IL7 genetic variation and toxicity to immune checkpoint blockade in patients with melanoma.

Treatment with immune checkpoint blockade (ICB) frequently triggers immune-related adverse events (irAEs), causing considerable morbidity. In 214 patients receiving ICB for melanoma, we observed increased severe irAE risk in minor allele carriers of rs16906115, intronic to IL7. We found that rs16906115 forms a B cell-specific expression quantitative trait locus (eQTL) to IL7 in patients. Patients carrying the risk allele demonstrate increased pre-treatment B cell IL7 expression, which independently associates with irAE risk, divergent immunoglobulin expression and more B cell receptor mutations. Consistent with the role of IL-7 in T cell development, risk allele carriers have distinct ICB-induced CD8+ T cell subset responses, skewing of T cell clonality and greater proportional repertoire occupancy by large clones. Finally, analysis of TCGA data suggests that risk allele carriers independently have improved melanoma survival. These observations highlight key roles for B cells and IL-7 in both ICB response and toxicity and clinical outcomes in melanoma.

Coeliac disease in patients with short stature: A tertiary care centre experience.

BACKGROUND: We aimed to determine the prevalence of coeliac disease among children with short stature at a tertiary care centre and to define the predictors for coeliac disease, if any, in them. METHODS: In this retrospective study, we reviewed the case records of children and adolescents with growth retardation attending the Paediatric Endocrinology Clinic from January 2008 to June 2011. All patients underwent the multi-tier stratified diagnostic protocol for complete evaluation of short stature. Coeliac disease was screened using IgA-anti-tissue transglutaminase antibody. The diagnosis of coeliac disease was made on the basis of the modified European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) criteria. RESULTS: Of 432 patients (238 boys) who presented with short stature, 72 (16.7%) had physiological, while 360 (83.3%) had pathological causes. Endocrine causes were growth hormone deficiency (86 patients, 19.9%), hypopituitarism (31, 7.2%), hypothyroidism (22, 5.1%) and others (7, 1.6%). The systemic causes were: coeliac disease (47, 10.9%), haematological diseases (14, 3.2%), renal diseases (11, 2.5%) and others (24, 5.6%). Chronic diarrhoea (OR 15.7, 95% CI 7.8-31.5) and anaemia (OR 4.9, 95% CI 1.9-12.7]) were significant predictors for coeliac disease in patients with short stature. There was a definite response to gluten-free diet in them and the mean (SD) growth velocity measured over at least 6 months of gluten-free diet was 8.1 (3.0) cm/year. CONCLUSION: Nearly 11% of patients presenting with short stature have coeliac disease. In these patients chronic diarrhoea and anaemia were significant predictors of coeliac disease.

Induction with NCB-02 (curcumin) enema for mild-to-moderate distal ulcerative colitis - a randomized, placebo-controlled, pilot study.

BACKGROUND AND AIMS: Curcumin, an active ingredient of turmeric with anti-inflammatory properties, has been demonstrated to be useful in experimental models of ulcerative colitis (UC). It's efficacy in humans needs to be investigated. METHODS: A randomized, double-blind, single-centre pilot trial was conducted in patients with distal UC (<25 cm involvement) and mild-to-moderate disease activity. Forty-five patients were randomized to either NCB-02 (standardized curcumin preparation) enema plus oral 5-ASA or placebo enema plus oral 5-ASA. Primary end point was disease response, defined as reduction in Ulcerative Colitis Diseases Activity Index by 3 points at 8 weeks, and secondary end points were improvement in endoscopic activity and disease remission at 8 weeks. RESULTS: Response to treatment was observed in 56.5% in NCB-02 group compared to 36.4% (p=0.175) in placebo group. At week 8, clinical remission was observed in 43.4% of patients in NCB-02 group compared to 22.7% in placebo group (p=0.14) and improvement on endoscopy in 52.2% of patients in NCB-02 group compared to 36.4% of patients in placebo group (p=0.29). Per protocol analysis revealed significantly better outcomes in NCB-02 group, in terms of clinical response (92.9% vs. 50%, p=0.01), clinical remission (71.4% vs. 31.3%, p=0.03), and improvement on endoscopy (85.7% vs. 50%, p=0.04). CONCLUSION: In this pilot study we found some evidence that use of NCB-02 enema may tend to result in greater improvements in disease activity compared to placebo in patients with mild-to-moderate distal UC. The role of NCB-02 as a novel therapy for UC should be investigated further.

Atrophic gastritis with high prevalence of Helicobacter pylori is a predominant feature in patients with dyspepsia in a high altitude area.

BACKGROUND: Dyspepsia is a common symptom in residents of Leh, a high-altitude region in Ladakh, India. Helicobacter pylori related gastritis is a common cause of such symptoms. However data regarding this association at high altitudes is sparse. AIM: To investigate the demographic, endoscopic and histopathology findings in patients presenting with dyspeptic symptoms in the high-altitude region of Leh. Methods: A cross-sectional study was done in 84 patients with dyspeptic symptoms, attending the outpatient department of local government hospital in Leh. Demographic details, endoscopy, histopathology of upper gastrointestinal biopsies and microbiology culture of gastric/duodenal aspirates were studied. RESULTS: The mean age was 38.4 years with 42% being males. Indigenous foods with high-salt content were consumed by 75% of patients. Epigastric pain was the most frequent symptom (in 96%) and pain radiating to the back was another peculiar symptom seen in 49% of patients. The predominant finding on endoscopy was antral gastritis in 71% of patients. Nodular gastritis was seen in 18% of patients. H. pylori was documented in 93% and histopathology revealed mild-to-moderate inflammation in 93% and mild-to-moderate atrophy in 90% of patients. Colonization with Gram-negative bacilli was observed in gastric/duodenal aspirate cultures. CONCLUSION: Dyspepsia at high-altitude commonly presents as pain radiating to the back with a very high (90%) prevalence of H. pylori, endoscopic findings of antral gastritis and nodular gastritis, and atrophic gastritis in biopsies. Further investigations are needed to determine whether these observations are related to the high-altitude or the high-salt content in their diet and also whether these further translate to carcinogenesis.

Primary sleep disorders seen at a Neurology service-based sleep clinic in India: Patterns over an 8-year period.

UNLABELLED: There is an increasing awareness for recognition of sleep disorders in India; however, there is still a huge gap in the number of people suffering from various sleep disorders, in the community versus those visiting hospital clinics for the same. Ours is a neurology services-based sleep disorders clinic, which has evolved successfully over the last decade. In this study, we aimed to evaluate the changes in referral patterns and distribution of various sleep disorders in the patients presenting to the clinic. MATERIALS AND METHODS: This is a retrospective chart review-based study on all patients seen over an 8-year period, divided into 2 groups comprising of patients seen during the first 4 years versus those seen over the next 4 years. Only those patients who had the sleep disorder as their presenting manifestation and those who had been formally interviewed with a pre-structured questionnaire detailing about the main features of the common sleep disorders according to the ICSD-R were included. Patients, in whom the sleep disorder could be clearly attributable to another neurological or systemic disorder, were excluded. Statistical analysis was carried out to identify the differences between the two groups as regards the distribution of various sleep disorders and other clinical data. RESULTS: Among 710 patients registered in the clinic, 469 were included for analysis and 222 patients formed group 1 while 247 formed group 2. The main differences observed were in the form of a clear increase in the percentage of patients with sleep-related breathing disorders, sleep-related movement disorder, and the hypersomnias on comparison of distribution over the first 4 years versus the last 4 years; while a clear decline was seen in the number of patients with insomnia and parasomnias. A 3-fold increase was observed in the number of patients in whom polysomnography was obtained. CONCLUSION: The distribution of various sleep disorders as seen in a neurology service-based sleep clinic is demonstrated in this study. Increasing referrals for sleep-disordered breathing, restless legs syndrome, and fewer referrals for insomnia and parasomnias might reflect on changing physician and patient awareness in our community.

Celiac disease and chronic liver disease: is there a relationship?

Celiac disease is a multisystem disease, and the liver is affected in a subset of patients. We herein present a case series of 25 patients with celiac disease who had evidence of cirrhosis of the liver. We retrospectively reviewed the case records of patients with celiac disease having concomitant cirrhosis. The diagnosis of celiac disease was made on the basis of the modified European Society of Pediatric Gastroenterology, Hepatology, and Nutrition criteria. Of 25 patients (nine males; mean age 28.8 ± 16.6 years) with celiac disease and cirrhosis, 17 patients presented predominantly with cirrhosis, while 8 presented primarily with celiac disease. Five patients had known cause of cirrhosis (autoimmune hepatitis, three; PBC, one; hepatic venous outflow tract obstruction, one); the remaining 20 were cryptogenic. Gluten-free diet led to improvement in diarrhea and anemia and to a better control of ascites and other features of liver failure. Some patients with cryptogenic cirrhosis have coexistent celiac disease, and they show response to gluten-free diet. Patients with cryptogenic cirrhosis should be screened for celiac disease.

Disease course in steroid sensitive nephrotic syndrome.

OBJECTIVE: To review the disease course in patients with steroid sensitive nephrotic syndrome (SSNS) and the factors that determine outcome DESIGN: Retrospective, analytical SETTING: Pediatric Nephrology Clinic at referral center in North India PARTICIPANTS/PATIENTS: All patients with SSNS evaluated between 1990 and 2005 INTERVENTION: None MAIN OUTCOME MEASURES: Disease course, in patients with at least 1-yr follow up, was categorized as none or infrequent relapses (IFR), frequent relapses or steroid dependence (FR), and late resistance. Details on complications and therapy with alternative agents were recorded. RESULTS: Records of 2603 patients (74.8% boys) were reviewed. The mean age at onset of illness and at evaluation was 49.7±34.6 and 67.5±37.9 months respectively. The disease course at 1-yr (n=1071) was categorized as IFR in 37.4%, FR in 56.8% and late resistance in 5.9%. During follow up, 224 patients had 249 episodes of serious infections. Alternative medications for frequent relapses (n=501; 46.8%) were chiefly cyclophosphamide and levamisole. Compared to IFR, patients with FR were younger (54.9±36.0 vs. 43.3±31.4 months), fewer had received adequate (=8 weeks) initial treatment (86.8% vs. 81.7%) and had shorter initial remission (7.5±8.6 vs. 3.1±4.8 months) (all P<0.001). At follow up of 56.0±42.6 months, 77.3% patients were in remission or had IFR, and 17.3% had FR. CONCLUSIONS: A high proportion of patients with SSNS show frequent relapses, risk factors for which were an early age at onset, inadequate initial therapy and an early relapse.