Instructor, Medicine - Gastroenterology & Hepatology
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
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
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
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
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
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
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
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
View details for Web of Science ID 000368375401014
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
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
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
View details for PubMedID 30543799
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
View details for Web of Science ID 000446020500093
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
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
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
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
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
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
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
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
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
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
View details for Web of Science ID 000385493804103
View details for Web of Science ID 000385493803163
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
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
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 Web of Science ID 000344483802412
View details for Web of Science ID 000322997206040
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
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
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
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 Web of Science ID 000310955601587
View details for Web of Science ID 000310955601547
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
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
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
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
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 Web of Science ID 000297625602029
View details for Web of Science ID 000288775600003
View details for Web of Science ID 000288775602394
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
View details for DOI 10.1016/j.jvir.2010.04.018
View details for Web of Science ID 000281045500008
View details for PubMedID 20656222
View details for Web of Science ID 000208852000687
View details for Web of Science ID 000208852000760
View details for Web of Science ID 000208852003627
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
View details for DOI 10.1002/jso.21522
View details for Web of Science ID 000277524100007
View details for PubMedID 20213741
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
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
View details for Web of Science ID 000270456000281
View details for Web of Science ID 000276606603115
View details for Web of Science ID 000276606603326
View details for Web of Science ID 000276606603332