Machine learning for individualized prediction of hepatocellular carcinoma development after the eradication of hepatitis C virus with antivirals.

BACKGROUND AND AIMS: Accurate risk stratification for hepatocellular carcinoma (HCC) after achieving a sustained viral response (SVR) is necessary for optimal surveillance. We aimed to develop and validate a machine learning (ML) model to predict the risk of HCC after achieving an SVR in individual patients. METHODS: In this multicenter cohort study, 1742 patients with chronic hepatitis C who achieved an SVR were enrolled. Five ML models were developed including DeepSurv, gradient boosting survival analysis, random survival forest (RSF), survival support vector machine, and a conventional Cox proportional hazard model. Model performance was evaluated using Harrel' c-index and was externally validated in an independent cohort (977 patients). RESULTS: During the mean observation period of 5.4 years, 122 patients developed HCC (83 in the derivation cohort and 39 in the external validation cohort). The RSF model showed the best discrimination ability using seven parameters at the achievement of an SVR with a c-index of 0.839 in the external validation cohort and a high discriminative ability when the patients were categorized into three risk groups (P <0.001). Furthermore, this RSF model enabled the generation of an individualized predictive curve for HCC occurrence for each patient with an app available online. CONCLUSIONS: We developed and externally validated an RSF model with good predictive performance for the risk of HCC after an SVR. The application of this novel model is available on the website. This model could provide the data to consider an effective surveillance method. Further studies are needed to make recommendations for surveillance policies tailored to the medical situation in each country. IMPACT AND IMPLICATIONS: A novel prediction model for HCC occurrence in patients after hepatitis C virus eradication was developed using machine learning algorithms. This model, using seven commonly measured parameters, has been shown to have a good predictive ability for HCC development and could provide a personalized surveillance system.

Radiofrequency Ablation of Liver Tumors in Patients on Antithrombotic Therapy: A Case-Control Analysis of over 10,000 Treatments.

PURPOSE: To evaluate the safety of radiofrequency ablation (RFA) for liver tumors in patients on antithrombotic therapy. MATERIALS AND METHODS: A total of 10,653 consecutive RFA treatments in 3,485 patients with liver tumors were analyzed. The incidence of complications was analyzed on a treatment basis. The treatments for patients who had received antithrombotic medication up to 1 week prior to RFA comprised the antithrombotic therapy group (n = 806), and the others comprised the control group (n = 9,847). Antithrombotic agents were ceased prior to RFA (aspirin, ticlopidine, clopidogrel, and prasugrel ceased 7 days before RFA; cilostazol, 2 or 3 days before RFA; warfarin, 3 days before RFA; and direct oral anticoagulants, 1 day before RFA) and resumed as soon as possible after RFA. Logistic regression analysis was performed to assess whether the antithrombotic therapy increased the risk of hemorrhagic complications. RESULTS: Hemorrhagic complications were diagnosed after 6 treatments (0.7%) in the antithrombotic group and 48 (0.5%) in the control group, and there was no significant difference between the groups (P = .30). In 3 treatments, hemorrhage was diagnosed on or after 8 days of RFA, all of which were in the antithrombotic group. Thrombotic complications were diagnosed after 2 treatments (0.2%) in the antithrombotic group and after 5 (0.1%) in the control group. In a multivariate analysis, receiving antithrombotic therapy was not an independent risk factor for hemorrhagic complications (adjusted odds ratio, 1.52; 95% confidence interval, 0.60-3.87; P = .38). CONCLUSIONS: RFA of liver tumors in patients on antithrombotic therapy is generally safe with appropriate cessation and resumption. Late-onset hemorrhage should be noted in the patients on antithrombotic therapy.

Change in hepatitis C virus positivity among needle-stick injury source patients: a 10-year experience in a Japanese tertiary hospital.

BACKGROUND: As a blood-borne pathogen, hepatitis C virus (HCV) has long been a major threat associated with needle-stick injuries (NSIs) mainly because no vaccine is available for HCV. Following an NSI, we usually test the source patient for HCV antibody (HCV-Ab). Since HCV-Ab positivity does not necessarily indicate current infection, HCV RNA is further examined in patients positive for HCV-Ab. Direct-acting antivirals (DAAs) have enabled us to treat most HCV-infected patients; therefore, we speculate that the rate of HCV RNA positivity among HCV-Ab-positive patients decreased after the emergence of DAAs. This cross-sectional study was performed to investigate the change in the actual HCV RNA positivity rate in source patients before and after the interferon (IFN)-free DAA era. METHODS: This was a cross-sectional study of NSI source patients at a tertiary academic hospital in Japan from 2009 to 2019. IFN-free DAA regimens were first introduced in Japan in 2014. Accordingly, we compared HCV status of NSI source patients that occurred between 2009 and 2014 (the era before IFN-free DAAs) with those that occurred between 2015 and 2019 (the era of IFN-free DAAs) in a tertiary care hospital in Japan. RESULTS: In total, 1435 NSIs occurred, and 150 HCV-Ab-positive patients were analyzed. The proportion of HCV RNA-positive patients significantly changed from 2009 through 2019 (p = 0.005, Cochran-Armitage test). Between 2009 and 2014, 102 source patients were HCV-Ab-positive, 78 of whom were also positive for HCV RNA (76.5%; 95%CI, 67.4-83.6%). Between 2015 and 2019, 48 patients were HCV-Ab-positive, 23 of whom were also positive for HCV RNA (47.9%; 95%CI, 34.5-61.7%; p = 0.0007 compared with 2009-2014). In the era of IFN-free DAAs, 9 of 23 HCV RNA-negative patients (39.1%) and 2 of 22 HCV RNA-positive patients (9.1%) were treated with an IFN-free combination of DAAs (p = 0.0351). Regarding the departments where NSIs occurred, HCV RNA-negative patients were predominant in departments not related to liver diseases in the era of IFN-free DAAs (p = 0.0078, compared with 2009-2014). CONCLUSIONS: Actual HCV RNA positivity in source patients of NSIs decreased after the emergence of IFN-free DAAs. IFN-free DAAs might have contributed to this reduction, and HCV RNA-negative patients were predominant in departments not related to liver diseases in the era of IFN-free DAAs.

Impact of direct-acting antivirals on early recurrence of HCV-related HCC: Comparison with interferon-based therapy.

BACKGROUND & AIMS: It remains controversial whether direct-acting antivirals (DAAs) accelerate the recurrence of hepatitis C-related hepatocellular carcinoma (HCC) after curative therapy. This study aimed to evaluate HCC recurrence after DAA treatment of chronic hepatitis C. METHODS: We enrolled patients with a history of successful radiofrequency ablation treatment for hepatitis C-related HCC who received antiviral therapy with DAAs (DAA group: 147 patients) or with interferon (IFN)-based therapy (IFN group: 156 patients). We assessed HCC recurrence rates from the initiation of antiviral therapy using the Kaplan-Meier method and evaluated risk factors for HCC recurrence by multivariate Cox proportional hazard regression analysis. The recurrence pattern was categorized as follows: intrahepatic recurrence with a single tumor <2 cm (stage 0), a single tumor or up to 3 tumors ≤3 cm (stage A), multinodular (stage B), and extrahepatic metastasis or macrovascular invasion (stage C). RESULTS: The recurrence rates at 1 and 2 years were 39% and 61% in the IFN group and 39% and 60% in the DAA group, respectively (p = 0.43). Multivariate analysis identified higher lens culinaris agglutinin-reactive fraction of alpha-fetoprotein level, a history of multiple HCC treatments, and a shorter interval between HCC treatment and initiation of antiviral therapy as independent risk factors for HCC recurrence. HCC recurrence in stage 0, A, B, and C was found in 56 (41%), 60 (44%), 19 (14%), and 1 (0.7%) patients in the IFN group and 35 (44%), 32 (40%), 11 (14%), and 2 (2.5%) patients in the DAA group, respectively (p = 0.70). CONCLUSIONS: HCC recurrence rates and patterns after initiation of antiviral therapy did not differ between patients who received IFN-based therapy and DAA therapy. LAY SUMMARY: We detected no significant difference in early hepatocellular carcinoma (HCC) recurrence rates and patterns between patients who received interferon-based and direct-acting antiviral therapy after HCC treatment. High lens culinaris agglutinin-reactive fraction of alpha-fetoprotein level, short recurrence-free period, and a history of multiple HCC treatments were independent risk factors for early HCC recurrence after the initiation of antiviral therapy.

Ischemic complications after percutaneous radiofrequency ablation of liver tumors: Liver volume loss and recovery.

AIM: The liver regrows after acute liver injury and liver resection. However, it is not clear whether the liver regenerates in advanced cirrhosis. This study aimed to evaluate the clinical course of, and liver volume change after, ischemic liver complications caused by radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC). METHODS: We enrolled 35 patients with ischemic complications after RFA. Ischemic complications were defined as rapid elevation of aspartate aminotransferase (AST) to over 500 U/L, with typical radiological findings. Patient characteristics and the ischemic liver volume were investigated. Long-term liver volume changes at 3-8 months after ischemic complications were also assessed in 32 patients. We also assessed the overall survival rate after ischemic complications. RESULTS: The median value of peak AST was 798 U/L (range, 531-4096 U/L). The median ischemic liver volume relative to the functional liver volume before RFA was 13% (range, 3.1-46.5%). There was a strong correlation between the peak AST value and the ischemic liver volume (r = 0.84, P < 0.001). The liver volume recovered to some extent in 18 of 32 (56%) patients after ischemic complications. The survival rate after ischemic complications was 45.7% at 5 years and correlated with the functional liver volume after ischemic complications (P = 0.02). CONCLUSIONS: Ischemic complications after RFA can lead to massive liver parenchymal loss. Although the liver volume recovered to some extent in the majority of our patients, ischemic liver complications after RFA should be avoided to improve the overall survival rate.

Liver stiffness measurements in chronic hepatitis C: Treatment evaluation and risk assessment.

BACKGROUND AND AIM: Liver stiffness (LS), measured by transient elastography, has been validated as a non-invasive surrogate for liver fibrosis. METHODS: We investigated the long-term predictive ability of LS for hepatocellular carcinoma (HCC) development and overall survival in 1146 patients with chronic hepatitis C by using LS value at enrollment. We also investigated chronological changes in LS based on antiviral therapy and its outcome in 752 patients. RESULTS: During the mean follow-up period of 6.6 years, 190 patients developed HCC. Cumulative HCC incidence rates at 5 years were clearly stratified as 1.7% in the ≤ 5 kPa, 3.3% in 5.1-10 kPa, 16.7% in 10.1-15 kPa, 24.4% in 15.1-20 kPa, 36.3% in 20.1-25 kPa, and 43.7% in > 25 kPa subgroups (P < 0.001). Overall survival was also stratified: 10-year survival rates were 99.3% in the ≤ 5 kPa, 95.4% in 5.1-10 kPa, 81.4% in 10.1-15 kPa, 79.5% in 15.1-20 kPa, 66.1% in 20.1-25 kPa, and 49.1% in > 25 kPa subgroups (P < 0.001). LS decreased at a rate of 8.1% per year in those who achieved sustained virological responses, but increased at 0.1% per year in those who could not achieve sustained virological response instead of antiviral therapy, and increased at 3.7% per year in those who did not undergo antiviral therapy. CONCLUSIONS: Liver stiffness measurements can be useful in the prediction of HCC development and overall survival and in the evaluation of chronological changes in liver fibrosis grade during and after antiviral therapy.

CPT2 downregulation adapts HCC to lipid-rich environment and promotes carcinogenesis via acylcarnitine accumulation in obesity.

OBJECTIVE: Metabolic reprogramming of tumour cells that allows for adaptation to their local environment is a hallmark of cancer. Interestingly, obesity-driven and non-alcoholic steatohepatitis (NASH)-driven hepatocellular carcinoma (HCC) mouse models commonly exhibit strong steatosis in tumour cells as seen in human steatohepatitic HCC (SH-HCC), which may reflect a characteristic metabolic alteration. DESIGN: Non-tumour and HCC tissues obtained from diethylnitrosamine-injected mice fed either a normal or a high-fat diet (HFD) were subjected to comprehensive metabolome analysis, and the significance of obesity-mediated metabolic alteration in hepatocarcinogenesis was evaluated. RESULTS: The extensive accumulation of acylcarnitine species was seen in HCC tissues and in the serum of HFD-fed mice. A similar increase was found in the serum of patients with NASH-HCC. The accumulation of acylcarnitine could be attributed to the downregulation of carnitine palmitoyltransferase 2 (CPT2), which was also seen in human SH-HCC. CPT2 downregulation induced the suppression of fatty acid ß-oxidation, which would account for the steatotic changes in HCC. CPT2 knockdown in HCC cells resulted in their resistance to lipotoxicity by inhibiting the Src-mediated JNK activation. Additionally, oleoylcarnitine enhanced sphere formation by HCC cells via STAT3 activation, suggesting that acylcarnitine accumulation was a surrogate marker of CPT2 downregulation and directly contributed to hepatocarcinogenesis. HFD feeding and carnitine supplementation synergistically enhanced HCC development accompanied by acylcarnitine accumulation in vivo. CONCLUSION: In obesity-driven and NASH-driven HCC, metabolic reprogramming mediated by the downregulation of CPT2 enables HCC cells to escape lipotoxicity and promotes hepatocarcinogenesis.

Imaging prediction of nonalcoholic steatohepatitis using computed tomography texture analysis.

OBJECTIVES: To determine if texture analysis of non-contrast-enhanced CT (NECT) images is able to predict nonalcoholic steatohepatitis (NASH). METHODS: NECT images from 88 patients who underwent a liver biopsy for the diagnosis of suspected NASH were assessed and texture feature parameters were obtained without and with filtration. The patient population was divided into a predictive learning dataset and a validation dataset, and further divided into groups according to the prediction of liver fibrosis as assessed by hyaluronic acid levels. The reference standard was the histological result of a liver biopsy. A predictive model for NASH was developed using parameters derived from the learning dataset that demonstrated areas under the receiver operating characteristic curve (AUC) of >0.65. The resulting model was then applied to the validation dataset. RESULTS: In patients without suspected fibrosis, the texture parameter mean without filter and skewness with a 2-mm filter were selected for the NASH prediction model. The AUC of the predictive model for the validation dataset was 0.94 and the accuracy was 94%. In patients with suspicion of fibrosis, the mean without filtration and kurtosis with a 4-mm filter were selected for the NASH prediction model. The AUC for the validation dataset was 0.60 and the accuracy was 42%. CONCLUSIONS: In patients without suspicion of fibrosis, NECT texture analysis effectively predicted NASH. KEY POINTS: • In patients without suspicion of fibrosis, NECT texture analysis effectively predicted NASH. • The mean without filtration and skewness with a 2-mm filter were modest predictors of NASH in patients without suspicion of liver fibrosis. • Hepatic fibrosis masks the characteristic texture features of NASH.

Impact of serum ferritin level on hepatocarcinogenesis in chronic hepatitis C patients.

AIM: To elucidate the impact of the serum ferritin level, a surrogate indicator of hepatic iron accumulation, on hepatocarcinogenesis in chronic hepatitis C patients. METHODS: Serum ferritin was measured in 487 chronic hepatitis C patients without history of hepatocellular carcinoma (HCC) after excluding patients in phlebotomy, those with overt chronic gastrointestinal bleeding and those who achieved sustained virological response before enrollment. Patients were divided into four groups (G1-G4) by quartile points of serum ferritin, with sexes separated. RESULTS: The serum ferritin level was positively correlated with total bilirubin, aspartate aminotransferase, alanine aminotransferase (ALT), γ-glutamyltransferase, hemoglobin and AFP, and inversely correlated with prothrombin activity in both sexes. A significant difference in HCC incidence was observed only in male patients; the incidence was higher in G1 (≤80 ng/mL, n = 54) and G4 (≥323 ng/mL, n = 54) compared with that of G2 (81-160 ng/mL, n = 54) and G3 (161-322 ng/mL, n = 52). The spline curve indicating the relationship between the hazard ratio and serum ferritin level took the form of a J-shape for male patients. In multivariate analysis, G1 and G4 showed higher incidence of HCC among men with a hazard ratio of 2.19 (95% confidence interval, 1.02-4.70; P = 0.045) compared with G2 and G3, together with older age, lower serum albumin and ALT above the normal upper limit. CONCLUSION: The serum ferritin level is an independent risk factor for HCC development in male patients with chronic hepatitis C when the level is extremely high or low.

Sarcopenia, intramuscular fat deposition, and visceral adiposity independently predict the outcomes of hepatocellular carcinoma.

BACKGROUND & AIMS: Obesity defined by body mass index (BMI) significantly increases the risk of hepatocellular carcinoma (HCC). In contrast, not only obesity but also underweight is associated with poor prognosis in patients with HCC. Differences in body composition rather than BMI were suggested to be true determinants of prognosis. However, this hypothesis has not been demonstrated conclusively. METHODS: We measured skeletal muscle index (SMI), mean muscle attenuation (MA), visceral adipose tissue index, subcutaneous adipose tissue index, and visceral to subcutaneous adipose tissue area ratios (VSR) via computed tomography in a large-scale retrospective cohort of 1257 patients with different stages of HCC, and comprehensively analyzed the impact of body composition on the prognoses. RESULTS: Among five body composition components, low SMI (called sarcopenia), low MA (called intramuscular fat [IMF] deposition), and high VSR (called visceral adiposity) were significantly associated with mortality, independently of cancer stage or Child-Pugh class. A multivariate analysis revealed that sarcopenia (hazard ratio [HR], 1.52; 95% confidence interval [CI], 1.18-1.96; p=0.001), IMF deposition (HR, 1.34; 95% CI, 1.05-1.71; p=0.020), and visceral adiposity (HR, 1.35; 95% CI, 1.09-1.66; p=0.005) but not BMI were significant predictors of survival. The prevalence of poor prognostic body composition components was significantly higher in underweight and obese patients than in normal weight patients. CONCLUSIONS: Sarcopenia, IMF deposition, and visceral adiposity independently predict mortality in patients with HCC. Body composition rather than BMI is a major determinant of prognosis in patients with HCC.

Helicobacter pylori infection is not associated with fatty liver disease including non-alcoholic fatty liver disease: a large-scale cross-sectional study in Japan.

BACKGROUND: Fatty liver disease (FLD) including non-alcoholic fatty liver disease (NAFLD), a rapidly emerging and widely recognized liver disease today, is regarded as a hepatic manifestation of metabolic syndrome. Helicobacter pylori, one of the most common pathogens worldwide, has been reported to be associated with metabolic syndrome, but whether there is a direct association with FLD is as of yet unclear. The aim of this study was to clarify the association of FLD and NAFLD with causative background factors including Helicobacter pylori infection. METHODS: This was a cross-sectional study of Japanese adults who received medical checkups at a single medical center in 2010.Univariate and multivariate statistical analysis was performed to evaluate background factors for ultrasonography diagnosed FLD. Subjects free from alcohol influence were similarly analyzed for NAFLD. RESULTS: Of a total of 13,737 subjects, FLD was detected in 1,456 of 6,318 females (23.0 %) and 3,498 of 7,419 males (47.1%). Multivariable analyses revealed that body mass index (standardized coefficients of females and males (ß-F/M) =143.5/102.5), serum ALT (ß-F/M = 25.8/75.7), age (ß-F/M = 34.3/17.2), and platelet count (ß-F/M = 17.8/15.2) were positively associated with FLD in both genders. Of the 5,289 subjects free from alcohol influence, NAFLD was detected in 881 of 3,473 females (25.4%) and 921 of 1,816 males (50.7%). Body mass index (ß-F/M = 113.3/55.3), serum ALT (ß-F/M = 21.6/53.8), and platelet count (ß-F/M = 13.8/11.8) were positively associated with NAFLD in both genders. Metabolic syndrome was positively associated with FLD and NAFLD only in males. In contrast, Helicobacter pylori infection status was neither associated with FLD nor NAFLD regardless of gender. CONCLUSIONS: Body mass index, serum ALT and platelet count were significantly associated with FLD and NAFLD, whereas infection of Helicobacter pylori was not.

Tumor markers are more useful in patients undergoing surveillance for hepatocellular carcinoma with unreliable results by ultrasonography.

AIM: The objectives of this study was to evaluate the utility of tumor markers in hepatocellular carcinoma (HCC) surveillance based on the reliability of ultrasonography. METHODS: We analyzed 313 patients with HCC detected through a surveillance program using ultrasonography combined with three tumor markers from February 2000 to December 2010. The patients were categorized into two groups based on the triggering event: the US group (n = 281) in which a tumor was first detected using ultrasonography and the TM group (n = 32) in which elevated tumor markers led to the diagnosis of a tumor that was undetected using ultrasonography. The reliability of ultrasonography was scored on a 4-point scale based on three items (coarseness of liver parenchyma, patient obesity and liver atrophy). Additionally, patient survival was assessed using the Kaplan-Meier method and log-rank test. RESULTS: The median tumor size was 20 mm (interquartile range, 15-24). The reliability of ultrasonography was evaluated as good in 208 (66.5%), satisfactory in 80 (8.0%), poor in 21 (6.7%) and unsatisfactory in four (1.2%) patients. The proportion of patients in the TM group increased significantly according to the score, from 7.2% to 25.0% (P = 0.01). The survival rates of patients at 3 and 5 years were 83.7% and 57.2% in the US group, and 79.3% and 59.4% in the TM group, respectively (P = 0.98). CONCLUSION: Tumor markers may play a diagnostic role in patients with unreliable ultrasonography results. The survival of patients diagnosed by elevated tumor markers was not significantly different from those diagnosed by ultrasonography.

Slight elevation of high-sensitivity C-reactive protein to predict recurrence and survival in patients with early stage hepatitis C-related hepatocellular carcinoma.

AIM: Hepatocellular carcinoma (HCC) is associated with chronic inflammation derived from various origins. We investigated whether high-sensitivity C-reactive protein (hsCRP) could predict recurrence and survival after curative treatment for early stage hepatitis C virus-related HCC (C-HCC). METHODS: We enrolled 387 patients with three or fewer C-HCC nodules, none of which exceeded 3 cm, and of Child-Pugh class A or B who underwent radiofrequency ablation. We divided the patients into high and low hsCRP groups based on the optimal cut-off value for recurrence using a split-sample method and maximally selected rank statistics. Differences in recurrence and survival rates were evaluated by the Kaplan-Meier method and the log-rank test. Hazard ratios of hsCRP were adjusted with confounding factors using a multiple Cox regression model. We also assessed the correlations between hsCRP levels and clinical parameters. RESULTS: The optimal hsCRP cut-off value was 0.08 mg/dL. The cumulative recurrence rates after 5 years in the high and low hsCRP groups were 90.0% and 82.2%, respectively (P = 0.028), and the corresponding survival rates were 50.9% and 71.8%, respectively (P < 0.001). Higher hsCRP was an independent predictor for recurrence (adjusted hazard ratio [aHR], 1.32; 95% confidence interval [CI], 1.03-1.67; P = 0.026) and survival (aHR, 1.59; 95% CI, 1.14-2.22; P = 0.007). hsCRP was correlated with central obesity as well as tumor burden and liver dysfunction. CONCLUSION: Slight elevation of the hsCRP level, even within the normal range, can predict recurrence and survival after curative treatment among patients with early stage C-HCC.

Comparison of improved prognosis between hepatitis B- and hepatitis C-related hepatocellular carcinoma.

AIM: Treatment strategies for hepatocellular carcinoma (HCC) have been advanced. The aim of this study was to compare the change of the prognosis between hepatitis B-related HCC (B-HCC) and hepatitis C-related HCC (C-HCC) in the last two decades. METHODS: We enrolled 166 B-HCC patients who underwent percutaneous ablation between 1990 and 2009. Patients were divided into three groups according to the treatment time period: 1990-1995 (cohort 1, n = 19), 1996-2002 (cohort 2, n = 49) and 2003-2009 (cohort 3, n = 98). We enrolled 1219 C-HCC patients who underwent percutaneous ablation during the same period (n = 190, 413 and 616, respectively.). Interferon and nucleoside/nucleotide analog use was investigated. Prognosis was evaluated for each cohort using the Kaplan-Meier method and a multivariate Cox proportional hazard regression model. RESULTS: Two (11%), 24 (49%) and 80 (82%) B-HCC patients received nucleoside/nucleotide analogs during the follow-up period in cohorts 1-3, respectively. Among them 1, 18 and 62 patients achieved viral remission, respectively. Thirty-four (18%), 35 (8%) and 84 (14%) C-HCC patients received interferon therapy, respectively. The 5-year B-HCC (P < 0.001) survival rates were 52.6%, 61.1% and 81.6% for cohorts 1-3, respectively. However, the survival rates were 55.6%, 58.8% and 61.1% for C-HCC (P = 0.12), respectively. The B-HCC prognosis improved dramatically (P < 0.001) over time, whereas the prognosis of C-HCC improved moderately (P = 0.01). CONCLUSION: The prognosis of B-HCC has improved dramatically over time, whereas that of C-HCC has improved moderately.

Impact of serum levels of interleukin-6 and adiponectin on all-cause, liver-related, and liver-unrelated mortality in chronic hepatitis C patients.

BACKGROUND AND AIM: Various inflammatory cytokines and adipokines have been implicated in hepatitis C virus (HCV)-mediated liver disease, and interleukin-6 (IL-6) and adiponectin may play key roles. In addition, these factors may be associated with chronic hepatitis C (CHC)-induced extrahepatic manifestations. However, little data are available on the role of these factors on future outcomes of CHC patients. This study aims to evaluate the impact of serum levels of IL-6 and adiponectin on all-cause mortality, liver-related mortality, and liver-unrelated mortality. METHODS: A long-term follow-up study was conducted, consisting of 325 CHC patients, for which we previously reported positive associations between these factors (Serum levels of IL-6 and adiponectin) and hepatocellular carcinoma (HCC) development. RESULTS: During the follow-up period (mean, 13.0 year), there were 92 events consisting of 91 deaths (liver related, 72; liver unrelated, 19) and 1 liver transplantation due to liver failure. High IL-6 and adiponectin levels, defined as being higher than each median value at baseline, were associated with significantly higher incidences of not only HCC development but also all-cause mortality. Interestingly, high IL-6 was strongly associated with only liver-related mortality, whereas high-serum adiponectin was associated with not only liver-related, but also liver-unrelated mortality. Multivariate analysis identified high IL-6 as an independent risk factor for liver-related mortality and high adiponectin as an independent risk factor for liver-unrelated mortality. CONCLUSION: High serum levels of IL-6 and adiponectin were associated with higher all-cause and liver-related mortality in CHC patients. In addition, high adiponectin was associated with liver-unrelated mortality. The measurement of these factors may provide information useful for predicting future outcomes in CHC patients.

Increased serum mitochondrial creatine kinase activity as a risk for hepatocarcinogenesis in chronic hepatitis C patients.

Serum mitochondrial creatine kinase (MtCK) activity was reportedly increased in cirrhotic patients although less prominent than that in hepatocellular carcinoma (HCC) patients. To elucidate the clinical significance of serum MtCK activity in chronic liver disease, 171 chronic hepatitis C patients were enrolled. Serum MtCK activity in study subjects was correlated with serum albumin, platelet counts, liver stiffness values and serum aspartate and alanine aminotransferase. In mouse fibrotic liver induced by bile duct ligation, ubiquitous MtCK mRNA and protein expressions were significantly enhanced and its immunoreactivity was increased, predominantly in hepatocytes. During the mean follow-up period of 2.7 years, HCC developed in 21 patients, in whom serum MtCK activity was significantly higher than that in patients without HCC development. Multivariate Cox regression analysis revealed that higher serum MtCK activity was a risk for HCC development. A cutoff value of MtCK for the prediction of HCC development was determined as 9.0 U/L on receiver operating characteristics analysis, where area under receiver operating characteristics curve was 0.754, with a sensitivity of 61.9%, a specificity of 92.8% and a high negative predictive value of 94.2%. Cumulative incidence of HCC was significantly higher in patients with serum MtCK activity of >9.0 U/L compared to those with serum MtCK activity of ≤ 9.0 U/L even in patients with elevated liver stiffness value, >15 kPa. In conclusion, serum MtCK activity may be increased correlatively with the stage of liver fibrosis and hepatocellular damage. Increased serum MtCK activity is an independent risk for hepatocarcinogenesis in chronic hepatitis C patients.

High ubiquitous mitochondrial creatine kinase expression in hepatocellular carcinoma denotes a poor prognosis with highly malignant potential.

We previously reported the increased serum mitochondrial creatine kinase (MtCK) activity in patients with hepatocellular carcinoma (HCC), mostly due to the increase in ubiquitous MtCK (uMtCK), and high uMtCK mRNA expression in HCC cell lines. We explored the mechanism(s) and the relevance of high uMtCK expression in HCC. In hepatitis C virus core gene transgenic mice, known to lose mitochondrial integrity in liver and subsequently develop HCC, uMtCK mRNA and protein levels were increased in HCC tissues but not in non-tumorous liver tissues. Transient overexpression of ankyrin repeat and suppressor of cytokine signaling box protein 9 (ASB9) reduced uMtCK protein levels in HCC cells, suggesting that increased uMtCK levels in HCC cells may be caused by increased gene expression and decreased protein degradation due to reduced ASB9 expression. The reduction of uMtCK expression by siRNA led to increased cell death, and reduced proliferation, migration and invasion in HCC cell lines. Then, consecutive 105 HCC patients, who underwent radiofrequency ablation with curative intent, were enrolled to analyze their prognosis. The patients with serum MtCK activity >19.4 U/L prior to the treatment had significantly shorter survival time than those with serum MtCK activity ≤ 19.4 U/L, where higher serum MtCK activity was retained as an independent risk for HCC-related death on multivariate analysis. In conclusion, high uMtCK expression in HCC may be caused by hepatocarcinogenesis per se but not by loss of mitochondrial integrity, of which ASB9 could be a negative regulator, and associated with highly malignant potential to suggest a poor prognosis.

Spontaneous clearance of serum hepatitis C virus RNA during the clinical course of hepatocellular carcinoma in patients with chronic hepatitis C.

AIM: Spontaneous clearance of serum hepatitis C virus (HCV) RNA in chronic HCV carriers is assumed to be rare especially after development of hepatocellular carcinoma (HCC). We analyzed patients with chronic hepatitis C who spontaneously resolved serum HCV RNA after the treatment for HCC. METHODS: A database search was performed to identify patients with HCC in whom serum HCV RNA was positive before the treatment for HCC and became negative during the clinical course. Those who received interferon therapy were excluded. RESULTS: A total of 1145 patients with HCC who had not received interferon therapy were positive for HCV RNA before the treatment. Among them, five patients (M/F = 4/1) spontaneously resolved viremia during the clinical course, with the incidence rate of at least 0.11%/person-year (95% confidence interval: 0.05%-0.26%). The mean age at the time of negative test for HCV RNA was 77 (range: 52-84). Three and two were infected with HCV genotype 1 and 2, respectively. The mean initial viral load was 9.0 K IU/mL (range: 1.6-31.6). The alanine aminotransferase level decreased to within the normal range in all patients after the clearance of serum HCV RNA. Fibrosis grade of background liver, evaluated according to METAVIR classification, was F1 in 1, F2 in 1, F4 in 2, and unknown in 1. All patients survived more than 7 years after the initial treatment for HCC. CONCLUSION: Spontaneous clearance of serum HCV RNA after HCC development possibly occurs even in elderly patients. The prognosis was good probably due to improved inflammation in the liver.

Development of a transformer model for predicting the prognosis of patients with hepatocellular carcinoma after radiofrequency ablation.

INTRODUCTION: Radiofrequency ablation (RFA) is a widely accepted, minimally invasive treatment modality for patients with hepatocellular carcinoma (HCC). Accurate prognosis prediction is important to identify patients at high risk for cancer progression/recurrence after RFA. Recently, state-of-the-art transformer models showing improved performance over existing deep learning-based models have been developed in several fields. This study was aimed at developing and validating a transformer model to predict the overall survival in HCC patients with treated by RFA. METHODS: We enrolled a total of 1778 treatment-naïve HCC patients treated by RFA as the first-line treatment. We developed a transformer-based machine learning model to predict the overall survival in the HCC patients treated by RFA and compared its predictive performance with that of a deep learning-based model. Model performance was evaluated by determining the Harrel's c-index and validated externally by the split-sample method. RESULTS: The Harrel's c-index of the transformer-based model was 0.69, indicating its better discrimination performance than that of the deep learning model (Harrel's c-index, 0.60) in the external validation cohort. The transformer model showed a high discriminative ability for stratifying the external validation cohort into two or three different risk groups (p < 0.001 for both risk groupings). The model also enabled output of a personalized cumulative recurrence prediction curve for each patient. CONCLUSIONS: We developed a novel transformer model for personalized prediction of the overall survival in HCC patients after RFA treatment. The current model may offer a personalized survival prediction schema for patients with HCC undergoing RFA treatment.

CT with hepatic arterioportography as a pretreatment examination for hepatocellular carcinoma patients: a randomized controlled trial.

OBJECTIVES: The combination of computed tomography with hepatic arteriography and arterial portography (CTHA/CTAP) can detect additional hepatocellular carcinoma (HCC) nodules undetected by conventional dynamic CT. METHODS: In this single-center, randomized, open-label, controlled trial, we randomly assigned 280 patients who were diagnosed as having HCC by conventional dynamic CT, and eligible for radiofrequency ablation (RFA), to undergo CTHA/CTAP before treatment, or to the control group. Newly detected HCC nodules by CTHA/CTAP were intended to be ablated completely. The primary end point was recurrence-free survival and the key secondary end point was overall survival. The analysis was conducted on an intention-to-treat basis. Those with nonablated nodules were treated as for recurrence. RESULTS: A total of 75 nodules were newly diagnosed as HCC by CTHA/CTAP in 45 patients. Three patients (one in the CTHA/CTAP group and two in the control group) who refused treatment were excluded from all analyses. The cumulative recurrence-free survival rates at 1, 2, and 3 years were 60.1, 29.0, and 18.9% in the CTHA/CTAP group and 52.2, 29.7, and 23.1% in the control group, respectively (P=0.66 by log-rank test; hazard ratio, 0.94 for CTHA/CTAP vs. control; 95% confidence interval (CI), 0.73-1.22). The cumulative overall survival rates at 3 and 5 years were 79.7 and 56.4% in the CTHA/CTAP group and 86.8 and 60.1% in the control group, respectively (P=0.50; hazard ratio, 1.15, 95% CI, 0.77-1.71). CONCLUSIONS: CTHA/CTAP may detect recurrent lesions earlier. However, CTHA/CTAP before RFA did not improve cumulative recurrence-free survival or overall survival.