The burden of hepatocellular carcinoma (HCC) is highest in East Asia and Africa, although its incidence and mortality are rapidly rising in the United States and Europe. With the implementation of ...hepatitis B vaccination and hepatitis C treatment programmes worldwide, the epidemiology of HCC is shifting away from a disease predominated by viral hepatitis – an increasing proportion of cases are now attributable to non-alcoholic steatohepatitis. Surveillance using ultrasound, with or without alpha-fetoprotein, every 6 months has been associated with improved early detection and improved overall survival; however, limitations in implementation lead to a high proportion of HCC being detected at late stages in clinical practice. Herein, we review the current state of HCC surveillance and highlight areas for future research, including improved risk stratification of at-risk patients, surveillance tools with higher sensitivity and specificity for early HCC, and interventions to increase surveillance utilisation.
Alcohol-related liver disease is the most prevalent type of chronic liver disease worldwide, accounting for 30% of hepatocellular carcinoma (HCC) cases and HCC-specific deaths. Alcohol has been ...associated with an increased risk of several malignancies, this risk starting at doses as low as 10 g/1 unit/day. The carcinogenic process includes direct acetaldehyde toxicity through the formation of protein and DNA adducts, an increased production of reactive oxygen species, changes to lipid peroxidation and metabolism, inflammation and an impaired immune response and modifications to DNA methylation. A high annual incidence of HCC has been observed in large European cohorts of patients with alcoholic cirrhosis, reaching 2.9%, with numerous host factors modulating this risk (age, gender, liver failure, genetic polymorphisms affecting oncogenic pathways). Because of impaired surveillance and poor patient compliance, HCC is often detected late in patients with chronic liver disease of alcoholic aetiology. This delay in detection, which is frequently made in the context of advanced liver cirrhosis rather than in surveillance programmes, results in more advanced HCC that is less amenable to curative treatment. Consequently, patients with alcohol-related HCC generally have a worse prognosis than those with non-alcoholic HCC.
Percutaneous treatment of hepatocellular carcinoma (HCC) encompasses a vast range of techniques, including monopolar radiofrequency ablation (RFA), multibipolar RFA, microwave ablation, cryoablation ...and irreversible electroporation. RFA is considered one of the main curative treatments for HCC of less than 5 cm developing on cirrhotic liver, together with surgical resection and liver transplantation. However, controversies exist concerning the respective roles of ablation and liver resection for HCC of less than 3 to 5 cm on cirrhotic liver. In line with the therapeutic algorithm of early HCC, percutaneous ablation could also be used as a bridge to liver transplantation or in a sequence of upfront percutaneous treatment, followed by transplantation if the patient relapses. Moreover, several innovations in ablation methods may help to efficiently treat early HCC, initially considered as “non-ablatable”, and might, in some cases, extend ablation criteria beyond early HCC, enabling treatment of more patients with a curative approach.
Hepatitis B is an eminent risk factor for hepatocellular carcinoma (HCC) in Southeast Asia and sub‐Saharan Africa, whereas hepatitis C is a key risk factor for HCC in Western Europe and North ...America. Increased awareness of the global burden of viral hepatitis resulted, in May 2016, in the adoption of the first global health sector strategy on viral hepatitis by the World Health Assembly, which calls for the elimination of viral hepatitis as a public health threat by 2030. Although the incidence of liver cancer resulting from viral infections has increased since the 1990s, the implementation of public health interventions, such as hepatitis B vaccination and antiviral therapies might have reduced the global burdens of HCC. Hepatitis B immunization in infancy has been associated with a reduction in the risk of infant fulminant hepatitis, chronic liver disease, and HCC in Taiwan. Achieving viral hepatitis elimination by 2030 can be accelerated by improving the access to HCC screening programs. HCC surveillance programs in developed countries must be refined to increase an access to personalized surveillance program, whereas the limited access to surveillance and treatment of HCC in developing countries remains a significant public health issue.
Among all the software packages available for discriminant analyses based on projection to latent structures (PLS-DA) or orthogonal projection to latent structures (OPLS-DA), SIMCA (Umetrics, Umeå ...Sweden) is the more widely used in the metabolomics field. SIMCA proposes many parameters or tests to assess the quality of the computed model (the number of significant components, R2, Q2, pCV-ANOVA, and the permutation test). Significance thresholds for these parameters are strongly application-dependent. Concerning the Q2 parameter, a significance threshold of 0.5 is generally admitted. However, during the last few years, many PLS-DA/OPLS-DA models built using SIMCA have been published with Q2 values lower than 0.5. The purpose of this opinion note is to point out that, in some circumstances frequently encountered in metabolomics, the values of these parameters strongly depend on the individuals that constitute the validation subsets. As a result of the way in which the software selects members of the calibration and validation subsets, a simple permutation of dataset rows can, in several cases, lead to contradictory conclusions about the significance of the models when a K-fold cross-validation is used. We believe that, when Q2 values lower than 0.5 are obtained, SIMCA users should at least verify that the quality parameters are stable towards permutation of the rows in their dataset.
To date, genomic analyses of hepatocellular carcinoma (HCC) have been limited to early stages obtained from liver resection. We aim to describe the genomic profiling of HCC from early to advanced ...stages. We analyzed 801 HCC from 720 patients (410 resections, 137 transplantations, 122 percutaneous ablations, and 52 noncurative) for 190 gene expressions and for 31 gene mutations. Forty‐one advanced HCC and 156 whole exome of Barcelona Clinic Liver Cancer (BCLC) 0/A were analyzed by whole‐exome sequencing. Genomic profiling was correlated with tumor stages, clinical features, and survival. Our cohort included patients classified in BCLC stage 0 (9.4%), A (59.5%), B (16.2%), and C (14.9%). Among the overall 801 HCC, the most frequently mutated genes were telomerase reverse transcriptase (TERT) (58.1%), catenin beta 1 (CTNNB1) (30.7%), tumor protein 53 (TP53; 18.7%), AT‐rich interaction domain 1A (ARID1A) (13%), albumin (11.4%), apolipoprotein B (APOB) (9.4%), and AXIN1 (9.2%). Advanced‐stage HCC (BCLC B/C) showed higher frequencies of splicing factor 3b subunit 1 (SF3B1) (P = 0.0003), TP53 (P = 0.0006), and RB Transcriptional Corepressor 1 mutations (P = 0.03). G1‐G6 transcriptomic classification and the molecular prognostic 5‐gene score showed different distributions according to the stage of the disease and the type of treatment with an enrichment of G3 (P < 0.0001), poor prognostic score (P < 0.0001), and increased proliferation and dedifferentiation at the transcriptomic level in advanced HCC. The 5‐gene score predicted survival in patients treated by resection (P < 0.0001) and ablation (P = 0.01) and in advanced HCC (P = 0.04). Twenty‐two percent of advanced HCC harbored potentially druggable genetic alterations, and MET amplification was associated with complete tumor response in patients with advanced HCC treated by a specific MET inhibitor. Conclusion: Genomic analysis across the different stages of HCC revealed the mechanisms of tumor progression and helped to identify biomarkers of response to targeted therapies.
The benefit of direct-acting antivirals (DAAs) against HCV following successful treatment of hepatocellular carcinoma (HCC) remains controversial. This meta-analysis of individual patient data ...assessed HCC recurrence risk following DAA administration.
We pooled the data of 977 consecutive patients from 21 studies of HCV-related cirrhosis and HCC, who achieved complete radiological response after surgical/locoregional treatments and received DAAs (DAA group). Recurrence or death risk was expressed as HCC recurrence or death per 100 person-years (100PY). Propensity score-matched patients from the ITA.LI.CA. cohort (n=328) served as DAA-unexposed controls (no-DAA group). Risk factors for HCC recurrence were identified using random-effects Poisson.
Recurrence rate and death risk per 100PY in DAA-treated patients were 20 (95% CI 13.9 to 29.8, I
=74.6%) and 5.7 (2.5 to 15.3, I
=54.3), respectively. Predictive factors for recurrence were alpha-fetoprotein logarithm (relative risk (RR)=1.11, 95% CI 1.03 to 1.19; p=0.01, per 1 log of ng/mL), HCC recurrence history pre-DAA initiation (RR=1.11, 95% CI 1.07 to 1.16; p<0.001), performance status (2 vs 0, RR=4.35, 95% CI 1.54 to 11.11; 2 vs 1, RR=3.7, 95% CI 1.3 to 11.11; p=0.01) and tumour burden pre-HCC treatment (multifocal vs solitary nodule, RR=1.75, 95% CI 1.25 to 2.43; p<0.001). No significant difference was observed in RR between the DAA-exposed and DAA-unexposed groups in propensity score-matched patients (RR=0.64, 95% CI 0.37 to 1.1; p=0.1).
Effects of DAA exposure on HCC recurrence risk remain inconclusive. Active clinical and radiological follow-up of patients with HCC after HCV eradication with DAA is justified.
Hepatocellular carcinoma (HCC) is the leading cause of death in patients with cirrhosis. Patients outside clinical trials seldom benefit from evidence‐based monitoring. The objective of this study ...was to estimate the cost‐effectiveness of complying with HCC screening guidelines. The economic evaluation compared surveillance of patients with cirrhosis as recommended by the guidelines (“gold‐standard monitoring”) to “real‐life monitoring” from the health care system perspective. A Markov model described the history of the disease and treatment course including current first‐line curative treatment: liver resection, radiofrequency ablation (RFA), and liver transplantation. Transition probabilities were derived mainly from two French cohorts, CIRVIR and CHANGH. Costs were computed using French and U.S. tariffs. Effectiveness was measured in life years gained (LYG). An incremental cost‐effectiveness ratio (ICER) was calculated for a 10‐year horizon and tested with one‐way and probabilistic sensitivity analyses. The cost difference between the two groups was $648 ($87,476 in the gold‐standard monitoring group vs. $86,829 in the real‐life monitoring group) in France and $11,965 ($93,795 vs. $81,829) in the United States. Survival increased by 0.37 years (7.18 vs. 6.81 years). The ICER was $1,754 per LYG in France and $32,415 per LYG in the United States. The health gain resulted from earlier diagnosis and access to first‐line curative treatments, among which RFA provided the best value for money. Conclusion: Our results indicate that gold‐standard monitoring for patients with cirrhosis is cost‐effective, attributed to a higher probability of benefiting from a curative treatment and so a higher survival probability. (Hepatology 2017;65:1237‐1248)
Recently, a loss of function variant (rs72613567) in 17‐beta‐hydroxysteroid dehydrogenase 13 (HSD17B13) has been identified as protective of nonalcoholic (NAFLD) and alcoholic liver disease (ALD). ...However, the role of this single‐nucleotide polymorphism (SNP) in the development of hepatocellular carcinoma (HCC) is currently unknown. A total of 3,315 European patients with HCC (n = 1,109) or without HCC, but with chronic liver disease (CLD; n = 2,206), from four centers were analyzed either by whole‐exome sequencing (WES; exploratory cohort, 285 HCC) or genotyped for HSD17B13 rs72613567 (validation cohort, 824 HCC and all CLD). We included a control group of 33,337 healthy European individuals from the Exome Aggregation Consortium. We compared distribution of genotype using the chi‐square test and logistic regression. In the exploratory cohort analyzed by WES, frequency of the TA allele of HSD17B13 rs72613567 was significantly decreased in HCC patients compared to healthy controls (P = 1.52 × 10−06). In the validation cohort, frequency of TA allele carriers was also decreased in patients with CLD and without HCC (39%) compared to healthy individuals (47%; P < 0.0001). The protective effect of the TA allele of HSD17B13 rs72613567 was identified in patients with ALD (odds ratio OR = 0.73; 95% confidence interval CI, 0.65‐0.82; P < 0.0001), NAFLD (OR = 0.64; 95% CI, 0.49‐0.83; P = 0.0007), and hepatitis C (OR = 0.71; 95% CI, 0.60‐0.85; P = 0.0002). In patients with ALD, the proportion of TA allele carriers with HCC was significantly lower (32%) than in CLD patients without HCC (40%), even after adjustment for age, sex, and fibrosis (OR = 0.64; 95% CI, 0.46‐0.87; P = 0.005). Conclusion: The HSD17B13 rs72613567 loss of function variant is protective of HCC development in patients with ALD.
Few single nucleotide polymorphisms (SNPs) have been reproducibly associated with hepatocellular carcinoma (HCC). Our aim was to test the association between nine SNPs and HCC occurrence. SNPs in ...genes linked to HCC (DEPDC5, GRIK1, KIF1B, STAT4, MICA, DLC1, DDX18) or to liver damage (PNPLA3‐rs738409, TM6SF2‐rs58542926) in GWAS were genotyped in discovery cohorts including 1,020 HCC, 2,021 controls with chronic liver disease and 2,484 healthy individuals and replication was performed in prospective cohorts of cirrhotic patients with alcoholic liver disease (ALD, n = 249) and hepatitis C (n = 268). In the discovery cohort, PNPLA3 and TM6SF2 SNPs were associated with HCC (OR = 1.67 CI95%:1.16–2.40, p = 0.005; OR = 1.45 CI95%:1.08–1.94, p = 0.01) after adjustment for fibrosis, age, gender and etiology. In contrast, STAT4‐rs7574865 was associated with HCC only in HBV infected patients (p = 0.03) and the other tested SNP were not linked with HCC risk. PNPLA3 and TM6SF2 variants were independently associated with HCC in patients with ALD (OR = 3.91 CI95%:2.52–6.06, p = 1.14E‐09; OR = 1.79 CI95%:1.25–2.56, p = 0.001) but not with other etiologies. PNPLA3 SNP was also significantly associated with HCC developed on a nonfibrotic liver (OR = 2.19 CI95%:1.22–3.92, p = 0.007). The association of PNPLA3 and TM6SF2 with HCC risk was confirmed in the prospective cohort with ALD. A genetic score including PNPLA3 and TM6SF2 minor alleles showed a progressive significant increased risk of HCC in ALD patients. In conclusion, PNPLA3‐rs738409 and TM6SF2‐rs58542926 are inherited risk variants of HCC development in patients with ALD in a dose dependent manner. The link between PNPLA3 and HCC on nonfibrotic liver suggests a direct role in liver carcinogenesis.
What's new?
Multiple single nucleotide polymorphisms (SNPs) have been associated with hepatocellular carcinoma (HCC) through genome‐wide association studies (GWAS). Few of these variants, however, have been cross‐validated, raising questions about their relation to HCC. Here, nine SNPs previously linked to HCC or liver damage were selected for investigation in European patients. Two of the variants, PNPLA3 rs738409 and TM6SF2 rs58542926, were found to be associated with HCC risk specifically in patients with alcoholic liver disease. PNPLA3 rs738409 was also associated with HCC in patients with nonfibrotic livers, where it potentially influences liver carcinogenesis via modification of protein function without altering gene expression.
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