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Background: Mirikizumab is a humanized monoclonal antibody targeting interleukin 23p19 with demonstrated efficacy in psoriasis and ulcerative colitis. We investigated the safety and efficacy of mirikizumab in patients with moderate-to-severe Crohn's disease (CD). Methods: Patients (N = 191) were randomized (2:1:1:2) to receive placebo (PBO), 200, 600, or 1000 mg mirikizumab, administered intravenously (IV) every 4 weeks. Patients who received mirikizumab and achieved ≥1 point improvement in Simple Endoscopic Score-CD at Week 12 (rerandomized maintenance cohort) were rerandomized to continue their induction IV treatment (combined IV groups [IV-C]) or receive 300 mg mirikizumab subcutaneously (SC) every 4 weeks. Nonrandomized maintenance cohort included endoscopic nonimprovers (1000 mg) and PBO patients (PBO/1000 mg) who received 1000 mg mirikizumab IV from Week 12. The primary objective was to evaluate superiority of mirikizumab to PBO in inducing endoscopic response (50% reduction from baseline in Simple Endoscopic Score-CD) at Week 12. Results: At Week 12, endoscopic response was significantly higher by the predefined 2-sided significance level of 0.1 for all mirikizumab groups compared with PBO (200 mg: 25.8%, 8/31, 95% confidence interval [CI], 10.4–41.2, P = .079; 600 mg: 37.5%, 12/32, 95% CI, 20.7–54.3, P = .003; 1000 mg: 43.8%, 28/64, 95% CI, 31.6–55.9, P < .001; PBO: 10.9 %, 7/64, 95% CI, 3.3–18.6). Endoscopic response at Week 52 was 58.5% (24/41) and 58.7% (27/46) in the IV-C and SC groups, respectively. Frequencies of adverse events (AE) in the mirikizumab groups were similar to PBO. Through Week 52, frequencies of treatment-emergent AEs were similar across all groups. Frequencies of serious AE and discontinuations due to AE were higher in the nonrandomized maintenance cohort. Conclusion: Mirikizumab effectively induced endoscopic response after 12 weeks in patients with moderate-to-severe CD and demonstrated durable efficacy to Week 52. A detailed summary can be found in the Video Abstract. ClinicalTrials.gov, Number: NCT02891226

Background & aims This study compared pharmacokinetics, symptomatic and endoscopic efficacy, safety, and immunogenicity of a subcutaneous formulation of the infliximab biosimilar CT-P13 (CT-P13 SC) vs intravenous CT-P13 (CT-P13 IV) in patients with inflammatory bowel disease (IBD). Methods This randomized, multicenter, open-label, parallel-group, phase 1 study enrolled tumor necrosis factor inhibitor–naive patients with active ulcerative colitis (total Mayo score 6–12 points with endoscopic subscore ≥2) or Crohn's disease (Crohn's Disease Activity Index 220–450 points) at 50 centers. After CT-P13 IV induction at Week (W) 0/W2, patients were randomized (1:1) to receive CT-P13 SC every 2 weeks (q2w) from W6 to W54 or CT-P13 IV every 8 weeks from W6 to W22. At W30, all patients receiving CT-P13 IV switched to CT-P13 SC q2w until W54. The primary endpoint was noninferiority of CT-P13 SC to CT-P13 IV for observed predose CT-P13 concentration at W22 (Ctrough,W22), concluded if the lower bound of the 2-sided 90% confidence interval (CI) for the ratio of geometric least-squares means exceeded 80%. Results Overall, 66 and 65 patients were randomized to CT-P13 SC and CT-P13 IV, respectively. The primary endpoint of noninferiority was met with a geometric least-squares means ratio for Ctrough,W22 of 1154.17% (90% CI 786.37–1694.00; n = 59 [CT-P13 SC]; n = 57 [CT-P13 IV]). W30/W54 clinical remission rates were comparable between arms. Other efficacy, safety, and immunogenicity assessments were also broadly comparable between arms, including after switching. Conclusions The pharmacokinetic noninferiority of CT-P13 SC to CT-P13 IV, and the comparable efficacy, safety, and immunogenicity profiles, support the potential suitability of CT-P13 SC treatment in IBD. ClinicalTrials.gov ID: NCT02883452.

Biologic treatment options are limited for children with ulcerative colitis. The aim of this study was to assess the safety and efficacy of adalimumab in children with moderate-to-severe ulcerative colitis.The double-blind ENVISION I study was done at 24 hospitals in ten countries. Children (4-17 years) with moderate-to-severe ulcerative colitis despite stable doses of concurrent treatment with oral corticosteroids or immunosuppressants were enrolled. Per the original study design, patients were randomly assigned with an Interactive Voice Response System (IVRS) to receive either high-dose induction adalimumab (2·4 mg/kg [maximum 160 mg] at weeks 0 and 1) or standard-dose induction adalimumab (2·4 mg/kg at week 0 and placebo at week 1); both groups received 1·2 mg/kg (maximum 80 mg) at week 2 and 0·6 mg/kg (maximum 40 mg) at weeks 4 and 6. Patients with partial Mayo score (PMS) response at week 8 (defined as a decrease of two or more points and a decrease of ≥30% from baseline in PMS) were randomly assigned (2:2:1)-using IVRS-to receive either high-dose maintenance adalimumab (0·6 mg/kg weekly), standard-dose maintenance adalimumab (0·6 mg/kg every other week), or placebo up to week 52 (random assignment to the placebo group was ceased mid-trial, as was randomisation in the induction phase with all subsequent patients receiving open-label high-dose induction adalimumab). Coprimary endpoints were the proportion of patients with PMS remission at week 8 (intent-to-treat [ITT]-E population, not including those patients who were not randomised in the induction phase) and full Mayo score (FMS) remission at week 52 in week 8 PMS responders (maintenance ITT-E [mITT-E] population), for which the pooled adalimumab group (patients who received high-dose or standard-dose adalimumab) and the individual dose groups were compared against external adult placebo rates. We report results of the final confirmatory analysis. This trial is registered with ClinicalTrials.gov, NCT02065557.93 children were recruited between Oct 13, 2014, and Sept 5, 2018, to the main study (77 [83%] were randomly assigned [double-blind] to receive high-dose or standard-dose induction adalimumab; 16 [17%] received open-label high-dose induction adalimumab after study design change). At week 8, 74 (80%) children who were PMS responders continued to the maintenance period. 62 (84%) patients were randomly assigned to receive high-dose or standard-dose maintenance adalimumab treatment; 12 (16%) patients received placebo. In patients in the ITT-E population who were randomly assigned to receive high-dose induction adalimumab, a significantly higher proportion of patients were in PMS remission at week 8 (28 [60%] of 47) compared with external placebo (19·8%; p=0·0001). 13 (43%) of 30 patients in the standard-dose induction adalimumab group were in PMS remission at week 8 versus an external placebo rate of 19·8%, but this difference was not significant (p=0·38). Similarly, FMS remission at week 52 in children who were week 8 PMS responders was reported in a significantly higher proportion of patients in mITT-E population who received high-dose maintenance adalimumab (14 [45%] of 31 patients) versus external placebo at week 52 (18·4%; p=0·0001). Nine (29%) of 31 patients in the standard-dose maintenance adalimumab group were in FMS remission at week 52 versus an external placebo rate of 18·4%, but this difference was not significant (p=0·38). Remission rates in the pooled adalimumab groups were significantly better compared with external placebo (PMS remission at week 8: 41 [53%] of 77 patients; p0·0001; FMS remission at week 52: 23 [37%] of 62 patients; p=0·0001). 21 (23%) of 93 patients in the main study had one or more treatment-emergent serious adverse events during any adalimumab exposure. The most common adverse events were headache, anaemia, and ulcerative colitis flare during the induction period and ulcerative colitis flare, headache, and nasopharyngitis during the maintenance period.Clinically meaningful rates of remission and response were reported in children who received adalimumab in this study. No new safety signals were observed, suggesting that adalimumab is an efficacious and safe treatment option for children with moderate-to-severe ulcerative colitis.AbbVie.

Summary Objective Constipation is one of the most common problems among children, with a prevalence ranging from 7 to 30%. It is treated with defecation training and laxative medications. However, many patients do not respond to the standard therapy. There is, therefore, an increasing interest in probiotics for the treatment of functional constipation. Study design The aim of this study was to assess the effectiveness of Lactobacillus reuteri DSM 17938 as an adjunct to macrogol in the treatment of functional, intractable constipation in children. A double-blind, placebo-controlled, randomized, multicentre trial involved a group of 129 children with functional constipation who were treated with a poor effect for at least two months prior to the study. Patients were randomly assigned to one of the two groups: 1. L. reuteri DSM 17938 and macrogol or 2. macrogol and matching placebo for 8 weeks. Results 121 patients completed the study. Almost all patients (119/129) increased their bowel movements in both groups (59 vs 60, ns.) and there was no statistically significant difference in the number of bowel movements per week in week 8 between the study and the placebo group (7.5 ± 3.3 vs 6.9 ± 2.5, respectively). Additionally, there were no significant differences between groups in the numbers of patients complaining of pain during defecation (13/47 vs 8/53), abdominal pain (19/41 vs 25/36), withholding stools (15/45 vs 13/48), passing hard stools (7/53 vs 3/58) or large stools (14/46 vs 12/49), and faecal incontinence (17/43 vs 11/50). Conclusion L. reuteri DSM 17938 supplementation as an additional therapy to macrogol did not have any beneficial effect on the treatment of functional constipation in children aged 3–7 years.

To evaluate the diagnostic accuracy of magnetic resonance cholangiopancreatography (MRCP) in the detection of chronic pancreatitis (CP)-specific changes in the pediatric population.The study included 48 children with pancreatic disorders subjected to both endoscopic retrograde cholangiopancreatography (ERCP) and MRCP within a 1- to 4-month interval. The sensitivity, specificity, positive predictive value, and negative predictive value of MRCP in the detection of CP-specific changes were determined using ERCP as a diagnostic standard.Diagnostic ERCP pancreatograms were obtained in 41 (85.4%) of 48 patients and diagnostic MRCP images in all 48 children. The sensitivity and positive predictive value of MRCP were 77.1% and 90%, respectively, and its specificity and negative predictive value amounted to 50% and 27.3%, respectively. The patients with consistent results of MRCP and ERCP (ie, true-positive and true-negative cases) and individuals with incompatible results of the tests (ie, false-positive and false-negative cases) differed in terms of their median age at MRCP (14.17 vs 10.33 years) and median CP stage according to the Cambridge Scale (4 vs 2).Magnetic resonance cholangiopancreatography provides diagnostic information equivalent to ERCP in a large percentage of pediatric patients with CP and should be used as the imaging method of choice, especially if the likelihood of therapeutic intervention is low.

Limited data on proton pump inhibitors in infants led regulatory agencies to request sponsors to conduct pediatric studies. To determine the pharmacodynamic response to pantoprazole in infants with GERD to aid the dose selection for an efficacy study. In two open-label studies, neonates and preterm infants (study 1, ~1.2 mg/kg [high dose]) and infants 1 through 11 months (study 2, ~0.6 [low dose] or ~1.2 mg/kg [high dose]) received once-daily pantoprazole. Twenty-four-hour dual-electrode pH-metry parameters were compared between predose and steady state (≥5 days) (two-sided paired t test). Treatment was administered for ≤6 weeks. In studies 1 and 2, 21 and 24 patients, respectively, were enrolled for pharmacodynamic evaluation. The high dose provided similar responses in the two studies and improved these parameters significantly: mean gastric pH and percent time gastric pH > 4 increased (p

Available data from adult patients do not reflect natural course of hereditary pancreatitis (HP) in children. To date, no study has assessed the clinical course of HP in children.To investigate the clinical course of HP in children and compare it to non-HP group with chronic pancreatitis (CP).A group of 265 children with CP, hospitalized from 1988 to 2014, were enrolled in the study. Medical records of those patients were reviewed for data on presentation, diagnostic findings and treatment. All children were screened for mutations in major pancreatitis-associated genes, i.e. PRSS1, SPINK1, and CFTR.HP was diagnosed in 41 children (15.5%). Family history was positive in 88% of children with HP. Mutations of PRSS1 gene were found in 80% (33/41) of HP patients. We detected p.R122H, p.R122C, p.N29I, and p.E79K mutation in 34% (14/41), 27% (11/41), 12% (5/41), and 7% (3/41) of HP patients, respectively. Patients with paternal inheritance had first symptoms earlier than those with maternal inheritance (5.9 vs. 9.1 years; P 0.05). Children with HP showed more severe changes in ERCP then those from non-HP group (2.05 Cambridge grade, vs. 1.6°; P 0.05). ESWL was performed more frequently in HP group (12.2% vs. 3.1%; P 0.05). There was no difference in age of disease onset (7.98 vs. 8.9 years; NS), pancreatic duct stenting (46.3% vs. 33%; NS), or number of surgical interventions (12.2% vs. 14.3%; NS) between both groups.Children with HP reveal significantly more severe clinical presentation of the disease than non-HP patients, despite the same age of onset.

Background/objectives The present study was undertaken to determine the prevalence of malnutrition among children with chronic pancreatitis (CP). Furthermore, we aimed to evaluate the relationship between etiological factors of CP, its clinical characteristics, and the severity of malnutrition. Methods The study included 208 children with CP (113 girls and 95 boys; mean age: 10.8 years, range: 1.6–18 years), hospitalized at our center between 1988 and 2012. The severity of malnutrition was graded on the basis of Cole's ratios, and its prevalence was analyzed according to the etiological factors of pancreatitis. Moreover, the analysis of discrimination was performed to identify the factors contributing to malnutrition among the following variables: age at CP onset, duration of CP, number of CP exacerbations, the number of ERCPs performed, the grade of pancreatic damage documented on imaging, co-occurrence of diabetes, and the results of 72-h fecal fat quantification. Results We documented features of malnutrition in 52 (25%) children with CP, including 36 (17.3%) patients with moderate malnutrition, and 2 (0.96%) with severe malnutrition. There was no significant difference in the prevalence of malnutrition between groups of patients with various etiological factors of chronic pancreatitis. The age at CP onset showed the best discrimination ability of malnourished patients: the mean age at disease onset in a subgroup of malnourished children was significantly higher than in children with Cole's index >85%. Conclusions A considerable percentage of children with CP can suffer from clinically significant malnutrition. Later age at CP onset predisposes to development of malnutrition.

Objective To assess the clinical efficacy and the impact of infliximab (IFX) induction therapy on mucosal healing in Polish children with Crohn's disease (CD). Methods A total of 66 children (29 boys and 37 girls) aged 14.06 ± 3.59 years with CD diagnosed at the mean age of 8.4 ± 7.3 years were included in the study. Patients received IFX (5 mg/kg) in three repeated infusions at 0, 2, and 6 weeks. The clinical activity of the disease was assessed using the Pediatric Crohn's Disease Activity Index (PCDAI) and the endoscopic activity was scored using the Simple Endoscopic Score for Crohn's disease at baseline and at week 10. Results Twenty-two (33%) of the studied patients reached clinical remission (PCDAI ≤ 10), 26 (39%) showed a clinical response (PCDAI between 15 and 30), and 18 (28%) did not respond to the therapy. When comparing data at baseline and at week 10, significant decreases were observed in the median PCDAI, C-reactive protein, and platelet count. In addition, a significant increase in BMI was noted. A significant decrease in the Simple Endoscopic Score for CD was observed between the initial and the control colonoscopies. Fifteen out of 66 patients (22.7%) had score 0 in the control endoscopy at week 10. No adverse events leading to therapy termination were observed. Conclusion Biological therapy with IFX enables mucosal healing in pediatric patients with CD. Induction therapy with infliximab was found to be clinically effective in 72% of Polish pediatric patients with CD and induced a remission in 33% of them. Induction therapy with infliximab helps to increase BMI.

The IMAgINE 1 study (NCT00409682) evaluated the safety and efficacy of adalimumab double-blind maintenance dosing regimens following open-label induction for pediatric patients with moderate to severe Crohn's disease (CD).We studied 192 patients with Pediatric Crohn's Disease Activity Index (PCDAI) scores30 for whom conventional treatment was unsuccessful. Patients received open-label induction therapy with subcutaneous adalimumab at weeks 0 and 2 (160 mg and 80 mg, or 80 mg and 40 mg, for body weight ≥40 kg or40 kg). At week 4, 188 patients were assigned to groups based on achievement of clinical response (defined as decrease in PCDAI ≥15 points from baseline; 155/188 [82.4%]) and prior exposure to infliximab (82/188 [43.6%]). Groups were given double-blind maintenance therapy with adalimumab at high (40 mg or 20 mg for body weight ≥40 kg or40 kg; n = 93) or low doses (20 mg or 10 mg for body weight ≥40 kg or40 kg; n = 95) every other week for 48 weeks. Clinical remission (PCDAI ≤10) at week 26 (the primary end point) was compared between groups using the Cochran-Mantel-Haenszel test, adjusting for strata, with nonresponder imputation. Adverse events were monitored to evaluate safety.A total of 152 of 188 patients (80.9%) completed all 26 weeks of the study. At week 26, 63 patients (33.5%) were in clinical remission, with no significant difference between high- and low-dose groups (36/93 [38.7%] vs 27/95 [28.4%]; P = .075). No new safety signals were detected.Adalimumab induced and maintained clinical remission of children with CD, with a safety profile comparable to that of adult patients with CD. More children who received high compared with low dose were in remission at week 26, but the difference between dose groups was not statistically significant.

Background: Hereditary Pancreatitis (HP) is a rare inherited condition. We reviewed our experience over the last 20 years. Aims: The aim of our study was to evaluate the clinical course of HP in children. Patients & methods: 240 children with chronic pancreatitis, hospitalized since 1988 to 2013, were enrolled into the study. The medical records of these patients were reviewed for data on the presentation, diagnostic findings and endoscopic treatment. All children were screened for the PRSS1 gene mutations. Results: Hereditary pancreatitis was diagnosed in 31 patients (12.9%). PRSS1 gene mutations were found in 27 patients. We detected R122H/in 13, R122C/in 8, N29I/in 5 and E79K/in 1 patient. Family history was positive in 26 children with HP (84%). In 4 patients without mutations diagnosis was made when patients satisfied the requirements of the family history. In one patient we found SPINK1 mutation. In 2 children CFTR mutation was present. There was no difference in age of the disease onset between HP group and non-HP group (8 vs. 9.1 years; NS). In children with PRSS1 mutation ERCP had mean 2,5o Cambridge grade, vs. 1.6o, p

s / Pancreatology 12 (2012) 502–597 565 We present the case of a 54 year old female patient, who underwent surgery for a neuroendocrine tumor, with a large pancreatic tail mass, diagnosed by computer tomography. Laparoscopic distal resection of the pancreas was conducted. The perioperative period was complicated by an infection of the wound and suppuration. The patient was discharged on the 7th day after the operation. Postoperative histopathological examination revealed the intrapancreatic accessory spleen. Accessory spleen mimicking a pancreatic tumor is difficult to diagnose. Some papers compare examination methods, but usually they are complicated, expensive and unavailable to patients. Moreover, in most of cases, EUS-FNA is impossible due to splenic vessels. In such cases, minimal invasive procedures appear to offer a good alternative to classic operations.

s / Pancreatology Background: Previous reports that the human equilibrative nucleoside transporter (hENT1) may be predictive of improved survival following adjuvant gemcitabine treatment have largely been based on retrospective non-randomized studies or studies of chemoradiotherapy. Here the therapeutic predictability of hENT1 expression and similar markers in patients undergoing resection for pancreatic cancer is assessed using the samples collected from the adjuvant ESPAC1/3 trials. Since these trials are randomized trials, this makes the results more scientifically compelling. Methods: An extensive purification processes was applied to antibodies to hENT1, deoxycytidine kinase-1 (dck1) and concentrative nucleoside transporter-1 (CNT1). These were validated (GCLP) using siRNA knockdowns, ICC and Western blotting prior and then optimized for immunohistochemistry. Tissue Micro Arrays (TMAs) containing tumour from non-trial pancreatic cancer patients (n1⁄469) were used to determine objective scoring systems of marker expression and then applied in a blinded manner on the ESPAC TMAs (n1⁄4434). Association between the different markers was measured using correlation of staining scores and this related to treatment group and other variables. Cox regression analysis was used to relate markers to survival prognosis, both individually and collectively, also taking in to account TNM status, tumour grade, resection margin status, smoking, age, and gender as well as survival status. Results: 59% of tumour samples had some level of hENT-1 staining, but only 3.7% had membranous staining. The median (IQR) survival was 15.2 (6.3, 37.7) months for observation (n1⁄431), 22.2 (11.7, 42.7) months for 5FU (n1⁄4201) and 23.8 (13.4, 41.6) for gemcitabine (n1⁄4202). Analysis of the relationship of staining and survival will be completed by the end March 2012. Conclusions: Potential extensive use of hENT1 staining as a stratification variable in trials means that verification of data for hENT1 is urgently required. The data generated from this trial will be potentially of great clinical value resulting in wide applicability given the unbiased nature of the randomised nature of the samples and the overall quality of the study based on GCLP and REMARK standards.

Background: Infliximab, a chimeric anti-tumour necrosis factor alpha antibody, is now an established therapy for both Crohn disease (CD) and psoriasis. Among patients treated for CD, however, the paradoxical development of new-onset psoriasis has been reported in up to 15% of adult patients. We reviewed the prevalence of psoriasis developing in pediatric CD patients during infliximabmaintenance therapy, and examined the role of polymorphisms in the interleukin 23-receptor (IL-23R) gene, known to contribute to CD and psoriasis susceptibility. Methods: The medical records of all CD patients with documented skin abnormalities following the instigation of infliximab, at our center, were reviewed. DNA from patients developing psoriasis following infliximab was compared with that of diseasematched controls to examine the association of Il-23R polymorphisms with this paradoxical event. Results: 118 children received infliximab from January 2000 to August 2008. Thirteen children (11%), (9 males), developed new onset psoriasis following infliximab therapy. Persistent luminal disease despite conventional therapy (n=10) and perianal disease (n=3) were the indications for initiation of infliximab. The median duration of infliximab exposure at the time of psoriasis onset was 1.0 year (IQR 0.6 2.1). The median age at diagnosis of psoriasis or psoriasiform lesions was 14.7 years (IQR 14.2 15.2). 11 of 13 responded well to topical steroid therapy. 2 patients discontinued infliximab, both with resolution of their psoriasis. DNA was available on 8 of the 13 patients who developed psoriasis, 137 diseasematched controls and 86 ulcerative colitis (UC) patients. 75% of cases were homozygous for the Il-23R rs10489629 single nucleotide polymorphism (SNP) compared with 42% of CD controls and 28% of UC controls, with an allele frequency of 88%, 65% and 53% for cases, CD controls and UC controls respectively. The odds ratio for an infliximab-exposed patient developing psoriasis was 3.8 for heterozygotes and 14 for homozygotes (p=0.07). Conclusion: The frequency of new-onset psoriasis in this pediatric cohort of CD patients treated with infliximab mirrors that reported in adult series. Most patients respond well to topical therapy and in the majority of cases, anti-TNF therapy can be continued. We found a trend towards association of this adverse event with a variation in the Il-23R gene. However, the true significance of this variation warrants further investigation in large, adequately powered, studies.