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The patients with positive celiac disease (CeD) specific serology, but no evidence of intestinal inflammation are defined as potential celiac disease (PCeD) patients. About one-third of PCeD patients develop intestinal inflammation over time. The present study investigated the metabolome of small intestinal biopsies, blood plasma, and urine of patients with PCeD to understand the biochemical changes underlying the CeD.The metabolic profiles of small intestinal biopsies, blood plasma, and urine of patients with PCeD (n = 7) were compared with CeD (n = 64) and controls (n = 15) [disease controls (DC) and healthy controls (HC)] usingThe intestinal mucosa of PCeD showed lower levels of histidine, glycine, tyrosine, and tryptophan compared to DC. Altered levels of 6 metabolites (glucose, acetate, acetoacetate, β-hydroxybutyrate, pyruvate, arginine) in blood plasma and two metabolites (succinate and aminohippurate) in urine were observed in PCeD compared to HC. The PLS-DA model built on the concentration of blood plasma showed separate clustering for PCeD and CeD patients.Altered metabolic profile of PCeD suggested that gluten intolerance was evident at the metabolic level before the intestinal damage. Altered energy metabolism and lower cytoprotective activity (histidine, glycine, arginine) indicated vulnerability to develop intestinal inflammation in PCeD over time. Our study may provide an insight into early biochemical processes of the progression of PCeD to CeD.

Background: Both noncirrhotic portal fibrosis (NCPF) and extrahepatic portal venous obstruction (EHPVO) are important causes of noncirrhotic portal hypertension (PH) in the Asian region. In this study, we analyzed the histopathological changes of liver needle-core biopsies from patients with NCPF and EHPVO. Patients and Methods: The patients were diagnosed as per the Asia Pacific Association for the Study of Liver (APASL) criteria. Minimum adequacy criteria for liver core biopsies were defined, and finally, 69 liver biopsies from patients with NCPF and 100 liver biopsies from patients with EHPVO were analyzed. All histological parameters were predefined, and three experienced pathologists analyzed the biopsies after reaching consensus. Institute ethics committee clearance was taken. Results: Although some histological features were overlapping, phlebosclerosis of intra-hepatic branches of the portal vein (PV), periportal aberrant vascular channels, remnant portal tracts, and hepatic fibrosis beyond the portal tracts without the formation of complete hepatic nodules (P < 0.001 for all) were common histological characteristics of NCPF on core-needle liver biopsies; while maintained lobular architecture, nonspecific dilatation of PV branches, absence of intra-hepatic PV phlebosclerosis, aberrant vascular channels, and significant fibrosis were characteristics of EHPVO. Conclusions: Despite the considerable histological overlap between NCPF and EHPVO, careful histological evaluation, supplemented by clinical features, radiological and biochemical findings can help in making a conclusive diagnosis. Patients with NCPF and EHPVO with clinical jaundice show transaminitis, high serum alkaline phosphatase level, more variceal bleed, and histological evidences of nodular regenerative hyperplasia.

The Indian Association of Pathologists and Microbiologists (IAPM) and Indian Society of Gastroenterology (ISG) decided to make a joint consensus recommendation for handling, processing, and interpretation of SI biopsies for the diagnosis and management of celiac disease (CD) recognizing the inhomogeneous practice of biopsy sampling, orientation, processing, and interpretation. A modified Delphi process was used to develop this consensus document containing a total of 42 statements and recommendations, which were generated by sharing the document draft, incorporating expert's opinion, followed by three cycles of electronic voting as well as a full-day face-to-face virtual ZOOM meeting and review of supporting literature. Of the 42 statements, 7 statements are on small intestinal (SI) biopsy in suspected patients of CD, site and the number of biopsies; 7 on handling, fixative, orientation, processing, and sectioning in pathology laboratories; 2 on histological orientation; 13 statements on histological interpretation and histological grading; 3 on the assessment of follow-up biopsies; 2 statements on gluten-free diet (GFD)-nonresponsive CD; 4 on challenges in the diagnosis of CD; 2 statements each on pathology reporting protocol and training and infrastructure in this area. The goal of this guideline document is to formulate a uniform protocol agreed upon both by the experienced pathologists and gastroenterologists to standardize the practice, improve the yield of small bowel biopsy interpretation, patients' compliance, overall management in CD, and generate unified data for patient care and research in the related field.

Differentiating Crohn's disease (CD) and intestinal tuberculosis (ITB) has remained a dilemma for most of the clinicians in the developing world, which are endemic for ITB, and where the disease burden of inflammatory bowel disease is on the rise. Although, there are certain clinical (diarrhea/hematochezia/perianal disease common in CD; fever/night sweats common in ITB), endoscopic (longitudinal/aphthous ulcers common in CD; transverse ulcers/patulous ileocaecal valve common in ITB), histologic (caseating/confluent/large granuloma common in ITB; microgranuloma common in CD), microbiologic (positive stain/culture for acid fast-bacillus in ITB), radiologic (long segment involvement/comb sign/skip lesions common in CD; necrotic lymph node/contiguous ileocaecal involvement common in ITB), and serologic differences between CD and ITB, the only exclusive features are caseation necrosis on biopsy, positive smear for acid-fast bacillus (AFB) and/or AFB culture, and necrotic lymph node on cross-sectional imaging in ITB. However, these exclusive features are limited by poor sensitivity, and this has led to the development of multiple multi-parametric predictive models. These models are also limited by complex formulae, small sample size and lack of validation across other populations. Several new parameters have come up including the latest Bayesian meta-analysis, enumeration of peripheral blood T-regulatory cells, and updated computed tomography based predictive score. However, therapeutic anti-tubercular therapy (ATT) trial, and subsequent clinical and endoscopic response to ATT is still required in a significant proportion of patients to establish the diagnosis. Therapeutic ATT trial is associated with a delay in the diagnosis of CD, and there is a need for better modalities for improved differentiation and reduction in the need for ATT trial.

Purpose The aim of this study was to evaluate the diagnostic performance of dual-time-point-PET/CT, CECT and EUS + FNA in diagnosing pancreatic-ductal-adenocarcinomas (PDAC), in context of concomitant Chronic Pancreatitis (CP). Methods 18F-FDG-PET/CTs were prospectively acquired in 22 confirmed CP and 23 confirmed PDAC patients (calculated for 90% power); and cut-offs of 2.2 for early-SUV(∼1hr), 2.4 for delayed-SUV(∼3hr) and 1.36 for Retention-index (RI), were derived. These cut-offs were validated in PET/CTs of 75 patients (51.9 ± 13.3years; 54 men) with pancreatic masses of unknown nature. Comparisons were made with triple-phase-CECT (73 patients) and EUS + FNA (54 patients). Histopathology was obtained in 68 patients (including all PDACs) and 7 were followed up for minimum of 2 years. Results In patients without concomitant CP, sensitivity, specificity and accuracy for diagnosing malignancy in standard-acquisition-PET/CT, dual-time-point-PET/CT, CECT and EUS + FNA were 97.4%, 83.3%, 94.0%; 97.4%, 75.0%, 92%; 94.6%, 66.7%, 87.8% and 92.6%, 88.9%, 91.7% respectively. Corresponding values in patients with concomitant CP were 88.9%, 57.1%, 80.0%; 100%, 57.1%, 88%; 82.4%, 57.1%, 75% and 100%, 100%, 100% respectively. In lesions ≤2 cm (AJCC-T1), dual-time-point-PET/CT was the most sensitive (95.8%). ROC-analysis revealed significantly higher area-under-the-curve for RI over early-SUV (p = 0.002) in cases with concomitant CP only. In patients with confirmed liver-metastases, PET/CT and CECT identified 15/16 and 13/16 lesions. PET/CT identified additional lung-metastases in 3 and bone-metastasis in one patient. Conclusion In patients without concomitant CP and with larger lesions, PET/CT and CECT are equivocal as screening modalities, with no benefit of dual-time-point-PET/CT acquisitions. However, in patients with concomitant CP and smaller lesions, dual-time-point PET/CT is better; with sensitivity comparable to EUS + FNA.

Bariatric surgery is associated with a positive impact on the degree of hepatic steatosis and inflammation in nonalcoholic associated fatty liver disease (NAFLD), although its effect on fibrosis is contentious. The role of Fibroscan in the post-bariatric assessment of hepatic steatosis and fibrosis is unclear. This work aims to study the impact of bariatric surgery on the course of NAFLD using both invasive (liver biopsy) and non-invasive tests (biochemical parameters and Fibroscan). In this prospective study, the impact of bariatric surgery on the course of NAFLD was assessed using paired liver biopsy (intra-operative and post-bariatric surgery 1-year follow-up). The liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) cutoffs for the assessment of hepatic fibrosis and steatosis, respectively, were calculated in both pre- and post-bariatric settings. Fifty-eight patients (70.7% females, mean age 39.2 years) underwent paired liver biopsy. Post-bariatric surgery 1-year liver biopsy showed significant improvement in all the histopathological parameters of NAFLD. The mean NAFLD Activity Score declined from 2.81 (± 1.08) to 1.31 (± 1.39) post-bariatric surgery. Thirty (51.7%) patients showed improvement in fibrosis, eighteen (31%) no change, and ten (17.2%) had worsening. Worsening of fibrosis was associated with a higher median age of 44.5 versus 38 years (p value = 0.033). The CAP cutoff values for the various stages of hepatic steatosis were higher pre-operatively as compared with those obtained post-bariatric surgery. Bariatric surgery is associated with significant improvement in histopathological parameters of NAFLD. Fibroscan shows good diagnostic accuracy in detecting advanced stage and grade of NAFLD.

Background and aim Computed tomographic (CT) features (long segment, ileocaecal area involvement, and lymph nodes > 1 cm) have demonstrated good specificity but poor sensitivity, while visceral to subcutaneous fat ratio on CT (VF/SC > 0.63) has moderate sensitivity and specificity in differentiating Crohn's disease (CD) and intestinal tuberculosis (ITB). This study aims to develop and validate an updated model incorporating CT features and VF/SC to improve the diagnostic accuracy of imaging in differentiating CD/ITB. Methods Computed tomographic features and VF/SC were documented in two cohorts (development [n = 59, follow-up: January 2012 to November 2014] and validation [n = 69, follow-up: December 2014 to December 2015]) of CD/ITB patients diagnosed by standard criteria. Patients with normal CT were excluded. Features significantly different between CD/ITB were incorporated into a model. Results In both the cohorts, necrotic lymph nodes were exclusive for ITB (23.1% vs 0% and 43.3% vs 0%), while long segment involvement (57.6% vs 7.7%, P 0.63 (72.7% vs 19.2%, P 0.63, had an excellent specificity of 100% and 100% and sensitivity of 54% and 50% for CD in development and validation cohorts, respectively. Based upon these features, in 43% patients with the diagnostic dilemma of CD/ITB, a definite diagnosis based only on imaging could be made. Conclusion Necrotic lymph nodes are exclusive for ITB, and the combination of long segment involvement and VF/SC ratio > 0.63 is exclusive for CD, and these features can make a definite diagnosis in 43% patients with a CD/ITB dilemma.

Introduction Celiac disease (CeD) associated liver dysfunctions (CALD) have wide range of manifestation ranging from milder symptoms alleviating on gluten free diet (GFD), to pathological conditions such as autoimmune hepatitis, cirrhosis etc. However, characteristic histopathological signatures diagnostic of this entity have not been described yet. Diagnosis relies solely on clinical suspicion due to co-occurrence of two pathologies. The aim of this study is to elucidate histological features of CALD and demonstrate IgA/IgG anti-tTG colocalization patterns as a hypothetic evidence towards etiology. Methods 28 formalin fixed paraffin embedded (FFPE) core liver biopsies from patients with treatment naive CeD with associated liver dysfunction and another 5 FFPE liver core biopsies from patients with other proven pathologies and normal serum anti-tTG titres, were retrieved and IgA/IgG anti-tTG colocalization was carried out both by dual immunohistochemistry (IHC) and dual confocal immunofluorescence (IF) techniques. After a period of GFD, clinically indicated liver biopsies from 5 of these 28 patients were obtained and subjected to repeat testing via the same techniques. Results Histopathological examination in CALD revealed the following spectrum: steatohepatitis 4 (14.2%), autoimmune hepatitis 4 (14.2%), non-cirrhotic portal venopathy 1 (3.5%), secondary hemochromatosis 1 (3.5%), steatohepatitis with necrotising granuloma 1 (3.5%), cirrhosis 3 (10.7%), irregular sinusoidal dilatation 14 (50%). In CALD, IgA/IgG anti-tTG colocalization was noted in 85.6% cases by dual IHC technique and in 92.8% cases by dual IF technique. Follow up biopsies in 5 CeD cases showed no co-localisation. Conclusions Deposition of the circulating IgA/IgG anti-tTG antibodies in suspected patients of CALD seems to be a sensitive and specific technique for diagnosing their celiac association, thereby opening up newer insights into management protocols.

Celiac disease (CeD) is an autoimmune enteropathy caused by gluten intake in genetically predisposed individuals. We investigated the metabolism of CeD by metabolic profiling of intestinal mucosa, blood plasma and urine using NMR spectroscopy and multivariate analysis. The metabolic profile of the small intestinal mucosa was compared between patients with CeD (n = 64) and disease controls (DCs, n = 30). The blood plasma and urinary metabolomes of CeD patients were compared with healthy controls (HCs, n = 39). Twelve metabolites (proline (Pro), arginine (Arg), glycine (Gly), histidine (His), glutamate (Glu), aspartate, tryptophan (Trp), fumarate, formate, succinate (Succ), glycerophosphocholine (GPC) and allantoin (Alln)) of intestinal mucosa differentiated CeD from controls. The metabolome of blood plasma with 18 metabolites (Pro, Arg, Gly, alanine, Glu, glutamine, glucose (Glc), lactate (Lac), acetate (Ace), acetoacetate (AcAc), β-hydroxybutyrate (β-OHB), pyruvate (Pyr), Succ, citrate (Cit), choline (Cho), creatine (Cr), phosphocreatine (PCr) and creatinine) and 9 metabolites of urine (Pro, Trp, β-OHB, Pyr, Succ, N-methylnicotinamide (NMN), aminohippurate (AHA), indoxyl sulfate (IS) and Alln) distinguished CeD from HCs. Our data demonstrated changes in nine metabolic pathways. The altered metabolites were associated with increased oxidative stress (Alln), impaired healing and repair mechanisms (Pro, Arg), compromised anti-inflammatory and cytoprotective processes (Gly, His, NMN), altered energy metabolism (Glc, Lac, β-OHB, Ace, AcAc, Pyr, Succ, Cit, Cho, Cr and PCr), impaired membrane metabolism (GPC and Cho) and intestinal dysbiosis (AHA and IS). An orthogonal partial least square discriminant analysis model provided clear differentiation between patients with CeD and controls in all three specimens. A classification model built by combining the distinguishing metabolites of blood plasma and urine samples gave an AUC of 0.99 with 97.7% sensitivity, 93.3% specificity and a predictive accuracy of 95.1%, which was higher than for the models built separately using small intestinal mucosa, blood plasma and urine. In conclusion, a panel of metabolic biomarkers in intestinal biopsies, plasma and urine samples has potential to differentiate CeD from controls and may complement traditional tests to improve the diagnosis of CeD.

ObjectivePharmacological treatment of non-alcoholic fatty liver disease (NAFLD) is still evolving. Probiotics could be a promising treatment option, but their effectiveness needs to be established. The present study aimed to evaluate the efficacy of a high potency multistrain probiotic in adult patients with NAFLD.MethodsThirty-nine liver biopsy-proven patients with NAFLD were randomised in a double-blind fashion to either lifestyle modifications plus an oral multistrain probiotic (675 billion bacteria daily, n=19) or identical placebo (n=20) for 1 year. Lifestyle modifications included regular exercise for all and control of overweight/obesity (with additional dietary restrictions), hypertension and hyperlipidaemia in those with these risk factors. Primary objective of the study was the histological improvement in NAFLD activity score (NAS) and its components and secondary objectives were improvement in alanine transaminase (ALT) and cytokine profile.ResultsThirty (76.9%) out of 39 patients with NAFLD completed the study with 1 year of follow-up. A repeat liver biopsy at 1 year could be done in 10 patients (52.6%) in probiotic group and five patients (25%) in placebo group. In comparison to baseline, hepatocyte ballooning (p=0.036), lobular inflammation (p=0.003) and NAS score (p=0.007) improved significantly at 1 year in the probiotic group. When compared with placebo, the NAS score improved significantly in the probiotic group (p=0.004), along with improvements in hepatocyte ballooning (p=0.05) and hepatic fibrosis (p=0.018). A significant improvement in levels of ALT (p=0.046), leptin (p=0.006), tumour necrosis factor-α (p=0.016) and endotoxins (p=0.017) was observed in probiotic group in comparison to placebo at 1 year. No significant adverse events were reported in the study.ConclusionPatients with NAFLD managed with lifestyle modifications and multistrain probiotic showed significant improvement in liver histology, ALT and cytokines.Trial registration numberThe clinical trial is registered with CLINICAL TRIAL REGISTRYINDIA (CTRI);http://ctri.nic.in, No. CTRI/2008/091/000074

Background: Aggressive pancreatobiliary tumors often require oxaliplatin-based therapies, instead of standard gemcitabine-based therapy and biomarker studies at diagnosis to decide the appropriate therapeutic regimen. The ribonucleotide Reductase catalytic subunit M1 (RRM1) and excision repair cross-complementing gene-1 (ERCC1) are related to DNA synthesis and repair and essential in this regard. However, apart from the therapeutic benefit, their prognostic implication is controversial. Methods: In this retrospective study, paraffin-embedded tissue from 51 cases of pancreatic cancer and 29 cases of cholangiocarcinoma were evaluated for RRM1 and ERCC1 expression by immunohistochemical technique along with 18 control pancreatic and biliary tissues. The semiquantitatively H score was calculated based on stain distribution and stain intensities. Results: Both RRM1 and ERCC1 expression were high in tumor epithelium than in controls (RRM1: the difference was statistically significant in cholangiocarcinoma (P = 0.008); ERCC1: the difference was statistically significant both in pancreatic and cholangiocarcinoma (P < 0.05)]. However, no correlation was noted between RRM1 and ERCC1-low and high tumors with histological markers of prognosis and overall survival in these patients. Conclusions: The present study adds further evidence against the controversy that if RRM1 and ERCC1 expression in pancreatic and biliary carcinomas have any prognostic significance apart from their proven therapeutic benefits in these tumors.

Objective The clinical spectrum of celiac disease (CeD) is wide and its symptoms overlap with those of functional bowel diseases. This study aimed to investigate the relationship among gluten-related disorders, irritable bowel syndrome (IBS) and uninvestigated dyspepsia in Indian patients. Methods Patients with IBS and uninvestigated dyspepsia (using Rome III criteria) were tested for immunoglobulin A (IgA) anti-tissue transglutaminase (anti-tTG) antibody and anti-gliadin antibody (AGA). Those with positive anti-tTG antibody were evaluated for the presence of villous abnormalities. Patients who were only IgA AGA-positive were considered to have gluten sensitivity and those with positive anti-tTG antibody and villous atrophy were considered to have CeD. Results Of 362 patients with IBS, 22 (6.1%) had positive anti-tTG antibody, among whom 3 (0.8%) had CeD and 19 had potential CeD. Of 358 patients with uninvestigated dyspepsia, 18 (5.0%) were anti-tTG antibody-positive and among them 4 (1.1%) had CeD and 14 had potential CeD. AGA was positive in 104 (28.7%) patients with IBS and 68 (19.0%) with uninvestigated dyspepsia, suggesting the presence of gluten sensitivity. Conclusion This study highlights the relationship between IBS or dyspepsia and CeD or gluten sensitivity.

Computed tomographic (CT) features (long segment, ileocaecal area involvement, and lymph nodes 1 cm) have demonstrated good specificity but poor sensitivity, while visceral to subcutaneous fat ratio on CT (VF/SC 0.63) has moderate sensitivity and specificity in differentiating Crohn's disease (CD) and intestinal tuberculosis (ITB). This study aims to develop and validate an updated model incorporating CT features and VF/SC to improve the diagnostic accuracy of imaging in differentiating CD/ITB.Computed tomographic features and VF/SC were documented in two cohorts (development [n = 59, follow-up: January 2012 to November 2014] and validation [n = 69, follow-up: December 2014 to December 2015]) of CD/ITB patients diagnosed by standard criteria. Patients with normal CT were excluded. Features significantly different between CD/ITB were incorporated into a model.In both the cohorts, necrotic lymph nodes were exclusive for ITB (23.1% vs 0% and 43.3% vs 0%), while long segment involvement (57.6% vs 7.7%, P 0.001, and 52.6% vs 16.1%, P 0.001) and VF/SC ratio 0.63 (72.7% vs 19.2%, P 0.001, and 81.6% vs 25.8%, P 0.001) were significantly more common in CD. A risk score of 2, based upon long segment involvement and VF/SC ratio 0.63, had an excellent specificity of 100% and 100% and sensitivity of 54% and 50% for CD in development and validation cohorts, respectively. Based upon these features, in 43% patients with the diagnostic dilemma of CD/ITB, a definite diagnosis based only on imaging could be made.Necrotic lymph nodes are exclusive for ITB, and the combination of long segment involvement and VF/SC ratio 0.63 is exclusive for CD, and these features can make a definite diagnosis in 43% patients with a CD/ITB dilemma.

The literature on resolution of intestinal strictures in patients with intestinal tuberculosis (ITB) after anti-tuberculous therapy (ATT) is sparse and ambivalent. We aimed to assess the frequency of stricture resolution after ATT and its predictors. This ambispective cohort study included consecutive ITB patients with strictures who received ATT for ≥6 months and were on regular follow-up between January 2004 and December 2015. Resolution of stricture was assessed at the end of ATT by endoscopy/radiology. Of 286 patients, 128 had strictures, and 106 were finally included (63 males, median age 35 years). The stricture location was distal ileum/ileocecal in 52 (49.1%), colon in 37 (34.9%), ileocolonic in 4 (3.8%), proximal small bowel in 10 (9.4%), and gastroduodenal in 4 (3.8%) patients. Although all patients demonstrated mucosal healing (indicating resolution of active infection), stricture resolution occurred only in 25/106 (23.6%) patients. Symptoms pertaining to stricture (pain abdomen/recurrent SAIO) were present in 104/106 (98%) patients, and after a median of 6 (6–9) months of ATT, these symptoms resolved only in half, 88% (22/25) in patients with stricture resolution and 38% (30/79) in patients with persistent strictures. Colonic strictures had the least resolution (5.4%) followed by proximal small intestinal (20%) and distal ileal/ileocecal (36.5%). Although not statistically significant, stricture resolution was less frequent in patients with multiple strictures, longer strictures (>3 cm), and strictures in which scope was not negotiable prior to ATT. Only one-fourth of ITB patients with strictures show resolution of stricture following ATT. The resolution of strictures is dependent on disease location, and majority of them exhibit symptoms pertaining to stricture even after ATT.

There is a need for effective chemotherapy protocols for gall bladder cancer (GBC). Gemcitabine has antitumor activity in pancreatic cancer. Oxaliplatin is effective in GI cancers. Based on evidence of synergy between these two, we designed this study to evaluate efficacy of this combination in unresectable GBC.Unresectable GBC was enrolled for single center phase II study. Drugs gemcitabine 900 mg/m2 and oxaliplatin 80 mg/m2 IV infusion (Oxigem) on days 1 and 8 every 3 weeks for a maximum of six cycles or unacceptable toxicity which ever was earlier.Fifty patients were enrolled and analysis was restricted to 48 who were treated. Median age was 50 years and 31 patients were females.CR 3 (6.2%), PR 7 (15%), SD 17 (35.4%), and PD 18. One had complete pathological response. Median OS and PFS were 7.5 and 3 months, respectively. OS in responders was 10.5 versus 4 months in non-responders (p0.0000). Eleven patients (23%) survived for a year or more. There was no toxic death and grade III/IV toxicity seen in 10 (22%) patients: diarrhea 3, vomiting 2, neutropenia and thrombocytopenia 5 patients.This combination of Oxigem effective in unresectable GBC. It may even induce complete pathological response. One-year survival was 20%. There is a need for controlled trial to assess efficacy of this combination.

Activated leukocyte cell adhesion molecule (ALCAM) has been proposed to function as a cell surface sensor for cell density, controlling the transition between local cell proliferation and tissue invasion in cancer progression. Herein, we determined ALCAM expression in 107 oral squamous cell carcinomas (OSCCs), 78 oral lesions (58 hyperplasias and 20 dysplasias) and 30 histologically normal oral tissues using immunohistochemistry and correlated with clinicopathological parameters. Significant increase in ALCAM immunopositivity was observed from normal oral mucosa, hyperplasia, dysplasia to OSCCs (ptrend < 0.001). Increased ALCAM expression was observed in cytoplasm of epithelial cells as early as in hyperplasia (p = 0.001, OR = 3.8). Sixty-five of 107 (61%) OSCCs showed significant overexpression of ALCAM protein in cytoplasm/membrane of tumor cells (p = 0.043; OR = 3.3) in comparison with the normal oral tissues. Among OSCCs, cytoplasmic ALCAM was associated with advanced tumor size, tumor stage and tobacco consumption. Importantly, cytoplasmic ALCAM was an independent predictor of poor prognosis of OSCCs in multivariate analysis (p = 0.012, OR = 6.2). In an attempt to understand the molecular basis of cytoplasmic localization of ALCAM, 14-3-3ζ and 14-3-3σ were identified as its novel binding partners in oral cancer cells. In conclusion, increased expression of ALCAM is an early event in oral tumorigenesis; its cytoplasmic accumulation in tumor cells is a predictor of poor prognosis of OSCCs, underscoring its potential as a candidate prognostic marker for oral cancer. © 2008 Wiley-Liss, Inc.

Activation of canonical Wnt/beta-catenin pathway in Invasive Ductal Carcinoma of Breast (IDCs) was recently reported from our laboratory. Herein, we analyzed promoter methylation status of CDH1 and Adenomatous polyposis coli (APC) genes in 50 IDCs and correlated with expression of E-cadherin (E-CD) and APC proteins and with activation of oncogenic Wnt/beta-catenin signaling pathway components, Dvl, beta-catenin and CyclinD1. Further, Wnt/beta-catenin driven epithelial mesenchymal transition (EMT) was investigated by correlating the expression of Dvl, beta-catenin and CyclinD1 with vimentin expression in these IDCs. Promoter hypermethylation was observed in 25/50 (50%) IDCs for CDH1 and in 11/50 (22%) tumors for APC, associated with loss of expression of E-CD and APC proteins; concordant hypermethylation of these genes was observed in paired patients' sera. Further, 57% of tumors harboring CDH1 methylation and 50% tumors harboring the methylated APC gene showed nuclear localization of beta-catenin, suggesting activation of the canonical Wnt/beta-catenin pathway. Our study demonstrates significant association between vimentin expression and nuclear beta-catenin (p=0.001; Odds ratio (OR)=25.6) and Dvl (p=0.023; OR=8.0), suggesting that EMT may be driven by Wnt/beta-catenin activation in IDCs. In conclusion, we demonstrate correlation of CDH1 and APC promoter methylation with loss of E-CD and APC proteins and with activation of Wnt/beta-catenin signaling pathway. Association of nuclear Dvl and beta-catenin with vimentin expression suggests the importance of Wnt/beta-catenin pathway driven EMT in IDCs. The concordance between CDH1 and APC methylation in IDCs and paired circulating DNA underscores the utility of serum DNA as a non-invasive tool for methylation analysis in IDC patients.

Background: Intestinal parasites not only cause diarrheal diseases but also significant malabsorption. Literature on the role of parasites, such as intestinal coccidia and microsporidia in malabsorption syndrome is limited. Methods: Three consecutive stool samples from 50 adult and 50 children patients with malabsorption syndrome and an equal number of healthy controls without diarrhea were examined for intestinal coccidia, microsporidia and other intestinal parasites by wet mount, Kinyoun’s modified acid-fast staining and chromotrope 2R staining. Results: Celiac disease was the commonest cause of malabsorption syndrome in both adults (52%) and children (74%). Forty (80%) and 41 (82%) adults and children, respectively, with malabsorption syndrome were infected with parasites. These results were significantly higher in comparison to those from the healthy adults and children controls (22% and 16%), respectively (P < 0.001). Of them, 48% and 46% of the adults and children, respectively, with malabsorption had pathogenic parasitic infections. The pathogenic parasites detected in adults were Giardia lamblia 12 (24%), E. histolytica / dispar 5 (10%), Ancylostoma duodenale 4 (8%), H. nana 2 (4%) and Cyclospora cayetanensis 1 (2%). The pathogenic parasites detected in children with malabsorption syndrome were Giardia lamblia 8 (16%), Cryptosporidium 7 (14%), E. histolytica / dispar 3 (6%), Ancylostoma duodenale 3 (6%), Isospora belli 1 (2%), and H. nana 1 (2%). None of the stool samples from healthy controls were positive for Cryptosporidium spp., Cyclospora and Isospora belli. All the patients infected with intestinal coccidia were HIV sero-negative. Conclusion: Celiac disease is the most common cause of malabsorption syndrome in both adults and children. These people harbor significantly more pathogenic parasites and are more frequently colonized with harmless commensals as compared to healthy controls. Intestinal coccidia are associated with malabsorption syndrome, particularly in malnourished children.

Background: The introduction of transgenic technology has made it possible to study the steps of carcinogenesis and directly establish the link between viral subgenomic fragments and specific types of cancer. Research directed at hepatitis B virus (HBV)-related carcinogenesis has benefited from this technology. We present a detailed pathological evaluation of the sequential steps of hepatocarcinogenesis in a hepatitis B 'x' (HBx) transgenic mouse model. In this model, the transgene incorporates the region encoding amino acids 58-154 of the HBV X protein and the murine c-myc gene. This model demonstrated changes in the liver from birth with foci of multicentric dysplasia evolving into nodules and overt hepatocellular carcinoma between 20 and 28 weeks. Methods and Results: The hepatocytes were mitotically active and showed increased proliferative capacity soon after birth, with exponential increase thereafter. This was accompanied by a high rate of apoptosis, which later declined as the tumors developed. Other functional and immunophenotypic characteristics included a high c-myc expression in the neoplastic lesions, no alteration in p53 expression, and no alteration in the expression of hepatic enzymes except for diffuse expression of succinic dehydrogenase. Conclusion: The entire process illustrates the disturbances of cell growth and death because of the collaborative influence of HBx and c-myc genes that result in the development of hepatocellular carcinoma after a prolonged latent period.

Etiopathogenesis of acute hepatic failure (AHF) in Eastern and Western countries is distinct. In the East hepatitis viruses cause AHF in more than 95% of such cases, while causes of AHF in the West are quite heterogenous. Hepatitis E virus is the major etiological agent of AHF in countries like India where the virus is hyperendemic. Occult HBV infection may also be causing AHF in a sizable proportion of cases in areas where chronic HBV infection frequency is high. Paracetamol causes AHF in about 70% cases in the UK and about 20% cases in USA, whereas in France and Denmark, non-steroidal anti-inflammatory drugs are more frequently associated with AHF. Hepatitis B virus causes AHF in about one-third of cases in the latter two countries. © 2002 Blackwell Publishing Asia Pty Ltd

Deleted in liver cancer (DLC1), a Rho GTPase-activating protein, was observed to be differentially expressed in oral squamous cell carcinoma in comparison with normal tissues using tissue proteomics. In the current study, we investigated the clinical significance of loss of DLC1 expression in different stages of development of oral squamous cell carcinoma to determine its potential as a biomarker for oral dysplasia and prognosis of oral squamous cell carcinoma. Immunohistochemical analysis of DLC1 expression was carried out in oral squamous cell carcinoma patients (n=214), dysplasia (n=51), hyperplastic squamous mucosa (n=45), and histologically normal oral tissues (n=80), and correlated with clinicopathological parameters and disease prognosis over 91 months for oral squamous cell carcinomas. Loss of DLC1 expression was observed in oral squamous cell carcinoma (64%), oral dysplasia (31%), hyperplastic squamous mucosa (22%), and normal mucosa (16%). Significant loss of DLC1 expression was observed in oral squamous cell carcinomas as compared with dysplasia (P

Background Tissue proteomic analysis of head and neck squamous cell carcinoma (HNSCC) and normal oral mucosa using iTRAQ (isobaric tag for relative and absolute quantitation) labeling and liquid chromatography-mass spectrometry, led to the identification of a panel of biomarkers including S100A7. In the multi-step process of head and neck tumorigenesis, the presence of dysplastic areas in the epithelium is proposed to be associated with a likely progression to cancer; however there are no established biomarkers to predict their potential of malignant transformation. This study aimed to determine the clinical significance of S100A7 overexpression in HNSCC. Methodology Immunohistochemical analysis of S100A7 expression in HNSCC (100 cases), oral lesions (166 cases) and 100 histologically normal tissues was carried out and correlated with clinicopathological parameters and disease prognosis over 7 years for HNSCC patients. Overexpression of S100A7 protein was significant in oral lesions (squamous cell hyperplasia/dysplasia) and sustained in HNSCC in comparison with oral normal mucosa (ptrend

Oral leukoplakia is a heterogeneous lesion with risk of cancer development; there are no biomarkers to predict its potential of malignant transformation. Tissue proteomic analysis of oral leukoplakia using iTRAQ labeling liquid chromatography-mass spectrometry showed overexpression of heterogeneous ribonucleoprotein K (hnRNP K), a transformation-related RNA-binding protein, in leukoplakia in comparison with normal tissue. Herein, we investigated the clinical significance of hnRNP K in identification of oral leukoplakic lesions in early stages and as a prognostic marker in head-and-neck/oral squamous cell carcinomas (HNOSCCs). Immunohistochemical analysis of hnRNP K was performed in 100 HNOSCCs, 199 leukoplakias and 55 nonmalignant tissues and correlated with clinicopathologic parameters and disease prognosis over 6 years for HNOSCCs. hnRNP K nuclear expression increased from normal tissues to leukoplakia, and frank malignancy (p < 0.001). Cytoplasmic hnRNP K increased significantly from leukoplakia to HNOSCCs (p < 0.001) and was associated with poor prognosis of HNOSCCs (p = 0.011) by Kaplan-Meier analysis. The most important finding of our follow-up study is that cytoplasmic hnRNP K is an independent predictor of disease recurrence in HNOSCC patients. In conclusion, nuclear hnRNP K may serve as a potential marker for early diagnosis, whereas its cytoplasmic accumulation can help to identify a subgroup of HNOSCC patients with poor prognosis, suggesting its putative utility in clinical management of HNOSCC.

Chronic exposure of the oral mucosa to carcinogens in tobacco is linked to inflammation and development of oral premalignant lesions (OPLs) with high risk of progression to cancer; there is currently no clinical methodology to identify high-risk lesions. We hypothesized that identification of differentially expressed proteins in OPLs in relation to normal oral tissues using proteomic approach will reveal changes in multiple cellular pathways and aid in biomarker discovery. Isobaric mass tags (iTRAQ)-labeled oral dysplasias and normal tissues were compared against pooled normal control by online liquid chromatography and tandem mass spectrometry. Verification of biomarkers was carried out in an independent set of samples by immunohistochemistry, immunoblotting, and RT-PCR. We identified 459 nonredundant proteins in OPLs, including structural proteins, signaling components, enzymes, receptors, transcription factors, and chaperones. A panel of three best-performing biomarkers identified by iTRAQ analysis and verified by immunohistochemistrystratifin (SFN), YWHAZ, and hnRNPKachieved a sensitivity of 0.83, 0.91, specificity of 0.74, 0.95, and predictive value of 0.87 and 0.96, respectively, in discriminating dysplasias from normal tissues, thereby confirming their utility as potential OPL biomarkers. Pathway analysis revealed direct interactions between all the three biomarkers and their involvement in two major networks involved in inflammation, signaling, proliferation, regulation of gene expression, and cancer. In conclusion, our work on determining the OPL proteome unraveled novel networks linking inflammation and development of epithelial dysplasia and their key regulatory proteins may serve as novel chemopreventive/therapeutic targets for early intervention. Additionally, we identified and verified a panel of OPL biomarkers that hold promise for large-scale validation for ultimate clinical use.

Patients with celiac disease, who remain undiagnosed or asymptomatic in childhood, may present in adulthood with either typical or atypical features.In a retrospective analysis, we reviewed the case records of 45 consecutive patients with celiac disease diagnosed in adulthood. The diagnosis of celiac disease was made on the basis of the modified European Society of Pediatric Gastroenterology, Hepatology and Nutrition criteria. The modes of presentation, clinical manifestations, endoscopic features and histological features were analyzed.The mean age of these patients at diagnosis was 28.7 (11.2) years. The median duration of symptoms before diagnosis was 2.5 years (range: 6 months to 40 years). Chronic diarrhea was the presenting manifestation in 20 (44%) patients only. Twenty-two (49%) patients were referred to us by hematologists, endocrinologists or gynecologists for evaluation of refractory anemia in 10 (2.2%), short stature in 6 (13.3%), metabolic bone disease in 2 (4.4%) and secondary infertility or delayed menarche in 4 (8.8%). Intestinal mucosal folds were scalloped in 31 (69%), attenuated in 34 (76%) and normal looking in 11 (24%) of them. Mild, moderate and severe villous abnormalities on intestinal mucosal biopsies were present in 10 (22.2%), 15 (33.3%) and 19 (42.2%) patients, respectively.More than half of adult patients with celiac disease present with atypical manifestations. A high index of suspicion is required for diagnosing variant forms of celiac disease in adults.

In vitro activity of rifampicin has been shown against H. pylori. It has also been reported that the prevalence of H. pylori is low in patients with tuberculosis treated with rifampicin. Clinical trials are required to establish the efficacy of rifampicin as a salvage therapy for eradication of H. pylori. We aimed to evaluate the efficacy of rifampicin-based salvage therapy for eradication of H. pylori in patients with peptic ulcer disease. Twenty-eight patients with peptic ulcer disease who either had failed eradication of H. pylori or had a recurrence of H. pylori following successful eradication were included in the prospective study. The inclusion criteria included one or more failed attempts at eradication and presence of H. pylori infection as evidenced by positivity of at least two of three tests: rapid urease test (RUT), 14C urea breath test (UBT), and histology. The subjects were treated with a 10-day regimen consisting of rifampicin, 450 mg od, tetracycline, 1 g bd, and esomeprazole, 40 mg bd. Four weeks after completion of therapy, H. pylori status was assessed by RUT, 14C, UBT, and histology. Liver function tests were done before and at the end of therapy. The study subjects included 25 males and 3 females with a mean age of 33.7 ± 8.92 years (range: 22–65 years). The median duration of symptoms was 42 months, with a range of 1–180 months. The median number of eradication attempts was two, with one prior attempt in 6 (21.4%), two attempts in 19 (67.9%), and three attempts in 3 (10.7%) patients. Successful H. pylori eradication as defined by concomitant negativity of RUT, UBT, and histology with special stains was achieved in 32.1% (9/28) of patients by intention-to-treat and 33.3% (9/27) of patients by per-protocol analysis. This pilot study suggests that rifampicin-based regimes have no role as salvage eradication therapy in refractory cases of H. pylori infection with peptic ulcer disease.

0020-7292/$ see front matter D 2005 International Federation of All rights reserved. doi:10.1016/j.ijgo.2005.03.016 * Corresponding author. Tel.: +91 11 26594425; fax.: +91 11 26588663. E-mail address: pgarg10@hotmail.com (P.K. Garg). veins (Fig. 1). Tests to determine whether the patient had an hypercoagulable state, i.e., for lupus anticoagulant, antinuclear antibody, anti-dsDNA, International Journal of Gynecology and Obstetrics (2005) 90, 70—71

A 30 year old woman with aggressive fibromatosis (desmoid) of the left upper arm and scapular region was treated with wide excision. Two years later she presented with extensive local recurrence of the scapular and deltoid regions. She was treated with tamoxifen (20 mg daily) and, over the next 6 months, the tumour regressed. She has been recurrence-free for the past year. We suggest that, in patients with desmoid tumours, hormone receptor determination and hormone therapy be attempted before subjecting patients to any form of radical treatment with surgery, radiotherapy or chemotherapy.

Viral hepatitis is a major public health problem in India, which is hyperendemic for HAV and HEV. Seroprevalence studies reveal that 90%-100% of the population acquires anti-HAV antibody and becomes immune by adolescence. Many epidemics of HEV have been reported from India. HAV related liver disease is uncommon in India and occurs mainly in children. HEV is also the major cause of sporadic adult acute viral hepatitis and ALF. Pregnant women and patients with CLD constitute the high risk groups to contract HEV infection, and HEV-induced mortality among them is substantial, which underlines the need for preventive measures for such groups. Children with HAV and HEV coinfection are prone to develop ALF. India has intermediate HBV endemicity, with a carrier frequency of 2%-4%. HBV is the major cause of CLD and HCC. Chronic HBV infection in India is acquired in childhood, presumably before 5 years of age, through horizontal transmission. Vertical transmission of HBV in India is considered to be infrequent. Inclusion of HBV vaccination in the expanded programme of immunization is essential to reduce the HBV carrier frequency and disease burden. HBV genotypes A and D are prevalent in India, which are similar to the HBV genotypes in the West. HCV infection in India has a population prevalence of around 1%, and occurs predominantly through transfusion and the use of unsterile glass syringes. HCV genotypes 3 and 2 are prevalent in 60%-80% of the population and they respond well to a combination of interferon and ribavirin. About 10%-15% of CLD and HCC are associated with HCV infection in India. HCV infection is also a major cause of post-transfusion hepatitis. HDV infection is infrequent in India and is present about 5%-10% of patients with HBV-related liver disease. HCC appears to be less common in India than would be expected from the prevalence rates of HBV and HCV. The high disease burden of viral hepatitis and related CLD in India, calls for the setting up of a hepatitis registry and formulation of government-supported prevention and control strategies.