S N Thung

Icahn School of Medicine at Mount Sinai, Borough of Manhattan, New York, United States

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Publications (358)2081.39 Total impact

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    ABSTRACT: In patients with hepatocellular carcinoma (HCC), liver transplantation (LT) is an excellent therapy if tumor characteristics are within the Milan criteria. We aimed to define genomic features enabling to identify HCC patients beyond Milan criteria who have acceptable transplant outcomes. Among 770 consecutive HCC patients transplanted between 1990 and 2013, 132 had tumors exceeding Milan criteria on pathology and were enrolled in the study; 44% of the patients satisfied the 'up-to-7 rule' [7=sum of the size of the largest tumor and the number of tumors]. Explant tumors were assessed for genomic signatures and immunohistochemical markers associated with poor outcome. At a median follow-up of 88 months, 64 patients had died and 45 recurred; the 5-year overall survival (OS) and recurrence rates were 57% and 35%, respectively. Cytokeratin 19 (CK19) gene signature was independently associated with recurrence [Hazard ratio (HR)=2.95, p<0.001], along with tumor size (HR=3.37, p=0.023) and presence of satellites (HR=2.98, p=0.001). S2 subclass signature was independently associated with poor OS (HR=3.18, p=0.001), along with tumor size (HR=5.06, p<0.001) and up-to-7 rule (HR=2.50, p=0.002). Using the presence of progenitor cells markers (either CK19 or S2 signatures) patients were classified into poor-prognosis (n=58; 5-year recurrence 53%, survival 45%) and good-prognosis (n=74; 5-year recurrence 19%, survival 67%) (HR=3.16, p<0.001 for recurrence, and HR=1.72, p=0.04 for OS). HCC patients transplanted beyond Milan criteria without gene signatures of progenitor markers (CK19 and S2) achieved survival rates similar as those within Milan criteria. Once prospectively validated, these markers may support a limited expansion of LT indications. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Jul 2015 · Journal of Hepatology
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    ABSTRACT: Focal nodular hyperplasia and nodular regenerative hyperplasia are occasionally seen in patients with hepatic venous outflow obstruction as a consequence of circulatory stress in the liver. In addition, neoplastic processes such as hepatic adenoma, hepatocellular carcinoma, and metastatic disease may arise in these patients. Histologic evaluation is necessary when imaging modalities are unable to distinguish these lesions. We present a case of multiple hepatic lesions, suspicious for metastases, in a patient with Budd-Chiari syndrome secondary to polycythemia vera. However, the biopsy findings were consistent with focal nodular hyperplasia. Budd-Chiari syndrome may be associated with multiple nodules of focal nodular hyperplasia, which may be difficult to diagnose radiologically.
    No preview · Article · May 2015 · Annals of hepatology: official journal of the Mexican Association of Hepatology
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    ABSTRACT: Liver biopsy diagnosis of primary sclerosing cholangitis (PSC) is difficult. We performed a detailed histologic analysis of PSC cases using novel bioinformatics analysis to identify histologic features that may be useful in its diagnosis. PSC liver explants were examined and compared with primary biliary cirrhosis and hepatitis C explants to act as controls. Demographic, macroscopic, and histologic variables were analyzed using both conventional statistics and an integrative bioinformatics approach, significance analysis of microarrays (SAM), and hierarchical clustering analysis (HCA). The PSC group was younger and had distinctive PSC features, including bile duct scars, onion-skin fibrosis, and arterial fibrointimal hyperplasia. SAM allowed the integration of variables by comparing PSC and control groups, whereas HCA was able to correctly categorize each group. This study demonstrates characteristic PSC histology as well as arterial hyperplasia to be distinctive features that may aid in PSC diagnosis and be confirmed by bioinformatics. Copyright© by the American Society for Clinical Pathology.
    No preview · Article · Apr 2015 · American Journal of Clinical Pathology
  • Sara Lewis · Badr Aljarallah · Anshu Trivedi · Swan N Thung
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    ABSTRACT: The authors report and discuss a rare case of a small vessel hepatic hemangioma in a 59-year-old patient with liver cirrhosis, which was pre-procedurally characterized as indeterminate due to atypical magnetic resonance imaging (MRI) features. This manuscript reviews the MRI features with pathologic correlation, emphasizes the importance of accurate characterization of liver lesions, and discusses the role of biopsy. We believe this is the first reported case of a small vessel hemangioma in liver cirrhosis with imaging and histopathologic correlation. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Feb 2015 · Clinical Imaging
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    ABSTRACT: Rapid induction of β-PDGF receptor (β-PDGFR) is a core feature of hepatic stellate cell activation, but its cellular impact in vivo is not well characterized. We explored the contribution of β-PDGFR-mediated pathway activation to hepatic stellate cell responses in liver injury, fibrogenesis, and carcinogenesis in vivo using genetic models with divergent β-PDGFR activity, and assessed its prognostic implications in human cirrhosis. The impact of either loss or constitutive activation of β-PDGFR in stellate cells on fibrosis was assessed following carbon tetrachloride (CCl4) or bile duct ligation. Hepatocarcinogenesis in fibrotic liver was tracked after a single dose of diethylnitrosamine (DEN) followed by repeated injections of CCl4. Genome-wide expression profiling was performed from isolated stellate cells that expressed or lacked β-PDGFR to determine deregulated pathways and evaluate their association with prognostic gene signatures in human cirrhosis. Depletion of β-PDGFR in hepatic stellate cells decreased injury and fibrosis in vivo, while its auto-activation accelerated fibrosis. However, there was no difference in development of DEN-induced pre-neoplastic foci. Genomic profiling revealed ERK, AKT, and NF-kB pathways and a subset of a previously identified 186-gene prognostic signature in hepatitis C virus (HCV)-related cirrhosis as downstream of β-PDGFR in stellate cells. In the human cohort, the β-PDGFR signature was not associated with HCC development, but was significantly associated with a poorer outcome in HCV cirrhosis. β-PDGFR is a key mediator of hepatic injury and fibrogenesis in vivo and contributes to the poor prognosis of human cirrhosis, but not by increasing HCC development. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Feb 2015 · Journal of Hepatology
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    ABSTRACT: IgG4 sclerosing cholangitis (IgG4-SC) is an immune-mediated process that results in inflammation and fibrosis of the pancreatobiliary tract. Although IgG4-SC is predominantly associated with autoimmune pancreatitis, IgG4-SC as its own entity can be difficult to diagnose. Patients with IgG4-SC are typically men over the age of 60, and present clinically with obstructive jaundice, abdominal pain, and weight loss. The diagnosis of IgG4-SC may be difficult to differentiate from primary sclerosing cholangitis (PSC) or cholangiocarcinoma. IgG4-SC is morphologically characterized by dense lymphoplasmacellular infiltration, particularly IgG4+ plasma cells and CD4+ T cells, extensive fibrosis in bile duct walls, and obliterative phlebitis. In contrast to PSC, those with IgG4-SC often have elevated serum IgG4 and can be successfully treated with immunosuppression. Here, we present the first reported case of IgG4-SC in a pediatric patient with asymptomatic elevation in liver enzymes, bile duct strictures on imaging, characteristic pathology findings, elevated serum IgG4, and excellent response to corticosteroids. Pediatric gastroenterologists and hepatologists, as well as pediatric hepatopathologists, need to be aware of IgG4-SC as a disease entity. Although certain clinical and imaging findings mimic PSC, diagnosis of IgG4-SC and its appropriate treatment with corticosteroids often lead to remission and reversal of disease. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.
    Full-text · Article · Feb 2015 · Seminars in Liver Disease
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    ABSTRACT: Intrahepatic cholangiocarcinoma (iCCA) is a fatal bile duct cancer with dismal prognosis and limited therapeutic options. By performing RNA- and exome-sequencing analyses, we report a novel fusion event, FGFR2-PPHLN1 (16%), and damaging mutations in the ARAF oncogene (11%). Here we demonstrate that the chromosomal translocation t(10;12)(q26;q12) leading to FGFR2-PPHLN1 fusion possesses transforming and oncogenic activity, which is successfully inhibited by a selective FGFR2 inhibitor in vitro. Among the ARAF mutations, N217I and G322S lead to activation of the pathway and N217I shows oncogenic potential in vitro. Screening of a cohort of 107 iCCA patients reveals that FGFR2 fusions represent the most recurrent targetable alteration (45%, 17/107), while they are rarely present in other primary liver tumours (0/100 of hepatocellular carcinoma (HCC); 1/21 of mixed iCCA-HCC). Taken together, around 70% of iCCA patients harbour at least one actionable molecular alteration (FGFR2 fusions, IDH1/2, ARAF, KRAS, BRAF and FGF19) that is amenable for therapeutic targeting.
    No preview · Article · Jan 2015 · Nature Communications
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    ABSTRACT: Fibrolamellar hepatocellular carcinoma (FLC) is a rare primary hepatic cancer that develops in children and young adults without cirrhosis. Little is known about its pathogenesis, and it can only be treated with surgery. We performed an integrative genomic analysis of a large series of patients with FLC to identify associated genetic factors. Using 78 clinically annotated FLC samples, we performed whole-transcriptome (n=58), single-nucleotide polymorphism array (n=41), and next-generation sequencing (n=48) analyses; we also assessed the prevalence of the DNAJB1-PRKACA fusion transcript associated with this cancer (n=73). We performed class discovery using non-negative matrix factorization, and functional annotation using gene set enrichment analyses, nearest template prediction, ingenuity pathway analyses, and immunohistochemistry. The genomic identification of significant targets in cancer algorithm was used to identify chromosomal aberrations, MuTect and VarScan2 were used to identify somatic mutations, and the random survival forest was used to determine patient prognoses. Findings were validated in an independent cohort. Unsupervised gene expression clustering revealed 3 robust molecular classes of tumors: the proliferation class (51% of samples) had altered expression of genes that regulate proliferation and mTOR signaling activation; the inflammation class (26% of samples) had altered expression of genes that regulate inflammation and cytokine production; and the unannotated class (23% of samples) had a gene expression signature not previously associated with liver tumors. Expression of genes that regulate neuroendocrine function, as well has histologic markers of cholangiocytes and hepatocytes, were detected in all 3 classes. FLCs had few copy number variations; the most frequent were focal amplification at 8q24.3 (in 12.5% of samples) and deletions at 19p13 (in 28% of samples) and 22q13.32 (in 25% of samples). The DNAJB1-PRKACA fusion transcript was detected in 79% of samples. FLC samples also contained mutations in cancer-related genes such as BRCA2 (in 4.2% of samples), which are uncommon in liver neoplasms. However, FLCs did not contain mutations most commonly detected in liver cancers. We identified an 8-gene signature that predicted survival of patients with FLC. In a genomic analysis of 78 FLC samples, we identified 3 classes based on gene expression profiles. FLCs contain mutations and chromosomal aberrations not previously associated with liver cancer, and almost 80% contain the DNAJB1-PRKACA fusion transcript. Using this information, we identified a gene signature that is associated with patient survival time. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.
    No preview · Article · Dec 2014 · Gastroenterology
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    Full-text · Article · Dec 2014 · Human pathology
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    ABSTRACT: Objectives The aim of this analysis was to examine prognostic features and outcomes in patients undergoing resection for intrahepatic cholangiocarcinoma (ICC).MethodsA retrospective chart review was performed in all patients who underwent R0 or R1 resection for primary ICC between 1995 and 2011. Clinical data were abstracted and statistical analyses were conducted in the standard fashion.ResultsA total of 82 patients underwent curative hepatectomy for primary ICC; 51 patients in this cohort developed recurrence. The median follow-up of survivors was 27 months (range: 1–116 months). Recurrences were intrahepatic (65%), associated with multiple tumours (54%) and occurred during the first 2 years after hepatectomy (86%). The main factor associated with recurrence after resection was the presence of satellite lesions. Overall 5-year disease-free survival after primary resection was 16%. Factors associated with poor survival were transfusion and perineural invasion. Treatment of recurrence was undertaken in 89% of patients and repeat surgical resection was performed in 15 patients. The 3-year survival rate after recurrence was 25%. Prolonged survival after recurrence was associated with a solitary tumour recurrence.Conclusions Despite curative resection of ICC, recurrence can be expected to occur in 79% of patients at 5 years. Predictors of survival and recurrence after resection vary in the literature. In patients with recurrence, selection of the optimal treatment remains challenging.
    No preview · Article · Dec 2014 · HPB
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    ABSTRACT: Background: MiRNAs are abundant ~22-nt non-coding RNAs that regulate hundreds of gene targets in a sequence- and context-specific manner. While miRNAs have been described in hepatic stellate cells (HSCs), only relative changes in miRNA expression have been reported and there is no genome wide-map of miRNA targets. Theoretical algorithms to predict miRNA binding-sites, while helpful, do not reflect context-dependent, real-time miRNA binding to target sites. In contrast, miRNA binding-sites in living cells can be directly analyzed using the PAR-CLIP method (photoactivatable ribonucleoside-enhanced cross-linking and immunoprecipitation) (Hafner et al, 2010, Cell). Our aim was to identify miRNAs targets and target-sites on a genome-wide scale in HSCs by Ago2 PAR-CLIP. Methods: Primary HSCs were isolated from human liver, culture activated by expanding on polystyrene cell culture dishes, and the purity confirmed by FACS. A barcoded small RNA-sequencing (miRNAseq) protocol developed in our laboratory was used to quantify HSC miRNA expression, which was combined with RNAseq of polyA-RNA using the Illumina TruSeq platform to analyze target gene expression. PAR-CLIP was performed using a mouse monoclonal human anti-Ago2 antibody (clone 9E8.2). Results: There was a consistent miRNA profile across 5 biological replicates of primary HSCs, clearly distinct from hepatocytes, which dominated whole liver miRNA expression. 55 unique miRNAs organized in 21 cistrons, and representing 28 miRNA families constituted 90% of the sequencing reads. The top 5 most abundant miRNA cistrons were mir-21(1), mir-98(13), mir-23a(6), mir-29a(4), and mir-22(1), respectively. We obtained 30,000 Ago2 binding-regions (clusters) by PAR-CLIP representing 8000 unique genes. The clusters were almost evenly distributed over the coding sequences and 3’ UTRs, and they were enriched in motifs complementary to the seed-sequence of almost all highly expressed miRNA families identified by miRNAseq. 8000 clusters contained canonical 6mer, 7mer-A1, 7mer-m8, and 8mer miRNA binding-sites for these highly expressed miRNAs. Among others, we identified over hundred miR-21 binding-sites, including, but not limited to genes involved in TGF-β1 signaling or tissue fibrosis. Conclusion: Using RNAseq and PAR-CLIP we have identified thousands of bona fide miRNA binding sites in primary human HSCs at single-nucleotide resolution, uncovering both known and novel miRNA targets. This comprehensive catalogue of HSC miRNAs provides fertile directions for clarifying regulatory events and identifying novel therapeutic targets.
    No preview · Conference Paper · Nov 2014
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    ABSTRACT: Transarterial radioembolization (TARE) with yttrium-90 is a minimally invasive locoregional therapy for hepatocellular carcinoma (HCC), and involves selective delivery of glass or resin microspheres impregnated with radioactive yttrium-90 into small arteries preferentially supplying the tumor for tumoricidal effect thus sparing the nontumoral liver, or into lobar artery to induce atrophy and contralateral hypertrophy. Clinically, post-TARE a small proportion of cases develop radioembolization-induced liver disease. Histological changes of TARE on nontumoral liver parenchyma have not been well characterized. Herein, we report two cases of liver resections for HCC post-TARE, and describe the histological changes in nontumoral liver parenchyma.
    No preview · Article · Nov 2014 · Seminars in Liver Disease
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    ABSTRACT: This is a case report of an asymptomatic 4-year-old girl who was found to have a nodule at the lateral left lobe of the liver. She underwent transabdominal liver ultrasound and abdominal MRI that showed calcification and intense arterial enhancement but they failed to clearly exclude malignancy. The patient underwent an unremarkable laparoscopic wedge liver resection of the lesion because of its location and size. Pathological examination showed features compatible with a benign telangiectatic hyperplastic nodule with vascular malformation and calcification. CD34 immunostained the proliferative vascular lining cells while CK7 and CK19 highlighted the normal bile ducts present within the lesion. The diagnosis of a telangiectatic hyperplastic nodule associated with vascular malformation has been scarcely reported in children and our case shows for the first time that it can also present with calcifications.
    No preview · Article · Oct 2014 · Fetal and Pediatric Pathology
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    ABSTRACT: Background: The role of liver transplantation (LT) in the management of cirrhotic patients with tumors exhibiting intrahepatic bile duct differentiation remains controversial. The objective of this study was to characterize the spectrum of these tumors and analyze post-LT outcomes. Methods: Retrospective pathology database search of explant histology analysis of liver transplants between April 1993 and November 2013. Results: Thirty-two patients were analyzed, 75% were men with a mean age of 60 years. Seven patients had nodules demonstrating intrahepatic cholangiocarcinoma (I-CCA), nine had I-CCA nodules occurring concomitantly with hepatocellular carcinoma (HCC), and 16 had mixed HCC-CCA nodules. The median number of tumors was 1 and size was 2.5 cm. Overall patient survival post-LT at 1 and 5 years was 71% and 57%, respectively. Patients within Milan criteria, especially with I-CCA features, showed a 5-year tumor recurrence rate (10%) and 5-year survival rate (78%) comparable with other patients having HCC within Milan criteria. Conclusion: This series showed that patients with CCA within Milan criteria may be able to achieve acceptable long-term post-LT survival.
    No preview · Article · Jul 2014 · Transplantation
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    ABSTRACT: Hepatocellular adenoma (HCA) is an uncommon benign hepatic tumor, and the use of oral contraceptives is known to contribute to the development of HCA. Recently, a genotype and phenotype classification system for HCA was suggested, and malignant transformation to hepatocellular carcinoma (HCC) was shown to be strongly associated with activating mutations in β-catenin. Here, we report three cases of HCA in Korean patients: 7-cm, inflammatory and β-catenin-activated HCA with HCC transformation in a 46-year-old man; 13-cm, β-catenin-activated HCA with cytological atypia in a 23-year-old woman; and 10-cm, pigmented, inflammatory and β-catenin-activated HCA in a 36-year-old man. All cases exhibited the nuclear expression of β-catenin and diffuse cytoplasmic expression of glutamine synthetase upon immunohistochemical staining. All tumors were completely resected, and the patients were followed for 3 to 6 years with no evidence of local recurrence or metastasis.
    Full-text · Article · Jul 2014 · Gut and liver
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    ABSTRACT: A 67-year-old woman with hypertension, hypothyroidism, and glaucoma was referred for jaundice and elevated liver function tests. She was treated for streptococcal endophthalmitis with 2 weeks of intravenous (IV) levofloxacin followed by 2 months of oral levofloxacin. The patient had no prior history of liver disease and denied alcohol intake. Her physical exam was remarkable for jaundice and scleral icterus without any stigmata of liver disease. Viral hepatitis serologies and antibodies, including myeloperoxidase, proteinase 3, and antinuclear, antimitochondrial, antiliver kidney microsome, antismooth muscle antibodies, were all within normal limits. The liver biopsy revealed severe cholestasis, extensive bile duct loss, and fibrosis. The patient had no known exposure to any other systemic medications or inciting factors other than levofloxacin. Although there are a few reported cases of drug-induced liver disease (DILI) related to levofloxacin, this case is believed to be the first reported case of ductopenia or vanishing bile duct syndrome (VBDS) associated with levofloxacin. Although fluoroquinolones, such as levofloxacin, are generally considered safe antibiotics, health practitioners must be aware of their association with DILI, as the diagnosis of DILI is one of exclusion and requires a high index of suspicion.
    No preview · Article · May 2014 · Seminars in Liver Disease

  • No preview · Article · Apr 2014 · Journal of Hepatology

  • No preview · Article · Apr 2014 · Journal of Hepatology
  • Brian Kim · Anshu Trivedi · Swan N Thung · Priya Grewal
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    ABSTRACT: Fibrosing cholestatic hepatitis is an unusual complication of hepatitis C virus (HCV) recurrence after liver transplant. Fibrosing cholestatic hepatitis is marked by aggressive progression of cholestasis and fibrosis, leading to accelerated graft loss and/or death. Sofosbuvir (GS-7977) is an oral nucleotide analogue inhibitor of HCV polymerase activity. It is a second-generation, direct-acting, antiviral for the treatment of HCV infection. This case illustrates a patient with recurrent HCV with fibrosing cholestatic hepatitis, who was successfully treated with a combination of sofosbuvir and ribavirin with normalization of liver enzyme activities and resolution of HCV-related symptoms. The favorable side effect profile and the lack of drug-drug interaction with immunosuppressive medications make the combination of sofosbuvir and ribavirin a promising regimen for severe HCV recurrence.
    No preview · Article · Feb 2014 · Seminars in Liver Disease
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    ABSTRACT: Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is an essential regulator of DNA methylation that is highly expressed in many cancers. Here, we use transgenic zebrafish, cultured cells, and human tumors to demonstrate that UHRF1 is an oncogene. UHRF1 overexpression in zebrafish hepatocytes destabilizes and delocalizes Dnmt1 and causes DNA hypomethylation and Tp53-mediated senescence. Hepatocellular carcinoma (HCC) emerges when senescence is bypassed. tp53 mutation both alleviates senescence and accelerates tumor onset. Human HCCs recapitulate this paradigm, as UHRF1 overexpression defines a subclass of aggressive HCCs characterized by genomic instability, TP53 mutation, and abrogation of the TP53-mediated senescence program. We propose that UHRF1 overexpression is a mechanism underlying DNA hypomethylation in cancer cells and that senescence is a primary means of restricting tumorigenesis due to epigenetic disruption.
    Full-text · Article · Jan 2014 · Cancer cell

Publication Stats

14k Citations
2,081.39 Total Impact Points


  • 1981-2015
    • Icahn School of Medicine at Mount Sinai
      • • Department of Pathology
      • • Division of Liver Diseases
      • • Department of Pediatrics
      Borough of Manhattan, New York, United States
    • Albert Einstein College of Medicine
      • Liver Research Center
      New York, New York, United States
  • 2010-2014
    • Memorial Sloan-Kettering Cancer Center
      • Department of Pathology
      New York, New York, United States
  • 1985-2014
    • Mount Sinai Medical Center
      New York City, New York, United States
  • 2011
    • Texas Transplant Institute
      San Antonio, Texas, United States
  • 1995-2009
    • New York Center for Liver Transplantation
      New York, New York, United States
    • United States Department of Veterans Affairs
      Бедфорд, Massachusetts, United States
  • 2008
    • Dana-Farber Cancer Institute
      • Department of Pediatric Oncology
      Boston, Massachusetts, United States
  • 1981-2008
    • Mount Sinai Hospital
      New York, New York, United States
  • 2000
    • The Scripps Research Institute
      La Jolla, California, United States
  • 1978-2000
    • CUNY Graduate Center
      New York City, New York, United States
  • 1999
    • Gracie Square Hospital, New York, NY
      New York City, New York, United States
  • 1998
    • Armed Forces Institute of Pathology
      Ralalpindi, Punjab, Pakistan
  • 1997
    • Cedars-Sinai Medical Center
      • Cedars Sinai Medical Center
      Los Angeles, California, United States
  • 1993
    • Tulane University
      • Department of Pathology and Laboratory Medicine
      New Orleans, Louisiana, United States
    • The Rockefeller University
      • Laboratory of Cell Biology
      New York, New York, United States
  • 1990
    • Sinai Hospital
      New York, New York, United States
  • 1986
    • Instituto Nacional de Salud