A 1-year follow-up study on checkpoint inhibitor-induced colitis: results from a European consortium.

BACKGROUND: Data regarding the clinical outcome of patients with immune checkpoint inhibitor (ICI)-induced colitis are scant. We aimed to describe the 12-month clinical outcome of patients with ICI-induced colitis. MATERIALS AND METHODS: This was a retrospective, European, multicentre study. Endoscopy/histology-proven ICI-induced colitis patients were enrolled. The 12-month clinical remission rate, defined as a Common Terminology Criteria for Adverse Events diarrhoea grade of 0-1, and the correlates of 12-month remission were assessed. RESULTS: Ninety-six patients [male:female ratio 1.5:1; median age 65 years, interquartile range (IQR) 55.5-71.5 years] were included. Lung cancer (41, 42.7%) and melanoma (30, 31.2%) were the most common cancers. ICI-related gastrointestinal symptoms occurred at a median time of 4 months (IQR 2-7 months). An inflammatory bowel disease (IBD)-like pattern was present in 74 patients (77.1%) [35 (47.3%) ulcerative colitis (UC)-like, 11 (14.9%) Crohn's disease (CD)-like, 28 (37.8%) IBD-like unclassified], while microscopic colitis was present in 19 patients (19.8%). As a first line, systemic steroids were the most prescribed drugs (65, 67.7%). The 12-month clinical remission rate was 47.7 per 100 person-years [95% confidence interval (CI) 33.5-67.8). ICI was discontinued due to colitis in 66 patients (79.5%). A CD-like pattern was associated with remission failure (hazard ratio 3.84, 95% CI 1.16-12.69). Having histopathological signs of microscopic colitis (P = 0.049) and microscopic versus UC-/CD-like colitis (P = 0.014) were associated with a better outcome. Discontinuing the ICI was not related to the 12-month remission (P = 0.483). Four patients (3.1%) died from ICI-induced colitis. CONCLUSIONS: Patients with IBD-like colitis may need an early and more aggressive treatment. Future studies should focus on how to improve long-term clinical outcomes.

Human endogenous retroviral protein triggers deficit in glutamate synapse maturation and behaviors associated with psychosis.

Mobile genetic elements, such as human endogenous retroviruses (HERVs), produce proteins that regulate brain cell functions and synaptic transmission and have been implicated in the etiology of neurological and neurodevelopmental psychiatric disorders. However, the mechanisms by which these proteins of retroviral origin alter brain cell communication remain poorly understood. Here, we combined single-molecule tracking, calcium imaging, and behavioral approaches to demonstrate that the envelope protein (Env) of HERV type W, which is normally silenced but expressed in patients with neuropsychiatric conditions, alters the N-methyl-d-aspartate receptor (NMDAR)-mediated synaptic organization and plasticity through glia- and cytokine-dependent changes. Env expression in the developing hippocampus was sufficient to induce behavioral impairments at the adult stage that were prevented by Env neutralization or tuning of NMDAR trafficking. Thus, we show that a HERV gene product alters glutamate synapse maturation and generates behavioral deficits, further supporting the possible etiological interplay between genetic, immune, and synaptic factors in psychosis.

The Pathogenesis of Extraintestinal Manifestations: Implications for IBD Research, Diagnosis, and Therapy.

This article reports on the sixth scientific workshop of the European Crohn's and Colitis Organisation [ECCO] on the pathogenesis of extraintestinal manifestations [EIMs] in inflammatory bowel disease [IBD]. This paper has been drafted by 15 ECCO members and 6 external experts [in rheumatology, dermatology, ophthalmology, and immunology] from 10 European countries and the USA. Within the workshop, contributors formed subgroups to address specific areas. Following a comprehensive literature search, the supporting text was finalized under the leadership of the heads of the working groups before being integrated by the group consensus leaders.

Inflammatory Bowel Disease [IBD] and Physical Activity: A Study on the Impact of Diagnosis on the Level of Exercise Amongst Patients With IBD.

BACKGROUND AND AIMS: Inflammatory bowel disease [IBD] can impair patients' functional capacity with significant negative effects on their quality of life. Our aim was to determine the impact of IBD diagnosis on fitness levels and to assess the levels of engagement in physical activity and fatigue in IBD patient before and after diagnosis. METHODS: A prospective multi-centre cross-sectional study was performed. Patients diagnosed with IBD in the previous 18 months were recruited. Inclusion criteria included clinical remission and/or no treatment changes within the previous 6 months. Physical exercise levels were assessed by the Godin score and fatigue levels was assessed by the functional assessment of chronic illness therapy [FACIT] score. RESULTS: In total, 158 patients (100 Crohn's disease [CD]) were recruited. Mean age was 35.1 years (95% confidence interval [CI] ± 2.0). Gender distribution was approximately equal [51.3% male]. The Mean Harvey Bradshaw and Simple Clinical Colitis Activity indices were 2.25 [95% CI ± 0.40] and 1.64 [95% CI ± 0.49], respectively. The mean Godin score difference before and after IBD diagnosis was 6.94 [p = 0.002]. Patients with ulcerative colitis [UC] [41.8%] were more likely than patients with CD [23.0%] to reduce their exercise levels [p = 0.04]. FACIT scores were lower in patients who had experienced relapses [p = 0.012] and had severe disease [p = 0.011]. Approximately one-third of patients reduced their activity level following IBD diagnosis. CONCLUSIONS: Patients were significantly less physically active after a diagnosis of IBD and this was more apparent in UC. Identification of the risk factors associated with loss of fitness levels would help to address the reduced patient quality of life.

Interleukin-1 ß-targeted treatment strategies in inflammatory depression: toward personalized care.

OBJECTIVES: It is unknown whether a cytokine signature may help the identification of subgroup of patient who would respond to personalized treatment. As interleukin-1 beta (Il-1ß) seems to play a major role in mood disorder, a systematic review and meta-analysis of its potential role in major depressive disorder (MDD) was carried out. METHODS: A systematic search was performed to identify appropriate MDD vs. control studies pertaining to Il-1ß. Methodological quality and possible moderators were also assessed. RESULTS: A total of 1922 studies were identified, and 53 articles were selected. Results showed an association between increased blood IL-1ß and MDD in high-quality studies only. No association with age was found. No IL-1ß gene-related polymorphisms has been associated with MDD. No effect of antidepressant on IL-1ß level has been found, although the antidepressants investigated were various. Qualitative analyses indicate that MDD coupled to a history of childhood trauma may be a subgroup for IL-1ß -targeted therapies. No difference in studies utilizing a stimulation method has been identified to date. CONCLUSIONS: The present work has confirmed IL-1ß as a biological marker of interest for innovative MDD treatments. However, further studies are needed to clarify the patients with MDD who may benefit from these therapies.

Streptococcus gallolyticus bacteraemia in hepatobiliary-pancreatic and colonic pathologies.

BACKGROUND: Streptococcus gallolyticus bacteraemia has been associated with several pathologies, including bacterial endocarditis and colorectal cancer. AIMS: In this study, we have analysed whether Streptococcus gallolyticus bacteraemia is associated with an increased risk of hepatobiliary and colonic pathology. The association with other pathologies and the antibiotic sensitivities of Streptococcus gallolyticus were also analysed. DESIGN: Observational retrospective study. METHODS: The case notes of patients with documented Streptococcus gallolyticus bacteraemia between 2007 and 2012 at Mater Dei hospital (Malta) were reviewed. Demographic and clinical data, including co-morbidities, clinical investigations, antibiotic sensitivities and mortality were analysed. RESULTS: A total of 42 patients (33 males, 9 females) were recruited. Two patients were pre-term infants and were therefore excluded from the study. Mean age of the cohort population studied was 72 years (SD ± 14). One-year survival rate was 62%. Gastrointestinal (colonic and hepatobiliary-pancreatic) pathologies were present in 59.5% of patients with 16% of this group having more than one gastrointestinal pathology. High incidence rates of underlying diabetes mellitus (28.6%), valvular heart disease (21.4%) and malignancies (21.4%) were noted in this study. Furthermore, we observed that 14.3% of patients had an underlying respiratory pathology. Streptococcus gallolyticus was 100% sensitive to cefotaxime and vancomycin but was highly resistant to clindamycin, erythromycin and tetracycline. CONCLUSION: Streptococcus gallolyticus bacteraemia is commoner in the elderly and in those with multiple underlying co-morbidities. The high incidence of gastrointestinal pathologies among patients with Streptococcus gallolyticus bacteraemia (59.5%) suggests that a thorough work-up for colonic and hepatobiliary/pancreatic pathology should be carried out in these patients.

The efficacy of shortening the dosing interval to once every six weeks in Crohn's patients losing response to maintenance dose of infliximab.

BACKGROUND: Patients treated with infliximab for Crohn's disease (CD) frequently require intensified dosage due to loss of response. There are scant data regarding the efficacy of shortening the dosing interval to 6 weeks. AIM: We sought to investigate the efficacy of a once every 6 weeks' strategy compared with dose-doubling. METHODS: This work was a multicentre retrospective study of infliximab-treated CD patients who required dose escalation. The clinical outcome of patients treated by intensification to 5 mg/kg/6 weeks (6-week group) was compared with the outcome of patients whose infliximab was double-dosed (10 mg/kg/8 weeks or 5 mg/kg/4 weeks). RESULTS: Ninety-four patients (mean age: 29.8 years) were included in the study, 55 (59%) in the 6-week group and 39 (41%) in the double-dose group. Demographics and disease characteristics were similar between the two groups, although patients with re-emerging symptoms 5-7 weeks postinfusion were more likely to receive 5 mg/kg/6 weeks dosing (OR: 3.4, 95% CI: 1.4-8.8, P < 0.01). Early response to dose-intensification occurred in 69% of patients in the 6-week group and 67% in the double-dose group (P = N.S.). Regained response was maintained for 12 months in 40% compared with 29% of the patients respectively (P = N.S.). CONCLUSION: In CD patients who lost response to standard infliximab dose, especially when symptoms re-emerge 5-7 weeks postinfusion, shortening the dosing interval to 6 weeks appears to be at least as effective as doubling the dose to 10 mg/kg or halving the infusion intervals to once in 4 weeks.

Downstaging of colorectal cancer by the National Bowel Cancer Screening programme in England: first round data from the first centre.

OBJECTIVE: Data from randomized controlled trials of Colorectal Cancer (CRC) screening in Nottingham, UK and Funen, Denmark and pilot data from the English and Scottish arms of the National Bowel Cancer Screening Programme (NBCSP) have demonstrated predominantly early-stage disease amongst the screened population. The aim of this study was to investigate whether downstaging of cancers occurred in the NBCSP in Wolverhampton. METHOD: A case-control study was performed to compare the staging of CRC diagnosed in the NBCSP-screened population during the prevalent round (2 years) of screening, with cancers diagnosed prior to the introduction of the NBCSP. RESULTS: The total population in the screening area is 899 000. A total of 108 346 FOB kits were sent out of which 55 931 were returned (51.6% uptake), A total of 1039 colonoscopies were performed with a 94.75% unadjusted caecal intubation rate. There were three complications (haemorrhages 3) and no perforations. The NBCSP in Wolverhampton identified 106 (75% male) CRC in the first 2 years with 45.3% Dukes A, 21.7% B, 29.2% C and 3.8% D. Two hundred and fifty-six (61% male) CRC were identified in the control group, 10.1% Dukes A, 50.0% B, 36.3% C and 3.5% D. There was a highly significant shift towards earlier stage disease in the screened group (P < 0.0001). CONCLUSION: The 2-year data from the first English centre to start bowel cancer screening demonstrates significant downstaging of cancer, consistent with both the RCT and pilot data.

Oesophageal stent insertion for palliation of dysphagia in a District General Hospital: experience from a case series of 137 patients.

BACKGROUND: Endoscopic oesophageal stent insertion is a widely used procedure to alleviate dysphagia caused by malignant strictures of the oesophagus and gastric cardia. It can, however, be associated with significant complications, mortality and morbidity. AIM AND METHOD: This retrospective case note study was undertaken to assess success rates, complications and mortality of oesophageal stenting when undertaken in a UK District General Hospital (DGH) setting. Patients who underwent oesophageal stenting for malignant disease from January 2000 to January 2006 were included. RESULTS: Of the 137 patients studied, oesophageal adenocarcinoma was present in 57% of patients, squamous cell oesophageal carcinoma in 37% and gastric adenocarcinoma in 6%. Indications for stent insertion were: presence of non-resectable tumours (65%), co-morbidities that contraindicated surgery (25%), refusal by patients for surgery for potentially resectable disease (6%) and a need for enhanced oral nutrition prior to surgery (4%). Prior to stenting 86.4% of patients suffered from advanced dysphagia. A significant improvement in symptoms was seen in 94% of patients. Discharge from hospital was within 48 h in 45% of cases. Chest pain was experienced by 13.9% of patients and serious acute stent-related complications (perforation or bleeding) occurred in 5.8% of patients. Overall 41.6% of patients had at least one complication. Mortality was 4.4% at 7 days and 24.8% at 30 days. CONCLUSION: Oesophageal stent insertion proved to be an effective palliation of dysphagia in group studied. It is a relatively safe procedure with a low rate of serious acute complications (5.8%) and can be done as a short stay in many patients.

The expression of the Saccharomyces cerevisiae HAL1 gene increases salt tolerance in transgenic watermelon [Citrullus lanatus (Thunb.) Matsun. & Nakai.].

An optimised Agrobacterium-mediated gene transfer protocol was developed in order to obtain watermelon transgenic plants [Citrullus lanatus (Thunb.) Matsun. & Nakai.]. Transformation efficiencies ranged from 2.8% to 5.3%, depending on the cultivar. The method was applied to obtain genetically engineered watermelon plants expressing the Saccharomyces cerevisiae HAL1 gene related to salt tolerance. In order to enhance its constitutive expression in plants, the HAL1 gene was cloned in a pBiN19 plasmid under control of the 35S promoter with a double enhancer sequence from the cauliflower mosaic virus and the RNA4 leader sequence of the alfalfa mosaic virus. This vector was introduced into Agrobacterium tumefaciens strain LBA4404 for further inoculation of watermelon half-cotyledon explants. The introduction of both the neomycin phosphotransferase II and HAL1 genes was assessed in primary transformants (TG1) by polymerase chain reaction analysis and Southern hybridisation. The expression of the HAL1 gene was determined by Northern analysis, and the diploid level of transgenic plants was confirmed by flow cytometry. The presence of the selectable marker gene in the expected Mendelian ratios was demonstrated in TG2 progenies. The TG2 kanamycin-resistant plantlets elongated better and produced new roots and leaves in culture media supplemented with NaCl compared with the control. Salt tolerance was confirmed in a semi-hydroponic system (EC=6 dS m(-1)) on the basis of the higher growth performance of homozygous TG3 lines with respect to their respective azygous control lines without the transgene. The halotolerance observed confirmed the inheritance of the trait and supports the potential usefulness of the HAL1 gene of S. cerevisiae as a molecular tool for genetic engineering of salt-stress protection in other crop species.

The ploidy level of transgenic plants in Agrobacterium-mediated transformation of tomato cotyledons ( Lycopersicon esculentum Mill.) is genotype and procedure dependent [corrected].

A protocol avoiding the feeder-layer cell system was optimized for Agrobacterium-mediated transformation of tomato cotyledonary explants. Over 500 transgenic plants from five tomato cultivars were regenerated in 15 independent experiments. Depending on both genotype and procedure, transformation frequencies ranged from 1.8% to 11.3%. The optimal transformation rate was obtained by inoculating explants with a bacterial suspension in exponential growth ( D(600) = 10(2)-10(3) cells/ml) and transferring cotyledon explants to fresh selective regeneration medium every 3 weeks. The ploidy level of both tomato genotypes used as explant source and primary transformants, was studied by flow cytometry. The inbred lines and cultivars were diploid but a polysomatic pattern in the cotyledon explant was confirmed. The rate of tetraploid transgenic plants ranged from 24.5% to 80% and depended on both the genotype and the transformation procedure. Surprisingly, the percentages of transformed plants with higher ploidy levels were not related to the proportion of 4C and 8C nuclei in the cotyledonary tissue. For some genotypes the optimisation of the transformation rate resulted in an increase of tetraploid transgenic plants. Results obtained in this work indicate the convenience of checking the ploidy level of the primary transformants before performing basic studies or introducing tomato transgenic material in a breeding program.