Significance of serum IP-10/CXCL10 measurement in predicting post-direct acting antiviral treatment liver function in patients with HCV-decompensated liver cirrhosis.

BACKGROUND: Recently, with the advent of sofosbuvir/velpatasvir therapy, sustained virological response (SVR) can now be achieved even in patients with decompensated cirrhosis (dLC). However, the prognosis after SVR does not always improve in dLC, and appropriate indicators enabling prediction of prognosis is desired. PATIENTS AND METHODS: Serum IP-10/CXCL10 levels were measured in 47 patients (15 chronic hepatitis [CH], 17 compensated cirrhosis [cLC], and 15 dLC) receiving direct acting antiviral (DAA) therapy, and their changes during the therapy were examined. RESULTS: All the patients achieved SVR. In patients with CH, the average IP-10 level was 367, 102, and 68 pg/ml respectively at baseline, at the end of therapy and at 12 weeks after SVR (SVR12), and was decreased upon DAA therapy (P < 0.001). In patients with cLC, IP-10 was respectively 215, 91, and 77 pg/ml, and was decreased upon DAA therapy (P < 0.001) while it was 283, 131, and 182 pg/ml in patients with dLC and there was no evident decrease (P = 0.55). When patients with dLC were further classified depending on the difference in Child-Pugh (CP) score improvement at SVR12, a significant decrease in IP-10 was observed after treatment in those with improvement (P = 0.023) while a significant increase was observed in those without improvement (P = 0.016). CONCLUSION: While serum IP-10 level was decreased in patients with CH/cLC and dLC with post-SVR-CP improvement following SVR, it was increased in patients with dLC without post-SVR CP improvement. The result indicates that IP-10 dynamics may be useful for predicting liver function after DAA therapy.

The Impact of Antiviral Therapy for Hepatitis C Virus on the Survival of Patients after Hepatocellular Carcinoma Treatment.

Objective Owing to advances in direct-acting antiviral (DAA) therapy, a considerable number of patients with hepatitis C virus (HCV)-positive hepatocellular carcinoma (HCC) are now able to achieve a sustained viral response (SVR) after curative treatment of HCC. However, the beneficial effect of a DAA-SVR on the survival remains unclear. Methods A total of 205 patients with HCC who were HCV-positive with Child-Pugh A at the onset from 2008 to 2018 were categorized into 2 groups: 140 patients untreated for HCV throughout the entire course after HCC development (untreated group) and 65 patients treated for HCV with DAAs following HCC treatment who achieved an SVR (SVR group). After propensity score matching, 63 patients from each group were selected. Using these patients, the survival and maintenance of Child-Pugh A after HCC treatment were compared between the untreated group and SVR group. Results There was a significant difference in the overall survival (p<0.001) and the rate of maintaining Child-Pugh A (p<0.001) between the groups. The 5-year survival rates were 96% (SVR group) and 60% (untreated group), and the proportions of patients with Child-Pugh A at 5 years after HCC treatment were 96% (SVR group) and 38% (untreated group). Conclusion In patients with HCV-positive HCC, achieving a DAA-SVR after HCC treatment significantly improved the overall survival rate compared with HCV-untreated patients. The contribution of DAA-SVR during the course of HCC treatment to a longer survival is mainly due to the prevention of the progression of Child-Pugh A to B/C. Further research is needed to determine whether aggressive antiviral therapy is also effective for HCC patients with Child-Pugh B/C.

Analysis of direct-acting antiviral-resistant hepatitis C virus haplotype diversity by single-molecule and long-read sequencing.

The method of analyzing individual resistant hepatitis C virus (HCV) by a combination of haplotyping and resistance-associated substitution (RAS) has not been fully elucidated because conventional sequencing has only yielded short and fragmented viral genomes. We performed haplotype analysis of HCV mutations in 12 asunaprevir/daclatasvir treatment-failure cases using the Oxford Nanopore sequencer. This enabled single-molecule long-read sequencing using rolling circle amplification (RCA) for correction of the sequencing error. RCA of the circularized reverse-transcription polymerase chain reaction products successfully produced DNA longer than 30 kilobase pairs (kb) containing multiple tandem repeats of a target 3 kb HCV genome. The long-read sequencing of these RCA products could determine the original sequence of the target single molecule as the consensus nucleotide sequence of the tandem repeats and revealed the presence of multiple viral haplotypes with the combination of various mutations in each host. In addition to already known signature RASs, such as NS3-D168 and NS5A-L31/Y93, there were various RASs specific to a different haplotype after treatment failure. The distribution of viral haplotype changed over time; some haplotypes disappeared without acquiring resistant mutations, and other haplotypes, which were not observed before treatment, appeared after treatment. Conclusion: The combination of various mutations other than the known signature RAS was suggested to influence the kinetics of individual HCV quasispecies in the direct-acting antiviral treatment. HCV haplotype dynamic analysis will provide novel information on the role of HCV diversity within the host, which will be useful for elucidating the pathological mechanism of HCV-related diseases.

Spontaneous portosystemic shunt diameter predicts liver function after balloon-occluded retrograde transvenous obliteration.

BACKGROUND AND AIM: Recently, balloon-occluded retrograde transvenous obliteration (BRTO), performed for spontaneous portosystemic shunts (SPSS), has been receiving attention as a measure to improve liver function in cirrhotic patients with portal hypertension. However, it is unclear whether SPSS diameter is associated with changes in hepatic venous pressure gradient (HVPG) and liver function after BRTO. METHODS: In 34 cirrhotic patients receiving BRTO for hepatic encephalopathy/gastric varices, the association of SPSS diameter with liver function at baseline and 6 months after BRTO and the accompanying changes in HVPG were investigated. RESULTS: Patients had Child-Pugh (CP) scores of A/B/C (7/19/8), SPSS diameters of ≤10 mm/11-20 mm/<20 mm (8/21/5), and an average observation period of 3.2 (0.3-8.5) years. SPSS diameter was significantly associated with male sex, alcohol use, and values of albumin, prothrombin time (PT%), and NH3 at baseline. Moreover, the SPSS diameter was significantly correlated with the changes in HVPG observed upon BRTO (r = 0.55, P = 0.005), and a large shunt diameter was significantly associated with a greater increase in HVPG. At 6 months, significant improvements in albumin, PT%, bilirubin, and NH3 were observed overall, but the improvement was marked in those with larger shunt diameters if they had CP A/B. CONCLUSION: SPSS diameter was strongly associated with liver function at baseline and after BRTO and also with changes in HVPG, indicating that SPSS diameter is an important predictor of BRTO outcome.

Usefulness of Cell-Free Human Telomerase Reverse Transcriptase Mutant DNA Quantification in Blood for Predicting Hepatocellular Carcinoma Treatment Efficacy.

Although the usefulness of liquid biopsy as a biomarker in the treatment of hepatocellular carcinoma (HCC) has been suggested, its usefulness in transcatheter arterial chemoembolization (TACE) or tyrosine kinase inhibitor (TKI) therapies has not been reported in detail. In this study, we investigated the clinical value of a cell-free (cf)DNA quantification system targeting the human telomerase reverse transcriptase (hTERT) promoter mutation in advanced HCC treatment. Plasma from 67 patients with advanced HCC, treated with TACE and TKI, was used for extraction of cfDNA. We defined cfDNA with the hTERT promoter C228T mutation as circulating mutant DNA (mutant DNA) and without the mutation as circulating wild-type DNA (wild-type DNA). We analyzed the changes in mutant and wild-type DNA levels during HCC treatment and examined the relationship between changes in the cfDNA level and the clinical course. Mutant DNA was detected in 73.1% (49/67) of the patients during HCC treatment. In univariate analysis, factors associated with detection of mutant DNA before treatment were the intrahepatic maximum tumor diameter (P = 0.015) and protein induced by vitamin K absence (PIVKAII) (P = 0.006). The degree of mutant DNA change after TACE was significantly correlated with tumor volume (P < 0.001), reflecting the treated tumor volume. Responders with peak cfDNA levels within 1 week of TKI initiation had significantly better progression-free survival than nonresponders (P = 0.004). Conclusion: Changes in blood hTERT promoter mutant DNA levels during TACE or TKI treatment indirectly reflect the amount of HCCs and are useful for predicting long-term treatment responses.

Role of magnifying endoscopy with narrow-band imaging in the diagnosis of noninvasive gastric neoplasia.

BACKGROUND AND AIM: There are no globally approved, distinguishing criteria enabling the classification of gastric adenomas and intramucosal carcinomas for differential diagnosis of noninvasive neoplasia (NIN). METHODS: Next-generation sequencing of 50 cancer-related genes was undertaken on 68 pathologically diagnosed microdissected gastric neoplasms (25 adenomas, 27 intramucosal carcinomas, and 16 submucosal carcinomas) obtained during endoscopic submucosal dissection. Findings from magnifying endoscopy with narrow-band imaging (M-NBI) of 52 NINs (the 25 adenomas and 27 intramucosal carcinomas) were compared with these data. RESULTS: Among all 68 neoplasms, the most frequently mutated genes were APC (76% in adenoma, 11.1% in intramucosal carcinoma, and 0% in submucosal carcinoma; P < 0.001) and TP53 in intramucosal and submucosal carcinomas (8% in adenoma, 48.1% in intramucosal carcinoma, and 75% in submucosal carcinoma; P < 0.001). Dividing the NIN neoplasms into five groups according to their mutational status (A1: APC mutation, A2: APC + α mutation, B: APC + TP53 mutation, C: TP53 mutation, D: no mutation in either APC or TP53) resulted in almost identical diagnoses by pathology and M-NBI for groups A1 (12/13, 92%), C (12/13, 92%), and D (16/17, 94%) but not for groups A2 (3/7, 43%) or B (0/2, 0%). This finding implies that NINs with the APC + α mutation have carcinoma-like endoscopic features despite most being judged as adenomas by pathology. CONCLUSION: A diagnosis of NINs by pathology or M-NBI in the subset of gastric tumors classified by cancer-related mutations is not completely identical, suggesting the possible additional role of M-NBI in diagnosing NINs. Further studies are needed to confirm this.

Deep sequencing analysis of serum hepatitis B virus-RNA during nucleot(s)ide analogue therapy.

AIM: Recently, serum hepatitis B virus (HBV)-RNA has been reported to be detectable even when HBV particle production is inhibited by nucleot(s)ide analogues (NAs). However, the dynamics of the HBV-RNA sequence compared with those of HBV-DNA during the emergence of antiviral resistance are yet to be elucidated. METHODS: First, we quantified serum HBV-RNA in 181 infected patients, and its relationships with clinical characteristics as well as HBV markers were investigated. Next, we undertook simultaneous deep sequencing of HBV-RNA/HBV-DNA and their dynamics among four patients receiving NA therapy who were experiencing viral breakthrough. RESULTS: Serum HBV-RNA was detected in 25% (31/123) of cases among patients with HBV without NAs, and the detection rate was significantly high in hepatitis B e antigen-positive cases with high viral activity. In patients with chronic hepatitis, hepatitis B core-related antigen was significantly correlated with serum HBV-RNA irrespective of NA use. In the analysis of the four patients experiencing viral breakthrough, no NA resistance mutation was detected in the serum HBV-RNA immediately before the breakthrough. However, NA-resistant sequences appeared at the rates of 0%, 3%, 14%, and 100%, and the NA-resistant HBV-RNA sequence rate was correlated with the peak HBV-DNA titer multiplied by the HBV-DNA detection duration during the breakthrough (R2 = 0.978) observed before redisappearance of HBV-DNA following the addition of new NA. CONCLUSION: Serum HBV-RNA could reflect the transcriptional activity of covalently closed circular DNA and hepatitis B core-related antigen. The dynamics of HBV-RNA could help understanding of the turnover process of HBV covalently closed circular DNA in the liver.

Fractionated small cell-free DNA increases possibility to detect cancer-related gene mutations in advanced colorectal cancer.

BACKGROUND AND AIM: Liquid biopsy is a method that can efficiently detect tumor genetic abnormalities from body fluids such as blood and urine. Detection sensitivity and the available number of mutations in cell-free DNA (cfDNA) are limited. In this study, we develop a highly sensitive and comprehensive method to detect mutations from cfDNA by concentrating tumor fractions of small cfDNA in advanced colorectal cancers. METHODS: Biopsied specimens and 37 serum samples were collected from 27 patients with advanced colorectal carcinoma. A serum-extracted cfDNA was divided into enriched fractionated small cfDNA and unfractionated cfDNA. Both cfDNAs were subjected to digital polymerase chain reaction (PCR) to evaluate their KRAS, BRAF, CDKN2A, and TP53 status. Consequently, their mutant allele frequencies (MAFs) were compared and analyzed by next-generation sequencing (NGS) in conjunction with tissue-derived DNA. RESULTS: NGS analyses revealed mutations in TP53 (63%), KRAS (63%), APC (30%), and PIK3CA (22%). Digital PCR could detect mutations in 25 of 27 samples (93%) of unfractionated cfDNA, a rate that increased to 100% when samples were enriched with fractionated small cfDNA (6.8 vs 10.7%, P < 0.001). NGS also showed increased MAFs in fractionated small cfDNA compared to unfractionated cfDNA (16.3 vs 18.8%, P = 0.012) and a tendency to detect a greater number of cancer-related genes in fractionated cfDNA. CONCLUSIONS: Fractionated small cfDNA increased MAFs of gene mutations and increases the possibilities to detect cancer-related genes even in advanced cancer patients from whom it is difficult to obtain tissue samples.

Cancer-related genetic changes in multistep hepatocarcinogenesis and their correlation with imaging and histological findings.

AIM: The landscape of cancer-related genetic aberrations in hepatocellular carcinoma (HCC) has gradually become clear through recent next-generation sequencing studies. However, it remains unclear how genetic aberrations correlate with imaging and histological findings. METHODS: Using 117 formalin-fixed paraffin-embedded specimens of primary liver tumors, we undertook targeted next-generation sequencing of 50 cancer-related genes and digital polymerase chain reaction of hTERT. After classifying tumors into several imaging groups by hierarchal clustering with the information from gadoxetic acid enhanced magnetic resonance imaging, contrast-enhanced computed tomography, contrast-enhanced ultrasound, and diffusion-weighted imaging magnetic resonance imaging, the correlation between genetic aberrations and imaging and histology were investigated. RESULTS: Most frequent mutations were hTERT (61.5%), followed by TP53 (42.7%), RB1 (24.8%), and CTNNB1 (18.8%). Liver tumors were classified into six imaging groups/grades, and the prevalence of hTERT mutations tended to increase with the advancement of imaging/histological grades (P = 0.026 and 0.13, respectively), whereas no such tendency was evident for TP53 mutation (P = 0.78 and 1.00, respectively). Focusing on the mutations in each tumor, although the variant frequency (VF) of hTERT did not change (P = 0.36 and 0.14, respectively) in association with imaging/histological grades, TP53 VF increased significantly (P = 0.004 and <0.001, respectively). In multivariate analysis, stage III or IV (hazard ratio, 3.64; P = 0.003), TP53 VF ≥ 50% (hazard ratio, 3.79; P = 0.020) was extracted as an independent risk for recurrence in primary HCC patients. CONCLUSIONS: Increased prevalence of hTERT mutation and increased TP53 mutation VF are characteristic features of HCC progression, diagnosed with imaging/histological studies.

HBV preS deletion mapping using deep sequencing demonstrates a unique association with viral markers.

AIM: Deletions are observed frequently in the preS1/S2 region of hepatitis B virus (HBV) genome, in association with liver disease advancement. However, the most significant preS1/S2 region and its influences on viral markers are unclear. METHODS: The preS1/S2 HBV regions of 90 patients without antiviral therapy were subjected to deep sequencing and deleted regions influencing viral markers were investigated. RESULTS: From the deletion frequency analysis in each patient, deletions were observed most frequently in the preS2 codon 132-141 region. When the patients were divided into three groups (0-0.1%: n = 27, 0.1%-10%: n = 34, 10-100%: n = 29), based on the deletion frequency, FIB-4 (p < 0.01), HBV DNA (p < 0.01), HBcrAg (p < 0.01) and preS1/S2 start codon mutations (p < 0.01, both) were significantly associated with the deletion. When clinical and viral markers were investigated by multivariate analysis for their association with the deletion, FIB-4 (p < 0.05), HBcrAg (p < 0.05), and preS1 start codon mutation (p < 0.01) were extracted as independent variables. When the influence of the preS codon 132-141deletions on HBsAg and HBcrAg, relative to HBV DNA, was investigated, the HBsAg/HBV DNA ratio was lower (0-10% vs. 10%-100%, p<0.05), while the HBcrAg/HBV DNA rati o was higher (0-0.1% vs. 10%-100%, p<0.05) in the presence of the preS codon 132-141deletions. CONCLUSION: The preS codon.132-141 deletions have a significant influence on the clinical characteristics and viral markers, even when present as a minor population. Importantly, the preS codon 132-141 deletions have a clear influence on the viral life cycle and pathogenesis.

Hepatitis B virus (HBV)-infected patients with low hepatitis B surface antigen and high hepatitis B core-related antigen titers have a high risk of HBV-related hepatocellular carcinoma.

AIM: Although the viral markers hepatitis B surface antigen (HBsAg) and hepatitis B core-related antigen (HbcrAg) could reflect intrahepatic hepatitis B virus (HBV) replication activity and constitute important biomarkers for hepatocellular carcinoma (HCC), the value of using these two markers in combination for assessing HCC risk has not been clarified in detail. METHODS: Four hundred and forty-nine consecutive patients with chronic HBV infection were included in the study and the association of HBsAg and HBcrAg with HCC risk was investigated cross-sectionally, as well as longitudinally. RESULTS: When the high value cut-offs of HBsAg and HBcrAg were defined as 3.0 log IU/mL and 3.0 log U/mL, respectively, patients with a history of HCC were found frequently in the low HBsAg group (P = 0.002) and high HBcrAg group (P < 0.001). When HBsAg and HBcrAg were combined, an HCC history was most frequent in the subset with low HBsAg and high HBcrAg, among the HBeAg-negative patients (odds ratio [OR], 7.83; P < 0.001), irrespective of nucleos(t) ide analogue (NA) therapy (NA: OR, 4.76; P < 0.001; non-NA: OR, 9.60; P < 0.001). In a longitudinal analysis of the subsequent development of HCC, carried out on the 338 patients without an HCC history at enrollment, HCC developed significantly more frequently in the low HBsAg/high HBcrAg group (P = 0.005). CONCLUSIONS: Patients with low HBsAg/high HBcrAg values are at high risk of developing HBV-related HCC, according to this cross-sectional and longitudinal analysis, indicating that the combination of HBsAg and HBcrAg values is an excellent biomarker for assessing HCC risk.

Association between alanine aminotransferase elevation and UGT1A1*6 polymorphisms in daclatasvir and asunaprevir combination therapy for chronic hepatitis C.

BACKGROUND: Liver damage presented as alanine aminotransferase (ALT) elevation and high ALT-caused treatment discontinuation occurs with high frequency in Japanese patients receiving daclatasvir plus asunaprevir (DCV/ASV) therapy for hepatitis C virus (HCV) infection, and its mechanism is unknown. METHODS: A total of 247 Japanese patients consisting of two independent cohorts with genotype-1b HCV infection receiving DCV/ASV therapy were included. The association of ALT levels during therapy and single nucleotide polymorphisms (SNP) of five drug-metabolizing enzyme loci selected for their possible influence on NS3/4A and NS5A inhibitors was investigated. RESULTS: Among five SNPs, we found a significant correlation between the presence of the UGT1A1 rs4148323 A allele and ALT elevation (Grade 3 elevation in AA 57%, AG 18%, and GG 4%, P = 8.4E - 06) and drug discontinuation (AA 22%, AG 11%, and GG 2.5%, P = 8.7E - 04), while no association was observed with ALT values at baseline (Grade 3 elevation AA 0%, AG 4%, and GG 2%, P = 0.5). In contrast, patients with risk A allele for drug-induced ALT elevation had a tendency to respond more favorably to treatment (AA 100%, AG 93%, and GG 90%, P = 0.29). CONCLUSIONS: Through the analysis we suggest that the A allele in UGT1A1 rs4148323 (UGT1A1*6), which is highly prevalent in the Japanese population, should be considered a risk for the development of DCV/ASV therapy-induced ALT elevation. Pretreatment SNP testing of UGT1A1*6 might be beneficial for the prediction of liver damage induced by DCV/ASV or even by DCV/ASV plus beclabuvir.

Semiannual Imaging Surveillance Is Associated with Better Survival in Patients with Non-B, Non-C Hepatocellular Carcinoma.

Since it remains elusive whether and how the imaging surveillance affects the survival in patients with non-B, non-C hepatocellular carcinoma (NBNC-HCC), we conducted this retrospective study which investigated the association between the semiannual surveillance prior to HCC diagnosis and the survival in patients with the initial diagnosis of HCC induced by hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections (N = 141) and non-B, non-C etiology (N = 30). It was demonstrated that surveillance was less frequently performed in the NBNC-HCC patients compared to that in HCC patients with HBV and/or HCV infections (B/C-HCC patients), and the survival was unfavorable in NBNC-HCC patients. On the other hand, the survival of NBNC-HCC patients with semiannual surveillance was significantly favorable than those patients without semiannual surveillance, and the survival was similar between B/C-HCCs and NBNC-HCCs with semiannual surveillance. In conclusion, though NBNC-HCC patients compared to B/C-HCC patients had poorer prognosis overall, these NBNC-HCC patients with semiannual surveillance had a better survival almost equivalent to the survival of B/C-HCC patients with semiannual surveillance, demonstrating the clinical utility of the semiannual imaging surveillance program for NBNC-HCCs.

Wisteria floribunda agglutinin positive human Mac-2-binding protein as a predictor of hepatocellular carcinoma development in chronic hepatitis C patients.

AIMS: Wisteria floribunda agglutinin (WFA)-positive human Mac-2-binding protein (WFA(+) -M2BP) is a new glycol marker related to liver fibrosis. The aim of the present study was to evaluate WFA(+) -M2BP as a predictor of hepatocellular carcinoma (HCC) development in patients with chronic hepatitis C. METHODS: This case-control study included 14 patients with chronic hepatitis C who developed HCC and 52controls, matched for age, gender, and fibrosis stage. WFA(+) -M2BP was measured at biopsy and follow-up. Time zero was set at the date of liver biopsy. RESULTS: WFA(+) -M2BP increased stepwise with progression of liver fibrosis (p < 0.001). Cumulative incidence of HCC development was significantly higher in patients with WFA(+) -M2BP ≥4.2 (p < 0.001) or in those with time-course changes in WFA(+) -M2BP (ΔWFA(+) -M2BP/year) ≥0.3 (p = 0.03). Multivariate analyses demonstrated that WFA(+) -M2BP ≥4.2 [hazard ratio (HR): 4.1, 95% confidence interval (CI): 1.1-15, p = 0.04], ΔWFA(+) -M2BP/year ≥0.3 (HR: 5.5, 95% CI: 1.5-19, p = 0.008), and AFP ≥10 ng/ml (HR: 4.7, 95% CI: 1.1-19, p = 0.03) were independent predictive factors of HCC development. Based on these data, we developed a simple scoring system to predict HCC development using these three factors. Using these scores, patients were classified into four groups; cumulative incidence of HCC development significantly increased with increasing scores (p < 0.001). CONCLUSIONS: WFA(+) -M2BP measurements and time-course changes in WFA(+) -M2BP can be used to identify patients at high risk of HCC development. Real-time monitoring of WFA(+) -M2BP can be a novel predictor of HCC development.

L-carnitine Reduces Muscle Cramps in Patients With Cirrhosis.

We performed a prospective study to evaluate the ability of L-carnitine, which is involved in the ß-oxidation of fatty acids, to reduce muscle cramps in patients with cirrhosis. Consecutive patients with cirrhosis and muscle cramps were given L-carnitine 300 mg, 3 times/day (900 mg/day, n = 19) or 4 times/day (1200 mg/day, n = 23) for 8 weeks. The frequency of muscle cramps was assessed by questionnaires, and the degree of muscle cramping was assessed by using the visual analogue scale (VAS). Muscle cramping was reduced in 88.1% of all subjects at the end of the 8-week study period and disappeared for 28.6% of patients. Overall VAS scores decreased significantly from 69.9 ± 22.5 at baseline to 26.2 ± 29.1 after 8 weeks (P < .0001). The dose of L-carnitine was significantly associated with percentages of patients with reduced muscle cramps after 8 weeks (43.5% in the 1200 mg/day group vs 10.5% in the 900 mg/day group, P = .037) and VAS scores at 8 weeks (9.9 ± 13.5 in the 1200 mg/day group vs 39.6 ± 31.9 in the 900 mg/day group, P = .003). No adverse events were reported. Therefore, L-carnitine appears to be safe and effective for reducing liver cramps in patients with cirrhosis.

Reduced organic anion transporter expression is a risk factor for hepatocellular carcinoma in chronic hepatitis C patients: a propensity score matching study.

OBJECTIVES: Recent reports indicated that reduced SLC22A7 (a gene-encoding organic anion transporter 2) expression in noncancerous liver tissue predicts hepatocellular carcinoma (HCC) recurrence after curative resection. Our study aimed to elucidate the association between SLC22A7 expression and HCC development in chronic hepatitis C patients. METHODS: HCC recurrence after local ablation therapy and SLC22A7 expression in noncancerous liver tissue were analyzed in 20 patients. Subsequently, the association between de novo HCC development and SLC22A7 expression was examined at baseline in 38 hepatitis C patients without HCC who subsequently developed HCC as well as in 76 hepatitis C patients who did not develop HCC and were matched for age, gender and stage of fibrosis. RESULTS: In the patients whose HCC had been cured, reduced SLC22A7 expression in noncancerous liver tissue was significantly associated with a high incidence of multifocal HCC recurrence. In patients without HCC at baseline, cumulative incidence of de novo HCC development was significantly higher with a reduced SLC22A7 expression than with a normal expression (p = 0.01). This difference remained significant among patients without known risk factors for HCC like age and advanced fibrosis. CONCLUSION: Reduced SLC22A7 expression in the liver indicates a significant risk for HCC development in chronic hepatitis C, independently of other risk factors.

Changes in plasma vascular endothelial growth factor at 8 weeks after sorafenib administration as predictors of survival for advanced hepatocellular carcinoma.

BACKGROUND: A new predictive biomarker for determining prognosis in patients with hepatocellular carcinoma (HCC) who receive sorafenib is required, because achieving a reduction in tumor size with sorafenib is rare, even in patients who have a favorable prognosis. Vascular endothelial growth factor (VEGF) receptor is a sorafenib target. In the current study, the authors examined changes in plasma VEGF concentrations during sorafenib treatment and determined the clinical significance of VEGF as a prognostic indicator in patients with HCC. METHODS: Plasma VEGF concentrations were serially measured in 63 patients with advanced HCC before and during sorafenib treatment. A plasma VEGF concentration that decreased >5% from the pretreatment level at 8 weeks was defined as a "VEGF decrease." An objective tumor response was determined using modified Response Evaluation Criteria in Solid Tumors 1 month after the initiation of therapy and every 3 months thereafter. RESULTS: Patients who had a VEGF decrease at week 8 (n=14) had a longer median survival than those who did not have a VEGF decrease (n=49; 30.9 months vs 14.4 months; P=.038). All patients who had a VEGF decrease survived for >6 months, and the patients who had both a VEGF decrease and an α-fetoprotein response (n=6) survived during the observation period (median, 19.7 months; range, 6.5-31.0 months). In univariate analyses, a VEGF decrease, radiologic findings classified as progressive disease, and major vascular invasion were associated significantly with 1-year survival; and, in multivariate analysis, a VEGF decrease was identified as an independent factor associated significantly with survival. CONCLUSIONS: A plasma VEGF concentration decrease at 8 weeks after starting sorafenib treatment may predict favorable overall survival in patients with advanced HCC.

Non-invasive prediction of hepatocellular carcinoma development using serum fibrosis marker in chronic hepatitis C patients.

BACKGROUND: The FIB-4 index is a simple formula to predict liver fibrosis. This study aimed to evaluate the utility of the FIB-4 index and associated time-course changes as a predictor of hepatocellular carcinoma (HCC) development. METHODS: A total of 171 chronic hepatitis C patients who underwent paired liver biopsies and 875 patients who underwent a single liver biopsy (validation group) were investigated during mean follow-up periods of 6.4 and 5.9 years, respectively. All patients had received interferon therapy and had not achieved a sustained virological response. Factors associated with HCC development were analyzed in these patients. RESULTS: HCC developed in 30 patients in the paired biopsy group and 89 patients in the validation group. Univariate analysis demonstrated that the FIB-4 index >3.25 and change in the FIB-4 index per year (ΔFIB-4/year) ≥ 0.3 were predictive factors for HCC development in both groups. Multivariate analysis in the combined population revealed that these two factors were independent. The hazard ratio (HR) for the FIB-4 index >3.25 was 2.7 (p < 0.001) and ΔFIB-4/year ≥ 0.3 was 1.8 (p = 0.003). Patients with a FIB-4 index >3.25 and a ΔFIB-4/year ≥ 0.3 were defined as high risk, and those with a FIB-4 index ≤ 3.25 and a ΔFIB-4/year <0.3 were defined as low risk. The HR of HCC development in patients at high risk was 7.3 (95% confidence interval 4.3-12.5, p < 0.001). CONCLUSIONS: It was possible to define a group at high risk of developing HCC by intermittently measuring the FIB-4 index and considering time-course changes in this index.

Prospective comparison of real-time tissue elastography and serum fibrosis markers for the estimation of liver fibrosis in chronic hepatitis C patients.

AIM: Real-time tissue elastography (RTE) is a non-invasive method for the measurement of tissue elasticity using ultrasonography. Liver fibrosis (LF) index is a quantitative method for evaluation of liver fibrosis calculated by RTE image features. This study aimed to investigate the significance of LF index for predicting liver fibrosis in chronic hepatitis C patients. METHODS: In this prospective study, 115 patients with chronic hepatitis C who underwent liver biopsy were included, and the diagnostic accuracy of LF index and serum fibrosis markers was evaluated. RESULTS: RTE imaging was successfully performed on all patients. Median LF index in patients with F0-1, F2, F3 and F4 were 2.61, 3.07, 3.54 and 4.25, respectively, demonstrating a stepwise increase with liver fibrosis progression (P < 0.001). LF index (odds ratio [OR] = 5.3, 95% confidence interval [CI] = 2.2-13.0) and platelet count (OR = 0.78, 95% CI = 0.68-0.89) were independently associated with the presence of advanced fibrosis (F3-4). Further, LF index was independently associated with the presence of minimal fibrosis (F0-1) (OR = 0.25, 95% CI = 0.11-0.55). The area under the receiver-operator curve (AUROC) of LF index for predicting advanced fibrosis (0.84) was superior to platelets (0.82), FIB-4 index (0.80) and aspartate aminotransferase/platelet ratio index (APRI) (0.76). AUROC of LF index (0.81) was superior to platelets (0.73), FIB-4 index (0.79) and APRI (0.78) in predicting minimal fibrosis. CONCLUSION: LF index calculated by RTE is useful for predicting liver fibrosis, and diagnostic accuracy of LF index is superior to serum fibrosis markers.