Hepatic and perihepatic PEComas: A study describing a series of five rare cases.

BACKGROUND: Perivascular epithelioid cell tumors (PEComas) encompass a group of rare mesenchymal neoplasms, with dual melanocytic and muscular differentiation. Hepatic PEComas are rare and difficult to diagnose, and their behavior is still unclear. MATERIALS AND METHODS: Herein, we report a total of five cases of hepatic and perihepatic PEComas over a period of the last 5 years from our and collaborating center's archive. A detailed histological evaluation was done. A comprehensive panel of immunohistochemical stains was used and fluorescence in-situ hybridization analysis was performed for the TFE3 gene using break-apart probes. RESULT: All these patients were women, with an average age of presentation of 44 years. The lesions were in the right hepatic lobe: three cases, the left hepatic lobe: one case, and gastrohepatic ligament: one case. The preoperative clinicoradiological diagnoses were hepatocellular carcinoma (HCC), focal nodular hyperplasia, hemangioma, metastasis, and gastrointestinal stromal tumor, respectively. Surgical excision was performed in four cases with no further adjuvant therapy. Histopathological examination and subsequent immunophenotyping revealed a diagnosis of PEComa. Fluorescence in-situ hybridization analysis was performed for TFE3 gene rearrangement in four cases. CONCLUSIONS: This series highlights the fact that accurate histological diagnosis of hepatic or perihepatic PEComas is important to prevent unnecessary aggressive treatment, unlike primary hepatocellular carcinomas or hepatoid/epithelioid metastatic tumors.

Cyanobacteria Based Nanoformulation of Biogenic CuO Nanoparticles for Plant Growth Promotion of Rice Under Hydroponics Conditions.

Synthesizing nanoparticles through a green synthesis approach is common nowadays. Cyanobacteria have attained great importance in the field of biosynthesis of nanoparticles as there is no use of toxic chemicals as reducing or capping agents for the synthesis of metal oxide nanoparticles. Micronutrient-based nano-formulations have become a topic of great interest in recent times due to their various advantageous properties and applications in agriculture. The current study aims to exploit the potential cyanobacterial strains isolated from different locations such as freshwater and soil ecosystems. The potential cyanobacterial isolates were screened based on their multiple plant growth promoting (PGP) attributes such as Indol acetic acid (IAA) production, siderophores, and phosphate solubilization. After the screening of cyanobacteria based on multiple PGP activities, the cyanobacterial strain was identified at the species level as Pseudanabaena foetida RJ1, based on microscopy and molecular characterization using 16S rRNA gene sequencing. The cyanobacterial biomass extract and cell-free extracts are utilized for the synthesis of CuO micronutrient Nanoparticles (NPs). The cyanobacterial strain Pseudanabaena foetida RJ1 possesses plant growth-promoting (PGP) attributes that provide reduction and capping for CuO NPs. The synthesized NPs were characterized and subjected to make a nano-formulation, utilizing the cyanobacteria-mediated CuO NPs along with low-cost zeolite as an adsorbent. The application of cyanobacterial biomass extract and cell-free extract provided an excellent comparative aspect in terms of micronutrient NP synthesis. The NPs in the form of formulations were applied to germinated paddy seeds (Pusa Basmati -1509) with varying concentrations (5, 10, 15 mg/l). Effects of cyanobacteria based CuO NPs on hydroponically grown paddy crops were analyzed. The application of nano-formulations has shown a significant increase in plant growth promotion in rice plants under hydroponics conditions. There is no such type of comparative investigation reported earlier, and NPs of micronutrients can be utilized as a new economic nanofertilizer and can be applied to plants for their growth promotion.

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.

Collinsella aerofaciens linked with increased ethanol production and liver inflammation contribute to the pathophysiology of NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is an emerging global health problem and a potential risk factor for metabolic diseases. The bidirectional interactions between liver and gut made dysbiotic gut microbiome one of the key risk factors for NAFLD. In this study, we reported an increased abundance of Collinsella aerofaciens in the gut of obese and NASH patients living in India. We isolated C. aerofaciens from the fecal samples of biopsy-proven NASH patients and observed that their genome is enriched with carbohydrate metabolism, fatty acid biosynthesis, and pro-inflammatory functions and have the potency to increase ethanol level in blood. An animal study indicated that mice supplemented with C. aerofaciens had increased levels of circulatory ethanol, high levels of hepatic hydroxyproline, triglyceride, and inflammation in the liver. The present findings indicate that perturbation in the gut microbiome composition is a key risk factor for NAFLD.

Diagnosis of peritoneal metastasis in an unruptured hepatocellular carcinoma on ascitic fluid cytology: A rare scenario with brief review of literature.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy in adults occurring in a background of cirrhosis. Peritoneal dissemination of HCC is an unusual presentation with an incidence of 2%-16%. Peritoneal metastasis of an unruptured HCC is extremely uncommon. Despite low yield, ascitic fluid cytology serves as a valuable tool for diagnostic evaluation in a patient of cirrhosis with suspicion of malignant transformation. We present a rare case scenario in an elderly female with cirrhosis where the diagnosis of peritoneal metastasis was established on ascitic fluid cytology and confirmed by immunocytochemistry. This report illustrates the unique clinical presentation of an unruptured HCC with its cytological features and a brief review of literature.

Poor Performance of Non-invasive Tests for Advanced Fibrosis in Nonalcoholic Fatty Liver Disease: A Multicentric Asian Study.

BACKGROUND: Non-invasive tests (NITs) are useful to assess advanced fibrosis (AF) in nonalcoholic fatty liver disease (NAFLD). Data from Asian countries suggest that these tests have poor performance. We aimed to assess diagnostic accuracy of established thresholds of biomarker-based NITs and Transient Elastography (TE) in identifying AF and evaluated the utility of a two-step test approach. METHODS: Biopsy-proven 641 NAFLD patients (55.2% males, median age 42 years) were included from three different centers of Asia. AF (≥ F3) was identified as per histological staging (24.8%). RESULTS: TE had the highest area under the receiver operating characteristic curve (AUROC) 0.82 (0.79-0.86), and all other biomarker-based NITs had low AUROC (< 0.7). NITs performed poorly at established thresholds. The combination of NITs utilizing liver stiffness measurement (LSM) and biomarkers, Agile 3+ and FAST, demonstrated acceptable diagnostic accuracy (AUROC 0.82 and 0.78, respectively), but none were superior to LSM alone. LSM measured using appropriate M and XL probes remained accurate regardless of body mass index (BMI); NFS and APRI scores were less accurate at higher BMI ranges. A two-step approach using NFS rule-out criteria (< - 2.97 to rule out) followed by LSM (< 7.3 kPa to rule out and ≥ 12.7 kPa to rule in) correctly classified 62.4% of patients, with only 10.2% of patients incorrectly classified. CONCLUSION: NITs have not been validated to identify AF in the Asian NAFLD population, and internationally accepted thresholds yield high false-negative rates. LSM and LSM-based combination tests remain the most accurate.

Involvement of DPP3 in modulating oncological features and oxidative stress response in esophageal squamous cell carcinoma.

Resistance to therapy in esophageal squamous cell carcinoma (ESCC) is a critical clinical problem and identification of novel therapeutic targets is highly warranted. Dipeptidyl peptidase III (DPP3) is a zinc-dependent aminopeptidase and functions in the terminal stages of the protein turnover. Several studies have reported overexpression and oncogenic functions of DPP3 in numerous malignancies. The present study aimed to determine the expression pattern and functional role of DPP3 in ESCC. DPP3 expression was assessed in normal and tumor tissues using quantitative real-time (qRT)-PCR and corroborated with ESCC gene expression datasets from Gene Expression Omnibus (GEO) and The cancer genome atlas (TCGA). DPP3 stable knockdown was performed in ESCC cells by shRNA and its effect on cell proliferation, migration, cell cycle, apoptosis, and activation of nuclear factor erythroid 2-related factor 2 (NRF2) pathway was assessed. The results suggested that DPP3 is overexpressed in ESCC and its knockdown leads to reduced proliferation, increased apoptosis, and inhibited migration of ESCC cells. Additionally, DPP3 knockdown leads to down-regulation of the NRF2 pathway proteins, such as NRF2, G6PD, and NQO1 along with increased sensitivity toward oxidative stress-induced cell death and chemotherapy. Conclusively, these results demonstrate critical role of DPP3 in ESCC and DPP3/NRF2 axis may serve as an attractive therapeutic target against chemoresistance in this malignancy.

Cytomorphology of paediatric hepatocellular carcinoma: A useful diagnostic adjunct.

INTRODUCTION: Hepatocellular carcinoma (HCC) is a common primary malignancy of the liver but is rare in the paediatric age group; thus, it may be misdiagnosed as the more common tumour, hepatoblastoma. Management varies in both these tumours, and pathological diagnosis thus plays an important role for definitive therapy. Only a few case reports available in the literature have described the cytological characteristics of paediatric HCC. The present study was thus planned to evaluate the cytomorphological features of paediatric HCC. METHODS: Cases diagnosed with HCC on ultrasound-guided fine needle aspiration cytology over a period of 14 years were retrieved. The cases were evaluated for detailed cytological features including cellularity, architecture, sinusoidal wrapping, trabecular thickness, necrosis, anisonucleosis, chromatin, nucleoli, nuclear contours, bi- or multinucleation, intranuclear and intracytoplasmic inclusions, naked nuclei, extra-medullary haematopoiesis, monomorphism, and nuclear overlapping. RESULTS: Twelve cases of HCC were included in the study. The median age at diagnosis was 10 years. Serum alpha-fetoprotein level was raised in most of them. Five of the 12 cases were characterised as moderately differentiated, three as poorly differentiated, two as well differentiated, and two as the fibrolamellar type of HCC. Cytohistological correlation was performed in seven cases. CONCLUSIONS: Ultrasound-guided fine needle aspiration serves as a useful tool to diagnose paediatric HCC and differentiate it from other primary hepatic malignancies, especially hepatoblastoma which closely mimics HCC in this age group, as serum alpha protein levels and imaging findings are unable to distinguish these two tumours.

Impact of body mass index on disease progression and outcomes in patients with nonalcoholic fatty liver disease.

BACKGROUND: The relationship between body mass index (BMI) and outcomes in patients with nonalcoholic fatty liver disease (NAFLD) is not well defined. This study aimed to assess the presentations, outcomes, and development of liver-related events (LREs) and non-LREs in patients with NAFLD stratified by BMI. METHODS: Records of NAFLD patients from 2000-2022 were reviewed. Patients were categorized as lean (18.5-22.9 kg/m2), overweight (23-24.9 kg/m2), and obese (>25 kg/m2) based on BMI. Stage of steatosis, fibrosis, and NAFLD activity score were noted in the patients undergoing liver biopsy in each group. RESULTS: Out of 1051 NAFLD patients, 127 (12.1%) had normal BMI, 177 (16.8%) and 747 (71.1%) were overweight and obese, respectively. Median [interquartile range] BMI was 21.9 [20.6-22.5], 24.2 [23.7-24.6], and 28.3 [26.6-30.6] kg/m2 in each group, respectively. Prevalence of metabolic syndrome and dyslipidemia were significantly higher in the obese. Obese patients had significantly higher median [interquartile range] liver stiffness (6.4 [4.9-9.4] kPa) than overweight and lean subjects. A higher proportion of obese patients had significant and advanced liver fibrosis. At follow-up, there were no significant differences in the progression of liver disease, new LREs, coronary artery disease, or hypertension across the BMI groups. Overweight and obese patients were more likely to develop new-onset diabetes by follow-up. The mortality rates in the three groups were comparable (0.47, 0.68, and 0.49 per 100 person-years, respectively), with similar causes of death (liver-related vs non-liver-related). CONCLUSIONS: Patients with lean NAFLD have similar disease severity and rates of progression as the obese. BMI is not a reliable determinant of outcomes in NAFLD patients.

Incidentally Detected Gastrointestinal Stromal Tumor in a Patient with Carcinoma Prostate: 68Ga-Prostate-Specific Membrane Antigen Versus 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography.

Uptake of 68Ga-prostate-specific membrane antigen (PSMA) in various nonprostatic tumors is well documented in the literature. We present a case of a gastrointestinal stromal tumor, incidentally detected on 68Ga-PSMA positron emission tomography/computed tomography imaging in a patient who underwent imaging for a suspected recurrence of carcinoma prostate.

Insights into the medical management of gastrointestinal stromal tumours: lessons learnt from a dedicated gastrointestinal stromal tumour clinic in North India.

Background: The advent of molecular driver alterations has brought in a revolutionary transformation in the treatment landscape of gastrointestinal stromal tumour (GIST). However, there is a paucity of data regarding mutational testing prevalence and associated outcomes from India. Methods: It was a retrospective study. We reviewed the case records of all patients diagnosed with GIST in a tertiary care centre from 2015 to 2021. The clinicopathological, mutational analysis and treatment plans were recorded. The study cohort was characterised by descriptive statistics. Results: Our study included 120 patients with a median age of 53 years (range: 28-77), with a male preponderance of 2:1. The most common site of the primary was the stomach (50%), followed by the small intestine (37%), with 55.8% of the patients having disseminated disease at presentation with a predominance of liver metastasis (67%). The prevalence of mutational analysis among patients prior to referral was 4%. 60.8% of the patients at our clinic had mutational analysis performed, and unavailability of analysis in the rest was due to financial constraints (12.5%), exhaustion of tissue (7.5%), reluctance to repeat biopsy (4.1%) and low-risk patients. We report c-kit in the majority (52%), platelet-derived growth factor receptor (PDGFR) in 19.2% and wild type in 16.4% along with the rarer subtypes: succinate dehydrogenase (SDH)-deficient GIST in 10.9% and Neurotrophic tyrosine receptor kinase (NTRK) fusion in 1.3%. Four of the eight SDH-deficient GIST patients had germline mutations (50%). The knowledge of driver mutations led to a change of treatment in 39.7% (29/73), i.e. stoppage of tyrosine kinase inhibitor (TKI) in 3, switch of TKI in 23, increase in TKI dose in 2 and upfront surgery in 1. The most common change was the use of sunitinib and regorafenib in patients with SDH-deficient GIST. Conclusion: Our study is one of the largest comprehensive series describing the clinical and mutational profile of GIST from India. The mutation testing rates at primary care centres continue to be low. Despite the hurdles, a large percentage of our patients underwent molecular testing, aiding in therapeutic decision-making.

Compensated Advanced Chronic Liver Disease in Nonalcoholic Fatty Liver Disease: Two-Step Strategy is Better than Baveno Criteria.

BACKGROUND: Advanced fibrosis and cirrhosis (compensated advanced chronic liver disease [cACLD]) are clinically indistinguishable and increase risk of developing clinically significant portal hypertension. Baveno VII recommends using elastography to rule out and diagnose cACLD with liver stiffness measurement (LSM) cut-offs of 10/15 kPa. METHODS: In a retrospective analysis of 330 nonalcoholic fatty liver disease (NAFLD) patients, performance of the Baveno VII cut-offs for diagnosing cACLD was compared with newly suggested lower cut-offs (8/12 kPa). A model for detecting cACLD among those with LSM between 8 and 12 kPa was developed and compared with recently published models. RESULTS: Seventy (21.2%) of the 330 NAFLD patients had biopsy-proven cACLD. The Baveno VII cut-offs (10/15 kPa) had a lower sensitivity of 72.8% (60.9-82.8%) and a specificity of 93.4% (89.7-96.1%). Sensitivity and specificity of lower cut-offs (8/12 kPa) were 91.4% (82.3-96.8%) and 88.5% (83.9-92.1%), respectively. Modeling based on the presence of diabetes (odds ratio [OR] 3.625[1.161-11.320], p = 0.027) and serum aspartate aminotransferase (AST) levels (OR 1.636[1.098-2.436], p = 0.015) correctly identified 75.7% of patients with LSM between 8 and 12 kPa. Our model performed best with an area under receiver operator curve (AUROC) of 0.725 (95%CI 0.609-0.822), compared to Papatheodoridi (AUROC 0.626, CI 0.506-.736) and Zhou (AUROC 0.523, CI 0.403-0.640) models. A two-step strategy comprising application of lower LSM cut-offs followed by the predictive model correctly identified the presence of cACLD in 83% of the patients as compared to 75% by the Baveno VII cut-offs. CONCLUSION: A two-step strategy employing lower LSM cut-offs and modeling based on diabetes and AST levels outperforms Baveno VII cut-offs for identifying cACLD in NAFLD patients.

Acute pancreatitis is characterized by generalized intestinal barrier dysfunction in early stage.

BACKGROUND AND AIMS: The role of intestinal-barrier in acute pancreatitis(AP) is poorly understood. We aimed to assess structural and functional changes in the intestinal-barrier in patients with early AP (time from onset<2 weeks) and the effect of enteral nutrition on them. METHODS: In this prospective observational study, patients with early AP not on enteral nutrition were compared with controls for baseline intestinal-permeability(lactulose: mannitol ratio(L:M)), endotoxinemia(serum IgM/IgG anti-endotoxin antibodies), bacterial-translocation(serum bacterial 16S rRNA) and duodenal epithelial tight-junction structure by immunohistochemistry(IHC) for tight-junction proteins(claudin-2,-3,-4, zonula occludens-1(ZO1), junctional adhesion molecule(JAM) and occludin) and electron microscopy. These parameters were reassessed after 2 weeks enteral feeding in a AP patients subset. RESULTS: 96 patients with AP(age: 38.0 ± 14.5 years; etiology: biliary[46.8%]/alcohol[39.6%]; severe:53.2%, mortality:11.4%) and 40 matched controls were recruited. Patients with AP had higher baseline intestinal permeability(median L:M 0.176(IQR 0.073-0.376) vs 0.049(0.024-0.075) in controls; p < 0.001) and more frequent bacteraemia(positive bacterial 16S rRNA in 24/48 AP vs 0/21 controls; p < 0.001) with trend towards higher serum endotoxinemia(median IgG anti-endotoxin 78(51.2-171.6) GMU/ml vs 51.2(26.16-79.2) in controls; p = 0.061). Claudin-2, claudin-3, ZO1 were downregulated in both duodenal crypts and villi while claudin-4 and JAM were downregulated in duodenal villi and crypts respectively. 22 AP patients reassessed after initiation of enteral nutrition showed trend towards improving intestinal permeability, serum endotoxinemia and bacteraemia, with significant improvement in claudin-2,-3 in duodenal villi. CONCLUSION: Patients with AP have significant disturbances in intestinal barrier structure and function in first 2 weeks from onset that persist despite institution of enteral nutrition.

Serum Matrix Metalloproteinase 7 as a Diagnostic and Prognostic Biomarker for Extrahepatic Biliary Atresia.

Background: Differentiation of neonatal cholestasis into neonatal hepatitis (NH) and extrahepatic biliary atresia (EHBA) is essential to formulate the treatment plan; promptness is indispensable for optimal outcomes. The clinical and nonoperative algorithms lack precision; the gold standard investigations (liver biopsy or per-operative cholangiogram) are invasive. There is a need for a noninvasive test which is both, sensitive and specific and has a high likelihood ratio. Aim: To study the (diagnostic) role of matrix metalloproteinase 7 (MMP-7) as a serum biomarker to differentiate between EHBA and NH and evaluate the prognostic significance in EHBA based on its correlation with liver histopathology and serological predictors of liver fibrosis - Aspartate-to-Platelet Ratio Index (APRI) and Fibrosis-4 (FIB-4). Materials and Methods: This was a prospective study conducted upon patients of neonatal cholestasis presenting with acholic stools (n = 46) with equal number of controls (n = 45) with no liver pathology. Observational parametric included disease-specific workup and serum MMP-7 levels (all participants); liver biopsyl and APRI-FIB-4 (EHBA). Results: (Diagnostic) Serum MMP-7 levels were significantly elevated in EHBA (n = 25; 28 ng/mL) as compared to those in NH (n = 21; 1.88 ng/mL) and normal infants (n = 45; 1.2 ng/mL) (P < 0.001 for both). Serum cutoff at 4.99 ng/mL differentiated EHBA-NH with a high sensitivity (96%), specificity (90.5%), and a negative predictive value (95%), with the number needed to misdiagnose being 23. (Prognostic) Inflammatory activity and fibrosis-stage on liver histopathology (METAVIR-and-Ishak scores) correlated with MMP-7 levels. APRI and FIB-4 scores also depicted a strong correlation with each other, age of the patient, and liver fibrosis. Conclusions: MMP-7 has a diagnostic value in differentiating EHBA from NH and may also be used as a prognostic biomarker in the follow-up of these patients. MMP-7 levels in controls may be used as a baseline for future studies.

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.

Demonstration of Gut-Barrier Dysfunction in Early Stages of Non-alcoholic Fatty Liver Disease: A Proof-Of-Concept Study.

Background/Aims: Gut-barrier dysfunction is well recognized in pathogenesis of both non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). However, comparison of components of this dysfunction between the two etiologies remains unexplored especially in early stages of NAFLD. Methods: Components of gut-barrier dysfunction like alterations in intestinal permeability (IP) by lactulose mannitol ratio (LMR) in urine, systemic endotoxemia (IgG and IgM anti-endotoxin antibodies), systemic inflammation (serum tumor necrosis factor alpha [TNF-α] and interleukin-1 [IL-1] levels), tight junction (TJ) proteins expression in duodenal biopsy and stool microbiota composition using Oxford Nanopore MinION device were prospectively evaluated in patients with NAFLD (n = 34) with no cirrhosis, ALD (n = 28) and were compared with disease free controls (n = 20). Results: Patients with ALD had more advanced disease than those with NAFLD (median liver stiffness -NAFLD:7.1 kPa [5.9-8.9] vs. ALD:14.3 kPa [9.6-24], P < 0.001]. Median LMR was significantly higher in NAFLD and ALD group when compared to controls (NAFLD 0.054 [0.037-0.17] vs. controls 0.027 [0.021-0.045] (P = 0.001)) and ALD 0.043 [0.03-0.068] vs. controls 0.027 [0.021-0.045] (P = 0.019)]. Anti-endotoxin antibody titer (IgM) (MMU/mL) was lowest in NAFLD 72.9 [3.2-1089.5] compared to ALD 120.6 [20.1-728]) (P = 0.042) and controls 155.3 [23.8-442.9]) (P = 0.021). Median TNF-α (pg/mL) levels were elevated in patients with NAFLD (53.3 [24.5-115]) compared to controls (16.1 [10.8-33.3]) (P < 0.001) and ALD (12.3 [10.1-42.7]) (P < 0.001). Expression of zonulin-1 and claudin-3 in duodenal mucosa was lowest in NAFLD. On principal co-ordinate analysis (PCoA), the global bacterial composition was significantly different across the three groups (PERMANOVA test, P < 0.001). Conclusion: While remaining activated in both etiologies, gut-barrier dysfunction abnormalities were more pronounced in NAFLD at early stages compared to ALD despite more advanced disease in the latter.

Comparison of Cisplatin Monotherapy and PLADO in the Management in Children with Standard-Risk Hepatoblastoma in a Resource-Challenged Nation.

Background: Recent SIOPEL studies have shown cisplatin monotherapy to be equally effective in management of Standard risk Hepatoblastoma (SRHB)as compared to PLADO. Aims and Objectives: To study the chemotherapy, response and outcomes in children with SRHB. Material and Methods: A retrospective study was conducted and all children with SRHB who presented to us from June 2007 to December 2017 were included. All patients with standard risk hepatoblastoma who had received at least 2 cycles of chemotherapy were included. Data regarding the demographics, PRETEXT stage, chemotherapy, response to chemotherapy and outcomes were recorded. Kaplan Meier survival analysis was performed to calculate 5 year overall survival (OS) and event free survival (EFS). Results: Thirty two children were included in the study. The disease was PRETEXT I in 5 (15.6%), II in 9 (28.1%) and 18 (56.2%). Nineteen children (59.4%) received Cisplatin monotherapy and of these 6 patients (all PREXT III) had poor response and the chemotherapy was upgraded to PLADO. The remaining 13 (40.6%) received upfront PLADO chemotherapy. Only 31 patients could be operated. Tumor recurred in 5 patients, 2 who had upfront PLADO and 3 patients had been upgraded to PLADO. The 5 year OS and EFS was 100% in the monotherapy group (n=13), 92% and 69% in the upfront PLADO group (n=13), and 62% and 22% in the upgraded to PLADO group (n=6). Patients with PRETEXT III disease in whom chemotherapy was upgraded to PLADO had significantly lower survival (p=0.036) compared to those who received upfront PLADO chemotherapy. Conclusion: Two thirds of patients with PRETEXT stage III who received cisplatin monotherapy showed poor response and were upgraded to PLADO chemotherapy. These patients had a significantly poorer outcome compared to the rest of the cohort. PRETEXT stage III standard-risk hepatoblastoma may benefit from PLADO chemotherapy instead of cisplatin monotherapy.

Progressive multifocal leukoencephalopathy in a patient with systemic lupus erythematosus and autoimmune hepatitis.

Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating central nervous system illness encountered in the setting of immunosuppressive conditions like human immunodeficiency virus / acquired immunodeficiency syndrome, autoimmune diseases and hematologic malignancies. We had a 54-year-old woman with systemic lupus erythematosus and coexisting autoimmune hepatitis who presented with progressive cognitive decline, right hemiparesis and ataxia who was found to have PML. She had severe CD4 lymphopenia. She was managed with low-dose prednisolone and plasma exchange after which she showed significant clinical improvement. This case highlights the diagnostic and therapeutic challenges encountered in managing a case of PML in the setting of autoimmune conditions with profound lymphopenia.

Acute Variceal Bleed in Cirrhosis is Associated With Reversible Changes in Tight Junction Protein Expression in the Intestine: A Proof-of-Concept Study.

BACKGROUND: Tight junction proteins (TJPs) play an important role in gut-barrier dysfunction in cirrhosis and its complications such as acute variceal bleed (AVB). However, the dynamics of TJPs expression after AVB, its relation to bacterial translocation, and impact on clinical outcome is largely unknown. AIMS: The aim of this study was to study the expression of TJPs in cirrhosis and assess its dynamic changes in AVB. In addition, the relation of TJP expression to endotoxemia and clinical outcomes was assessed. METHODS: In this prospective pilot study, 17 patients of cirrhosis with AVB, 59 patients of cirrhosis without AVB (non-AVB cirrhosis), and 20 controls were assessed for claudin-2 and claudin-4 expression in the duodenal biopsy. In the AVB-cirrhosis group, additional biopsies were obtained after 3 weeks. Endotoxemia was assessed by measuring IgG anti-endotoxin antibody levels. Claudin expression was correlated with a 6-month survival. RESULTS: Claudin-2 expression was downregulated in patients with AVB and non-AVB cirrhosis in villi (P < 0.001 and 0.013) and crypts (P < 0.001 and 0.012), respectively, compared with the controls. Claudin-4 expression was similar in villi (P = 0.079), but lower in crypts (P = 0.007) in patients with cirrhosis. Claudin-2 expression was upregulated on serial biopsies in both villi and crypts (P = 0.003 and 0.001, respectively) in AVB-cirrhosis with postbleed expression comparable with those with non-AVB cirrhosis. IgG anti-endotoxin antibody levels were elevated in cirrhosis with no correlation with claudin-2/4 expression. Claudin-2 expression independently predicted survival at 6 months. CONCLUSION: Both claudin-2 and claudin-4 expression are downregulated in cirrhosis. AVB is associated with dynamic changes in TJPs expression. Gut-barrier dysfunction might predict outcomes independent of bacterial endotoxemia in cirrhosis.