki-67 proliferative index for P-NETs Grading can improve the accuracy of prognostic stratification. Material and methods: Our retrospective study is composed of 285 patients with P-NETs observed at San Raffaele Scientific Institute from 1988 to 2012. Out of these, 90 and 42, respectively, were classified according to a new presurgical classification, composed of pre-operative Staging (CT, MRI, EUS) and Grading (EUS-guided FNA and cytological Ki-67 evaluation).Comparison between pre and post-operative models (Pre-Stage vs. Stage e Pre-Grade vs. Grade) was possible for 88 and 33 neoplasms, respectively. Ki-67 proliferative index was evaluated through immunocytochemical (Pre-Grade) and immunohistochemical (Grade) analyses. Agreement between pre-operative and post-operative models was performed through k-statistics (Cohen). A p-value

Background and study aims Acute pancreatitis is still the most common complication after endoscopic sphincterotomy (ES) and cholangiopancreatography (ERCP). The aim of this study was to detect the time when the peak of serum amylase was predictive for postprocedure pancreatitis or long-lasting severe hyperamylasemia, in order to plan the follow-up of patients. Methods Serum amylase activity was measured in a prospective series of 409 consecutive patients after ES, immediately before ES and two, four, eight and 24 hours thereafter; the two, four and eight-hour data were compared with those at 24 hours and with the outcome. Evaluation was done separately for the 198 cases with pancreatic duct opacification and for the 202 cases at high risk for postprocedure pancreatitis. Results Twenty-four hours after ES, amylase was still more than five times the upper normal limit in 26 patients, associated with pancreatic-like pain in 19 of them (mild/moderate pancreatitis) and asymptomatic in the remaining seven (long-lasting severe hyperamylasemia). There was a significant difference at all sampling times between the 26 patients with 24-hour severe hyperamylasemia and those with the lower level. Although the sensitivity of amylase measurement in detecting pancreatitis was highest at eight hours, in practice the four-hour assessment appears a reliable predictor. Almost all patients with serum amylase levels more than five times the upper normal limit at four, eight and 24 hours had had pancreatic duct opacification. In contrast, patient-related risk factors for postprocedure pancreatitis did not play a significant role in the present series. Conclusions Serum amylase assessment four hours after ES is a reliable, cost-effective follow-up and minimizes the likelihood of underestimating the risk of post-procedure pancreatic reaction. It should be recommended particularly in out-patients and when pancreatic duct opacification has occurred.

56 patients with large CBD or intrahepatic stones underwent endoscopic and/or percutaneous treatment followed by extracorporeal shock wave lithotripsy. Percutaneous access to the biliary tract was chosen when an endoscopic approach was not possible (hepaticojejunostomy in 5 patients, 1 juxtapapillary diverticulum and I inflammatory bile duct stricture). Visualization of stones was achieved radiologically in 32 patients and by ultrasound in 24. The procedure was successful in 47 of 56 treated patients (83.9%). Clearance of the biliary tract was obtained in 25 cases (53%), whereas in 22 cases (47%) complete clearing of biliary tract was obtained only after endoscopic extraction of fragments (17 cases) or percutaneous (5 cases). The median number of shock waves in each session was 1725 (range 300–3166), which were applied during one (n=30), two (n=22) or three sessions (n=4). The only complications were 1 case of symptomatic hyperamylasemia and 3 cases of macrohematuria. In conclusion, extracorporeal lithotripsy combined with endoscopic and/or percutaneous treatment is a real alternative to surgery for difficult stones.

Background Type 1 sphincter of Oddi dysfunction is a clinical entity characterised by biliary-type pain, elevated liver biochemical tests, and common bile duct dilation. Sphincter fibrosis is a common finding in this type of dysfunction and may require in some cases a differential diagnosis with a malignant intra-papillary disease. Optical coherence tomography permits high-resolution, real-time imaging of the sphincter of Oddi microstructure by a probe inserted into the common bile duct through an ERCP catheter. No data exist on the evaluation of sphincter of Oddi fibrosis by optical coherence tomography during ERCP in vivo. Objective To assess the feasibility of optical coherence tomography investigation of the sphincter of Oddi structure and assess its potential for diagnosing type 1 sphincter of Oddi dysfunction. Patients Ten consecutive patients, five with biliary-type 1 sphincter of Oddi dysfunction and five with pancreatic head/mid-body adenocarcinoma not involving the papillary region, who underwent both endoscopic ultrasound and therapeutic ERCP, were investigated by optical coherence tomography immediately before biliary sphincterotomy or stenting. Results In all sphincter of Oddi dysfunction patients optical coherence tomography recognised a hyper-reflective intermediate, fibro-muscular layer, significantly thicker than in patients with non-pathological sphincter of Oddi (p Conclusions Optical coherence tomography imaging recognised an increased thickness and reflectance of the fibro-muscular layer of the sphincter of Oddi, very likely determined by fibrosis, and was not time-consuming; it can be safely used during ERCP to confirm the diagnosis in difficult cases. Its use in clinical practice has one important limitation since it requires magnification in the post-procedure computer analysis to obtain images useful for diagnosis.

BACKGROUND AND STUDY AIMS: Open, laparoscopic, or percutaneous radiofrequency (RF) ablation of the pancreas is still dangerous, whereas endoscopic ultrasound (EUS)-guided ablation might reduce risk because it is less invasive and provides real-time monitoring. We aimed to demonstrate the feasibility of transluminal RF ablation and to evaluate the efficacy and safety of a new flexible bipolar ablation probe combining RF and cryotechnology. METHODS: 14 ablations were performed in 14 pigs. Energy input (16 W) and simultaneous cryogenic cooling with carbon dioxide (650 psi) were standardized. Application time range was 120 - 900 seconds. Ablation area was measured by EUS immediately after ablation (area T0), and before euthanasia (area T1). Macroscopic findings (area T2) and histological findings after necropsy served as gold standard. The interval from application to euthanasia was either 1 or 2 weeks. RESULTS: The correlation between EUS findings (area T1) and macroscopic appearance (area T2) was good ( R = 0.89). The correlation between the T2 ablation area and the application time showed a fitted ratio of 2.3 ( P > 0.0001) with a 1-week interval and 0.2 ( P = 0.01) with a 2-week interval. No pig died because of the procedure. Two pigs showed histochemical pancreatitis, which was clinically overt in one. Necropsy additionally revealed one burn to the gastric wall and four gut adhesions. CONCLUSIONS: Selective transluminal RF ablation of the pancreas under EUS control in a living pig model is feasible. The new flexible bipolar probe creates an ablation area with extent related to the duration of application, and with fewer complications than conventional RF ablation techniques.