Methylation study of tumor suppressor genes in human aberrant crypt foci, colorectal carcinomas, and normal colon.

BACKGROUND: Aberrant crypt foci (ACF) are the earliest preneoplastic lesions in human colon, identifiable on chromoendoscopic screening. Our objective was to evaluate the %methylation of APC, CDKN2A, MLH1, RASSF1, MGMT, and WIF1 tumor suppressor genes (TSG) in ACF, corresponding colorectal carcinomas (CRC), and normal colonic mucosal controls. METHODS: In this study, macroscopically normal-appearing mucosal flaps were sampled 5-10 cm away from the tumor mass from 302 fresh colectomy specimens to identify ACF-like lesions. Thirty-five cases with multiple ACFs were selected (n 35) as the main study group, with corresponding sections from CRC (n 35) as disease controls, and mucosal tissue blocks from 20 colectomy specimens (normal controls), operated for non-neoplastic pathologies. Genomic DNA was extracted, and methylation-specific polymerase chain reaction (PCR) was performed on a customized methylation array model. %Methylation data were compared among the groups and with clinicopathological parameters. Selected target mRNA and protein expression studies were performed. RESULTS: %Methylation of TSGs in ACF was intermediate between normal colon and CRC, although a statistically significant difference was observed only for the WIF1 gene (P < 0.01). Also, there was increased nuclear ß-catenin expression and upregulation of CD44-positive cancer-stem cells in ACF and CRCs than in controls. Right-sided ACFs and dysplastic ACFs had a higher %methylation of CDKN2A (P < 0.01), whereas hyperplastic ACFs had a higher %methylation of RASSF1 (P 0.04). The topographic characteristics of ACFs did not correlate with TSG %methylation. CONCLUSIONS: Early epigenetic methylation of WIF1 gene is one of the mechanisms for ACF development in human colon.

Correlation between intestinal stem cell niche changes and small bowel crypt failure in patients with treatment-naïve celiac disease.

OBJECTIVES: We hypothesized that crypt failure in the small bowel results in villous flattening in patients with celiac disease (CeD). We investigated whether alterations in the stem cell niche (ISC) are responsible for this phenomenon. MATERIALS AND METHODS: We included 92 duodenal (D2/3) biopsies from treatment-naive patients of CeD and 37 controls. All underwent screening for serum anti-tissue transglutaminase and endoscopic upper small bowel biopsy. Immunohistochemical markers were used to investigate ISC niche alterations, including LGR5 for crypt basal cells (CBC), Bmi1 for position 4+ cells, ß-Defensin for Paneth cells, R-spondin1 as WNT activator, transcription factor-4 as WNT transcription factor, BMP receptor1A as WNT inhibitor, fibronectin-1 as periepithelial stromal cell marker, H2AX as apoptosis marker, and Ki67 as proliferation marker. We also analyzed IgA anti-tTG2 antibody deposits by using dual-color immunofluorescence staining. RESULTS: We found that in biopsies from patients with treatment-naive CeD with modified Marsh grade 3a-3c changes, the epithelial H2AX apoptotic index was upregulated than in controls. LGR5+ crypt basal cells were upregulated in all modified Marsh grades compared to controls. However, the Ki67 proliferation index, expressions of WNT-activator RSPO1, and position-4 cell marker Bmi1 did not significantly alter in patients' biopsies as compared to controls ( P = 0.001). We also observed depletion of pericrypt stromal fibronectin-1 in patients with CeD compared to controls. In addition, we identified IgA anti-TG2 antibody deposits in pericrypt stroma. CONCLUSIONS: Our data suggests that ISC niche failure is a plausible hypothesis for villous flattening in patients with CeD, resulting from pericrypt IgA anti-TG2 antibody complex-mediated stromal depletion.

Novel Scoring Systems and Age-Based Hepatic Shear Wave Stiffness Cut-Offs for Improving Sonographic Diagnosis of Biliary Atresia.

OBJECTIVES: To make sonographic evaluation for biliary atresia (BA) more objective and reproducible using scoring systems, and evaluate hepatic shear wave elastography (SWE) as an adjunct in sonographic diagnosis of BA. METHODS: Sixty-four infants with cholestatic jaundice were enrolled between June 2016 and March 2018 in this prospective observational cohort study. Sonography and SWE was performed with SuperSonic Aixplorer system. Novel scoring systems were developed incorporating established sonographic parameters and hepatic stiffness values and analysed using SPSS software. RESULTS: Of the 18 patients confirmed as BA, 3 were misdiagnosed on conventional sonography (16.7%) as non-BA. Gall bladder (GB) wall irregularity and fasting GB length were the most accurate (93.8%) and most specific (97.8%) individual parameters, respectively. A significant difference was noted in the triangular cord (TC) thickness of BA and non-BA infants (p <0.001), with a high specificity of 95.6% for a 4 mm cut-off value for a positive TC sign. Comparison of hepatic SWE stiffness among age-matched groups of BA and non-BA showed significant differences (≤60 d: p = 0.003; >60 d: p <0.001) but with a reduced accuracy (93.8%). Diagnostic accuracy of greyscale scoring system (96.9%), greyscale + elastography scoring system in ≤60 d (94.4%) and >60 d (97.8%) were better than that of conventional sonographic diagnosis (93.8%). CONCLUSIONS: Grey scale scoring system improves the accuracy of sonographic diagnosis of BA without any additional cost or time penalty along with making it universally reproducible. SWE has only an adjunctive role, if any, in the sonographic diagnosis of BA.

Pancreatic Mass Characterization Using IVIM-DKI MRI and Machine Learning-Based Multi-Parametric Texture Analysis.

Non-invasive characterization of pancreatic masses aids in the management of pancreatic lesions. Intravoxel incoherent motion-diffusion kurtosis imaging (IVIM-DKI) and machine learning-based texture analysis was used to differentiate pancreatic masses such as pancreatic ductal adenocarcinoma (PDAC), pancreatic neuroendocrine tumor (pNET), solid pseudopapillary epithelial neoplasm (SPEN), and mass-forming chronic pancreatitis (MFCP). A total of forty-eight biopsy-proven patients with pancreatic masses were recruited and classified into pNET (n = 13), MFCP (n = 6), SPEN (n = 4), and PDAC (n = 25) groups. All patients were scanned for IVIM-DKI sequences acquired with 14 b-values (0 to 2500 s/mm2) on a 1.5T MRI. An IVIM-DKI model with a 3D total variation (TV) penalty function was implemented to estimate the precise IVIM-DKI parametric maps. Texture analysis (TA) of the apparent diffusion coefficient (ADC) and IVIM-DKI parametric map was performed and reduced using the chi-square test. These features were fed to an artificial neural network (ANN) for characterization of pancreatic mass subtypes and validated by 5-fold cross-validation. Receiver operator characteristics (ROC) analyses were used to compute the area under curve (AUC). Perfusion fraction (f) was significantly higher (p < 0.05) in pNET than PDAC. The f showed better diagnostic performance for PDAC vs. MFCP with AUC:0.77. Both pseudo-diffusion coefficient (D*) and f for PDAC vs. pNET showed an AUC of 0.73. ADC and diffusion coefficient (D) showed good diagnostic performance for pNET vs. MFCP with AUC: 0.79 and 0.76, respectively. In the TA of PDAC vs. non-PDAC, f and combined IVIM-DKI parameters showed high accuracy ≥ 84.3% and AUC ≥ 0.84. Mean f and combined IVIM-DKI parameters estimated that the IVIM-DKI model with TV texture features has the potential to be helpful in characterizing pancreatic masses.

Role of Whole body PET/CT and Examination under anesthesia with multi-site biopsy in evaluating CUP.

To evaluate the role of 18FDG-WBPET-CT, Examination under anesthesia (EUA), and multiple-site biopsy in detecting the occult site in head & neck carcinoma of unknown primary (HN-CUP). In this prospective study, 22 patients with diagnosed CUP, after a thorough outpatient endoscopic evaluation of upper airway and radiological evaluation (CT/MRI) that ruled out a primary lesion were included. These patients subsequently underwent whole-body PET-CT and EUA. Based on the presence of suspicious findings ( +) or their absence (-) on 18FDG-WBPET-CT (P) and EUA (E), we divided the patients into 5 groups: P-E-, P-E + , P + E-, P + E + , and P + or E + . All these patients underwent bilateral palatine tonsillectomy, bilateral nasopharyngeal biopsy, and ipsilateral lingual tonsillectomy for identification of occult primary. Out of 22 patients, the primary could be detected in 4 patients (18%) after the workup (three in the oropharynx and one in the hypopharynx, all ipsilateral). 18FDG-PET-CT suspected primaries in 7 patients; biopsy was positive for three (sensitivity-75%, specificity-77%, PPV-43%, NPV-93%). Out of 5 patients, who had suspicious findings on EUA, 3 of the biopsies revealed malignancy (sensitivity-75%, specificity-88%, PPV-60%, NPV-94%). Both PET-CT and EUA when combined, yield a NPV of 100% if both are negative and PPV of 100% when both are positive for suspicious findings. No primary was identified in the absence of a suspicion by PET-CT or EUA. Without a suspicion on 18FDG-WBPET-CT and EUA, there is a limited role of multiple-site biopsies in patients of HN-CUP.

Serum Survivin in Oral Submucosal Fibrosis and Squamous Cell Carcinoma.

Survivin, an inhibitor of apoptosis protein is a biomarker of significance in prognostication of many malignancies. In the current study we investigated the serum survivin levels in patients with oral submucosal fibrosis (OSMF) and squamous cell carcinoma (OSCC). Serum was isolated from, peripheral blood collected of clinically and histopathologically confirmed OSMF and OSCC patients. Circulating level of survivin was measured in patients and control subjects by ELISA and analyzed further using Kruskal-Wallis test and two-sample Wilcoxon rank-sum (Mann-Whitney) test. Serum Survivin levels were significantly reduced in the OSCC group as compared to the control group. No significant correlation was noted between the serum survivin level and various clinicopathological characteristics of OSCC and OSMF patients. Our study suggests that free, wild form of circulating survivin probably has no role in predicting the prognosis of oral cancer or the malignant transformation potential of oral submucosal fibrosis.

Impact of Cytomegalovirus Infection on Short-Term Clinical Outcomes and Operative Histopathology in Infants with Biliary Atresia: A Single-Center Prospective Cohort Study.

Background: There is limited information on the impact of cytomegalovirus (CMV) infection on clinical outcomes and operative histopathology in children with biliary atresia (BA). We hypothesized that CMV infection is associated with greater histopathological damage and unfavorable short-term clinical outcomes. Materials and Methods: A prospective single-center study was conducted with effect from January 2011-July 2012 including all infants with BA who underwent surgery. Diagnosis of CMV infection was confirmed by serum immunoglobulin M (IgM) positivity or the presence of CMV-deoxyribonucleic acid (DNA) in the liver tissue. Four short-term outcome variables were observed. The cohort was divided into subgroups on the basis of seropositivity (IgM + or IgM-); the presence of CMV-DNA in the liver (polymerase chain reaction [PCR]+ or PCR-); and composite CMV groups (Group 1 - IgM+, PCR+; Group 2 - IgM+, PCR-; Group 3 -- IgM-, PCR+; and Group 4 - IgM-, PCR-). Outcomes and histopathology were compared in these subgroups. Results: A total of 32 infants with BA were operated at a mean age of 3.5 (range: 1-6) months. Serum IgM+ and PCR+ were observed in 50% and 37.5% of the patients. Unfavorable outcomes showed a significant association with IgM+ and not PCR+. Similarly, outcomes were poor for CMV Groups 1 and 2 at 1-month follow-up. Infants with IgM+ and PCR+ showed a greater degree of histopathological damage in terms of bile duct proliferation and severe bile duct fibrosis, respectively. Conclusion: In the present study, there was a high incidence of serum IgM+ (50%) and PCR+ of biopsy specimens (37.5%) in infants with BA. This CMV-infected subgroup was associated with greater histopathological damage and unfavorable short-term outcomes after surgery.

Correlation of Helicobacter pylori virulence genotype & severity of mucosal inflammation in gastric biopsies from two geographically diverse regions in India.

Background: H. pylori-associated gastritis in patients from the high-altitude area of Ladakh showed severe gastritis, mucosal nodularity, atrophy, and cancer in comparison to those from North India. This study served to analyze if differences in the H. pylori virulence genotypes decide the extent of gastric mucosal inflammation. Methods: Fifty gastric biopsies each from patients with H. pylori-associated gastritis from Ladakh and a tertiary care center in North India were included. The presence of H. pylori strain was confirmed with Warthin starry stain and polymerase chain amplification of the H. pylori-specific 16S rRNA. The cagA, vacA s1, s2, and m1, m2 alleles, and dupA virulence genotypes were studied in all archival samples, followed by their histological correlations. Results: cagA (P 0.009) and vacAs1 m1 (P 0.009) genes were distinctly more in H. pylori strains colonizing the biopsies of North Indian patients. In contrast, the cagA -ve vacAs2 m2 strains were significantly more in H. pylori strain colonizing the biopsies from Ladakhi patients. dupA genotype was almost similarly present in strains from both regions. Among these, only cagA and dupA virulence genes were associated with severe mucosal neutrophilic activity and deep infiltration of H. pylori strains in North Indian patients. Conclusions: Differences in virulence genotypes of H. pylori in gastric biopsies from North Indian and Ladakhi patients were found not significant in deciding the severity of H. pylori-associated gastritis.

Erratum to 'Indian National Association for the Study of Liver Consensus Statement on Acute Liver Failure (Part-2): Management of Acute Liver Failure' [J Clin Exp Hepatol 10 (2020) 477-517].

[This corrects the article DOI: 10.1016/j.jceh.2020.04.011.].

Histologic Changes in Core-Needle Liver Biopsies From Patients With Acute-on-Chronic Liver Failure and Independent Histologic Predictors of 28-Day Mortality.

CONTEXT.­: The histologic features in patients with acute-on-chronic liver failure (ACLF) are evolving, and histologic indicators of patients' poor prognosis are not yet fully established. OBJECTIVE.­: To evaluate the independent histologic predictors of 28-day mortality in ACLF patients on core-needle liver biopsies. DESIGN.­: Core-needle biopsies from patients with a diagnosis of ACLF (n = 152) as per the European Association for the Study of the Liver criteria were included during 8 years. Liver biopsies from 98 patients with compensated chronic liver disease were included as disease controls for histologic comparison. Features of ongoing changes, such as hepatic necrosis, hepatic apoptosis, cholestasis, hepatocyte degeneration, bile ductular proliferation, Mallory-Denk bodies, steatosis, and extent of liver fibrosis, were analyzed for predicting short-term mortality (28 days). A P value of <.05 was considered significant. RESULTS.­: In our cohort of ACLF patients, the following etiologies for acute decompensation were identified: alcohol, 47 of 152 (30.9%); sepsis, 24 of 152 (15.7%); hepatotropic viruses, 20 of 152 (13.1%); drug-induced liver injury, 11 of 152 (7.2%); autoimmune flare, 9 of 152 (5.9%); mixed etiologies, 5 of 152 (3.2%); and cryptogenic, 36 of 152 (23.6%). On histologic examination, hepatic necrosis (P < .001), dense lobular inflammation (P = .03), cholestasis (P < .001), ductular reaction (P = .001), hepatocyte degeneration (P < .001), and absence of advanced fibrosis stages (P < .001) were identified significantly more othen in ACLF patients than in disease controls on univariate analysis. On multivariate Cox regression analysis, the absence of advanced Ishak histologic activity index fibrosis stages (P = .02) and the presence of dense lobular inflammation (P = .04) were associated with increased 28-day mortality in ACLF patients. After adjusting the clinical causes of acute decompensation, only dense lobular inflammation was found as an independent predictor of short-term mortality (P = .04) in ACLF patients. CONCLUSIONS.­: Dense lobular necroinflammatory activity is a clinically independent histologic predictor of 28-day short-term mortality in patients with ACLF.

Inhibition of the neuromuscular acetylcholine receptor with atracurium activates FOXO/DAF-16-induced longevity.

Transcriptome-based drug screening is emerging as a powerful tool to identify geroprotective compounds to intervene in age-related disease. We hypothesized that, by mimicking the transcriptional signature of the highly conserved longevity intervention of FOXO3 (daf-16 in worms) overexpression, we could identify and repurpose compounds with similar downstream effects to increase longevity. Our in silico screen, utilizing the LINCS transcriptome database of genetic and compound interventions, identified several FDA-approved compounds that activate FOXO downstream targets in mammalian cells. These included the neuromuscular blocker atracurium, which also robustly extends both lifespan and healthspan in Caenorhabditis elegans. This longevity is dependent on both daf-16 signaling and inhibition of the neuromuscular acetylcholine receptor subunit unc-38. We found unc-38 RNAi to improve healthspan, lifespan, and stimulate DAF-16 nuclear localization, similar to atracurium treatment. Finally, using RNA-seq transcriptomics, we identify atracurium activation of DAF-16 downstream effectors. Together, these data demonstrate the capacity to mimic genetic lifespan interventions with drugs, and in doing so, reveal that the neuromuscular acetylcholine receptor regulates the highly conserved FOXO/DAF-16 longevity pathway.

Liver involvement in patients with coeliac disease: proof of causality using IgA/anti-TG2 colocalisation techniques.

AIMS: Despite clinical evidence of liver involvement in patients with coeliac disease (CeD), there is a lack of a method to prove this association. METHODS: Of 146 treatment-naive patients with CeD, 26 had liver dysfunction. Liver biopsies and corresponding small intestinal biopsies were obtained from these 26 patients. Multicolour immunohistochemical and immunofluorescence confocal microscopic studies were performed on paraffin-embedded tissue to detect the IgA/anti-TG2 deposits. Follow-up liver biopsies were taken after a gluten-free diet. RESULTS: Twenty-six out of the 146 patients (17.8%) with suspected coeliac-associated liver disease on histological examination revealed irregular sinusoidal dilatation in 15 (57.6%), steatohepatitis in 4 (15.3%), non-specific chronic hepatitis in 3 (11.5%), autoimmune hepatitis in 2 (7.6%) biopsies, including cirrhosis in one of them, irregular perisinusoidal fibrosis and changes of non-cirrhotic portal fibrosis in one biopsy each (3.8%). IgA/anti-tTG deposits were observed in 22 (84.6%) liver biopsies by dual immunohistochemistry technique, and in 24 (92.3%) by confocal immunofluorescence technique and in all corresponding duodenal biopsies (100%). Overall, IgA/anti-tTG deposits showed 100% sensitivity, 77% specificity and 85% positive predictive value for establishing an association of extraintestinal pathology and CeD using archived tissues. Follow-up liver biopsies could be obtained in five patients; four of them showed not only resolution of the histological lesions but disappearance of IgA/anti-tTG co-localisation. CONCLUSIONS: Data of the present study adds to the body of evidence that liver lesions in patients with CeD are disease related and may have been caused by a similar pathogenic mechanism that causes intestinal changes.

Long-term outcomes of anti-tumor necrosis factor therapy and surgery in nonperianal fistulizing Crohn's disease.

BACKGROUND: Unlike perianal fistula, long-term outcomes of nonperianal fistulae (NPF) in Crohn's disease (CD) are not clear. We aimed to compare the outcomes of medical and surgical therapies in patients with NPF. METHODS: We retrospectively analyzed the records of patients of CD with NPF who were prospectively followed from January 2005 to December 2018. RESULTS: Of the 53 patients with NPF [mean age at presentation:29 ± 14 years; 54.7% male; median duration of follow-up: 47 months (interquartile range [IQR]:26-76 months)], enteroenteric fistula (37.8%) was the most common presentation. Of 22 patients treated with anti-tumor necrosis factor (TNF) therapy, complete response was achieved in 40.9% (n = 9). Overall probability of maintaining response was similar between the anti-TNF and surgical groups (95.2% vs 82.4%; 71% vs 76%; and 63% vs 69%% [P = 0.8] at 1, 2, and 3 years, respectively), with only 13.6% of patients treated with biologicals requiring surgery over 56 months. Twenty-one patients required upfront surgery (small bowel or ileocolonic resection with/without diversion; 28.5% emergent), with 47.6% postoperative recurrence over 36 months, of which nine patients required biologicals (77.7% response to anti-TNF therapy). Long-term outcome was comparable between medically and surgically treated patients; 6.4% developed tuberculosis on anti-TNF therapy. Two patients (3.7%) developed malignancy (one - enteroenteric, one - colovesical). CONCLUSION: Anti-TNF therapy appears to be as effective as surgery in this retrospective analysis of patients with NPFCD, and it may be indicated in the absence of abscess and other complications. These patients are at higher risk of fistula-associated malignancy, which requires a lower threshold for suspicion, especially over the long term in the presence of nonresponse to medical therapy.

Dual blockade of EGFR and CDK4/6 delays head and neck squamous cell carcinoma progression by inducing metabolic rewiring.

Despite preclinical success, monotherapies targeting EGFR or cyclin D1-CDK4/6 in Head and Neck squamous cell carcinoma (HNSCC) have shown a limited clinical outcome. Here, we aimed to determine the combined effect of palbociclib (CDK4/6) and afatinib (panEGFR) inhibitors as an effective strategy to target HNSCC. Using TCGA-HNSCC co-expression analysis, we found that patients with high EGFR and cyclin D1 expression showed enrichment of gene clusters associated with cell-growth, glycolysis, and epithelial to mesenchymal transition processes. Phosphorylated S6 (p-S6), a downstream effector of EGFR and cyclin D1-CDK4/6 signalling, showed a progressive increase from normal oral tissues to leukoplakia and frank malignancy, and associated with poor outcome of the patients. This increased p-S6 expression was drastically reduced after combination treatment with afatinib and palbociclib in the cell lines and mouse models, suggesting its utiliy as a prognostic marker in HNSCC. Combination treatment also reduced the cell growth and induced cell senescence via increasing reactive oxygen species with concurrent ablation of glycolytic and tricarboxylic acid cycle intermediates. Finally, our findings in sub-cutaneous and genetically engineered mouse model (K14-CreERtam;LSL-KrasG12D/+;Trp53R172H/+) studies showed a significant reduction in the tumor growth and delayed tumor progression after combination treatment. This study collectively demonstrates that dual targeting may be a critical therapeutic strategy in blocking tumor progression via inducing metabolic alteration and warrants clinical evaluation.

Surgical and Neurological Outcome of Minimally Invasive Thymectomy in Patients With Myasthenia Gravis: An Experience of 100 Cases Over 6 Years at a Tertiary Care Center in North India.

BACKGROUND: Minimally invasive thymectomy (MIT) is emerging as an effective alternative to open thymectomy in the management of patients with myasthenia gravis (MG). The primary objective of our study is to assess the surgical and neurological outcome of MIT in patients with MG. MATERIALS AND METHODS: It is a retrospective evaluation of prospectively collected data of 100 patients with MG, who underwent MIT from April 2012 to January 2018 at a tertiary care center in India. Surgical outcome was assessed for success of minimal invasive approach, conversion, perioperative morbidity, and postoperative hospital course. Neurological outcome was assessed, after at least 1 year of follow-up, according to Myasthenia Gravis Foundation of America postintervention status. Factors predicting complete stable remission (CSR) were evaluated. RESULTS: MIT was successfully performed in 98% patients with 2% conversion. There was no mortality. Overall, 10% of patients had perioperative morbidity with 5% having exacerbation of neurological symptoms. Two of these needed postoperative ventilation, whereas 3 recovered on conservative treatment. Median operative time and hospital stay were 140 minutes and 3 days, respectively. At a median follow-up of 47 months, CSR was seen in 20% with improvement in 73.3%. Overall, 63% patients were taken off steroids and patients requiring 3 drugs decreased by 70.7%. There was significant reduction in the dosage of pyridostigmine (P<0.001), prednisolone (P<0.001), and azathioprine (P=0.002) after thymectomy. Milder disease (Myasthenia Gravis Foundation of America class 1 and 2) predicted CSR on multivariate analysis. CONCLUSIONS: MIT is a safe and effective procedure that leads to improvement in neurological status with significant reduction in number and dosage of medications after thymectomy. Mild disease predicts CSR.

Indian National Association for the Study of Liver Consensus Statement on Acute Liver Failure (Part-2): Management of Acute Liver Failure.

Acute liver failure (ALF) is not an uncommon complication of a common disease such as acute hepatitis. Viral hepatitis followed by antituberculosis drug-induced hepatotoxicity are the commonest causes of ALF in India. Clinically, such patients present with appearance of jaundice, encephalopathy, and coagulopathy. Hepatic encephalopathy (HE) and cerebral edema are central and most important clinical event in the course of ALF, followed by superadded infections, and determine the outcome in these patients. The pathogenesis of encephalopathy and cerebral edema in ALF is unique and multifactorial. Ammonia plays a crucial role in the pathogenesis, and several therapies aim to correct this abnormality. The role of newer ammonia-lowering agents is still evolving. These patients are best managed at a tertiary care hospital with facility for liver transplantation (LT). Aggressive intensive medical management has been documented to salvage a substantial proportion of patients. In those with poor prognostic factors, LT is the only effective therapy that has been shown to improve survival. However, recognizing suitable patients with poor prognosis has remained a challenge. Close monitoring, early identification and treatment of complications, and couseling for transplant form the first-line approach to manage such patients. Recent research shows that use of dynamic prognostic models is better for selecting patients undergoing liver transplantation and timely transplant can save life of patients with ALF with poor prognostic factors.

Indian National Association for the Study of the Liver Consensus Statement on Acute Liver Failure (Part 1): Epidemiology, Pathogenesis, Presentation and Prognosis.

Acute liver failure (ALF) is an infrequent, unpredictable, potentially fatal complication of acute liver injury (ALI) consequent to varied etiologies. Etiologies of ALF as reported in the literature have regional differences, which affects the clinical presentation and natural course. In this part of the consensus article designed to reflect the clinical practices in India, disease burden, epidemiology, clinical presentation, monitoring, and prognostication have been discussed. In India, viral hepatitis is the most frequent cause of ALF, with drug-induced hepatitis due to antituberculosis drugs being the second most frequent cause. The clinical presentation of ALF is characterized by jaundice, coagulopathy, and encephalopathy. It is important to differentiate ALF from other causes of liver failure, including acute on chronic liver failure, subacute liver failure, as well as certain tropical infections which can mimic this presentation. The disease often has a fulminant clinical course with high short-term mortality. Death is usually attributable to cerebral complications, infections, and resultant multiorgan failure. Timely liver transplantation (LT) can change the outcome, and hence, it is vital to provide intensive care to patients until LT can be arranged. It is equally important to assess prognosis to select patients who are suitable for LT. Several prognostic scores have been proposed, and their comparisons show that indigenously developed dynamic scores have an edge over scores described from the Western world. Management of ALF will be described in part 2 of this document.

NOVEL USE OF FLUORESCEIN DYE IN DETECTION OF ORAL DYSPLASIA AND ORAL CANCER.

BACKGROUND: India is now regarded as the country with one of the highest incidence of oral cancer in the world. Considering poor survival in cases with late diagnosis, early detection can reduce morbidity and mortality of cancer patients and may impede malignant transformation in cases of oral potentially malignant disorders (OPMD). Most of the diagnostic aids are expensive and not available for mass screenings in developing countries. There is a need to develop a sensitive and affordable technique for screening of oral cancer, which can be accurate even in hands of health care workers with limited experience. Fluorescein dye has been used for tumour detection in colon, stomach, breast and brain. However, its utility in the diagnosis of oral cancer and OPMD has not yet been explored. METHODS: This is the first study to report the role of fluorescein in the detection of oral cancer and OPMD. The present cross sectional study was conducted at a tertiary care dental centre. It included 100 individuals presenting with 42 OPMDs, 40 oral squamous cell carcinoma (OSCC) and 18 controls. RESULTS: The sensitivity and specificity for the fluorescein detection method for OPMDs and OSCC was found to be 96.6% and 52.4% respectively. The positive predictive value was 73.7% and the negative predictive value was 91.7% for the fluorescein method. The likelihood ratios stood at 2.03 for a positive test and 0.066 for a negative test. CONCLUSION: We conclude that fluorescein staining along with blue light is likely to improve detection of early oral cancers and dysplasia and can play a vital role in mass screening programmes of oral cancer.

2019 Update of Indian National Association for Study of the Liver Consensus on Prevention, Diagnosis, and Management of Hepatocellular Carcinoma in India: The Puri II Recommendations.

Hepatocellular carcinoma (HCC) is one of the major causes of morbidity, mortality, and healthcare expenditure in patients with chronic liver disease in India. The Indian National Association for Study of the Liver (INASL) had published its first guidelines on diagnosis and management of HCC (The Puri Recommendations) in 2014, and these guidelines were very well received by the healthcare community involved in diagnosis and management of HCC in India and neighboring countries. However, since 2014, many new developments have taken place in the field of HCC diagnosis and management, hence INASL endeavored to update its 2014 consensus guidelines. A new Task Force on HCC was constituted that reviewed the previous guidelines as well as the recent developments in various aspects of HCC that needed to be incorporated in the new guidelines. A 2-day round table discussion was held on 5th and 6th May 2018 at Puri, Odisha, to discuss, debate, and finalize the revised consensus statements. Each statement of the guideline was graded according to the Grading of Recommendations Assessment Development and Evaluation system with minor modifications. We present here the 2019 Update of INASL Consensus on Prevention, Diagnosis, and Management of Hepatocellular Carcinoma in India: The Puri-2 Recommendations.

Clear cell sarcoma like tumor of gastrointestinal tract: Experience of three cases and review of literature.

Clear cell sarcoma-like tumor of the gastrointestinal tract (CCSGT) is a rare, aggressive tumor with many histological mimickers. Herein, we have documented our experience of three cases of CCSGT and reviewed the literature. The index cases were identified in male patients in their twenties, one in jejunum and two in the distal colon. Histomorphological examination revealed the characteristic heterogeneous histomorphology with patchy immunohistochemical positivity with S100 protein and negative melanocytic markers. The fluorescence in-situ hybridization test showed translocation of the EWSR1 (22q12) gene in >80% tumor cells. While one of our patients died after 2 years with lung metastasis, the other two patients are still alive on 1.5 years and 3 months follow up, respectively. CCSGT is a rare malignant tumor of the gastrointestinal tract. Although characteristic morphology, use of a judicial panel of immunohistochemical stains, and translocation study for EWSR1 gene can establish the diagnosis, experience in adjuvant therapy is still limited.