Therapy In UC Research Articles

MicroRNA 429 Regulates Mucin Gene Expression and Secretion in Murine Model of Colitis.

miRNAs are non-coding RNAs that play important roles in the pathogenesis of human diseases by regulating target gene expression in specific cells or tissues. We aimed to detect miRNAs related to ulcerative colitis [UC], identify their target molecules, and analyse the correlation between the miRNAs and their target genes in colorectal cells and dextran sulphate sodium [DSS]-induced mouse colitis. UC-associated miRNAs were identified by miRNA microarray analysis using DSS-induced colitis and normal colon tissues. The results were validated by quantitative real-time polymerase chain reaction [RT-PCR]. We identified target genes of MIR429, a colitis-associated miRNA, from our screen by comparing the mRNA microarray analysis in MIR429-overexpressed cells with predicted candidate target genes. We constructed luciferase reporter plasmids to confirm the effect of MIR429 on target gene expression. The protein expression of the target genes was measured by western blot,enzyme-linked immunosorbent assay [ELISA] analysis, or immunohistochemistry. We identified 37 DSS-induced colitis associated miRNAs. We investigated MIR429 that is down-regulated in DSS-induced colitis, and identified 41 target genes of MIR429. We show that the myristoylated alanine-rich protein kinase C substrate [MARCKS] is a direct target of MIR429. MARCKS mRNA and protein expression levels are down-regulated by MIR429, and MIR429 regulates the expression of MARCKS and MARCKS-mediated mucin secretion in colorectal cells and DSS-induced colitis. In addition, anti-MIR429 up-regulates MARCKS expression in colorectal cell lines. Our findings suggest that MIR429 modulates mucin secretion in human colorectal cells and mouse colitis tissues by up-regulating of MARCKS expression, thereby making MIR429 a candidate for anti-colitis therapy in human UC.

Inhibiting Immune Checkpoints for the Treatment of Bladder Cancer

Background:Increasing evidence supporting the role of immune checkpoint blockade in cancer management has been bolstered by recent reports demonstrating significant and durable clinical responses across multiple tumour types, including metastatic urothelial carcinoma (mUC). The majority of these results are achieved via blockade of the programmed death (PD) axis, which like CTLA-4 blockade permits T-cell activation and immune-mediated anti-tumour activity- essentially harnessing the patient’s own immune system to mount an anti-neoplastic response. However, while clinical responses can be striking, our understanding of the biology of immune checkpoint blockade is only beginning to shed light on how to maximize and even improve patient outcomes with immune checkpoint blockade, especially in UC.Methods:We performed a literature review for immune checkpoint blockade with a focus on rationale for checkpoint therapy and outcomes in UC. We also highlight the advances made in other tumour types, with a focus on the recent 2015 meeting of the American Society for Clinical Oncology.Results:In heavily pre-treated UC, trials are suggesting objective response rates above 30% . These impressive results are seen across multiple different tumour types, especially those with high burden of DNA level mutations. Identification of prognostic biomarkers is currently under investigation, in order to improve patient selection. Interestingly, response to PD-1 directed therapy is seen even in patients with no evidence of PD-1 positivity on immunohistochemistry. This has led to the development of enhanced biomarkers including assessing DNA mutation rates and immune gene signatures, to improve patient selection.Conclusions:Immune checkpoint blockade is an exciting cancer treatment modality which is demonstrating impressive clinical results across multiple tumour types. For UC, anti-PD directed therapy represents a much needed treatment in the metastatic, post chemotherapy context. Potential for these agents to have clinical utility in non-metastatic UC is still to be assessed.

OPTIMIZATION OF BIOLOGICAL THERAPY IN PATIENTS WITH ULCERATIVE COLITIS (CASE REPORT)

Now in Russia registered two biological drugs for the treatment of UC is infliximab and golimumab. The largest experience with the use of infliximab (IFX) shows that, despite the high efficiency, in some patients the IBD (20-30%) will develop acquired secondary loss of response to the drug. The development of secondary loss of anti-cytokine therapy is influenced by the following causes - irregular administration of the drug, monotherapy with monoclonal antibodies, initial high levels of TNF-α and low albumin, the presence of antibodies to the drug, activation of opportunistic infections, and changes in pathogenesis of the disease. The appearance at present in the arsenal of gastroenterologists of golimumab (GLM) has expanded the possibilities of treatment of patients with UC in the case of secondary loss of response to therapy with anti-TNF-α or the development of adverse events on IFX. This clinical case shows that after discontinuation IFX, there is a risk of recurrence of the disease, which according to the literature is 50 %. The example also demonstrated that GLM is well tolerated in patients who develop adverse events on IFX in the form of anaphylaxis. This is because GLM are fully human inhibitor of TNF-α. Golimumab is a new, effective inhibitor of TNF-α, which may help to optimize therapy in UC.

Tu1351 Crohn's Disease Patients Currently or Previously on Natalizumab Can Be Safely and Effectively Switched to Vedolizumab

G A A b st ra ct s multicentre, observational cohort was designed to examine the safety and efficacy of CTP13 infliximab biosimilar in induction and maintenance of remission in Crohn's disease (CD, 108 weeks follow-up) and ulcerative colitis (UC, 54 weeks follow-up). Demographic data were prospectively collected at inclusion. A harmonized, tight monitoring strategy is applied in terms of clinical scores (CDAI, PDAI, pMAYO at each visit), biochemical markers (including CRP, at least every 3 months) and endoscopic/imaging (at least every 12 months) as requested by the National Health Fund. Sera are collected for drug through and antibody measurement at 0, 12, 24 and 52 weeks. Safety data are meticulously registered during follow-up. Results: 90 consecutive IBD patients were included in the present cohort (57 CD patients (27 males) and 33 UC patients (16 males)). Age at disease onset was 26.0 (SD:10.9) years in CD and 30.5 (SD:14.1) years in UC. In CD ileocolonic and perianal disease was present in 40.4% and 37.5% of patients, respectively. 55.2% of UC patients had extensive colitis. 21.4% of CD patients had previous surgery. In CD and UC, 60.4%/ 50% and 55.2%/74.2% of patients received concomitant immunosuppressives and steroids, while 30.4% of CD and 16.1% of UC patients received previous anti-TNFs. At induction, mean CDAI was 289 (SD:107), while MAYO/pMAYO scores were 8.8 (SD 3.1) and 6.4 (SD 2.6) in UC. There was a significant decrease in CDAI after 2 and 6 weeks of treatment compared to baseline (p<0.001, ANOVA-Scheffe). In addition there was a numeric decrease in the mean CRP level (from 23.5mg/L to W2:11.3mg/L and W6:15.3mg/L). There was a significant decrease also in the mean pMAYO score (from 6.4 to (n=16) W2: 3.7 and W6: 3.6) with a numeric decrease in CRP level during induction therapy in UC . 4 allergic reactions occurred, all in patients who had received previous anti-TNF medication. Conclusions: This is the first prospective nationwide cohort examining the safety and efficacy of the biosimilar infliximab in IBD. A significant decrease of disease activity (CDAI and pMAYO) was observed coupled with a decrease in CRP levels during induction with the infliximab biosimilar. A complete analysis of the induction data will be available at the time of congress.

Tu1350 Vedolizumab in the Treatment of IBD: The University of Chicago Experience

G A A b st ra ct s multicentre, observational cohort was designed to examine the safety and efficacy of CTP13 infliximab biosimilar in induction and maintenance of remission in Crohn's disease (CD, 108 weeks follow-up) and ulcerative colitis (UC, 54 weeks follow-up). Demographic data were prospectively collected at inclusion. A harmonized, tight monitoring strategy is applied in terms of clinical scores (CDAI, PDAI, pMAYO at each visit), biochemical markers (including CRP, at least every 3 months) and endoscopic/imaging (at least every 12 months) as requested by the National Health Fund. Sera are collected for drug through and antibody measurement at 0, 12, 24 and 52 weeks. Safety data are meticulously registered during follow-up. Results: 90 consecutive IBD patients were included in the present cohort (57 CD patients (27 males) and 33 UC patients (16 males)). Age at disease onset was 26.0 (SD:10.9) years in CD and 30.5 (SD:14.1) years in UC. In CD ileocolonic and perianal disease was present in 40.4% and 37.5% of patients, respectively. 55.2% of UC patients had extensive colitis. 21.4% of CD patients had previous surgery. In CD and UC, 60.4%/ 50% and 55.2%/74.2% of patients received concomitant immunosuppressives and steroids, while 30.4% of CD and 16.1% of UC patients received previous anti-TNFs. At induction, mean CDAI was 289 (SD:107), while MAYO/pMAYO scores were 8.8 (SD 3.1) and 6.4 (SD 2.6) in UC. There was a significant decrease in CDAI after 2 and 6 weeks of treatment compared to baseline (p<0.001, ANOVA-Scheffe). In addition there was a numeric decrease in the mean CRP level (from 23.5mg/L to W2:11.3mg/L and W6:15.3mg/L). There was a significant decrease also in the mean pMAYO score (from 6.4 to (n=16) W2: 3.7 and W6: 3.6) with a numeric decrease in CRP level during induction therapy in UC . 4 allergic reactions occurred, all in patients who had received previous anti-TNF medication. Conclusions: This is the first prospective nationwide cohort examining the safety and efficacy of the biosimilar infliximab in IBD. A significant decrease of disease activity (CDAI and pMAYO) was observed coupled with a decrease in CRP levels during induction with the infliximab biosimilar. A complete analysis of the induction data will be available at the time of congress.

Tu1349 The Efficacy and Safety of Calcineurin Inhibitors in Inducing and Maintaining Clinical Remission in IBD Patients Commencing Vedolizumab

G A A b st ra ct s multicentre, observational cohort was designed to examine the safety and efficacy of CTP13 infliximab biosimilar in induction and maintenance of remission in Crohn's disease (CD, 108 weeks follow-up) and ulcerative colitis (UC, 54 weeks follow-up). Demographic data were prospectively collected at inclusion. A harmonized, tight monitoring strategy is applied in terms of clinical scores (CDAI, PDAI, pMAYO at each visit), biochemical markers (including CRP, at least every 3 months) and endoscopic/imaging (at least every 12 months) as requested by the National Health Fund. Sera are collected for drug through and antibody measurement at 0, 12, 24 and 52 weeks. Safety data are meticulously registered during follow-up. Results: 90 consecutive IBD patients were included in the present cohort (57 CD patients (27 males) and 33 UC patients (16 males)). Age at disease onset was 26.0 (SD:10.9) years in CD and 30.5 (SD:14.1) years in UC. In CD ileocolonic and perianal disease was present in 40.4% and 37.5% of patients, respectively. 55.2% of UC patients had extensive colitis. 21.4% of CD patients had previous surgery. In CD and UC, 60.4%/ 50% and 55.2%/74.2% of patients received concomitant immunosuppressives and steroids, while 30.4% of CD and 16.1% of UC patients received previous anti-TNFs. At induction, mean CDAI was 289 (SD:107), while MAYO/pMAYO scores were 8.8 (SD 3.1) and 6.4 (SD 2.6) in UC. There was a significant decrease in CDAI after 2 and 6 weeks of treatment compared to baseline (p<0.001, ANOVA-Scheffe). In addition there was a numeric decrease in the mean CRP level (from 23.5mg/L to W2:11.3mg/L and W6:15.3mg/L). There was a significant decrease also in the mean pMAYO score (from 6.4 to (n=16) W2: 3.7 and W6: 3.6) with a numeric decrease in CRP level during induction therapy in UC . 4 allergic reactions occurred, all in patients who had received previous anti-TNF medication. Conclusions: This is the first prospective nationwide cohort examining the safety and efficacy of the biosimilar infliximab in IBD. A significant decrease of disease activity (CDAI and pMAYO) was observed coupled with a decrease in CRP levels during induction with the infliximab biosimilar. A complete analysis of the induction data will be available at the time of congress.

Association of HER2 and ErbB3 molecular alterations with afatinib sensitivity in platinum-refractory metastatic urothelial carcinoma (UC) in a phase II trial.

312 Background: Platinum-refractory UC has a dismal prognosis, with no FDA-approved second-line therapies. Somatic mutations and copy number (CN) variation in EGFR (ErbB1), HER2 (ErbB2), and ErbB3 are frequent in UC and may represent viable targets for novel therapies. We aimed to investigate whether afatinib, an oral, irreversible Erb family blocker, has clinical benefit in metastatic UC. Methods: In this single arm, phase II trial, patients (pts) with unresectable platinum-refractory UC who received ≤1 chemotherapy in the metastatic setting received afatinib 40 mg/day continuously until disease progression or intolerable toxicity.Primary endpoint was 3-month progression-free survival (PFS3), with drug deemed promising if ≥42% pts had PFS3. Pre-specified analysis for EGFR, HER2, ErbB3, and ErbB4 was conducted using targeted next-generation sequencing (Life Technologies) and CN analysis (Taqman). Results: 15 ptshave enrolled: median age 66 (44-78), 11 M/4 F, ECOG PS 0 in 20%, PS 1 in 80%, Hb&lt;10 g/dl in 20%, liver metastases in 13%, median time from prior chemotherapy=4.4 mo. Rash (73%), diarrhea (33%), and fatigue (13%) were the most common drug-related toxicities; 1 pt required dose-reduction (grade 3 fatigue). 3/14 pts (21%) had PFS3 (1 partial response (PR), 2 stable disease); 1 pt has not reached 3 mo on therapy. All 3 responders had molecular alterations in Erb genes: 1 pt with 4 copies of HER2 achieved PR and responded for 6.9 mo; 1 pt with Gly284Arg ErbB3 mutation responded for 7 mo; and 1 pt with 73 copies of HER2 and Arg103Gly ErbB3 mutation never progressed on therapy, but discontinued after 10.3 mo due to depressed left ventricular ejection fraction. None of the 10 non-responders had alterations in these four genes. Time to progression/discontinuation was 8.1 mo in pts with molecular alterations vs. 1.8 for pts without alterations (p=0.02). Conclusions: Afatinib demonstrates activity in platinum-refractory UC, with all responders bearing HER2 and/or ErbB3 alterations. The potential contribution of ErbB3 to afatinib sensitivity is novel. These data support ongoing testing of afatinib as a potential therapy for refractory UC in marker-selected pts. Clinical trial information: NCT02122172.

Systematic review of complementary and alternative medicine treatments in inflammatory bowel diseases.

We performed a systematic review for Complementary and Alternative Medicine [CAM] as defined by the National Institute of Health in Inflammatory Bowel Disease [IBD], ie Crohn's disease [CD] and ulcerative colitis [UC], with the exception of dietary and nutritional supplements, and manipulative therapies. A computerized search of databases [Cochrane Library, Pubmed/Medline, PsychINFO, and Scopus] through March 2014 was performed. We screened the reference sections of original studies and systematic reviews in English language for CAM in IBD, CD and UC. Randomized controlled trials [RCT] and controlled trials [CT] were referred and assessed using the Cochrane risk of bias tool. A total of: 26 RCT and 3 CT for herbal medicine, eg aloe-vera gel, andrographis paniculata, artemisia absinthium, barley foodstuff, boswellia serrata, cannabis, curcumin, evening primrose oil, Myrrhinil intest®, plantago ovata, silymarin, sophora, tormentil, wheatgrass-juice and wormwood; 1 RCT for trichuris suis ovata; 7 RCT for mind/body interventions such as lifestyle modification, hypnotherapy, relaxation training and mindfulness; and 2 RCT in acupuncture; were found. Risk of bias was quite heterogeneous. Best evidence was found for herbal therapy, ie plantago ovata and curcumin in UC maintenance therapy, wormwood in CD, mind/body therapy and self-intervention in UC, and acupuncture in UC and CD. Complementary and alternative therapies might be effective for the treatment of inflammatory bowel diseases; however, given the low number of trials and the heterogeneous methodological quality of trials, further in-depth research is necessary.

O-001 Budesonide MMX® 9 mg for Inducing Remission in Patients With Mild-to-Moderate Ulcerative Colitis Not Adequately Controlled With Oral 5-ASAs

Budesonide MMX® (B-MMX) is a once-daily, extended release oral formulation designed to provide targeted delivery of budesonide throughout the colon. Previous post-hoc analyses of randomized, controlled studies of B-MMX monotherapy suggested that it was effective for induction of remission of mildly to moderately active UC in patients with or without prior 5-ASA use. Here we present data from a prospectively designed, randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of B-MMX in patients experiencing an active UC flare despite treatment with an oral 5-ASA. Patients with mildly to moderately active UC (UCDAI ≥4 and ≤10) inadequately controlled with oral 5-ASA monotherapy were randomized 1:1 to add once-daily B-MMX 9 mg or placebo (PBO) for 8 weeks to their existing 5-ASA. Patients were required to be on a stable, therapeutic dose of an oral 5-ASA (e.g., mesalamine ≥2.4 g/day or equivalent dose of another 5-ASA) throughout the study. Patients who increased their 5-ASA dose or administered other UC therapies were considered non-responders. The primary efficacy endpoint was combined clinical and endoscopic remission at Week 8, as defined by a UCDAI score of ≤1, with subscores of 0 for rectal bleeding, stool frequency and mucosal appearance. Secondary and exploratory endpoints assessed clinical remission (rectal bleeding and stool frequency subscores = 0), endoscopic remission (mucosal appearance subscore = 0) and histological healing (histological activity grade = 0, as assessed via central reading). Missing data were handled using a worst case imputation scheme, in which patients with missing data were considered non-responders. Adverse events (AEs) were assessed throughout the study. Of 510 patients enrolled, 458 (230 B-MMX, 228 PBO) were included in the intent-to-treat population (46% female, mean age: 44.5), which excluded patients with normal baseline mucosal histology or infectious colitis. Combined clinical and endoscopic remission was achieved in a greater percentage of B-MMX-treated patients than PBO-treated patients (13% versus 7.5%, P = 0.0488, worst case analysis). This treatment effect was driven primarily by the mucosal appearance subscore. On this measure, a greater percentage of B-MMX-treated patients than PBO-treated patients achieved a score of 0 (20% versus 12.3%, P = 0.0248), indicative of endoscopic remission. B-MMX also induced histological healing in a greater percentage of patients than placebo (27% versus 17.5%, P = 0.0155). Overall, 31.8% and 27.1% of patients treated with B-MMX or placebo reported an AE, and the majority were mild or moderate in severity. Study discontinuation due to AEs occurred in 4.7% and 3.5% of the B-MMX and placebo groups, respectively. In patients experiencing an active flare of UC despite baseline oral 5-ASA therapy, adding B-MMX 9 mg was significantly more effective than placebo at inducing combined clinical and endoscopic remission as well as histological healing. B-MMX was generally well-tolerated when given in combination with an oral 5-ASA.

Incomplete Cross-Resistance Between Taxanes for Advanced Urothelial Carcinoma: Implications for Clinical Practice and Trial Design

BackgroundTaxanes such as paclitaxel and docetaxel are commonly used for second- or third-line salvage systemic therapy for metastatic UC. Although trials have generally excluded previous exposure to taxanes when using a taxane in a salvage therapy trial, taxanes might not be completely cross-resistant. Hence, we aimed to study outcomes with docetaxel after previous paclitaxel and the reverse sequence, to identify the level of cross-resistance between these taxanes. Patients and MethodsData from a randomized phase II trial that compared salvage therapy with docetaxel combined with either placebo or vandetanib for advanced UC were analyzed. Both arms were combined for analysis because no differences in any outcomes were observed. Data were also requested from institutions for patients who received paclitaxel after previous docetaxel treatment. Descriptive statistics were used to summarize patient and treatment characteristics and outcomes. The primary clinical end point of interest was overall survival (OS). ResultsOf 148 patients who received docetaxel with either vandetanib or placebo, 21 had received previous paclitaxel treatment. No difference in OS, progression-free survival, or response rate was observed with docetaxel based on previous paclitaxel treatment after adjusting for known prognostic factors. Among the 8 patients who received paclitaxel after previous docetaxel treatment, partial response was observed in 1 patient (12.5%) and stable disease in 2 patients (25%). ConclusionDocetaxel treatment after previous paclitaxel treatment and the reverse sequence demonstrates activity in advanced UC. There is no strong evidence to disallow patients with previous exposure to a taxane to enroll in a clinical trial involving another taxane.

Cisplatin-Based First-Line Therapy for Advanced Urothelial Carcinoma After Previous Perioperative Cisplatin-Based Therapy

BackgroundOutcomes with cisplatin-based first-line therapy for advanced UC after previous perioperative cisplatin-based chemotherapy are unclear. In this study we evaluated outcomes with a focus on the effect of time from previous cisplatin-based perioperative chemotherapy. Patients and MethodsData were collected for patients who received cisplatin-based first-line therapy for advanced UC after previous perioperative cisplatin-based therapy. Cox proportional hazards models were used to investigate the prognostic ability of visceral metastasis, ECOG PS, TFPC, anemia, leukocytosis, and albumin on overall survival (OS). ResultsData were available for 41 patients from 8 institutions including 31 men (75.6%). The median age was 61 (range, 41-77) years, most received gemcitabine plus cisplatin (n = 26; 63.4%), and the median number of cycles was 4 (range, 1-8). The median OS was 68 weeks (95% confidence interval [CI], 48.0-81.0). Multivariable Cox regression analysis results showed an independent prognostic effect on OS for PS > 0 versus 0 (hazard ratio [HR], 4.56 [95% CI, 1.66-12.52]; P = .003) and TFPC ≥ 78 weeks versus < 78 weeks (HR, 0.48 [95% CI, 0.21-1.07]; P = .072). The prognostic model for OS was internally validated with c-index = 0.68. Patients with TFPC < 52 weeks, 52 to 104 weeks, and ≥ 104 weeks had median survival of 42, 70, and 162 weeks, respectively. ConclusionLonger TFPC ≥ 78 weeks and ECOG PS = 0 were independently prognostic for better survival with cisplatin-based first-line chemotherapy for advanced UC after previous perioperative cisplatin-based chemotherapy. The data support using TFPC ≥ 52 weeks to rechallenge with cisplatin-based first-line chemotherapy for metastatic disease.

867P - Outcomes with Cisplatin-Based First-Line Therapy for Advanced Urothelial Carcinoma (Uc) Following Previous Perioperative Cisplatin-Based Therapy

ABSTRACT Aim: Outcomes with cisplatin-based first-line therapy for advanced UC following previous perioperative cisplatin-based chemotherapy are unclear. We conducted a retrospective study to evaluate outcomes and identify a threshold of time from prior cisplatin-based perioperative chemotherapy (TFPC) when repeating cisplatin-based chemotherapy may not be justified. Methods: Data were collected for patients who received cisplatin-based first-line therapy for advanced UC following previous perioperative cisplatin-based therapy. The Kaplan-Meier method was used to estimate survival. Cox proportional hazards models were used to investigate the prognostic ability of variables on overall survival (OS). The multivariable model included patients with complete data for the all factors (visceral metastasis, ECOG performance status [PS], TFPC, anemia, leukocytosis, albumin). All tests and confidence intervals were two-sided and at p = 0.05 level of significance. Results: Individual level data for 40 patients from 8 institutions were obtained. The study included 33 men (77.5%), the median age was 61 years (range 41 to 71), the majority received gemcitabine plus cisplatin (N = 25, 62.5%) and the median number of cycles was 4 (range 1-8). The median OS was 70 weeks (95% CI: 48.0-81.0). Multivariable Cox regression analysis results showed an independent prognostic impact on OS for PS >0 vs. 0 (HR 4.34 [1.52-12.36], p = 0.006) and TFPC ≥1.5 years vs. Conclusions: Longer TFPC ≥1.5 years and ECOG-PS = 0 were independently prognostic for better survival with cisplatin-based first-line chemotherapy for advanced UC following prior perioperative cisplatin-based chemotherapy. The present analysis supports employing >1 year from prior perioperative cisplatin-based chemotherapy to re-challenge with cisplatin-based first-line chemotherapy for metastatic disease. Disclosure: All authors have declared no conflicts of interest.

865P - The Significance of Complete Response (Cr) in Patients Receiving Salvage Therapy for Advanced Urothelial Carcinoma (Uc)

ABSTRACT Aim: Molecular interrogation of tumors showing CR with salvage therapy for UC may provide insights regarding biology, as suggested by the discovery of TSC1 mutations in those with durable CR on everolimus. We hypothesized that CR with salvage therapy is robustly associated with long term outcomes, and may represent an intermediate endpoint and identify tumors warranting molecular interrogation. Methods: Phase II trials of salvage chemotherapy and/or biologic agent therapy were utilized. Data on CR or PR (partial response) as best response by RECIST were required in addition to previously recognized prognostic factors: time from prior chemotherapy (TFPC), hemoglobin (Hb), performance status (PS) and liver metastasis (LM) status. Cox proportional hazards regression was used to evaluate the association of CR and other response parameters with overall survival (OS) and progression free survival (PFS). Trial was a stratification factor. Results: 789 of 814 patients enrolled in 14 phase II trials evaluating chemotherapeutic, biologic or chemobiologic regimens were evaluable with all required data available. The overall median PFS and OS were 2.7 (95% CI: 2.5-2.8) and 6.8 (95% CI: 6.2-7.1) months, respectively. CR and partial response (PR) were seen in 14 (1.8%) and 109 (13.8%) patients. Median (95% CI) OS for those with a CR was 21.5 (14.2-34.3) months, compared with 6.7 (6.0-7.0) months in those without a CR (p Conclusions: CR occurred in a small minority (1.8%) of patients receiving salvage therapy for advanced UC. CR warrants validation as an intermediate endpoint and may help select tumors for molecular interrogation, given the robust association with durable PFS and OS. Disclosure: R. Fougeray: Employee of Pierre Fabre, but not relevant to subject matter of abstract. All other authors have declared no conflicts of interest.

PTU-086 Ulcerative Colitis (uc) And Anti-tumour Necrosis Factor (a-tnf) Therapy; A Single Unit’s Real World Experience

IntroductionPrescription of a-TNF therapy in UC in the UK is limited to acute severe colitis by NICE. Increasingly physicians are under pressure from patients to offer an alternative to the...

P322 The effects of anti TNF therapy on growth in Scottish children with IBD

pMayo of 0 1 points and endoscopic Mayo subscore of 0 points at week 52. The time elapsed between the diagnosis and the first biological therapy was assessed in every patient, who was then categorized to groups according to the elapsed time (0 2 years, 2 5 years, 5 10 years etc). Data were collected from five Hungarian IBD centres. Results: The mean elapsed time between the diagnosis and the start of biological therapy was 7 years. 50.4% of patients started infliximab therapy within 5 years after diagnosis. After induction with infliximab 65.6% of the enrolled patients achieved remission and 34.4% achieved response. After oneyear treatment period, the remission and response rates remained 67.7% and 21.8%. 10.6% of patients showed loss of efficacy at one year infliximab therapy. 74.6% of subjects achieved clinical remission at week 14 and remained in remission at week 52. Complete mucosal healing was detected in 31.2% and deep remission in 13.9% of the patients at week 52. Response rates to infliximab therapy at one year were significantly lower compared to rates at week 14 (p = 0.029). The rate of response, remission and loss of efficacy did not depend on the elapsed time between the diagnosis and the start of biological therapy. Conclusions: Our results did not reveal an association between the remission rates and the elapsed time between the diagnosis and the first biological therapy in UC.

Tu1167 Infliximab Is More Immunogenic and Reaches Lower Trough Levels in Ulcerative Colitis Patients Compared to Crohn's Disease Patients

The aim of this study is to evaluate the clinical and endoscopic efficacy, and safety of infliximab therapy for UC following liver transplantation in patients with PSC. Methods: We evaluated all patients clear diagnosis of UC who underwent Orthotopic Liver Transplantation (OLT) at Ospedali Riuniti of Bergamo between January 2001 and September 2012 and who had received inflixamab therapy for refractory IBD following liver transplantation. Results: Four patients (all men; median age 39 years, range 22 54 years) with UC (3) and pouchitis (1) who underwent OLT were identified. Three patients (75%) experienced sustained improvement of IBD. Mucosal healing was observed in one of three patients (33%). Steroid treatment was interrupted during infiximab therapy in all patients. Adverse events included only one infection: molluscum contagiosum on face of one patient, treated with laser-therapy with resolution of symptoms. No malignancies were observed in all patients following infliximab therapy. No hepatic reject was documented while on infliximab therapy. One patient 25%) presented a recurrence of PSC two years before infliximab therapy (three years after OLT) and he underwent a second OLT after 5 years after the first. Conclusions: Infliximab therapy appears to be effective in patients with refractory ulcerative colitis after liver transplantation. Although no complications of hepatic graft function or reject were observed, additional largest studies are need to evaluate the safety’s profile of biological therapy combined to anti-reject treatment in patients with refractory IBD following liver transplantation.

P371 Short- and long-term efficacy of infliximab in intestinal Behcet's disease refractory to conventional medications indicates a major role for tumour necrosis factor-alpha

Results: 9/17 (52.9%) pts achieved clinical remission (R), 4 (23.5%) pts experienced a low clinical response (LR) and 4 (23.5%) pts were non responder (nR). The mean Mayo score at T0 was 9.1 points in RG and 8.87 points in nLR-nR; at T6 the mean Mayo score was 2.66 points in RG and 7.37 points in LR-nR. In R group the mean duration of the disease was 2.66 years vs 7.1 years in the LR-nR. In R group at the end of the follow-up (mean 13.8 m, range 7 28 m) 6/9 (66.7%) pts remain in clinical remission, 2/9 (22.2%) pts were in clinical remission in IFX therapy and 1/9 (11.2%) had colectomy. In LRnR group at the end of follow-up (mean 14.7 m, range 2 31 m) 1/8 (12.5%) pt were in clinical remission, 4/8 (50%) pts remain in clinical remission with IFX therapy and 3/8 (37.5%) pts had colectomy. Experienced minor side effects 5/17 (30%) pts and 1/17 (5.8%) experienced EBV/CMV opportunistic infection successfully treated with valganciclovir. Conclusions: A short onset of UC show a long-term benefit of CyS bridging therapy in severe refractory UC; in our experience 4/17 (76.4%) pts avoided colectomy; in R group (short onset of UC) only one patient had colectomy. None of our pts developed neurotoxicity, nephrotoxicity or anaphylaxis.

Sa1895 The First Clinical Pilot Study of Adrenomedullin Therapy in Refractory Ulcerative Colitis: the Initial Six Cases

were analyzed. 68.4% of the CD patients received infliximab, 31.6% adalimumab. 21.1% of the CD patients received previous episodic/continuous biological therapy. Extraintestinal manifestations were present in 54.5% of the patients. Concomitant immunosuppressions at induction therapy were steroids in 62% and azathioprine in 81.8% of patients. Medical records were captured prospectively; data of the CD and UC groups were analyzed separately. Results: 78.5% of the patients were in remission after a one-year treatment period. Dose intensification was needed in 13.8% of CD and in 11.4% of UC patients. Biological therapy had to be restarted because of clinical flare after remission in 45.9% of CD patients and in 28.6% of UC patients after a median of 8 months. 41.1% of these IBD patients with restarted biologics were in remission at the end of the second year. In a logistic regression analysis corticosteroid use at induction (p=0.034, OR: 1.58, 95% CI: 1.04-2.41), previous anti-TNFα therapy (p=0.03, OR: 2.84, 95% CI: 1.11-7.30) and dose intensification (p=0.008, OR: 6.25, 95% CI: 1.62-24.2) were associated with the need for restarting biological therapy in CD. Numerically, need for restarting of biological therapy was more common in men, in smokers and in patients who underwent appendectomy. None of the examined factors were associated to the need for restarting biological therapy in UC. Discussion. Biological therapy had to be restarted in almost half of the CD patients after the discontinuation within a median of 8 months after the discontinuation, despite being in remission at one-year. Steroid use, previous biological therapy and dose intensification but not CRP was identified as predictors for the need for restarting biological therapy.

Soybean and fish oil mixture increases IL-10, protects against DNA damage and decreases colonic inflammation in rats with dextran sulfate sodium (DSS) colitis

It was investigated whether dietary polyunsaturated fatty acids (PUFA) could influence colonic injury, tissue DNA damage, cytokines and myeloperoxidase activity (MPO) and plasma corticosterone in DSS-induced colitis rats. Male weaning Wistar rats were fed for 47 days with an AIN-93 diet with control (C), fish (F) or a mixture of fish and soybean oil (SF). The colitis was induced from day 36 until day 42 by 3% DSS in drinking water. On day 48, blood samples were collected for corticosterone determination. The distal colon was excised for histological analysis and to quantify the cytokine (IL-4, IL-10 and INF-γ), MPO and DNA damage. The disease activity index (DAI) was recorded daily during colitis induction. The DAI, MPO, histological analyses showed decreases only in the SF group compared with the C group. IL-10 was increased and DNA damage was reduced in the groups F and SF, and an inverse correlation between these variables was found. There were no differences in corticosterone, IFN-γ and IL-4 levels. Soybean and fish oil mixture may be effective in improving colonic injury and DNA damage, and it could be an important complementary therapy in UC to reduce the use of anti-inflammatory drugs and prevent colorectal cancer.

150 Intralesional Corticosteroid Injection Following Endoscopic Balloon Dilation in Stricturing Pediatric Crohn's Disease: A Prospective Randomized, DoubleBlind, Controlled Trial

Aim: 30% of patients hospitalized with severe UC prove steroid-refractory. We aimed to evaluate outcomes and predictors of response to infliximab as rescue therapy in severe pediatric UC. Methods: As part of a prospective multicenter study, we evaluated factors associated with immediate and 1-year response to infliximab in steroid-refractory severe pediatric UC. Data were recorded at admission, days 3 and 5, at introduction of infliximab, at discharge and 1-year thereafter, using standardized data collection forms. Disease activity was determined using the validated Pediatric UC Activity Index (PUCAI). Serum TNF alpha level was determined before infliximab treatment using a cytokine antibody panel (TransSignal, CA). Concurrently, fecal calprotectin and lactoferrin levels were ascertained using standard assays in a central laboratory. Results: Of 128 children admitted, 33 failed steroids and treated with infliximab within 10.5±6 days. Mean PUCAI score at introduction of infliximab was 66±13 points, indicating persistence of severe colitis. 25/33 children (76%) responded and were discharged within 5±4 days of infliximab therapy; 7 in complete clinical remission (PUCAI 0.2). CRP, ESR, albumin and hemoglobin were not predictive of response to infliximab. Neither fecal calprotectin nor lactoferrin values were predictive of response (area under ROC curve 0.61 and 0.63, respectively; P>0.2). Serum TNF-alpha level was similar between responders and non-responders (10.6pg/ml (IQR 4-30) vs. 8.3pg/ml (5.7-11); P=0.4). 8 of the 25 responders received only 3-dose induction, and the others continued maintenance therapy without concomitant immunomodulation. Cumulative 1-year sustained response rate was 55% (18/33). There were no deaths and only 1 patient stopped treatment due to infusion reaction. Conclusion: Infliximab is safe and effective in inducing and maintaining clinical remission in steroid-refractory pediatric UC. Serum TNF-alpha level and fecal biomarkers are not useful in predicting outcome, but higher disease severity, judged clinically, and new onset disease are associated with reduced response.