Renumathy Dhanasekaran MD is an Assistant Professor in the Division of Gastroenterology and Hepatology at the School of Medicine, Stanford University. Her primary research goal is to explore the molecular biology of liver cancer in order to identify novel biomarkers and molecular-targeted therapies. She conducts basic and translational research to understand the molecular mechanisms of liver cancer metastasis and dormancy using mouse models of liver cancer. Also, she plays an active role in the cancer genome atlas (TCGA) consortium effort to translate the knowledge gained from the study of genomics of liver cancer. She maintains a bio-repository of tissue and blood samples from patients with liver cancer and has also developed several patient derived xenograft (PDX) models for preclinical testing. Dr. Dhanasekaran is a recipient of the American College of Gastroenterology (ACG) Junior Faculty Career Development award and the NIH/NCI K08 career development award.

Dr. Dhanasekaran completed her medical school training in India, and pursued her Internal Medicine residency at the University of Florida, Gainesville followed by Gastroenterology fellowship at Mayo Clinic, Rochester and Transplant Hepatology fellowship at Stanford University. Dr. Dhanasekaran is board certified in Internal Medicine and Gastoenterology. Her clinical practice is mainly focused on liver cancer and she runs a clinic specifically for patients with liver masses.

Lab Website

Clinical Focus

  • Liver cancer
  • Liver translant
  • Hepatology
  • Gastroenterology

Academic Appointments

Administrative Appointments

  • Member, Stanford Cancer Institute (SCI), Cancer Therapeutics Research Program (2021 - Present)
  • Associate Member, Canary Center at Stanford (2021 - Present)
  • Working Group member, CCG Tumor Molecular Pathology (TMP) Analysis Working Group (2017 - Present)
  • Media Spokesperson, American Gastroenterological Association (AGA) (2016 - Present)
  • Member and Manuscript Co-ordinator, Analysis Working Group, The Cancer Genome Atlas (TCGA), Liver Cancer (2014 - 2017)
  • Working group Member, AGA Young Delegates Program (2016 - 2018)

Honors & Awards

  • AGA-AASLD MasterClass 2018- Selected to attend, AGA/AASLD (Nov 2018)
  • 2018 Academic Skills Workshop- Selected to Attend, AGA/AASLD (March 2018)
  • 2015 William H. Summerskill award for outstanding achievement in research, Mayo Clinic, Rochester (June 2015)
  • Nominated for Edward C. Rosenow II award for Outstanding Trainee Teaching Award, Mayo Clinic, Rochester (June 2015)
  • 2016 AGA Women's Leadership Program- Selected to Attend, AGA (Feb 2016)
  • Travel Bursary to present abstract, EASL HCC SUMMIT Geneva, Switzerland, (Feb 2014)
  • Travel Bursary to present at the Basic science session, ILCA Liver Meeting, Austria (April 2015)
  • B Braun Medical Trust Foundation Scholarship, B Braun (2007)

Boards, Advisory Committees, Professional Organizations

  • Member, National Liver Cancer Review Board (2019 - Present)
  • Member, AASLD Communications Subcommittee (2018 - Present)
  • Member, AASLD Hepatobiliary neoplasia Special Interest Group (SIG) (2017 - Present)
  • Member, AGA Research Advocacy Subcommittee (2016 - Present)
  • Member, AGA Practice management and Economics Committee (2016 - 2017)
  • Member, AGA Young GI and Trainee Committee (2015 - 2017)

Professional Education

  • Fellowship: Stanford University Division of Gastroenterology and Hepatology (2016) CA
  • Fellowship: Mayo Clinic Gastroenterology Fellowship (2015) MN
  • Residency: University of Florida Internal Medicine Residency (2012) FL
  • MD, Madras Medical College, Internal Medicine (2008)
  • Medical Education: Bangalore Medical College (2005) India

Research Interests

  • Data Sciences
  • Leadership and Organization
  • Professional Development
  • Research Methods
  • Science Education

Current Research and Scholarly Interests

The overall goal of my research is to understand the molecular pathogenesis of liver cancer and identify biologically relevant prognostic biomarkers and molecular targets for therapy in patients with hepatocellular carcinoma (HCC).

My current ongoing projects focus on these areas-
1. Drivers of tumor dormancy and recurrence of hepatocellular carcinoma (HCC)
2. Drivers of metastatic tumor progression in HCC
3. Prognostic gene signature for HCC
4. Glycoproteomic biomarkers of HCC
5. Using tumor cell free DNA (cfDNA) as biomarkers for HCC
6. Tumor progression of HCC in non alcoholic steatohepatitis (NASH)

Current Clinical Interests

  • Liver cancer
  • Liver transplant
  • Non alcoholic steatohepatitis (NASH)
  • Benign Liver Lesions

Clinical Trials

  • COVID-19 in Patients With Chronic Liver Diseases Not Recruiting

    This study seeks to determine how COVID-19 affects the clinical outcome of patients with chronic liver disease, and whether the clinical course of COVID-19 is influenced by underlying chronic liver disease.

    Stanford is currently not accepting patients for this trial.

    View full details

Stanford Advisees

All Publications

  • Nuclear to cytoplasmic transport is a druggable dependency in MYC-driven hepatocellular carcinoma. Nature communications Deutzmann, A., Sullivan, D. K., Dhanasekaran, R., Li, W., Chen, X., Tong, L., Mahauad-Fernandez, W. D., Bell, J., Mosley, A., Koehler, A. N., Li, Y., Felsher, D. W. 2024; 15 (1): 963


    The MYC oncogene is often dysregulated in human cancer, including hepatocellular carcinoma (HCC). MYC is considered undruggable to date. Here, we comprehensively identify genes essential for survival of MYChigh but not MYClow cells by a CRISPR/Cas9 genome-wide screen in a MYC-conditional HCC model. Our screen uncovers novel MYC synthetic lethal (MYC-SL) interactions and identifies most MYC-SL genes described previously. In particular, the screen reveals nucleocytoplasmic transport to be a MYC-SL interaction. We show that the majority of MYC-SL nucleocytoplasmic transport genes are upregulated in MYChigh murine HCC and are associated with poor survival in HCC patients. Inhibiting Exportin-1 (XPO1) in vivo induces marked tumor regression in an autochthonous MYC-transgenic HCC model and inhibits tumor growth in HCC patient-derived xenografts. XPO1 expression is associated with poor prognosis only in HCC patients with high MYC activity. We infer that MYC may generally regulate and require altered expression of nucleocytoplasmic transport genes for tumorigenesis.

    View details for DOI 10.1038/s41467-024-45128-y

    View details for PubMedID 38302473

  • Matrix viscoelasticity promotes liver cancer progression in the pre-cirrhotic liver. Nature Fan, W., Adebowale, K., Váncza, L., Li, Y., Rabbi, M. F., Kunimoto, K., Chen, D., Mozes, G., Chiu, D. K., Li, Y., Tao, J., Wei, Y., Adeniji, N., Brunsing, R. L., Dhanasekaran, R., Singhi, A., Geller, D., Lo, S. H., Hodgson, L., Engleman, E. G., Charville, G. W., Charu, V., Monga, S. P., Kim, T., Wells, R. G., Chaudhuri, O., Török, N. J. 2024


    Type 2 diabetes mellitus is a major risk factor for hepatocellular carcinoma (HCC). Changes in extracellular matrix (ECM) mechanics contribute to cancer development1,2, and increased stiffness is known to promote HCC progression in cirrhotic conditions3,4. Type 2 diabetes mellitus is characterized by an accumulation of advanced glycation end-products (AGEs) in the ECM; however, how this affects HCC in non-cirrhotic conditions is unclear. Here we find that, in patients and animal models, AGEs promote changes in collagen architecture and enhance ECM viscoelasticity, with greater viscous dissipation and faster stress relaxation, but not changes in stiffness. High AGEs and viscoelasticity combined with oncogenic β-catenin signalling promote HCC induction, whereas inhibiting AGE production, reconstituting the AGE clearance receptor AGER1 or breaking AGE-mediated collagen cross-links reduces viscoelasticity and HCC growth. Matrix analysis and computational modelling demonstrate that lower interconnectivity of AGE-bundled collagen matrix, marked by shorter fibre length and greater heterogeneity, enhances viscoelasticity. Mechanistically, animal studies and 3D cell cultures show that enhanced viscoelasticity promotes HCC cell proliferation and invasion through an integrin-β1-tensin-1-YAP mechanotransductive pathway. These results reveal that AGE-mediated structural changes enhance ECM viscoelasticity, and that viscoelasticity can promote cancer progression in vivo, independent of stiffness.

    View details for DOI 10.1038/s41586-023-06991-9

    View details for PubMedID 38297127

    View details for PubMedCentralID 7733542

  • Battle of the Biopsies: Role of tissue and liquid biopsy in hepatocellular carcinoma. Journal of hepatology Lehrich, B. M., Zhang, J., Monga, S. P., Dhanasekaran, R. 2023


    Hepatocellular carcinoma (HCC) diagnosis and management have undergone significant improvements in recent years. With the introduction of immunotherapy-based combination therapy, there has been a notable expansion in treatment options for patients with unresectable HCC. Simultaneously, innovative molecular tests for early detection and management of HCC are emerging. This progress prompts a key question: as liquid biopsy techniques rise in prominence, will they replace traditional tissue biopsies, or will both techniques remain relevant? Given the ongoing challenges of early HCC detection, including issues with ultrasound sensitivity, accessibility, and patient adherence to surveillance, the evolution of diagnostic techniques is more relevant than ever. Furthermore, the accurate stratification of HCC is limited by the absence of reliable biomarkers which can predict response to therapies. While the advantages of molecular diagnostics are evident, their potential has not yet been fully harnessed, largely because tissue biopsies are not routinely performed for HCC. Liquid biopsies, analyzing components such as circulating tumor cells, DNA, and extracellular vesicles, provide a promising alternative, though they still face challenges in sensitivity, cost, and accessibility. The early results from multianalyte liquid biopsy panels are promising and suggest they could play a transformative role in HCC detection and management, however, comprehensive clinical validation is still ongoing. In this review, we explore the challenges and potential of both tissue and liquid biopsy, highlighting that these diagnostic methods, while distinct in their approaches, are set to jointly reshape the future of HCC management.

    View details for DOI 10.1016/j.jhep.2023.11.030

    View details for PubMedID 38104635

  • EXPOSURE TO GLP1RA THERAPY IS ASSOCIATED WITH IMPROVED SURVIVAL IN POST LIVER TRANSPLANT PATIENTS WITH TYPE I I DIABETES MELLITUS Achalu, S., Berry, R., Manikat, R., Yeoh, A., Gombar, S., Kim, S. H., Ghaziani, T., Dronamraju, D., Dhanasekaran, R., Kwong, A. J., Torok, N. J., Goel, A., Kim, W., Kwo, P. LIPPINCOTT WILLIAMS & WILKINS. 2023: S311-S312
  • Downstaging Hepatocellular Carcinoma before Liver Transplantation: A Multicenter Analysis of the "All-Comers" Protocol in the MERITS-LT Consortium. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Natarajan, B., Tabrizian, P., Hoteit, M., Frenette, C., Parikh, N., Ghaziani, T., Dhanasekaran, R., Guy, J., Shui, A., Florman, S., Yao, F. Y., Mehta, N. 2023


    Patients with HCC meeting UNOS-downstaging (DS) criteria have excellent liver transplant (LT) outcomes after downstaging. However, outcomes for "all-comers" (AC) patients with tumors initially exceeding UNOS-DS are poorly understood. Patients meeting AC (n=82) or UNOS-DS (n=229) at 7 LT centers in 4 UNOS regions were prospectively followed from 2015-2020. AC patients had a lower probability of successful DS (67% vs 83% within 12 months;p<0.001). 3-year-survival was 69% for UNOS-DS vs. 58% for AC (p=0.05) and reduced to 30% in patients with Child-Pugh B/C cirrhosis or AFP >500. Five-year LT probability was 42% for AC vs. 74% in UNOS-DS (p=0.10). Thirty-eight percent were under-staged on explant with increasing sum of largest tumor diameter plus number of lesions prior to LT (OR 1.3;p=0.01) and AFP>20 (OR 5.9;p=0.005) associated with understaging. Post-LT 3-year survival was 91% for AC vs 81% for UNOS-DS (p=0.67). In this first prospective multi-regional study of AC patients from the MERITS-LT Consortium, we observed a 65% probability of successful downstaging. Three-year survival in AC was nearly 60% though AC with Child-Pugh B/C or AFP >500 had poor survival. Explant pathology and 3-year post-LT outcomes were similar between cohorts suggesting that LT is a reasonable goal in selected AC patients.

    View details for DOI 10.1016/j.ajt.2023.07.021

    View details for PubMedID 37532179

  • Molecular and immune landscape of hepatocellular carcinoma to guide therapeutic decision making. Hepatology (Baltimore, Md.) Dhanasekaran, R., Suzuki, H., Lemaitre, L., Kubota, N., Hoshida, Y. 2023


    Liver cancer, primarily hepatocellular carcinoma (HCC), exhibits highly heterogeneous histological and molecular aberrations across tumors and within individual tumor nodules. Such inter- and intra-tumor heterogeneity may lead to diversity in the natural history of disease progression and various clinical disparities across the patients. Recently developed multi-modality, single-cell, and spatial omics profiling technologies have enabled interrogation of the inter-/intra-tumor heterogeneity in the cancer cells as well as the tumor immune microenvironment. These features may influence the natural history and efficacy of emerging therapies targeting novel molecular and immune pathways, some of which had been deemed undruggable. Thus, comprehensive characterization of the heterogeneities at various levels may facilitate discovery of biomarkers that enable personalized and rational treatment decisions and optimize treatment efficacy while minimizing the risk of adverse effects. Such companion biomarkers will also refine HCC treatment algorithms across disease stages for cost-effective patient management by optimizing the allocation of limited medical resources. Despite this promise, the complexity of the inter-/intra-tumor heterogeneity and ever-expanding inventory of therapeutic agents and regimens have made clinical evaluation and translation of biomarkers increasingly challenging. To address this issue, novel clinical trial designs have been proposed and incorporated into recent studies. In this review, we discuss the latest findings in the molecular and immune landscape of HCC for their potential and utility as biomarkers, framework of evaluation and clinical application of predictive/prognostic biomarkers, and ongoing biomarker-guided therapeutic clinical trials. These new developments may revolutionize patient care and substantially impact the still dismal HCC mortality.

    View details for DOI 10.1097/HEP.0000000000000513

    View details for PubMedID 37300379

  • MYC-driven synthesis of Siglec ligands is a glycoimmune checkpoint. Proceedings of the National Academy of Sciences of the United States of America Smith, B. A., Deutzmann, A., Correa, K. M., Delaveris, C. S., Dhanasekaran, R., Dove, C. G., Sullivan, D. K., Wisnovsky, S., Stark, J. C., Pluvinage, J. V., Swaminathan, S., Riley, N. M., Rajan, A., Majeti, R., Felsher, D. W., Bertozzi, C. R. 2023; 120 (11): e2215376120


    The Siglecs (sialic acid-binding immunoglobulin-like lectins) are glycoimmune checkpoint receptors that suppress immune cell activation upon engagement of cognate sialoglycan ligands. The cellular drivers underlying Siglec ligand production on cancer cells are poorly understood. We find the MYC oncogene causally regulates Siglec ligand production to enable tumor immune evasion. A combination of glycomics and RNA-sequencing of mouse tumors revealed the MYC oncogene controls expression of the sialyltransferase St6galnac4 and induces a glycan known as disialyl-T. Using in vivo models and primary human leukemias, we find that disialyl-T functions as a "don't eat me" signal by engaging macrophage Siglec-E in mice or the human ortholog Siglec-7, thereby preventing cancer cell clearance. Combined high expression of MYC and ST6GALNAC4 identifies patients with high-risk cancers and reduced tumor myeloid infiltration. MYC therefore regulates glycosylation to enable tumor immune evasion. We conclude that disialyl-T is a glycoimmune checkpoint ligand. Thus, disialyl-T is a candidate for antibody-based checkpoint blockade, and the disialyl-T synthase ST6GALNAC4 is a potential enzyme target for small molecule-mediated immune therapy.

    View details for DOI 10.1073/pnas.2215376120

    View details for PubMedID 36897988

  • Long-term clinical outcomes of patients with COVID-19 and chronic liver disease: US multicenter COLD study. Hepatology communications Aby, E. S., Moafa, G., Latt, N., Sultan, M. T., Cacioppo, P. A., Kumar, S., Chung, R. T., Bloom, P. P., Gustafson, J., Daidone, M., Reinus, Z., Debes, J. D., Sandhu, S., Sohal, A., Khalid, S., Roytman, M., Catana, A. M., Wegermann, K., Carr, R. M., Saiman, Y., Kassab, I., Chen, V. L., Rabiee, A., Rosenberg, C., Nguyen, V., Gainey, C., Zhou, K., Chavin, K., Lizaola-Mayo, B. C., Chascsa, D. M., Varelas, L., Moghe, A., Dhanasekaran, R. 2023; 7 (1): e8874


    COVID-19 is associated with higher morbidity and mortality in patients with chronic liver diseases (CLDs). However, our understanding of the long-term outcomes of COVID-19 in patients with CLD is limited.We conducted a multicenter, observational cohort study of adult patients with CLD who were diagnosed with COVID-19 before May 30, 2020, to determine long-term clinical outcomes. We used a control group of patients with CLD confirmed negative for COVID-19.We followed 666 patients with CLD (median age 58 years, 52.8% male) for a median of 384 (interquartile range: 31-462) days. The long-term mortality was 8.1%; with 3.6% experiencing delayed COVID-19-related mortality. Compared to a propensity-matched control group of patients with CLD without COVID-19 (n=1332), patients with CLD with COVID-19 had worse long-term survival [p<0.001; hazards ratio (HR): 1.69; 95% CI: 1.19-2.41] and higher rate of hospitalization (p<0.001, HR: 2.00, 1.62-2.48) over a 1-year follow-up period. Overall, 29.9% of patients reported symptoms of long-COVID-19. On multivariable analysis, female sex (p=0.05, HR: 2.45, 1.01-2.11), Hispanic ethnicity (p=0.003, HR: 1.94, 1.26-2.99), and severe COVID-19 requiring mechanical ventilation (p=0.028, HR: 1.74, 1.06-2.86) predicted long-COVID-19. In survivors, liver-related laboratory parameters showed significant improvement after COVID-19 resolution. COVID-19 vaccine status was available for 72% (n=470) of patients with CLD and history of COVID-19, of whom, 70% (n=326) had received the COVID-19 vaccine.Our large, longitudinal, multicenter study demonstrates a high burden of long-term mortality and morbidity in patients with CLD and COVID-19. Symptoms consistent with long-COVID-19 were present in 30% of patients with CLD. These results illustrate the prolonged implications of COVID-19 both for recovering patients and for health care systems.

    View details for DOI 10.1097/

    View details for PubMedID 36633476

  • MYC Overexpression Drives Immune Evasion in Hepatocellular Carcinoma that is Reversible Through Restoration of Pro-Inflammatory Macrophages. Cancer research Dhanasekaran, R., Hansen, A. S., Park, J., Lemaitre, L., Lai, I., Adeniji, N., Kuruvilla, S., Suresh, A., Zhang, J., Swamy, V., Felsher, D. W. 2022


    Cancers evade immune surveillance, which can be reversed through immune checkpoint therapy in a small subset of cases. Here we report that the MYC oncogene suppresses innate immune surveillance and drives resistance to immunotherapy. In 33 different human cancers, MYC genomic amplification and overexpression increased immune checkpoint expression, predicted non-responsiveness to immune checkpoint blockade, and was associated with both Th2-like immune profile and reduced CD8 T cell infiltration. MYC transcriptionally suppressed innate immunity and MHCI mediated antigen presentation, which in turn impeded T cell response. Combined, but not individual, blockade of PDL1 and CTLA4 could reverse MYC-driven immune suppression by leading to recruitment of pro-inflammatory antigen-presenting macrophages with increased CD40 and MHCII expression. Depletion of macrophages abrogated the anti-neoplastic effects of PDL1 and CTLA4 blockade in MYC-driven hepatocellular carcinoma (HCC). Hence, MYC is a predictor of immune checkpoint responsiveness and a key driver of immune evasion through the suppression of pro-inflammatory macrophages. The immune evasion by MYC in HCC can be overcome by combined PDL1 and CTLA4 blockade.

    View details for DOI 10.1158/0008-5472.CAN-22-0232

    View details for PubMedID 36525476

  • MYC oncogene elicits tumorigenesis associated with embryonic, ribosomal biogenesis, and tissue-lineage dedifferentiation gene expression changes. Oncogene Sullivan, D. K., Deutzmann, A., Yarbrough, J., Krishnan, M. S., Gouw, A. M., Bellovin, D. I., Adam, S. J., Liefwalker, D. F., Dhanasekaran, R., Felsher, D. W. 2022


    MYC is a transcription factor frequently overexpressed in cancer. To determine how MYC drives the neoplastic phenotype, we performed transcriptomic analysis using a panel of MYC-driven autochthonous transgenic mouse models. We found that MYC elicited gene expression changes mostly in a tissue- and lineage-specific manner across B-cell lymphoma, T-cell acute lymphoblastic lymphoma, hepatocellular carcinoma, renal cell carcinoma, and lung adenocarcinoma. However, despite these gene expression changes being mostly tissue-specific, we uncovered a convergence on a common pattern of upregulation of embryonic stem cell gene programs and downregulation of tissue-of-origin gene programs across MYC-driven cancers. These changes are representative of lineage dedifferentiation, that may be facilitated by epigenetic alterations that occur during tumorigenesis. Moreover, while several cellular processes are represented among embryonic stem cell genes, ribosome biogenesis is most specifically associated with MYC expression in human primary cancers. Altogether, MYC's capability to drive tumorigenesis in diverse tissue types appears to be related to its ability to both drive a core signature of embryonic genes that includes ribosomal biogenesis genes as well as promote tissue and lineage specific dedifferentiation.

    View details for DOI 10.1038/s41388-022-02458-9

    View details for PubMedID 36207533

  • SARS-CoV-2 vaccination and risk of severe COVID-19 outcomes in patients with autoimmune hepatitis. Journal of autoimmunity Efe, C., Tascilar, K., Gerussi, A., Bolis, F., Lammert, C., Ebik, B., Stattermayer, A. F., Cengiz, M., Gokce, D. T., Cristoferi, L., Peralta, M., Massoumi, H., Montes, P., Cerda, E., Rigamonti, C., Yapali, S., Adali, G., Caliskan, A. R., Balaban, Y., Eren, F., Eskazan, T., Barutcu, S., Lytvyak, E., Zazueta, G. M., Kayhan, M. A., Heurgue-Berlot, A., De Martin, E., Yavuz, A., Biyik, M., Narro, G. C., Duman, S., Hernandez, N., Gatselis, N. K., Aguirre, J., Idilman, R., Silva, M., Mendizabal, M., Atay, K., Guzelbulut, F., Dhanasekaran, R., Montano-Loza, A. J., Dalekos, G. N., Ridruejo, E., Invernizzi, P., Wahlin, S. 2022; 132: 102906


    BACKGROUND: Data regarding outcome of Coronavirus disease 2019 (COVID-19) in vaccinated patients with autoimmune hepatitis (AIH) are lacking. We evaluated the outcome of COVID-19 in AIH patients who received at least one dose of Pfizer- BioNTech (BNT162b2), Moderna (mRNA-1273) or AstraZeneca (ChAdOx1-S) vaccine.PATIENTS AND METHODS: We performed a retrospective study on AIH patients with COVID-19. The outcomes of AIH patients who had acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection after at least one dose of COVID-19 vaccine were compared to unvaccinated patients with AIH. COVID-19 outcome was classified according to clinical state during the disease course as: (i) no hospitalization, (ii) hospitalization without oxygen supplementation, (iii) hospitalization with oxygen supplementation by nasal cannula or mask, (iv) intensive care unit (ICU) admission with non-invasive mechanical ventilation, (v) ICU admission with invasive mechanical ventilation or (vi) death, and data was analyzed using ordinal logistic regression.RESULTS: We included 413 (258 unvaccinated and 155 vaccinated) patients (81%, female) with a median age of 52 (range: 17-85) years at COVID-19 diagnosis. The rates of hospitalization were (36.4% vs. 14.2%), need for any supplemental oxygen (29.5% vs. 9%) and mortality (7% vs. 0.6%) in unvaccinated and vaccinated AIH patients with COVID-19. Having received at least one dose of SARS-CoV-2 vaccine was associated with a significantly lower risk of worse COVID-19 severity, after adjusting for age, sex, comorbidities and presence of cirrhosis (adjusted odds ratio [aOR] 0.18, 95% confidence interval [CI], 0.10-0.31). Overall, vaccination against SARS-CoV-2 was associated with a significantly lower risk of mortality from COVID-19 (aOR 0.20, 95% CI 0.11-0.35).CONCLUSIONS: SARS-CoV-2 vaccination significantly reduced the risk of COVID-19 severity and mortality in patients with AIH.

    View details for DOI 10.1016/j.jaut.2022.102906

    View details for PubMedID 36088883

  • Clinical characteristics and outcomes in those with primary extrahepatic malignancy and malignant ascites. BMC gastroenterology Alshuwaykh, O., Cheung, A., Goel, A., Kwong, A., Dhanasekaran, R., Ghaziani, T. T., Ahmed, A., Daugherty, T., Dronamraju, D., Kumari, R., Nguyen, M., Kim, W. R., Kwo, P. Y. 2022; 22 (1): 410


    BACKGROUND: Malignancy-related ascites accounts for approximately 10% of causes of ascites. Our AIM was to characterize the ascites fluid and correlate clinical outcomes in those with extrahepatic malignancy and ascites.METHODS: 241 subjects with extrahepatic solid tumors and ascites were reviewed from 1/1/2000 to 12/31/2019, 119 without liver metastasis and 122 with liver metastasis.RESULTS: Ascites fluid consistent with peritoneal carcinomatosis (PC) was most common, 150/241 (62%), followed by fluid reflecting the presence of portal hypertension (PH), 69/241 (29%). 22/241 (9%) had low SAAG and low ascites fluid total protein, with evidence of PC on cytology and or imaging in 20/22. Lung cancer was the most common malignancy in subjects with ascites due to PC at 36/150 (24%), pancreatic cancer was the most common in subjects with ascites with features of PH at 16/69 (23%). Chemotherapy or immunotherapy alone was the most common management approach. Significantly higher 5-year, 3-year and 1-year mortality rate were noted in subjects with evidence of PC on cytology/imaging versus subjects with no evidence of PC, and in subjects with liver metastasis compared to subjects without liver metastasis. Subjects with pancreatic cancer and evidence of PC on cytology/imaging had higher 1 and 5-year mortality rates compared to subjects without PC.CONCLUSIONS: Ascites in solid tumor malignancy is most commonly due to PC. We also observed ascites fluid with characteristics of PH in 29% of subjects. Higher mortality rates in subjects with peritoneal carcinomatosis and liver metastasis were noted. These findings may help inform prognosis and treatment strategies.

    View details for DOI 10.1186/s12876-022-02487-4

    View details for PubMedID 36064324

  • Incidence of hepatocellular carcinoma in chronic hepatitis B virus infection in those not meeting criteria for antiviral therapy. Hepatology communications Alshuwaykh, O., Daugherty, T., Cheung, A., Goel, A., Dhanasekaran, R., Ghaziani, T. T., Ahmed, A., Dronamraju, D., Kumari, R., Kwong, A., Nguyen, M., Kim, W. R., Kwo, P. Y. 2022


    Chronic hepatitis B virus (HBV) infection is the leading risk factor for hepatocellular carcinoma (HCC). The aim of this study was to explore the incidence of HCC in a cohort of subjects with HBV and correlate with HBV treatment current guidance. We identified 2846 subjects with HBV over the study period. HCC was diagnosed in 386 of 2846 (14%) subjects; 209 of 386 (54%) were on nucleos(t)ide analogue (NA) therapy at time of HCC diagnosis, and 177 of 386 (46%) were not on NA therapy. Of the 177 subjects not on NAs who developed HCC during follow-up, 153 of 177 (86%) had cirrhosis. Within the 177 subjects not on NAs, 158 of 177 (89%) had undetectable HBV DNA, 10 of 177 (6%) had detectable HBV DNA < 2000 IU/L, and 9 of 177 (5%) had HBV DNA > 2000 IU/L. Of those with cirrhosis and undetectable HBV DNA, 115 of 141 had compensated cirrhosis, and 26 of 141 had decompensated cirrhosis. Significant predictors of HCC on time to event analysis included cirrhosis (hazard ratio [HR] 10, 95% confidence interval [CI] 5.8-17.5; p < 0.001), alanine aminotransferase level (HR 1.004, 95% CI 1.002-1.006; p < 0.001), age (HR 1.04, 95% CI 1.03-1.06; p < 0.001), (HR 1.9, 95% CI 1.2-3.1; p 0.007), and nonalcoholic fatty liver disease (HR 1.7, 95% CI 1.1-2.8; p 0.02). Kaplan-Meier analysis demonstrated the cumulative incidence of HCC in subjects with compensated cirrhosis receiving NA therapy was significantly lower compared to subjects with compensated cirrhosis outside current HBV treatment practice guidance (undetectable HBV DNA) (32% vs. 51%; p < 0.001). Conclusion: Those with untreated compensated cirrhosis with undetectable HBV DNA who do not meet current guidance for treatment had higher rates of HCC than those with compensated cirrhosis and suppressed HBV DNA by NA therapy. This study highlights the need for earlier diagnosis and treatment of HBV.

    View details for DOI 10.1002/hep4.2064

    View details for PubMedID 36004713

  • Implications of genetic heterogeneity in hepatocellular cancer. Advances in cancer research Suresh, A., Dhanasekaran, R. 2022; 156: 103-135


    Hepatocellular carcinoma (HCC) exhibits a remarkable degree of heterogeneity, not only at an inter-patient level but also between and within tumors in the same patient. The advent of next-generation sequencing (NGS)-based technologies has allowed the creation of high-resolution atlases of HCC. This review outlines recent findings from genomic, epigenomic, transcriptomic, and proteomic sequencing that have yielded valuable insights into the spatial and temporal heterogeneity of HCC. The high heterogeneity of HCC has both clinical and therapeutic implications. The challenges in prospectively validating molecular classifications for HCC either for prognostication or for prediction of therapeutic response are partly due to the immense heterogeneity in HCC. Moreover, the heterogeneity of HCC tumors combined with the lack of commonly mutated, druggable targets severely limits treatment options for HCC. Recently, immune checkpoint inhibitors and combination therapies have shown promise for advanced HCC, while T cell therapies and vaccines are currently being investigated. Yet, immunotherapies show benefit only in a limited subset of patients, making it imperative to decipher tumor heterogeneity in HCC in order to enable optimal patient selection. This review summarizes the cutting-edge research on heterogeneity in HCC and explores the implications of heterogeneity on stratifying patients and developing biomarkers and therapies for HCC.

    View details for DOI 10.1016/bs.acr.2022.01.007

    View details for PubMedID 35961697

  • Treacherous apoptosis- cancer cells sacrifice themselves at the altar of heterogeneity. Hepatology (Baltimore, Md.) Dhanasekaran, R. 2022

    View details for DOI 10.1002/hep.32433

    View details for PubMedID 35218240

  • Effects of Immunosuppressive Drugs on COVID-19 severity in Patients with Autoimmune Hepatitis. Liver international : official journal of the International Association for the Study of the Liver Efe, C., Lammert, C., Tascilar, K., Dhanasekaran, R., Ebik, B., Higuera-de la Tijera, F., Caliskan, A. R., Peralta, M., Gerussi, A., Massoumi, H., Catana, A. M., Purnak, T., Rigamonti, C., Gomez Aldana, A. J., Khakoo, N., Nazal, L., Frager, S., Demir, N., Irak, K., Melekoglu Ellik, Z., Kacmaz, H., Balaban, Y., Atay, K., Eren, F., Alvares-da-Silva, M. R., Cristoferi, L., Urzua, A., Eskazan, T., Magro, B., Snijders, R., Barutcu, S., Lytvyak, E., Miranda Zazueta, G., Demirezer Bolat, A., Aydin, M., Heurgue-Berlot, A., De Martin, E., Ekin, N., Yildirim, S., Yavuz, A., Biyik, M., Castro Narro, G., Kiyici, M., Akyildiz, M., Kahramanoglu-Aksoy, E., Vincent, M., Carr, R. M., Gunsar, F., Cerda Reyes, E., Harputoglu, M., Aloman, C., Gatselis, N. K., Ustundag, Y., Brahm, J., Chris Escajadillo Vargas, N., Guzelbulut, F., Ruiz Garcia, S., Aguirre, J., Anders, M., Ratusnu, N., Hatemi, I., Mendizabal, M., Floreani, A., Fagiuoli, S., Silva, M., Idilman, R., Satapathy, S. K., Silveira, M., Drenth, J. P., Dalekos, G. N., Assis, D. N., Bjornsson, E., Boyer, J. L., Yoshida, E. M., Invernizzi, P., Levy, C., Montano-Loza, A. J., Schiano, T. D., Ridruejo, E., Wahlin, S. 2021


    BACKGROUND: We investigated associations between baseline use of immunosuppressive drugs and severity of Coronavirus Disease 2019 (COVID-19) in autoimmune hepatitis (AIH).PATIENTS AND METHODS: Data of AIH patients with laboratory confirmed COVID-19 were retrospectively collected from 15 countries. The outcomes of AIH patients who were on immunosuppression at the time of COVID-19 were compared to patients who were not on AIH-medication. The clinical courses of COVID-19 was classified as (i)-no hospitalization, (ii)-hospitalization without oxygen supplementation, (iii)-hospitalization with oxygen supplementation by nasal cannula or mask, (iv)-intensive care unit (ICU) admission with non-invasive mechanical ventilation, (v)-ICU admission with invasive mechanical ventilation or (vi)-death and analyzed using ordinal logistic regression.RESULTS: We included 254 AIH patients (79.5%, female) with a median age of 50 (range,17-85) years. At the onset of COVID-19, 234 patients (92.1%) were on treatment with glucocorticoids (n=156), thiopurines (n=151), mycophenolate mofetil (n=22) or tacrolimus (n=16), alone or in combinations. Overall, 94 (37%) patients were hospitalized and 18 (7.1%) patients died. Use of systemic glucocorticoids (adjusted odds ratio [aOR] 4.73, 95% CI 1.12-25.89) and thiopurines (aOR 4.78, 95% CI 1.33-23.50) for AIH was associated with worse COVID-19 severity, after adjusting for age-sex, comorbidities and presence of cirrhosis. Baseline treatment with mycophenolate mofetil (aOR 3.56, 95% CI 0.76-20.56) and tacrolimus (aOR 4.09,95% CI 0.69-27.00) were also associated with more severe COVID-19 courses in a smaller subset of treated patients.CONCLUSION: Baseline treatment with systemic glucocorticoids or thiopurines prior to the onset of COVID-19 was significantly associated with COVID-19 severity in patients with AIH.

    View details for DOI 10.1111/liv.15121

    View details for PubMedID 34846800

  • THE INCIDENCE OF HEPATOCELLULAR CARCINOMA IN CHRONIC HEPATITIS B VIRUS INFECTION SUBJECTS WITH CIRRHOSIS NOT MEETING CURRENT TREATMENT GUIDANCE Alshuwaykh, O., Goel, A., Ghaziani, T., Daugherty, T., Dhanasekaran, R., Ahmed, A., Dronamraju, D., Kwong, A. J., Nguyen, M. H., Cheung, A., Kwo, P. WILEY. 2021: 500A-501A
  • LONG-TERM CLINICAL OUTCOMES OF PATIENTS WITH COVID-19 AND CHRONIC LIVER DISEASE: US MULTICENTER STUDY COLD STUDY Aby, E., Gustafson, J. L., Daidone, M., Chung, R. T., Sandhu, S., Sohal, A., Khalid, S., Roytman, M., Varelas, L., Moghe, A., Moafa, G., Latt, N. L., Carr, R. M., Saiman, Y., Catana, A. M., Kassab, I., Chen, V., Rosenberg, C., Debes, J. D., Rabiee, A., Nguyen, V., Gainey, C., Zhou, K., Chavin, K. D., Lizaola-Mayo, B., Kumar, S., Dhanasekaran, R. WILEY. 2021: 48A-49A
  • DISTINCT IMMUNE MECHANISMS OF COMBINED PD-L1 AND CTLA-4 BLOCKADE IN HEPATOCELLULAR CARCINOMA (HCC) Dhanasekaran, R., Hansen, A., Park, J., Lai, I., Adeniji, N., Kuruvilla, S., Felsher, D. WILEY. 2021: 110A
  • Hepatocellular carcinoma in nonalcoholic fatty liver disease: A growing challenge WORLD JOURNAL OF HEPATOLOGY Mattos, A. Z., Debes, J. D., Dhanasekaran, R., Benhammou, J. N., Arrese, M., Patricio, A., Zilio, A. C., Mattos, A. A. 2021; 13 (9): 1107-1121


    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide, and its prevalence increases continuously. As it predisposes to hepatocellular carcinoma both in the presence and in the absence of cirrhosis, it is not surprising that the incidence of NAFLD-related hepatocellular carcinoma would also rise. Some of the mechanisms involved in hepatocarcinogenesis are particular to individuals with fatty liver, and they help explain why liver cancer develops even in patients without cirrhosis. Genetic and immune-mediated mechanisms seem to play an important role in the development of hepatocellular carcinoma in this population. Currently, it is consensual that patients with NAFLD-related cirrhosis should be surveilled with ultrasonography every 6 mo (with or without alpha-fetoprotein), but it is known that they are less likely to follow this recommendation than individuals with other kinds of liver disease. Moreover, the performance of the methods of surveillance are lower in NAFLD than they are in other liver diseases. Furthermore, it is not clear which subgroups of patients without cirrhosis should undergo surveillance. Understanding the mechanisms of hepatocarcinogenesis in NAFLD could hopefully lead to the identification of biomarkers to be used in the surveillance for liver cancer in these individuals. By improving surveillance, tumors could be detected in earlier stages, amenable to curative treatments.

    View details for DOI 10.4254/wjh.v13.i9.1107

    View details for Web of Science ID 000702511700010

    View details for PubMedID 34630878

    View details for PubMedCentralID PMC8473502

  • Current and Emerging Tools for Hepatocellular Carcinoma Surveillance. Hepatology communications Adeniji, N., Dhanasekaran, R. 2021


    Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Early detection of HCC enables patients to avail curative therapies that can improve patient survival. Current international guidelines advocate for the enrollment of patients at high risk for HCC, like those with cirrhosis, in surveillance programs that perform ultrasound every 6months. In recent years, many studies have further characterized the utility of established screening strategies and have introduced new promising tools for HCC surveillance. In this review, we provide an overview of the most promising new imaging modalities and biomarkers for the detection of HCC. We discuss the role of imaging tools like ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) in the early detection of HCC, and describe recent innovations which can potentially enhance their applicability, including contrast enhanced ultrasound, low-dose CT scans, and abbreviated MRI. Next, we outline the data supporting the use of three circulating biomarkers (i.e., alpha-fetoprotein [AFP], AFP lens culinaris agglutinin-reactive fraction, and des-gamma-carboxy prothrombin) in HCC surveillance, and expand on multiple emerging liquid biopsy biomarkers, including methylated cell-free DNA (cfDNA), cfDNA mutations, extracellular vesicles, and circulating tumor cells. These promising new imaging modalities and biomarkers have the potential to improve early detection, and thus improve survival, in patients with HCC.

    View details for DOI 10.1002/hep4.1823

    View details for PubMedID 34533885

  • The MYC oncogene - the grand orchestrator of cancer growth and immune evasion. Nature reviews. Clinical oncology Dhanasekaran, R., Deutzmann, A., Mahauad-Fernandez, W. D., Hansen, A. S., Gouw, A. M., Felsher, D. W. 2021


    The MYC proto-oncogenes encode a family of transcription factors that are among the most commonly activated oncoproteins in human neoplasias. Indeed, MYC aberrations or upregulation of MYC-related pathways by alternate mechanisms occur in the vast majority of cancers. MYC proteins are master regulators of cellular programmes. Thus, cancers with MYC activation elicit many of the hallmarks of cancer required for autonomous neoplastic growth. In preclinical models, MYC inactivation can result in sustained tumour regression, a phenomenon that has been attributed to oncogene addiction. Many therapeutic agents that directly target MYC are under development; however, to date, their clinical efficacy remains to be demonstrated. In the past few years, studies have demonstrated that MYC signalling can enable tumour cells to dysregulate their microenvironment and evade the host immune response. Herein, we discuss how MYC pathways not only dictate cancer cell pathophysiology but also suppress the host immune response against that cancer. We also propose that therapies targeting the MYC pathway will be key to reversing cancerous growth and restoring antitumour immune responses in patients with MYC-driven cancers.

    View details for DOI 10.1038/s41571-021-00549-2

    View details for PubMedID 34508258

  • Screening for Hepatocellular Carcinoma in Patients with Hepatitis B. Viruses Sachar, Y., Brahmania, M., Dhanasekaran, R., Congly, S. E. 2021; 13 (7)


    Chronic hepatitis B (CHB) infection is a significant risk factor for developing hepatocellular carcinoma (HCC). As HCC is associated with significant morbidity and mortality, screening patients with CHB at a high risk for HCC is recommended in an attempt to improve these outcomes. However, the screening recommendations on who to screen and how often are not uniform. Identifying patients at the highest risk of HCC would allow for the best use of health resources. In this review, we evaluate the literature on screening patients with CHB for HCC, strategies for optimizing adherence to screening, and potential risk stratification tools to identify patients with CHB at a high risk of developing HCC.

    View details for DOI 10.3390/v13071318

    View details for PubMedID 34372524

    View details for PubMedCentralID PMC8310362

  • Screening for Hepatocellular Carcinoma in Patients with Hepatitis B VIRUSES-BASEL Sachar, Y., Brahmania, M., Dhanasekaran, R., Congly, S. E. 2021; 13 (7)

    View details for DOI 10.3390/v13071318

    View details for Web of Science ID 000676972200001

  • Outcomes of Downstaging Hepatocellular Carcinoma (HCC) to within Milan Criteria Before Liver Transplantation (LT): A Multicenter Analysis of the "All-comers" Protocol Natarajan, B., Tabrizian, P., Hoteit, M., Frenette, C., Ghaziani, T., Dhanasekaran, R., Parikh, N., Guy, J., Shui, A., Florman, S., Yao, F., Mehta, N. WILEY. 2021: 324
  • Outcome of COVID-19 in Patients with Autoimmune Hepatitis: an International Multi-Centre Study. Hepatology (Baltimore, Md.) Efe, C., Dhanasekaran, R., Lammert, C., Ebi, B., Higuera-de la Tijera, F., Aloman, C., Riza Caliskan, A., Peralta, M., Gerussi, A., Massoumi, H., Catana, A. M., Torgutalp, M., Purnak, T., Rigamonti, C., Gomez Aldana, A. J., Khakoo, N., Kacmaz, H., Nazal, L., Frager, S., Demir, N., Irak, K., Ellik, Z. M., Balaban, Y., Atay, K., Eren, F., Cristoferi, L., Batibay, E., Urzua, A., Snijders, R., Kiyici, M., Akyildiz, M., Ekin, N., Carr, R. M., Harputoglu, M., Hatemi, I., Mendizabal, M., Silva, M., Idilman, R., Silveira, M., Drenth, J. P., Assis, D. N., Bjornsson, E., Boyer, J. L., Invernizzi, P., Levy, C., Schiano, T. D., Ridruejo, E., Wahlin, S. 2021


    BACKGROUND: Data regarding outcome of Coronavirus disease 2019 (COVID-19) in patients with autoimmune hepatitis (AIH) are lacking.PATIENTS AND METHODS: We performed a retrospective study on AIH patients with COVID-19 from 34 centres in Europe and the Americas. We analyzed factors associated with severe COVID-19 outcomes defined as the need for mechanical ventilation, intensive care admission, and/or death. The outcomes of patients with AIH were compared to a propensity-score matched cohort of non-AIH patients with chronic liver diseases (CLD) and COVID-19. The frequency and clinical significance of new-onset liver injury (alanine aminotransferase>2xupper limit of normal) during COVID-19 was also evaluated.RESULTS: We included 110 AIH patients (80%,female) with a median age of 49 (range:18-85) years at COVID-19 diagnosis. New-onset liver injury was observed in 37.1% (33/89) of the patients. Use of antivirals was associated with liver injury (p=0.041; odds ratio (OR) 3.36[1.05-10.78]) while continued immunosuppression during COVID-19 was associated with a lower rate of liver injury (p=0.009; OR 0.26[0.09-0.71]). The rates of severe COVID-19 (15.5% vs 20.2% p=0.231) and all-cause mortality (10% vs 11.5%; p=0.852) were not different between AIH and non-AIH CLD. Cirrhosis was an independent predictor of severe COVID-19 in patients with AIH (p<0.001; OR 17.46[4.22-72.13]). Continuation of immunosuppression or presence of liver injury during COVID-19 was not associated with severe COVID-19.CONCLUSIONS: This international, multi-center study reveals that patients with AIH were not at risk for worse outcomes with COVID-19 than other causes of CLD. Cirrhosis was the strongest predictor for severe COVID-19 in AIH patients. Maintenance of immunosuppression during COVID-19 was not associated with increased risk for severe COVID-19, but did lower the risk for new-onset liver injury during COVID-19.

    View details for DOI 10.1002/hep.31797

    View details for PubMedID 33713486

  • Predictors of Outcomes of Patients Referred to a Transplant Center for Urgent Liver Transplantation Evaluation. Hepatology communications Alshuwaykh, O., Kwong, A., Goel, A., Cheung, A., Dhanasekaran, R., Ahmed, A., Daugherty, T., Dronamraju, D., Kumari, R., Kim, W. R., Nguyen, M. H., Esquivel, C. O., Concepcion, W., Melcher, M., Bonham, A., Pham, T., Gallo, A., Kwo, P. Y. 2021; 5 (3): 516-525


    Liver transplantation (LT) is definitive treatment for end-stage liver disease. This study evaluated factors predicting successful evaluation in patients transferred for urgent inpatient LT evaluation. Eighty-two patients with cirrhosis were transferred for urgent LT evaluation from January 2016 to December 2018. Alcohol-associated liver disease was the common etiology of liver disease (42/82). Of these 82 patients, 35 (43%) were declined for LT, 27 (33%) were wait-listed for LT, 5 (6%) improved, and 15 (18%) died. Psychosocial factors were the most common reasons for being declined for LT (49%). Predictors for listing and receiving LT on multivariate analysis included Hispanic race (odds ratio [OR], 1.89; P = 0.003), Asian race (OR, 1.52; P = 0.02), non-Hispanic ethnicity (OR, 1.49; P = 0.04), hyponatremia (OR, 1.38; P = 0.04), serum albumin (OR, 1.13; P = 0.01), and Model for End-Stage Liver Disease (MELD)-Na (OR, 1.02; P = 0.003). Public insurance (i.e., Medicaid) was a predictor of not being listed for LT on multivariate analysis (OR, 0.77; P = 0.02). Excluding patients declined for psychosocial reasons, predictors of being declined for LT on multivariate analysis included Chronic Liver Failure Consortium (CLIF-C) score >51.5 (OR, 1.26; P = 0.03), acute-on-chronic liver failure (ACLF) grade 3 (OR, 1.41; P = 0.01), hepatorenal syndrome (HRS) (OR, 1.38; P = 0.01), and respiratory failure (OR, 1.51; P = 0.01). Predictors of 3-month mortality included CLIF-C score >51.5 (hazard ratio [HR], 2.52; P = 0.04) and intensive care unit (HR, 8.25; P < 0.001). Conclusion: MELD-Na, albumin, hyponatremia, ACLF grade 3, HRS, respiratory failure, public insurance, Hispanic race, Asian race, and non-Hispanic ethnicity predicted liver transplant outcome. Lack of psychosocial support was a major reason for being declined for LT. The CLIF-C score predicted being declined for LT and mortality.

    View details for DOI 10.1002/hep4.1644

    View details for PubMedID 33681683

    View details for PubMedCentralID PMC7917272

  • Hepatitis C and Hepatocellular Cancer: To Treat or Not to Treat. Clinical liver disease Dhanasekaran, R., Kwo, P. Y. 2021; 17 (3): 169–73

    View details for DOI 10.1002/cld.1003

    View details for PubMedID 33868660

  • Deciphering Tumor Heterogeneity in Hepatocellular Carcinoma (HCC)-Multi-Omic and Singulomic Approaches SEMINARS IN LIVER DISEASE Dhanasekaran, R. 2021
  • Morphological heterogeneity in beta-catenin-mutated hepatocellular carcinomas: implications for tumor molecular classification. Human pathology Torbenson, M., McCabe, C. E., O'Brien, D. R., Yin, J., Bainter, T., Tran, N. H., Yasir, S., Chen, Z. E., Dhanasekaran, R., Ahn, K. S., Roberts, L. R., Wang, C. 2021; 119: 15-27


    Beta-catenin (CTNNB1) is commonly mutated in hepatocellular carcinoma (HCC). CTNNB1-mutated HCC has important clinical correlates, such as being immune cold and less likely to respond to immune checkpoint inhibitor therapies. It remains unclear, however, if they are a morphologically homogenous group of tumors. To better understand the association between the morphology, CTNNB1 mutations, and other molecular features, a detailed study of 338 The Cancer Genome Atlas cases was performed. A characteristic histological morphology was strongly associated with CTNNB1 mutations but was present in only 58% of CTNNB1-mutated HCCs. Tumors with APC mutations tended to have the classic morphology; those with AXIN mutations did not. Pseudoglands are a key feature of the classic morphology, and they were associated with CTNNB1 mutations, male gender, specific CTNNB1 mutation site, and lack of TP53 mutations. Differential gene expression analysis stratified by the presence/absence of pseudoglands identified 60 differentially expressed genes (FDR <5%); clustering according to these differentially expressed genes revealed three groups of tumors, one with pseudoglands and a strong association with genes regulated by Wnt signaling; within this group, TP53 mutations were associated with a loss of the typical morphology of CTNNB1-mutated HCCs. When stratified by gender, further differential gene expression showed Wnt-regulated genes were associated with pseudoglands in men but not women. These findings indicate HCC with CTNNB1 mutations are morphologically heterogeneous, with gene penetrance for morphology dependent in part on gender, specific CTNNB1 mutations, and co-occurring TP53 mutations. This heterogeneity has important implications for the classification of HCC.

    View details for DOI 10.1016/j.humpath.2021.09.009

    View details for PubMedID 34592239

  • Recent Progress in Systemic Therapy for Hepatocellular Cancer (HCC). Current Treatment Options in Gastroenterology Ghaziani, T., Dhanasekaran, R. 2021; 19 (1): 351–368
  • Down-staging Outcomes for Hepatocellular Carcinoma: Results from the Multicenter Evaluation of Reduction in Tumor Size before Liver Transplantation (MERITS-LT) Consortium. Gastroenterology Mehta, N., Frenette, C., Tabrizian, P., Hoteit, M., Guy, J., Parikh, N., Ghaziani, T. T., Dhanasekaran, R., Dodge, J. L., Natarajan, B., Holzner, M. L., Frankul, L., Chan, W., Fobar, A., Florman, S., Yao, F. Y. 2021


    United Network of Organ Sharing (UNOS) has adopted uniform criteria for down-staging (UNOS-DS) of hepatocellular carcinoma (HCC) prior to liver transplantation (LT), but down-staging success rate and intention-to-treat outcomes across broad geographic regions are unknown.In this first multi-regional study (7 centers, 4 UNOS regions), consecutive patients with HCC undergoing down-staging based on UNOS-DS criteria were prospectively evaluated from 2016-2019 (n=209).Probability of successful down-staging to Milan criteria and dropout at 2 years from initial down-staging procedure was 87.7% and 37.3%, respectively. Pre-treatment AFP-L3 >10% (HR 3.7, p=0.02) was associated with increased dropout risk. When comparing chemoembolization (n=132) and Y-90 radioembolization (n=62) as initial down-staging treatment, there were no differences in mRECIST response, probability of or time to successful down-staging, waitlist dropout or LT. Probability of LT at 3 years was 46.6% after a median of 17.2 months. In the explant, 17.5% had vascular invasion and 42.8% exceeded Milan criteria (under-staging). The only factor associated with under-staging was the sum of the number of lesions plus largest tumor diameter on last pre-LT imaging, and odds of under-staging increased by 35% per 1 unit increase in this sum. Post-LT survival at 2 years was 95% and HCC recurrence occurred in 7.9%.In this first prospective multi-regional study based on UNOS-DS criteria, we observed successful down-staging rate of >80%, and similar efficacy of chemoembolization and Y-90 radioembolization as initial down-staging treatment. A high rate of tumor under-staging was observed despite excellent 2-year post-LT survival of 95%. Additional LRT to reduce viable tumor burden may reduce tumor under-staging.

    View details for DOI 10.1053/j.gastro.2021.07.033

    View details for PubMedID 34331914

  • Deciphering Tumor Heterogeneity in Hepatocellular Carcinoma (HCC)-Multi-Omic and Singulomic Approaches. Seminars in liver disease Dhanasekaran, R. 2021; 41 (1): 9-18


    Tumor heterogeneity, a key hallmark of hepatocellular carcinomas (HCCs), poses a significant challenge to developing effective therapies or predicting clinical outcomes in HCC. Recent advances in next-generation sequencing-based multi-omic and single cell analysis technologies have enabled us to develop high-resolution atlases of tumors and pull back the curtain on tumor heterogeneity. By combining multiregion targeting sampling strategies with deep sequencing of the genome, transcriptome, epigenome, and proteome, several studies have revealed novel mechanistic insights into tumor initiation and progression in HCC. Advances in multiparametric immune cell profiling have facilitated a deeper dive into the biological complexity of HCC, which is crucial in this era of immunotherapy. Moreover, studies using liquid biopsy have demonstrated their potential to circumvent the need for tissue sampling to investigate heterogeneity. In this review, we discuss how multi-omic and single-cell sequencing technologies have advanced our understanding of tumor heterogeneity in HCC.

    View details for DOI 10.1055/s-0040-1722261

    View details for PubMedID 33764481

  • Predictors of Outcomes of Patients Referred to a Transplant Center for Urgent Liver Transplantation Evaluation HEPATOLOGY COMMUNICATIONS Alshuwaykh, O., Kwong, A., Goel, A., Cheung, A., Dhanasekaran, R., Ahmed, A., Daugherty, T., Dronamraju, D., Kumari, R., Kim, W., Esquivel, C. O., Concepcion, W., Melcher, M., Bonham, A., Pham, T., Gallo, A., Kwo, P. 2020

    View details for DOI 10.1002/hep4.1644

    View details for Web of Science ID 000602465100001

  • Genomic Landscape of HCC. Current hepatology reports Nia, A., Dhanasekaran, R. 2020; 19 (4): 448–61


    Introduction: Hepatocellular carcinoma (HCC) is a leading cause of cancer related mortality in the world and it has limited treatment options. Understanding the molecular drivers of HCC is important to develop novel biomarkers and therapeutics.Purpose of Review: HCC arises in a complex background of chronic hepatitis, fibrosis and liver regeneration which lead to genomic changes. Here, we summarize studies that have expanded our understanding of the molecular landscape of HCC.Recent Findings: Recent technological advances in next generation sequencing (NGS) have elucidated specific genetic and molecular programs involved in hepatocarcinogenesis. We summarize the major somatic mutations and epigenetic changes have been identified in NGS-based studies. We also describe promising molecular therapies and immunotherapies which target specific genetic and epigenetic molecular events.Summary: The genomic landscape of HCC is incredibly complex and heterogeneous. Promising new developments are helping us decipher the molecular drivers of HCC and leading to new therapies.

    View details for DOI 10.1007/s11901-020-00553-7

    View details for PubMedID 33816052

  • Socioeconomic Factors Contribute to the Higher Risk of COVID-19 in Racial and Ethnic Minorities with Chronic Liver Diseases (CLD). Gastroenterology Adeniji, N., Carr, R. M., Aby, E. S., Catana, A. M., Wegermann, K., Dhanasekaran, R. 2020

    View details for DOI 10.1053/j.gastro.2020.11.035

    View details for PubMedID 33227281

  • THE INCIDENCE OF HEPATOCELLULAR CARCINOMA IN CHRONIC HEPATITIS B VIRUS INFECTION SUBJECTS NOT MEETING CRITERIA FOR ANTIVIRAL THERAPY Alshuwaykh, O., Goel, A., Daugherty, T., Cheung, A., Kim, W., Kwong, A. J., Ahmed, A., Ghaziani, T., Torok, N. J., Nguyen, M. H., Dronamraju, D., Dhanasekaran, R., Kumari, R., Kwo, P. Y. WILEY. 2020: 472A–473A
  • Clinical Response to Treatment for Acute Kidney Injury (AKI) in Patients With Cirrhosis John, N., Alshuwaykh, O., Goel, A., Ahmed, A., Cheung, A., Dronamraju, D., Kumari, R., Daugherty, T., Dhanasekaran, R., Kim, R. W., Nguyen, M. H., Kwo, P. Y. LIPPINCOTT WILLIAMS & WILKINS. 2020: S587–S588
  • Outcomes following SARS-CoV-2 infection in patients with chronic liver disease: an international registry study. Journal of hepatology Marjot, T., Moon, A. M., Cook, J. A., Abd-Elsalam, S., Aloman, C., Armstrong, M. J., Pose, E., Brenner, E. J., Cargill, T., Catana, M., Dhanasekaran, R., Eshraghian, A., Garcia-Juarez, I., Gill, U. S., Jones, P. D., Kennedy, J., Marshall, A., Matthews, C., Mells, G., Mercer, C., Perumalswami, P. V., Avitabile, E., Qi, X., Su, F., Ufere, N. N., Wong, Y. J., Zheng, M., Barnes, E., Barritt, A. S., Webb, G. J. 2020


    BACKGROUND: Chronic liver disease (CLD) and cirrhosis are associated with immune dysregulation leading to concerns that these patients may be at risk of adverse outcomes following SARS-CoV-2 infection. However, the impact of COVID-19 among patients with pre-existing liver disease remains ill-defined.METHODS: Data for CLD patients with SARS-CoV-2 were collected by two international registries. Comparisons were made with non-CLD patients with SARS-CoV-2 from a UK hospital network.RESULTS: Between 25th March and 8th July 2020, 745 CLD patients were reported from 29 countries including 386 with cirrhosis and 359 without. Mortality was 32% in patients with cirrhosis compared with 8% in those without (p<0.001). Mortality in cirrhosis patients increased according to Child-Turcotte-Pugh class (CTP-A (19%), CTP-B (35%), CTP-C (51%)) and the main cause of death was respiratory failure (71%). After adjusting for baseline characteristics, factors associated with death in the total CLD cohort were age (OR 1.02; 1.01-1.04), CTP-A (OR 1.90; 1.03-3.52), CTP-B (OR 4.14; 2.4-7.65), CTP-C cirrhosis (OR 9.32; 4.80-18.08) and alcohol related liver disease (ALD) (OR 1.79; 1.03-3.13). When comparing CLD versus non-CLD (n=620) in propensity-score-matched analysis there were significant increases in mortality with CTP-B +20.0% (8.8%-31.3%) and CTP-C cirrhosis +38.1% (27.1%-49.2%). Acute hepatic decompensation occurred in 46% of patients with cirrhosis, of which 21% had no respiratory symptoms. 50% of those with hepatic decompensation had acute-on-chronic liver failure.CONCLUSIONS: This is the largest reported cohort of CLD and cirrhosis patients with SARS-CoV-2 infection to date. We demonstrate that baseline liver disease stage and ALD are independent risk factor for death from COVID-19. These data have important implications for the risk stratification of patients with CLD across the globe during the COVID-19 pandemic.

    View details for DOI 10.1016/j.jhep.2020.09.024

    View details for PubMedID 33035628

  • Characterizing Ascites in Subjects With Nonhepatic Solid Tumors Alshuwaykh, O., Cheung, A., Goel, A., Dhanasekaran, R., Ahmed, A., Dronamraju, D., Daugherty, T., Kim, R. W., Kumari, R., Torok, N., Ghaziani, T., Kwo, P. Y. LIPPINCOTT WILLIAMS & WILKINS. 2020: S507
  • Liver Injury in Liver Transplant Recipients with Coronavirus Disease 2019 (COVID-19): US Multicenter Experience. Hepatology (Baltimore, Md.) Rabiee, A., Sadowski, B., Adeniji, N., Perumalswami, P., Nguyen, V., Moghe, A., Latt, N., Kumar, S., Aloman, C., Catana, A. M., Bloom, P. P., Chavin, K., Carr, R. M., Dunn, W., Chen, V., Aby, E. S., Debes, J., Dhanasekaran, R., COLD Consortium, Kim, D., Roytman, M., Viveiros, K., Chan, W., Li, M., Vogel, A., Wegerman, K., Lee, T., Zhou, K. 2020


    BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with liver injury, but the prevalence and patterns of liver injury in liver transplant (LT) recipients with COVID-19 is not defined.APPROACH AND RESULTS: We conducted a multicenter study in the US of 112 adult LT recipients with COVID-19. The median age was 61 years (IQR 20), 54.5% (n=61) were male, and 39.3% (n=44) Hispanic. The mortality rate was 22.3% (n=25); 72.3% (n=81) were hospitalized and 26.8% (n=30) admitted to the ICU. Analysis of peak values of alanine aminotransferase (ALT) during COVID-19 showed moderate liver injury (ALT 2-5x ULN) in 22.2% (n= 18) and severe liver injury (ALT > 5x ULN) in 12.3% (n= 10). Compared to age and gender matched non-transplant patients with CLD and COVID-19 (n=375), the incidence of acute liver injury was lower in LT recipients (47.5% vs. 34.6%; p=0.037). Variables associated with liver injury in LT recipients were younger age (p= 0.009, odds ratio (OR) 2.06 [1.20-3.54]), Hispanic ethnicity (p= 0.011; OR 6.01 [1.51-23.9]), metabolic syndrome (p= 0.016; OR 5.87 [1.38-24.99]), vasopressor use (p= 0.018; OR 7.34 [1.39-38.52]) and antibiotic use (p= 0.046; OR 6.93 [1.04-46.26]). Reduction in immunosuppression (49.4%) was not associated with liver injury (p= 0.156) or mortality (p= 0.084). Liver injury during COVID-19 was significantly associated with mortality (p= 0.007; OR 6.91 [95% CI: 1.68-28.48]) and ICU admission (p=0.007; OR 7.93[1.75-35.69]) in LT recipients.CONCLUSION: Liver injury is associated with higher mortality and ICU admission in LT recipients with COVID-19. Hence, monitoring liver enzymes closely can help in early identification of patients at risk for adverse outcomes. Reduction of immunosuppression during COVID-19 did not increase risk for mortality or graft failure.

    View details for DOI 10.1002/hep.31574

    View details for PubMedID 32964510

  • MYC ASO Impedes Tumorigenesis and Elicits Oncogene Addiction in Autochthonous Transgenic Mouse Models of HCC and RCC MOLECULAR THERAPY-NUCLEIC ACIDS Dhanasekaran, R., Park, J., Yevtodiyenko, A., Bellovin, D. I., Adam, S. J., Rajan, A., Gabay, M., Fernando, H., Arzeno, J., Arjunan, V., Gryanzov, S., Felsher, D. W. 2020; 21: 850–59
  • Roadmap to Resuming Care for Liver Diseases after COVID-19. Journal of gastroenterology and hepatology Kapuria, D., Bollipo, S., Rabiee, A., Ben Yakov, G., Kumar, G., Siau, K., Lee, H., Congly, S., Turnes, J., Dhanasekaran, R., Lui, R. N., Global Online Alliance for Liver Studies (GOAL) 2020


    The global pandemic of coronavirus disease-2019 (COVID-19) has led to significant disruptions in care delivery. Patients with chronic liver diseases require a high level of care and are therefore particularly vulnerable to disruptions in medical services during COVID-19. Recent data has also identified chronic liver disease as an independent risk factor for COVID-19 related hospital mortality. In response to the pandemic, national and international societies have recommended interim changes to the management of patients with liver diseases. These modifications included the implementation of telehealth, postponement or cancellation of elective procedures and other non-urgent patient care-related activities. There is concern that reduced access to diagnosis and treatment can also lead to increased morbidity in patients with liver diseases and we may witness a delayed surge of hospitalizations related to decompensated liver disease after the COVID-19 pandemic has receded. Therefore, it is paramount that liver practices craft a comprehensive plan for safe resumption of clinical operations while minimizing the risk of exposure to patients and healthcare professionals. Here, we provide a broad roadmap for how to safely resume care for patients with chronic liver disease according to various phases of the pandemic with particular emphasis on outpatient care, liver transplantation, liver cancer care and endoscopy.

    View details for DOI 10.1111/jgh.15178

    View details for PubMedID 32656794

  • MYC ASO Impedes Tumorigenesis and Elicits Oncogene Addiction in Autochthonous Transgenic Mouse Models of HCC and RCC. Molecular therapy. Nucleic acids Dhanasekaran, R., Park, J., Yevtodiyenko, A., Bellovin, D. I., Adam, S. J., Kd, A. R., Gabay, M., Fernando, H., Arzeno, J., Arjunan, V., Gryanzov, S., Felsher, D. W. 2020; 21: 850–59


    The MYC oncogene is dysregulated in most human cancers and hence is an attractive target for cancer therapy. We and others have shown experimentally in conditional transgenic mouse models that suppression of the MYC oncogene is sufficient to induce rapid and sustained tumor regression, a phenomenon known as oncogene addiction. However, it is unclear whether a therapy that targets the MYC oncogene could similarly elicit oncogene addiction. In this study, we report that using antisense oligonucleotides (ASOs) to target and reduce the expression of MYC impedes tumor progression and phenotypically elicits oncogene addiction in transgenic mouse models of MYC-driven primary hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC). Quantitative image analysis of MRI was used to demonstrate the inhibition of HCC and RCC progression. After 4weeks of drug treatment, tumors had regressed histologically. ASOs depleted MYC mRNA and protein expression in primary tumors invivo, as demonstrated by real-time PCR and immunohistochemistry. Treatment with MYC ASO invivo, but not with a control ASO, decreased proliferation, induced apoptosis, increased senescence, and remodeled the tumor microenvironment by recruitment of CD4+ Tcells. Importantly, although MYC ASO reduced both mouse Myc and transgenic human MYC, the ASO was not associated with significant toxicity. Lastly, we demonstrate that MYC ASO inhibits the growth of human liver cancer xenografts invivo. Our results illustrate that targeting MYC expression invivo using ASO can suppress tumorigenesis by phenotypically eliciting both tumor-intrinsic and microenvironment hallmarks of oncogene addiction. Hence, MYC ASO therapy is a promising strategy to treat MYC-driven human cancers.

    View details for DOI 10.1016/j.omtn.2020.07.008

    View details for PubMedID 32805488

  • MYC functions as a switch for natural killer cell-mediated immune surveillance of lymphoid malignancies. Nature communications Swaminathan, S., Hansen, A. S., Heftdal, L. D., Dhanasekaran, R., Deutzmann, A., Fernandez, W. D., Liefwalker, D. F., Horton, C., Mosley, A., Liebersbach, M., Maecker, H. T., Felsher, D. W. 2020; 11 (1): 2860


    The MYC oncogene drives T- and B- lymphoid malignancies, including Burkitt's lymphoma (BL) and Acute Lymphoblastic Leukemia (ALL). Here, we demonstrate a systemic reduction in natural killer (NK) cell numbers in SRalpha-tTA/Tet-O-MYCON mice bearing MYC-driven T-lymphomas. Residual mNK cells in spleens of MYCON T-lymphoma-bearing mice exhibit perturbations in the terminal NK effector differentiation pathway. Lymphoma-intrinsic MYC arrests NK maturation by transcriptionally repressing STAT1/2 and secretion of Type I Interferons (IFNs). Treating T-lymphoma-bearing mice with Type I IFN improves survival by rescuing NK cell maturation. Adoptive transfer of mature NK cells is sufficient to delay both T-lymphoma growth and recurrence post MYC inactivation. In MYC-driven BL patients, low expression of both STAT1 and STAT2 correlates significantly with the absence of activated NK cells and predicts unfavorable clinical outcomes. Our studies thus provide a rationale for developing NK cell-based therapies to effectively treat MYC-driven lymphomas in the future.

    View details for DOI 10.1038/s41467-020-16447-7

    View details for PubMedID 32503978

  • One world, one pandemic, many guidelines: management of liver diseases during COVID-19. Gut Bollipo, S., Kapuria, D., Rabiee, A., Ben-Yakov, G., Lui, R. N., Lee, H. W., Kumar, G., Siau, K., Turnes, J., Dhanasekaran, R. 2020

    View details for DOI 10.1136/gutjnl-2020-321553

    View details for PubMedID 32499304

  • Decline in Annual Mortality of Hepatitis C Virus-related Hepatocellular Carcinoma in the United States, From 2009 to 2018. Gastroenterology Kim, D., Konyn, P., Cholankeril, G., Wong, R. J., Younossi, Z. M., Ahmed, A. 2020

    View details for DOI 10.1053/j.gastro.2020.05.007

    View details for PubMedID 32389664

  • MYC and Twist1 cooperate to drive metastasis by eliciting crosstalk between cancer and innate immunity. eLife Dhanasekaran, R., Baylot, V., Kim, M., Kuruvilla, S., Bellovin, D. I., Adeniji, N., Rajan Kd, A., Lai, I., Gabay, M., Tong, L., Krishnan, M., Park, J., Hu, T., Barbhuiya, M. A., Gentles, A. J., Kannan, K., Tran, P. T., Felsher, D. W. 2020; 9


    Metastasis is a major cause of cancer mortality. We generated an autochthonous transgenic mouse model whereby conditional expression of MYC and Twist1 enables hepatocellular carcinoma (HCC) to metastasize in >90% of mice. MYC and Twist1 cooperate and their sustained expression is required to elicit a transcriptional program associated with the activation of innate immunity, through secretion of a cytokinome that elicits recruitment and polarization of tumor associated macrophages (TAMs). Systemic treatment with Ccl2 and Il13 induced MYC-HCCs to metastasize; whereas, blockade of Ccl2 and Il13 abrogated MYC/Twist1-HCC metastasis. Further, in 33 human cancers (n = 9502) MYC and TWIST1 predict poor survival (p=4.3*10-10), CCL2/IL13 expression (p<10-109) and TAM infiltration (p<10-96). Finally, in the plasma of patients with HCC (n = 25) but not cirrhosis (n = 10), CCL2 and IL13 were increased and IL13 predicted invasive tumors. Therefore, MYC and TWIST1 generally appear to cooperate in human cancer to elicit a cytokinome that enables metastasis through crosstalk between cancer and immune microenvironment.

    View details for DOI 10.7554/eLife.50731

    View details for PubMedID 31933479

  • Spontaneous Regression of HCC- When the Immune System Stands Up to Cancer. Hepatology (Baltimore, Md.) Arjunan, V. n., Hansen, A. n., Deutzmann, A. n., Sze, D. Y., Dhanasekaran, R. n. 2020


    Spontaneous regression of cancer is rare and has been observed mostly in immunogenic cancers like melanoma. A few cases of spontaneous regression of hepatocellular carcinoma (HCC) have been reported, but the mechanisms of regression have not been elucidated. Here, we report a patient with advanced HCC who experienced spontaneous regression of her tumor and present evidence for a putative immune-mediated mechanism for tumor regression.

    View details for DOI 10.1002/hep.31489

    View details for PubMedID 32740961

  • Genomic analysis of Vascular Invasion in Hepatocellular Carcinoma (HCC) Reveals Molecular Drivers and Predictive Biomarkers. Hepatology (Baltimore, Md.) Krishnan, M. S., Rajan Kd, A. n., Park, J. n., Arjunan, V. n., Garcia Marques, F. J., Bermudez, A. n., Girvan, O. A., Hoang, N. S., Yin, J. n., Nguyen, M. H., Kothary, N. n., Pitteri, S. n., Felsher, D. W., Dhanasekaran, R. n. 2020


    Vascular invasion is a critical risk factor for hepatocellular carcinoma (HCC) recurrence and poor survival. The molecular drivers of vascular invasion in HCC are largely unknown. Deciphering the molecular landscape of invasive HCC will help identify novel therapeutic targets and noninvasive biomarkers. To this end, we undertook this study to evaluate the genomic, transcriptomic, and proteomic profile of tumors with vascular invasion using the multi-platform cancer genome atlas (TCGA) data (n=373). In the TCGA liver hepatocellular carcinoma (LIHC) cohort, macrovascular invasion was present in 5% (n=17) of tumors and microvascular invasion in 25% (n=94) of tumors. Functional pathway analysis revealed that the MYC oncogene was a common upstream regulator of the mRNA, miRNA and proteomic changes in vascular invasion. We performed comparative proteomic analyses of invasive human HCC and MYC driven murine HCC and identified fibronectin to be proteomic biomarker of invasive HCC (mouse Fn1 p= 1.7 X 10-11 ; human FN1 p=1.5 X 10-4 ) conserved across the two species. Mechanistically, we show that FN1 promotes the migratory and invasive phenotype of HCC cancer cells. We demonstrate tissue overexpression of fibronectin in human HCC using a large independent cohort of human HCC tissue microarray (n=153; p<0.001). Lastly, we showed that plasma fibronectin levels were significantly elevated in patients with HCC (n=35, mean=307.7 μg/ml, SEM=35.9) when compared to cirrhosis (n=10, mean=41.8 μg/ml, SEM=13.3; p<0.0001). CONCLUSION: Our study evaluates the molecular landscape of tumors with vascular invasion, identifying distinct transcriptional, epigenetic and proteomic changes driven by the MYC oncogene. We show that MYC upregulates fibronectin expression which promotes HCC invasiveness. In addition, we identify fibronectin to be a promising non-invasive proteomic biomarker of vascular invasion in HCC.

    View details for DOI 10.1002/hep.31614

    View details for PubMedID 33140851

  • Outcomes following SARS-CoV-2 infection in liver transplant recipients: an international registry study. The lancet. Gastroenterology & hepatology Webb, G. J., Marjot, T. n., Cook, J. A., Aloman, C. n., Armstrong, M. J., Brenner, E. J., Catana, M. A., Cargill, T. n., Dhanasekaran, R. n., García-Juárez, I. n., Hagström, H. n., Kennedy, J. M., Marshall, A. n., Masson, S. n., Mercer, C. J., Perumalswami, P. V., Ruiz, I. n., Thaker, S. n., Ufere, N. N., Barnes, E. n., Barritt, A. S., Moon, A. M. 2020


    Despite concerns that patients with liver transplants might be at increased risk of adverse outcomes from COVID-19 because of coexisting comorbidities and use of immunosuppressants, the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on this patient group remains unclear. We aimed to assess the clinical outcomes in these patients.In this multicentre cohort study, we collected data on patients with laboratory-confirmed SARS-CoV-2 infection, who were older than 18 years, who had previously received a liver transplant, and for whom data had been submitted by clinicians to one of two international registries (COVID-Hep and SECURE-Cirrhosis) at the end of the patient's disease course. Patients without a known hospitalisation status or mortality outcome were excluded. For comparison, data from a contemporaneous cohort of consecutive patients with SARS-CoV-2 infection who had not received a liver transplant were collected from the electronic patient records of the Oxford University Hospitals National Health Service Foundation Trust. We compared the cohorts with regard to several outcomes (including death, hospitalisation, intensive care unit [ICU] admission, requirement for intensive care, and need for invasive ventilation). A propensity score-matched analysis was done to test for an association between liver transplant and death.Between March 25 and June 26, 2020, data were collected for 151 adult liver transplant recipients from 18 countries (median age 60 years [IQR 47-66], 102 [68%] men, 49 [32%] women) and 627 patients who had not undergone liver transplantation (median age 73 years [44-84], 329 [52%] men, 298 [48%] women). The groups did not differ with regard to the proportion of patients hospitalised (124 [82%] patients in the liver transplant cohort vs 474 [76%] in the comparison cohort, p=0·106), or who required intensive care (47 [31%] vs 185 [30%], p=0·837). However, ICU admission (43 [28%] vs 52 [8%], p<0·0001) and invasive ventilation (30 [20%] vs 32 [5%], p<0·0001) were more frequent in the liver transplant cohort. 28 (19%) patients in the liver transplant cohort died, compared with 167 (27%) in the comparison cohort (p=0·046). In the propensity score-matched analysis (adjusting for age, sex, creatinine concentration, obesity, hypertension, diabetes, and ethnicity), liver transplantation did not significantly increase the risk of death in patients with SARS-CoV-2 infection (absolute risk difference 1·4% [95% CI -7·7 to 10·4]). Multivariable logistic regression analysis showed that age (odds ratio 1·06 [95% CI 1·01 to 1·11] per 1 year increase), serum creatinine concentration (1·57 [1·05 to 2·36] per 1 mg/dL increase), and non-liver cancer (18·30 [1·96 to 170·75]) were associated with death among liver transplant recipients.Liver transplantation was not independently associated with death, whereas increased age and presence of comorbidities were. Factors other than transplantation should be preferentially considered in relation to physical distancing and provision of medical care for patients with liver transplants during the COVID-19 pandemic.European Association for the Study of the Liver, US National Institutes of Health, UK National Institute for Health Research.

    View details for DOI 10.1016/S2468-1253(20)30271-5

    View details for PubMedID 32866433

  • Post-Transplant Outcomes in Older Patients with Hepatocellular Carcinoma (HCC) are Driven by non-HCC Factors. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society Adeniji, N. n., Arjunan, V. n., Prabhakar, V. n., Mannalithara, A. n., Ghaziani, T. n., Ahmed, A. n., Kwo, P. n., Nguyen, M. n., Melcher, M. L., Busuttil, R. W., Florman, S. S., Haydel, B. n., Ruiz, R. M., Klintmalm, G. B., Lee, D. D., Taner, C. B., Hoteit, M. A., Verna, E. C., Halazun, K. J., Tevar, A. D., Humar, A. n., Chapman, W. C., Vachharajani, N. n., Aucejo, F. n., Nydam, T. L., Markmann, J. F., Mobley, C. n., Ghobrial, M. n., Langnas, A. N., Carney, C. A., Berumen, J. n., Schnickel, G. T., Sudan, D. L., Hong, J. C., Rana, A. n., Jones, C. M., Fishbein, T. M., Agopian, V. n., Dhanasekaran, R. n. 2020


    The incidence of hepatocellular carcinoma (HCC) is growing in the US, especially among the elderly. Older patients are increasingly getting transplanted for HCC, but the impact of advancing age on long-term post-transplant outcomes is not clear. To study this, we used data from the US Multicenter HCC Transplant Consortium (UMHTC) of 4980 patients. We divided the patients into 4 groups by age at transplantation- 18-64 (n = 4001), 65-69 (n = 683), 70-74 (n = 252) and ≥ 75 years (n = 44). There were no differences in HCC tumor stage, type of bridging locoregional therapy or explant residual tumor between the groups. Older age was confirmed to be an independent and significant predictor of overall survival even after adjusting for demographic, etiologic and cancer-related factors on multivariable analysis. A dose-response effect of age on survival was observed, with every 5-year increase in age over 50 years resulting in an absolute increase of 8.3% in the mortality rate. Competing risk analysis revealed that older patients experienced higher rates of non-HCC-related mortality (p = 0.004), and not HCC-related death (p = 0.24). To delineate the precise cause of death, we further analyzed a single-center cohort of patients transplanted for HCC (n = 302). Patients older than 65 years had a higher incidence of de-novo cancer (18.1% vs 7.6%, p = 0.006) after transplantation and higher overall cancer-related mortality (14.3% vs 6.6%, p = 0.03). CONCLUSION: Even carefully selected elderly patients with HCC have significantly worse post-transplant survival, which are mostly driven by non-HCC related causes. Minimizing immunosuppression and closer surveillance for de novo cancers can potentially improve outcomes in elderly patients transplanted for HCC.

    View details for DOI 10.1002/lt.25974

    View details for PubMedID 33306254

  • High Mortality Rates for SARS-CoV-2 Infection in Patients with Pre-existing Chronic Liver Disease and Cirrhosis: Preliminary Results from an International Registry. Journal of hepatology Moon, A. M., Webb, G. J., Aloman, C. n., Armstrong, M. J., Cargill, T. n., Dhanasekaran, R. n., Genescà, J. n., Gill, U. S., James, T. W., Jones, P. D., Marshall, A. n., Mells, G. n., Perumalswami, P. V., Qi, X. n., Su, F. n., Ufere, N. N., Barnes, E. n., Barritt, A. S., Marjot, T. n. 2020

    View details for DOI 10.1016/j.jhep.2020.05.013

    View details for PubMedID 32446714

  • Impact of Bridging Locoregional Therapies for Hepatocellular Carcinoma on Post-Transplant Clinical Outcome. Clinical transplantation Adeniji, N. n., Arjunan, V. n., Prabhakar, V. n., Tulu, Z. n., Kambham, N. n., Ahmed, A. n., Kwo, P. n., Dhanasekaran, R. n. 2020: e14128


    Long waiting times due to ongoing organ shortage has led to increased utilization of locoregional therapies (LRTs) to bridge patients with hepatocellular carcinoma (HCC) to liver transplantation (LT). We performed this study to evaluate the impact of LRTs on post-LT outcomes. We conducted a retrospective study of patients who were transplanted for HCC at Stanford University Hospital between 2008 and 2018 (n = 302). We found that receipt of ≥ 5 LRTs was an independent and significant predictor of poor overall 5-year survival (58.3% vs. 83.3%; HR 2.26, p = 0.03), poor recurrence-free 5-year survival (51.9% vs. 80.4%; HR 2.12, p = 0.03), and was associated with higher rates of recurrence (25.0% vs. 7.4%, p = 0.001). Moreover, recurrent HCC was more likely to be the cause of death (58.3% vs. 41.7%, p = 0.04) in patients who received ≥ 5 LRTs. Also, patients who required ≥ 5 LRTs showed an overall lower rate of radiological complete response (46.9% vs. 97.8%, p = 0.001) and were more likely to have more advanced pathological stage tumors in the explant (65.6% vs. 29.6%, p < 0.001). In conclusion, receipt of ≥ 5 bridging LRTs prior to LT is associated with worse post-transplant clinical outcomes.

    View details for DOI 10.1111/ctr.14128

    View details for PubMedID 33098134

  • Predictors of Outcomes of COVID-19 in Patients with Chronic Liver Disease: US Multi-center Study. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association Kim, D. n., Adeniji, N. n., Latt, N. n., Kumar, S. n., Bloom, P. P., Aby, E. S., Perumalswami, P. n., Roytman, M. n., Li, M. n., Vogel, A. S., Catana, A. M., Wegermann, K. n., Carr, R. M., Aloman, C. n., Chen, V. n., Rabiee, A. n., Sadowski, B. n., Nguyen, V. n., Dunn, W. n., Chavin, K. n., Zhou, K. n., Lizaola-Mayo, B. n., Moghe, A. n., Debes, J. n., Lee, T. H., Branch, A. n., Viveiros, K. n., Chan, W. n., Chascsa, D. n., Kwo, P. n., Dhanasekaran, R. n. 2020


    Chronic liver disease (CLD) represents a major global health burden. We undertook this study to identify the factors associated with adverse outcomes in patients with CLD who acquire the novel coronavirus-2019 (COVID-19).We conducted a multi-center, observational cohort study across 21 institutions in the United States (US) of adult patients with CLD and laboratory-confirmed diagnosis of COVID-19 between March 1, 2020 and May 30, 2020. We performed survival analysis to identify independent predictors of all-cause mortality and COVID-19 related mortality, and multivariate logistic regression to determine the risk of severe COVID-19 in patients with CLD.Of the 978 patients in our cohort, 867 patients (mean age 56.9±14.5 years, 55% male) met inclusion criteria. The overall all-cause mortality was 14.0% (n = 121), and 61.7% (n = 535) had severe COVID-19. Patients presenting with diarrhea or nausea/vomiting were more likely to have severe COVID-19. The liver-specific factors associated with independent risk of higher overall mortality were alcohol-related liver disease (ALD) (hazard ratio [HR] 2.42, 95% confidence interval [CI] 1.29-4.55), decompensated cirrhosis (HR 2.91 [1.70-5.00]) and hepatocellular carcinoma (HCC) (HR 3.31 [1.53-7.16]). Other factors were increasing age, diabetes, hypertension, chronic obstructive pulmonary disease and current smoker. Hispanic ethnicity (odds ratio [OR] 2.33 [1.47-3.70]) and decompensated cirrhosis (OR 2.50 [1.20-5.21]) were independently associated with risk for severe COVID-19.The risk factors which predict higher overall mortality among patients with CLD and COVID-19 are ALD, decompensated cirrhosis and HCC. Hispanic ethnicity and decompensated cirrhosis are associated with severe COVID-19. Our results will enable risk stratification and personalization of the management of patients with CLD and COVID-19.

    View details for DOI 10.1016/j.cgh.2020.09.027

    View details for PubMedID 32950749

  • MYC Oncogene Abrogates Natural Killer (NK) Cell-Mediated Immune Surveillance of B- and T-Lymphoid Malignancies By Suppressing STAT1/2-Type I IFN Signaling Swaminathan, S., Heftdal, L., Liefwalker, D., Dhanasekaran, R., Deutzmann, A., Horton, C., Mosley, A., Liebersbach, M., Gentles, A., Maecker, H. T., Felsher, D. AMER SOC HEMATOLOGY. 2019
  • IS IT GOOD IDEA TO OFFER TRANSPLANT EXCEPTION POINTS FOR SEPTUAGENARIANS WITH HEPATOCELLULAR CARCINOMA (HCC)? Arjunan, V., Prabhakar, V., Raghavan, S., Tulu, Z., Kambham, N., Ahmed, A., Kwo, P., Dhanasekaran, R. WILEY. 2019: 557A–558A
  • CLINICOPATHOLOGICAL FEATURES OF NONALCOHOLIC STEATOHEPATITIS (NASH)-RELATED HEPATOCELLULAR CARCINOMA (HCC) Arjunan, V., Prabhakar, V., Raghavan, S., Tulu, Z., Kambham, N., Ahmed, A., Kwo, P., Dhanasekaran, R. WILEY. 2019: 548A
  • DIRECT-ACTING ANTIVIRAL THERAPY IS ASSOCIATED WITH IMPROVED SURVIVAL IN PATIENTS WITH A HISTORY OF HEPATOCELLULAR CARCINOMA: A MULTICENTER NORTH AMERICAN COHORT STUDY Singal, A. G., Rich, N. E., Mehta, N., Branch, A. D., Pillai, A. A., Hoteit, M. A., Volk, M., Odewole, M., Scaglione, S. J., Guy, J. E., Said, A., Feld, J. J., John, B., Frenette, C. T., Mantry, P. S., Rangnekar, A. S., Oloruntoba, O., Leise, M. D., Jou, J., Bhamidimarri, K., Kulik, L. M., Ioannou, G., Huang, A., Tran, T. T., Samant, H. V., Dhanasekaran, R., Duarte-Rojo, A., Salgia, R. J., Eswaran, S. L., Jalal, P. K., Flores, A., Satapathy, S., Parikh, N. D., Murphy, C. WILEY. 2019: 130A–131A
  • THE ROLE OF LOCOREGIONAL THERAPY (LRT), POST LRT IMAGING, AND EXPLANT PATHOLOGY AS PREDICTORS OF HEPATOCELLULAR CARCINOMA (HCC) RECURRENCE POST ORTHOTOPIC LIVER TRANSPLANT (OLT) Prabhakar, V., Dhanasekaran, R., Arjunan, V., Tulu, Z., Ahmed, A., Daugherty, T., Kumari, R., Patel, B., Kim, W., Goel, A., Esquivel, C. O., Concepcion, W., Melcher, M., Bonham, C., Gallo, A., Kwo, P. WILEY. 2019: 691A–692A
  • A Tale of Two Complications of Obesity: NASH and Hepatocellular Carcinoma HEPATOLOGY Dhanasekaran, R., Felsher, D. W. 2019; 70 (3): 1056–58

    View details for DOI 10.1002/hep.30649

    View details for Web of Science ID 000483692800023

  • The Immune Landscape of Cancer. Immunity Thorsson, V., Gibbs, D. L., Brown, S. D., Wolf, D., Bortone, D. S., Ou Yang, T., Porta-Pardo, E., Gao, G. F., Plaisier, C. L., Eddy, J. A., Ziv, E., Culhane, A. C., Paull, E. O., Sivakumar, I. K., Gentles, A. J., Malhotra, R., Farshidfar, F., Colaprico, A., Parker, J. S., Mose, L. E., Vo, N. S., Liu, J., Liu, Y., Rader, J., Dhankani, V., Reynolds, S. M., Bowlby, R., Califano, A., Cherniack, A. D., Anastassiou, D., Bedognetti, D., Mokrab, Y., Newman, A. M., Rao, A., Chen, K., Krasnitz, A., Hu, H., Malta, T. M., Noushmehr, H., Pedamallu, C. S., Bullman, S., Ojesina, A. I., Lamb, A., Zhou, W., Shen, H., Choueiri, T. K., Weinstein, J. N., Guinney, J., Saltz, J., Holt, R. A., Rabkin, C. S., Cancer Genome Atlas Research Network, Lazar, A. J., Serody, J. S., Demicco, E. G., Disis, M. L., Vincent, B. G., Shmulevich, I., Caesar-Johnson, S. J., Demchok, J. A., Felau, I., Kasapi, M., Ferguson, M. L., Hutter, C. M., Sofia, H. J., Tarnuzzer, R., Wang, Z., Yang, L., Zenklusen, J. C., Zhang, J. J., Chudamani, S., Liu, J., Lolla, L., Naresh, R., Pihl, T., Sun, Q., Wan, Y., Wu, Y., Cho, J., DeFreitas, T., Frazer, S., Gehlenborg, N., Getz, G., Heiman, D. I., Kim, J., Lawrence, M. S., Lin, P., Meier, S., Noble, M. S., Saksena, G., Voet, D., Zhang, H., Bernard, B., Chambwe, N., Dhankani, V., Knijnenburg, T., Kramer, R., Leinonen, K., Liu, Y., Miller, M., Reynolds, S., Shmulevich, I., Thorsson, V., Zhang, W., Akbani, R., Broom, B. M., Hegde, A. M., Ju, Z., Kanchi, R. S., Korkut, A., Li, J., Liang, H., Ling, S., Liu, W., Lu, Y., Mills, G. B., Ng, K., Rao, A., Ryan, M., Wang, J., Weinstein, J. N., Zhang, J., Abeshouse, A., Armenia, J., Chakravarty, D., Chatila, W. K., de Bruijn, I., Gao, J., Gross, B. E., Heins, Z. J., Kundra, R., La, K., Ladanyi, M., Luna, A., Nissan, M. G., Ochoa, A., Phillips, S. M., Reznik, E., Sanchez-Vega, F., Sander, C., Schultz, N., Sheridan, R., Sumer, S. O., Sun, Y., Taylor, B. S., Wang, J., Zhang, H., Anur, P., Peto, M., Spellman, P., Benz, C., Stuart, J. M., Wong, C. K., Yau, C., Hayes, D. N., Parker, J. S., Wilkerson, M. D., Ally, A., Balasundaram, M., Bowlby, R., Brooks, D., Carlsen, R., Chuah, E., Dhalla, N., Holt, R., Jones, S. J., Kasaian, K., Lee, D., Ma, Y., Marra, M. A., Mayo, M., Moore, R. A., Mungall, A. J., Mungall, K., Robertson, A. G., Sadeghi, S., Schein, J. E., Sipahimalani, P., Tam, A., Thiessen, N., Tse, K., Wong, T., Berger, A. C., Beroukhim, R., Cherniack, A. D., Cibulskis, C., Gabriel, S. B., Gao, G. F., Ha, G., Meyerson, M., Schumacher, S. E., Shih, J., Kucherlapati, M. H., Kucherlapati, R. S., Baylin, S., Cope, L., Danilova, L., Bootwalla, M. S., Lai, P. H., Maglinte, D. T., Van Den Berg, D. J., Weisenberger, D. J., Auman, J. T., Balu, S., Bodenheimer, T., Fan, C., Hoadley, K. A., Hoyle, A. P., Jefferys, S. R., Jones, C. D., Meng, S., Mieczkowski, P. A., Mose, L. E., Perou, A. H., Perou, C. M., Roach, J., Shi, Y., Simons, J. V., Skelly, T., Soloway, M. G., Tan, D., Veluvolu, U., Fan, H., Hinoue, T., Laird, P. W., Shen, H., Zhou, W., Bellair, M., Chang, K., Covington, K., Creighton, C. J., Dinh, H., Doddapaneni, H., Donehower, L. A., Drummond, J., Gibbs, R. A., Glenn, R., Hale, W., Han, Y., Hu, J., Korchina, V., Lee, S., Lewis, L., Li, W., Liu, X., Morgan, M., Morton, D., Muzny, D., Santibanez, J., Sheth, M., Shinbrot, E., Wang, L., Wang, M., Wheeler, D. A., Xi, L., Zhao, F., Hess, J., Appelbaum, E. L., Bailey, M., Cordes, M. G., Ding, L., Fronick, C. C., Fulton, L. A., Fulton, R. S., Kandoth, C., Mardis, E. R., McLellan, M. D., Miller, C. A., Schmidt, H. K., Wilson, R. K., Crain, D., Curley, E., Gardner, J., Lau, K., Mallery, D., Morris, S., Paulauskis, J., Penny, R., Shelton, C., Shelton, T., Sherman, M., Thompson, E., Yena, P., Bowen, J., Gastier-Foster, J. M., Gerken, M., Leraas, K. M., Lichtenberg, T. M., Ramirez, N. C., Wise, L., Zmuda, E., Corcoran, N., Costello, T., Hovens, C., Carvalho, A. L., de Carvalho, A. C., Fregnani, J. H., Longatto-Filho, A., Reis, R. M., Scapulatempo-Neto, C., Silveira, H. C., Vidal, D. O., Burnette, A., Eschbacher, J., Hermes, B., Noss, A., Singh, R., Anderson, M. L., Castro, P. D., Ittmann, M., Huntsman, D., Kohl, B., Le, X., Thorp, R., Andry, C., Duffy, E. R., Lyadov, V., Paklina, O., Setdikova, G., Shabunin, A., Tavobilov, M., McPherson, C., Warnick, R., Berkowitz, R., Cramer, D., Feltmate, C., Horowitz, N., Kibel, A., Muto, M., Raut, C. P., Malykh, A., Barnholtz-Sloan, J. S., Barrett, W., Devine, K., Fulop, J., Ostrom, Q. T., Shimmel, K., Wolinsky, Y., Sloan, A. E., De Rose, A., Giuliante, F., Goodman, M., Karlan, B. Y., Hagedorn, C. H., Eckman, J., Harr, J., Myers, J., Tucker, K., Zach, L. A., Deyarmin, B., Hu, H., Kvecher, L., Larson, C., Mural, R. J., Somiari, S., Vicha, A., Zelinka, T., Bennett, J., Iacocca, M., Rabeno, B., Swanson, P., Latour, M., Lacombe, L., Tetu, B., Bergeron, A., McGraw, M., Staugaitis, S. M., Chabot, J., Hibshoosh, H., Sepulveda, A., Su, T., Wang, T., Potapova, O., Voronina, O., Desjardins, L., Mariani, O., Roman-Roman, S., Sastre, X., Stern, M., Cheng, F., Signoretti, S., Berchuck, A., Bigner, D., Lipp, E., Marks, J., McCall, S., McLendon, R., Secord, A., Sharp, A., Behera, M., Brat, D. J., Chen, A., Delman, K., Force, S., Khuri, F., Magliocca, K., Maithel, S., Olson, J. J., Owonikoko, T., Pickens, A., Ramalingam, S., Shin, D. M., Sica, G., Van Meir, E. G., Zhang, H., Eijckenboom, W., Gillis, A., Korpershoek, E., Looijenga, L., Oosterhuis, W., Stoop, H., van Kessel, K. E., Zwarthoff, E. C., Calatozzolo, C., Cuppini, L., Cuzzubbo, S., DiMeco, F., Finocchiaro, G., Mattei, L., Perin, A., Pollo, B., Chen, C., Houck, J., Lohavanichbutr, P., Hartmann, A., Stoehr, C., Stoehr, R., Taubert, H., Wach, S., Wullich, B., Kycler, W., Murawa, D., Wiznerowicz, M., Chung, K., Edenfield, W. J., Martin, J., Baudin, E., Bubley, G., Bueno, R., De Rienzo, A., Richards, W. G., Kalkanis, S., Mikkelsen, T., Noushmehr, H., Scarpace, L., Girard, N., Aymerich, M., Campo, E., Gine, E., Guillermo, A. L., Van Bang, N., Hanh, P. T., Phu, B. D., Tang, Y., Colman, H., Evason, K., Dottino, P. R., Martignetti, J. A., Gabra, H., Juhl, H., Akeredolu, T., Stepa, S., Hoon, D., Ahn, K., Kang, K. J., Beuschlein, F., Breggia, A., Birrer, M., Bell, D., Borad, M., Bryce, A. H., Castle, E., Chandan, V., Cheville, J., Copland, J. A., Farnell, M., Flotte, T., Giama, N., Ho, T., Kendrick, M., Kocher, J., Kopp, K., Moser, C., Nagorney, D., O'Brien, D., O'Neill, B. P., Patel, T., Petersen, G., Que, F., Rivera, M., Roberts, L., Smallridge, R., Smyrk, T., Stanton, M., Thompson, R. H., Torbenson, M., Yang, J. D., Zhang, L., Brimo, F., Ajani, J. A., Gonzalez, A. M., Behrens, C., Bondaruk, J., Broaddus, R., Czerniak, B., Esmaeli, B., Fujimoto, J., Gershenwald, J., Guo, C., Lazar, A. J., Logothetis, C., Meric-Bernstam, F., Moran, C., Ramondetta, L., Rice, D., Sood, A., Tamboli, P., Thompson, T., Troncoso, P., Tsao, A., Wistuba, I., Carter, C., Haydu, L., Hersey, P., Jakrot, V., Kakavand, H., Kefford, R., Lee, K., Long, G., Mann, G., Quinn, M., Saw, R., Scolyer, R., Shannon, K., Spillane, A., Stretch, O., Synott, M., Thompson, J., Wilmott, J., Al-Ahmadie, H., Chan, T. A., Ghossein, R., Gopalan, A., Levine, D. A., Reuter, V., Singer, S., Singh, B., Tien, N. V., Broudy, T., Mirsaidi, C., Nair, P., Drwiega, P., Miller, J., Smith, J., Zaren, H., Park, J., Hung, N. P., Kebebew, E., Linehan, W. M., Metwalli, A. R., Pacak, K., Pinto, P. A., Schiffman, M., Schmidt, L. S., Vocke, C. D., Wentzensen, N., Worrell, R., Yang, H., Moncrieff, M., Goparaju, C., Melamed, J., Pass, H., Botnariuc, N., Caraman, I., Cernat, M., Chemencedji, I., Clipca, A., Doruc, S., Gorincioi, G., Mura, S., Pirtac, M., Stancul, I., Tcaciuc, D., Albert, M., Alexopoulou, I., Arnaout, A., Bartlett, J., Engel, J., Gilbert, S., Parfitt, J., Sekhon, H., Thomas, G., Rassl, D. M., Rintoul, R. C., Bifulco, C., Tamakawa, R., Urba, W., Hayward, N., Timmers, H., Antenucci, A., Facciolo, F., Grazi, G., Marino, M., Merola, R., de Krijger, R., Gimenez-Roqueplo, A., Piche, A., Chevalier, S., McKercher, G., Birsoy, K., Barnett, G., Brewer, C., Farver, C., Naska, T., Pennell, N. A., Raymond, D., Schilero, C., Smolenski, K., Williams, F., Morrison, C., Borgia, J. A., Liptay, M. J., Pool, M., Seder, C. W., Junker, K., Omberg, L., Dinkin, M., Manikhas, G., Alvaro, D., Bragazzi, M. C., Cardinale, V., Carpino, G., Gaudio, E., Chesla, D., Cottingham, S., Dubina, M., Moiseenko, F., Dhanasekaran, R., Becker, K., Janssen, K., Slotta-Huspenina, J., Abdel-Rahman, M. H., Aziz, D., Bell, S., Cebulla, C. M., Davis, A., Duell, R., Elder, J. B., Hilty, J., Kumar, B., Lang, J., Lehman, N. L., Mandt, R., Nguyen, P., Pilarski, R., Rai, K., Schoenfield, L., Senecal, K., Wakely, P., Hansen, P., Lechan, R., Powers, J., Tischler, A., Grizzle, W. E., Sexton, K. C., Kastl, A., Henderson, J., Porten, S., Waldmann, J., Fassnacht, M., Asa, S. L., Schadendorf, D., Couce, M., Graefen, M., Huland, H., Sauter, G., Schlomm, T., Simon, R., Tennstedt, P., Olabode, O., Nelson, M., Bathe, O., Carroll, P. R., Chan, J. M., Disaia, P., Glenn, P., Kelley, R. K., Landen, C. N., Phillips, J., Prados, M., Simko, J., Smith-McCune, K., VandenBerg, S., Roggin, K., Fehrenbach, A., Kendler, A., Sifri, S., Steele, R., Jimeno, A., Carey, F., Forgie, I., Mannelli, M., Carney, M., Hernandez, B., Campos, B., Herold-Mende, C., Jungk, C., Unterberg, A., von Deimling, A., Bossler, A., Galbraith, J., Jacobus, L., Knudson, M., Knutson, T., Ma, D., Milhem, M., Sigmund, R., Godwin, A. K., Madan, R., Rosenthal, H. G., Adebamowo, C., Adebamowo, S. N., Boussioutas, A., Beer, D., Giordano, T., Mes-Masson, A., Saad, F., Bocklage, T., Landrum, L., Mannel, R., Moore, K., Moxley, K., Postier, R., Walker, J., Zuna, R., Feldman, M., Valdivieso, F., Dhir, R., Luketich, J., Pinero, E. M., Quintero-Aguilo, M., Carlotti, C. G., Dos Santos, J. S., Kemp, R., Sankarankuty, A., Tirapelli, D., Catto, J., Agnew, K., Swisher, E., Creaney, J., Robinson, B., Shelley, C. S., Godwin, E. M., Kendall, S., Shipman, C., Bradford, C., Carey, T., Haddad, A., Moyer, J., Peterson, L., Prince, M., Rozek, L., Wolf, G., Bowman, R., Fong, K. M., Yang, I., Korst, R., Rathmell, W. K., Fantacone-Campbell, J. L., Hooke, J. A., Kovatich, A. J., Shriver, C. D., DiPersio, J., Drake, B., Govindan, R., Heath, S., Ley, T., Van Tine, B., Westervelt, P., Rubin, M. A., Lee, J. I., Aredes, N. D., Mariamidze, A. 2019; 51 (2): 411–12

    View details for DOI 10.1016/j.immuni.2019.08.004

    View details for PubMedID 31433971

  • A Tale of Two Complications of Obesity: Nonalcoholic steatohepatitis (NASH) and Hepatocellular carcinoma (HCC). Hepatology (Baltimore, Md.) Dhanasekaran, R., Felsher, D. W. 2019


    Nonalcoholic steatohepatitis (NASH) is the most common cause of chronic liver disease in developed countries and its incidence is rapidly increasing. Cirrhosis, and the dreaded complication of hepatocellular carcinoma (HCC), are the major drivers of morbidity and mortality in NASH. Conventional understanding has been that chronic liver damage leads to a cycle of cell death, regeneration and fibrosis during which HCC precursor cells undergo malignant transformation and lead to cancer initiation. This article is protected by copyright. All rights reserved.

    View details for PubMedID 30958566

  • Prospective Multi-Regional Study of Down-Staging of Hepatocellular Carcinoma to within Milan Criteria before Liver Transplantation. Mehta, N., Guy, J., Frenette, C., Tabrizian, P., Hoteit, M., Dhanasekaran, R., Dodge, J., Holzner, M. L., Frankul, L., Florman, S., Parikh, N., Yao, F. WILEY. 2019: 378–79
  • Hepatocellular Carcinoma Surveillance: An Effective But Complex Process GASTROENTEROLOGY Singal, A. G., Murphy, C. C. 2019; 156 (4): 1215

    View details for PubMedID 30543799

  • Direct-Acting Antiviral Therapy Not Associated With Recurrence of Hepatocellular Carcinoma in a Multicenter North American Cohort Study. Gastroenterology Singal, A. G., Rich, N. E., Mehta, N. n., Branch, A. n., Pillai, A. n., Hoteit, M. n., Volk, M. n., Odewole, M. n., Scaglione, S. n., Guy, J. n., Said, A. n., Feld, J. J., John, B. V., Frenette, C. n., Mantry, P. n., Rangnekar, A. S., Oloruntoba, O. n., Leise, M. n., Jou, J. H., Bhamidimarri, K. R., Kulik, L. n., Tran, T. n., Samant, H. n., Dhanasekaran, R. n., Duarte-Rojo, A. n., Salgia, R. n., Eswaran, S. n., Jalal, P. n., Flores, A. n., Satapathy, S. K., Wong, R. n., Huang, A. n., Misra, S. n., Schwartz, M. n., Mitrani, R. n., Nakka, S. n., Noureddine, W. n., Ho, C. n., Konjeti, V. R., Dao, A. n., Nelson, K. n., Delarosa, K. n., Rahim, U. n., Mavuram, M. n., Xie, J. J., Murphy, C. C., Parikh, N. D. 2019; 156 (6): 1683–92.e1


    There is controversy over the effects of direct-acting antiviral (DAA) therapies for hepatitis C virus (HCV) infection on hepatocellular carcinoma (HCC) recurrence and tumor aggressiveness. We compared HCC recurrence patterns between DAA-treated and untreated HCV-infected patients who had achieved a complete response to HCC treatment in a North American cohort.We conducted a retrospective cohort study of patients with HCV-related HCC with a complete response to resection, local ablation, transarterial chemo- or radioembolization, or radiation therapy from January 2013 through December 2017 at 31 health systems throughout the United States and Canada. Cox regression was used to examine the association between DAA therapy and time to recurrence after a complete response, with DAA therapy analyzed as a time-varying exposure. We also estimated the association between DAA therapy and risk of early HCC recurrence (defined as 365 days after complete response).Of 793 patients with HCV-associated HCC, 304 (38.3%) received DAA therapy and 489 (61.7%) were untreated. HCC recurred in 128 DAA-treated patients (42.1%; early recurrence in 52 patients) and 288 untreated patients (58.9%; early recurrence in 227 patients). DAA therapy was not associated with HCC recurrence (hazard ratio 0.90, 95% confidence interval 0.70-1.16) or early HCC recurrence (hazard ratio 0.96, 95% confidence interval 0.70-1.34) after we adjusted for study site, age, sex, Child-Pugh score, α-fetoprotein level, tumor burden, and HCC treatment modality. In DAA-treated and untreated patients, most recurrences were within the Milan criteria (74.2% vs 78.8%; P = .23). A larger proportion of DAA-treated than untreated patients received potentially curative HCC therapy for recurrent HCC (32.0% vs 24.6%) and achieved a complete or partial response (45.3% vs 41.0%) but this did not achieve statistical significance.In a large cohort of North American patients with complete response to HCC treatment, DAA therapy was not associated with increased overall or early HCC recurrence. HCC recurrence patterns, including treatment response, were similar in DAA-treated and untreated patients.

    View details for PubMedID 30660729

  • Genomic Medicine and Implications for Hepatocellular Carcinoma Prevention and Therapy GASTROENTEROLOGY Dhanasekaran, R., Nault, J., Roberts, L. R., Zucman-Rossi, J. 2019; 156 (2): 492–509
  • Provider Attitudes and Practice Patterns for Direct-Acting Antiviral Therapy for Patients with Hepatocellular Carcinoma. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association Rich, N. E., Yang, J. D., Perumalswami, P. V., Alkhouri, N. n., Jackson, W. n., Parikh, N. D., Mehta, N. n., Salgia, R. n., Duarte-Rojo, A. n., Kulik, L. n., Rakoski, M. n., Said, A. n., Oloruntoba, O. n., Ioannou, G. N., Hoteit, M. A., Moon, A. M., Rangnekar, A. S., Eswaran, S. L., Zheng, E. n., Jou, J. H., Hanje, J. n., Pillai, A. n., Hernaez, R. n., Wong, R. n., Scaglione, S. n., Samant, H. n., Kapuria, D. n., Chandna, S. n., Rosenblatt, R. n., Ajmera, V. n., Frenette, C. n., Satapathy, S. K., Mantry, P. n., Jalal, P. n., John, B. V., Fix, O. K., Leise, M. n., Lindenmeyer, C. C., Flores, A. n., Patel, N. n., Jiang, Z. G., Latt, N. n., Dhanasekaran, R. n., Odewole, M. n., Kagan, S. n., Marrero, J. A., Singal, A. G. 2019


    Direct-acting antivirals (DAAs) are effective against hepatitis C virus and sustained virologic response is associated with reduced incidence of hepatocellular carcinoma (HCC). However, there is controversy over the use of DAAs in patients with active or treated HCC and uncertainty about optimal management of these patients. We aimed to characterize attitudes and practice patterns of hepatology practitioners in the United States regarding the use of DAAs in patients with HCC.We conducted a survey of hepatology providers at 47 tertiary care centers in 25 states. Surveys were sent to 476 providers and we received 279 responses (58.6%).Provider beliefs about risk of HCC recurrence after DAA therapy varied: 48% responded that DAAs reduce risk, 36% responded that DAAs do not change risk, and 16% responded that DAAs increase risk of HCC recurrence. However, most providers believed DAAs to be beneficial to and reduce mortality of patients with complete responses to HCC treatment. Accordingly, nearly all providers (94.9%) reported recommending DAA therapy to patients with early-stage HCC who received curative treatment. However, fewer providers recommended DAA therapy for patients with intermediate (72.9%) or advanced (57.5%) HCC undergoing palliative therapies. Timing of DAA initiation varied among providers based on HCC treatment modality: 49.1% of providers reported they would initiate DAA therapy within 3 months of surgical resection whereas 45.9% and 5.0% would delay DAA initiation for 3-12 months and >1 year post-surgery, respectively. For patients undergoing transarterial chemoembolization (TACE), 42.0% of providers would provide DAAs within 3 months of the procedure, 46.7% would delay DAAs until 3-12 months afterward, and 11.3% would delay DAAs more than 1 year after TACE.Based on a survey sent to hepatology providers, there is variation in provider attitudes and practice patterns regarding use and timing of DAAs for patients with HCC. Further studies are needed to characterize the risks and benefits of DAA therapy in this patient population.

    View details for DOI 10.1016/j.cgh.2019.07.042

    View details for PubMedID 31357028

  • Direct-Acting Antiviral Therapy for HCV Infection is Associated with Increased Survival in Patients With a History of Hepatocellular Carcinoma. Gastroenterology Singal, A. G., Rich, N. E., Mehta, N. n., Branch, A. n., Pillai, A. n., Hoteit, M. n., Volk, M. n., Odewole, M. n., Scaglione, S. n., Guy, J. n., Said, A. n., Feld, J. J., John, B. V., Frenette, C. n., Mantry, P. n., Rangnekar, A. S., Oloruntoba, O. n., Leise, M. n., Jou, J. H., Bhamidimarri, K. R., Kulik, L. n., Ioannou, G. N., Huang, A. n., Tran, T. n., Samant, H. n., Dhanasekaran, R. n., Duarte-Rojo, A. n., Salgia, R. n., Eswaran, S. n., Jalal, P. n., Flores, A. n., Satapathy, S. K., Kagan, S. n., Gopal, P. n., Wong, R. n., Parikh, N. D., Murphy, C. C. 2019


    There is controversy over benefits of direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection for patients with a history of hepatocellular carcinoma (HCC). We performed a multicenter cohort study to compare overall survival between patients with HCV infection treated with DAAs vs patients who did not receive DAA treatment for their HCV infection after complete response to prior HCC therapy.We conducted a retrospective cohort study of patients with HCV-related HCC who achieved a complete response to resection, local ablation, trans-arterial chemo- or radioembolization, or radiation therapy, from January 2013 through December 2017 at 31 healthcare systems throughout the United States and Canada. We used Cox proportional hazards regression to determine the association between receipt of DAA therapy, modeled as a time-varying covariate, and all-cause mortality, accounting for informative censoring and confounding using inverse probability weighting.Of 797 patients with HCV-related HCC, 383 patients (48.1%) received DAA therapy and 414 patients (51.9%) did not receive treatment for their HCV infection after complete response to prior HCC therapy. Among DAA-treated patients, 43 deaths occurred during 941 person-years of follow up, compared with 103 deaths during 526.6 person-years of follow up among patients who did not receive DAA therapy (crude rate ratio, 0.23; 95% CI, 0.16-0.33). In inverse probability-weighted analyses, DAA therapy was associated with a significant reduction in risk of death (hazard ratio [HR], 0.54; 95% CI, 0.33-0.90). This association differed by sustained virologic response (SVR) to DAA therapy; risk of death was reduced in patients with SVR to DAA therapy (HR, 0.29; 95% CI, 0.18-0.47) but not in patients without an SVR (HR, 1.13; 95% CI, 0.55-2.33).In an analysis of nearly 800 patients with complete response to HCC treatment, DAA therapy was associated with a significant reduction in risk of death.

    View details for DOI 10.1053/j.gastro.2019.07.040

    View details for PubMedID 31374215

  • Lipid nanoparticles that deliver IL-12 messenger RNA suppress tumorigenesis in MYC oncogene-driven hepatocellular carcinoma JOURNAL FOR IMMUNOTHERAPY OF CANCER Lai, I., Swaminathan, S., Baylot, V., Mosley, A., Dhanasekaran, R., Gabay, M., Felsher, D. W. 2018; 6
  • Lipid nanoparticles that deliver IL-12 messenger RNA suppress tumorigenesis in MYC oncogene-driven hepatocellular carcinoma. Journal for immunotherapy of cancer Lai, I., Swaminathan, S., Baylot, V., Mosley, A., Dhanasekaran, R., Gabay, M., Felsher, D. W. 2018; 6 (1): 125


    Interleukin-12 (IL-12) is a promising candidate for cancer immunotherapy because of its ability to activate a number of host immune subsets that recognize and destroy cancer cells. We found that human hepatocellular carcinoma (HCC) patients with higher than median levels of IL-12 have significantly favorable clinical outcomes. Here, we report that a messenger RNA (mRNA) lipid nanoparticle delivering IL-12 (IL-12-LNP) slows down the progression of MYC oncogene-driven HCC. IL-12-LNP was well distributed within the HCC tumor and was not associated with significant animal toxicity. Treatment with IL-12-LNP significantly reduced liver tumor burden measured by dynamic magnetic resonance imaging (MRI), and increased survival of MYC-induced HCC transgenic mice in comparison to control mice. Importantly, IL-12-LNP exhibited no effect on transgenic MYC levels confirming that its therapeutic efficacy was not related to the downregulation of a driver oncogene. IL-12-LNP elicited marked infiltration of activated CD44+ CD3+ CD4+ T helper cells into the tumor, and increased the production of Interferon gamma (IFNgamma). Collectively, our findings suggest that IL-12-LNP administration may be an effective immunotherapy against HCC.

    View details for PubMedID 30458889

  • Genomic Medicine and Implications for Hepatocellular Carcinoma Prevention and Therapy. Gastroenterology Dhanasekaran, R., Nault, J., Roberts, L. R., Zucman-Rossi, J. 2018


    The pathogenesis of hepatocellular carcinoma (HCC) is poorly understood, but recent advances in genomics have increased our understanding of the mechanisms by which HBV, HCV, alcohol, fatty liver disease, and other environmental factors, such as aflatoxin, cause liver cancer. Genetic analyses of liver tissues from patients have provided important information about tumor initiation and progression. Findings from these studies can potentially be used to individualize the management of HCC. In addition to sorafenib, other multi-kinase inhibitors have recently been approved for treatment of HCC and the preliminary success of immunotherapy has raised hopes. Continued progress in genomic medicine could improve classification of HCCs based on their molecular features and lead to new treatments for patients with liver cancer.

    View details for PubMedID 30404026

  • Comprehensive Molecular Characterization of the Hippo Signaling Pathway in Cancer CELL REPORTS Wang, Y., Xu, X., Maglic, D., Dill, M. T., Mojumdar, K., Ng, P., Jeong, K., Tsang, Y., Moreno, D., Bhavana, V., Peng, X., Ge, Z., Chen, H., Li, J., Chen, Z., Zhang, H., Han, L., Du, D., Creighton, C. J., Mills, G. B., Camargo, F., Liang, H., Canc Genome Atlas Res Network 2018; 25 (5): 1304-+


    Hippo signaling has been recognized as a key tumor suppressor pathway. Here, we perform a comprehensive molecular characterization of 19 Hippo core genes in 9,125 tumor samples across 33 cancer types using multidimensional "omic" data from The Cancer Genome Atlas. We identify somatic drivers among Hippo genes and the related microRNA (miRNA) regulators, and using functional genomic approaches, we experimentally characterize YAP and TAZ mutation effects and miR-590 and miR-200a regulation for TAZ. Hippo pathway activity is best characterized by a YAP/TAZ transcriptional target signature of 22 genes, which shows robust prognostic power across cancer types. Our elastic-net integrated modeling further reveals cancer-type-specific pathway regulators and associated cancer drivers. Our results highlight the importance of Hippo signaling in squamous cell cancers, characterized by frequent amplification of YAP/TAZ, high expression heterogeneity, and significant prognostic patterns. This study represents a systems-biology approach to characterizing key cancer signaling pathways in the post-genomic era.

    View details for DOI 10.1016/j.celrep.2018.10.001

    View details for Web of Science ID 000448675900018

    View details for PubMedID 30380420

    View details for PubMedCentralID PMC6326181

  • Direct-Acting Antiviral Therapy Significantly Reduces Early HCC Recurrence: A Multicenter US Cohort Study Singal, A. G., Mehta, N., Rich, N. E., Murphy, C., Branch, A. D., Pillai, A. A., Hoteit, M. A., Volk, M., Odewole, M., Scaglione, S. J., Guy, J. E., Said, A., Feld, J. J., John, B., Frenette, C. T., Mantry, P. S., Rangnekar, A. S., Oloruntoba, O., Leise, M. D., Jou, J., Bhamidimarri, K., Kulik, L. M., Tran, T. T., Samant, H. V., Dhanasekaran, R., Duarte-Rojo, A., Salgia, R. J., Eswaran, S. L., Modi, A. A., Flores, A., Satapathy, S., Wong, R. J., Huang, A., Misra, S., Schwartz, M. E., Mitrani, R., Ho, C. K., Sharma, S., Konjeti, V. R., Dao, A., Nelson, K., Gulau, M., Delarosa, K., Rahim, U., Mavuram, M., Xie, J. J., Parikh, N. WILEY. 2018: 58A–59A
  • Comprehensive Analysis of Alternative Splicing Across Tumors from 8,705 Patients CANCER CELL Kahles, A., Lehmann, K., Toussaint, N. C., Huser, M., Stark, S. G., Sachsenberg, T., Stegle, O., Kohlbacher, O., Sander, C., Ratsch, G., Canc Genome Atlas Res Network 2018; 34 (2): 211-+


    Our comprehensive analysis of alternative splicing across 32 The Cancer Genome Atlas cancer types from 8,705 patients detects alternative splicing events and tumor variants by reanalyzing RNA and whole-exome sequencing data. Tumors have up to 30% more alternative splicing events than normal samples. Association analysis of somatic variants with alternative splicing events confirmed known trans associations with variants in SF3B1 and U2AF1 and identified additional trans-acting variants (e.g., TADA1, PPP2R1A). Many tumors have thousands of alternative splicing events not detectable in normal samples; on average, we identified ≈930 exon-exon junctions ("neojunctions") in tumors not typically found in GTEx normals. From Clinical Proteomic Tumor Analysis Consortium data available for breast and ovarian tumor samples, we confirmed ≈1.7 neojunction- and ≈0.6 single nucleotide variant-derived peptides per tumor sample that are also predicted major histocompatibility complex-I binders ("putative neoantigens").

    View details for DOI 10.1016/j.ccell.2018.07.001

    View details for Web of Science ID 000441424600006

    View details for PubMedID 30078747

  • Comprehensive Characterization of Cancer Driver Genes and Mutations (vol 173, 371.e1, 2018) CELL Bailey, M. H., Tokheim, C., Porta-Pardo, E., Sengupta, S., Bertrand, D., Weerasinghe, A., Colaprico, A., Wendl, M. C., Kim, J., Reardon, B., Ng, P., Jeong, K., Cao, S., Wang, Z., Gao, J., Gao, Q., Wang, F., Liu, E., Mularoni, L., Rubio-Perez, C., Nagarajan, N., Cortes-Ciriano, I., Zhou, D., Liang, W., Hess, J. M., Yellapantula, V. D., Tamborero, D., Gonzalez-Perez, A., Suphavilai, C., Ko, J., Khurana, E., Park, P. J., Van Allen, E. M., Liang, H., Lawrence, M. S., Godzik, A., Lopez-Bigas, N., Stuart, J., Wheeler, D., Getz, G., Chen, K., Lazar, A. J., Mills, G. B., Karchin, R., Ding, L., MC3 Working Grp, Canc Genome Atlas Res Network 2018; 174 (4): 1034-1035
  • The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma (vol 23, pg 313, 2018) CELL REPORTS Ricketts, C. J., De Cubas, A. A., Fan, H., Smith, C. C., Lang, M., Reznik, E., Bowlby, R., Gibb, E. A., Akbani, R., Beroukhim, R., Bottaro, D. P., Choueiri, T. K., Gibbs, R. A., Godwin, A. K., Haake, S., Hakimi, A., Henske, E. P., Hsieh, J. J., Ho, T. H., Kanchi, R. S., Krishnan, B., Kwiatkowski, D. J., Lui, W., Merino, M. J., Mills, G. B., Myers, J., Nickerson, M. L., Reuter, V. E., Schmidt, L. S., Shelley, C., Shen, H., Shuch, B., Signoretti, S., Srinivasan, R., Tamboli, P., Thomas, G., Vincent, B. G., Vocke, C. D., Wheeler, D. A., Yang, L., Kim, W. Y., Robertson, A., Spellman, P. T., Rathmell, W., Linehan, W., Canc Genome Atlas Res Network 2018; 23 (12): 3698

    View details for DOI 10.1016/j.celrep.2018.06.032

    View details for Web of Science ID 000435818300024

    View details for PubMedID 29925010

  • The Immune Landscape of Cancer IMMUNITY Thorsson, V., Gibbs, D. L., Brown, S. D., Wolf, D., Bortone, D. S., Yang, T., Porta-Pardo, E., Gao, G. F., Plaisier, C. L., Eddy, J. A., Ziv, E., Culhane, A. C., Paull, E. O., Sivakumar, I., Gentles, A. J., Malhotra, R., Farshidfar, F., Colaprico, A., Parker, J. S., Mose, L. E., Nam Sy Vo, Liu, J., Liu, Y., Rader, J., Dhankani, V., Reynolds, S. M., Bowlby, R., Califano, A., Cherniack, A. D., Anastassiou, D., Bedognetti, D., Rao, A., Chen, K., Krasnitz, A., Hu, H., Malta, T. M., Noushmehr, H., Pedamallu, C., Bullman, S., Ojesina, A. I., Lamb, A., Zhou, W., Shen, H., Choueiri, T. K., Weinstein, J. N., Guinney, J., Saltz, J., Holt, R. A., Rabkin, C. E., Lazar, A. J., Serody, J. S., Demicco, E. G., Disis, M. L., Vincent, B. G., Shmulevich, L., Canc Genome Atlas Res Network 2018; 48 (4): 812-+


    We performed an extensive immunogenomic analysis of more than 10,000 tumors comprising 33 diverse cancer types by utilizing data compiled by TCGA. Across cancer types, we identified six immune subtypes-wound healing, IFN-γ dominant, inflammatory, lymphocyte depleted, immunologically quiet, and TGF-β dominant-characterized by differences in macrophage or lymphocyte signatures, Th1:Th2 cell ratio, extent of intratumoral heterogeneity, aneuploidy, extent of neoantigen load, overall cell proliferation, expression of immunomodulatory genes, and prognosis. Specific driver mutations correlated with lower (CTNNB1, NRAS, or IDH1) or higher (BRAF, TP53, or CASP8) leukocyte levels across all cancers. Multiple control modalities of the intracellular and extracellular networks (transcription, microRNAs, copy number, and epigenetic processes) were involved in tumor-immune cell interactions, both across and within immune subtypes. Our immunogenomics pipeline to characterize these heterogeneous tumors and the resulting data are intended to serve as a resource for future targeted studies to further advance the field.

    View details for PubMedID 29628290

  • Comparative Molecular Analysis of Gastrointestinal Adenocarcinomas CANCER CELL Liu, Y., Sethi, N. S., Hinoue, T., Schneider, B. G., Cherniack, A. D., Sanchez-Vega, F., Seoane, J. A., Farshidfar, F., Bowlby, R., Islam, M., Kim, J., Chatila, W., Akbani, R., Kanchi, R. S., Rabkin, C. S., Willis, J. E., Wang, K. K., McCall, S. J., Mishra, L., Ojesina, A. I., Bullman, S., Pedamallu, C., Lazar, A. J., Sakai, R., Thorsson, V., Bass, A. J., Laird, P. W., Canc Genome Atlas Res Network 2018; 33 (4): 721-+


    We analyzed 921 adenocarcinomas of the esophagus, stomach, colon, and rectum to examine shared and distinguishing molecular characteristics of gastrointestinal tract adenocarcinomas (GIACs). Hypermutated tumors were distinct regardless of cancer type and comprised those enriched for insertions/deletions, representing microsatellite instability cases with epigenetic silencing of MLH1 in the context of CpG island methylator phenotype, plus tumors with elevated single-nucleotide variants associated with mutations in POLE. Tumors with chromosomal instability were diverse, with gastroesophageal adenocarcinomas harboring fragmented genomes associated with genomic doubling and distinct mutational signatures. We identified a group of tumors in the colon and rectum lacking hypermutation and aneuploidy termed genome stable and enriched in DNA hypermethylation and mutations in KRAS, SOX9, and PCBP1.

    View details for PubMedID 29622466

  • Genomic and Functional Approaches to Understanding Cancer Aneuploidy CANCER CELL Taylor, A. M., Shih, J., Ha, G., Gao, G. F., Zhang, X., Berger, A. C., Schumacher, S. E., Wang, C., Hu, H., Liu, J., Lazar, A. J., Cherniack, A. D., Beroukhim, R., Meyerson, M., Canc Genome Atlas Res Network 2018; 33 (4): 676-+


    Aneuploidy, whole chromosome or chromosome arm imbalance, is a near-universal characteristic of human cancers. In 10,522 cancer genomes from The Cancer Genome Atlas, aneuploidy was correlated with TP53 mutation, somatic mutation rate, and expression of proliferation genes. Aneuploidy was anti-correlated with expression of immune signaling genes, due to decreased leukocyte infiltrates in high-aneuploidy samples. Chromosome arm-level alterations show cancer-specific patterns, including loss of chromosome arm 3p in squamous cancers. We applied genome engineering to delete 3p in lung cells, causing decreased proliferation rescued in part by chromosome 3 duplication. This study defines genomic and phenotypic correlates of cancer aneuploidy and provides an experimental approach to study chromosome arm aneuploidy.

    View details for DOI 10.1016/j.ccell.2018.03.007

    View details for Web of Science ID 000429531300013

    View details for PubMedID 29622463

    View details for PubMedCentralID PMC6028190

  • lncRNA Epigenetic Landscape Analysis Identifies EPIC1 as an Oncogenic lncRNA that Interacts with MYC and Promotes Cell-Cycle Progression in Cancer CANCER CELL Wang, Z., Yang, B., Zhang, M., Guo, W., Wu, Z., Wang, Y., Jia, L., Li, S., Xie, W., Yang, D., Canc Genome Atlas Res Network 2018; 33 (4): 706-+


    We characterized the epigenetic landscape of genes encoding long noncoding RNAs (lncRNAs) across 6,475 tumors and 455 cancer cell lines. In stark contrast to the CpG island hypermethylation phenotype in cancer, we observed a recurrent hypomethylation of 1,006 lncRNA genes in cancer, including EPIC1 (epigenetically-induced lncRNA1). Overexpression of EPIC1 is associated with poor prognosis in luminal B breast cancer patients and enhances tumor growth in vitro and in vivo. Mechanistically, EPIC1 promotes cell-cycle progression by interacting with MYC through EPIC1's 129-283 nt region. EPIC1 knockdown reduces the occupancy of MYC to its target genes (e.g., CDKN1A, CCNA2, CDC20, and CDC45). MYC depletion abolishes EPIC1's regulation of MYC target and luminal breast cancer tumorigenesis in vitro and in vivo.

    View details for DOI 10.1016/j.ccell.2018.03.006

    View details for Web of Science ID 000429531300015

    View details for PubMedID 29622465

    View details for PubMedCentralID PMC6143179

  • Machine Learning Identifies Stemness Features Associated with Oncogenic Dedifferentiation CELL Malta, T. M., Sokolov, A., Gentles, A. J., Burzykowski, T., Poisson, L., Weinstein, J. N., Kaminska, B., Huelsken, J., Omberg, L., Gevaert, O., Colaprico, A., Czerwinska, P., Mazurek, S., Mishra, L., Heyn, H., Krasnitz, A., Godwin, A. K., Lazar, A. J., Stuart, J. M., Hoadley, K. A., Laird, P. W., Noushmehr, H., Wiznerowicz, M., Cancer Genome Atlas Res Network 2018; 173 (2): 338-+


    Cancer progression involves the gradual loss of a differentiated phenotype and acquisition of progenitor and stem-cell-like features. Here, we provide novel stemness indices for assessing the degree of oncogenic dedifferentiation. We used an innovative one-class logistic regression (OCLR) machine-learning algorithm to extract transcriptomic and epigenetic feature sets derived from non-transformed pluripotent stem cells and their differentiated progeny. Using OCLR, we were able to identify previously undiscovered biological mechanisms associated with the dedifferentiated oncogenic state. Analyses of the tumor microenvironment revealed unanticipated correlation of cancer stemness with immune checkpoint expression and infiltrating immune cells. We found that the dedifferentiated oncogenic phenotype was generally most prominent in metastatic tumors. Application of our stemness indices to single-cell data revealed patterns of intra-tumor molecular heterogeneity. Finally, the indices allowed for the identification of novel targets and possible targeted therapies aimed at tumor differentiation.

    View details for PubMedID 29625051

  • Comprehensive Characterization of Cancer Driver Genes and Mutations CELL Bailey, M. H., Tokheim, C., Porta-Pardo, E., Sengupta, S., Bertrand, D., Weerasinghe, A., Colaprico, A., Wendl, M. C., Kim, J., Reardon, B., Ng, P., Jeong, K., Cao, S., Wang, Z., Gao, J., Gao, Q., Wang, F., Liu, E., Mularoni, L., Rubio-Perez, C., Nagarajan, N., Cortes-Ciriano, I., Zhou, D., Liang, W., Hess, J. M., Yellapantula, V. D., Tamborero, D., Gonzalez-Perez, A., Suphavilai, C., Ko, J., Khurana, E., Park, P. J., Van Allen, E. M., Liang, H., Lawrence, M. S., Godzik, A., Lopez-Bigas, N., Stuart, J., Wheeler, D., Getz, G., Chen, K., Lazar, A. J., Mills, G. B., Karchin, R., Ding, L., MC3 Working Grp, Canc Genome Atlas Res Network 2018; 173 (2): 371-+

    View details for DOI 10.1016/j.cell.2018.02.060

    View details for Web of Science ID 000429320200012

    View details for PubMedID 30096302

    View details for PubMedCentralID PMC8045146

  • Perspective on Oncogenic Processes at the End of the Beginning of Cancer Genomics CELL Ding, L., Bailey, M. H., Porta-Pardo, E., Thorsson, V., Colaprico, A., Bertrand, D., Gibbs, D. L., Weerasinghe, A., Huang, K., Tokheim, C., Cortes-Ciriano, I., Jayasinghe, R., Chen, F., Yu, L., Sun, S., Olsen, C., Kim, J., Taylor, A. M., Cherniack, A. D., Akbani, R., Suphavilai, C., Nagarajan, N., Stuart, J. M., Mills, G. B., Wyczalkowski, M. A., Vincent, B. G., Hutter, C. M., Zenklusen, J., Hoadley, K. A., Wendl, M. C., Shmulevich, L., Lazar, A. J., Wheeler, D. A., Getz, G., Cancer Genome Atlas Res Network 2018; 173 (2): 305-+


    The Cancer Genome Atlas (TCGA) has catalyzed systematic characterization of diverse genomic alterations underlying human cancers. At this historic junction marking the completion of genomic characterization of over 11,000 tumors from 33 cancer types, we present our current understanding of the molecular processes governing oncogenesis. We illustrate our insights into cancer through synthesis of the findings of the TCGA PanCancer Atlas project on three facets of oncogenesis: (1) somatic driver mutations, germline pathogenic variants, and their interactions in the tumor; (2) the influence of the tumor genome and epigenome on transcriptome and proteome; and (3) the relationship between tumor and the microenvironment, including implications for drugs targeting driver events and immunotherapies. These results will anchor future characterization of rare and common tumor types, primary and relapsed tumors, and cancers across ancestry groups and will guide the deployment of clinical genomic sequencing.

    View details for DOI 10.1016/j.cell.2018.03.033

    View details for Web of Science ID 000429320200008

    View details for PubMedID 29625049

    View details for PubMedCentralID PMC5916814

  • A Pan-Cancer Analysis of Enhancer Expression in Nearly 9000 Patient Samples CELL Chen, H., Li, C., Peng, X., Zhou, Z., Weinstein, J. N., Liang, H., Canc Genome Atlas Res Network 2018; 173 (2): 386-+


    The role of enhancers, a key class of non-coding regulatory DNA elements, in cancer development has increasingly been appreciated. Here, we present the detection and characterization of a large number of expressed enhancers in a genome-wide analysis of 8928 tumor samples across 33 cancer types using TCGA RNA-seq data. Compared with matched normal tissues, global enhancer activation was observed in most cancers. Across cancer types, global enhancer activity was positively associated with aneuploidy, but not mutation load, suggesting a hypothesis centered on "chromatin-state" to explain their interplay. Integrating eQTL, mRNA co-expression, and Hi-C data analysis, we developed a computational method to infer causal enhancer-gene interactions, revealing enhancers of clinically actionable genes. Having identified an enhancer ∼140 kb downstream of PD-L1, a major immunotherapy target, we validated it experimentally. This study provides a systematic view of enhancer activity in diverse tumor contexts and suggests the clinical implications of enhancers.

    View details for DOI 10.1016/j.cell.2018.03.027

    View details for Web of Science ID 000429320200013

    View details for PubMedID 29625054

    View details for PubMedCentralID PMC5890960

  • Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer CELL Hoadley, K. A., Yau, C., Hinoue, T., Wolf, D. M., Lazar, A. J., Drill, E., Shen, R., Taylor, A. M., Cherniack, A. D., Thorsson, V., Akbani, R., Bowlby, R., Wong, C. K., Wiznerowicz, M., Sanchez-Vega, F., Robertson, A., Schneider, B. G., Lawrence, M. S., Noushmehr, H., Malta, T. M., Stuart, J. M., Benz, C. C., Laird, P. W., Cancer Genome Atlas Network 2018; 173 (2): 291-+


    We conducted comprehensive integrative molecular analyses of the complete set of tumors in The Cancer Genome Atlas (TCGA), consisting of approximately 10,000 specimens and representing 33 types of cancer. We performed molecular clustering using data on chromosome-arm-level aneuploidy, DNA hypermethylation, mRNA, and miRNA expression levels and reverse-phase protein arrays, of which all, except for aneuploidy, revealed clustering primarily organized by histology, tissue type, or anatomic origin. The influence of cell type was evident in DNA-methylation-based clustering, even after excluding sites with known preexisting tissue-type-specific methylation. Integrative clustering further emphasized the dominant role of cell-of-origin patterns. Molecular similarities among histologically or anatomically related cancer types provide a basis for focused pan-cancer analyses, such as pan-gastrointestinal, pan-gynecological, pan-kidney, and pan-squamous cancers, and those related by stemness features, which in turn may inform strategies for future therapeutic development.

    View details for DOI 10.1016/j.cell.2018.03.022

    View details for Web of Science ID 000429320200007

    View details for PubMedID 29625048

    View details for PubMedCentralID PMC5957518

  • An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics CELL Liu, J., Lichtenberg, T., Hoadley, K. A., Poisson, L. M., Lazar, A. J., Cherniack, A. D., Kovatich, A. J., Benz, C. C., Levine, D. A., Lee, A. V., Omberg, L., Wolf, D. M., Shriver, C. D., Thorsson, V., Hu, H., Canc Genome Atlas Res Network 2018; 173 (2): 400-+


    For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale.

    View details for DOI 10.1016/j.cell.2018.02.052

    View details for Web of Science ID 000429320200014

    View details for PubMedID 29625055

    View details for PubMedCentralID PMC6066282

  • Oncogenic Signaling Pathways in The Cancer Genome Atlas CELL Sanchez-Vega, F., Mina, M., Armenia, J., Chatila, W. K., Luna, A., La, K. C., Dimitriadoy, S., Liu, D. L., Kantheti, H. S., Saghafinia, S., Chakravarty, D., Daian, F., Gao, Q., Bailey, M. H., Liang, W., Foltz, S. M., Shmulevich, I., Ding, L., Heins, Z., Ochoa, A., Gross, B., Gao, J., Zhang, H., Kundra, R., Kandoth, C., Bahceci, I., Dervishi, L., Dogrusoz, U., Zhou, W., Shen, H., Laird, P. W., Way, G. P., Greene, C. S., Liang, H., Xiao, Y., Wang, C., Iavarone, A., Berger, A. H., Bivona, T. G., Lazar, A. J., Hammer, G. D., Giordano, T., Kwong, L. N., McArthur, G., Huang, C., Tward, A. D., Frederick, M. J., McCormick, F., Meyerson, M., Van Allen, E. M., Cherniack, A. D., Ciriello, G., Sander, C., Schultz, N., Cancer Genome Atlas Res Network 2018; 173 (2): 321-+


    Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, p53 and β-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy.

    View details for DOI 10.1016/j.cell.2018.03.035

    View details for Web of Science ID 000429320200009

    View details for PubMedID 29625050

    View details for PubMedCentralID PMC6070353

  • Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas CELL REPORTS Campbell, J. D., Yau, C., Bowlby, R., Liu, Y., Brennan, K., Fan, H., Taylor, A. M., Wang, C., Walter, V., Akbani, R., Byers, L., Creighton, C. J., Coarfa, C., Shih, J., Cherniack, A. D., Gevaert, O., Prunello, M., Shen, H., Anur, P., Chen, J., Cheng, H., Hayes, D., Bullman, S., Pedamallu, C., Ojesina, A. I., Sadeghi, S., Mungall, K. L., Robertson, A., Benz, C., Schultz, A., Kanchi, R. S., Gay, C. M., Hegde, A., Diao, L., Wang, J., Ma, W., Sumazin, P., Chiu, H., Chen, T., Gunaratne, P., Donehower, L., Rader, J. S., Zuna, R., Al-Ahmadie, H., Lazar, A. J., Flores, E. R., Tsai, K. Y., Zhou, J. H., Rustgi, A. K., Drill, E., Shen, R., Wong, C. K., Stuart, J. M., Laird, P. W., Hoadley, K. A., Weinstein, J. N., Peto, M., Pickering, C. R., Chen, Z., Van Waes, C., Canc Genome Atlas Res Network 2018; 23 (1): 194-+


    This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smoking and/or human papillomavirus (HPV). SCCs harbor 3q, 5p, and other recurrent chromosomal copy-number alterations (CNAs), DNA mutations, and/or aberrant methylation of genes and microRNAs, which are correlated with the expression of multi-gene programs linked to squamous cell stemness, epithelial-to-mesenchymal differentiation, growth, genomic integrity, oxidative damage, death, and inflammation. Low-CNA SCCs tended to be HPV(+) and display hypermethylation with repression of TET1 demethylase and FANCF, previously linked to predisposition to SCC, or harbor mutations affecting CASP8, RAS-MAPK pathways, chromatin modifiers, and immunoregulatory molecules. We uncovered hypomethylation of the alternative promoter that drives expression of the ΔNp63 oncogene and embedded miR944. Co-expression of immune checkpoint, T-regulatory, and Myeloid suppressor cells signatures may explain reduced efficacy of immune therapy. These findings support possibilities for molecular classification and therapeutic approaches.

    View details for PubMedID 29617660

  • Driver Fusions and Their Implications in the Development and Treatment of Human Cancers CELL REPORTS Gao, Q., Liang, W., Foltz, S. M., Mutharasu, G., Jayasinghe, R. G., Cao, S., Liao, W., Reynolds, S. M., Wyczalkowski, M. A., Yao, L., Yu, L., Sun, S. Q., Chen, K., Lazar, A. J., Fields, R. C., Wendl, M. C., Van Tine, B. A., Vij, R., Chen, F., Nykter, M., Shmulevich, I., Ding, L., Fusion Anal Working Grp, Canc Genome Atlas Res Network 2018; 23 (1): 227-+


    Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy.

    View details for DOI 10.1016/j.celrep.2018.03.050

    View details for Web of Science ID 000429092900020

    View details for PubMedID 29617662

    View details for PubMedCentralID PMC5916809

  • Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types CELL REPORTS Ge, Z., Leighton, J. S., Wang, Y., Peng, X., Chen, Z., Chen, H., Sun, Y., Yao, F., Li, J., Zhang, H., Liu, J., Shriver, C. D., Hu, H., Piwnica-Worms, H., Ma, L., Liang, H., Canc Genome Atlas Res Network 2018; 23 (1): 213-+


    Protein ubiquitination is a dynamic and reversible process of adding single ubiquitin molecules or various ubiquitin chains to target proteins. Here, using multidimensional omic data of 9,125 tumor samples across 33 cancer types from The Cancer Genome Atlas, we perform comprehensive molecular characterization of 929 ubiquitin-related genes and 95 deubiquitinase genes. Among them, we systematically identify top somatic driver candidates, including mutated FBXW7 with cancer-type-specific patterns and amplified MDM2 showing a mutually exclusive pattern with BRAF mutations. Ubiquitin pathway genes tend to be upregulated in cancer mediated by diverse mechanisms. By integrating pan-cancer multiomic data, we identify a group of tumor samples that exhibit worse prognosis. These samples are consistently associated with the upregulation of cell-cycle and DNA repair pathways, characterized by mutated TP53, MYC/TERT amplification, and APC/PTEN deletion. Our analysis highlights the importance of the ubiquitin pathway in cancer development and lays a foundation for developing relevant therapeutic strategies.

    View details for DOI 10.1016/j.celrep.2018.03.047

    View details for Web of Science ID 000429092900019

    View details for PubMedID 29617661

    View details for PubMedCentralID PMC5916807

  • Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context CELL REPORTS Chiu, H., Somvanshi, S., Patel, E., Chen, T., Singh, V. P., Zorman, B., Patil, S. L., Pan, Y., Chatterjee, S. S., Sood, A. K., Gunaratne, P. H., Sumazin, P., Canc Genome Atlas Res Network 2018; 23 (1): 297-+


    Long noncoding RNAs (lncRNAs) are commonly dysregulated in tumors, but only a handful are known to play pathophysiological roles in cancer. We inferred lncRNAs that dysregulate cancer pathways, oncogenes, and tumor suppressors (cancer genes) by modeling their effects on the activity of transcription factors, RNA-binding proteins, and microRNAs in 5,185 TCGA tumors and 1,019 ENCODE assays. Our predictions included hundreds of candidate onco- and tumor-suppressor lncRNAs (cancer lncRNAs) whose somatic alterations account for the dysregulation of dozens of cancer genes and pathways in each of 14 tumor contexts. To demonstrate proof of concept, we showed that perturbations targeting OIP5-AS1 (an inferred tumor suppressor) and TUG1 and WT1-AS (inferred onco-lncRNAs) dysregulated cancer genes and altered proliferation of breast and gynecologic cancer cells. Our analysis indicates that, although most lncRNAs are dysregulated in a tumor-specific manner, some, including OIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergistically dysregulate cancer pathways in multiple tumor contexts.

    View details for DOI 10.1016/j.celrep.2018.03.064

    View details for Web of Science ID 000429092900025

    View details for PubMedID 29617668

    View details for PubMedCentralID PMC5906131

  • Somatic Mutational Landscape of Splicing Factor Genes and Their Functional Consequences across 33 Cancer Types CELL REPORTS Seiler, M., Peng, S., Agrawal, A. A., Palacino, J., Teng, T., Zhu, P., Smith, P. G., Buonamici, S., Yu, L., Canc Genome Atlas Res Network 2018; 23 (1): 282-+


    Hotspot mutations in splicing factor genes have been recently reported at high frequency in hematological malignancies, suggesting the importance of RNA splicing in cancer. We analyzed whole-exome sequencing data across 33 tumor types in The Cancer Genome Atlas (TCGA), and we identified 119 splicing factor genes with significant non-silent mutation patterns, including mutation over-representation, recurrent loss of function (tumor suppressor-like), or hotspot mutation profile (oncogene-like). Furthermore, RNA sequencing analysis revealed altered splicing events associated with selected splicing factor mutations. In addition, we were able to identify common gene pathway profiles associated with the presence of these mutations. Our analysis suggests that somatic alteration of genes involved in the RNA-splicing process is common in cancer and may represent an underappreciated hallmark of tumorigenesis.

    View details for DOI 10.1016/j.celrep.2018.01.088

    View details for Web of Science ID 000429092900024

    View details for PubMedID 29617667

    View details for PubMedCentralID PMC5933844

  • Systematic Analysis of Splice-Site-Creating Mutations in Cancer CELL REPORTS Jayasinghe, R. G., Cao, S., Gao, Q., Wendl, M. C., Vo, N., Reynolds, S. M., Zhao, Y., Climente-Gonzalez, H., Chai, S., Wang, F., Varghese, R., Huang, M., Liang, W., Wyczalkowski, M. A., Sengupta, S., Li, Z., Payne, S. H., Fenyo, D., Miner, J. H., Walter, M. J., Vincent, B., Eyras, E., Chen, K., Shmulevich, I., Chen, F., Ding, L., Canc Genome Atlas Res Network 2018; 23 (1): 270-+


    For the past decade, cancer genomic studies have focused on mutations leading to splice-site disruption, overlooking those having splice-creating potential. Here, we applied a bioinformatic tool, MiSplice, for the large-scale discovery of splice-site-creating mutations (SCMs) across 8,656 TCGA tumors. We report 1,964 originally mis-annotated mutations having clear evidence of creating alternative splice junctions. TP53 and GATA3 have 26 and 18 SCMs, respectively, and ATRX has 5 from lower-grade gliomas. Mutations in 11 genes, including PARP1, BRCA1, and BAP1, were experimentally validated for splice-site-creating function. Notably, we found that neoantigens induced by SCMs are likely several folds more immunogenic compared to missense mutations, exemplified by the recurrent GATA3 SCM. Further, high expression of PD-1 and PD-L1 was observed in tumors with SCMs, suggesting candidates for immune blockade therapy. Our work highlights the importance of integrating DNA and RNA data for understanding the functional and the clinical implications of mutations in human diseases.

    View details for DOI 10.1016/j.celrep.2018.03.052

    View details for Web of Science ID 000429092900023

    View details for PubMedID 29617666

    View details for PubMedCentralID PMC6055527

  • Machine Learning Detects Pan-cancer Ras Pathway Activation in The Cancer Genome Atlas CELL REPORTS Way, G. P., Sanchez-Vega, F., La, K., Armenia, J., Chatila, W. K., Luna, A., Sander, C., Cherniack, A. D., Mina, M., Ciriello, G., Schultz, N., Sanchez, Y., Greene, C. S., Canc Genome Atlas Res Network 2018; 23 (1): 172-+


    Precision oncology uses genomic evidence to match patients with treatment but often fails to identify all patients who may respond. The transcriptome of these "hidden responders" may reveal responsive molecular states. We describe and evaluate a machine-learning approach to classify aberrant pathway activity in tumors, which may aid in hidden responder identification. The algorithm integrates RNA-seq, copy number, and mutations from 33 different cancer types across The Cancer Genome Atlas (TCGA) PanCanAtlas project to predict aberrant molecular states in tumors. Applied to the Ras pathway, the method detects Ras activation across cancer types and identifies phenocopying variants. The model, trained on human tumors, can predict response to MEK inhibitors in wild-type Ras cell lines. We also present data that suggest that multiple hits in the Ras pathway confer increased Ras activity. The transcriptome is underused in precision oncology and, combined with machine learning, can aid in the identification of hidden responders.

    View details for DOI 10.1016/j.celrep.2018.03.046

    View details for Web of Science ID 000429092900016

    View details for PubMedID 29617658

    View details for PubMedCentralID PMC5918694

  • Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images CELL REPORTS Saltz, J., Gupta, R., Hou, L., Kurc, T., Singh, P., Vu Nguyen, Samaras, D., Shroyer, K. R., Zhao, T., Batiste, R., Van Arnam, J., Shmulevich, I., Rao, A. K., Lazar, A. J., Sharma, A., Thorsson, V., Canc Genome Atlas Res Network 2018; 23 (1): 181-+


    Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumor-infiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment.

    View details for DOI 10.1016/j.celrep.2018.03.086

    View details for Web of Science ID 000429092900017

    View details for PubMedID 29617659

    View details for PubMedCentralID PMC5943714

  • Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas CELL REPORTS Knijnenburg, T. A., Wang, L., Zimmermann, M. T., Chambwe, N., Gao, G. F., Cherniack, A. D., Fan, H., Shen, H., Way, G. P., Greene, C. S., Liu, Y., Akbani, R., Feng, B., Donehower, L. A., Miller, C., Shen, Y., Karimi, M., Chen, H., Kim, P., Jia, P., Shinbrot, E., Zhang, S., Liu, J., Hu, H., Bailey, M. H., Yau, C., Wolf, D., Zhao, Z., Weinstein, J. N., Li, L., Ding, L., Mills, G. B., Laird, P. W., Wheeler, D. A., Shmulevich, I., Monnat, R. J., Xiao, Y., Wang, C., Canc Genome Atlas Res Network 2018; 23 (1): 239-+


    DNA damage repair (DDR) pathways modulate cancer risk, progression, and therapeutic response. We systematically analyzed somatic alterations to provide a comprehensive view of DDR deficiency across 33 cancer types. Mutations with accompanying loss of heterozygosity were observed in over 1/3 of DDR genes, including TP53 and BRCA1/2. Other prevalent alterations included epigenetic silencing of the direct repair genes EXO5, MGMT, and ALKBH3 in ∼20% of samples. Homologous recombination deficiency (HRD) was present at varying frequency in many cancer types, most notably ovarian cancer. However, in contrast to ovarian cancer, HRD was associated with worse outcomes in several other cancers. Protein structure-based analyses allowed us to predict functional consequences of rare, recurrent DDR mutations. A new machine-learning-based classifier developed from gene expression data allowed us to identify alterations that phenocopy deleterious TP53 mutations. These frequent DDR gene alterations in many human cancers have functional consequences that may determine cancer progression and guide therapy.

    View details for DOI 10.1016/j.celrep.2018.03.076

    View details for Web of Science ID 000429092900021

    View details for PubMedID 29617664

    View details for PubMedCentralID PMC5961503

  • Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas CELL SYSTEMS Schaub, F. X., Dhankani, V., Berger, A. C., Trivedi, M., Richardson, A. B., Shaw, R., Zhao, W., Zhang, X., Ventura, A., Liu, Y., Ayer, D. E., Hurlin, P. J., Cherniack, A. D., Eisenman, R. N., Bernard, B., Grandori, C., Canc Genome Atlas Network 2018; 6 (3): 282-+


    Although the MYC oncogene has been implicated in cancer, a systematic assessment of alterations of MYC, related transcription factors, and co-regulatory proteins, forming the proximal MYC network (PMN), across human cancers is lacking. Using computational approaches, we define genomic and proteomic features associated with MYC and the PMN across the 33 cancers of The Cancer Genome Atlas. Pan-cancer, 28% of all samples had at least one of the MYC paralogs amplified. In contrast, the MYC antagonists MGA and MNT were the most frequently mutated or deleted members, proposing a role as tumor suppressors. MYC alterations were mutually exclusive with PIK3CA, PTEN, APC, or BRAF alterations, suggesting that MYC is a distinct oncogenic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such as immune response and growth factor signaling; chromatin, translation, and DNA replication/repair were conserved pan-cancer. This analysis reveals insights into MYC biology and is a reference for biomarkers and therapeutics for cancers with alterations of MYC or the PMN.

    View details for DOI 10.1016/j.cels.2018.03.003

    View details for Web of Science ID 000428798600015

    View details for PubMedID 29596783

    View details for PubMedCentralID PMC5892207

  • Scalable Open Science Approach for Mutation Calling of Tumor Exomes Using Multiple Genomic Pipelines CELL SYSTEMS Ellrott, K., Bailey, M. H., Saksena, G., Covington, K. R., Kandoth, C., Stewart, C., Hess, J., Ma, S., Chiotti, K. E., McLellan, M., Sofia, H. J., Hutter, C., Getz, G., Wheeler, D., Ding, L., MC3 Working Grp, Canc Genome Atlas Res Network 2018; 6 (3): 271-+


    The Cancer Genome Atlas (TCGA) cancer genomics dataset includes over 10,000 tumor-normal exome pairs across 33 different cancer types, in total >400 TB of raw data files requiring analysis. Here we describe the Multi-Center Mutation Calling in Multiple Cancers project, our effort to generate a comprehensive encyclopedia of somatic mutation calls for the TCGA data to enable robust cross-tumor-type analyses. Our approach accounts for variance and batch effects introduced by the rapid advancement of DNA extraction, hybridization-capture, sequencing, and analysis methods over time. We present best practices for applying an ensemble of seven mutation-calling algorithms with scoring and artifact filtering. The dataset created by this analysis includes 3.5 million somatic variants and forms the basis for PanCan Atlas papers. The results have been made available to the research community along with the methods used to generate them. This project is the result of collaboration from a number of institutes and demonstrates how team science drives extremely large genomics projects.

    View details for DOI 10.1016/j.cels.2018.03.002

    View details for Web of Science ID 000428798600014

    View details for PubMedID 29596782

    View details for PubMedCentralID PMC6075717

  • Ribosomal protein S15a promotes tumor angiogenesis via enhancing Wnt/β-catenin-induced FGF18 expression in hepatocellular carcinoma. Oncogene Guo, P. n., Wang, Y. n., Dai, C. n., Tao, C. n., Wu, F. n., Xie, X. n., Yu, H. n., Zhu, Q. n., Li, J. n., Ye, L. n., Yu, F. n., Shan, Y. n., Yu, Z. n., Dhanasekaran, R. n., Zheng, R. n., Chen, G. n. 2018; 37 (9): 1220–36


    Ribosomal protein s15a (RPS15A) plays a promotive role in the mRNA/ribosome interactions during early translation. Our previous study has found that inhibiting RPS15A expression can decrease proliferation and induce cell cycle arrest in hepatocellular carcinoma (HCC) cell lines. However, the mechanism underlying the involvement of RPS15A in HCC pathogenesis and the clinical significance of RPS15A expression remain unclear. In this study, an evaluation of RPS15A expression in 110 surgically resected HCCs and matched tumor-adjacent normal tissues revealed an overexpression of RPS15A in HCC, which was correlated with worse survival. In addition, tumor tissue with higher RPS15A expression demonstrated a higher microvascular density (MVD). Subsequently, two HCC cell lines, Huh7 (low-level constitutive RPS15A expression) and HepG2 (high RPS15A expression) were used to further evaluate the role of RPS15A in angiogenesis. The co-culture experiment of HCC cells with endothelial cells revealed that the induced overexpression of RPS15A in Huh7 cells increased the angiogenic potential of HUVEC in a paracrine fashion; conversely, knockdown of RPS15A in HepG2 cells showed an opposite effect. Further analysis indicated that RPS15A modulated FGF signaling by enhancing Wnt/beta-catenin-mediated FGF18 expression in HCC cells. FGF18, in turn, through binding to its FGFR3 receptor on endothelial cells, can activate the AKT and ERK pathway and promotes angiogenesis in a tumor microenvironment. Our in vivo experiment further confirmed that inhibition of RPS15A expression in HCC xenografts dramatically hindered tumor growth and inhibited tumor angiogenesis. Together, our findings suggest that RPS15A promotes angiogenesis in HCCs by enhancing Wnt/beta-catenin induced FGF18 expression. The RPS15A/FGF18 pathway may be a rational target for anti-angiogenic therapy of HCC.

    View details for PubMedID 29242604

  • Pathogenic Germline Variants in 10,389 Adult Cancers. Cell Huang, K. L., Mashl, R. J., Wu, Y. n., Ritter, D. I., Wang, J. n., Oh, C. n., Paczkowska, M. n., Reynolds, S. n., Wyczalkowski, M. A., Oak, N. n., Scott, A. D., Krassowski, M. n., Cherniack, A. D., Houlahan, K. E., Jayasinghe, R. n., Wang, L. B., Zhou, D. C., Liu, D. n., Cao, S. n., Kim, Y. W., Koire, A. n., McMichael, J. F., Hucthagowder, V. n., Kim, T. B., Hahn, A. n., Wang, C. n., McLellan, M. D., Al-Mulla, F. n., Johnson, K. J., Lichtarge, O. n., Boutros, P. C., Raphael, B. n., Lazar, A. J., Zhang, W. n., Wendl, M. C., Govindan, R. n., Jain, S. n., Wheeler, D. n., Kulkarni, S. n., Dipersio, J. F., Reimand, J. n., Meric-Bernstam, F. n., Chen, K. n., Shmulevich, I. n., Plon, S. E., Chen, F. n., Ding, L. n. 2018; 173 (2): 355–70.e14


    We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, and PTPN11 associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer.

    View details for DOI 10.1016/j.cell.2018.03.039

    View details for PubMedID 29625052

    View details for PubMedCentralID PMC5949147

  • A Comprehensive Pan-Cancer Molecular Study of Gynecologic and Breast Cancers. Cancer cell Berger, A. C., Korkut, A. n., Kanchi, R. S., Hegde, A. M., Lenoir, W. n., Liu, W. n., Liu, Y. n., Fan, H. n., Shen, H. n., Ravikumar, V. n., Rao, A. n., Schultz, A. n., Li, X. n., Sumazin, P. n., Williams, C. n., Mestdagh, P. n., Gunaratne, P. H., Yau, C. n., Bowlby, R. n., Robertson, A. G., Tiezzi, D. G., Wang, C. n., Cherniack, A. D., Godwin, A. K., Kuderer, N. M., Rader, J. S., Zuna, R. E., Sood, A. K., Lazar, A. J., Ojesina, A. I., Adebamowo, C. n., Adebamowo, S. N., Baggerly, K. A., Chen, T. W., Chiu, H. S., Lefever, S. n., Liu, L. n., MacKenzie, K. n., Orsulic, S. n., Roszik, J. n., Shelley, C. S., Song, Q. n., Vellano, C. P., Wentzensen, N. n., Weinstein, J. N., Mills, G. B., Levine, D. A., Akbani, R. n. 2018; 33 (4): 690–705.e9


    We analyzed molecular data on 2,579 tumors from The Cancer Genome Atlas (TCGA) of four gynecological types plus breast. Our aims were to identify shared and unique molecular features, clinically significant subtypes, and potential therapeutic targets. We found 61 somatic copy-number alterations (SCNAs) and 46 significantly mutated genes (SMGs). Eleven SCNAs and 11 SMGs had not been identified in previous TCGA studies of the individual tumor types. We found functionally significant estrogen receptor-regulated long non-coding RNAs (lncRNAs) and gene/lncRNA interaction networks. Pathway analysis identified subtypes with high leukocyte infiltration, raising potential implications for immunotherapy. Using 16 key molecular features, we identified five prognostic subtypes and developed a decision tree that classified patients into the subtypes based on just six features that are assessable in clinical laboratories.

    View details for DOI 10.1016/j.ccell.2018.03.014

    View details for PubMedID 29622464

    View details for PubMedCentralID PMC5959730

  • A Pan-Cancer Analysis Reveals High-Frequency Genetic Alterations in Mediators of Signaling by the TGF-β Superfamily. Cell systems Korkut, A. n., Zaidi, S. n., Kanchi, R. S., Rao, S. n., Gough, N. R., Schultz, A. n., Li, X. n., Lorenzi, P. L., Berger, A. C., Robertson, G. n., Kwong, L. N., Datto, M. n., Roszik, J. n., Ling, S. n., Ravikumar, V. n., Manyam, G. n., Rao, A. n., Shelley, S. n., Liu, Y. n., Ju, Z. n., Hansel, D. n., de Velasco, G. n., Pennathur, A. n., Andersen, J. B., O'Rourke, C. J., Ohshiro, K. n., Jogunoori, W. n., Nguyen, B. N., Li, S. n., Osmanbeyoglu, H. U., Ajani, J. A., Mani, S. A., Houseman, A. n., Wiznerowicz, M. n., Chen, J. n., Gu, S. n., Ma, W. n., Zhang, J. n., Tong, P. n., Cherniack, A. D., Deng, C. n., Resar, L. n., Weinstein, J. N., Mishra, L. n., Akbani, R. n. 2018; 7 (4): 422–37.e7


    We present an integromic analysis of gene alterations that modulate transforming growth factor β (TGF-β)-Smad-mediated signaling in 9,125 tumor samples across 33 cancer types in The Cancer Genome Atlas (TCGA). Focusing on genes that encode mediators and regulators of TGF-β signaling, we found at least one genomic alteration (mutation, homozygous deletion, or amplification) in 39% of samples, with highest frequencies in gastrointestinal cancers. We identified mutation hotspots in genes that encode TGF-β ligands (BMP5), receptors (TGFBR2, AVCR2A, and BMPR2), and Smads (SMAD2 and SMAD4). Alterations in the TGF-β superfamily correlated positively with expression of metastasis-associated genes and with decreased survival. Correlation analyses showed the contributions of mutation, amplification, deletion, DNA methylation, and miRNA expression to transcriptional activity of TGF-β signaling in each cancer type. This study provides a broad molecular perspective relevant for future functional and therapeutic studies of the diverse cancer pathways mediated by the TGF-β superfamily.

    View details for DOI 10.1016/j.cels.2018.08.010

    View details for PubMedID 30268436

    View details for PubMedCentralID PMC6370347

  • Molecular Characterization and Clinical Relevance of Metabolic Expression Subtypes in Human Cancers. Cell reports Peng, X. n., Chen, Z. n., Farshidfar, F. n., Xu, X. n., Lorenzi, P. L., Wang, Y. n., Cheng, F. n., Tan, L. n., Mojumdar, K. n., Du, D. n., Ge, Z. n., Li, J. n., Thomas, G. V., Birsoy, K. n., Liu, L. n., Zhang, H. n., Zhao, Z. n., Marchand, C. n., Weinstein, J. N., Bathe, O. F., Liang, H. n. 2018; 23 (1): 255–69.e4


    Metabolic reprogramming provides critical information for clinical oncology. Using molecular data of 9,125 patient samples from The Cancer Genome Atlas, we identified tumor subtypes in 33 cancer types based on mRNA expression patterns of seven major metabolic processes and assessed their clinical relevance. Our metabolic expression subtypes correlated extensively with clinical outcome: subtypes with upregulated carbohydrate, nucleotide, and vitamin/cofactor metabolism most consistently correlated with worse prognosis, whereas subtypes with upregulated lipid metabolism showed the opposite. Metabolic subtypes correlated with diverse somatic drivers but exhibited effects convergent on cancer hallmark pathways and were modulated by highly recurrent master regulators across cancer types. As a proof-of-concept example, we demonstrated that knockdown of SNAI1 or RUNX1-master regulators of carbohydrate metabolic subtypes-modulates metabolic activity and drug sensitivity. Our study provides a system-level view of metabolic heterogeneity within and across cancer types and identifies pathway cross-talk, suggesting related prognostic, therapeutic, and predictive utility.

    View details for PubMedID 29617665

  • YAP-associated chromosomal instability and cholangiocarcinoma in mice. Oncotarget Rizvi, S. n., Fischbach, S. R., Bronk, S. F., Hirsova, P. n., Krishnan, A. n., Dhanasekaran, R. n., Smadbeck, J. B., Smoot, R. L., Vasmatzis, G. n., Gores, G. J. 2018; 9 (5): 5892–5905


    Deregulated Hippo pathway signaling is associated with aberrant activation of the downstream effector yes-associated protein (YAP), an emerging key oncogenic mediator in cholangiocarcinoma (CCA). In our prior work, we have demonstrated that biliary transduction of YAP along with Akt as a permissive factor induces CCA in mice. To further delineate the mechanisms associated with YAP-associated biliary oncogenesis, we have established seven malignant murine cell lines from our YAP-driven murine CCA model. These cells express the CCA markers SRY (Sex Determining Region Y)-Box 9 (SOX9), cytokeratin (CK)-7 and 19 but lack hepatocyte nuclear factor 4 alpha and alpha-smooth muscle actin, markers of hepatocellular carcinoma and cancer-associated fibroblasts, respectively. Notably, the murine CCA cells can be readily implanted into mouse livers with resultant orthotopic tumor formation. In this unique syngeneic orthotopic murine model, tumors exhibit histopathologic features resembling human CCA. We analyzed transcriptome data from YAP-associated parent CCA tumor nodules and identified a gene expression pattern associated with chromosomal instability, known as CIN25. Similarly, mate-pair sequencing of the murine CCA cells revealed chromosomal missegregation with gains and losses of several whole chromosomes demonstrating aneuploidy. Of the CIN25 genes, forkhead box M1 (Foxm1), a key cell cycle regulator, was the most significantly upregulated CIN25 gene product. Accordingly, small interfering RNA (siRNA)-mediated silencing of YAP as well as FOXM1 inhibition with thiostrepton induced CCA cell death. These preclinical data imply a role for YAP-mediated chromosomal instability in cholangiocarcinoma, and suggest FOXM1 inhibition as a therapeutic target for CCA.

    View details for PubMedID 29464042

  • The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma. Cell reports Ricketts, C. J., De Cubas, A. A., Fan, H. n., Smith, C. C., Lang, M. n., Reznik, E. n., Bowlby, R. n., Gibb, E. A., Akbani, R. n., Beroukhim, R. n., Bottaro, D. P., Choueiri, T. K., Gibbs, R. A., Godwin, A. K., Haake, S. n., Hakimi, A. A., Henske, E. P., Hsieh, J. J., Ho, T. H., Kanchi, R. S., Krishnan, B. n., Kwiatkowski, D. J., Lui, W. n., Merino, M. J., Mills, G. B., Myers, J. n., Nickerson, M. L., Reuter, V. E., Schmidt, L. S., Shelley, C. S., Shen, H. n., Shuch, B. n., Signoretti, S. n., Srinivasan, R. n., Tamboli, P. n., Thomas, G. n., Vincent, B. G., Vocke, C. D., Wheeler, D. A., Yang, L. n., Kim, W. Y., Robertson, A. G., Spellman, P. T., Rathmell, W. K., Linehan, W. M. 2018; 23 (1): 313–26.e5


    Renal cell carcinoma (RCC) is not a single disease, but several histologically defined cancers with different genetic drivers, clinical courses, and therapeutic responses. The current study evaluated 843 RCC from the three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC, and 81 chromophobe RCC. Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers. Somatic alteration of BAP1, PBRM1, and PTEN and altered metabolic pathways correlated with subtype-specific decreased survival, while CDKN2A alteration, increased DNA hypermethylation, and increases in the immune-related Th2 gene expression signature correlated with decreased survival within all major histologic subtypes. CIMP-RCC demonstrated an increased immune signature, and a uniform and distinct metabolic expression pattern identified a subset of metabolically divergent (MD) ChRCC that associated with extremely poor survival.

    View details for PubMedID 29617669

    View details for PubMedCentralID PMC6075733

  • Anti-miR-17 therapy delays tumorigenesis in MYC-driven hepatocellular carcinoma (HCC). Oncotarget Dhanasekaran, R. n., Gabay-Ryan, M. n., Baylot, V. n., Lai, I. n., Mosley, A. n., Huang, X. n., Zabludoff, S. n., Li, J. n., Kaimal, V. n., Karmali, P. n., Felsher, D. W. 2018; 9 (5): 5517–28


    Hepatocellular carcinoma (HCC) remains a significant clinical challenge with few therapeutic options. Genomic amplification and/or overexpression of the MYC oncogene is a common molecular event in HCC, thus making it an attractive target for drug therapy. Unfortunately, currently there are no direct drug therapies against MYC. As an alternative strategy, microRNAs regulated by MYC may be downstream targets for therapeutic blockade. MiR-17 family is a microRNA family transcriptionally regulated by MYC and it is commonly overexpressed in human HCCs. In this study, we performed systemic delivery of a novel lipid nanoparticle (LNP) encapsulating an anti-miR-17 oligonucleotide in a conditional transgenic mouse model of MYC driven HCC. Treatment with anti-miR-17in vivo, but not with a control anti-miRNA, resulted in significant de-repression of direct targets of miR-17, robust apoptosis, decreased proliferation and led to delayed tumorigenesis in MYC-driven HCCs. Global gene expression profiling revealed engagement of miR-17 target genes and inhibition of key transcriptional programs of MYC, including cell cycle progression and proliferation. Hence, anti-miR-17 is an effective therapy for MYC-driven HCC.

    View details for PubMedID 29464015

  • MYC functions as a master switch for natural killer cell-mediated immune surveillance of lymphoid malignancies Swaminathan, S., Mosley, A., Horton, C., Liefwalker, D. F., Deutzmann, A., Dhanasekaran, R., Gouw, A., Gentles, A., Eilers, M., Maecker, H. T., Felsher, D. W. AMER ASSOC CANCER RESEARCH. 2017
  • Management of Immunosuppression in Liver Transplantation CLINICS IN LIVER DISEASE Dhanasekaran, R. 2017; 21 (2): 337-?


    Liver transplantation outcomes have significantly improved over the past few decades owing largely to the introduction of effective immunosuppression medications. Further comprehension of the unique immune microenvironment of the liver has led to the development of newer molecular targeted therapeutics. Understanding the mechanism of action and adverse effect profiles of these medications is crucial for appropriate management of posttransplant patients. In this review, the author describes the immunologic response elicited by liver transplantation, chronicles the various immunosuppressant drug classes, discusses the evidence behind their use, and evaluates the management of special subpopulations of posttransplantation patients.

    View details for DOI 10.1016/j.cld.2016.12.007

    View details for PubMedID 28364817

  • Bridging Locoregional Therapy Prolongs Survival in Patients Listed for Liver Transplant with Hepatocellular Carcinoma. Cardiovascular and interventional radiology Xing, M., Sakaria, S., Dhanasekaran, R., Parekh, S., Spivey, J., Knechtle, S. J., Zhang, D., Kim, H. S. 2017; 40 (3): 410-420


    To evaluate the long-term survival benefit of bridging locoregional therapy (LRT) prior to orthotopic liver transplantation (OLT) in patients with hepatocellular carcinoma (HCC) within Milan criteria.Our transplant center registry was studied for all HCC patients within the Milan criteria who were listed for OLT from 1998 to 2013. Baseline clinical characteristics and median overall survival (OS) were calculated and stratified by LRT, OLT status, and wait times. Survival analysis was conducted using Kaplan-Meier estimation and log-rank test.Of 265 listed, 205 underwent OLT (mean follow-up 7.6 years). Of 205, 111 received bridging LRT (A), and 94 did not (B). Both were similar in demographics and tumor characteristics (p > 0.05). Median OS from HCC for A/B were 86.4 vs. 68.9 months (p = 0.01). Median OS from OLT for A/B were 74.6 vs. 63.6 months (p = 0.03). On multivariate analysis, independent predictors for survival from HCC were bridging LRT (p = 0.002) and high wait time (p = 0.008); independent predictors for survival from OLT were bridging LRT (p = 0.005) and high wait time (p = 0.005). Of 60 who were listed but did not undergo transplant, 44 received LRT (C) and 16 received best supportive care (D). Median OS from HCC for C/D were 37.1 vs. 24.8 months (p = 0.03).Bridging LRT and high wait times were independent positive prognostic factors for survival from HCC diagnosis and OLT.

    View details for DOI 10.1007/s00270-016-1505-0

    View details for PubMedID 27900445

  • Transcriptional Induction of Periostin by a Sulfatase 2-TGF beta 1-SMAD Signaling Axis Mediates Tumor Angiogenesis in Hepatocellular Carcinoma CANCER RESEARCH Chen, G., Nakamura, I., Dhanasekaran, R., Iguchi, E., Tolosa, E. J., Romecin, P. A., Vera, R. E., Almada, L. L., Miamen, A. G., Chaiteerakij, R., Zhou, M., Asiedu, M. K., Moser, C. D., Han, S., Hu, C., Banini, B. A., Oseini, A. M., Chen, Y., Fang, Y., Yang, D., Shaleh, H. M., Wang, S., Wu, D., Song, T., Lee, J., Thorgeirsson, S. S., Chevet, E., Shah, V. H., Fernandez-Zapico, M. E., Roberts, L. R. 2017; 77 (3): 632-645


    Existing antiangiogenic approaches to treat metastatic hepatocellular carcinoma (HCC) are weakly effectual, prompting further study of tumor angiogenesis in this disease setting. Here, we report a novel role for sulfatase 2 (SULF2) in driving HCC angiogenesis. Sulf2-deficient mice (Sulf2 KO) exhibited resistance to diethylnitrosamine-induced HCC and did not develop metastases like wild-type mice (Sulf2 WT). The smaller and less numerous tumors formed in Sulf2 KO mice exhibited a markedly lower microvascular density. In human HCC cells, SULF2 overexpression increased endothelial proliferation, adhesion, chemotaxis, and tube formation in a paracrine fashion. Mechanistic analyses identified the extracellular matrix protein periostin (POSTN), a ligand of αvβ3/5 integrins, as an effector protein in SULF2-induced angiogenesis. POSTN silencing in HCC cells attenuated SULF2-induced angiogenesis and tumor growth in vivo The TGFβ1/SMAD pathway was identified as a critical signaling axis between SULF2 and upregulation of POSTN transcription. In clinical HCC specimens, elevated levels of SULF2 correlated with increased microvascular density, POSTN levels, and relatively poorer patient survival. Together, our findings define an important axis controlling angiogenesis in HCC and a mechanistic foundation for rational drug development. Cancer Res; 77(3); 632-45. ©2016 AACR.

    View details for DOI 10.1158/0008-5472.CAN-15-2556

    View details for PubMedID 27872089

  • Selective Internal Yttrium-90 Radioembolization Therapy (Y-90-SIRT) Versus Best Supportive Care in Patients With Unresectable Metastatic Melanoma to the Liver Refractory to Systemic Therapy Safety and Efficacy Cohort Study AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS Xing, M., Prajapat, H. J., Dhanasekaran, R., Lawson, D. H., Kokabi, N., Eaton, B. R., Kim, H. S. 2017; 40 (1): 27-34


    To investigate survival, efficacy, and safety of selective internal yttrium-90 radioembolization therapy (Y-SIRT) in patients with unresectable metastatic melanoma (MM) to liver refractory to systemic therapy.An IRB-approved retrospective review of 58 patients diagnosed with unresectable MM to the liver, refractory to systemic therapy, between February 2003 and March 2012 was conducted. Of these, 28 received resin-based Y-SIRT (group A), and 30 patients received best supportive care (group B). Survival was calculated using the Kaplan-Meier method and Cox proportional hazard models.Groups A and B were similar for the Child-Pugh class, ECOG scores, age, sex, and race. Median overall survival (OS) from diagnosis of primary melanoma in groups A and B were 119.9 and 26.1 months, respectively (P<0.001). Median OS from hepatic metastasis in groups A and B were 19.9 and 4.8 months, respectively (P<0.0001). In group A, median OS from hepatic metastasis in the Child-Pugh A, B, and C patients was 37.7, 4.2, and 3.6 months, respectively (P<0.001). In group B, median OS from hepatic metastasis in the Child-Pugh A, B, and C patients was 7.8, 4.2, and 1.9 months, respectively (P=0.04). Within group A, median OS from first Y-SIRT was 10.1 months; median OS of the Child-Pugh A, B, and C patients from first Y-SIRT was 10.3, 1.2, and 0.9 months, respectively (P=0.04). Median OS from first Y-SIRT was significantly greater in the absence of diffuse (>10) liver metastases (15.1 vs. 4.7 mo, P=0.02), and in the absence of extrahepatic metastases (21.3 vs. 8.6 mo, P<0.001). Common clinical toxicities following Y-SIRT included abdominal pain (17.9%), fatigue (14.3%), and self-limiting grade III bilirubin toxicity (10.7%).For patients with unresectable MM to the liver refractory to systemic therapy, resin-based Y was associated with longer survival from liver metastases than best supportive care. Child-Pugh A patients with <10 metastatic lesions and absence of extrahepatic metastases demonstrated greatest survival following Y-SIRT.

    View details for DOI 10.1097/COC.0000000000000109

    View details for Web of Science ID 000393348100005

  • Selective Internal Yttrium-90 Radioembolization Therapy (90Y-SIRT) Versus Best Supportive Care in Patients With Unresectable Metastatic Melanoma to the Liver Refractory to Systemic Therapy: Safety and Efficacy Cohort Study. American journal of clinical oncology Xing, M., Prajapati, H. J., Dhanasekaran, R., Lawson, D. H., Kokabi, N., Eaton, B. R., Kim, H. S. 2017; 40 (1): 27-34


    To investigate survival, efficacy, and safety of selective internal yttrium-90 radioembolization therapy (Y-SIRT) in patients with unresectable metastatic melanoma (MM) to liver refractory to systemic therapy.An IRB-approved retrospective review of 58 patients diagnosed with unresectable MM to the liver, refractory to systemic therapy, between February 2003 and March 2012 was conducted. Of these, 28 received resin-based Y-SIRT (group A), and 30 patients received best supportive care (group B). Survival was calculated using the Kaplan-Meier method and Cox proportional hazard models.Groups A and B were similar for the Child-Pugh class, ECOG scores, age, sex, and race. Median overall survival (OS) from diagnosis of primary melanoma in groups A and B were 119.9 and 26.1 months, respectively (P<0.001). Median OS from hepatic metastasis in groups A and B were 19.9 and 4.8 months, respectively (P<0.0001). In group A, median OS from hepatic metastasis in the Child-Pugh A, B, and C patients was 37.7, 4.2, and 3.6 months, respectively (P<0.001). In group B, median OS from hepatic metastasis in the Child-Pugh A, B, and C patients was 7.8, 4.2, and 1.9 months, respectively (P=0.04). Within group A, median OS from first Y-SIRT was 10.1 months; median OS of the Child-Pugh A, B, and C patients from first Y-SIRT was 10.3, 1.2, and 0.9 months, respectively (P=0.04). Median OS from first Y-SIRT was significantly greater in the absence of diffuse (>10) liver metastases (15.1 vs. 4.7 mo, P=0.02), and in the absence of extrahepatic metastases (21.3 vs. 8.6 mo, P<0.001). Common clinical toxicities following Y-SIRT included abdominal pain (17.9%), fatigue (14.3%), and self-limiting grade III bilirubin toxicity (10.7%).For patients with unresectable MM to the liver refractory to systemic therapy, resin-based Y was associated with longer survival from liver metastases than best supportive care. Child-Pugh A patients with <10 metastatic lesions and absence of extrahepatic metastases demonstrated greatest survival following Y-SIRT.

    View details for DOI 10.1097/COC.0000000000000109

    View details for PubMedID 25089529

  • Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma. Cell 2017; 169 (7): 1327–41.e23


    Liver cancer has the second highest worldwide cancer mortality rate and has limited therapeutic options. We analyzed 363 hepatocellular carcinoma (HCC) cases by whole-exome sequencing and DNA copy number analyses, and we analyzed 196 HCC cases by DNA methylation, RNA, miRNA, and proteomic expression also. DNA sequencing and mutation analysis identified significantly mutated genes, including LZTR1, EEF1A1, SF3B1, and SMARCA4. Significant alterations by mutation or downregulation by hypermethylation in genes likely to result in HCC metabolic reprogramming (ALB, APOB, and CPS1) were observed. Integrative molecular HCC subtyping incorporating unsupervised clustering of five data platforms identified three subtypes, one of which was associated with poorer prognosis in three HCC cohorts. Integrated analyses enabled development of a p53 target gene expression signature correlating with poor survival. Potential therapeutic targets for which inhibitors exist include WNT signaling, MDM4, MET, VEGFA, MCL1, IDH1, TERT, and immune checkpoint proteins CTLA-4, PD-1, and PD-L1.

    View details for DOI 10.1016/j.cell.2017.05.046

    View details for PubMedID 28622513

    View details for PubMedCentralID PMC5680778

  • The Liver in Oncology. Clinics in liver disease Dhanasekaran, R. n., Kwo, P. Y. 2017; 21 (4): 697–707


    Gastroenterologists and hepatologists will encounter oncology patients who develop abnormal liver tests, patients with hepatic malignancies, and patients with acute and chronic liver disease who require chemotherapy or immediate evaluation. Chemotherapy can cause liver injury owing to toxic effects or idiosyncratic reactions. Immune checkpoint inhibitors may be associated with autoimmune-mediated liver toxicities. Venoocclusive disease requires immediate evaluation. Nodular regenerative hyperplasia is a chronic progressive disorder. Screening and prophylaxis for reactivation of hepatitis B is important to minimize complications in patients receiving chemotherapy. Patients with metastatic lesions can undergo resection or ablation. Hepatic injury may occur in those receiving radiation-based therapies.

    View details for PubMedID 28987257

  • Differences in Hepatocellular Carcinoma Incidence and Survival Rates among Asian Mono-Ethnicities Cholankeril, G., Perumpail, R. B., Hu, M., Pham, E. A., Kumari, R., Gish, R., So, S. K., Dhanasekaran, R., Ahmed, A. WILEY. 2016: 860A
  • Rising Inpatient Healthcare Resource Utilization in Baby Boomers with Hepatocellular Carcinoma Cholankeril, G., Al Juboori, A., Perumpail, R. B., Yoo, E. R., Hu, M., Dhanasekaran, R., Kanwal, F., Ahmed, A. WILEY. 2016: 679A
  • Identification of Novel Fusions in Gallbladder Cancer by Next Generation Sequencing RNA Analysis - Potential for Targeted Therapy Allotey, L. K., Nair, A., Chaiteerakij, R., Oliver, G., O'Brien, D., Sarangi, V., Moser, C. D., Giama, N. H., Dhanasekaran, R., Bonilla, L., Klee, E., Borad, M., Roberts, L. W B SAUNDERS CO-ELSEVIER INC. 2016: S295-S296
  • Clinical implications of basic research in hepatocellular carcinoma JOURNAL OF HEPATOLOGY Dhanasekaran, R., Venkatesh, S. K., Torbenson, M. S., Roberts, L. R. 2016; 64 (3): 736-745


    A 58-year old Caucasian female has compensated hepatitis C related cirrhosis. Her surveillance ultrasound showed hypodense liver nodules and subsequent triple phase CT scan showed five tumor nodules with diameters ranging from 3-5cms involving both hepatic lobes. The nodules showed characteristic radiologic findings on the CT scan and she was diagnosed with hepatocellular carcinoma (HCC) based on non-invasive criteria. There was also associated right portal vein tumor thrombosis. Her functional capacity at diagnosis was slightly limited, but she was capable of performing all activities of daily living and self-care. Her laboratory tests at diagnosis were as follows: sodium 129mmol/L, potassium 3.6mmol/L, blood urea nitrogen 22mg/dL, creatinine 1.0mg/dL, albumin 2.9g/dl, bilirubin 1.8mg/dl, alanine aminotransferase 87U/L, aspartate aminotransferase 68U/L, alkaline phosphatase 139U/L, white blood cell 3.5x10(9)/L, hemoglobin 10.4, platelet count 73x10(9)/L, international normalized ratio 1.9 and alpha-fetoprotein 5200ng/ml. An upper endoscopy was negative for esophageal or gastric varices. Based on the tumor burden, presence of macrovascular invasion, ECOG performance status of 1 and Child-Pugh class A she was classified to have BCLC stage C HCC. She was started on sorafenib therapy at 400mg oral twice daily but unfortunately this had to be discontinued since she experienced severe diarrhea and skin rash. She now returns for follow-up and requests information on the available therapeutic options. This particular case scenario is not uncommon and does raise several clinically relevant questions: This review provides a comprehensive overview of the current state of HCC management and also examines the clinical implications of recent basic research in HCC.

    View details for Web of Science ID 000370292300025

    View details for PubMedID 26450813

  • Molecular pathogenesis of hepatocellular carcinoma and impact of therapeutic advances. F1000Research Dhanasekaran, R., Bandoh, S., Roberts, L. R. 2016; 5


    Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality and has an increasing incidence worldwide. HCC can be induced by multiple etiologies, is influenced by many risk factors, and has a complex pathogenesis. Furthermore, HCCs exhibit substantial heterogeneity, which compounds the difficulties in developing effective therapies against this highly lethal cancer. With advances in cancer biology and molecular and genetic profiling, a number of different mechanisms involved in the development and progression of HCC have been identified. Despite the advances in this area, the molecular pathogenesis of hepatocellular carcinoma is still not completely understood. This review aims to elaborate our current understanding of the most relevant genetic alterations and molecular pathways involved in the development and progression of HCC, and anticipate the potential impact of future advances on therapeutic drug development.

    View details for DOI 10.12688/f1000research.6946.1

    View details for PubMedID 27239288

  • Response to Fibrosis progression in patients treated for hepatitis C recurrence LIVER INTERNATIONAL Dhanasekaran, R., Sanchez, W., Charlton, M. 2015; 35 (12): 2625-2625

    View details for DOI 10.1111/liv.12969

    View details for Web of Science ID 000367723200023

    View details for PubMedID 26386267

  • Impact of fibrosis progression on clinical outcome in patients treated for post- transplant hepatitis C recurrence LIVER INTERNATIONAL Dhanasekaran, R., Sanchez, W., Mounajjed, T., Wiesner, R. H., Watt, K. D., Charlton, M. R. 2015; 35 (11): 2433-2441


    Patients who achieve sustained virological response (SVR) following the treatment of post-liver transplant (LT) recurrence of hepatitis C virus (HCV) infection have improved outcomes. The full impact of eradication of HCV on allograft histology is, however, not clearly known.We studied allograft histology in protocol-based paired liver biopsies in consecutive LT recipients who underwent post-LT treatment of recurrence of HCV.A total of 116 patients were treated with interferon-based therapy for recurrent HCV. Paired pre-treatment baseline biopsies and post-treatment biopsies were available in 83.2% of patients. SVR was achieved in 37.9% of patients. Among the patients who achieved SVR, 20.5% had progression of fibrosis on post-treatment biopsies vs. 65.5% of patients with non-response/relapse (P < 0.001). The impact of virological response on fibrosis progression was sustained and a similar outcome was observed in the subset of patients who had 4-5 year post-treatment biopsies available. In the SVR group, 12.8% progressed to fibrosis stage ≥3 on post-treatment biopsies vs. 37.9% in the non-response/relapse group (P = 0.001). The 5-year survival in patients with progression of fibrosis 86% vs. 98% among patients who had improvement/stable fibrosis [P = 0.003; HR 3.8 (1.2-11.8)]. A small subset of patients who achieve SVR unfortunately still experience progression of fibrosis, most commonly associated with plasma cell hepatitis.In post-transplant patients treated for HCV, SVR is associated with improved graft survival and also with sustained and significant improvement in histological outcome. Importantly, progression of fibrosis still occurred in a small subset of patients who achieved SVR.

    View details for DOI 10.1111/liv.12890

    View details for Web of Science ID 000363411900012

    View details for PubMedID 26058570

  • Quality of Cancer Care in Patients with Cirrhosis and Hepatocellular Carcinoma. Current gastroenterology reports Dhanasekaran, R., Talwalkar, J. A. 2015; 17 (9): 34-?


    Hepatocellular carcinoma is the most common primary liver cancer in patients with cirrhosis and is the leading cause of mortality in these patients. Despite existence of robust clinical practice guidelines for surveillance, diagnosis, and management for hepatocellular carcinoma (HCC), the quality of care received by patients with HCC has been inconsistent. Several studies have reported disappointingly low surveillance rates in high-risk groups which likely contribute to most HCC cases being diagnosed at advanced stages. There is also data from large studies showing that significant under-referral to specialists and delay in initiation of treatment are linked to poor clinical outcomes. Given above circumstances, it is very important to perform studies which can identify areas in need of improvement in the care processes of HCC and design interventions to enhance quality of care. Unfortunately, data on validated quality indicators and quality metrics for HCC are non-existent. In this article, we review the existing literature pertaining to this issue and identify areas that need further research.

    View details for DOI 10.1007/s11894-015-0459-8

    View details for PubMedID 26238927

  • Activation of the Transforming Growth Factor-beta/SMAD Transcriptional Pathway Underlies a Novel Tumor-Promoting Role of Sulfatase 1 in Hepatocellular Carcinoma HEPATOLOGY Dhanasekaran, R., Nakamura, I., Hu, C., Chen, G., Oseini, A. M., Seven, E. S., Miamen, A. G., Moser, C. D., Zhou, W., van Kuppevelt, T. H., van Deursen, J. M., Mounajjed, T., Fernandez-Zapico, M. E., Roberts, L. R. 2015; 61 (4): 1269-1283


    In vitro studies have proposed a tumor suppressor role for sulfatase 1 (SULF1) in hepatocellular carcinoma (HCC); however, high expression in human HCC has been associated with poor prognosis. The reason underlying this paradoxical observation remains to be explored. Using a transgenic (Tg) mouse model overexpressing Sulf1 (Sulf1-Tg), we assessed the effects of SULF1 on the diethylnitrosamine model of liver carcinogenesis. Sulf1-Tg mice show a higher incidence of large and multifocal tumors with diethylnitrosamine injection compared to wild-type mice. Lung metastases were found in 75% of Sulf1-Tg mice but not in wild-type mice. Immunohistochemistry, immunoblotting, and reporter assays all show a significant activation of the transforming growth factor-β (TGF-β)/SMAD transcriptional pathway by SULF1 both in vitro and in vivo. This effect of SULF1 on the TGF-β/SMAD pathway is functional; overexpression of SULF1 promotes TGF-β-induced gene expression and epithelial-mesenchymal transition and enhances cell migration/invasiveness. Mechanistic analyses demonstrate that inactivating mutation of the catalytic site of SULF1 impairs the above actions of SULF1 and diminishes the release of TGF-β from the cell surface. We also show that SULF1 expression decreases the interaction between TGF-β1 and its heparan sulfate proteoglycan sequestration receptor, TGFβR3. Finally, using gene expression from human HCCs, we show that patients with high SULF1 expression have poorer recurrence-free survival (hazard ratio 4.1, 95% confidence interval 1.9-8.3; P = 0.002) compared to patients with low SULF1. We also found strong correlations of SULF1 expression with TGF-β expression and with several TGF-β-related epithelial-mesenchymal transition genes in human HCC.Our study proposes a novel role of SULF1 in HCC tumor progression through augmentation of the TGF-β pathway, thus defining SULF1 as a potential biomarker for tumor progression and a novel target for drug development for HCC.

    View details for DOI 10.1002/hep.27658

    View details for Web of Science ID 000352099700023

    View details for PubMedID 25503294

    View details for PubMedCentralID PMC4376661

  • Vasodilator-Stimulated Phosphoprotein Promotes Activation of Hepatic Stellate Cells by Regulating Rab11-Dependent Plasma Membrane Targeting of Transforming Growth Factor Beta Receptors HEPATOLOGY Tu, K., Li, J., Verma, V. K., Liu, C., Billadeau, D. D., Lamprecht, G., Xiang, X., Guo, L., Dhanasekaran, R., Roberts, L. R., Shah, V. H., Kang, N. 2015; 61 (1): 361-374


    Liver microenvironment is a critical determinant for development and progression of liver metastasis. Under transforming growth factor beta (TGF-β) stimulation, hepatic stellate cells (HSCs), which are liver-specific pericytes, transdifferentiate into tumor-associated myofibroblasts that promote tumor implantation (TI) and growth in the liver. However, the regulation of this HSC activation process remains poorly understood. In this study, we tested whether vasodilator-stimulated phosphoprotein (VASP) of HSCs regulated the TGF-β-mediated HSC activation process and tumor growth. In both an experimental liver metastasis mouse model and cancer patients, colorectal cancer cells reaching liver sinusoids induced up-regulation of VASP and alpha-smooth muscle actin (α-SMA) in adjacent HSCs. VASP knockdown in HSCs inhibited TGF-β-mediated myofibroblastic activation of HSCs, TI, and growth in mice. Mechanistically, VASP formed protein complexes with TGF-β receptor II (TβRII) and Rab11, a Ras-like small GTPase and key regulator of recycling endosomes. VASP knockdown impaired Rab11 activity and Rab11-dependent targeting of TβRII to the plasma membrane, thereby desensitizing HSCs to TGF-β1 stimulation.Our study demonstrates a requirement of VASP for TGF-β-mediated HSC activation in the tumor microenvironment by regulating Rab11-dependent recycling of TβRII to the plasma membrane. VASP and its effector, Rab11, in the tumor microenvironment thus present therapeutic targets for reducing TI and metastatic growth in the liver.

    View details for DOI 10.1002/hep.27251

    View details for Web of Science ID 000347005100042

    View details for PubMedID 24917558

    View details for PubMedCentralID PMC4262723

  • Challenges of recurrent hepatitis C in the liver transplant patient WORLD JOURNAL OF GASTROENTEROLOGY Dhanasekaran, R., Firpi, R. J. 2014; 20 (13): 3391-3400


    Cirrhosis secondary to hepatitis C virus (HCV) is a very common indication for liver transplant. Unfortunately recurrence of HCV is almost universal in patients who are viremic at the time of transplant. The progression of fibrosis has been shown to be more rapid in the post-transplant patients than in the transplant naïve, hence treatment of recurrent HCV needs to be considered for all patients with documented recurrent HCV. Management of recurrent HCV is a challenging situation both for patients and physicians due to multiple reasons as discussed in this review. The standard HCV treatment with pegylated interferon and Ribavarin can be considered in these patients but it leads to a lower rate of sustained virologic clearance than in the non-transplanted population. Some of the main challenges associated with treating recurrent HCV in post-transplant patients include the presence of cytopenias; need to monitor drug-drug interactions and the increased incidence of renal compromise. In spite of these obstacles all patients with recurrent HCV should be considered for treatment since it is associated with improvement in survival and a delay in fibrosis progression. With the arrival of direct acting antiviral drugs there is renewed hope for better outcomes in the treatment of post-transplant HCV recurrence. This review evaluates current literature on this topic and identifies challenges associated with the management of post-transplant HCV recurrence.

    View details for DOI 10.3748/wjg.v20.i13.3391

    View details for Web of Science ID 000334423300001

    View details for PubMedID 24707122

    View details for PubMedCentralID PMC3974506

  • A potential role for type XVIII collagen as a suppressor of hepatocellular carcinoma 65th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases Duncan, M., Dhanasekaran, R., Thakur, P., Roberts, L. R. WILEY-BLACKWELL. 2014: 642A–642A
  • Comparing Internet Search Patterns for Gastroenterological Diagnoses to Physician Visit Data Dhanasekaran, R., Oxentenko, A. NATURE PUBLISHING GROUP. 2013: S477
  • Analysis of Paired Biopsies to Assess Progression of Fibrosis in Patients Treated for Post-Transplant Hepatitis C Recurrence Digestive Disease Week / 28th Annual Residents and Fellows Research Conference of the Society-for-Surgery-of-the-Alimentary-Tract (SSAT) Dhanasekaran, R., Charlton, M. R., Sanchez, W. W B SAUNDERS CO-ELSEVIER INC. 2013: S1028–S1028
  • Hepatic Preservation Injury: Severity of Hepatitis C Recurrence and Survival After Liver Transplantation DIGESTIVE DISEASES AND SCIENCES Michaels, A. J., Dhanasekaran, R., Foley, D. P., Alkhasawneh, A., Dixon, L., Soldevila-Pico, C., Morelli, G., Cabrera, R., Clark, V. C., Firpi, R. J. 2013; 58 (5): 1403-1409


    Preservation injury in the HCV liver transplant population has been reported to correlate with poorer survival outcomes compared to preservation injury in the non-HCV liver transplant population. However, determinants of progression to cirrhosis in HCV infection remain poorly defined in this population.This study aimed to determine if the presence and severity of preservation injury impact the acceleration of HCV recurrence and survival after liver transplant.We retrospectively reviewed liver transplant HCV patients over a 10-year period. Biopsies from postoperative day 7 were assessed for preservation injury and 4- and 12-month biopsies were assessed for fibrosis. Patients with Ishak fibrosis >0.8 Units/year were considered rapid fibrosers.Our study group consisted of 255 patients. The mean age was 49.3 years old, 180 (70.6 %) were male, and 221 (86.7 %) were Caucasian. The incidence of preservation injury on the 7-day biopsy was 69.0 %. A strong correlation between postoperative peak AST within the first week and preservation injury was found. The overall prevalence of rapid fibrosers at 4 months, 1 and 2 years was 47.4, 75.2, and 58.9 %, respectively. The prevalence of rapid fibrosers at 4 months, 1 and 2 years between patients with or without preservation injury was not statistically significant (p = 0.39, p = 0.46, and p = 0.53, respectively). No differences were seen between patients with and without PI in terms of patient and graft survival.In this study, the presence and severity of preservation injury were not associated with development of rapid HCV recurrence or worsening in survival.

    View details for DOI 10.1007/s10620-012-2521-9

    View details for Web of Science ID 000319350300037

    View details for PubMedID 23306846

    View details for PubMedCentralID PMC3665404

  • Treatment outcomes and prognostic factors of intrahepatic cholangiocarcinoma ONCOLOGY REPORTS Dhanasekaran, R., Hemming, A. W., Zendejas, I., George, T., Nelson, D. R., Soldevila-Pico, C., Firpi, R. J., Morelli, G., Clark, V., Cabrera, R. 2013; 29 (4): 1259-1267


    The aim of the present study was to determine the treatment outcome and prognostic factors for survival in patients with peripheral intrahepatic cholangiocarcinoma (ICC). A retrospective chart review was performed for patients diagnosed with ICC between 2000 and 2009 at a single institution. We identified a total of 105 patients with ICC. Among them, 63.8% were older than 60 years of age, 50.5% were male and 88.6% were Caucasian. By preoperative imaging approximately half of the patients (50.5%) were surgical candidates and underwent resection. The other half of the patients (49.5%) were unresectable. The unresectable group received chemoradiotherapy (53%) and transarterial chemoembolization (7.7%) as palliative treatments while 23.0% of the patients (12/52) received best supportive care alone. The median survival rates were 16.1 months (13.1‑19.2) for the entire cohort, 27.6 months (17.7-37.6) for curative resection, 12.9 months (6.5-19.2) for palliative chemoradiotherapy and 4.9 months (0.4-9.6) for best supportive care (p<0.001). Independent predictors on multivariate analysis were advanced stage at diagnosis and treatment received. In those patients who underwent resection, advanced AJCC stage and presence of microvascular invasion were also independent predictors of poor survival. We concluded that surgery offers the most beneficial curative option and outcome, emphasizing the importance of resectability as a major prognostic factor. The present study also revealed that use of chemoradiotherapy in the adjuvant setting failed to improve survival but its palliative use in those patients with unresectable ICC offered a modest survival advantage over best supportive care. The overriding factors influencing outcome were stage and the presence of microvascular invasion on pathology.

    View details for DOI 10.3892/or.2013.2290

    View details for Web of Science ID 000316510600001

    View details for PubMedID 23426976

    View details for PubMedCentralID PMC3621732

  • Safety and Efficacy of Doxorubicin Drug-eluting Bead Transarterial Chemoembolization in Patients with Advanced Hepatocellular Carcinoma JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY Prajapati, H. J., Dhanasekaran, R., El-Rayes, B. F., Kauh, J. S., Maithel, S. K., Chen, Z., Kim, H. S. 2013; 24 (3): 307-315


    To investigate the safety and efficacy of transarterial chemoembolization using doxorubicin drug-eluting beads (DEBs) in patients with Barcelona Clinic Liver Cancer (BCLC) C stage hepatocellular carcinoma (HCC).Consecutive patients with initial staging of BCLC C HCC who received DEB transarterial chemoembolization over the last 5 years were studied. The study included 121 patients (mean age, 61.2 years old). Adverse events (AEs) after DEB transarterial chemoembolization were studied in detail and were recorded as per the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 criteria. Survivals were analyzed according to parameters from the time of first DEB transarterial chemoembolization. Kaplan-Meier method by log-rank test and Cox proportional hazard model were used for survival analysis.AEs occurred in 30.2% of patients. No AEs were greater than Common Terminology Criteria for Adverse Events grade III. Grade I and II AEs included nausea and vomiting in 7.8% of patients and abdominal pain in 23.8% of patients. Grade III AEs were noted in 1.06% of patients. There were no gastrointestinal or hepatic complications. There were no deaths within 30 days after DEB transarterial chemoembolization. The overall median survival was 13.5 months. Among the Child-Pugh class A patients, those without PVT and metastasis (28.9%) had better survival when treated with DEB transarterial chemoembolization than those with PVT and metastases (9.9%) (18.8 mo versus 4.4 mo, P = .001). Ascites, performance status, Okuda stage HCC, serum alpha fetoprotein levels, and etiologic factor for chronic liver disease predicted survival.DEB transarterial chemoembolization appears to be a safe and effective treatment option for patients with BCLC C HCC. Patients with Child-Pugh class A without PVT and metastasis benefited most from DEB transarterial chemoembolization.

    View details for DOI 10.1016/j.jvir.2012.11.026

    View details for Web of Science ID 000315543600002

    View details for PubMedID 23375519

  • Chinese skullcap in move free arthritis supplement causes drug induced liver injury and pulmonary infiltrates. Case reports in hepatology Dhanasekaran, R., Owens, V., Sanchez, W. 2013; 2013: 965092-?


    Herbal medications are being increasingly used by the American population especially for common conditions like arthritis. They have been reported to cause adverse effects, including significant hepatotoxicity, but reporting remains sporadic. We report here a patient who developed drug induced liver injury following the intake of Move Free, which is an over-the-counter arthritis supplement. We propose that Chinese skullcap, which is one of the herbal ingredients of the medication, is responsible for the adverse event. There was a strong temporal association between the intake of supplement and onset of symptoms, and also there have been a few recent case reports implicating the same component. A unique observation in our case is the occurrence of pulmonary infiltrates simultaneously with the hepatotoxicity, and this side effect has not been well documented before. Both the hepatic and pulmonary complications completely resolved over few weeks after the patient stopped taking the medication. Since these supplements are readily available over the counter, we feel that it is important to document possible adverse outcomes to raise awareness in the medical community and also among patients.

    View details for DOI 10.1155/2013/965092

    View details for PubMedID 25431706

    View details for PubMedCentralID PMC4238172

  • Liver Test Results Do Not Identify Liver Disease in Adults With alpha(1)-Antitrypsin Deficiency CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Clark, V. C., Dhanasekaran, R., Brantly, M., Rouhani, F., Schreck, P., Nelson, D. R. 2012; 10 (11): 1278-1283


    Liver disease is a significant cause of death among adults with α(1)-antitrypsin (A-AT) deficiency. Age and male sex are reported risk factors for liver disease. In the absence of adequate risk stratification, current recommendations are to intermittently test A-AT-deficient adults for liver function. We evaluated this recommendation in a large group of adults with A-AT deficiency to determine the prevalence of increased levels of alanine aminotransferase (ALT) and identify risk factors for liver disease.We used the Alpha-1 Foundation DNA and Tissue Bank to identify a cross section of A-AT-deficient adults (n = 647) with and without liver disease; individuals without A-AT deficiency were used as controls (n = 152). Results from ALT tests were compared between groups.The prevalence of liver disease among individuals with A-AT deficiency was 7.9%; an increased level of ALT was observed in 7.8% of A-AT-deficient individuals, which did not differ significantly from controls. Mean levels of ALT fell within normal range for all groups. An increased level of ALT identified patients with liver disease with 11.9% sensitivity. The level of only γ-glutamyl transpeptidase was significantly higher in the A-AT-deficient group than in controls (43 vs 30 IU/mL; P < .003). A childhood history of liver disease and male sex were risk factors for adult liver disease in the multivariate analysis.An increased level of ALT does not identify adults with A-AT deficiency who have liver disease. Male sex and liver disease during childhood might help identify those at risk.

    View details for DOI 10.1016/j.cgh.2012.07.007

    View details for Web of Science ID 000310780200021

    View details for PubMedID 22835581

    View details for PubMedCentralID PMC3482934

  • Incidentally discovered HCC (iHCC) in explant liver- Clinical and histopathologic features and outcome 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Disease (AASLD) Dhanasekaran, R., Pannu, D. S., Ismail, B., Zendejas, I., Firpi, R. L., Soldevila-Pico, C., Morelli, G., Clark, V. C., Suman, A., Nelson, D. R., Cabrera, R. WILEY-BLACKWELL. 2012: 476A–477A
  • The Impact of Pre transplant Transarterial Therapy in Hepatocellular Carcinoma 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Disease (AASLD) Pannu, D. S., Dhanasekaran, R., Bahaaeldeen, I., Zendejas, I., Firpi, R. J., Soldevila-Pico, C., Morelli, G., Clark, V. C., Nelson, D. R., Suman, A., Cabrera, R. WILEY-BLACKWELL. 2012: 458A–459A
  • Impact of Transarterial Therapy in Hepatitis C-Related Hepatocellular Carcinoma on Long-term Outcomes After Liver Transplantation AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS Cabrera, R., Dhanasekaran, R., Caridi, J., Clark, V., Morelli, G., Soldevila-Pico, C., Magglioca, J., Nelson, D., Firpi, R. J. 2012; 35 (4): 345-350


    To evaluate the impact of long-term outcomes of transarterial embolization (TAE) therapy in patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) on the waiting list for liver transplantation (LT).We retrospectively evaluated the post-LT patients with HCV-related HCC who received TAE intervention (n=33) and those who had no treatment (n=47) while on the waiting list to determine long-term outcomes.Over a 10-year period, of the 424 patients transplanted with HCV, 80 patients had HCC with a tumor burden within Milan criteria. For the entire study cohort, the mean duration of post-LT follow-up was 3.5 years; mean time of transplant waiting list was 120 days; and median post-LT survival was 8.9 years. The survival rates at 1, 3, 5, and 10 years were 82%, 70%, 55%, and 35%, respectively. From the study cohort, 33 patients received TAE and 47 patients did not while on the waiting list. The 2 groups were well matched, except, that the intervention patients received post-LT interferon more often and had a shorter time on the waiting list (56.2 d) when compared with the no treatment group (164.6 d, P<0.001). Median survival in the TAE group was 4.8 years and 8.9 years in the no treatment group. The recurrence rate was 15.6% in the treatment group and 6.9% in the no therapy group (P=0.275).Pre-LT transarterial therapy has no benefit on post-LT survival and tumor recurrence in patients with HCV-related HCC who underwent a mean waiting period of <3 months to transplant.

    View details for DOI 10.1097/COC.0b013e31821631f6

    View details for Web of Science ID 000306599200008

    View details for PubMedID 21552101

    View details for PubMedCentralID PMC3155640

  • Prognostic Value of F-18-Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography in Predicting Survival in Patients with Unresectable Metastatic Melanoma to the Liver Undergoing Yttrium-90 Radioembolization JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY Piduru, S. M., Schuster, D. M., Barron, B. J., Dhanasekaran, R., Lawson, D. H., Kim, H. S. 2012; 23 (7): 943-948


    To investigate the prognostic value of (18)F-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) in predicting survival in patients with unresectable metastatic melanoma to the liver undergoing yttrium-90 ((90)Y) radioembolization.A retrospective review of 12 patients with unresectable hepatic melanoma metastases (5 patients with cutaneous metastases, 7 patients with ocular metastases) who underwent (18)F-FDG PET-CT before (90)Y was performed. Metabolically significant tumors, defined as having a long-axis diameter ≥ 1 cm and maximum standardized uptake value (SUV(max)) ≥ 2.5, were identified on (18)F-FDG PET-CT. SUV(max), glycolytic activity, and volume were determined for each tumor. Overall SUV(max), total tumor glycolytic activity (TGA), total metabolic tumor volume (MTV), and metabolic tumor burden (MTB) based on percentage of liver involvement (MTV/total liver volume) were calculated. Kaplan-Meier method, life-table analysis, and Cox proportional hazards model were used for statistical analysis.Median SUV(max) was 10.9 (range, 4.6-15.3), median TGA was 377.0 SUV/cm(3) (range, 53.6-20,393.4 SUV/cm(3)), median MTV was 85.4 cm(3) (range, 11.5-2,504.1 cm(3)), and median MTB was 5.5% (range, 0.1%-54.0%). MTB was found to be a significant negative prognostic marker of survival on univariate (P = .020) and multivariate (P = .018) analyses accounting for age and duration from metastatic diagnosis to first (90)Y treatment. A 60th percentile MTB of 7.0% (hazard ratio, 5.704; P = .040) was a statistically significant cutoff. Median survivals from first (90)Y treatment in patients with MTB < 7.0% and ≥ 7.0% were 10.8 months (95% confidence interval [CI], 6.8-14.8) and 4.7 months (95% CI, 1.6-7.8), respectively. SUV(max) (P = .422), TGA (P = .064), and MTV (P = .065) were not found to be statistically significant.MTB based on (18)F-FDG PET-CT performed before treatment was found to be a negative prognostic factor for patient survival after (90)Y radioembolization for unresectable metastatic melanoma to liver.

    View details for DOI 10.1016/j.jvir.2012.04.010

    View details for Web of Science ID 000305930300014

    View details for PubMedID 22609292

  • Tumoral and angiogenesis factors in hepatocellular carcinoma after locoregional therapy PATHOLOGY RESEARCH AND PRACTICE Farris, A. B., Dursun, N., Dhanasekaran, R., Coban, I., McIntosh, E. B., Adsay, N. V., Kim, H. S. 2012; 208 (1): 15-21


    Locoregional therapy (LRT) is used as a bridge to orthotopic liver transplant (OLT) for hepatocellular carcinoma (HCC) patients. Liver explants in OLT patients with HCC were studied regarding both tumor stage, histology, and immunohistochemical staining for cytokeratin (CK)7, CK19, P53, Ki-67, and vascular endothelial growth factor (VEGF). Patients receiving no LRT (control) (n=30) were compared with LRT treatment groups with conventional transarterial chemoembolization (cTACE) (n=25) or drug-eluting bead transarterial chemoembolization (DEB TACE) (n=17). Tumor stage and histology were similar between treatment and control groups. The mean percent necrosis was significantly higher for treatment groups versus the control group (p<0.0001 for both groups versus control) and was significantly higher in the cTACE group versus the DEB TACE group. Only the DEB TACE group showed peritumoral CK19 positivity, and tumors were all CK19-negative. Using a threshold of 50% of tumoral cells, tumoral VEGF was significantly different between groups, with the control group having the highest degree of positivity; however, peritumoral VEGF was not significantly different between the groups. The Ki-67 proliferation fraction was higher in the treated groups with a statistically significant difference between the DEB-treated group and those without treatment (p=0.02). There were no statistically significant differences in tumoral or peritumoral CK7 or p53. Percent necrosis and percent Ki-67 positivity were higher with LRT, with a significant difference between groups for percent necrosis, confirming that LRT causes necrosis and suggesting that treatment leads to increased proliferation and decreased tumoral VEGF.

    View details for DOI 10.1016/j.prp.2011.10.005

    View details for Web of Science ID 000300602900003

    View details for PubMedID 22088254

  • Rare case of adult undifferentiated (embryonal) sarcoma of the liver treated with liver transplantation: excellent long-term survival. Case reports in hepatology Dhanasekaran, R., Hemming, A., Salazar, E., Cabrera, R. 2012; 2012: 519741-?


    We present the case of a 54-year-old gentleman who presented with abdominal distension and a CT scan of his abdomen revealed a large (25 cm) left hepatic lobe tumor. He received chemotherapy for over 1.5 years. The CT scans at the completion of this therapy revealed that the tumor had actually slightly grown in size. He underwent orthotopic liver transplantation without any major complications. The explant histopathology revealed an undifferentiated embryonal cell sarcoma (UECS) composed of relatively bland spindled cells arranged in short fascicles. It is now 10 years and 3 months since his last transplant and the patient remains well with no tumor recurrence.

    View details for DOI 10.1155/2012/519741

    View details for PubMedID 25374706

    View details for PubMedCentralID PMC4208439

  • Hepatocellular carcinoma: current trends in worldwide epidemiology, risk factors, diagnosis, and therapeutics. Hepatic medicine : evidence and research Dhanasekaran, R., Limaye, A., Cabrera, R. 2012; 4: 19-37


    Hepatocellular carcinoma (HCC) is a common malignancy in developing countries and its incidence is on the rise in the developing world. The epidemiology of this cancer is unique since its risk factors, including hepatitis C and B, have been clearly established. The current trends in the shifting incidence of HCC in different regions of the world can be explained partly by the changing prevalence of hepatitis. Early detection offers the only hope for curative treatment for patients with HCC, hence effective screening strategies for high-risk patients is of utmost importance. Liver transplantation and surgical resection remains the cornerstone of curative treatment. But major advances in locoregional therapies and molecular-targeted therapies for the treatment of advanced HCC have occurred recently. In this review, current trends in the worldwide epidemiology, surveillance, diagnosis, standard treatments, and the emerging therapies for HCC are discussed.

    View details for DOI 10.2147/HMER.S16316

    View details for PubMedID 24367230

    View details for PubMedCentralID PMC3846594

  • KLATSKIN TUMOR- CLINICAL OUTCOME AND PROGNOSTIC FACTORS Dhanasekaran, R., Hemming, A. W., Nelson, D. R., Soldevila-Pico, C., Firpi, R. J., Morelli, G., Clark, V. C., George, T. J., Cabrera, R. WILEY-BLACKWELL. 2011: 1372A
  • ALT ABNORMALITIES IN ADULTS WITH ALPHA-1 ANTITRYPSIN DEFICIENCY 46th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL) Clark, V., Brantly, M., Dhanasekaran, R., Schreck, P., Rouhani, F., Nelson, D. ELSEVIER SCIENCE BV. 2011: S354–S354
  • PANCRELIPASE FOR PANCREATIC DISORDERS: AN UPDATE DRUGS OF TODAY Dhanasekaran, R., Toskes, P. P. 2010; 46 (11): 855-866


    Pancrelipase is a porcine pancreatic extract which contains the digestive enzymes lipases, proteases and amylases. In patients with pancreatic exocrine insufficiency (PEI) from conditions such as chronic pancreatitis, pancreatectomy and cystic fibrosis, pancrelipase can be used as pancreatic enzyme replacement therapy (PERT). Pancrelipase can reverse steatorrhea, prevent weight loss, control pain and correct other nutritional deficiencies resulting from exocrine insufficiency. Various forms of pancreatic enzymes were being marketed as over-the-counter medications prior to the recent FDA declaration that all pancreatic enzyme products had to obtain approval as new drugs before marketing. On the basis of evidence from recent randomized controlled trials, three pancrelipase formulations (Creon®, Zenpep® and Pancreaze®) have been approved by the FDA as effective treatments for PEI. Although several tests exist for the detection of PEI, early diagnosis still remains a challenge. Individualization of the timing of treatment initiation and dosage requirements is needed to achieve optimal effectiveness. When used at recommended doses, pancrelipase is a safe medication. Appropriate use of pancrelipase in patients with pancreatic exocrine insufficiency can achieve symptomatic relief, prevent morbidity/mortality and also improve quality of life.

    View details for DOI 10.1358/dot.2010.46.11.1541553

    View details for Web of Science ID 000289870700005

    View details for PubMedID 21225024

  • THE IMPACT OF PRESERVATION INJURY ON ACCELERATED HEPATITIS C RECURRENCE AFTER LIVER TRANSPLANTATION 61st Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases Michaels, A., Dhanasekaran, R., Alkhasawneh, A., Dixon, L., Soldevila-Pico, C., Morelli, G. (., Cabrera, R., Clark, V., Nelson, D. R., Firpi, R. J. WILEY-BLACKWELL. 2010: 320A–320A
  • The Effectiveness of Locoregional Therapies versus Supportive Care in Maintaining Survival within the Milan Criteria in Patients with Hepatocellular Carcinoma JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY Dhanasekaran, R., Khanna, V., Kooby, D. A., Spivey, J. R., Parekh, S., Knechtle, S. J., Carew, J. D., Kauh, J. S., Kim, H. S. 2010; 21 (8): 1197-1204


    To compare survival after treatment with either locoregional therapy (LRT) or supportive care in patients with hepatocellular carcinoma (HCC) within the Milan criteria.Patients with HCC who were classified within the Milan criteria (solitary HCC

    View details for DOI 10.1016/j.jvir.2010.04.018

    View details for Web of Science ID 000281045500008

    View details for PubMedID 20656222

  • Long-term survival after locoregional therapy in patients with unresectable hepatocellular carcinoma: Improvements over two decades. Dhanasekaran, R., McIntosh, E. B., Kauh, J. S., Kooby, D. A., El-rayes, B. F., Kim, H. S. AMER SOC CLINICAL ONCOLOGY. 2010
  • Chemoembolization with doxorubicin drug-eluting beads for unresectable hepatocelluar carcinoma with portal vein thrombosis McIntosh, E. B., Dhanasekaran, R., Kauh, J. S., El-rayes, B. F., Kooby, D. A., Williams, R. S., Kim, H. S. AMER SOC CLINICAL ONCOLOGY. 2010
  • Tumoral and angiogenesis factors in hepatocellular carcinoma (HCC) after drug eluting bead (DEB) transarterial chemoembolization (TACE) with doxorubicin Farris, A. B., Dhanasekaran, R., Dursun, N., Coban, I., McIntosh, E. B., Adsay, V., Kim, H. S. AMER SOC CLINICAL ONCOLOGY. 2010
  • Comparison of Conventional Transarterial Chemoembolization (TACE) and Chemoembolization With Doxorubicin Drug Eluting Beads (DEB) for Unresectable Hepatocelluar Carcinoma (HCC) JOURNAL OF SURGICAL ONCOLOGY Dhanasekaran, R., Kooby, D. A., Staley, C. A., Kauh, J. S., Khanna, V., Kim, H. S. 2010; 101 (6): 476-480


    Chemoembolization with doxorubicin drug eluting beads (DEB) is a novel locoregional treatment modality for unresectable hepatocellular carcinoma (HCC). Initial animal studies and clinical trials suggest that treatment with DEB may provide safer and more effective short-term outcomes than conventional chemoembolization. Current study explores long-term survival benefits.Consecutive patients who received transcatheter therapy with DEB or conventional chemoembolization as sole therapy between 1998 and 2008 were studied. Statistical analysis was performed using Kaplan-Meier estimator with log-rank testing, chi-squared, and independent t-tests.Seventy-one patients were included in this study, 45 (63.4%) received therapy with DEB (group A) and 26 (36.6%) underwent conventional chemoembolization (group B). Median survival from diagnosis of HCC in groups A and B were 610 (351-868) and 284 days (4-563; P = 0.03), respectively. In Okuda stage I, survival in groups A and B were 501 (421-528) and 354 days (148-560, P = 0.02). In Child-Pugh classes A and B, survival in groups A and B were 641 (471-810) and 323 days (161-485, P = 0.002). Median survival in patients with Cancer of Liver Italian Program (CLIP) score

    View details for DOI 10.1002/jso.21522

    View details for Web of Science ID 000277524100007

    View details for PubMedID 20213741

  • Influence of Patient Age on Short Term and Long Term Survival After Tips Dhanasekaran, R., Parekh, S., Kim, H. S. W B SAUNDERS CO-ELSEVIER INC. 2010: S817
  • Prognostic factors for survival in patients with unresectable hepatocellular carcinoma undergoing chemoembolization with doxorubicin drug-eluting beads: a preliminary study HPB Dhanasekaran, R., Kooby, D. A., Staley, C. A., Kauh, J. S., Khanna, V., Kim, H. S. 2010; 12 (3): 174-180


    Transarterial chemoembolization (TACE) with drug-eluting beads (DEB) is a new treatment modality. Little is known about prognostic factors affecting survival after DEB TACE for patients with hepatocellular carcinoma (HCC).Patients who underwent TACE with doxorubicin DEB for unresectable HCC during 2006-2008 were studied. Survival was calculated from the day of first transcatheter therapy. Survival analysis was performed using Kaplan-Meier estimations. Survival curves were compared using the log-rank test.Fifty patients underwent chemoembolization with doxorubicin DEB. They included 39 women and 11 men, with a median age of 57.5 years (range 28-91 years). Eighteen patients died during the study period and 32 remained alive. Overall survival rates at 6 months, 1 year and 2 years from the first administration of doxorubicin DEB TACE were 71%, 65% and 51%, respectively. Prognostic factors found to be significant on univariate analysis were Child-Pugh class, Okuda staging, bilirubin > 2 mg/dl, albumin < 3.0 g/dl, Model for End-stage Liver Disease (MELD) score, serum alphafetoprotein (AFP), Cancer of the Liver Italian Programme (CLIP) score, tumour satisfying Milan criteria, Eastern Cooperative Oncology Group (ECOG) performance status (PS) and Barcelona Clinic Liver Cancer (BCLC) staging.Child-Pugh class, Okuda staging, bilirubin > 2 mg/dl, albumin < 3 g/dl, MELD score, serum AFP, CLIP score, Milan criteria, ECOG PS and BCLC staging were found to be prognostic markers of survival after treatment with doxorubicin DEB TACE in patients with unresectable HCC.

    View details for DOI 10.1111/j.1477-2574.2009.00138.x

    View details for Web of Science ID 000286435700003

    View details for PubMedID 20590884

    View details for PubMedCentralID PMC2889269

  • Transjugular Intrahepatic Portosystemic Shunt for Symptomatic Refractory Hepatic Hydrothorax in Patients With Cirrhosis AMERICAN JOURNAL OF GASTROENTEROLOGY Dhanasekaran, R., West, J. K., Gonzales, P. C., Subramanian, R., Parekh, S., Spivey, J. R., Martin, L. G., Kim, H. S. 2010; 105 (3): 635-641


    We sought to study effectiveness, survival, and complications after transjugular intrahepatic portosystemic shunt (TIPS) in patients with cirrhosis and symptomatic refractory hepatic hydrothorax.Consecutive patients who underwent TIPS between January 1992 and December 2008 for refractory hydrothorax were reviewed retrospectively. Clinical, laboratory, and procedural data were collected for all patients by retrospective chart review. Chi-square test was used to compare categorical variables and t-test to compare continuous variables. The Kaplan-Meier method was used for survival analysis. Survival curves were compared using the log-rank test.Seventy-three patients were included in the study, and their mean age at TIPS creation was 55.62 years (s.d. 11.65). The mean pre- and post-TIPS portosystemic gradients were 18.9 (s.d. 4.7) mm Hg and 5.7 (s.d. 2.4) mm Hg (P<0.001), respectively. The rates of favorable clinical response within 1 month and at 6 months after TIPS were 79% (58/73) and 75% (30/40), respectively. Median survival of the study group was 517 days (95% CI 11-626). The short-term survival rates at 30, 60, and 90 days were 81, 78, and 72%, respectively. The long-term survival rates at 1, 3, and 5 years were 48, 26, and 15%, respectively. Multivariate analysis by Cox proportional hazards method showed that pre-TIPS model for end-stage liver disease (MELD) score (P=0.039, HR 1.9 (95% CI 1.0-3.7)) and clinical response (P=0.003, HR 2.5 (95% CI 1.4-4.5)) were significantly and independently associated with overall survival. The 30-day mortality rate was 19%. Pre-TIPS creatinine levels (P=0.024, HR 3.42 (95% CI 1.2-9.9)) were significantly associated with 30-day mortality.TIPS can be successfully used to achieve symptomatic relief in patients with refractory hepatic hydrothorax. Better clinical response after TIPS and pre-TIPS MELD score less than 15 were associated with longer survival after TIPS.

    View details for DOI 10.1038/ajg.2009.634

    View details for Web of Science ID 000275458300027

    View details for PubMedID 19904245

  • PREDICTORS OF EARLY MORTALITY AFTER TRAN-SJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNTS (TIPS) 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases Dhanasekaran, R., Gonzales, P. C., West, J., Subramanian, R., Parekh, S., Spivey, J. R., Reshamwala, P., Martin, L. G., Kim, H. S. WILEY-BLACKWELL. 2009: 436A–437A
  • Drug eluting beads versus conventional TACE for unresectable hepatocellular carcinoma: Survival benefits and safety 45th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Dhanasekaran, R., Kooby, D. A., Staley, C. A., Kauh, J. S., Kim, H. S. AMER SOC CLINICAL ONCOLOGY. 2009
  • Locoregional therapies as a bridge to transplant in patients with hepatocellular carcinoma 45th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Sakaria, S. S., Dhanasekaran, R., Pankonin, M., Parekh, S., Kauh, J. S., Kim, H. S. AMER SOC CLINICAL ONCOLOGY. 2009
  • High-risk factors affecting survival after transcatheter therapy with doxorubicin-eluting beads for unresectable hepatocellular carcinoma 45th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) West, J. K., Dhanasekaran, R., Kooby, D. A., Staley, C. A., Kauh, J., Kim, H. S. AMER SOC CLINICAL ONCOLOGY. 2009
  • Radioembolization for unresectable chemorefractory hepatic metastases - Safety and efficacy Dhanasekaran, R., Kooby, D., Staley, C., Kauh, J., Montilla-Soler, J., Barron, B., Kim, H. SOC NUCLEAR MEDICINE INC. 2009
  • Chemoembolization Combined with Radiofrequency Ablation for Hepato cellular Carcinoma; Survival Benefits and Tumor Treatment Response Dhanasekaran, R., Khanna, Kooby, D., Delman, K., Staley, C., Kauh, J., Carew, J., Kim, H. AMER ROENTGEN RAY SOC. 2009
  • Liver transplantation for hepatocellular carcinoma BRITISH JOURNAL OF SURGERY Lo, C. M., Fan, S. T. 2004; 91 (2): 131-133

    View details for DOI 10.1002/bjs.4503

    View details for Web of Science ID 000188966300001

    View details for PubMedID 14760656