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Background & Aims There is no histologic classification system to determine prognoses of patients with alcoholic hepatitis (AH). We identified histologic features associated with disease severity and created a histologic scoring system to predict short-term (90 day) mortality. Methods We analyzed data from 121 patients admitted to the Liver Unit (Hospital Clinic, Barcelona, Spain) from January 2000 through January 2008 with features of AH, and developed a histologic scoring system to determine risk of death using logistic regression. The system was tested and updated in a test set of 96 patients from 5 academic centers in the US and Europe, and a semi-quantitative scoring system was developed, called the alcoholic hepatitis histologic score (AHHS). The system was validated in an independent set of 109 patients. Inter-observer agreement was evaluated by weighted statistic analysis. Results Degree of fibrosis, neutrophil infiltration, type of bilirubinostasis, and presence mega-mitochondria were independently associated with 90 day mortality. We used these 4 parameters to develop the AHHS to identify patients with low (0–3 points), moderate (4–5 points), and high (6–9 points) risks of death within 90 days (3%, 19%, and 51%, respectively; P<.0001). The AHHS estimated 90 day mortality in the training and test sets with an area under the receiver operating characteristic value of 0.77 (95% confidence interval, 0.71–0.83). Inter-rate agreement values were 0.65 for fibrosis, 0.86 for bilirubinostasis, 0.60 for neutrophil infiltration, and 0.46 for megamitochondria. Interestingly, the type of bilirubinostasis predicted the development of bacterial infections. Conclusions We identified histologic features associated with severity of AH and developed a patient classification system that might be used in clinical decision making.

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Complete abstinence after an episode of AH positively impacts long-term survival. The combination of 2 variables easily obtained at admission might be useful to predict long-term abstinence after an episode of AH. Strategies aimed at promoting alcohol abstinence in these patients are necessary. (Hepatology 2017;66:1842-1853).

BACKGROUND: Checkpoint inhibitors have shown modest activity in patients with advanced hepatocellular carcinoma (HCC). Herein, the authors report a prospective single-institution clinical/translational phase 2 study of pembrolizumab in patients with advanced HCC and circulating biomarkers closely related to response. METHODS: Pembrolizumab was administered at a dose of 200 mg intravenously every 3 weeks among patients who may have developed disease progression while receiving, were intolerant of, or refused sorafenib. The circulating levels of cytokines, chemokines, programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and PD-L2 were correlated with response, tumor PD-L1 expression, and other clinicopathological features. RESULTS: A total of 29 patients were treated and 28 patients were evaluable for response. The most common laboratory grade 3/4 adverse events were increases in aspartate aminotransferase and/or alanine aminotransferase and serum bilirubin, which for the most part were reversible. In terms of efficacy, one patient achieved a complete response and 8 patients achieved partial responses for an overall response rate of 32%. Four other patients had stable disease. The median progression-free survival was 4.5 months and the median overall survival was 13 months. Response did not correlate with prior sorafenib therapy, PD-L1 tumor staining, or a prior history of hepatitis. Correlative studies revealed that high baseline plasma TGF-β levels (≥200 pg/mL) significantly correlated with poor treatment outcomes after pembrolizumab. Tumor PD-L1 and plasma PD-L1/PD-1 levels were associated with plasma IFN-γ or IL-10. CONCLUSIONS: Pembrolizumab was found to demonstrate activity in patients with advanced HCC. Toxicity generally was tolerable and reversible. A set of immunological markers in blood plasma as well as PD-L1 staining indicated that baseline TGF-β could be a predictive biomarker for response to pembrolizumab. Cancer 2019;125:3603-3614.