Clinical and morpho-molecular classifiers for prediction of hepatocellular carcinoma prognosis and recurrence after surgical resection Abstract Background Approximately 50% hepatocellular carcinoma (HCC) patients die within 5 year after surgical resection. The present staging systems do not fully allow to accurately predict the HCC prognosis and recurrence. This study aimed to identify clinicopathological characteristics and molecular markers to establish classifiers to predict the 5-year overall survival (OS) and the 3-year recurrence in HCC patients post-operatively. Methods We enrolled 647 HCC patients from two institutions, underwent surgical resection and divided the patients into one training and two validation cohorts. Clinicopathologic characteristics and tumor protein expression of 29 biomarkers by immunohistochemical (IHC) analysis were used to develop and validate a prognostic and a recurrent classifier, using the maximum relevance minimum redundancy algorithm jointly with the multivariable regression method. Results The prognostic classifier distinguished HCC patients into high- and low-probability survival groups with significant differences in 5-year OS rate in all three cohorts (training cohort: 57.36% vs. 22.97%; p < 0.0001; internal validation cohort: 61.90% vs. 28.85%; p < 0.0001; independent validation cohort: 64.28% vs. 22.45%; p < 0.0001). The recurrent classifier also demonstrated good discrimination in all three cohorts. Conclusion This study presented a prognostic classifier and a recurrent classifier using clinicopathologic and IHC characteristics. The developed classifiers stratified HCC patients into high- and low-probability survival or recurrent groups, which can help clinicians judge whether adjuvant therapy is beneficial post-operatively.

Significant decrease in Faecalibacterium among gut microbiota in nonalcoholic fatty liver disease: a large BMI- and sex-matched population study Abstract Background Compositional changes of the gut microbiota are known to occur in patients with nonalcoholic fatty liver disease (NAFLD); however, the changes did not corroborate between the studies. We evaluated the gut microbiota between NAFLD and non-NAFLD participants, excluding the influence of obesity and sex in this study involving a large number of participants. Methods In total, 1148 adults participated in the health survey. NAFLD was defined as fatty liver by ultrasonography in the absence of other causes of steatosis. To exclude the influence of obesity and sex, NAFLD participants were matched to non-NAFLD participants based on BMI and sex. The relative abundance of each bacterial taxa in fecal samples was calculated using 16S ribosomal RNA amplification and was compared between NAFLD and non-NAFLD participants. Results There were 205 (23.5%) participants defined as having NAFLD. Before matching, there were significant differences in the relative abundance of more than 1% in two classes, two orders, three families, and three genera including Faecalibacterium between NAFLD and non-NAFLD participants. After matching, 153 matched pairs were obtained. In terms of the relative abundance of more than 1%, the relative abundance of two taxa, including the family Ruminococcaceae and the genus Faecalibacterium, was significantly lower in NAFLD participants than in non-NAFLD participants (p = 0.016 and p = 0.018). Conclusions The significant decrease in Faecalibacterium is a remarkable characteristic on BMI- and sex-matched analysis in NAFLD participants in a large study population. The decrease in Faecalibacterium is related to the pathogenesis of NAFLD.

Generic sofosbuvir/ledipasvir for the treatment of genotype 4 chronic hepatitis C in Egyptian children (9–12 years) and adolescents Abstract Background/purpose of the study Worldwide and national efforts are directed against eradication of HCV. The introduction of direct-acting antivirals (DAAs) has changed dramatically the outcome of HCV treatment. In spite of the Food and Drug Administration approval of the oral drugs sofosbuvir (SOF) and ledipasvir (LED) for the treatment of HCV in adolescents more than or equal to 12 years old, sufficient real-world experience is still lacking. The aim of this study was to assess the safety and efficacy of the generic SOF/LED fixed-dose combination 400/90 (400 mg SOF + 90 mg LED) for the treatment of adolescents and children (9–12 years) with chronic hepatitis C (CHC). Methods In this prospective observational study, 100 cases of genotype 4 CHC were recruited consecutively from those fulfilling the inclusion and exclusion criteria. All cases received the generic fixed-dose combination SOF/LED (400/90), one tablet daily for 12 weeks. All clinical, laboratory, and virologic characteristics were evaluated at base line, and week (W) 2, 4, 8, and 12 of therapy and W12 post-treatment (SVR12). Results Recruited children (9–12) and adolescents weighed 28–83 and 31–90 kg, respectively. Eighty cases were naïve and 20 cases were pegylated interferon/ribavirin treatment-experienced. Very rapid virologic response (vRVR) at W2 was 96%, while at W4 response rate was 100% and maintained till the end of treatment and at W12 post-treatment (SVR12). All reported side effects were mild and did not lead to treatment termination and disappeared at W12 post-treatment. Conclusion The generic SOF/LED fixed-dose combination is safe and effective in children, 9–12 years, and adolescents with vRVR rate of 96%, 100% EOT response and SVR12.

Cellular and functional loss of liver endothelial cells correlates with poor hepatocyte regeneration in acute-on-chronic liver failure Abstract Background and aim Acute hepatic insult triggers regeneration. If acute-on-chronic liver failure (ACLF) patients have a poorer regenerative response than acute liver failure (ALF) patients, and if so, the mechanisms underlying this, are not well understood. Methods We investigated the status of hepatocyte proliferation, hepatic progenitor cell (HPC) mediated regeneration, non-parenchymal cells (through immunohistochemistery), cytokines and growth factors (cytokine bead array) in liver and peripheral blood of ACLF (n = 29) and ALF (n = 17) patients. Liver endothelial cells, mesenchymal cells and Kupffer cells were isolated from explant livers and analysis of regenerative factors was done by qRT-PCR. Results Unlike ALF, the ACLF livers showed decreased hepatocyte proliferation (p < 0.001) and profound ductular-reaction with increased CK19 + hepatocytes (p < 0.0001). However, only decrease in Ki67+ hepatocytes was associated with 28 day mortality in ACLF (p < 0.001; HR = 0.78; 95% CI 0.69–0.88). In both groups, increase in plasma hepatocyte growth factor (HGF) (OR = 21.87 p = 0.002;), macrophage colony stimulating factor (MCSF) (OR = 21.73; p = 0.002) and stromal derived factor (SDF1)(OR = 10.2; p = 0.001) were associated with hepatocyte proliferation and decreased (> fivefolds) levels were associated with poor hepatocyte regeneration in ACLF patients. ACLF livers showed decrease in endothelial cells (p < 0.01) and expression of regenerative angiocrine factors C-X-C chemokine receptor type 7 (CXCR7), Inhibitor of DNA Binding 1(IDI) and HGF compared to ALF. In co-culture, while ALF liver mesenchymal stromal cells (LMSCs) induced the expression of CXCR7, IDI and HGF in human umbilical cord endothelial cells (HUVECs), the ACLF LMSCs were defective and showed decreased production of SDF-1, HGF and MCSF compared to ALF. Conclusions Decrease in hepatic endothelial cells and their regenerative angiocrine functions indicated by defective CXCR7-ID1 dependent HGF expression underlie the poor hepatocyte proliferation in ACLF compared to ALF patients. A robust hepatocyte self-replication is lacking in the livers of ACLF patients and is associated with poor survival.

Preoperative transcatheter arterial chemoembolization for surgical resection of huge hepatocellular carcinoma (≥ 10 cm): a multicenter propensity matching analysis Abstract Background and Aims Surgical resection for hepatocellular carcinoma (HCC) is potentially curative, but long-term survival remains unsatisfactory. There is currently no effective neoadjuvant or adjuvant therapy for HCC. We sought to evaluate the impact of preoperative transcatheter arterial chemoembolization (TACE) on long-term prognosis after surgical resection of huge HCCs (≥ 10 cm). Methods Using a multicenter database, consecutive patients who underwent curative-intent resection for huge HCC without macrovascular invasion between 2004 and 2014 were identified. The association between preoperative TACE with perioperative outcomes, long-term overall survival (OS), and recurrence-free survival (RFS) was assessed before and after propensity score matching (PSM). Results Among the 377 enrolled patients, 88 patients (23.3%) received preoperative TACE. The incidence of perioperative mortality and morbidity was comparable among patients who did and did not undergo preoperative TACE (3.4% vs. 2.4%, p= 0.704, and 33.0% vs. 31.1%, p= 0.749, respectively). PSM analysis created 84 matched pairs of patients. In examining the entire cohort as well as the PSM cohort, median OS (overall cohort: 32.8 vs. 22.3 months, p= 0.035, and PSM only: 32.8 vs. 18.1 months, p= 0.023, respectively) and RFS (12.9 vs. 6.4 months, p= 0.016, and 12.9 vs. 4.1 months, p= 0.009, respectively) were better among patients who underwent preoperative TACE vs. patients who did not. After adjustment for other confounding factors on multivariable analyses, preoperative TACE remained independently associated with a favorable OS and RFS after the resection of huge HCC. Conclusion Preoperative TACE did not increase perioperative morbidity or mortality, yet was associated with an improved OS and RFS after liver resection of huge HCC (≥ 10 cm).

Prognostic four-gene signature for overall survival in patients with hepatocellular carcinoma

Reversal of NASH fibrosis with pharmacotherapy Abstract NAFLD is a spectrum of liver disease starting with fatty liver at one end of the spectrum and cirrhosis or liver cancer at the other end. Worldwide, NAFLD has become one of the most common liver diseases and it has also become one of the leading indications for liver transplantation. Our understanding of the NAFLD epidemiology, pathogenesis and its progression to cirrhosis has improved over the last 2 decades. Currently, however, there are no FDA-approved treatment options for fibrosis resulting from NAFLD. A number of compounds targeting multiple pathways involved in the progression of NAFLD are currently in phase 2–3 trials. In this review, we will briefly discuss the epidemiology, the pathogenesis and the current status of treatment of NAFLD.

The change in the nationwide seroprevalence of hepatitis C virus and the status of linkage to care in South Korea from 2009 to 2015 Abstract Background Hepatitis C virus (HCV) requires epidemiological monitoring to estimate its disease burden and to develop countermeasures. This study aimed to investigate the difference between the 2015 and 2009 nationwide anti-HCV seroprevalence and to determine linkage to care estimates in South Korea. Methods A total 268,422 examinees ≥ 20 years old were included in 2015 from 33 medical institutions nationwide. Electronically extracted data were retrospectively analyzed to calculate the age-, sex-, and area-adjusted anti-HCV prevalence. Seroprevalence in 2015 was measured using the same method as that in 2009. For anti-HCV-positive subjects, medical records were reviewed to see whether HCV RNA testing or antiviral treatment was performed. Results Adjusted anti-HCV prevalence was 0.60% (95% confidence interval, 0.57–0.63) based on general Korean population in 2015. It showed an increasing trend according to age; 0.23% in thirties, 0.38% in forties, 0.63% in fifties, 1.08% in sixties, and 1.65% in those aged ≥ 70 years. From 2009 to 2015, the adjusted anti-HCV prevalence decreased by 30%, with odds ratio of 0.70 (95% CI 0.70–0.71). There was significant intranational regional variation and changing pattern of seroprevalence. Among 1359 anti-HCV-positive subjects, HCV RNA test was performed in 60% and 25.4% had positivity. Treatment-initiated and cured rates in 2015 were 18.5% and 10.9%, respectively. Conclusions Anti-HCV prevalence in South Korea was 0.6% in 2015, showing a 30% decrease from that in 2009. Although the HCV RNA testing rate was increased since 2009, this remains suboptimal. Moreover, the treatment uptake rate should be improved in South Korea.

Radiomics in hepatocellular carcinoma: a quantitative review Abstract Radiomics is an emerging field which extracts quantitative radiology data from medical images and explores their correlation with clinical outcomes in a non-invasive manner. This review aims to assess whether radiomics is a useful and reproducible method for clinical management of hepatocellular carcinoma (HCC) by reviewing the strengths and weaknesses of current radiomics literature pertaining specifically to HCC. From an initial set of 48 articles recovered through database searches, 23 articles were retained to be included in this review after full screening. Among these 23 studies, 7 used a radiomics approach in magnetic resonance imaging (MRI). Only two studies applied radiomics to positron emission tomography–computed tomography (PET–CT). In the remaining 14 articles, a radiomics analysis was performed on computed tomography (CT). Eight studies dealt with the relationship between biological signatures and imaging findings, and can be classified as radiogenomic studies. For each study included in our review, we computed a Radiomics Quality Score (RQS) as proposed by Lambin et al. We found that the RQS (mean ± standard deviation) was 8.35 ± 5.38 (out of a possible maximum value of 36). Although these scores are fairly low, and radiomics has not yet reached clinical utility in HCC, it is important to underscore the fact that these early studies pave the way for the radiomics field with a focus on HCC. Radiomics is still a very young field, and is far from being mature, but it remains a very promising technology for the future for developing adequate personalized treatment as a non-invasive approach, for complementing or replacing tumor biopsies, as well as for developing novel prognostic biomarkers in HCC patients.

An imbalance between stellate cells and γδT cells contributes to hepatocellular carcinoma aggressiveness and recurrence Abstract Purpose The diagnostic potential of hepatic stellate cells (HSCs) and γδT cells for patients with hepatocellular carcinoma (HCC) and their synergistic contributions to the prognosis of these patients have not yet been investigated. The aim of this study was to elucidate the prognostic value of these cells in HCC. Methods The prognostic significance of the ratio of HSCs to γδT cells (SGR) was assessed in a total of 339 HCC patients undergoing resection. The correlation between the circulating tumor cell (CTC) level and SGR in 71 HCC patients was determined using the CellSearch system. In vitro experiments were performed to validate the synergistic effects of HSCs and γδT cells on hepatoma cells. Results Peritumoral SGR was closely associated with overall survival (OS) and recurrence-free survival (RFS) of HCC patients after resection. In the testing cohort, two nomograms incorporating the SGR were constructed for the prediction of OS and RFS. The predictive accuracy of the two nomograms was verified by the validation cohort. CTC levels were positively correlated with SGR (r = 0.479, p < 0.001). Among the patients with CTCs > 2/7.5 ml, those with a high SGR exhibited higher early recurrence rates than those with a low SGR. In vitro experiments revealed that the secretion of INF-γ, IL-17, and TNF-α from γδT cells was increased after culture with HSC-conditioned medium. In addition, γδT cells cultured with HSC-conditioned medium decreased the proliferative and invasive abilities of hepatoma cells. Conclusions The peritumoral SGR is related to aggressive tumor behavior and has a powerful predictive value in HCC. Early recurrence in patients with a high peritumoral SGR might be associated with high CTC levels.