Radioresistant Pulmonary Oligometastatic and Oligoprogressive Lesions From Nonlung Primaries: Impact of Histology and Dose-Fractionation on Local Control After Radiation Therapy.

Purpose: We investigated whether pulmonary metastases from historically considered radioresistant primaries would have inferior local control after radiation therapy than those from nonradioresistant nonlung primaries, and whether higher biologically effective dose assuming alpha/beta=10 (BED10) would be associated with superior local control. Methods and Materials: We identified patients treated with radiation therapy for oligometastatic or oligoprogressive pulmonary disease to 1 to 5 lung metastases from nonlung primaries in 2013 to 2020 at a single health care system. Radioresistant primary cancers included colorectal carcinoma, endometrial carcinoma, renal cell carcinoma, melanoma, and sarcoma. Nonradioresistant primary cancers included breast, bladder, esophageal, pancreas, and head and neck carcinomas. The Kaplan-Meier estimator, log-rank test, and multivariable Cox proportional hazards regression were used to compare local recurrence-free survival (LRFS), new metastasis-free survival, progression-free survival, and overall survival. Results: Among 114 patients, 73 had radioresistant primary cancers. The median total dose was 50 Gy (IQR, 50-54 Gy) and the median number of fractions was 5 (IQR, 3-5). Median follow-up time was 59.6 months. One of 41 (2.4%) patients with a nonradioresistant metastasis experienced local failure compared with 18 of 73 (24.7%) patients with radioresistant metastasis (log-rank P = .004). Among radioresistant metastases, 12 of 41 (29.2%) patients with colorectal carcinoma experienced local failure compared with 6 of 32 (18.8%) with other primaries (log-rank P = .018). BED10 ≥100 Gy was associated with decreased risk of local recurrence. On univariable analysis, BED10 ≥100 Gy (hazard ratio [HR], 0.263; 95% CI, 0.105-0.656; P = .004) was associated with higher LRFS, and colorectal primary (HR, 3.060; 95% CI, 1.204-7.777; P = .019) was associated with lower LRFS, though these were not statistically significant on multivariable analysis. Among colorectal primary patients, BED10 ≥100 Gy was associated with higher LRFS (HR, 0.266; 95% CI, 0.072-0.985; P = .047) on multivariable analysis. Conclusions: Local control after radiation therapy was encouraging for pulmonary metastases from most nonlung primaries, even for many of those classically considered to be radioresistant. Those from colorectal primaries may benefit from testing additional strategies, such as resection or systemic treatment concurrent with radiation.

Magnetic resonance elastography (MRE) outperforms acoustic force radiation impulse (ARFI) in predicting oesophageal varices in obese NAFLD cirrhosis.

PURPOSE: Liver stiffness measurement (LSM) by transient elastography has been shown to underperform in high-risk varices (HRVs) prediction in obese non-alcoholic fatty liver disease (NAFLD) compensated cirrhosis (CC). LSM by magnetic resonance elastography (MRE) and acoustic force radiation impulse (ARFI) has been shown to be useful in prediction of oesophageal varices (EVs), but has limited evidence in obese NAFLD-CC. METHODS: Obese patients with NAFLD-CC who underwent MRE and ARFI for LSM and endoscopy for screening of varices were enrolled. Performance of MRE and ARFI for predicting EVs or HRVs was evaluated using area under receiver operating characteristics (AUROC) curves and regression analyses were performed for predictor variables. RESULTS: One hundred eight patients [mean age 54.7 ± 9.6 years, median BMI, 28.5 (26.4-30.0) kg/m2. 72.2% diabetics, 45.4% hypertensive] were enrolled. Fifty-two (48.1%) had no varices, while 29 (26.8%) and 27 (25%) had low-risk varices (LRVs) and HRVs, respectively. MRE-LSM was higher in patients with LRVs (p = 0.01) or HRVs (p = 0.001) against those without varices. ARFI-LSM did not differ significantly between those without and with LRVs or HRVs (p > 0.05 for all). There was a low correlation between ARFI-LSM and MRE-LSM in the overall cohort (r = 0.19). Only platelet count (PC) [0.98 (0.97-0.99)] and MRE-LSM [1.8 (1.26-2.79)] were predictors of HRVs. At a cut-off of 4.75, MRE showed a sensitivity of 96.3%. Model combining MRE-LSM with PC had a diagnostic AUROC of 0.77 and 0.76 for EVs and HRVs. CONCLUSION: In obese NAFLD-CC, MRE-LSM is significantly higher in patients with varices. MRE combined with PC predicts EVs and HRVs with better accuracy than ARFI.

Clinical criteria accurately diagnose severe but not moderate alcohol-associated hepatitis: A systematic review and meta-analysis.

BACKGROUND: The precision of clinical criteria and the utility of liver biopsy for diagnosis or prognosis remain unclear in patients with alcohol-associated hepatitis (AH). We systematically reviewed the literature to answer these questions. METHODS: Four databases were searched for studies describing the precision of clinical criteria (National Institute on Alcohol Abuse and Alcoholism, European Association for Study of Liver, or classical) and the role of histology in AH. The precision(positive predictive value) of criteria was pooled through random-effects meta-analysis, and its variation was investigated through subgroups and meta-regression of study-level factors with their percent contribution to variation (R2). The risk of bias among studies was evaluated through the QUADAS2 tool (PROSPERO-ID-CRD4203457250). RESULTS: Of 4320 studies, 18 in the systematic review and 15 (10/5: low/high risk of bias, N=1639) were included in the meta-analysis. The pooled precision of clinical criteria was 80.2% (95% CI: 69.7-89.7, I2:93%, p < 0.01), higher in studies with severe AH (mean-Model for End-Stage Liver Disease > 20) versus moderate AH (mean-Model for End-Stage Liver Disease < 20): 92% versus 67.1%, p < 0.01, and in studies with serum bilirubin cutoff 5 versus 3 mg/dL (88.5% vs.78.8%, p = 0.01). The factors contributing to variation in precision were Model for End-Stage Liver Disease (R2:72.7%), upper gastrointestinal bleed (R2:56.3%), aspartate aminotransferase:aspartate aminotransferase ratio (R2:100%), clinical criteria (R2:40.9%), bilirubin (R2:22.5%), and Mallory body on histology (R2:19.1%).The net inter-pathologist agreement for histologic findings of AH was variable (0.33-0.97), best among 2 studies describing AH through simple and uniform criteria, including steatosis, ballooning, and neutrophilic inflammation. Few studies reported the utility of histology in estimating steroid responsiveness (N = 1) and patient prognosis (N = 4); however, very broad septa, pericellular fibrosis, and cholestasis were associated with mortality. Bilirubinostasis was associated with infection in 1 study. CONCLUSIONS: Clinical criteria are reasonably precise for diagnosing severe AH, while there is an unmet need for better criteria for diagnosing moderate AH. Histologic diagnosis of AH should be simple and uniform.

Machine learning improves the prediction of significant fibrosis in Asian patients with metabolic dysfunction-associated steatotic liver disease - The Gut and Obesity in Asia (GO-ASIA) Study.

BACKGROUND: The precise estimation of cases with significant fibrosis (SF) is an unmet goal in non-alcoholic fatty liver disease (NAFLD/MASLD). AIMS: We evaluated the performance of machine learning (ML) and non-patented scores for ruling out SF among NAFLD/MASLD patients. METHODS: Twenty-one ML models were trained (N = 1153), tested (N = 283), and validated (N = 220) on clinical and biochemical parameters of histologically-proven NAFLD/MASLD patients (N = 1656) collected across 14 centres in 8 Asian countries. Their performance for detecting histological-SF (≥F2fibrosis) were evaluated with APRI, FIB4, NFS, BARD, and SAFE (NPV/F1-score as model-selection criteria). RESULTS: Patients aged 47 years (median), 54.6% males, 73.7% with metabolic syndrome, and 32.9% with histological-SF were included in the study. Patients with SFvs.no-SF had higher age, aminotransferases, fasting plasma glucose, metabolic syndrome, uncontrolled diabetes, and NAFLD activity score (p < 0.001, each). ML models showed 7%-12% better discrimination than FIB-4 to detect SF. Optimised random forest (RF) yielded best NPV/F1 in overall set (0.947/0.754), test set (0.798/0.588) and validation set (0.852/0.559), as compared to FIB4 in overall set (0.744/0.499), test set (0.722/0.456), and validation set (0.806/0.507). Compared to FIB-4, RF could pick 10 times more patients with SF, reduce unnecessary referrals by 28%, and prevent missed referrals by 78%. Age, AST, ALT fasting plasma glucose, and platelet count were top features determining the SF. Sequential use of SAFE < 140 and FIB4 < 1.2 (when SAFE > 140) was next best in ruling out SF (NPV of 0.757, 0.724 and 0.827 in overall, test and validation set). CONCLUSIONS: ML with clinical, anthropometric data and simple blood investigations perform better than FIB-4 for ruling out SF in biopsy-proven Asian NAFLD/MASLD patients.

Bloody Lips - Gluing Bleeding Lower Lip Spider Angioma in Decompensated Cirrhosis.

Spider angiomas are dilated vascular channels in the skin. They have a central arteriole with surrounding vascular channels resembling legs of a spider, hence the name. They are frequently associated with liver cirrhosis, thyrotoxicosis, and pregnancy. We present the case of a 49-year-old gentleman who was referred to our liver clinic with complaints of jaundice and ascites of one-month duration. The patient was a chronic alcohol consumer, consuming country-made liquor, 80-100 grams/day for past 8-10 years. He was diagnosed with Acute on chronic liver failure with a model for end-stage liver disease score of 38. During his hospital stay, he developed active spurting from a spider angioma on his lower lip (video 1), which was initially tackled with hand compressions, which stopped bleeding for a few minutes, restarting again after the compressions were lifted. It was then decided to inject 0.1 mL cyanoacrylate glue injection using a 21-gauge needle, immediately stopping active spurt (video 2), (Figure 1). A small ulcer formed at the injection site, which healed in few days, and the patient was discharged to home. Spider angiomas are characteristic cutaneous manifestation of liver cirrhosis with a specificity of 95%.1 The prevalence of spider angiomas in cirrhosis is reported to be around 30-40%. Li Hongyu et al. in their study on 198 individuals reported the prevalence to be 47%.2 They can be graded from grade 1+ (readily recognizable containing a body, legs, and surrounding erythema) to grade 4+ (visible pulsations with a hand lens and raised central punctum with many obvious "spider legs" radiating from it).3 Underlying pathogenesis in cirrhosis is multifactorial including decrease levels of testosterone and high levels of estradiol,4 hyperdynamic circulation, high levels of substance-P, and vascular endothelial growth factor leading to angiogenesis and vasodilation.5,6 Spider angiomas can be single or multiple and are usually seen in the territory of superior vena cava-the face (nose, lips, forehead), upper chest, and arms.2 These lesions have been associated with bleeding esophageal varices and hepatopulmonary syndrome. Bleeding from spider angiomas is unusual. Rarely, fine-needle electrocautery, potassium-titanyl-phosphate (KTP) laser, or electro desiccation has been used to clear spider angiomas for cosmetic concerns. Treatment includes hand or ice compressions and treating the underlying cause. Use of cyanoacrylate glue for bleeding spider angioma has not been reported in the literature. We think this can be a handy bedside tool to combat an active spurt of bleeding when conventional methods have failed, as in our case; however, further studies are warranted.

Genome scale CRISPR screens identify actin capping proteins as key modulators of therapeutic responses to radiation and immunotherapy.

Radiotherapy (RT), is a fundamental treatment for malignant tumors and is used in over half of cancer patients. As radiation can promote anti-tumor immune effects, a promising therapeutic strategy is to combine radiation with immune checkpoint inhibitors (ICIs). However, the genetic determinants that impact therapeutic response in the context of combination therapy with radiation and ICI have not been systematically investigated. To unbiasedly identify the tumor intrinsic genetic factors governing such responses, we perform a set of genome-scale CRISPR screens in melanoma cells for cancer survival in response to low-dose genotoxic radiation treatment, in the context of CD8 T cell co-culture and with anti-PD1 checkpoint blockade antibody. Two actin capping proteins, Capza3 and Capg, emerge as top hits that upon inactivation promote the survival of melanoma cells in such settings. Capza3 and Capg knockouts (KOs) in mouse and human cancer cells display persistent DNA damage due to impaired homology directed repair (HDR); along with increased radiation, chemotherapy, and DNA repair inhibitor sensitivity. However, when cancer cells with these genes inactivated were exposed to sublethal radiation, inactivation of such actin capping protein promotes activation of the STING pathway, induction of inhibitory CEACAM1 ligand expression and resistance to CD8 T cell killing. Patient cancer genomics analysis reveals an increased mutational burden in patients with inactivating mutations in CAPG and/or CAPZA3, at levels comparable to other HDR associated genes. There is also a positive correlation between CAPG expression and activation of immune related pathways and CD8 T cell tumor infiltration. Our results unveil the critical roles of actin binding proteins for efficient HDR within cancer cells and demonstrate a previously unrecognized regulatory mechanism of therapeutic response to radiation and immunotherapy.

Evaluation of terlipressin-related patient outcomes in hepatorenal syndrome-acute kidney injury using point-of-care echocardiography.

BACKGROUND AND AIMS: Treatment of hepatorenal syndrome-acute kidney injury (HRS-AKI), with terlipressin and albumin, provides survival benefits, but may be associated with cardiopulmonary complications. We analyzed the predictors of terlipressin response and mortality using point-of-care echocardiography (POC-Echo) and cardiac and renal biomarkers. APPROACH: Between December 2021 and January 2023, patients with HRS-AKI were assessed with POC-Echo and lung ultrasound within 6 hours of admission, at the time of starting terlipressin (48 h), and at 72 hours. Volume expansion was done with 20% albumin, followed by terlipressin infusion. Clinical data, POC-Echo data, and serum biomarkers were prospectively collected. Cirrhotic cardiomyopathy (CCM) was defined per 2020 criteria. RESULTS: One hundred and forty patients were enrolled (84% men, 59% alcohol-associated disease, mean MELD-Na 25±SD 5.6). A median daily dose of infused terlipressin was 4.3 (interquartile range: 3.9-4.6) mg/day; mean duration 6.4 ± SD 1.9 days; the complete response was in 62% and partial response in 11%. Overall mortality was 14% and 16% at 30 and 90 days, respectively. Cutoffs for prediction of terlipressin nonresponse were cardiac variables [ratio of early mitral inflow velocity and mitral annular early diastolic tissue doppler velocity > 12.5 (indicating increased left filling pressures, C-statistic: 0.774), tissue doppler mitral velocity < 7 cm/s (indicating impaired relaxation; C-statistic: 0.791), > 20.5% reduction in cardiac index at 72 hours (C-statistic: 0.885); p < 0.001] and pretreatment biomarkers (CysC > 2.2 mg/l, C-statistic: 0.640 and N-terminal proBNP > 350 pg/mL, C-statistic: 0.655; p <0.050). About 6% of all patients with HRS-AKI and 26% of patients with CCM had pulmonary edema. The presence of CCM (adjusted HR 1.9; CI: 1.8-4.5, p = 0.009) and terlipressin nonresponse (adjusted HR 5.2; CI: 2.2-12.2, p <0.001) were predictors of mortality independent of age, sex, obesity, DM-2, etiology, and baseline creatinine. CONCLUSIONS: CCM and reduction in cardiac index, reliably predict terlipressin nonresponse. CCM is independently associated with poor survival in HRS-AKI.

Intravenous BCAA Infusion Does Not Lead to a Sustained Recovery From Overt HE in ACLF - An Open Label Randomized Clinical Trial.

Background: Hepatic encephalopathy (HE) in acute-on-chronic liver failure (ACLF) is associated with significant morbidity and mortality. We conducted a prospective, randomized controlled clinical trial to study the efficacy of intravenous branched chain amino acids (IV-BCAA) with lactulose versus lactulose alone for improvement in HE at 24 h, day 3, and day 7. The primary outcome was an improvement in encephalopathy by ≥ 1 grade at 72 h. Patients and methods: European association for study of liver (EASL) defined ACLF patients with overt HE were assessed and randomized into the experimental arm (IV-BCAA - 500 mL/day for 3 days + Lactulose; n = 39) and the comparator arm (Lactulose alone; n = 37). Six patients developed COVID-19 after randomization and were excluded (4-experimental arm and 2-comparator arm). Results: Of 222 screened patients, 70 (35 in each arm) were included in the analysis. Baseline characteristics, including HE grade (2.9 ± 0.7 vs 2.8 ± 0.7; P = 0.86) and (chronic liver failure) CLIF-C ACLF score (54.2 ± 5.6 vs 54.8 ± 5.7; P = 0.65), were similar. Overall survival was 40% at 28 days (48.5% vs 31.4%; P = 0.14). Improvement in hepatic encephalopathy scoring algorithm (HESA) by ≥ 1 grade at 24 h occurred in 14 patients (40%) in the BCAA arm and 6 patients (17.1%) in the control group (P = 0.03) which translated to a shorter intensive care unit (ICU) stay. The median change in HESA at 24 h was greater in the BCAA arm than the control arm (P = 0.006), which was not sustained at days 3 or 7. Ammonia levels did not correlate with the grade of HE (Spearman's correlation coefficient (ρ) = - 0.0843; P = 0.29). Conclusion: Intravenous BCAA does not lead to a sustained improvement in HE grade in ACLF. Trial registration no: NCT04238416 (clinicaltrials.gov).

Machine learning can guide suitability of consultation and patient referral through telemedicine for hepatobiliary diseases.

BACKGROUND AND AIM: Telemedicine is an evolving tool to provide health-care services. We evaluated the suitability of telemedicine to deliver effective consultation for hepatobiliary disorders. METHODS: In this prospective study spanning over a year, we interviewed hepatologists delivering the teleconsultations through a pre-validated questionnaire. A consult was deemed suitable based on the physician's judgment in the absence of unplanned hospitalization. We evaluated factors determining the suitability through inferential statistics and machine learning models, namely, extreme gradient boosting (XGB) and decision tree (DT). RESULTS: Of 1118 consultations, 917 (82.0%) were deemed suitable. On univariable analysis, patients with skilled occupation, higher education, out-of-pocket expenses, and diseases such as chronic hepatitis B, C, and non-alcoholic fatty liver disease (NAFLD) without cirrhosis were associated with suitability (P < 0.05). Patients with cirrhosis (compensated or decompensated), acute-on-chronic liver failure (ACLF), and biliary obstruction were likely unsuitable (P < 0.05). XGB and DT models predicted suitability with an area under the receiver operating curve of 0.808 and 0.780, respectively. DT demonstrated that compensated cirrhosis with higher education or skilled occupation with age < 55 years had 78% chance of suitability whereas hepatocellular carcinoma, decompensated cirrhosis, and ACLF patients were unsuitable with a 60-95% probability. In non-cirrhotic liver diseases, hepatitis B, C, and NAFLD were suitable, with a probability of 89.7%. Biliary obstruction and previous failure of teleconsultation were unsuitable, with a probability of 70%. Non-cirrhotic portal fibrosis, dyspepsia, and dysphagia not requiring intervention were suitable (probability: 88%). CONCLUSION: A simple decision tree can guide the referral of unsuitable and the management of suitable patients with hepatobiliary diseases through telemedicine.

Spectrum of Autoimmune Liver Disease and Real-World Treatment Experience from a Tertiary Care Hospital.

Background and aims: Autoimmune liver disease (AILD) comprises of autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) with a spectrum of overlap amongst the three. We analyzed the spectrum and treatment outcomes of patients with AILD presenting to a tertiary care center in India. Methods: A retrospective analysis of AILD patients from June 2008 to April 2021 was performed. The diagnosis was based on clinical, biochemical, imaging, serological, and histological characteristics. Eligible patients received treatment depending on the disease stage. Biochemical response to treatment was defined as normalization of AST, ALT, bilirubin, and immunoglobulin G levels at 6 months in AIH, normalization of total bilirubin and/or albumin at 1 year in PBC and decrease in alkaline phosphatase (ALP) levels by 40% in PSC. Results: Two hundred seventy-five patients were analyzed. AIH (58.54%) was most common, followed by an overlap of AIH-PBC (24%) and AIH-PSC (6.54%), PSC (6.18%), and PBC (4.72%). Most patients presented in 3rd or 4th decade, except PBC which occurred predominantly in 5th decade. The majority of patients were females (72.72%). Jaundice was the most common presentation seen in 60% of patients. Cirrhosis was present in 57.47% of patients. Patients with overlap had more pruritus (54.76 vs 6.83%), fatigue (63.1% vs 49.7%), hepatomegaly (52.4% vs 25.5%), and higher ALP (80.9% vs 37.7%) than patients with AIH alone. Acute presentation was seen in 33 patients (13.5%) with most having AIH flare. Five patients had acute liver failure (ALF) and 9 had acute-on-chronic liver failure (ACLF). ALF was associated with 80% mortality while 55.56% of patients with ACLF had a complete biochemical response to immunosuppression. Among patients with AIH and/or overlap who received immunosuppression, a complete biochemical response to immunosuppression was seen in 60.69% of patients. High ALT (OR 1.001 [1.000-1.003], P = 0.034), high albumin (OR 1.91 [1.05-3.48], P = 0.034) and low fibrosis on biopsy (OR 0.54 [0.33-0.91], P = 0.020) predicted complete response. Conclusion: AIH is the most common AILD followed by overlap syndromes, PSC and PBC in our cohort. Biochemical response to immunosuppression is seen in 60% of patients with AIH & low fibrosis score on histopathology predicts a complete response.

IgG4-Related Sclerosing Cholangitis with Cholecystitis Mimicking Cholangiocarcinoma: A Case Report.

IgG4-related diseases are rare multisystem disorders involving salivary glands, retroperitoneum, pancreas, biliary tract, and liver. Isolated biliary strictures and gall bladder involvement are rare in such patients, and presentation with cholangitis and weight loss can misguide the diagnosis toward malignancy. Here, we report an interesting case of IgG4-related biliary stricture with gall bladder involvement, presented with cholangitis and weight loss. The initial symptoms and imaging were guided toward the malignant possibilities of cholangiocarcinoma and pancreatic carcinoma. However, endosonography, serology, and histopathology clinched the diagnosis of IgG4-related disease. The patient was managed without any biliary intervention and with antibiotics, steroids, and steroid-sparing agents. There was a relapse of disease during the steroids taper that improved after hiking its doses. The disease responded with medical management on follow-up. We demonstrated the effectiveness of steroid-sparing agents to treat IgG4-related diseases, especially to avert the steroid-related adverse effects. This case highlights the possible mislead for the diagnosis and delayed management of IgG4 disease due to shared clinical features with hepatobiliary malignancies and the effectiveness of noninvasive measures of management.

High Prevalence of Hormonal Changes and Hepatic Osteodystrophy in Frail Patients with Cirrhosis-An Observational Study.

Background/Aim: Hormonal changes and hepatic osteodystrophy are less often studied complications of cirrhosis. This study describes the variance in hormones and osteodystrophy between Frail and Not frail patients with cirrhosis. Methods: 116 outpatients with cirrhosis were prospectively enrolled in this study. Frailty assessment was done using Liver Frailty Index (LFI). Sociodemographic assessment, anthropometry, nutritional assessment, hormone profile, and dual-energy X-ray absorptiometry scan were done in all patients. Results: 116 patients, predominantly males (100 (86.2%) with mean age of 50.16 years (95% CI, 48.43-51.89) were included. Malnutrition was more common in Frail group as compared to Not frail group. Subjective global assessment (SGA) class-B patients were significantly more in Frail group (37 (74%) vs 3 (4.5%), P = 0.001). The prevalence of lower parathyroid hormone (PTH) (14 (28%) vs 2 (3%)), testosterone (33 (66%) vs 15 (22.7%)), vitamin D3 (44 (88%) vs 39 (59.1%)), and cortisol (37 (74%) vs 37 (56.1) levels was higher in Frail group (P < 0.05). The number of patients diagnosed with osteodystrophy (34 (68%) vs 21 (31.8%), P = 0.001) was significantly higher in Frail group. The marker of osteoclastic activity, ß-cross laps, was significantly elevated in the Frail group both in males (736 (655-818) vs 380 (329-432), P = 0.001) and (females 619 (479-758) vs 313 (83-543), P = 0.02). Bone mineral density (BMD) at lumbar spine (LS) and neck of femur (NF) had significant correlation with LFI (ρ = 0.60, P = 0.001 for LS and ρ = 0.59, P = 0.001 for NF), serum testosterone (ρ = 0.58, P = 0.001 for LS and ρ = 0.53, P = 0.001 for NF), ß-cross laps (ρ = 0.38, P = 0.001for LS and ρ = 0.35, P = 0.000 for NF), vitamin D3 (ρ = 0.23, P = 0.04 for LS and ρ = 0.25, P = 0.01 for NF), PTH (ρ = 0.52, P = 0.001 for LS and ρ = 0.48. P = 0.001 for NF), and cortisol (ρ = 0.50, P = 0.001 for LS and ρ = 0.45, P = 0.001 for NF) levels. Conclusion: This is the first study that highlights the high prevalence of hormonal changes and hepatic osteodystrophy in frail patients with cirrhosis and opens a new dimension for research and target of therapy in this field.

Immune-mediated liver injury following COVID-19 vaccination: A systematic review.

Immune-mediated liver injury (ILI) following coronavirus disease 2019 (COVID-19) vaccination is not well-characterized. Therefore, we systematically reviewed the literature on ILI after COVID-19 vaccination. We searched PubMed, Cochrane, Ovid, Embase, and gray literature to include articles describing ILI following COVID-19 vaccination. Reports without confirmatory evidence from liver biopsy were excluded. Descriptive analysis, and study quality were reported as appropriate. Of the 1,048 articles found, 13 (good/fair quality; 23 patients) were included. Studies were primarily from Europe (n = 8), America (n = 2), Asia (n = 2), or Australia (n = 1). Patients were predominantly females (62.5%) of age 55.3 years (49.1-61.4), with an antecedent exposure to Moderna messenger RNA (mRNA)-1273 (47.8%), Pfizer-BioNTech BNT162b2 mRNA (39.2%), or ChAdOx1 nCoV-19 vaccine (13%). Pre-existing comorbidities (69.6%) were common, including liver disease in 26.1% and thyroid disorders in 13% of patients. About two-thirds of the patients were on concurrent medications (paracetamol, levothyroxine, statins, and non-steroidal anti-inflammatory drugs). Jaundice was the most common symptom (78.3%). Peak bilirubin, alanine aminotransferase, and alkaline phosphatase levels were 10.8 (6.8-14.8) mg/dl, 1,106.5 (757.0-1,702.5) U/L, and 229 (174.6-259.6) U/L, respectively. Histological findings were intense portal lymphoplasmacytic infiltrate with interface hepatitis. Steroids were used in 86.9% of patients, and complete response, recovering course, and death were reported in 56.5%, 39.1%, and 4.3% of patients, respectively. ILI following COVID-19 vaccination is rare. The diagnosis is established on temporal correlation, biochemical findings, and histopathology. Prognosis is excellent with corticosteroids. Causality establishment remains a challenge.

FibroScan-AST (FAST) Score for Nonalcoholic Steatohepatitis - Validation in an Indian Cohort.

Background: The FibroScan-AST (FAST) score was recently described to detect patients with nonalcoholic steatohepatitis (NASH) having elevated nonalcoholic fatty liver disease (NAFLD) activity score (NAS ≥ 4) and significant fibrosis (≥ F2) on liver biopsy (NASH+ NAS ≥ 4 + F ≥ 2). Aim: The aim of this study was to validate the FAST score in Indian patients with NAFLD and to derive optimal cut-offs. Methods: Sixty patients with biopsy-proven NAFLD [men: 38 (63.3%), age 40 (32-52) years] with all parameters for assessing the FAST score within 3 months of liver histology were retrospectively analysed. Results: Histological NASH was present in 17 patients (28.3%), while 11 (18.3%) patients had NASH + NAS ≥ 4 + F ≥ 2. The area under the curve (AUROC) of the FAST score for discriminating NASH + NAS ≥ 4 + F ≥ 2 was 0.81. Using cut-offs by Newsome et al, the rule-out cut-off (FAST: ≤ 0.35) had a negative predictive value (NPV) of 0.88 [sensitivity: 0.91, specificity: 0.14, negative likelihood ratio (LR): 0.64], while the rule-in cut-off (FAST: ≥ 0.67) had a positive predictive value (PPV) of 0.33 (sensitivity: 0.73, specificity: 0.67, positive LR: 2.22). Fifteen (25%) patients were correctly classified as per histology, while 28 (46.67%) patients fell in the grey zone. On recalculating the optimal cut-offs for our patients, the rule-out cut-off (FAST: ≤ 0.55) had an NPV of 0.95 (sensitivity: 0.90, specificity: 0.45, negative LR: 0.21), while the optimal rule-in cut-off (FAST: ≥ 0.78) had a PPV of 0.70 (sensitivity: 0.64, specificity 0.94, positive LR: 10.39). With these cut-offs, 27 (45%) patients fell in the grey zone and 29 (48.3%) were correctly classified as per histology, performing better than the cut-offs by Newsome et al (P < 0.001). Conclusion: The FAST score demonstrates good AUROC for detecting NASH with significant fibrosis and inflammation on histology. Cut-offs should be recalibrated based on prevalence of disease. Lay summary: India has a high burden of NAFLD with an estimated 25 million patients at potential risk for significant liver disease. Liver biopsy remains the gold standard for diagnosing NASH, although its application in routine clinical practice is limited. Noninvasive tests for the simultaneous detection of steatosis, inflammation and fibrosis are thus the need of the hour. The FAST score has been recently suggested for the noninvasive detection of NASH with significant fibrosis (≥ F2) and inflammation (NAS ≥ 4) on liver biopsy. We validated the utility of the FAST score for detecting NASH with significant fibrosis and inflammation on liver biopsy in Indian patients with NAFLD. This noninvasive, easy-to-use and nonproprietary FAST score can correctly classify disease severity in more than 50% patients. However, our results suggest that cut-offs should be recalibrated based on the anticipated prevalence of NASH + NAS ≥ 4 + F ≥ 2 in the given population.

Tuberculosis in Cirrhosis - A Diagnostic and Management Conundrum.

Background: Diagnosis and management of tuberculosis (TB) in patients with cirrhosis remains challenging. We studied the clinical spectrum, diagnosis, and management of TB along with the assessment of the diagnostic utility of various laboratory investigations in this cohort. Methods: A retrospective review of records of patients with cirrhosis (July 2017 and December 2019) was done. Out of 30 patients with cirrhosis and TB, 20 patients with pleural/peritoneal TB (cases) were compared with 20 consecutively selected spontaneous bacterial peritonitis (SBP) controls. Composite of clinical, laboratory, radiologic features and response to antituberculosis therapy (ATT) was taken as the gold standard to diagnose TB. Results: Extrapulmonary TB (EPTB) (n = 23, 76.7%) was more common. Overall, 9 (30%) patients presented with ATT-induced hepatitis. Patients with pleural/peritoneal TB had less severe hepatic dysfunction as compared to SBP group with significantly lower CTP [8 ± 1.5 vs. 9 ± 1.7 (P = 0.01)], MELD [16.3 ± 5.8 vs. 20.2 ± 6.6 (P = 0.02)] and MELD-Na [18.8 ± 5.9 vs. 22.5 ± 7.1 (P = 0.03)] scores. Median ascitic/pleural fluid total protein [2.7 (2.4-3.1) vs. 1.1 (0.9-1.2); P < 0.0001] and adenosine deaminase (ADA) levels [34.5 (30.3-42.7) vs. 15 (13-16); P < 0.0001] were significantly higher in the TB group. Total protein levels had a sensitivity and specificity 81% and 93.3%, respectively, at cut off value of >2 g/dl with an AUROC of 0.89 [(0.79-0.96); P < 0.001] whereas ADA levels at cutoff >26 IU/L showed 80% sensitivity and 90% specificity to diagnose pleural/peritoneal TB with an AUROC of 0.93 [(0.82-0.97); P < 0.001]. Only 11 (36.7%), and 8 (26.6%) patients showed positivity on GeneXpert and mTB-PCR, respectively. Patients with Child-Turcotte-Pugh scores of ≤7 and 8-10 tolerated well two and one hepatotoxic drugs, respectively. Conclusions: EPTB is more frequent in patients with cirrhosis. Relatively lower cutoffs of ascitic/pleural fluid total protein and ADA may be useful to diagnose EPTB in patients with high pretest probability. Individualized ATT with close monitoring and dynamic modifications is effective and well-tolerated.

A Comparison of Different Frailty Scores and Impact of Frailty on Outcome in Patients With Cirrhosis.

Background & aims: There is no "gold standard" tool for the assessment of frailty in cirrhosis. This study compares Liver Frailty Index (LFI), Short Physical Performance Battery (SPPB), Fried Frailty Criteria (FFC), and Clinical Frailty Scale (CFS) for frailty assessment and ascertains its impact on predicting mortality and hospitalizations in a cohort of outpatients with cirrhosis. Methods: 116 patients were enrolled in this prospective observational cohort study. Frailty assessment was done using LFI, SPPB, FFC, and CFS. All patients were followed up for 6 months. The primary outcome was the first of either all-cause unplanned hospitalization or all-cause mortality occurring within 6 months of the study period. Results: 100 (86.2%) males and 16 (13.8%) females with a mean age of 50.2 (48.4-51.9, 95% CI) years were included. The most common cause of cirrhosis was alcoholic liver disease (47.4%) followed by hepatitis C (12.9%) and Nonalcoholic steatohepatitis (NASH) (10.3%). There was no significant difference in prevalence of frailty based on LFI (43.1%), FFC (36.2%), CFS (44%), and SPPB (47.4%) (P > 0.05). Frail patients had worse outcomes compared to the Not frail group. At 6 months, the mortality rate in Frail patients was 42% versus 1.5% for the Not frail; hospitalization in Frail patients occurred in 92% versus 6% in the Not frail. On multivariable analysis, independent predictors of mortality were Frailty [OR 14 (1.4-54.2)], alcohol-related cirrhosis [OR 4.2 (1.1-16.3)], Child-Turcotte-Pugh (CTP) [OR 2.1 (1.4-2.9)] and Chronic liver disease questionnaire (CLDQ) [OR 0.1 (0.1-0.4)] scores. Conclusions: LFI, SPPB, FFC, and CFS are comparable in frailty assessment in patients with cirrhosis. Importantly, comparability of the commonly used scores for frailty assessment and prediction of hospitalization and mortality allows flexibility for clinical application.

Consolidative Thoracic Radiation Therapy After First-Line Chemotherapy and Immunotherapy in Extensive-Stage Small Cell Lung Cancer: A Multi-Institutional Case Series.

Purpose: Survival for patients with extensive-stage small cell lung cancer (ES-SCLC) remains poor. Consolidative thoracic radiation therapy (cTRT) and upfront immunotherapy with chemotherapy have each incrementally improved patient outcomes, but have not yet been combined in clinical trials. We sought to characterize outcomes and toxicities after first-line chemotherapy and immunotherapy followed by cTRT. Methods and Materials: Patients with ES-SCLC who were treated with first-line chemotherapy and immunotherapy followed by cTRT were identified at 2 institutions. Patient outcomes including overall survival (OS), progression-free survival, local progression-free survival, distant progression free-survival, and toxicity were assessed. Results: Twenty patients were included in our data set treated from 2018 to 2021 with a median follow-up of 12 months. Median OS in this cohort was 16 months with 6-month OS of 94.7% and 12-month OS of 77.5% (comparable to historical controls). There were also low rates of toxicity, including 0% grade 3+ toxicity, 0% grade 2 pneumonitis, and 5% grade 2 esophagitis. Conclusions: Treatment of ES-SCLC with first-line chemoimmunotherapy followed by cTRT appears to be safe and to have outcomes comparable to published modern clinical trials. Further studies are warranted to determine the therapeutic effect of cTRT after chemoimmunotherapy.

Multiple cycles of granulocyte colony-stimulating factor in decompensated cirrhosis: a double-blind RCT.

BACKGROUND: Liver transplant, the definitive treatment of decompensated cirrhosis (DC), is constrained by donor shortage and long-term complications. Granulocyte colony-stimulating factor (G-CSF) has been explored as an alternative option in open-label studies. This double-blind, randomized, placebo-controlled trial was designed to elucidate the efficacy of G-CSF in DC. METHODS: Seventy patients were randomized to either G-CSF plus standard medical therapy (group A, n = 35) or placebo plus standard medical therapy (group B, n = 35). Primary outcome was 12-month overall survival in patients who received at least one cycle of intervention. Secondary outcomes were mobilization of CD34+ cells at day 6, improvement in Child-Turcotte-Pugh (CTP), and model for end-stage liver disease (MELD), liver stiffness measurement, quality of life, nutrition, hepatic decompensation, infection, hospitalization, and acute kidney injury. RESULTS: Survival in group A was higher than that in Group B although the difference was not statistically significant (87.9% vs 66.7%; p = 0.053). CD34+ cells at day 6 were significantly higher in group A as compared to baseline (p < 0.001). Ascites control (p = 0.03) and CTP score improvement (p = 0.02) were better in group A at 12-months. Encephalopathy episodes (p = 0.005), infections (p = 0.005) were fewer in group A than group B at 12 months. Other secondary outcomes did not improve post-therapy. There were no treatment-related discontinuations or severe adverse events. CONCLUSIONS: G-CSF therapy is safe. The improvement in survival at 12 months is not statistically significant. Better control of ascites, improvement of CTP score, fewer encephalopathy episodes and decreased rate of infections were observed with G-CSF therapy (NCT03911037). Trials Registration NCT03911037.

Prevalence, Predictors, and Outcomes of Esophageal Candidiasis in Cirrhosis: An Observational Study With Systematic Review and Meta-Analysis (CANDID-VIEW).

BACKGROUND: Gastrointestinal candidiasis is often neglected and potentially serious infection in cirrhosis patients. Therefore, we evaluated the prevalence, risk factors, and outcomes of esophageal candidiasis (EC) in cirrhotics and did a systematic review to summarize EC's available evidence in cirrhosis. METHODS: Consecutive patients with cirrhosis posted for esophagogastroduodenoscopy (EGD) at a tertiary care institute were screened for EC (cases) between January 2019 and March 2020. EC was diagnosed on EGD findings and/or brush cytology. Controls (without EC) were recruited randomly, and EC's risk factors and outcomes were compared between cases and controls.Four electronic databases were searched for studies describing EC in cirrhosis. Prevalence estimates of EC were pooled on random-effects meta-analysis, and heterogeneity was assessed by I2. A checklist for prevalence studies was used to evaluate the risk of bias in studies. RESULTS: EC was diagnosed in 100 of 2762 patients with cirrhosis (3.6%). Patients with EC had a higher model for end-stage liver disease (MELD) (12.4 vs. 11.2; P = 0.007), acute-on-chronic liver failure (ACLF) (26% vs. 10%; P = 0.003) and concomitant bacterial infections (24% vs. 7%; P = 0.001), as compared with controls. A multivariable model, including recent alcohol binge, hepatocellular carcinoma (HCC), upper gastrointestinal (UGI) bleed, ACLF, diabetes, and MELD, predicted EC's development in cirrhosis with excellent discrimination (C-index: 0.918). Six percent of cases developed the invasive disease and worsened with multiorgan failures, and four patients with EC died on follow-up.Of 236 articles identified, EC's pooled prevalence from 8 studies (all with low-risk of bias) was 2.1% (95% CI: 0.8-5.8). Risk factors and outcomes of EC in cirrhosis were not reported in the literature. CONCLUSIONS: EC is not a rare infection in cirrhosis patients, and it may predispose to invasive candidiasis and untimely deaths. Alcohol binge, HCC, UGI bleed, ACLF, diabetes, and higher MELD are the independent predictors of EC in cirrhosis. At-risk patients with cirrhosis or those with deglutition symptoms should be rapidly screened and treated for EC.