Early-stage Hepatocellular Cancer Research Articles

Discriminatory Changes in Circulating Metabolites as a Predictor of Hepatocellular Cancer in Patients with Metabolic (Dysfunction) Associated Fatty Liver Disease

Introduction: The burden of metabolic (dysfunction) associated fatty liver disease (MAFLD) is rising mirrored by an increase in hepatocellular cancer (HCC). MAFLD and its sequelae are characterized by perturbations in lipid handling, inflammation, and mitochondrial damage. The profile of circulating lipid and small molecule metabolites with the development of HCC is poorly characterized in MAFLD and could be used in future studies as a biomarker for HCC. Methods: We assessed the profile of 273 lipid and small molecule metabolites by ultra-performance liquid chromatography coupled to high-resolution mass spectrometry in serum from patients with MAFLD (n = 113) and MAFLD-associated HCC (n = 144) from six different centers. Regression models were used to identify a predictive model of HCC. Results: Twenty lipid species and one metabolite, reflecting changes in mitochondrial function and sphingolipid metabolism, were associated with the presence of cancer on a background of MAFLD with high accuracy (AUC 0.789, 95% CI: 0.721–0.858), which was enhanced with the addition of cirrhosis to the model (AUC 0.855, 95% CI: 0.793–0.917). In particular, the presence of these metabolites was associated with cirrhosis in the MAFLD subgroup (p < 0.001). When considering the HCC cohort alone, the metabolic signature was an independent predictor of overall survival (HR 1.42, 95% CI: 1.09–1.83, p < 0.01). Conclusion: These exploratory findings reveal a metabolic signature in serum which is capable of accurately detecting the presence of HCC on a background of MAFLD. This unique serum signature will be taken forward for further investigation of diagnostic performance as biomarker of early stage HCC in patients with MAFLD in the future.

Novel extracellular RNA biomarkers for early stage hepatocellular cancer

Novel extracellular RNA biomarkers for early stage hepatocellular cancer

Abstract 1984: Crosstalk between sirtuins and TGF-β signaling suppresses liver cancer

Abstract Background: Cancer stem cells that escape suppression by key pathways such as TGF-β represent one of the mechanisms for poor prognosis in hepatocellular cancer (HCC). Our mouse models with disruption of TGF-β signaling (β2SP+/-/Smad3+/-) develop HCC and phenocopy an epigenetically human cancer stem cell disorder, providing clues towards the role of TGF-β in the switch in stem cell transformation to HCC. An examination of HCC genomics revealed a surprising and strong correlation between TGF-β and Sirtuins (SIRTs) expression. SIRTs are also implicated in cancer stem cell and HCC suppression. Here we hypothesized that the TGF-β pathway harnesses Sirtuin members to maintain stem cell homeostasis, which may mediate the progression of HCC. Methods: Overall Survival (OS) analysis was carried out by using early-stage HCC (TCGA, Firehose Legacy, stage N1, n=186) from cBioportal. ChIP assay was performed in HepG2 cells using anti-Smad3 and normal rabbit IgG. Biotinylated SIRT6 promoter with/without SMAD binding sites was used as probes to pull down the DNA-interacting proteins in HepG2 cells treated with/without TGF-β for 2h. Results: Analysis of TCGA HCC dataset (cBioportal, stage N1, n=186) indicated reduced OS for HCC patients with decreased SIRT6 together with loss of SPTBN1 in the early stage (Median survival months: 40.37 vs 83.18, p=0.0417). • Chip-qPCR and the DNA-protein pulldown assay revealed that Smad3 positively upregulates the SIRT6 mRNA expression (Smad3 vs IgG, SBE1: 3.27±0.53 vs 0.99±0.01, p&amp;lt;0.05; SBE2: 3.32±0.74 vs 1.12±0.3, p&amp;lt;0.05) through direct binding to the SIRT6 promoter in HepG2 cells after TGF-β treatment. • Co-IP analysis revealed directly binding of SIRT6 with β2sp and Smad3. • Overexpression of SIRT6 represses Smad3 and β2sp expression (p&amp;lt;0.01) and results in inhibition of the TGF-β target genes (p&amp;lt;0.05) such as MMP9 (68.2% inhibited), HMGA2 (53.4% inhibited), and PAI-1 (35.4% inhibited); whereas knockdown of SIRT6 increases β2sp expression in HepG2 cells (3 fold, p&amp;lt;0.05). • Similar to mice with disruption of SIRT6 (SIRT6-/-) that develop liver inflammation, steatosis with progression to tumorigenesis, mice with TGF-β signaling defect (Smad3+/-Sptbn1+/-) also develop fatty liver with progression to tumorigenesis under HFD. Interestingly, we found that SIRT6 was significantly downregulated in MEF cells from mice with loss of TGF-β signaling (Smad3+/-Sptbn1+/-). Conclusions: Our findings suggest that the TGF-β signaling participates in positively regulating the expression of SIRT6. In turn, SIRT6 acts as a negative regulator of TGF-β signaling through de-acetylating Smad3 and β2sp. SIRT6 and TGF-β signaling exert integrative yet complex roles in inhibiting hepatic steatosis, inflammation, and HCC that when disrupted lead to poor prognosis in HCC. The data provide new combined driving roles for the two pathways in suppressing NASH and HCC. Citation Format: Xiyan Xiang, Sobia Zaidi, Shuyun Rao, Kazufumi Ohshiro, Zhanhuai Wang, Wilma Jogunoori, Chuxia Deng, Patricia Latham, Lopa Mishra. Crosstalk between sirtuins and TGF-β signaling suppresses liver cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1984.

Perspectives on the Neoadjuvant Use of Immunotherapy in Hepatocellular Carcinoma.

Immune checkpoint inhibitor (ICI) therapy is an increasingly used treatment modality across the various stages of hepatocellular cancer (HCC). There is currently no standard peri-operative therapy for HCC, despite a high probability of recurrence. Emerging studies in a variety of tumors demonstrate significant pathologic and immune responses to neoadjuvant immunotherapy. Unlike kinase inhibitors and other targeted therapies, which demonstrated no benefit in the adjuvant setting and fail to induce significant responses, ICIs can induce radiologically appreciable reduction in disease burden, which make ICI combinations an appealing downstaging strategy in patients early or locally advanced disease. Additionally, induction of anti-tumor immunity in the pre-operative setting may induce protracted T-cell response that, in the post-operative phase, may be capable of eliminating micro-metastatic disease and prevent future recurrence. In this review, we discuss the rationale and clinical hurdles that underlie optimal integration of immunotherapy in the pre-operative setting, highlighting the positive impact on surgical and oncological outcomes in patients with early-stage HCC.

PRIME-HCC: Phase Ib study of neoadjuvant ipilimumab and nivolumab prior to liver resection for hepatocellular carcinoma.

e16131 Background: There are no approved peri-operative anti‐cancer therapies for patients with hepatocellular cancer (HCC) who are candidates for liver resection (LR). Combination immunotherapy induces radiologically measurable responses in &gt; 25% of patients with HCC, providing a rationale for neoadjuvant use in surgical candidates. Methods: PRIME‐HCC is a two-part, multi-centre, phase Ib study to assess safety and bioactivity of the nivolumab (3 mg/kg, day 1 and day 22) plus ipilimumab (1mg/kg, day 1 only) combination prior to LR in early-stage HCC. The primary objective of the study is to determine the treatment-related adverse events (trAE) and delays to surgery. Efficacy endpoints include overall response rates (ORR) by RECIST v1.1 and pathologic responses on resection specimens. Results: At the data censoring time of Jan 29th 2021, 7 patients were enrolled, all were of Child-Pugh class A, with cirrhosis (n = 6, 85.7%) secondary to viral etiology (n = 4, 57.2%). Male/female ratio was 6/1 and median age was 66 (range: 57-70). The median diameter of the dominant liver lesion was 3.3 cm (inter quartile range, IQR 1.2, range 1.1-4.1 cm) and the median number of nodules was 2 (IQR 0.5; range 1-3). Study part I (n = 6) was completed with no surgical delays. TrAEs of all grade were observed in 6/7 safety-evaluable patients (85%). TrAEs of grade &gt;2 occurred in 3 patients (42%) and included grade 3 transaminitis (n = 1), grade 2 thyroid toxicity (n = 1), grade 2 infusion reaction (n = 1) and fatigue (n = 1). One patient was diagnosed with cholangiocarcinoma after dosing and was removed from efficacy analyses. ORR according to RECIST v1.1 criteria in efficacy-evaluable patients (n = 5) was 20%, including 1 partial response and 4 disease stabilisations. Pathological responses were observed in 3 out of 5 pathologically evaluable patients (60%). Conclusions: Neoadjuvant immunotherapy with nivolumab plus ipilimumab is tolerable, does not compromise management of patients on a radical pathway of care and is characterised by anti-tumour efficacy in early-stage HCC. Clinical trial information: NCT03682276.

Circulating Cell-Free DNA Combined to Magnetic Resonance Imaging for Early Detection of HCC in Patients with Liver Cirrhosis.

Simple SummaryLiver cirrhosis can develop into malignant disease over time. Frequent monitoring would be advisable to detect the earliest signs of HCC progress resulting in a possible earlier treatment of the patient. Our study showed that the combination of genetic analysis of DNA freely circulating in the blood of the cirrhotic patients with MRI can represent a powerful strategy to timely identify suspect lesions, which can then be followed up more closely and thus potentially be treated earlier. In this way, personalized medicine can be applied to liver diseases such as cirrhosis.Liquid biopsy based on circulating cell-free DNA (cfDNA) is a promising non-invasive tool for the prognosis of hepatocellular cancer (HCC). In this exploratory study we investigated whether cfDNA and gene variants associated with HCC may be found in patients with liver cirrhosis (LC) and thus identify those at an increased risk for HCC. A cohort of 40 LC patients with no suspect neoplastic lesions was included in this study. Next generation sequencing (NGS) of cfDNA isolated from plasma was performed on a panel of 597 selected genes. Images of the patients who underwent MRI with hepatospecific contrast media during the study period were retrospectively re-evaluated (imaging was not part of the prospective study). cfDNA was detected in the plasma of 36 patients with LC. NGS-based analyses identified 20 variants in different combinations. Re-evaluation of the MRI images that were available for a proportion of the patients (n = 27) confirmed the absence of lesions in 8 cases carrying cfDNA without variants. In 6 of 19 patients with identified variants and MRI images available, MRI revealed a precursor lesion compatible with HCC and new lesions were discovered at follow-up in two patients. These precursor lesions were amenable for curative treatments. Mutation analysis revealed selective HCC related gene mutations in a subset of patients with LC, raising the suspect that these patients were at an increased risk for HCC development. MRI findings confirmed suspect nodular lesions of early stage HCC not detected with current standard screening procedures, which were only seen in patients carrying cfDNA variants. This opens a perspective for an HCC screening strategy combining both liquid biopsy and MRI in patients with LC.

Issue Highlights

Issue Highlights

Development of Quality Measures in Cirrhosis by the Practice Metrics Committee of the American Association for the Study of Liver Diseases.

Health care delivery is increasingly evaluated according to quality measures, yet such measures are underdeveloped for cirrhosis. The Practice Metrics Committee of the American Association for the Study of Liver Diseases was charged with developing explicit process-based and outcome-based measures for adults with cirrhosis. We identified candidate measures from comprehensive reviews of the literature and input from expert clinicians and patient focus groups. We conducted an 11-member expert clinician panel and used a modified Delphi method to systematically identify a set of quality measures in cirrhosis. Among 119 candidate measures, 46 were identified as important measures to define the quality of cirrhosis care, including 26 process measures, 7 clinical outcome measures, and 13 patient-reported outcome measures. The final process measures captured care processes for ascites (n = 5), varices/bleeding (n = 7), hepatic encephalopathy (n = 4), hepatocellular cancer (HCC) screening (n = 1), liver transplantation evaluation (n = 2), and other care (n = 7). Clinical outcome measures included survival, variceal bleeding and rebleeding, early-stage HCC, liver-related hospitalization, and rehospitalization within 7 and 30 days. Patient-reported outcome measures covered physical symptoms, physical function, mental health, general function, cognition, social life, and satisfaction with care. The final list of patient-reported outcomes was validated in 79 patients with cirrhosis from nine institutions in the United States. Conclusion: We developed an explicit set of evidence-based quality measures for adult patients with cirrhosis. These measures are a tool for providers and institutions to evaluate their care quality, drive quality improvement, and deliver high-value cirrhosis care. The quality measures are intended to be applicable in any clinical care setting in which care for patients with cirrhosis is provided.

Abstract 3201: Therapeutic potential of anti-angiogenic multimodal biomimetic peptide in hepatocellular carcinoma

Abstract Hepatocellular carcinoma (HCC) related mortality ranks second worldwide and stands one step behind lung cancer. Due to the asymptomatic nature of the cancer, early diagnosis is a major problem. Currently only liver transplantation is curative for early stage hepatocellular cancer. There are other multidisciplinary treatment options like radiation and chemotherapy available for advanced patients. However, chemotherapy resistance is a common problem in the treatment of liver cancer. Newer therapeutics are needed for better management of advanced HCC. Angiogenesis and lymphangiogenesis are processes that are vital for tumorigenesis and metastasis. HCC is known to be a hypervascular tumor and many pro-angiogenic proteins are found significantly overexpressed in HCC. We explored the therapeutic potential of the anti-angiogenic and anti-lymphangiogenic, biomimetic peptide SP2043 developed by our group in HCC. Hepatocellular carcinoma cell lines HuH-7, Hep3b and HepG2 showed significant disruption of cell adhesion and migration following treatment. Furthermore, SP2043 was found to impair microvascular endothelial cell (MEC) tube formation induced by HepG2 tumor conditioned media and to significantly inhibit HepG2 tumor xenograft growth compared to untreated controls. The peptide drug was also found to improve the survival of autochthonous Myc induced HCC in a transgenic mouse model from two weeks to four weeks. We discovered the peptide to be a multi-modal anti-angiogenic drug that also inhibits IGF1R and MET signaling pathways in HCC cell lines. We also found that SP2043 treatment reduced the microvascular density in both subcutaneous and autochthonous liver tumors with reduced tumor cell proliferation and increased apoptosis. This study shows the therapeutic potential of SP2043 in the treatment of hepatocellular carcinoma. Note: This abstract was not presented at the meeting. Citation Format: Mustafa A. Barbhuiya, Adam C. Mirando, Brian W. Simons, Ghali Lemtiri-Chlieh, Jordan J. Green, Aleksander S. Popel, Niranjan B. Pandey, Phuoc T. Tran. Therapeutic potential of anti-angiogenic multimodal biomimetic peptide in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3201. doi:10.1158/1538-7445.AM2017-3201

Liver resection for early hepatocellular cancer: Comparison of centers in 3 different countries.

AIMTo compare patients who underwent resection of early stage hepatocellular cancer (HCC) in three different countries.METHODSThis retrospective study characterizes 573 stage I/II HCC patients treated with liver resection in 3 tertiary-referral centers: Tokyo (n = 250), Honolulu (n = 146) and Shanghai (n = 177).RESULTSShanghai patients were younger, predominantly male, hepatitis-B seropositive (94%) and cirrhotic (93%). Tokyo patients were older and more likely to have hepatitis-C (67%), smaller tumors, low albumin, and normal alpha-fetoprotein. The Honolulu cohort had the largest tumors and 30% had no viral hepatitis. Age-adjusted mortality at 1 and 5-years were lower in the Tokyo cohort compared to Honolulu and there was no difference in mortality between Shanghai and Honolulu cohorts. Elevated alpha-fetoprotein, low albumin and tumor > 5 cm were associated with increased 1-year mortality. These factors and cirrhosis were independently associated with increased 5-year mortality. Independent risk factors of survival varied when examined separately by center.CONCLUSIONThe profile of early-stage HCC patients is strikingly different across countries and likely contributes to survival differences. Underlying differences in patient populations including risk factors/comorbidities influencing disease progression may also account for variation in outcomes.

Abstract 3900: Genomic landscape of human cancer reveals dysregulated TGF-β signaling with prognostic significance

Abstract Objective: Genome-wide analysis enables predictive modeling of genetic pathways driving many cancers. While somatic mutations and patterns reflecting key pathways have been identified for many cancers, an integrated analysis of driver mutations identified through mouse/human genetics have yet to be comprehensively defined for hepatocellular cancer (HCC). Previously our group and others have identified that loss of TGF-β signaling leads to spontaneous HCC development, through mouse models and human genetics. Patients with hepatocellular cancer have a poor survival of 9-11 months. Recent clinical studies show that targeting TGF-β improves survival up to 21 months, yet prognostic significances are undefined. The relationships between patterns of mutations and transcriptomic phenotypes for the TGF-β pathway are unclear. Methods: (1) We analyzed the transcriptome of 488 hepatocellular cancers and screened for mutations in the TGF-β pathway in 202 HCCs from The Cancer Genome Atlas (TCGA). (2) Increased levels of TGF-β-related genes were designated as an “activated” signature that is associated with hepatic fibrosis. Conversely, decreased levels of TGF-β-related genes were defined as an “inactivated” signature, which was associated with the loss of TGF-β tumor suppressor function. (3) We further performed high-fidelity (80x) whole-genome sequence analysis and transcriptome sequencing analysis of eight additional HCCs to define the role of TGF-β in their development and characterize a potential novel “driver mutations” in HCV- and alcohol-associated hepatocellular cancer. (4) We validated the clinical relevance of β2SP alterations in 22 human liver specimens. Results: (1) Transcriptomic analyses revealed aberrant TGF-β superfamily profiles in 72% of hepatocellular cancers, with mutations in 38% of patients. (2) HCCs characterized by the “inactivated” TGF-β signature were associated with a significantly poorer survival particularly in early stage HCCs, compared to HCCs with the “activated” TGF-β signature (p = 0.0027). (3) We observed the greatest number of functional mutations in the SPTBN1 gene (6%), which encodes a tumor suppressor TGF-β/Smad3 adaptor protein. (4) Furthermore, we found a strong association between DNA damage response genes and the TGF-β pathway at both transcriptomic and genomic levels. Conclusions: The TGF-β pathway plays a pivotal role in liver tumorigenesis and the molecular signatures we characterize here appear to have prognostic significance. The additional association with the DNA repair pathway supports new approaches to developing biomarkers. Targeting of TGF-β, has the potential for improving survival of liver cancer. Citation Format: Jian Chen, Jiun-Sheng Chen, Jianping Zhang, Liem Phan, Nina M. Muñoz, Lior H Katz, YoungJin Gi, Vipin Kumar Menon, Ji-Hyun Shin, Yun Seong Jeong, Wilma Jogunoori, Patrizia Farci, Kirti Shetty, Xiaoping Su, Tej K Pandita, Jon White, Bibhuti Mishra, Fausto Zamboni, Xifeng Wu, Asif Rashid, Shulin Li, Milind Javle, Mien-Chie Hung, Franklin Herlong, Marta Davila, John Stroehlein, Kenna R Shaw, Xuemei Wang, Jeffrey S Morris, Rehan Akbani, Lopa Mishra. Genomic landscape of human cancer reveals dysregulated TGF-β signaling with prognostic significance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3900. doi:10.1158/1538-7445.AM2015-3900

Treatment of early stage hepatocellular cancer by transplant, ablation or resection: a 21-year population-based analysis

Treatment of early stage hepatocellular cancer by transplant, ablation or resection: a 21-year population-based analysis

Methylation profiling of serum DNA from hepatocellular carcinoma patients using an Infinium Human Methylation 450 BeadChip.

Alterations in DNA methylation frequently occur in hepatocellular cancer (HCC). The methylation status of circulating DNA might serve as a potential biomarker for cancers. Six early stage HCC patients with chronic hepatitis B virus (HBV) infection and six age-matched healthy controls were selected for genome-scale DNA methylation screening of serum by Illumina Infinium Human Methylation 450 BeadChip. The chosen methylation sites were reassessed by bisulfite sequencing in four healthy controls and four early stage HCC patients with chronic HBV infection and were used for bead array screening. Another 27 healthy controls and 31 early stage HCC patients with chronic HBV infection were also chosen for further bisulfite sequencing validation. Whole-genome methylation was significantly lower in serum from HCC patients than in that from healthy controls. After bioinformatics analysis, methylation at DBX2 and Thy-1 membrane glycoprotein (THY1) was reassessed by bisulfite sequencing. The correlation coefficients of DBX2 and THY1 between the Illumina 450 BeadChip and bisulfite sequencing were respectively 0.9145 and 0.8232. Twenty-seven healthy controls and 31 early stage HCC patients with chronic HBV infection were chosen for further validation. The diagnostic sensitivity and specificity of DBX2 for differentiating healthy controls and early stage HCC were 88.89 and 87.10% and of THY1 were 85.19 and 80.65%. The results demonstrated that the 450K BeadChip is a useful tool for whole-genome serum DNA methylation screening of HCC, and some HCC-related DNA methylation sites were screened.

High expression of trimethylated histone H3 lysine 4 is associated with poor prognosis in hepatocellular carcinoma

Tumor-associated epigenetic alterations including DNA methylation and histone modifications are important determinants in the initiation and progression of hepatocellular cancer (HCC) and represent promising biomarkers and therapeutic targets. Locus-specific trimethylation of histone H3 lysine 4 (H3K4me) is a well-known modification linked to the enhanced transcriptional expression of many genes activated in HCC. Our aim was to assess the cellular expression pattern of H3K4me3 in HCC and its association with clinicopathologic variables and outcome. Expression of H3K4me3 and the histone methyltransferase (HMT) SET and MYND domain-containing protein 3 (SMYD3) was studied by Western blotting and immunohistochemistry in cell lines and tumor tissue microarray from a well-characterized series of HCC patients (n = 168). The optimal cut-point of H3K4me3 expression for prognosis was determined by the X-tile program. The prognostic significance was evaluated using Kaplan-Meier survival estimates and log-rank tests. Tumor tissue microarray from another independent HCC patients cohort (n = 147) was used for validation studies. Expression of H3K4me3 and SMYD3 were enhanced in HCC cell lines. In tumor specimens, enhanced expression of H3K4me3 was correlated with reduced overall survival (P < .0001), especially in early-stage HCC patients (TNM I/II). Furthermore, both univariate and multivariate analyses revealed that H3K4me3 level was a significant and independent predictor of poor survival (hazard ratio, 3.592; 95% confidence interval, 2.302-5.605). In addition, H3K4m3 expression was positively correlated with SMYD3 expression in both testing and validation cohorts (P < .0001). In conclusion, H3K4me3 level defines unrecognized subsets of HCC patients with distinct epigenetic phenotype and clinical outcome and can thus be a novel predictor for poor prognosis of HCC patients, especially at TNM I/II stage.

Association of high histone H3K4 trimethylation level and prognosis of patients with low-TNM-stage hepatocellular carcinoma.

171 Background: Along with genetic events, tumor associated epigenetic alterations including DNA methylation and post-translational histone modifications are important determinants in the initiation and progression of hepatocellular cancer (HCC) and represent promising biomarkers and therapeutic targets. Locus-specific trimethylation of histone H3 lysine 4 (H3K4me) is a well-known modification linked to the enhanced transcriptional expression of many genes activated in HCC. However its expression and association with prognosis of HCC patients remain unclear. Our aim was to assess the cellular expression pattern of H3K4me3 in HCC and its association with clinicopathologic variables and outcome. Methods: Expression of H3K4me3 and the histone methyltransferase SMYD3 was studied by western blotting and immunohistochemistry in human HCC cell lines and tumor tissue micmicroarray, which is from a well–characterized series of HCC patients(n=168). Tissue staining were assessed using blinded semiquantitative scoring. The optimal cut-point of H3K4me3 expression for prognosis was determined by the X-tile program. The prognostic significance was evaluated using Kaplan-Meier survival estimates and log-rank tests. Tumor tissue micmicroarray from another independent HCC patients cohort(n=147) was used for validation studies. Results: Expression of H3K4me3 and the histone methyltransferase SMYD3 were enhanced in HCC cell lines.In clinical tumor specimens, enhanced expression of H3K4me3 was correlated with reduced overall survival (P &lt; 0.0001), especially in early-stage HCC patients(TNM I/II).Furthermore,both univariate and multivariate analysis revealed that H3K4me3 level was a significant and independent predictor of poor survival (hazard ratio,3.592; 95% CI, 2.302-5.605). In addition, H3K4m3 expression was positively correlated with SMYD3 expression in both testing and validation cohorts (P&lt;0.0001). Conclusions: H3K4me3 level defines previously unrecognized subsets of HCC patients with distinct epigenetic phenotype and clinical outcome, thus can be a novel predictor for poor prognosis of HCC patients, especially within TNM I/IIstage.

Liver Transplantation for Hepatocellular Carcinoma: Racial Disparities?

Liver transplantation for patients with early-stage hepatocellular cancer evidently represents an extremely effective treatment as compared to other modalities, at least by one analysis of a cancer database. However, less than one-fourth of the apparently acceptable candidates receive this treatment and African Americans are underrepresented in this group. The cause of these results, however, remains obscure with the need for a more in-depth confirmation of these findings readily apparent.

Model for end-stage liver disease (MELD) for liver allocation: A 5-year score card

Model for end-stage liver disease (MELD) for liver allocation: A 5-year score card

Increasing incidence and pretransplantation screening of hepatocellular carcinoma.

The incidence of hepatocellular cancer (HCC) in the United States and other traditionally "low-incidence" countries is increasing. 2. The rise in incidence of HCC is related to chronic hepatitis C. 3. Timely performance of liver transplantation is curative in patients with early-stage HCC. 4. Cirrhotic patients, especially those with viral hepatitis, should be screened for HCC. 5. The performance characteristics of current tests are suboptimal, but serial ultrasonography and alphafetaprotein are recommended. 6. Estimated medical charges related to screening and treatment suggest that $285,294 is required per "cured" case. Assuming that this cure is associated with a 75% to 85% chance for high-quality 10-year survival, the charges approximate $35,000 to $40,000/quality-adjusted life-year (QALY). This cost-benefit analysis is nearly identical to published rates for breast cancer screening ($30,000/QALY).