Impact of Diabetes, Drug-Induced Liver Injury, and Sepsis on Outcomes in Metabolic Dysfunction Associated Fatty Liver Disease-Related Acute-on-Chronic Liver Failure.

INTRODUCTION: The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) and its complication, MAFLD-related acute-on-chronic liver failure (MAFLD-ACLF), is rising. Yet, factors determining patient outcomes in MAFLD-ACLF remain understudied. METHODS: Patients with MAFLD-ACLF were recruited from the Asian Pacific Association for the Study of the Liver-ACLF Research Consortium (AARC registry). The diagnosis of MAFLD-ACLF was made when the treating unit had identified the etiology of chronic liver disease as MAFLD (or previous nomenclature such as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, or non-alcoholic steatohepatitis-cirrhosis). Patients with coexisting other etiologies of chronic liver disease (such as alcohol, hepatitis B virus, hepatitis C virus, etc.) were excluded. Data were randomly split into derivation (n = 258) and validation (n = 111) cohorts at a 70:30 ratio. The primary outcome was 90-day mortality. Only the baseline clinical, laboratory features and severity scores were considered. RESULTS: The derivation group had 258 patients; 60% were male, with a mean age of 53. Diabetes was noted in 27% and hypertension in 29%. The dominant precipitants included viral hepatitis (hepatitis A virus and hepatitis E virus, 32%), drug-induced injury (drug-induced liver injury, 29%), and sepsis (23%). Model for End-Stage Liver Disease-Sodium (MELD-Na) and AARC scores on admission averaged 32 ± 6 and 10.4 ± 1.9. At 90 days, 51% survived. Nonviral precipitant, diabetes, bilirubin, international normalized ratio, and encephalopathy were independent factors influencing mortality. Adding diabetes and precipitant to MELD-Na and AARC scores, the novel MAFLD-MELD-Na score (+12 for diabetes, +12 for nonviral precipitant), and MAFLD-AARC score (+5 for each) were formed. These outperformed the standard scores in both cohorts. DISCUSSION: Almost half of patients with MAFLD-ACLF die within 90 days. Diabetes and nonviral precipitants such as drug-induced liver injury and sepsis lead to adverse outcomes. The new MAFLD-MELD-Na and MAFLD-AARC scores provide reliable 90-day mortality predictions for patients with MAFLD-ACLF.

Serum miR-215-5p, miR-192-5p and miR-378a-5p as novel diagnostic biomarkers for periampullary adenocarcinoma.

OBJECTIVE: MicroRNAs (miRNAs) are present in human serum in a stable form. Circulating miRNAs are increasingly recognized as promising biomarkers for early cancer detection. The aim of this study was to identify serum miRNAs as biomarkers for periampullary adenocarcinoma (PAC). PATIENTS AND METHODS: 68 patients with PAC and 50 healthy controls (HCs) subjects were recruited in this study. The expression levels of 11 selected miRNAs were determined in serum samples using the SYBR-green quantitative reverse transcription polymerase chain reaction (qRT-PCR) method. Receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic potential of serum miRNAs. RESULTS: The expression levels of three miRNAs (miR-215-5p, miR-192-5p, and miR-378a-5p) were significantly upregulated in the serum samples derived from the PAC patients compared with those from the HC (p < 0.001). The ROC analysis showed that all three significantly altered miRNAs (miR-215-5p, miR-192-5p, and miR-378a-5p) could potentially discriminate patients with PAC from HC with AUC value of 0.771 (95% CI: 0.684-0.843), 0.877 (95% CI: 0.799-0.927) and 0.768 (95% CI: 0.674-0.853) respectively. Further comparisons showed that these three serum miRNAs (miR-215-5p, miR-192-5p, and miR-378a-5p) can strongly discriminate early-stage PAC patients from HC with an AUC value of 0.802 (95% CI: 0.719-0.886), 0.870 (95% CI: 0.793-0.974) and 0.793 (95% CI: 0.706-0.880) respectively, may aid in early detection of PAC. CONCLUSIONS: Taken together, our findings demonstrated that these three serum miRNAs (miR-215-5p, miR-192-5p, and miR-378a-5p) may serve as noninvasive biomarkers for the early detection of PAC.

Clinical Significance of MUC4 and Associated Proteins in Pancreatic and Periampullary Cancers.

OBJECTIVE: This study primarily aimed to assess the expression of MUC4 in patients with pancreatic ductal adenocarcinoma (PDAC) as compared with controls and assess its clinical relevance. MATERIALS AND METHODS: Serum MUC4 levels and MUC4 gene expression in snap-frozen tissue were analyzed through surface plasmon resonance and quantitative polymerase chain reaction, respectively. Tumor tissues and control tissues were analyzed for MUC4 and other mucins through immunohistochemistry. RESULT: MUC4 expression in tumor tissue was found to be significantly elevated in PDAC patients as compared with chronic pancreatitis tissues and normal pancreatic tissues. Periampullary carcinoma and cholangiocarcinoma tissue also showed increased expression of MUC4 and other mucins. CONCLUSIONS: Differential expression of MUC4 in pancreatic tumor tissues can help to differentiate PDAC from benign conditions.

Longitudinal changes in bone mineral density may be associated with long-term survival in patients with cirrhosis: A proof of concept of study.

INTRODUCTION: The impact of longitudinal changes in different body components measured via body composition analysis (BCA) on liver-related outcomes in patients with cirrhosis is poorly understood. We evaluated the prognostic relevance of longitudinal changes in body composition over one year in patients with cirrhosis. METHODS: This was a follow-up study of a randomized controlled trial evaluating changes in bone density measured via dual energy X-ray absorptiometry (DEXA) upon vitamin D supplementation. Patients with available anthropometric indices, fat mass (FM), fat-free mass (FFM), bone-density at lumbar spine (LD) and left femur-neck (FD) (assessed by T score) at two time points one year apart were assessed for outcomes. The prognostic relevance of change in parameters such as ΔFM, ΔFFM, ΔLD and ΔFD over one year was assessed and compared with baseline model for end-stage liver disease (MELD) score. RESULTS: Patients with cirrhosis (n=112) (mean age 41.8±12 years, 58.5% males) were followed up for median duration of 5.7 years interquartile range [IQR 3.5-5.7], with five-year survival rate of 77%. On serial BCA, ΔLD (p=0.029) and ΔFD (p=0.003) emerged as significant predictors of survival, whereas ΔFM (p=0.479), ΔFFM (p=0.245) and ΔBMI (p=0.949) were not. The area under curve of ΔLD and MELD score for predicting survival was 0.636 (0.5-0.773) and 0.664 (0.555-0.773), respectively. ΔFD<0.1 over one year had sensitivity and specificity of 70.4% and 56.5% to predict poor survival. The combination of ΔFD, MELD and ascites predicted five-year survival with an optimism-corrected c-statistic of 0.785. CONCLUSION: Among body composition parameters, changes in bone mineral density correlate best with survival and have prognostic relevance similar to that of ascites and MELD score.

Randomized Controlled Trial of Intravenous Ferric Carboxymaltose vs Oral Iron to Treat Iron Deficiency Anemia After Variceal Bleed in Patients With Cirrhosis.

INTRODUCTION: Limited evidence exists on the optimal strategy to correct iron deficiency anemia after variceal bleeding (VB) in cirrhosis. This trial compared the efficacy and safety of intravenous ferric carboxymaltose (IV-FCM) with those of oral iron therapy in this cohort. METHODS: In this open-label, single-center, randomized controlled trial, eligible patients with hemoglobin <10 g/dL and iron deficiency (ferritin <100 ng/mL) after VB received either IV-FCM (1,500-2,000 mg) divided into 2 doses (n = 48) or oral carbonyl iron (100 mg elemental iron/day) (n = 44) for 3 months. The primary outcome was change in hemoglobin at 3 months. Secondary outcomes included improvement in anemia (last hemoglobin >12 g/dL), normalization of iron stores (ferritin >100 ng/mL), liver-related adverse events, adverse drug reactions, and changes in quality of life (CLDQOL questionnaire). RESULTS: Baseline characteristics, including median Child-Turcotte-Pugh score 7 (interquartile range [IQR] 6-9), Model for End-Stage Liver Disease score 12 (IQR 10-17), blood hemoglobin (8.25 ± 1.06 g/dL), and ferritin (30.00 ng/mL [15.00-66.50]), were comparable in both arms. The median increase in hemoglobin at 3 months in the IV and oral arms was 3.65 g/dL (IQR 2.55-5.25) and 1.10 g/dL (IQR 0.05-2.90 g/dL) ( P < 0.001), respectively. Iron stores normalized in 84.6% and 21% of the IV and oral arms, respectively ( P < 0.001). Anemia improved in 50% and 21.9% in the IV and oral arms, respectively ( P < 0.009). Patients in the IV arm showed a significant improvement in all domains of CLDQOL. Liver-related adverse events were comparable in both arms. Transient mild/moderate hypophosphatemia developed in 43% of patients receiving IV-FCM. DISCUSSION: Intravenous iron replacement is efficacious and safe to treat iron deficiency anemia after VB in patients with cirrhosis.

MicroRNA Signatures for Pancreatic Cancer and Chronic Pancreatitis: Expression Profiling by NGS.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease due to the lack of early detection. Because chronic pancreatitis (CP) patients are a high-risk group for pancreatic cancer, this study aimed to assess the differential miRNA profile in pancreatic tissue of patients with CP and pancreatic cancer. METHODS: MiRNAs were isolated from formalin-fixed paraffin-embedded pancreatic tissue of 22 PDAC patients, 18 CP patients, and 10 normal pancreatic tissues from autopsy (C) cases and processed for next-generation sequencing. Known and novel miRNAs were identified and analyzed for differential miRNA expression, target prediction, and pathway enrichment between groups. RESULTS: Among the miRNAs identified, 166 known and 17 novel miRNAs were found exclusively in PDAC tissues, while 106 known and 10 novel miRNAs were found specifically in CP tissues. The pathways targeted by PDAC-specific miRNAs and differentially expressed miRNAs between PDAC versus CP tissues and PDAC versus control tissues were the proteoglycans pathway, Hippo signaling pathway, adherens junction, and transforming growth factor-ß signaling pathway. CONCLUSIONS: This study resulted in a set of exclusive and differentially expressed miRNAs in PDAC and CP can be assessed for their diagnostic value. In addition, studying the role of miRNA-target gene interactions in carcinogenesis may open new therapeutic avenues.

Kitchen-based diet versus commercial polymeric formulation in acute pancreatitis: a pilot randomized comparative study.

INTRODUCTION: Nutrition plays an important role in management of acute pancreatitis (AP) and decreases its severity and infectious complications. Various formulations of enteral nutrition (EN) are available and are costly. For developing countries, cost and availability is a major issue and kitchen-based diet should be explored in patients with AP. AIM: Comparison of kitchen-based diet with a commercially available polymeric formulation in terms of various outcomes in patients with AP within 14 days after the onset of pain. METHODS: Sixty patients (39 male, mean age 36.1 ± 12.7 years) of moderately severe and severe AP of any etiology were randomized (30 in each group) to either kitchen-based diet or commercial polymeric formulation group. Outcome measures were refeeding pain, tolerability, infectious complications, mortality, total hospital/intensive care unit stay; and change in serum C-reactive protein (CRP), transferrin and pre albumin. RESULTS: There was no significant difference in baseline demographic and biochemical parameters in both groups. No difference was observed in refeeding pain (7.1% vs 8%, p = 0.99), tolerability (28.6% vs 12%, p = 0.17), infectious complications (57.14% vs 36%, p = 0.12), mortality (31.7% vs 20%, p = 0.69), hospital stay (19.5 vs 23.5 days, p = 0.86), CRP (74.4 vs 59 mg/L, p = 0.97), transferrin levels (23.6 vs 25.6 mg/dL, p = 0.75) and pre albumin (9.45 vs 13.09 mg/dL, p = 0.68) in both groups. CONCLUSION: Kitchen-based diet is comparable to commercial polymeric formulation for the early initiation of enteral nutrition in patients with severe or moderately severe acute pancreatitis. CLINICAL TRIAL REGISTRATION: Trial registered with the Clinical Trials registry-India (CTRI/2018/01/011188).

Elevated levels of peripheral Th17 cells and Th17-related cytokines in patients with periampullary adenocarcinoma.

AIM: Periampullary adenocarcinoma (PAC) is a malignant tumor originating at the ampulla of Vater, distal common bile duct, head of the pancreas, ampulla and duodenum. The levels of circulating Th17 cells and Th17-related cytokines in patients with PAC remain unreported. Therefore, the aim of this study was to determine the levels of circulating Th17 cells and Th17-related cytokines in patients with PAC. MATERIALS AND METHODS: Flow cytometry was used to measure Th17 cell proportions in PBMCs from 60 PAC patients and 30 healthy controls. Enzyme-linked immunosorbent assay (ELISA) was used to quantify IL-17A and IL-23 levels in serum samples, while quantitative reverse transcription polymerase chain reaction (qRT-PCR) assessed IL-17A mRNA expression and Th17-related transcription factors (RORγt and STAT3) in tissue samples. RESULTS: The findings showed a substantial increase in Th17 cell percentages, elevated concentrations of IL-17A and IL-23, and higher mRNA expression levels of IL-17A, RORγt, and STAT3 in patients with PAC when compared to healthy controls (HCs). CONCLUSION: Th17 cells play an important role in the pathogenesis of PAC and may represent potential therapeutic targets.

Combination of Serum CA 19-9 and Endoscopic Ultrasound Findings Can Predict Malignancy Risk in Patients With Chronic Pancreatitis Presenting With Pancreatic Head Mass: A Proof-of-Concept Study.

BACKGROUND AND AIMS: Inflammatory head mass of pancreas (IMP) developing in background of chronic pancreatitis (CP) is difficult to distinguish from carcinoma pancreas. We aimed to delineate natural course of IMP and predict their malignancy risk, avoiding unnecessary biopsies. MATERIALS AND METHODS: In this retrospective single-center study, clinical records of patients with CP with diagnosed pancreatic head mass were reviewed. Clinical, laboratory, imaging, endoscopic findings, and follow-up details were retrieved from prospectively maintained database. A diagnostic nomogram was developed combining serum cancer antigen 19-9 and endoscopic ultrasound (EUS) findings to predict the risk of malignancy. RESULTS: We identified 107 patients with pancreatic head mass with CP of whom 87 (81.3%) were IMP and 20 (18.7%) were malignant. Patients with IMP were more frequently young males with alcohol-related CP and low CA 19-9 in comparison with those with malignancy (age IMP: 41.3 ± 11.3 vs carcinoma: 49.3 ± 14.5 years [ P = 0.009]; males 89.7% vs 65% [ P = 0.011]; alcoholic etiology: 71.3% vs 20% [ P < 0.001]; median CA 19-9: 25.78 [interquartile range, 7.20-120.60] vs 1034.50 [106.65-7808.25] [ P < 0.001]). A diagnostic nomogram combining CA 19-9 and EUS findings could identify malignancy with an optimism-corrected c-statistic of 0.905, which was better than both CA 19-9 (0.80) and EUS alone (0.826). Patients with IMP had relatively benign disease course with 40.2% biliary obstruction, 20.7% portal venous thrombosis, 14.9% gastric outlet obstruction, and 1-, 3-, and 5-year survival being 97.3%, 92.7%, and 92.0%, respectively. Surgery was required in only 12 patients (13.8%) with IMP. CONCLUSIONS: Combination of CA 19-9 and EUS best identifies malignancy risk in patients with IMP, who have otherwise benign course.

Elucidating the Role of miRNA-326 Modulating Hedgehog Signaling in Pancreatic Carcinoma.

BACKGROUND AND AIM: Pancreatic ductal adenocarcinoma (PDAC) is one of the lethal malignancies worldwide characterized by poor prognosis. MicroRNAs (miRNAs) function as the key regulators in carcinogenesis and may act as noninvasive biomarkers in various malignancies including PDAC. The present study aimed to elucidate the role of miR-326, a known modulator of hedgehog (Hh) pathway in PDAC. MATERIALS AND METHODS: miR-326 circulating levels were assessed in 105 PDAC patients, 31 with chronic pancreatitis (CP) and 36 healthy controls by quantitative Polymerase chain reaction. The expression of miR-326 and smoothened (SMO) was checked in surgical PDAC tissue. SMO protein expression was analyzed by immunohistochemistry in different groups. Finally, the role of miR-326 as a modulator of Hh pathway was assessed in vitro. RESULTS: Our results demonstrate that miR-326 is downregulated in both blood and tissue of PDAC patients as compared with controls. In contrast, the target gene/protein expression of SMO is upregulated in PDAC. Moreover, the tumor stromal expression of SMO was found to be clinically associated with lymph-node metastasis and vascular encasement in PDAC. Overexpression of miR-326 in Panc1 cell line was found to induce downregulation of SMO suggesting the tumor suppressor role of miR-326 in PDAC. CONCLUSIONS: Taken together, miR-326 acts as a tumor suppressor in PDAC by modulating Hh pathway. It may be a promising target for the development of efficient drug therapies for the treatment of PDAC.

Opportunistic screening for osteopathy with routine abdominal computed tomography scan in chronic pancreatitis.

BACKGROUND AND AIMS: Lumbar vertebral bone attenuation, measured in Hounsfield units (HU) can indirectly indicate the bone mineral density (BMD). The aim of this study is to determine the optimal HU threshold on abdominal computed tomography (CT) scans to detect osteopathy in patients with chronic pancreatitis (CP). METHODS: This cross-sectional study included patients with CP who underwent CT scans to measure HU at L1 to L4 vertebrae. The mean lumbar vertebral attenuation of female renal transplant donors, aged 20-30 years was utilized to calculate the T-scoreHU of all patients at each vertebral level. Receiver operator characteristic analysis was used to determine the HU and T-scoreHU for diagnosis of osteopathy in patients with CP. Dual-energy X-ray absorptiometry value was used to categorize osteopenia and osteoporosis. RESULTS: A total of 175 patients (mean age, 34.5 ± 10.9 years; 72 % males) and 33 female renal transplant donors (mean age, 28 ± 2.4 years) were included. A threshold HU value 212 or T scoreHU of -1.80 at L1 vertebra was found to have a 78 % sensitivity and 70 % specificity for differentiating between osteoporosis and non-osteoporosis (osteopenia and normal BMD). Similarly, a threshold HU value of 254 or a T-scoreHU of -0.46 at L1 vertebra had 78 % sensitivity and 71 % specificity for distinguishing between normal and low BMD (osteoporosis and osteopenia). CONCLUSION: Abdominal CT images, which are routinely performed in chronic pancreatitis, can be used for opportunistic screening of osteoporosis and osteopenia without additional cost or radiation exposure.

An Open-label Randomized Controlled Trial of Early Initiation of Nasogastric Feeding After Endotherapy in Variceal Bleeding: A Proof-of-concept Study.

Background and aims: Limited data exist on the safety of early nasogastric (NG) feeding in patients with cirrhosis after endotherapy for variceal bleeding (VB). We studied the impact of early NG tube feeding in these patients in this proof-of-concept open-label randomized controlled trial. Methods: Eligible patients with cirrhosis undergoing endotherapy for VB were randomized to receive either a liquid diet through a 14 Fr NG tube (commencing 1 h after endotherapy) (early feeding [EF] group) or sips of water and lemon water orally (standard-of-care [SOC] group) for total duration of 48 h. The primary outcome was 5-day rebleeding in both arms. Other outcomes included 5-day infection rate, hepatic encephalopathy during hospitalization, and 6-week mortality. Results: Eighty patients (Mean age: 41 ± 11.5 years; males [82.5%]; alcohol etiology [55%]) were included. Baseline median Child-Pugh and MELD scores were similar (CTP: 8 [IQR: 8-9] vs 9 [8-9.25]; P = 0.47 and MELDNa: 13 [10.75-16.25] vs 15 [12-18.25]; P = 0.16). The 5-day rebleeding rates in EF and SOC groups were 2.5% and 5%, respectively (P = 0.55), and non-inferiority or superiority of either could not be demonstrated. The incidence of infection (2.5% [EF] vs 2.5% [SOC]; P = 1.00) and development of HE (5% [EF] vs 2.5% [SOC]; P = 0.36) during hospitalization were comparable. The average daily calorie and protein intake in the EF group during the 48 h was 1318 ± 240 Kcals and 43.4 ± 9.2 g of proteins. No patient in the EF group had feed intolerance. Conclusion: Early initiation of NG tube-based feeding after endotherapy in VB appears safe and well tolerated without the additional risk of rebleeding or encephalopathy.

Utility of different Baveno criteria to detect esophageal varices irrespective of their size in patients with compensated cirrhosis.

BACKGROUND AND AIMS: Esophageal varices (EVs), irrespective of size, are the most-reliable indicators of clinically significant portal hypertension (CSPH) in patients with compensated advanced chronic liver disease (cACLD). While non-invasive tools (NITs) accurately identify those with varices needing treatment (VNTs), their role in identifying any EVs in patients with cACLD is not known. METHODS: Patients with cACLD with reliable liver stiffness measurements (LSM), blood parameters and gastroscopy were retrospectively recruited from a multinational cohort. The performance of Baveno-VI (LSM > 20kPa and platelet count < 150,000/mm3) and expanded Baveno-VI criteria (LSM > 25kPa or platelet count < 110,000/mm3) was assessed to detect VNTs as well as any EVs. This performance was compared with the Baveno-VII possible CSPH criteria (LSM ≥ 15 kPa and platelet ≤ 150,000/mm3) to evaluate its utility in detecting any EVs. RESULTS: Patients with cACLD (n = 1200) of predominantly viral etiology (hepatitis B virus, 269; hepatitis C virus, 564; non-alcoholic fatty liver disease, 145; alcoholic liver disease, 130; other, 92) were included. Any EVs and VNTs were present in 514 (42.8%) and 70 (5.8%) patients, respectively. The Baveno-VI, expanded Baveno-VI and Baveno-VII criteria missed 29/514 (5.6%), 115/514 (22.4%) and 19/514 (3.7%) patients with any EVs, respectively, whereas they misclassified 517/686 (75.4%), 211/686 (30.8%) and 598/686 (87.4%) patients with no EVs as having a high risk of EVs. The Baveno-VI, expanded Baveno-VI and possible CSPH criteria missed 3/70 (4.3%), 15/70 (21.4%) and 0/70 (0%) VNTs, respectively. CONCLUSION: Both original Baveno-VI and Baveno-VII criteria were highly sensitive in detecting varices in cACLD, albeit with high misclassification rates.

Vitamin D status & bone health in patients with liver cirrhosis.

Background & objectives: Vitamin D plays an important role in bone metabolism, and liver is the intermediary site of vitamin D metabolism. The purpose of this study was to study the prevalence of vitamin D deficiency and bone health in patients with cirrhosis. Methods: Prospectively, serum 25-hydroxy vitamin D [25(OH)D] level were assessed in cirrhotics by chemiluminescence method. Endocrine Society Clinical practice guideline was used to define deficiency and insufficiency of vitamin D. Bone mineral density (BMD) was assessed using dual-energy X-ray absorptiometry and the World Health Organization criteria was used to define osteoporosis and osteopenia. The lowest T score at the left hip neck or lumbar spine was taken as osteoporosis or osteopenia. The Child-Turcotte-Pugh score was used to assess the severity of cirrhosis. Results: Cirrhotics (n=350, male: 278, compensated: 210) were included. Mean serum 25(OH)D level was 8.75 ng/ml. The prevalence of vitamin D deficiency (VDD) and low-BMD (osteopenia and osteoporosis) was 89.4 and 86 per cent, respectively. VDD, insufficiency and osteoporosis was found in 86.7, 11.9 and 33.8 per cent, respectively, in patients with compensated cirrhosis; and 93.6, 3.6 and 40 per cent, respectively, in patients with decompensated cirrhosis. Body mass index of >25 kg/m2 was protective for bone health. Interpretation & conclusions: VDD and low-BMD is prevalent in Indian patients with cirrhosis and should be looked for in patients with cirrhosis for its prevention.

An LSM Based Strategy is Comparable to HVPG Measurement to Predict Further Events in Patients with Cirrhosis with Variceal Bleeding as Their Index Decompensation.

Background and aims: Limited data exist on strategies other than hepatic venous pressure gradient (HVPG) estimation to predict future events in patients with cirrhosis presenting with variceal bleed (VB) but are otherwise compensated. We assessed whether liver stiffness measurement (LSM) during VB episode could accurately predict this risk. Methods: Consecutive patients with cirrhosis with VB as their index decompensation event underwent HVPG and LSM estimation during the VB episode in this prospective study. New onset further decompensation events (ascites, VB, encephalopathy) was assessed over follow-up. The performance characteristics of postbleed LSM were compared with model for end stage liver disease (MELD) score and HVPG to predict future decompensation and were cross-validated. Results: Mean age of the cohort (n = 68) was 44.2 years and alcohol-related liver disease (55.9%) was the most common etiology. Over a median follow-up of 14 (9-18) months, 18(26.4%) patients developed further decompensation with ascites being the most common event. Patients with further decompensation had a higher median postbleed LSM [60.5 kPa (53-70) vs. 25 kPa (18-34), P < 0.001], HVPG [ 19 mm Hg vs. 16 mmHg, P = 0.005], and MELD score [ 12.5 (11-14.7) vs. 10 (8-12) P < 0.001]. The area under receiver-operator characteristics curve for postbleed LSM [0.928 (95%CI: 0.868-0.988)] was higher than both HVPG [0.733(0.601-0.865), P = 0.003] and MELD score [0.776(0.664-0.889), P = 0.019] to predict further decompensation. Optimism-corrected c-statistic using MELD and postbleed LSM was similar to a combination of HVPG, MELD, and postbleed LSM. Conclusion: Postbleed LSM is comparable to HVPG estimation in predicting further decompensation events in patients with otherwise compensated cirrhosis presenting with VB.

Vascular complications of chronic pancreatitis and its management.

Chronic pancreatitis is a chronic fibro-inflammatory disorder of the pancreas, resulting in recurrent abdominal pain, diabetes mellitus, and malnutrition. It may lead to various other complications such as pseudocyst formation, benign biliary stricture, gastric outlet obstruction; and vascular complications like venous thrombosis, variceal and pseudoaneurysmal bleed. Development of varices is usually due to chronic venous thrombosis with collateral formation and variceal bleeding can easily be tackled by endoscopic therapy. Pseudoaneurysmal bleed can be catastrophic and requires radiological interventions including digital subtraction angiography followed by endovascular obliteration, or sometimes with a percutaneous or an endoscopic ultrasound-guided approach in technically difficult situations. Procedure-related bleed is usually venous and mostly managed conservatively. Procedure-related arterial bleed, however, may require radiological interventions.

Increased circulating Th17 cell populations in patients with pancreatic ductal adenocarcinoma.

T-helper 17 (Th17) cells are a subset of CD4+ helper T cells that produce interleukin 17 (IL-17) and play a crucial role in the pathogenesis of inflammatory and autoimmune diseases. Few studies have been conducted to determine the role of Th17 cells in the tumorigenesis and development of pancreatic ductal adenocarcinoma (PDAC); however, its role is still unclear. In this study, the percentage of circulating Th17 cells and serum levels of IL-17A and IL-23 were analyzed using flow cytometry and ELISA, respectively, in 40 PDAC patients, 30 chronic pancreatitis (CP) patients and 30 healthy controls (HC). In addition, the mRNA expression levels of IL-17A, STAT3 and RORγt in tissue samples were quantified by qRT-PCR. The results showed that the percentage of circulating Th17 cells and the concentrations of serum IL-17A and IL-23 were significantly increased in PDAC patients as compared to CP and HC (P < 0.001). In addition, the higher level of IL-17A was significantly correlated with the poor overall survival of the PDAC patients. Furthermore, the frequencies of Th17 cells and IL-17A were significantly higher in stage III+IV PDAC patients versus stage I+II. A significant increase in IL-17A, STAT3 and RORγT mRNA was observed in patients with PDAC. Taken together, these findings suggest that the increased circulating Th17 cells and serum IL-17A may be involved in the development and metastasis of PDAC, and thus represent potential targets for the treatment of PDAC.

Assessments of TP53 and CTNNB1 gene hotspot mutations in circulating tumour DNA of hepatitis B virus-induced hepatocellular carcinoma.

Background: Hepatitis B virus (HBV) infection is one of the major causes of chronic liver disease, which progresses from chronic hepatitis B (CHB) to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Early detection and laboratory-based screening of hepatocellular carcinoma are still major challenges. This study was undertaken to determine whether the cancer hallmark gene signatures that are released into circulation as circulating tumour DNA (ctDNA) can be used as a liquid biopsy marker for screening, early detection, and prognosis of HCC. Methods: A total of 130 subjects, including HBV-HCC (n = 80), HBV-cirrhotic and non-cirrhotic (n = 35), and healthy (n = 15) controls, were evaluated for TP53 and beta-catenin (CTNNB1) gene hotspot mutations in ctDNA by Sanger-based cycle sequencing and droplet digital PCR (ddPCR) assays. Mutation detection frequency, percentage mutant fractions, and their association with tumour stage, mortality, and smoking habits were determined. Results: Sanger-based cycle sequencing was carried out for 32 HCC patients. Predict SNP Tools analysis indicated several pathogenic driver mutations in the ctDNA sequence, which include p.D228N, p.C229R, p.H233R, p.Y234D, p.S240T, p.G245S, and p.R249M for TP53 gene exon 7 and p.S33T for CTNNB1 gene exon 3. The TP53 c.746G>T (p.R249M) mutation was detected predominately (25% cases) by sequencing, but there was no dominant mutation at position c.747G>T (p.R249S) that was reported for HBV-HCC patients. A dual-probe ddPCR assay was developed to determine mutant and wild-type copy numbers of TP53 (p.R249M and p.R249S) and CTNNB1 (p.S45P) and their percentage mutant fraction in all 130 subjects. The TP53 R249M and CTNNB1 S45P mutations were detected in 31.25% and 26.25% of HCC patients, respectively, with a high mutant-to-wild-type fraction percentage (1.81% and 1.73%), which is significant as compared to cirrhotic and non-cirrhotic patients. Poor survival was observed in HCC patients with combined TP53 and CTNNB1 gene driver mutations. The TP53 R249M mutation was also significantly (p < 0.0001) associated with smoking habits (OR, 11.77; 95% CI, 3.219-36.20), but not the same for the TP53 R249S mutation. Conclusion: Screening of ctDNA TP53 and CTNNB1 gene mutations by ddPCR may be helpful for early detection and identifying the risk of HCC progression.