S N Thung

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

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Publications (337)1894.24 Total impact

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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.
    American Journal of Clinical Pathology 04/2015; 143(4):505-13. DOI:10.1309/AJCPVKFVIPRBXQR2 · 3.01 Impact Factor
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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.
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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.
    Journal of Hepatology 02/2015; DOI:10.1016/j.jhep.2015.01.036 · 10.40 Impact Factor
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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.
    Seminars in Liver Disease 02/2015; 35(1):89-94. DOI:10.1055/s-0034-1398475 · 5.12 Impact Factor
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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.
    Nature Communications 01/2015; 6:6087. DOI:10.1038/ncomms7087 · 10.74 Impact Factor
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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.
    Gastroenterology 12/2014; DOI:10.1053/j.gastro.2014.12.028 · 13.93 Impact Factor
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    Human pathology 12/2014; DOI:10.1016/j.humpath.2014.10.029 · 2.81 Impact Factor
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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.
    HPB 12/2014; 17(4). DOI:10.1111/hpb.12359 · 2.05 Impact Factor
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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.
    Seminars in Liver Disease 11/2014; 34(4):465-8. DOI:10.1055/s-0034-1394145 · 5.12 Impact Factor
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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.
    Fetal and Pediatric Pathology 10/2014; DOI:10.3109/15513815.2014.970264 · 0.40 Impact Factor
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    ABSTRACT: 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.
    Transplantation 07/2014; DOI:10.1097/TP.0000000000000286 · 3.78 Impact Factor
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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.
    Gut and liver 07/2014; 8(4):452-8. DOI:10.5009/gnl.2014.8.4.452 · 1.49 Impact Factor
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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.
    Seminars in Liver Disease 05/2014; 34(2):246-251. DOI:10.1055/s-0034-1375964 · 5.12 Impact Factor
  • Journal of Hepatology 04/2014; 60(1):S38-S39. DOI:10.1016/S0168-8278(14)60095-7 · 10.40 Impact Factor
  • Journal of Hepatology 04/2014; 60(1):S41. DOI:10.1016/S0168-8278(14)60102-1 · 10.40 Impact Factor
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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.
    Seminars in Liver Disease 02/2014; 34(1):108-112. DOI:10.1055/s-0034-1371084 · 5.12 Impact Factor
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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.
    Cancer cell 01/2014; DOI:10.1016/j.ccr.2014.01.003 · 23.89 Impact Factor
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    ABSTRACT: Autophagy is a cellular lysosomal degradation mechanism has been implicated in chronic liver diseases and hepatocellular carcinoma (HCC). Association of autophagy defect with the development of human HCC has been shown in transgenic mouse model. Aim We performed this study to verify whether a defect in autophagy would play a role in human hepatocellular carcinoma (HCC). Archival tissue sections of 20 patients with HCC with or without hepatitis C virus (HCV) infection were studied. All slides were immunostained using monoclonal antibodies to p62 and glypican-3 with appropriate positive and negative controls. The expression of p62 and glycican-3 in the HCC and the surrounding non-tumor were semiquantitated. The cytoplasmic staining was graded as negative, weak or strong. Positive p62 staining was found in 20 out of 20 (100%) HCCs and negative staining was observed in 20 out of 20 non-tumor areas and cirrhotic nodules. Positive glypican-3 staining was found in 70% of HCCs and negative staining was seen in all non-tumor areas. An autophagy defect leading to increased expression of p62 and glypican-3 was also seen in the HCC cell line (Huh-7.5), but not in the primary human hepatocytes. Activation of cellular autophagy in Huh-7.5 cells efficiently cleared p62 and glypican-3 expression and inhibition of autophagy induced the expression of p62 and glypican-3. This study shows that p62 is increased in HCC compared to the surrounding non-tumorous liver tissue suggesting that human HCCs are autophagy defective. We provide further evidence that glypican-3 expression in HCC may be also related to defective autophagy. Our study indicates that p62 immunostain may represent a novel marker for HCC.
    Experimental and Molecular Pathology 12/2013; 96(2). DOI:10.1016/j.yexmp.2013.12.002 · 2.88 Impact Factor
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    ABSTRACT: To report the co-existence of inflammatory hepatocellular adenoma (HCA) and HNF1 inactivated HCA (H-HCA) coming from a multicentric study. We report 9 cases with co-existence of inflammatory HCA and HNF1 inactivated HCA (H-HCA); 8 occurred in women and 1 in a man. The number of nodules and the sizes of the largest and smallest HCA were variable. In one case, the nodules of the 2 different subtypes were even discovered at different times. In all women, HCAs were histologically typical regardless of their subtype; while H-HCA in the man differed histologically from classical H-HCA. These cases suggest that predisposition to develop multiple adenomas, hypothetically caused by a "benign tumorigenic field effect" while common to all HCA, may result in different genotypes/phenotypes. Even rare, it is anticipated that more cases with co-existence of different genotypes will emerge due to progress in the use of specific immunohistochemistry. This article is protected by copyright. All rights reserved.
    Histopathology 11/2013; DOI:10.1111/his.12326 · 3.30 Impact Factor
  • Xianzhong Ding, Swan N Thung, Priya Grewal
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    ABSTRACT: A 24-year-old woman with congenital adrenal hyperplasia (CAH) was referred for evaluation of elevated liver enzyme activities over the preceding 6 months. The patient was diagnosed with CAH at the age 12 when she presented with irregular menses and hirsutism. Since then, she had been on dexamethasone to maintain a normal menstrual cycle and prevent hirsutism and acne. She had no history of chronic liver disease and drank alcohol socially. An extensive workup for other treatable causes of liver disease was unrevealing. Therefore, a liver biopsy was performed, which revealed extensive ballooned degenerative hepatocytes containing Mallory-Denk hyalines. The ballooned hepatocytes were located predominantly in centrilobular areas and without any accompanying steatosis. Even though the histopathologic features are most compatible with alcoholic and/or nonalcoholic steatohepatitis, it was not supported by the patient's medical history and clinical presentation. The patient had a normal body mass index and only occasional alcohol use. Based on the biopsy finding and clinical presentation, we postulated that the abnormal liver enzyme and pathological features seen on the liver biopsy were secondary to CAH and long-term use of glucocorticoid. A few studies have shown that patients with CAH often develop metabolic abnormalities and insulin resistance, particularly women treated with glucocorticoid for several years. To our knowledge, this is the first report describing steatohepatitis secondary to CAH and prolonged glucocorticoid treatment. It is important to be aware that steatohepatitis can develop in these patients due to long-term glucocorticoid use and potentially lead to progressive liver damage. Furthermore, in patients with CAH who develop abnormal liver enzyme activities a liver biopsy is warranted to assess for steatohepatitis and any associated fibrosis. If indeed fibrosis is already present, a consultation with the endocrinologist should be undertaken in an effort to lower the dose of the glucocorticoids as much as possible while still controlling the symptoms of the disease.
    Seminars in Liver Disease 11/2013; 33(4):389-92. DOI:10.1055/s-0033-1358526 · 5.12 Impact Factor

Publication Stats

11k Citations
1,894.24 Total Impact Points

Institutions

  • 1981–2015
    • Icahn School of Medicine at Mount Sinai
      • • Department of Pathology
      • • Division of Liver Diseases
      • • Department of Medicine
      Borough of Manhattan, New York, United States
  • 2001–2014
    • 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
  • 2010
    • Weill Cornell Medical College
      New York, New York, United States
  • 2008
    • Dana-Farber Cancer Institute
      • Department of Pediatric Oncology
      Boston, Massachusetts, United States
  • 1981–2004
    • Mount Sinai Hospital
      New York City, New York, United States
  • 2002
    • Aristotle University of Thessaloniki
      Saloníki, Central Macedonia, Greece
  • 1995–2001
    • Tulane University
      • Department of Pathology and Laboratory Medicine
      New Orleans, LA, United States
  • 2000
    • The Scripps Research Institute
      La Jolla, California, United States
    • Yonsei University
      • Department of Pathology
      Seoul, Seoul, South Korea
  • 1984–2000
    • 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
    • Seoul Medical Center
      Sŏul, Seoul, South Korea
  • 1997
    • Cedars-Sinai Medical Center
      • Cedars Sinai Medical Center
      Los Angeles, California, United States
  • 1993
    • The Rockefeller University
      New York, New York, United States
  • 1986
    • Instituto Nacional de Salud
      Colombia