Higher Rates Of Hepatocellular Carcinoma Research Articles

MBOAT7 rs641738 Variant Is Not Associated with an Increased Risk of Hepatocellular Carcinoma in a Latin American Cohort

BackgroundThe rs641738 C > T single-nucleotide polymorphism of MBOAT7 has been associated with hepatocellular carcinoma (HCC) and nonalcoholic fatty liver disease (NAFLD). Latin Americans have high rates of HCC and NAFLD, but no assessment between MBOAT7 and HCC has been performed in this population.AimsWe provide the first assessment of the impact of MBOAT7 on HCC risk in Latin Americans.MethodsPatients were prospectively recruited into the ESCALON network, designed to collect samples from Latin American patients with HCC in 6 South American countries (Argentina, Ecuador, Brazil, Chile, Peru, and Colombia). A European cohort and the general Hispanic population of gnomAD database were included for comparison. Associations between HCC and MBOAT7 were evaluated using logistic regression.ResultsIn total, 310 cases of HCC and 493 cases of cirrhosis without HCC were assessed. The MBOAT7 TT genotype was not predictive of HCC in Latin Americans (TT vs CC OR adjusted = 1.15, 95% CI 0.66–2.01, p = 0.610) or Europeans (TT vs CC OR adjusted = 1.20, 95% CI 0.59–2.43, p = 0.621). No significant association was noted on subgroup analysis for NAFLD, viral hepatitis, or alcohol-related liver disease. The TT genotype was increased in the NAFLD-cirrhosis cohort of Latin Americans compared to a non-cirrhotic NAFLD cohort (TT vs CC + CT OR = 2.75, 95% CI 1.10–6.87, p = 0.031).ConclusionThe rs631738 C > T allele of MBOAT7 was not associated with increased risk of HCC in Latin Americans or Europeans. An increase in the risk of cirrhosis was noted with the TT genotype in Latin Americans with NAFLD.Graphical

Trends in hepatocellular carcinoma rates by age, region, race, and ethnicity: A SEER database population study 2000-2019.

e16179 Background: Liver cancer (LC) incidence has tripled over the past four decades, with hepatocellular carcinoma (HCC) being the most common type (72%). Further, LC mortality often coincides with incidence, as the disease is often fatal. To illustrate, the five-year survival rate (2012-2018) for LC is 21% at all stages, compared to lung cancer at 23% and colon cancer at 65%. While incidence and death rates of LC have stabilized in the past 5 years, troubling disparities have been identified when rates are stratified by region, age, race, and ethnicity. For example, HCC incidence in rural areas has increased by 5.7% annually, with rates approaching that of urban ones, despite a historically lower incidence. Consequently, as several inequalities in HCC have been established, the study herein aims to identify whether recognition of these disparities has helped to reduce their growth. Methods: We identified incidence rates of HCC from the Surveillance, Epidemiology and End Results Program database at 4-year time intervals from 2000-2019, stratified by age above (>) and below (<) 60, metropolitan (M) vs nonmetropolitan (NM) counties, race, and ethnicity. Next, we calculated percent change and percent difference in HCC rates across time intervals and groups to evaluate trends. Results: Percent change in rates of HCC has increased since 2000 in those >60 in both M and NM areas with larger growth observed in NM counties. Conversely, between 2010 and 2019 HCC rates have declined in those <60, with a steeper decline observed in M (-18.2%) vs NM (-10.0%) counties. Alarmingly, when 2015-2019 HCC rates are stratified by race/ethnicity, each minority group studied exhibited considerably higher rates of HCC when compared to whites and non-Latinos of the same age group and region (percent difference = >60 M; >60 NM; <60 M; <60 NM): Black (50.3%; 37.2%; 24.1%; 26.6%), American Indian (21.2%; 85.8%; 7.6%; 77.5%), Asian (17.3%; 17.8%; 21.1%; 28.1%), and Latino (39.0%; 45.6%; 40.0%; 36.1%). [Reference: white rates = 35.4; 31.7; 5.1; 4.9 and non-Latino rates = 36.5; 33; 2.4; 2.5, respectively, per 100,000 and age adjusted to the 2000 US Standard Population]. Conclusions: Recent data describes a stabilization in LC incidence and death rates over the past 5 years. However, when HCC incidence is stratified by age, region, race, and ethnicity, disconcerting trends continue to be revealed. As such, interventions should be targeted at those >60, living in NM areas, and in the minority groups studied to combat these disparities. [Table: see text]

Transcriptional Analysis of TP53 Gene in Chronic Hepatitis C Patients Treated with Sofosbuvir, Daclatasvir, Pegylated Interferon, and Ribavirin.

Hepatitis C virus (HCV) is a major public health problem that affects more than 170 million people globally. HCV is a principal cause of hepatocellular carcinoma (HCC) around the globe due to the high frequency of hepatitis C infection, and the high rate of HCC is seen in patients with HCV cirrhosis. TP53 is considered as a frequently altered gene in all cancer types, and it carries an interferon response element in its promoter region. In addition to that, the TP53 gene also interacts with different HCV proteins. HCV proteins especially NS3 protein and core protein induce the mutations in the TP53 gene that lower the expression of this gene in HCV patients and leads to HCC development. In this study, we examined the transcriptional analysis of the TP53 gene in HCV-infected patients administered with different combinations of antiviral therapies including sofosbuvir + daclatasvir, sofosbuvir + ribavirin, and pegylated interferon + ribavirin. This study included 107 subjects; 15 treated with sofosbuvir + daclatasvir, 58 treated with sofosbuvir + ribavirin, 11 treated with interferon + ribavirin, 8 untreated, 10 HCC patients, and 5 were healthy controls. Total RNA was extracted from the PMBCs of HCV infected patients and reverse transcribed into cDNA using a gene specific reverse primer. The expression level of TP53 mRNA was analyzed using quantitative PCR. The expression of TP53 mRNA was notably upregulated in rapid virological response (RVR), early virological response (EVR), and sustained virological response (SVR) groups as compared to non-responders and naïve groups. The expression of TP53 mRNA was seen high in HCC as compared to control groups. Additionally, it has been demonstrated that sofosbuvir + daclatasvir treatment stimulates significant elevation in TP53 gene expression as compared to (sofosbuvir + ribavirin) and (IFN + ribavirin) treatment. This study indicates that the TP53 gene expression is highly upregulated in RVR, EVR, and SVR groups as compared to control groups. Moreover, sofosbuvir + daclatasvir therapy induces significant rise in TP53 mRNA expression levels as compared to (sofosbuvir + ribavirin) and (IFN + ribavirin) treatment. According to these results, it can be concluded that sofosbuvir + daclatasvir plays a significant role in preventing HCV patients from developing severe liver complications as compared to other administered therapies. This study is novel as no such type of study has been conducted previously on the expression of TP53 in local HCV-infected population treated with different combinations of therapies. This study is helpful for the development of new therapeutic strategies and for improving existing therapies.

Molecular Classification of Hepatocellular Carcinoma Using Wnt-Hippo Signaling Pathway-Related Genes.

Simple SummaryThe characters of Taiwanese hepatocellular carcinoma (HCC) are different from other parts of the world. We characterized the molecular features of HCC using a newly developed classification system based on the expression of the Wnt–Hippo signaling pathway-related genes. We analyzed the data in terms of prognostic value, transcriptome features, immune infiltration, and clinical characteristics, and compared the resulting subclasses with previously published classifications. A new molecular classification method based on a 272 gene panel of Wnt–Hippo pathways that may provide a new target for the treatment.In Taiwan, a combination of hepatitis B and C infection, economic boom-related food and alcohol overconsumption, and Chinese medicine prescriptions has led to a high rate of hepatocellular carcinoma (HCC). However, the causative factors and underlying tumor biology for this unique HCC environment have not been identified. Wnt and Hippo signaling pathways play an important regulatory role in HCC development, and their functions are generally considered as positive and negative regulators of cell proliferation, respectively. In this study, we characterized the molecular features of HCC using a newly developed classification system based on the expression of the Wnt–Hippo signaling pathway-related genes. RNA sequencing (RNA-Seq) was performed on liver tumor tissues from 100 patients with liver cancer. RNA-Seq data for 272 previously characterized Wnt–Hippo signaling pathway-related genes were used for hierarchical clustering. We analyzed the data in terms of prognostic value, transcriptome features, immune infiltration, and clinical characteristics, and compared the resulting subclasses with previously published classifications. Four subclasses of HCC (HCCW1–4) were identified. Subclass HCCW1 displayed the highest PCDHB4 expression. Subclass HCCW2 displayed lower Edmondson–Steiner grades (I and II) and CTNNB1 mutation frequencies. Subclass HCCW3 was associated with a good prognosis, the highest PCDHGB7 expression, high CD8+ naïve T cells abundance, and relatively low TP53 mutation rates. Subclass HCCW4 was associated with a poor prognosis, the highest PCDHB2 and PCDHB6 expression, a relatively high abundance of Th1 cells, NKT and class-switched memory B cells, relatively low enrichment of cDC, iDC, and CD4+ memory T cells, and high Edmondson–Steiner grades (III and IV). We also identified Wnt–Hippo signaling pathway-related genes that may influence immune cell infiltration. We developed a panel of 272 Wnt–Hippo signaling pathway-related genes to classify HCC into four groups based on Taiwanese HCC and The Cancer Genome Atlas Liver Hepatocellular Carcinoma datasets. This novel molecular classification system may aid the treatment of HCC.

Incidence of hepatocellular carcinoma in chronic hepatitis B virus infection in those not meeting criteria for antiviral therapy.

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.

Retraction Note: Activation of PERK-Nrf2 oncogenic signaling promotes Mdm2-mediated Rb degradation in persistently infected HCV culture

The mechanism of how chronic hepatitis C virus (HCV) infection leads to such a high rate of hepatocellular carcinoma (HCC) is unknown. We found that the PERK axis of endoplasmic reticulum (ER) stress elicited prominent nuclear translocation of Nrf2 in 100% of HCV infected hepatocytes. The sustained nuclear translocation of Nrf2 in chronically infected culture induces Mdm2-mediated retinoblastoma protein (Rb) degradation. Silencing PERK and Nrf2 restored Mdm2-mediated Rb degradation, suggesting that sustained activation of PERK/Nrf2 axis creates oncogenic stress in chronically infected HCV culture model. The activation of Nrf2 and its nuclear translocation were prevented by ER-stress and PERK inhibitors, suggesting that PERK axis is involved in the sustained activation of Nrf2 signaling during chronic HCV infection. Furthermore, we show that HCV clearance induced by interferon-α based antiviral normalized the ER-stress response and prevented nuclear translocation of Nrf2, whereas HCV clearance by DAAs combination does neither. In conclusion, we report here a novel mechanism for how sustained activation of PERK axis of ER-stress during chronic HCV infection activates oncogenic Nrf2 signaling that promotes hepatocyte survival and oncogenesis by inducing Mdm2-mediated Rb degradation.

Circulating Fatty Acids Associated with Advanced Liver Fibrosis and Hepatocellular Carcinoma in South Texas Hispanics.

Hispanics in South Texas have high rates of hepatocellular carcinoma (HCC) and nonalcoholic fatty liver disease (NAFLD). Liver fibrosis severity is the strongest predictive factor of NAFLD progression to HCC. We examined the association between free fatty acids (FA) and advanced liver fibrosis or HCC in this population. We quantified 45 FAs in plasma of 116 subjects of the Cameron County Hispanic Cohort, 15 Hispanics with HCC, and 56 first/second-degree relatives of Hispanics with HCC. Liver fibrosis was assessed by FibroScan. Advanced liver fibrosis was significantly associated with low expression of very long chain (VLC) saturated FAs (SFA), odd chain SFAs, and VLC n-3 polyunsaturated FAs [PUFA; AOR; 95% confidence interval (CI), 10.4 (3.7-29.6); P < 0.001; 5.7 (2.2-15.2); P < 0.001; and 3.7 (1.5-9.3); P = 0.005]. VLC n3-PUFAs significantly improved the performance of the noninvasive markers for advanced fibrosis - APRI, FIB-4, and NFS. Plasma concentrations of VLC SFAs and VLC n-3 PUFAs were further reduced in patients with HCC. Low concentrations of these FAs were also observed in relatives of patients with HCC and in subjects with the PNPLA3 rs738409 homozygous genotype. Low plasma concentrations of VLC n-3 PUFAs and VLC SFAs were strongly associated with advanced liver fibrosis and HCC in this population. Genetic factors were associated with low concentrations of these FAs as well. These results have implications in identifying those at risk for liver fibrosis progression to HCC and in screening this population for advanced fibrosis. They also prompt the evaluation of VLC n-3 PUFA or VLC SFA supplementation to prevent cirrhosis and HCC.

Long-term Patient-Centered Outcomes in Cirrhotic Patients With Chronic Hepatitis C After Achieving Sustained Virologic Response

Achieving sustained virologic response (SVR) among patients with hepatitis C virus (HCV) leads to patient reported outcome (PRO) improvement. We aimed to assess the long-term post-SVR PRO trends in HCV patients with cirrhosis. Patients with HCV and cirrhosis treated in clinical trials with direct acting antiviral agents (DAAs) who achieved SVR-12 were prospectively enrolled in a long-term registry (clinicaltrials.gov #NCT02292706). PROs were collected every 24 weeks using the Short Form-36v2 (SF-36), CLDQ-HCV, and WPAI-HCV. Pre-treatment baseline data were available for 854 cirrhotic patients who achieved SVR after DAAs. Of these, 730 had compensated (CC) and 124 had decompensated cirrhosis (DCC) before treatment- patients with DCC reported severe impairment in their PROs in comparison to CC patients (by mean -5% to -16% of a PRO range size; p < .05 for 16 out of 20 studied PROs]. After achieving SVR and registry enrollment, significant PRO improvements were noted from pre-treatment levels in 11/20 domains for those with DCC (+4% to+21%) and 19/20 PRO domains in patients with CC (+3% to+17%). Patients with baseline DCC had higher rates of hepatocellular carcinoma and mortality (P < .05). In patients with CC, the PRO gains persisted up to 168 weeks (3.5 years) of registry follow-up. In patients with DCC, the improvements lasted for at least 96 weeks but a declining trend after year2. Patients with HCV cirrhosis experience severe PRO impairment at baseline with sustainable improvement after SVR. Though those with DCC experience improvement, there is a decline after 2 years.

Peretinoin, an Acyclic Retinoid, for the Secondary Prevention of Hepatocellular Carcinoma.

The high rates of hepatocellular carcinoma (HCC) recurrence after initially successful curative therapy emphasize ongoing unmet needs to prevent or reduce HCC recurrence. Retinoid acid (RA), a metabolite of vitamin A and its related analogues (termed retinoids) has been suggested as a promising chemotherapeutic agent in cancer treatment. The synthetic oral retinoid peretinoin is the only agent for the secondary chemoprevention of HCC after curative therapy that is currently well applied into clinical development. Here we present an updated summary of the molecular pathogenesis of HCC and of preclinical and clinical findings with peretinoin, including its clinical characteristics, safety and tolerability profile and future perspectives for clinical use.

A Sweet Connection? Fructose's Role in Hepatocellular Carcinoma.

Hepatocellular carcinoma is one of few cancer types that continues to grow in incidence and mortality worldwide. With the alarming increase in diabetes and obesity rates, the higher rates of hepatocellular carcinoma are a result of underlying non-alcoholic fatty liver disease. Many have attributed disease progression to an excess consumption of fructose sugar. Fructose has known toxic effects on the liver, including increased fatty acid production, increased oxidative stress, and insulin resistance. These effects have been linked to non-alcoholic fatty liver (NAFLD) disease and a progression to non-alcoholic steatohepatitis (NASH). While the literature suggests fructose may enhance liver cancer progression, the precise mechanisms in which fructose induces tumor formation remains largely unclear. In this review, we summarize the current understanding of fructose metabolism in liver disease and liver tumor development. Furthermore, we consider the latest knowledge of cancer cell metabolism and speculate on additional mechanisms of fructose metabolism in hepatocellular carcinoma.

P-148 - High rates of hepatocellular carcinoma within two years of starting treatment for chronic hepatitis C with direct antiviral agents but not with PEG-interferon/ Ribavirin (HORRID Study)

Introduction: Direct acting antivirals (DAA) have revolutionized the treatment of chronic hepatitis C (CHC). DAAs have replaced previous therapy regimes based on PEG-interferon (PEG-IFN) and Ribavirin (RBV). An increased risk for hepatocellular carcinoma (HCC) in patients with advanced liver disease and CHC is known. Effects of DAA-based hepatitis C treatment on subsequent HCC incidence are insufficiently understood. Methods: This retrospective single-institution analysis included 220 consecutive patients after PEG-IFN/RBV and 259 patients after DAA treatment for CHC. HCC, viral load, genotype, treatment type, duration and outcome, fibrosis stage, age, gender, BMI and serum albumin were retrieved. A Cox-proportional hazard model was fit to predict survival regarding HCC, need for liver transplantation, and death. Patient blood samples were retrieved prior, during, and after therapy to compare neutrophil-to-lymphocyte ratio. Results: There were 8 HCC cases among patients treated with DAA observed compared with 17 cases after PEG-INF/RBV treatment. In a multivariate Cox-proportional hazard model, DAA treatment (HR 5.5; P = .047), age (HR 1.07/year; P = .004) and SVR (HR 0.23; P = .002) were significant predictors for HCC. After DAA treatment, time to HCC diagnosis was significantly shorter compared with after PEG-INF/RBV (0.84 years, range: 0.5-2.1 vs. 6.8 years, range: 2.3-15). HCC occurrence was highest within the first year after the start of DAA treatment (5 cases) but lower thereafter (3 cases). Death and the need for liver transplantation did not differ between both groups. Neutrophil-to-lymphocyte ratio results will be ready for the poster presentation. Conclusion: Our data show higher rates of HCC immediately after DAA compared with after PEG-IFN/RBV treatment. A high degree of suspicion regarding HCC seems warranted especially within the first year after the start of DAA treatment.

Improved Graft Survival After Liver Transplantation for Recipients With Hepatitis C Virus in the Direct‐Acting Antiviral Era

Highly effective direct-acting antiviral (DAA) therapy has transformed outcomes of liver transplantation in hepatitis C virus (HCV) patients. We examined longer-term outcomes in HCV-positive recipients in the DAA era and analyzed the Scientific Registry of Transplant Recipients for primary adult, single-organ, nonfulminant liver transplant recipients in the United States from January 1, 2008 to June 30, 2018. Graft loss was compared among HCV-positive liver transplant recipients who received either an HCV-negative or HCV-positive donor (donor [D]-/recipient [R]+; D+/R+) and HCV-negative liver transplant recipients who received a HCV-negative donor (D-/R-). The groups were further divided between the pre-DAA and DAA eras. There were 52,526 patients included: 31,193 were D-/R- patients; 18,746 were D-/R+ patients; and 2587 were D+/R+ patients. The number of D-/R+ transplants decreased from 2010 in 2008 to 1334 in 2017, with this decline particularly noticeable since 2015. D-/R+ patients in the DAA era (n=7107) were older, had higher rates of hepatocellular carcinoma, and lower Model for End-Stage Liver Disease scores than those in the pre-DAA era. Graft survival improved for all recipients in the DAA era but improved most dramatically in HCV-positive recipients: D-/R+ 1-year survival was 92.4% versus 88.7% and 3-year survival was 83.7% versus 77.7% (DAA versus pre-DAA era, respectively) compared with D-/R- 1-year survival of 92.7% versus 91.0% and 3-year survival of 85.7% versus 84.0% (DAA versus pre-DAA era, respectively). The magnitude of improvement in 3-year graft survival was almost 4-fold greater for D-/R+ patients. The 3-year survival for D+/R+ patients was similar to HCV-negative patients. In conclusion, the number of liver transplants for HCV has decreased by more than one-third over the past decade. Graft survival among HCV-positive recipients has increased disproportionately in the DAA era with HCV-positive recipients now achieving similar outcomes to non-HCV recipients.

No evidence for higher rates of hepatocellular carcinoma after direct-acting antiviral treatment: a meta-analysis.

Aim:Hepatitis C virus (HCV) is the leading cause of hepatocellular carcinoma (HCC) in the United States. Achieving sustained viral response with interferon (IFN) treatment reduces the risk from 3%-5% to 0.5%-1% annually. Several studies reported unexpectedly high rates of HCC after treatment with direct-acting antivirals (DAAs). The aim of our study was to compare HCC rates in DAA-, IFN-treated and untreated populations.Methods:A literature search was conducted using ScienceDirect, Ovid®, Web of Science and MEDLINE through January 2019. Studies were included if they measured rates of de novo or recurrent HCC (following curative treatment) in HCV-infected persons. We included 138 studies (n = 177,512). Simple pooling of data and meta-analysis were performed, using the random effects method.Results:Mean age was higher in the DAA-treated vs. IFN-treated group (58.4 years vs. 52.6 years; P = 0.0073), as were diabetes prevalence (34.5% vs. 11.7%; P ≤ 0.001) and incident cirrhosis (47.8% vs. 34.2%, P = 0.0017). The incidence rate of de novo HCC was 2.01/100 person-years (py) (95%CI: 1.38, 2.67) in the DAA group and 1.45/100py (95%CI: 0.98, 1.94) in the IFN-treated group. HCC recurred at 16.76/100py (95%CI: 10.75, 22.91) in the DAA-treated group vs. 20.04/100py (95%CI: 2.58, 45.21) after IFN. After adjusting for factors such as age and cirrhosis, the hazard ratio was 0.58 (95%CI: 0.20, 1.07) for HCC occurrence and 0.59 (95%CI: 0.24, 1.03) for HCC recurrence after DAA treatment compared to IFN-based treatment.Conclusion:We did not find evidence for increased rates of HCC in DAA-treated compared with IFN-treated patients. Compared to those treated with IFN, older patients with additional risk factors for HCC were treated with DAAs. This imbalance appears to explain the higher numerical incidence of HCC among DAA-treated patients.

Long-term outcomes and predictive scores for hepatocellular carcinoma and hepatitis B surface antigen seroclearance after hepatitis B e-antigen seroclearance.

Male sex, older age at ESC, ALT, and higher level of HBV DNA were associated with higher rates of HCC after ESC. HCC-ESC and HBsAg-ESC predictive scores can determine the likelihood of developing HCC and achieving HBsAg seroclearance. (Hepatology 2018).

Hepatocellular carcinoma recurrence in hepatitis C virus-related cirrhosis treated with direct-acting antivirals: a case-control study.

Direct-acting antivirals (DAAs) therapy against hepatitis C viral (HCV) infection has markedly improved the sustained viral response. However, recent studies have suggested an unsuspected high rate of hepatocellular carcinoma (HCC) recurrence. A retrospective case-control study was carried out to investigate the impact of DAAs on tumor recurrence in patients with complete response to HCC treatment within our HCV-related cirrhosis cohort. Patients who received [group 1 (G1), n=22] or not [group 2 (G2), n=49] a DAAs therapy were matched 1 : 2 for age, sex, liver function, HCC stage, and treatment. Initial HCC were mostly Barcelona Clinic Liver Cancer stage A (95% G1, 94% G2). Sustained viral response with DAAs was achieved in 86% of patients. After a similar median overall follow-up time with similar radiologic surveillance after HCC treatment, 41% of patients developed radiologic tumor recurrence in G1 versus 35% of patients in G2 (P=0.7904). There was no significant difference in time to progression between the two groups [12 (9-16) months G1 vs. 14 (8-21) months G2, P=0.7688], or Barcelona Clinic Liver Cancer stage at recurrence. However, the interval between HCC treatment and antiviral therapy was significantly different among DAAs patients with recurrence and those without recurrence [7.0 (2.5-9.0) months vs. 36.0 (9.0-58.0) months, P=0.0235, respectively]. In our case-control study, HCV therapy with DAAs does not accelerate or prevent early HCC recurrence compared with untreated patients. The rate of recurrence, time to progression, and HCC pattern are similar. Early DAAs treatment (<12 months) after HCC cure should be discouraged considering the HCC recurrence rate during this period.

Small-for-size grafts increase recurrence of hepatocellular carcinoma in liver transplantation beyond milan criteria.

Living donor liver transplantation (LDLT) has been reported to have high rates of hepatocellular carcinoma (HCC) recurrence compared with deceased donor liver transplantation (DDLT). This has been assumed to be due to the frequent use of small-for-size grafts (SFSGs) in LDLT rather than DDLT, but the relationship between graft size and prognosis remains controversial. This study aimed to clarify the effect of SFSGs on the oncologic outcomes of patients with HCC who underwent LDLT. Between January 2005 and December 2015, 597 consecutive patients underwent LDLT. Among these patients, those with HCC who underwent LDLT were randomly matched at a 1:3 ratio (graft-to-recipient body weight ratio [GRWR] < 0.8%:GRWR > 0.8%) according to propensity score. HCC recurrence and patient survival were analyzed using the Kaplan-Meier method and log-rank test. In addition, stratified subgroup analysis based on the Milan criteria was performed. SFSG was defined as a GRWR < 0.8%. Using propensity score matching, 82 patients with GRWR < 0.8% and 246 patients with GRWR ≥ 0.8% were selected. For patients with HCC within the Milan criteria, no significant difference of HCC recurrence (P = 0.82) and patient survival (P = 0.95) was found based on GRWR. However, for patients with HCC beyond the Milan criteria, 1-, 3-, and 5-year recurrence-free survival rates were 52.4%, 49.3%, and 49.3%, respectively, for patients with GRWR < 0.8%, and 76.5%, 68.3%, and 64.3%, respectively, for patients with GRWR ≥ 0.8% (P = 0.049). The former group exhibited poor patient survival rates (P = 0.047). In conclusion, for patients with HCC within the Milan criteria, no significant difference in oncologic outcomes was found based on liver graft size. However, among the patients with HCC beyond the Milan criteria, SFSG recipients showed poor oncologic outcomes. Because extended criteria are frequently used in LDLT for HCC, a recipient's prognosis can be improved if a liver graft of appropriate size is carefully selected during donor selection. Liver Transplantation 24 35-43 2018 AASLD.

Delta hepatitis: Toward improved diagnostics.

Delta hepatitis: Toward improved diagnostics.

The Incidence of Hepatocellular Carcinoma Is not Increased in Individuals with Chronic Hepatitis C After Treatment with Interferon-free Regimens: an ERCHIVES Study

BackgroundSustained virologic response (SVR) after interferon-based treatment for chronic hepatitis C virus (HCV) infection has been strongly linked with decreased incidence of hepatocellular carcinoma (HCC). Surprisingly, several recent studies have reported higher rates of HCC in individuals treated with direct-acting antivirals (DAAs). However, making definitive conclusions has been challenging due to the heterogeneous populations and methodologies of these reports. As such, we sought to investigate whether DAA use is associated with increased rates of incident HCC.MethodsUsing the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES) database, we identified 17,836 patients without a prior diagnosis of HCC and divided them into 3 groups based on treatment: (a) pegylated interferon and ribavirin (IFN) (n = 3,534); (b) DAA-based therapy (n = 5,734); and (c) an untreated control group (n = 8,468). Predictors of HCC were identified using multivariate Cox proportional hazards analysis. HCC-free survival in cirrhotics was assessed by Kaplan–Meier analysis.ResultsSVR was achieved by 66.6% and 96.2% of the IFN and DAA groups, respectively. In our cohort, the incidence rate of HCC was not different between IFN and DAA groups (7.48/1000 vs. 7.92/1000 patient-years of follow-up; P = 0.72). Moreover, DAA treatment was not associated with an increased risk of HCC (HR 1.16; [95% CI: 0.79, 1.71]) compared to IFN treatment. Other risk factors for HCC included older age, alcohol abuse/dependance history, smoking history, HCV genotype 3 infection, proton-pump inhibitor use, AFP > 20, and cirrhosis. Notably, among cirrhotics who achieve SVR, HCC-free survival was not different between IFN and DAA treated groups, and both groups had significantly improved HCC-free survival compared with untreated patients.ConclusionAmong cirrhotic patients with HCV, DAA treatment is associated with a comparable risk of HCC to IFN treatment. Furthermore, the rate of HCC after SVR by any treatment was significantly lower than for those untreated or who failed to achieve SVR. Previously reported increases in HCC associated with DAA treatment appear to be explained by the presence of pre-existing risk factors for HCC.Disclosures R. T. Chung, Gilead: Investigator, Research grant; Abbvie: Investigator, Research grant; Merck: Investigator, Research grant; Janssen: Investigator, Research grant; A. Butt, Merck: Investigator, Grant recipient

RETRACTED ARTICLE: Activation of PERK-Nrf2 oncogenic signaling promotes Mdm2-mediated Rb degradation in persistently infected HCV culture

The mechanism of how chronic hepatitis C virus (HCV) infection leads to such a high rate of hepatocellular carcinoma (HCC) is unknown. We found that the PERK axis of endoplasmic reticulum (ER) stress elicited prominent nuclear translocation of Nrf2 in 100% of HCV infected hepatocytes. The sustained nuclear translocation of Nrf2 in chronically infected culture induces Mdm2-mediated retinoblastoma protein (Rb) degradation. Silencing PERK and Nrf2 restored Mdm2-mediated Rb degradation, suggesting that sustained activation of PERK/Nrf2 axis creates oncogenic stress in chronically infected HCV culture model. The activation of Nrf2 and its nuclear translocation were prevented by ER-stress and PERK inhibitors, suggesting that PERK axis is involved in the sustained activation of Nrf2 signaling during chronic HCV infection. Furthermore, we show that HCV clearance induced by interferon-α based antiviral normalized the ER-stress response and prevented nuclear translocation of Nrf2, whereas HCV clearance by DAAs combination does neither. In conclusion, we report here a novel mechanism for how sustained activation of PERK axis of ER-stress during chronic HCV infection activates oncogenic Nrf2 signaling that promotes hepatocyte survival and oncogenesis by inducing Mdm2-mediated Rb degradation.

Geographic epidemiology of hepatocellular carcinoma, viral hepatitis, and socioeconomic position in New York City.

Liver cancer (hepatocellular carcinoma (HCC)) incidence and mortality rates are increasing in the United States. New York City (NYC) has a high burden of liver cancer risk factors, including hepatitis C (HCV) and hepatitis B (HBV) infection, which disproportionately affect persons of low socioeconomic position. Identifying neighborhoods with HCC disparities is essential to effectively define targeted cancer control strategies. New York State Cancer Registry data from 1 January 2001 through 31 December 2012 were matched with NYC HCV and HBV surveillance data. HCC data were aggregated to NYC Zip Code Tabulation Areas (ZCTAs). Moran's I cluster analysis, Poisson regression, and geographically weighted Poisson regression were used to identify hotspots in HCC incidence and to examine the spatial associations with viral hepatitis rates, poverty, and uninsured status. Among NYC residents, 8,827 HCC cases were diagnosed during 2001-2012. Significant clustering was detected in the HCC rates (Moran's I=0.25) with the strongest clustering found in HCC patients with comorbid HCV infection (Moran's I=0.47). Poverty and uninsured status were associated (p<0.05) with increased rates of HCC patients with HBV or HCV infection. Neighborhoods with high rates of HCC without viral hepatitis infection had lower rates of poverty and uninsured status. The geographic variation in HCC highlights the need for neighborhood-targeted interventions to address risk factors and barriers to care. The clusters of HCC by viral hepatitis status may serve as a basis for healthcare policymakers and practitioners to prioritize neighborhoods for cancer screening and control efforts.