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Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and fibrosis of intrahepatic and extrahepatic bile ducts. PSC is frequently associated with inflammatory bowel disease (IBD). Nodular regenerative hyperplasia (NRH) can occur in IBD with the use or even in the absence of thiopurine treatment. We aimed to study the significance of the presence of NRH and obliterative portal venopathy (OPV), both causes of non-cirrhotic portal hypertension (NCPH), in patients having PSC.Patients with PSC and concurrent NRH on liver biopsy were identified from the digital pathology database covering the period 2003-2019. Evaluation of liver biopsy and the original diagnoses were confirmed on review based on standard histological features diagnostic for NRH and OPV. Clinical and laboratory data were obtained from electronic medical records.Thirty-one patients (21 male, 10 female; median age at biopsy 40.1 years) were included in the study. Twelve (38.7%) patients had OPV in addition to NRH on the liver biopsy. Nineteen (61.2%) patients had IBD including 11 with Crohn's disease (CD), 7 with ulcerative colitis (UC), and 1 with indeterminate colitis. Thirteen (41.9%) patients had evidence of portal hypertension, 10 (32.2%) with esophageal varices, 4 (12.9%) with history of variceal bleeding, 6 (19.3%) with ascites, and 14 (12.9%) with splenomegaly. Eleven (35.4%) patients had a cirrhotic-appearing liver on imaging. Twelve (38.7%) patients had a history of prior or current thiopurine use.The current study suggests that NRH with or without OPV independently occurs in patients having PSC and may lead to NCPH, even in the absence of concurrent IBD and/or thiopurine therapy.

BACKGROUND: Surgical resection of early stage hepatocellular carcinoma is standard clinical practice; however, most tumours recur despite surgery, and no perioperative intervention has shown a survival benefit. Neoadjuvant immunotherapy has induced pathological responses in multiple tumour types and might decrease the risk of postoperative recurrence in hepatocellular carcinoma. We aimed to evaluate the clinical activity of neoadjuvant cemiplimab (an anti-PD-1) in patients with resectable hepatocellular carcinoma. METHODS: For this single-arm, open-label, phase 2 trial, patients with resectable hepatocellular carcinoma (stage Ib, II, and IIIb) were enrolled and received two cycles of neoadjuvant cemiplimab 350 mg intravenously every 3 weeks followed by surgical resection. Eligible patients were aged 18 years or older, had confirmed resectable hepatocellular carcinoma, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate liver function. Patients were excluded if they had metastatic disease, if the surgery was not expected to be curative, if they had a known additional malignancy requiring active treatment, or if they required systemic steroid treatment or any other immunosuppressive therapy. After resection, patients received an additional eight cycles of cemiplimab 350 mg intravenously every 3 weeks in the adjuvant setting. The primary endpoint was significant tumour necrosis on pathological examination (defined as >70% necrosis of the resected tumour). Secondary endpoints included delay of surgery, the proportion of patients with an overall response, change in CD8(+) T-cell density, and adverse events. Tumour necrosis and response were analysed in all patients who received at least one dose of cemiplimab and completed surgical resection; safety and other endpoints were analysed in the intention-to-treat population. Patients underwent pre-treatment biopsies and blood collection throughout treatment. This trial is registered with ClinicalTrials.gov (NCT03916627, Cohort B) and is ongoing. FINDINGS: Between Aug 5, 2019, and Nov 25, 2020, 21 patients were enrolled. All patients received neoadjuvant cemiplimab, and 20 patients underwent successful resection. Of the 20 patients with resected tumours, four (20%) had significant tumour necrosis. Three (15%) of 20 patients had a partial response, and all other patients maintained stable disease. 20 (95%) patients had a treatment-emergent adverse event of any grade during the neoadjuvant treatment period. The most common adverse events of any grade were increased aspartate aminotransferase (in four patients), increased blood creatine phosphokinase (in three), constipation (in three), and fatigue (in three). Seven patients had grade 3 adverse events, including increased blood creatine phosphokinase (in two patients) and hypoalbuminaemia (in one). No grade 4 or 5 events were observed. One patient developed pneumonitis, which led to a delay in surgery by 2 weeks. INTERPRETATION: This report is, to our knowledge, the largest clinical trial of a neoadjuvant anti-PD-1 monotherapy reported to date in hepatocellular carcinoma. The observed pathological responses to cemiplimab in this cohort support the design of larger trials to identify the optimal treatment duration and definitively establish the clinical benefit of preoperative PD-1 blockade in patients with hepatocellular carcinoma. FUNDING: Regeneron Pharmaceuticals.

Objectives The 8th edition American Joint Committee on Cancer (AJCC) staging system for hepatocellular carcinoma (HCC) has been criticized for failing to stratify patients. We aimed to reassess and modify the tumor staging criteria for HCC. Methods Three independent study cohorts were collected and analyzed. Results The initial cohort consists of 103 patients with HCC. By Kaplan-Meier survival analysis, the 8th edition failed to distinguish between T1b and T2. Only tumor size and large vessel invasion, but not small vessel invasion or other histopathologic parameters, predicted HCC survival. We modified the T staging criteria by eliminating small vessel invasion while emphasizing tumor size in the middle categories (T2 and T3), which achieved more even distribution of cases and significantly improved risk stratifications (P Conclusions Our study showed that tumor size, but not small vessel invasion, predicts survival in patients with HCC. We suggest incorporating our modified T staging criteria in future AJCC revisions.

ObjectivesPlasma cell–rich rejection (PCCR), also known as “plasma cell hepatitis” or “de novo autoimmune hepatitis,” is a cause of allograft dysfunction occurring post–liver transplantation (LT). Patients often develop allograft failure and may require repeat LT. PCRR may fall within the spectrum of different histologies associated with antibody-mediated rejection (AMR), which is associated with donor-specific antibodies (DSAs) and positive complement component C4 (C4d) immunostaining. We sought to analyze the histologic and clinical outcomes of patients having biopsy-proven PCRR as well as to examine its C4d staining and DSA profiles.MethodsWe identified patients having PCRR between 2000 and 2020 using the electronic pathology database at our institution. We included patients who underwent at least one follow-up liver biopsy after establishing the PCRR diagnosis to assess future histologic progression and outcomes. Mean fluorescence intensity for at least one single DSA of 2,000 or higher was considered positive. Histologic diagnosis of PCRR was independently made by an experienced liver pathologist.ResultsA total of 35 patients were included in the study. Hepatitis C virus was the most common etiology for LT (59.5%). Mean ± SD age at LT was 49.0 ± 12.7 years. Forty percent of patients developed PCRR within 2 years of LT. Most patients (68.5%) had negative outcomes, with progression from PCRR to cirrhosis or chronic ductopenic rejection (CDR). Patients who had hepatitis C virus were more likely to develop cirrhosis rather than CDR following the PCRR diagnosis (P = .01). Twenty-three (65.7%) patients had at least one prior episode of T-cell–mediated rejection before being diagnosed with PCRR. DSAs were positive in 16 of 19 patients assessed, and C4d immunostaining was positive in 9 of 10 patients.ConclusionsDevelopment of PCRR negatively affects liver allograft outcomes and patient survival after LT. The presence of DSA and C4d in PCRR patients supports it to be within the histologic spectrum of AMR.

Background & aims Tufting enteropathy (TE) is a rare congenital disorder often caused by mutations in the gene encoding epithelial cell adhesion molecule (EpCam). The disease leads to diarrhea, intestinal failure and dependence on total parenteral nutrition (TPN). These patients often have liver impairments, but the pathology and mechanism of the damage are not well understood. We evaluated liver biopsies from TE patients to understand the pathophysiology. Methods We identified three patients with TE who underwent liver biopsy. Two normal controls and 45 patients on TPN secondary to short gut syndrome were selected for comparison (5 were age- and TPN duration-matched to the TE patients). Results We found that all TE patients showed a complete loss of EpCam expression in enterocytes and biliary epithelial cells, while the normal and TPN groups show basolateral expression. Histologically TE patients showed ductopenia, which was not seen in control groups. E-cadherin and β-catenin are normally located along the lateral membrane of biliary epithelial cells. However, they were relocated to the apical membrane in TE patients, indicating a defect in the apical-basal polarity of cholangiocytes. We examined hepatic reparative cells and found near absence of hepatic progenitor cells and intermediate hepatobiliary cells with mild reactive ductular cells in TE patients. Conclusion Our findings show that TE is associated with disrupted polarity of cholangiocyte and ductopenia. We demonstrate for the first time a role of EpCam in the maintenance of integrity of biliary epithelium. We also provided evidence for a disrupted development of hepatic reparative cells.

Purpose: We evaluated ctDNA as a pharmacodynamic and predictive biomarker in patients (pts) with resectable HCC treated with cemiplimab (anti-programmed cell death-1). Background: A biomarker-focused study of neoadjuvant cemiplimab in resectable HCC demonstrated acceptable safety and pathologic responses that were associated with immune signatures of intratumoral T-cell response (Marron TU et al. Lancet Gastroenterol. Hepatol. 2022). ctDNA is emerging as a tool to monitor therapy responses and predict RFS in perioperative HCC studies. Methods: We enrolled 21 pts who received 2 cycles of neoadjuvant cemiplimab (350 mg intravenous every 3 weeks), followed by surgical resection and 8 cycles of adjuvant cemiplimab (NCT03916627). The primary endpoint was significant tumor necrosis (STN; >70% necrosis). Secondary endpoints included safety, RFS, and overall survival. A post hoc analysis examined pathological response (≥50% necrosis). Pts underwent pretreatment biopsies and longitudinal blood collection for ctDNA analyses using bespoke multiplex PCR-next generation sequencing (Signatera). We evaluated correlatives of ctDNA changes and the prognostic value undetectable ctDNA after surgery on RFS. Results: Median pt age was 68 years; 52% were Asian, 43% white, and 5% Black; 19% were also Hispanic; 62% had a history of viral hepatitis. ctDNA measurements at baseline and after 1 dose of cemiplimab were available from 19 pts who completed neoadjuvant cemiplimab and underwent successful surgical resection. Pre-surgical absolute ctDNA levels decreased by >50% in 10 pts, including all with greater than 50% tumor necrosis. As of August 1, 2022; median follow-up for the adjuvant period was 23 months (interquartile range: 20-26 months). 8 pts of the 19 pts have relapsed. Pts with a >50% decrease in ctDNA had median RFS of 28 months (95% CI 10, 28), vs 17 months (95% CI 4, not evaluable [NE]) in those with ≤50% decrease in ctDNA. 17 pts had a baseline ctDNA measurement, surgical resection, and data following surgery. ctDNA detection following surgery was associated with disease relapse (Fischer’s exact test, p=0.015), shorter RFS (median 10 months, 95% CI: 4, 28) compared to ctDNA-negative pts (not reached, 95% CI 13 months, NE; hazard ratio 0.14, p=0.006), and identified molecular relapse based on ctDNA with a median lead time of 5 months before imaging relapse. 20 pts (95%) were alive at last follow-up. Interpretation: Changes in ctDNA identify early response to immunotherapy more accurately than standard modalities such as imaging, correlating closely with pathological responses and RFS. ctDNA monitoring during neoadjuvant treatment and following surgery may identify pts with early antitumor responses, improve the prediction of disease relapse or RFS, and inform additional early treatment decisions. Citation Format: Thomas U. Marron, Laura Brennan, Pauline Hamon, Maria Isabel Fiel, Stephen C. Ward, Yuan O. Zhu, Edward Kim, Alice O. Kamphorst, Pradeep Thanigaimani, Thomas S. Uldrick, Natalie Lucas, Kathy Wu, Olivia Hapanowicz, Paula King, Siyu Li, Elizabeth Miller, Nina Bhardwaj, Gavin Thurston, Israel Lowy, Sacha Gnjatic, Myron E. Schwartz, Vladimir Jankovic, Miriam Merad. Circulating tumor DNA (ctDNA) correlates closely with tumor necrosis and relapse-free survival (RFS) in hepatocellular carcinoma (HCC) patients treated with perioperative cemiplimab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2178.

Obesity-induced chronic liver inflammation is a hallmark of nonalcoholic steatohepatitis (NASH)-an aggressive form of nonalcoholic fatty liver disease. However, it remains unclear how such a low-grade, yet persistent, inflammation is sustained in the liver. Here, we show that the macrophage phagocytic receptor TREM2, induced by hepatocyte-derived sphingosine-1-phosphate, was required for efferocytosis of lipid-laden apoptotic hepatocytes and thereby maintained liver immune homeostasis. However, prolonged hypernutrition led to the production of proinflammatory cytokines TNF and IL-1β in the liver to induce TREM2 shedding through ADAM17-dependent proteolytic cleavage. Loss of TREM2 resulted in aberrant accumulation of dying hepatocytes, thereby further augmenting proinflammatory cytokine production. This ultimately precipitated a vicious cycle that licensed chronic inflammation to drive simple steatosis transition to NASH. Therefore, impaired macrophage efferocytosis is a previously unrecognized key pathogenic event that enables chronic liver inflammation in obesity. Blocking TREM2 cleavage to restore efferocytosis may represent an effective strategy to treat NASH.

Giant pedunculated hepatocellular adenomas are extremely rare tumors and often detected incidentally on cross-sectional imaging studies. We report the case of a 34-year-old woman who underwent cross-sectional imaging for staging evaluation of a uterine tumor. A large left subdiaphragmatic mass, without clear connection to the liver, was seen prompting diagnostic laparoscopy; during which a large pedunculated mass attached to the left lobe of the liver was found and resected. This case report highlights the challenges and pitfalls in the imaging diagnosis of pedunculated hepatocellular adenomas, such as difficulty in characterizing the mass or inability to identify the vascular attachment to the liver. Image-guided biopsy and diagnostic laparoscopy are valuable tools to establish diagnosis; most of these lesions are amenable to laparoscopic resection.

BACKGROUND AND AIMS: Cholangiocarcinoma (CCA), a deadly malignancy of the bile ducts, can be classified on the basis of its anatomical location into either intrahepatic (iCCA) or extrahepatic (eCCA), each with different pathogenesis and clinical management. There is marginal understanding of the molecular landscape of eCCA and no targeted therapy with clinical efficacy has been approved. We aimed to provide a molecular classification of eCCA and identify potential targets for molecular therapies. METHODS: An integrative genomic analysis of an international multi-center cohort of 189 eCCA cases was conducted. Genomic analysis included whole-genome expression, targeted DNA-sequencing and immunohistochemistry. Molecular findings were validated in an external set of 181 biliary tract tumors from ICGC. RESULTS: KRAS (36.7%), TP53 (34.7%), ARID1A (14%) and SMAD4 (10.7%) were the most prevalent mutations, with ~25% of tumors having a putative actionable genomic alteration according to OncoKB. Transcriptome-based unsupervised clustering helped us define four molecular classes of eCCA. Tumors classified within the Metabolic class (19%) showed a hepatocyte-like phenotype with activation of the transcription factor HNF4A and enrichment in gene signatures related to bile acid metabolism. The Proliferation class (23%), more common in patients with distal CCA, was characterized by enrichment of MYC targets, ERBB2 mutations / amplifications and mTOR signaling activation. The Mesenchymal class (47%) was defined by signatures of epithelial-mesenchymal transition, aberrant TGF-β signaling and poor overall survival. Finally, tumors in the Immune class (11%) had a higher lymphocyte infiltration, overexpression of PD-1/PD-L1 and molecular features associated with a better response to immune checkpoint inhibitors. CONCLUSION: An integrative molecular characterization identified distinct subclasses of eCCA. Genomic traits of each class provide the rationale for exploring patient stratification and novel therapeutic approaches. LAY SUMMARY: Targeted therapies have not been approved for the treatment of extrahepatic cholangiocarcinoma. We performed a multi-platform molecular characterization of this tumor in a cohort of 189 patients. These analyses revealed four novel transcriptome-based molecular classes of extrahepatic cholangiocarcinoma and identified ~25% of tumors with actionable genomic alterations, which has potential prognostic and therapeutic implications.

PURPOSE National Cancer Institute (NCI)–sponsored clinical trial network studies frequently require biopsy specimens for pharmacodynamic and molecular biomarker analyses, including paired pre- and post-treatment samples. The purpose of this meeting of NCI-sponsored investigators was to identify local institutional standard procedures found to ensure quantitative and qualitative specimen adequacy. METHODS NCI convened a conference on best biopsy practices, focusing on the clinical research community. Topics discussed were (1) criteria for specimen adequacy in the personalized medicine era, (2) team-based approaches to ensure specimen adequacy and quality control, and (3) risk considerations relevant to academic and community practitioners and their patients. RESULTS AND RECOMMENDATIONS Key recommendations from the convened consensus panel included (1) establishment of infrastructure for multidisciplinary biopsy teams with a formalized information capture process, (2) maintenance of standard operating procedures with regular team review, (3) optimization of tissue collection and yield methodology, (4) incorporation of needle aspiration and other newer techniques, and (5) commitment of stakeholders to use of guideline documents to increase awareness of best biopsy practices, with the goal of universally improving tumor biopsy practices.

Background Lysosomal acid lipase (LAL) deficiency is an ultra-rare, progressive, autosomal recessive disorder. Functional mutations in LIPA, the gene that encodes LAL, result in accumulation of cholesteryl esters and triglycerides in hepatocytes and in the macrophages of the intestines, vascular endothelial system, and numerous other organs. LAL deficiency has a broad clinical spectrum; children and adults can present with dyslipidemia, liver enzyme elevations, hepatosplenomegaly, hepatic steatosis, liver fibrosis and/or cirrhosis, and vascular disease, which may lead to significant morbidity and premature mortality in some patients. Given the systemic involvement and the wide range of healthcare specialists who manage patients with LAL deficiency, there is a need for guidelines to assess and monitor disease involvement. Objectives To provide a set of recommendations for the initial assessment and ongoing monitoring of patients with LAL deficiency to help physicians in various disciplines effectively manage the disease based on the observed presentation and progression in each case. Methods A group of internationally recognized healthcare specialists with expertise in clinical genetics, pathology, hepatology, gastroenterology, cardiology, and lipidology convened to develop an evidence-based consensus of best practices for the initial assessment and ongoing monitoring of children and adults with LAL deficiency, regardless of treatment status; infants with LAL deficiency have been excluded from these guidelines because they require specialized care. Results The authors present guidance for the assessment and monitoring of patients with LAL deficiency based on age and disease manifestations that include the hepatic, cardiovascular, and gastrointestinal systems. A schedule for ongoing monitoring of disease progression is provided. In addition, the need to establish an interdisciplinary and integrated care team to optimize the approach to managing this systemic disease is highlighted. Conclusions There is currently no published guidance on the assessment and monitoring of patients with LAL deficiency. These consensus recommendations for the initial assessment and ongoing monitoring of children and adults with LAL deficiency are intended to help improve the management of these patients.

Window-of-opportunity trials, during which patients receive short-duration pre-surgical therapies, provide a platform for understanding the therapies’ mechanisms of action, but will require a paradigm shift in trial design, specimen collection and analysis.

Non-alcoholic steatohepatitis (NASH) is a rising health challenge, with no approved drugs. We used a computational drug repositioning strategy to uncover a novel therapy for NASH, identifying a GABA-B receptor agonist, AZD3355 (Lesogaberan) previously evaluated as a therapy for esophageal reflux. AZD3355’s potential efficacy in NASH was tested in human stellate cells, human precision cut liver slices (hPCLS), and in vivo in a well-validated murine model of NASH. In human stellate cells AZD3355 significantly downregulated profibrotic gene and protein expression. Transcriptomic analysis of these responses identified key regulatory nodes impacted by AZD3355, including Myc, as well as MAP and ERK kinases. In PCLS, AZD3355 down-regulated collagen1α1, αSMA and TNF-α mRNAs as well as secreted collagen1α1. In vivo, the drug significantly improved histology, profibrogenic gene expression, and tumor development, which was comparable to activity of obeticholic acid in a robust mouse model of NASH, but awaits further testing to determine its relative efficacy in patients. These data identify a well-tolerated clinical stage asset as a novel candidate therapy for human NASH through its hepatoprotective, anti-inflammatory and antifibrotic mechanisms of action. The approach validates computational methods to identify novel therapies in NASH in uncovering new pathways of disease development that can be rapidly translated into clinical trials.

Patients with hepatitis C virus (HCV) often have elevated serum markers and histologic features of autoimmune hepatitis (AIH). We evaluated an HCV‐positive (HCV+) study group that had elevated serum markers of AIH before starting direct‐acting antiviral (DAA) therapy (n = 21) and compared them to an HCV+ control group that did not have laboratory studies suggesting AIH (n = 21). Several patients in the study (17/21) and control (11/21) groups had liver biopsies before DAA treatment, and many were biopsied due to elevated serum markers of AIH. Evaluation of pre‐DAA treatment liver biopsies showed histologic features suggestive of AIH in 64.7% (11/17) of the study group and 45.5% (5/11) of the control group. Patients who were HCV+ with elevated serum markers of AIH had significantly increased hepatitis activity (P

Objectives Amiodarone-induced liver injury (AILI) is histopathologically similar to alcoholic steatohepatitis (ASH). We sought to elucidate their histologic differences and develop a scoring system to differentiate these two entities. Methods A cohort of 17 AILI and 17 ASH cases was included in the initial study. Cases from three different institutions were included for further validation. Results Macrovesicular steatosis was usually below 10% of the liver parenchyma in AILI. Hepatocyte ballooning degeneration was more common in ASH than in AILI. “Balloon-like” hepatocyte was more common in AILI than in ASH. Lobular neutrophilic inflammation, satellitosis, and cholestasis were more common in ASH. Mallory-Denk bodies and pericellular fibrosis in AILI were mainly located in zone 1 compared with a panacinar or zone 3 distribution in ASH. A scoring system was developed in which points were assigned to different histologic features; a total sum of less than 5 suggests AILI, more than 5 is ASH, and 5 is equivocal. This scoring system was then evaluated on a test cohort comprising 14 AILI cases, in which 13 cases were correctly assigned with a score less than 5. The sensitivity, specificity, and accuracy for diagnosing AILI in the test cohort were 92.9%, 91.7%, and 92.3%, respectively. Conclusions This scoring system can aid pathologists to differentiate AILI from ASH.

Background Neoadjuvant chemotherapy (NAC) is frequently used in gastrointestinal cancers (GIC), and pathological, radiological, and tumor marker responses are assessed during and after NAC. Aim To evaluate the relationship between pathologic, radiologic, tumor marker responses and recurrence‐free survival (RFS), overall survival (OS), adjuvant chemotherapy (AC) decisions, and the impact of changing to a different AC regimen after poor response to NAC. Methods and results Medical records of GIC patients treated with NAC at Mount Sinai between 1/2012 and 12/2018 were reviewed. One hundred fifty‐six patients (58.3% male, mean age 63 years) were identified. Primary tumor sites were: 43 (27.7%) pancreas, 62 (39.7%) gastroesophageal, and 51 (32.7%) colorectal. After NAC, 31 (19.9%) patients had favorable pathologic response (FPR; defined as College of American Pathologists [CAP] score 0–1). Of 107 patients with radiological data, 59 (55.1%) had an objective response, and of 113 patients with tumor marker data, 61 (54.0%) had a ≥50% reduction post NAC. FPR, but not radiographic or serological responses, was associated with improved RFS (HR 0.28; 95% CI 0.11–0.72) and OS (HR 0.13; 95% CI 0.2–0.94). Changing to a different AC regimen from initial NAC, among all patients and specifically among those with unfavorable pathological response (UPR; defined as CAP score 2–3) after NAC, was not associated with improved RFS or OS. Conclusions GIC patients with FPR after NAC experienced significant improvements in RFS and OS. Patients with UPR did not benefit from changing AC. Prospective studies to better understand the role of pathological response in AC decisions and outcomes in GIC patients are needed.

Non-alcoholic steatohepatitis (NASH) is a rising health challenge, with no approved drugs. We used a computational drug repositioning strategy to uncover a novel therapy for NASH, identifying a GABA-B receptor agonist, AZD3355 (lesogaberan) previously evaluated as a therapy for esophageal reflux. AZD3355’s potential efficacy in NASH was tested in human stellate cells, human precision cut liver slices (hPCLS), and in vivo in a well-validated murine model of NASH. In human stellate cells AZD3355 significantly downregulated profibrotic gene and protein expression. Transcriptomic analysis of these responses identified key regulatory nodes impacted by AZD3355, including Myc, as well as MAP and ERK kinases. In PCLS, AZD3355 down-regulated collagen1α1, aSMA and TNF-a mRNA as well as secreted collagen1a1. In vivo, the drug significantly improved histology, profibrogenic gene expression, and tumor development in a robust murine model of NASH, which was comparable to activity of obeticholic acid, an advanced investigational therapy for this disease. These data identify a well-tolerated clinical stage asset as a novel therapy for human NASH through its hepatoprotective, anti-inflammatory and antifibrotic mechanisms of action. The approach validates computational methods to identify novel therapies in NASH in uncovering new pathways of disease development that can be rapidly translated into clinical trials.

Steatohepatitic hepatocellular carcinoma (SH-HCC) is a variant of hepatocellular carcinoma (HCC) with established association with nonalcoholic steatohepatitis (NASH), while its association with alcoholic steatohepatitis (ASH) is unclear. We studied 2 cohorts of patients who underwent resection for HCC in the setting of steatohepatitis. In our Mount Sinai (New York) cohort, we found SH-HCC in 17/24 (71%) patients with NASH and in 14/19 (74%) patients with ASH, while SH-HCC was the predominant tumor morphology in 12/24 (50%) in the NASH group and 9/19 (47%) in the ASH group. Upon review, 12/19 patients diagnosed with ASH also had diabetes and/or a body mass index >30. When these patients were removed, we still found similar rates of SH-HCC (6/7 [86%] showed SH-HCC, while SH-HCC was predominant in 3/7 [43%]. Interestingly, glycogenated hepatocyte nuclei were seen in the nontumor liver in 4/7 (57%) of these cases. In our Japan cohort, we also found similar rates of SH-HCC in NASH and ASH patients with HCC, 15/58 (26%), and 16/45 (36%), respectively. We determined molecular subclassification of tumors from the Japan cohort and found no difference in the distribution of S1, S2 and S3 subclasses among the ASH and NASH groups, though, among cases of SH-HCC, there was a trend toward an association of ASH with S1 (P=0.054) and NASH with S3 (P=0.052). Our study shows that SH-HCC is common in both ASH and NASH and that both underlying liver diseases produce tumors with similar molecular profiles, though different pathways may underlie the development of SH-HCC in ASH versus NASH.

Cancer heterogeneity and evolution are not fully understood. Here, we show that mitochondrial DNA of the normal liver shapes tumor progression, histology, and immune environment prior to the acquisition of oncogenic mutation. Using conplastic mice, we show that mtDNA dictates the expression of the mitochondrial unfolded protein response (UPRmt) in the normal liver. Activation of oncogenic mutations in UPRmt-positive liver increases tumor incidence and histological heterogeneity. Further, in a subset of UPRmt-positive mice, invasive liver cancers develop. RNA sequencing (RNA-seq) analysis of the normal liver reveals that, in this subset, the PAPP-A/DDR2/SNAIL axis of invasion pre-exists along with elevated collagen. Since PAPP-A promotes immune evasion, we analyzed the immune signature and found that their livers are immunosuppressed. Further, the PAPP-A signature identifies the immune exhausted subset of hepatocellular carcinoma (HCC) in humans. Our data suggest that mtDNA of normal liver shapes the entire liver cancer portrait upon acquisition of oncogenic mutations. This work was supported by an RO1 AG059635 award from the NIH to D.G. Sí

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated clinical syndrome COVID-19 are causing overwhelming morbidity and mortality around the globe and disproportionately affected New York City between March and May 2020. Here, we report on the first 100 COVID-19-positive autopsies performed at the Mount Sinai Hospital in New York City. Autopsies revealed large pulmonary emboli in six cases. Diffuse alveolar damage was present in over 90% of cases. We also report microthrombi in multiple organ systems including the brain, as well as hemophagocytosis. We additionally provide electron microscopic evidence of the presence of the virus in our samples. Laboratory results of our COVID-19 cohort disclose elevated inflammatory markers, abnormal coagulation values, and elevated cytokines IL-6, IL-8, and TNFα. Our autopsy series of COVID-19-positive patients reveals that this disease, often conceptualized as a primarily respiratory viral illness, has widespread effects in the body including hypercoagulability, a hyperinflammatory state, and endothelial dysfunction. Targeting of these multisystemic pathways could lead to new treatment avenues as well as combination therapies against SARS-CoV-2 infection.

Nivolumab is an immune checkpoint inhibitor (ICI) approved for treatment of many cancers, including hepatocellular carcinoma (HCC). Liver injury is a known complication in patients treated with nivolumab for nonliver tumors. To date, the morphologic changes to tumor and nontumor liver have not been well-characterized in HCC patients. We identified 20 patients who underwent partial hepatectomy or liver transplantation after receiving nivolumab for HCC. Demographics, laboratory values, and imaging results were obtained from medical records. All available slides from resection specimens were evaluated for tumor necrosis, tumor-infiltrating lymphocytes (TILs), and features of liver injury. Patients in the study included 16 males and 4 females with median age of 56 years. The underlying liver disease was HBV in 10, HCV in 6, and unknown/other in 4. Twelve patients were treated with nivolumab in the neoadjuvant setting, whereas eight were treated with nivolumab, usually along with other therapies, before undergoing liver transplantation. On review of resection specimens, three patients (all from the neoadjuvant group) demonstrated marked treatment response attributable to nivolumab. TILs were present in 17/20 cases. One case that showed treatment response in the neoadjuvant group demonstrated non-necrotizing granulomas and prominent bile duct intraepithelial lymphocytes (IELs) in the nontumor liver. One case from the transplant group showed bile duct damage and prominent ductular reaction after long-term nivolumab therapy (32 doses). Our findings indicate that nivolumab is effective in a subset of patients, including in the neoadjuvant setting. Granulomas and bile duct IELs are rare findings in cases treated with nivolumab but, when seen, may indicate potential response to therapy. Bile duct damage and ductular reaction may be manifestations of long-term nivolumab therapy. Future prospective and longitudinal studies with pretreatment tumor biopsies may help identify patients apt to respond to ICI therapy and further characterize patterns of ICI-related liver injury.

Case series Patients: Male, 76-year-old • Male, 53-year-old Final Diagnosis: Disseminate tuberculosis and liver tuberculoma Symptoms: Fatigue Medication: — Clinical Procedure: — Specialty: Surgery Objective: Unknown ethiology Background: Miliary tuberculosis (MT) is the disseminated form of tuberculosis (TB) and it is a potentially fatal condition. Diagnosis is often delayed because symptoms are typically nonspecific or absent, and misdiagnosis in favor of other diseases is common. We report 2 cases of disseminated TB that were diagnosed during or after surgeries performed for other suspected diseases. Case Report: Imaging findings are not specific and cannot be relied upon to raise suspicion of MT. In the first case, besides other imaging techniques, we also performed a positron emission tomography-computed tomography (PET-CT) on the patient and the resulting, thick, fluorodeoxyglucose (FDG)-avid ring surrounding the liver first led to concern for peritoneal carcinomatosis. TB peritonitis was only identified on laparoscopy and biopsy. In the second case, CT and magnetic resonance imaging (MRI) findings of a solitary liver mass with an irregular enhancing rim and progressive enhancement led to a radiographic diagnosis of likely intrahepatic cholangiocarcinoma, The subsequent finding that the lesion was intensely FDG-avid without other foci of FDG uptake led to the decision to proceed with resection without a prior biopsy. Conclusions: We have presented 2 patients with TB in whom clinical and imaging findings, and in particular, FDG-PET imaging, led to an erroneous clinical diagnosis of malignancy. An awareness that TB remains very much an active clinical problem in North America and that there are other reasons for FDG uptake on PET imaging besides cancer, is necessary in order to avoid unnecessary and potentially deleterious interventions in patients with TB.

Clonal evolution of a tumor ecosystem depends on different selection pressures that are principally immune and treatment mediated. We integrate RNA-seq, DNA sequencing, TCR-seq and SNP array data across multiple regions of liver cancer specimens to map spatio-temporal interactions between cancer and immune cells. We investigate how these interactions reflect intra-tumor heterogeneity (ITH) by correlating regional neo-epitope and viral antigen burden with the regional adaptive immune response. Regional expression of passenger mutations dominantly recruits adaptive responses as opposed to hepatitis B virus and cancer-testis antigens. We detect different clonal expansion of the adaptive immune system in distant regions of the same tumor. An ITH-based gene signature improves single-biopsy patient survival predictions and an expression survey of 38,553 single cells across 7 regions of 2 patients further reveals heterogeneity in liver cancer. These data quantify transcriptomic ITH and how the different components of the HCC ecosystem interact during cancer evolution., Immune-mediated selection pressures impact the clonal evolution of tumours. Here, in hepatocellular carcinoma the authors map spatio-temporal interactions between tumor and immune cells, highlighting the regulatory substrate of intra-tumoural heterogeneity that correlates with regional adaptive immune responses.

Background & Aims: Primary sclerosing cholangitis (PSC) is characterized by chronic cholestasis and inflammation, which promotes cirrhosis and an increased risk of cholangiocellular carcinoma (CCA). The transcription factor Krueppel-like-factor-6 (KLF6) is a mediator of liver regeneration, steatosis, and hepatocellular carcinoma (HCC), but no data are yet available on its potential role in cholestasis. Here, we aimed to identify the impact of hepatic KLF6 expression on cholestatic liver injury and PSC and identify potential effects on farnesoid-X-receptor (FXR) signalling. Methods: Hepatocellular KLF6 expression was quantified by immunohistochemistry (IHC) in liver biopsies of PSC patients and correlated with serum parameters and clinical outcome. Liver injury was analysed in hepatocyte-specific Klf6-knockout mice following bile duct ligation (BDL). Chromatin-immunoprecipitation-assays (ChIP) and KLF6-overexpressing HepG2 cells were used to analyse the interaction of KLF6 and FXR target genes such as NR0B2. Results: Based on IHC, PSC patients could be subdivided into two groups showing either low (80%) hepatocellular KLF6 expression. In patients with high KLF6 expression, we observed a superior survival in Kaplan-Meier analysis. Klf6-knockout mice showed reduced hepatic necrosis following BDL when compared to controls. KLF6 suppressed NR0B2 expression in HepG2 cells mediated through binding of KLF6 to the NR0B2 promoter region. Conclusion: Here, we show an association between KLF6 expression and the clinical course and overall survival in PSC patients. Mechanistically, we identified a direct interaction of KLF6 with the FXR target gene NR0B2.

Sclerosing hemangiomas of the liver are rare benign tumors of the liver. Although hepatic hemangiomas are the most common benign liver tumor, they are mostly cavernous in nature. A hepatic sclerosing hemangioma is defined by presence of fibrosis and hyalinization as a result of degenerative changes in a cavernous hemangioma. The radiological features of sclerosing hepatic hemangioma can resemble those of cholangiocarcinoma, fibrolamellar carcinoma, or metastasis. We present a case of a hepatic sclerosing hemangioma in which an unusual magnetic resonance imaging (MRI) and computed tomography (CT) appearance lead to radiographic concern for gallbladder carcinoma. To the best of our knowledge, this is the first case in the literature of a hepatic sclerosing hemangioma mimicking a gallbladder carcinoma.

Introduction: Hepatic resection is the accepted treatment of early-stage hepatocellular carcinoma (HCC), however, the majority of tumors recur despite surgery and no perioperative intervention has demonstrated a survival advantage. Neoadjuvant immunotherapy has shown success in inducing pathological responses alongside induction of immune memory in multiple tumor types and is being evaluated to determine its potential in HCC. Methods: We recently completed accrual into a trial of perioperative cemiplimab (anti-PD-1) for resectable HCC (NCT03916627, Cohort B). This trial enrolled 21 patients to receive 2 cycles of neoadjuvant cemiplimab (350 mg Q3W) followed by surgical resection and an additional 8 adjuvant cycles. The primary endpoint was significant tumor necrosis, defined as >70% necrosis of the resected tumor. Secondary endpoints included delay of surgery, overall response rate, adverse events (AEs), and change in lymphocyte infiltration. Patients underwent pre-treatment biopsies and regular blood collection throughout treatment to enable exploratory analyses including multiplex IHC and single-cell proteomic and transcriptomic analysis. The final patient enrolled underwent resection on December 28, 2020. Results: Over the course of 18 months, 21 patients were enrolled. All patients received 2 cycles of preoperative cemiplimab, and all but 1 patient underwent successful resection; 1 patient was found to have metastatic disease at the time of surgery and resection was aborted. Cemiplimab demonstrated an acceptable risk-benefit profile: 90.5% of patients experienced any treatment-emergent AE (TEAE) of any grade during the neoadjuvant treatment period through the perioperative period; 28.6% of patients experienced any Grade 3 TEAE. One patient experienced Grade 3 pneumonitis during neoadjuvant therapy and surgery was delayed by 2 weeks past protocol defined surgical window. Of the 20 patients with resected tumors, 4 (20%) met the predefined endpoint of >70% tumor necrosis and 7 (35%) had ≥50% tumor necrosis. Three (15%) of the 4 patients with >70% tumor necrosis had a pathological complete response, defined as 100% tumor necrosis. We observed similar patterns of change in degree of necrosis on pathological assessment and 3D MRI at baseline and following completion of immunotherapy. Initial pathological assessment suggests an association between immune cell infiltration and tumor response. Tissue analysis is ongoing and multiplex IHC relating myeloid and lymphoid infiltration patterns with response to cemiplimab will be presented at the meeting. Conclusion: This is the largest trial reported to date of neoadjuvant PD-1 targeted monotherapy in HCC. Pathological response data support larger trials to identify optimal clinical endpoints that correlate with improvement in survival, and to establish the utility and safety of perioperative PD-1 blockade. Citation Format: Thomas Urban Marron, Ganesh Gunasekaran, Parissa Tabrizian, Edward Kim, Maria Isabel Fiel, Stephen Ward, Zhen Zhao, Deborah Doroshow, Meredith Legg, Ashley Hammad, Paul Kennedy, Guray Akturk, Pauline Hamon, Antoinette Bonaccorso, Daniel Labow, Sacha Gnjatic, Bachir Taouli, Elizabeth Miller, Pradeep Thanigaimani, Nathalie Fiaschi, Jennifer Sims, Jayakumar Mani, Nicola James, Sara Hamon, Vladimir Jankovic, Siyu Li, Hung Kam Cheung, Gavin Thurston, Israel Lowy, Myron Schwartz, Miriam Merad. Neoadjuvant cemiplimab demonstrates complete pathological responses in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT182.

Krüppel-like factor 6 (KLF6) is a transcription factor and tumor suppressor. We previously identified KLF6 as mediator of hepatocyte glucose and lipid homeostasis. The loss or reduction of KLF6 is linked to the progression of hepatocellular carcinoma, but its contribution to liver regeneration and repair in acute liver injury are lacking so far. Here we explore the role of KLF6 in acute liver injury models in mice, and in patients with acute liver failure (ALF). KLF6 was induced in hepatocytes in ALF, and in both acetaminophen (APAP)- and carbon tetrachloride (CCl4)-treated mice. In mice with hepatocyte-specific Klf6 knockout (DeltaKlf6), cell proliferation following partial hepatectomy (PHx) was increased compared to controls. Interestingly, key autophagic markers and mediators LC3-II, Atg7 and Beclin1 were reduced in DeltaKlf6 mice livers. Using luciferase assay and ChIP, KLF6 was established as a direct transcriptional activator of ATG7 and BECLIN1, but was dependent on the presence of p53. Here we show, that KLF6 expression is induced in ALF and in the regenerating liver, where it activates autophagy by transcriptional induction of ATG7 and BECLIN1 in a p53-dependent manner. These findings couple the activity of an important growth inhibitor in liver to the induction of autophagy in hepatocytes.

Introduction/Objective Variable histologic findings that may be seen in porto-sinusoidal vascular disease (PSVD) liver biopsies are subject to high interobserver variability, requiring correlation with clinical history of portal hypertension (traditionally interpreted as non-cirrhotic portal hypertension NCPH). We investigated which histologic features are reproducible in PSVD biopsies. Methods Archived liver biopsies (n=38) from patients with NCPH (n=14) and without NCPH (n=21) were reviewed. Static H&E images of lobules (L, x100, NCPH=27, non-NCPH=23) and portal tracts (P, x200, NCPH=23, non- NCPH=27) were distributed among 9 gastrointestinal pathologists blinded to clinical history. Each pathologist answered multiple choice questions based on the presence (Q2) or absence (Q1) of portal hypertension clinically. The choice selected by 6 pathologists or more was considered consensus answer for the image. The interpretation of the image was considered reproducible when consensus was reached on both Q1 and Q2. Results The interpretations of 27 (54%; 17L, 10P) images from NCPH and 21 (42%; 10L, 11P) from non-NCPH were reproducible. In NCPH, the interpretations of normal (n=10, 4L, 6P), sinusoidal dilatation (n=7), and increased parenchymal draining vessels (n=3) were reproducible, while there was no consensus on the diagnoses of nodular regeneration and increased number of portal vessels. In non-NCPH, the interpretations of normal (n=8, 2L, 6P), sinusoidal dilatation (n=6), and paraportal shunting vessel(s) (n=4) were reproducible, whereas no consensus was reached on the diagnoses of nodular regeneration, incomplete fibrous septa, and increased number of portal vessels. Conclusion Histologic assessment of normal L and P as well as sinusoidal dilatation appears to be reproducible independent of clinical history. The findings of increased parenchymal draining vessels in NCPH group and paraportal shunting vessels in non-NCPH group may be consistently diagnosed to a certain extent. The assessment for nodular regeneration without reticulin stain, incomplete fibrous septa, or increased number of portal vessels appears to be unreliable.

Background There are little data on the pre- and post-liver transplantation (LT) outcomes of patients having autoimmune hepatitis-primary biliary cholangitis (AIH-PBC), AIH-primary sclerosing cholangitis (AIH-PSC), and AIH-small-duct PSC (AIH-SDPSC). The aim of this study was to analyze pre- and post-LT outcomes and survival of patients having different overlap syndromes (OS) undergoing LT. Methods Patients with compatible clinical and pathologic features of AIH-PBC (n = 86), AIH-PSC (n = 22), and AIH-SDPSC (n = 9) were included in the study. Demographic, laboratory, clinical, and survival data were analyzed. Multivariable analyses were performed to determine factors predicting transplant-free survival. Results AIH-primary sclerosing cholangitis patients were less treatment-responsive and were more likely to undergo LT than other OS. No survival difference was noted among the 3 groups. Liver decompensation was independently associated with higher mortality (HR 21.78; 95% CI 2.50-190.01). Thirteen patients with OS underwent LT. One-year survival post-LT was 91.7%. Overall recurrence rate for OS post-LT was 8%. Conclusions AIH-primary sclerosing cholangitis patients were more likely to require LT compared with patients having AIH-PBC. Transplant-free survival was similar among the three AIH-overlap syndromes. Allograft recurrence of OS occurred in about 10% of cases. Patients with OS appear to have good short- and medium-term post-LT outcomes in terms of graft function and overall survival.

BACKGROUND The clinical importance of hypovascular liver lesions in cirrhotic patients awaiting liver transplantation (LT) has not been fully investigated. The objective of this study was to characterize the clinicopathologic features and management of these tumors and to assess their impact on post-LT outcomes. METHODS We performed a retrospective review of cirrhotic patients with lesions suspicious for hypovascular hepatocellular carcinoma (HCC) who underwent LT at a single institution from 2011- 2017. RESULTS We identified 22 pre-LT patients with radiologic diagnosis of a lesion(s) suspicious for hypovascular HCC. There were 28 hypovascular lesions within the 22 patient cohort; 9 lesions (32%) converted to hypervascular HCC before LT and 19 lesions remained hypovascular at LT. 88% of hypovascular lesions were HCC on explant pathology. Compared to patients with hyper-vascular HCC lesions, hypovascular HCC lesions underwent less preoperative tumor ablation (58% vs 89%; P

Ruxolitinib is increasingly being utilized for the treatment of myelofibrosis and polycythemia vera, but the potential for hepatic toxicity is poorly understood. We performed a retrospective review of hepatic damage occurring in patients with myeloproliferative neoplasms receiving ruxolitinib. Relevant histologic images of liver biopsies were reviewed by an experienced liver pathologist and reported to a multidisciplinary team including hepatology and hematology. A variety of liver pathology was observed including extramedullary hematopoiesis, obliterative portal venopathy, and drug-induced liver injury. In all cases reviewed, the liver biopsy had significant treatment implications. We conclude that hepatology referral and liver biopsy in patients receiving ruxolitinib therapy with biochemical evidence of liver injury reveals a variety of etiologies which have significant treatment impact. Clinicians should be aware of the potential causes of liver damage in this population and initiate prompt referral and liver biopsy.

The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.

Background & Aims Interleukin-15 (IL-15) and its high affinity receptor interleukin-15 receptor alpha (IL-15Rα) are widely expressed in immune cells and hepatic resident cells. IL-15 signaling has important functions in homeostasis of natural killer (NK), natural killer T (NKT) and cytotoxic T (CD8 + T) cells, and in liver regeneration. We hypothesized that IL-15 has a protective role in liver fibrosis progression by maintaining NK cell homeostasis. Methods Fibrosis was induced using two mechanistically distinct models. Congenic bone marrow transplantation was used to evaluate the contribution of IL-15 signaling from various compartments to NK, CD8 + T and NKT cell homeostasis and fibrogenesis. The gene expression profile of hepatic stellate cell (HSC) from IL-15Rα knockout ( IL-15Rα KO) mice and wild-type mice were captured using microarray analysis and validated in isolated HSC. Quantitative real-time PCR was used to assess repressors of collagen transcription. Results IL-15Rα KO mice exhibited more fibrosis in both models. IL-15 signaling from specific types of hepatic cells had divergent roles in maintaining liver NK, CD8 + T and NKT cells, with a direct and protective role on radio-resistant non-parenchymal cells beyond the control of NK homeostasis. HSCs isolated from IL-15Rα KO mice demonstrated upregulation of collagen production. Finally, IL-15Rα KO HSC with or without transforming growth factor beta (TGF-β) stimulation exhibited increased expression of fibrosis markers and decreased collagen transcription repressors expression. Conclusions IL-15Rα signaling has a direct anti-fibrotic effect independent of preserving NK homeostasis. These findings establish a rationale to further explore the anti-fibrotic potential of enhancing IL-15 signaling in HSCs. Lay summary We investigated how a cellular protein, Interleukin-15 (IL-15), decreases the amount of scar tissue that is formed upon liver injury. We found that IL-15 and its receptor decrease the amount of scar tissue that is created by specialized liver cells (called stellate cells) and increase the number of a specific subgroup of immune cells (natural killer cells) that are known to eliminate stellate cells. Transcript profiling accession number GSE45612, GSE 68001 and GSE 25097.

The Hippo signaling pathway is a major regulator of organ size. In the liver, Hippo pathway deregulation promotes hyperplasia and hepatocellular carcinoma primarily through hyperactivation of its downstream effector, YAP. The LATS2 tumor suppressor is a core member of the Hippo pathway. A screen for LATS2-interacting proteins in liver-derived cells identified the transcription factor SREBP2, master regulator of cholesterol homeostasis. LATS2 down-regulation caused SREBP activation and accumulation of excessive cholesterol. Likewise, mice harboring liver-specific Lats2 conditional knockout (Lats2-CKO) displayed constitutive SREBP activation and overexpressed SREBP target genes and developed spontaneous fatty liver disease. Interestingly, the impact of LATS2 depletion on SREBP-mediated transcription was clearly distinct from that of YAP overexpression. When challenged with excess dietary cholesterol, Lats2-CKO mice manifested more severe liver damage than wild-type mice. Surprisingly, apoptosis, inflammation, and fibrosis were actually attenuated relative to wild-type mice, in association with impaired p53 activation. Subsequently, Lats2-CKO mice failed to recover effectively from cholesterol-induced damage upon return to a normal diet. Additionally, decreased LATS2 mRNA in association with increased SREBP target gene expression was observed in a subset of human nonalcoholic fatty liver disease cases. Together, these findings further highlight the tight links between tumor suppressors and metabolic homeostasis.

Little is known about autoantibody pattern in liver transplantation (LT). The aim of the study was to examine autoantibodies (AAB) and immunoglobulins in patients with end-stage liver disease before and after LT. Patients with LT who underwent post-LT biopsies between 10/2008 and 8/2011 were enrolled. AAB were assessed at the time of LT and liver biopsy. Demographics, serum immunoglobulins, AAB, and liver histology (explant, post-LT biopsies) were analyzed. Two hundred and twenty patients (M/F 143/77; age at LT 54 (19-73)) were included; AAB and immunoglobulins were evaluated in 76 patients. Length of follow-up from LT was 285 (30-1462) days. Sixty-one percent of patients had hepatitis C (HCV); 83% developed recurrent HCV. A significant decrease in IgG, IgA, IgM (p < 0.001 each), anticardiolipin antibodies IgG and IgM (p = 0.02), and beta-2 microglobulin (p = 0.004) was observed post-LT. HCV patients had higher IgG (p = 0.005), rheumatoid factor (p = 0.044) before LT; elevated IgM was associated with increased inflammation in the explant (p = 0.007). Lower IgG levels and antismooth muscle antibodies were present before LT in a higher percentage in patients who would develop recurrent HCV (p = 0.004, p = 0.077, respectively). In conclusion, AAB change significantly after LT and have a different pattern in HCV. Some immunological markers are associated with HCV recurrence and advanced inflammation on explant.

Lysosomal acid lipase deficiency (LAL-D) results in progressive microvesicular hepatosteatosis, fibrosis, cirrhosis, dyslipidemia, and vascular disease. Interventions available prior to enzyme replacement therapy development, including lipid lowering medications, splenectomy, hematopoietic stem cell and liver transplantation were unsuccessful at preventing multi-systemic disease progression, and were associated with significant morbidity and mortality. We report two sisters, diagnosed in infancy, who succumbed to LAL-D with accelerated disease progression following splenectomy and liver transplantation. The index patient died one year after hematopoietic stem cell transplant and liver transplantation. Her younger sister survived five years post liver-transplantation, complicated by intermittent, acute rejection. Typical LAL-D hepatopathology, including progressive, microvesicular steatosis, foamy macrophage aggregates, vacuolated Kupffer cells, advanced fibrosis and micronodular cirrhosis recurred in the liver allograft. She died before a second liver transplant could occur for decompensated liver failure. Neither patient received sebelipase alfa enzyme replacement therapy, human, recombinant, lysosomal acid lipase enzyme, FDA approved in 2015. Here are reviewed 18 LAL-D post-liver transplantation cases described in the literature. Multi-systemic LAL-D progression occurred in 11 patients (61%) and death in six (33%). These reports demonstrate that liver transplantation may be necessary for LAL-D-associated liver failure, but is not sufficient to prevent disease progression, or liver disease recurrence, since the pathophysiology is predominantly mediated by deficient enzyme activity in bone marrow-derived monocyte-macrophages. Enzyme replacement therapy addresses systemic disease and hepatopathology, potentially improving liver-transplantation outcomes. This is the first systematic review of liver transplantation for LAL-D, and the first account of liver allograft LAL-D-associated hepatopathology recurrence.

Purpose To quantify baseline relaxation rates R2* and R1 in the abdomen, their changes after respiratory challenges, and their reproducibility in healthy volunteers and patients with hepatocellular carcinoma (HCC) at 1.5T and 3.0T. Materials and Methods R2* measurements were acquired in the liver in 8 volunteers and 27 patients with 34 HCCs using multiecho T2* at baseline and after respiratory challenges with 100% oxygen (O2) and carbogen (CB = 95%O2/5%CO2). R1 was measured at 1.5T in one volunteer and 21 patients with 23 HCCs. Test–retest coefficient of variation (CV) was assessed in 10 subjects. Intra- and interobserver variability of R2* and R1 measurements was assessed in 12 and 10 patients, respectively. Parameters for HCC, liver, and muscle were compared between baseline and after gas challenges. Results We observed that R2* and R1 imaging of HCCs with O2 and CB is feasible and reproducible (test–retest CV R2* 0.88/R1>0.7 and CV R2*

Background & Aims Hepatocellular carcinoma (HCC) is the second most lethal cancer caused by lack of effective therapies. Although promising, HCC molecular classification, which enriches potential responders to specific therapies, has not yet been assessed in clinical trials of anti-HCC drugs. We aimed to overcome these challenges by developing clinicopathological surrogate indices of HCC molecular classification. Methods Hepatocellular carcinoma classification defined in our previous transcriptome meta-analysis (S1, S2 and S3 subclasses) was implemented in an FDA-approved diagnostic platform (Elements assay, NanoString). Ninety-six HCC tumours (training set) were assayed to develop molecular subclass-predictive indices based on clinicopathological features, which were independently validated in 99 HCC tumours (validation set). Molecular deregulations associated with the histopathological features were determined by pathway analysis. Sample sizes for HCC clinical trials enriched with specific molecular subclasses were determined. Results Hepatocellular carcinoma subclass-predictive indices were steatohepatitic (SH)-HCC variant and immune cell infiltrate for S1 subclass, macrotrabecular/compact pattern, lack of pseudoglandular pattern, and high serum alpha-foetoprotein (>400 ng/ml) for S2 subclass, and microtrabecular pattern, lack of SH-HCC and clear cell variants, and lower histological grade for S3 subclass. Macrotrabecular/compact pattern, a predictor of S2 subclass, was associated with the activation of therapeutically targetable oncogene YAP and stemness markers EPCAM/KRT19. BMP4 was associated with pseudoglandular pattern. Subclass-predictive indices-based patient enrichment reduced clinical trial sample sizes from 121, 184 and 53 to 30, 43 and 22 for S1, S2 and S3 subclass-targeting therapies respectively. Conclusions Hepatocellular carcinoma molecular subclasses can be enriched by clinicopathological indices tightly associated with deregulation of therapeutically targetable molecular pathways.

Background The utilization of extended criteria liver allografts (ECD) shortens time to transplantation. Objective To characterize the effect of liver allograft fibrosis on graft and patient survival after liver transplantation (LT), with particular attention to fibrosis progression. Methods Retrospective database search of donor and recipient liver allograft histology of liver transplants performed between 2007 and 2011. Donor and patient characteristics were analyzed. Results One hundred and one patients underwent LT with donor liver allografts with early-stage fibrosis (stage 1 fibrosis and stage 2 fibrosis). The level of liver fibrosis did not progress in 40% of the patients tested, and there was a regression of fibrosis in 30%. At a median follow-up of 71 months, of 101 patients transplanted with fibrotic livers, 63 patients (63%) were alive with functioning initial grafts, six patients (6%) were retransplanted, and 35 patients expired. The graft survival rates were 82% and 69% at 1 and 5 years, respectively. Graft survival differences were not found to be statistically significant between the degrees of liver allograft fibrosis: 5-year graft survival (73% for stage 1 fibrosis and 62% for stage 2 fibrosis, P = .24). The entire fibrosis group was further compared with a control group of 208 consecutive primary liver transplant patients with allografts having no fibrosis. The 5-year graft survival was not significantly different between the groups (69% for the fibrosis group vs 75% for the nonfibrosis group, P = .19). Survival was also not statistically different between the groups (5-year survival of 73% for the fibrosis group vs 79% for the nonfibrosis group, P = .2). In patients with HCV, graft survival differences were not found to be statistically significant with the use of early-stage fibrotic livers: 5-year graft survival of 60% for fibrosis group vs 70% for the nonfibrosis group, P = .22). Conclusion This study demonstrates that allografts with early-stage fibrosis achieve acceptable long-term survival after liver transplantation. Given these preliminary results, the use of organs with early-stage fibrosis warrants further studies at a larger scale to validate these results.

Long-term parenteral nutrition (PN) may be complicated by PN-associated liver disease (PNALD), and some studies suggest an association between the use of soy-based fat emulsions and PNALD development. Patients' liver function typically improves and PNALD resolves after reducing or stopping a soy-based fat emulsion, and thus lipid minimization has been the primary strategy for managing PNALD in many intestinal rehabilitation programs. However, fat emulsions often cannot be stopped entirely, leading some patients to develop PNALD even after lipid reduction strategies have been implemented. Smoflipid emulsion (Kabi-Fresenius, Bad Homburg, Germany), a balanced mixture of soybean oil, medium-chain triglycerides (MCTs), olive oil, and fish oil, was recently approved by the Food and Drug Administration for use in the United States as an equivalent alternative to Intralipid (Baxter Healthcare Corporation, Deerfield, IL). In several pediatric studies, patients who received Smoflipid had significantly lower serum bilirubin levels than those who received Intralipid. In this case report, we present a patient who developed severe PNALD with subsequent resolution after 20 weeks on Smoflipid.

Background & Aims According to the clonal model of tumor evolution, trunk alterations arise at early stages and are ubiquitous. Through the characterization of early stages of hepatocarcinogenesis, we aimed to identify trunk alterations in hepatocellular carcinoma (HCC) and study their intra- and inter-tumor distribution in advanced lesions. Methods A total of 151 samples representing the multistep process of hepatocarcinogenesis were analyzed by targeted-sequencing and a single nucleotide polymorphism array. Genes altered in early lesions (31 dysplastic nodules [DNs] and 38 small HCCs [sHCC]) were defined as trunk. Their distribution was explored in: a) different regions of large tumors (43 regions, 21 tumors), and b) different nodules of the same patient (39 tumors, 17 patients). Multinodular lesions were classified as intrahepatic metastases (IMs) or synchronous tumors based on chromosomal aberrations. Results TERT promoter mutations (10.5%) and broad copy-number aberrations in chromosomes 1 and 8 (3–7%) were identified as trunk gatekeepers in DNs and were maintained in sHCCs. Trunk drivers identified in sHCCs included TP53 (23%) and CTNNB1 (11%) mutations, and focal amplifications or deletions in known drivers (6%). Overall, TERT , TP53 and CTNNB1 mutations were the most frequent trunk events and at least one was present in 51% of sHCCs. Around 90% of mutations in these genes were ubiquitous among different regions of large tumors. In multinodular HCCs, 35% of patients harbored IMs; 85% of mutations in TERT , TP53 and/or CTNNB1 were retained in primary and metastatic tumors. Conclusions Trunk events in early stages ( TERT , TP53 , CTNNB1 mutations) were ubiquitous across different regions of the same tumor and between primary and metastatic nodules in >85% of cases. This concept supports the knowledge that single biopsies would suffice to capture trunk mutations in HCC. Lay summary Trunk alterations arise at early stages of cancer and are shared among all malignant cells of the tumor. In order to identify trunk alterations in HCC, we characterized early stages of hepatocarcinogenesis represented by dysplastic nodules and small lesions. Mutations in TERT , TP53 and CTNNB1 genes were the most frequent. Analyses in more advanced lesions showed that mutations in these same genes were shared between different regions of the same tumor and between primary and metastatic tumors, suggesting their trunk role in this disease.

The number of patients with HCV-related cirrhosis is increasing, leading to a rising risk of complications and death. Prognostic stratification in patients with early-stage cirrhosis is still challenging. We aimed to develop and validate a clinically useful prognostic index based on genomic and clinical variables to identify patients at high risk of disease progression.We developed a prognostic index, comprised of a 186-gene signature validated in our previous genome-wide profiling study, bilirubin (1 mg/dL) and platelet count (100,000/mm(3)), in an Italian HCV cirrhosis cohort (training cohort, n=216, median follow-up 10 years). The gene signature test was implemented using a digital transcript counting (nCounter) assay specifically developed for clinical use and the prognostic index was evaluated using archived specimens from an independent cohort of HCV-related cirrhosis in the USA (validation cohort, n=145, median follow-up 8 years).In the training cohort, the prognostic index was associated with hepatic decompensation (HR=2.71, p=0.003), overall death (HR=6.00, p0.001), hepatocellular carcinoma (HR=3.31, p=0.001) and progression of Child-Turcotte-Pugh class (HR=6.70, p0.001). The patients in the validation cohort were stratified into high-risk (16%), intermediate-risk (42%) or low-risk (42%) groups by the prognostic index. The high-risk group had a significantly increased risk of hepatic decompensation (HR=7.36, p0.001), overall death (HR=3.57, p=0.002), liver-related death (HR=6.49, p0.001) and all liver-related adverse events (HR=4.98, p0.001).A genomic and clinical prognostic index readily available for clinical use was successfully validated, warranting further clinical evaluation for prognostic prediction and clinical trial stratification and enrichment for preventive interventions.