Trends in hepatocellular carcinoma incident cases in Japan between 1996 and 2019.

We examined the epidemiological trends, including the distribution of sex, age, and disease etiology, in HCC incident cases, over 24 years. Data of 20,547 HCC patients (1996-2019) were analyzed in this prospective study. We divided the study period into four 6-yearly quarters. HCC etiology was categorized as hepatitis B virus (HBV) infection, HBV + hepatitis C virus (HCV) infection, HCV infection, and both negative (non-BC). The incident cases of HCC per quarter of the study period were 4311 (21.0%), 5505 (26.8%), 5776 (28.1%), and 4955 (24.1%), sequentially. Overall, 14,020 (68.2%) patients were male. The number of HCC cases in patients < 60 years, 60-69 years, 70-79 years, and ≥ 80 years were 3711 (18.1%), 6652 (32.4%), 7448 (36.2%), and 2736 (13.3%), respectively. The average age of newly-diagnosed patients increased in each quarter. HCC was associated with HBV, HBV + HCV, and HCV infections and non-BC in 2997 (14.6%), 187 (0.9%), and 12,019 (58.5%), and 5344 (26.0%) cases, respectively. The number of HCV-associated cases decreased in each quarter, while that of non-BC-associated cases increased. HCC incident cases tend to increase in the elderly and in non-BC patients; in contrast, HCC incident cases due to HCV tend to decrease.

Screening for Gaucher Disease Using Dried Blood Spot Tests: A Japanese Multicenter, Cross-sectional Survey.

Objective For patients with Gaucher disease (GD), a rare, inherited lysosomal storage disease, obtaining a definitive diagnosis is currently time-consuming and costly. A simplified screening method to measure the glucocerebrosidase (GBA) activity using dried blood spots (DBS) on filter paper has recently been developed. Using this newly developed screening method, we evaluated real-world GD screening in patients suspected of having GD. Methods This multicenter, cross-sectional, observational study with a diagnostic intervention component evaluated real-world screening in patients suspected of having GD based on their clinical symptoms and a platelet count <120,000/µL. The endpoint was the number of patients with low GBA activity determined using DBS. Results In 994 patients who underwent initial DBS screening, 77 had low GBA activity. The assay was not repeated in 1 patient who was diagnosed as having a high possibility of GD due to clinical symptoms, and a further 21 patients completed the study without undergoing the second assay. Of the remaining 55 patients who had 2 DBS assays performed, 11 had a low GBA activity in both assays. Overall, DBS screening identified 12 (1.2%) patients with a low GBA activity, a proportion consistent with prior screening studies. Conclusion These results suggest that the simplified DBS method was less burdensome to patients, was easily utilized by many physicians, and could be a useful first-tier screening assay for GD prior to initiating burdensome genetic testing.

Metformin dose increase versus added linagliptin in non-alcoholic fatty liver disease and type 2 diabetes: An analysis of the J-LINK study.

We validated the effect of linagliptin, an oral dipeptidyl peptidase-4 inhibitor, on nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM). A total of 50 patients with NAFLD and T2DM treated with metformin were randomized (1:1) to metformin plus add-on linagliptin (linagliptin group) or to an increased dose of metformin (metformin group) for 52 weeks. The primary endpoint was change in hepatic steatosis from baseline to week 52 as quantified by unenhanced computed tomography imaging. Secondary endpoints included changes in the levels of anthropometric, biochemical and adipokinetic markers. The linagliptin group showed no statistically significant reduction in hepatic steatosis as compared to the metformin group (P = 0.97), although changes in hepatic steatosis were significantly correlated with decreased liver enzymes in both groups. Body weight was significantly reduced in the metformin group but not in the linagliptin group (P = 0.002). Serum leptin levels were significantly increased in the linagliptin group compared to the metformin group (P = 0.003), and were correlated with the changes body weight in whole samples. Adverse events were not different between the two groups (P = 0.78). Add-on linagliptin demonstrated a safe profile but was not superior to increased metformin in reducing hepatic steatosis.

Risk estimation model for nonalcoholic fatty liver disease in the Japanese using multiple genetic markers.

The genetic factors affecting the natural history of nonalcoholic fatty liver disease (NAFLD), including the development of nonalcoholic steatohepatitis (NASH) and NASH-derived hepatocellular carcinoma (NASH-HCC), are still unknown. In the current study, we sought to identify genetic factors related to the development of NAFLD, NASH, and NASH-HCC, and to establish risk-estimation models for them. For these purposes, 936 histologically proven NAFLD patients were recruited, and genome-wide association (GWA) studies were conducted for 902, including 476 NASH and 58 NASH-HCC patients, against 7,672 general-population controls. Risk estimations for NAFLD and NASH were then performed using the SNPs identified as having significant associations in the GWA studies. We found that rs2896019 in PNPLA3 [p = 2.3x10-31, OR (95%CI) = 1.85 (1.67-2.05)], rs1260326 in GCKR [p = 9.6x10-10, OR (95%CI) = 1.38(1.25-1.53)], and rs4808199 in GATAD2A [p = 2.3x10-8, OR (95%CI) = 1.37 (1.23-1.53)] were significantly associated with NAFLD. Notably, the number of risk alleles in PNPLA3 and GATAD2A was much higher in Matteoni type 4 (NASH) patients than in type 1, type 2, and type 3 NAFLD patients. In addition, we newly identified rs17007417 in DYSF [p = 5.2x10-7, OR (95%CI) = 2.74 (1.84-4.06)] as a SNP associated with NASH-HCC. Rs641738 in TMC4, which showed association with NAFLD in patients of European descent, was not replicated in our study (p = 0.73), although the complicated LD pattern in the region suggests the necessity for further investigation. The genetic variants of PNPLA3, GCKR, and GATAD2A were then used to estimate the risk for NAFLD. The obtained Polygenic Risk Scores showed that the risk for NAFLD increased with the accumulation of risk alleles [AUC (95%CI) = 0.65 (0.63-0.67)]. CONCLUSIONS: We demonstrated that NASH is genetically and clinically different from the other NAFLD subgroups. We also established risk-estimation models for NAFLD and NASH using multiple genetic markers. These models can be used to improve the accuracy of NAFLD diagnosis and to guide treatment decisions for patients.

Efficacy and safety of a 14-day administration of tolvaptan in the treatment of patients with ascites in hepatic oedema.

OBJECTIVE: To investigate the efficacy and safety of 14 days' orally administered tolvaptan as adjunctive treatment for hepatic oedema in Japanese liver cirrhosis patients with insufficient response to conventional diuretics, with the option to increase dose in those who did not respond initially. METHODS: This multicentre, single-arm, phase 3 study allocated patients with liver cirrhosis and persistent ascites to 7-day treatment with 7.5 mg/day tolvaptan followed by an additional 7 days' treatment. Responders at day 7 (achieving ≥ 1 kg body-weight reduction) continued on 7.5 mg/day tolvaptan; nonresponders (<1 kg body-weight reduction) received 15 mg/day tolvaptan. Conventional diuretic treatment continued throughout. The primary endpoint was change in body weight from baseline, as a marker of ascites volume. RESULTS: A total of 51 patients received 7.5 mg/day tolvaptan for 7 days, which caused a significant reduction in mean body weight (55% response rate). During the second 7-day treatment period, 30 patients received 7.5 mg/day tolvaptan and 13 patients received tolvaptan 15 mg/day: response rates were 43% and 23%, respectively. Two serious adverse events were observed. Serum sodium was within normal range. CONCLUSIONS: Tolvaptan therapy for 14 days (with possible dose increase as necessary), in combination with conventional diuretics, effectively reduced body weight in patients with hepatic oedema.

Clinical and pathological progression of non-alcoholic steatohepatitis to hepatocellular carcinoma.

AIM: Non-alcoholic steatohepatitis (NASH) can progress to hepatocellular carcinoma (HCC). We aimed to examine the clinical and pathological course of how NASH progresses to HCC. METHODS: In this retrospective multicenter study conducted in Japan, we examined 19 patients (53% female), who had been previously diagnosed with histologically proven NASH and developed HCC during the follow-up period. The median age of the patients at the time of initial diagnosis of NASH was 65 years. RESULTS: NASH progressed to HCC after a median follow-up period of 3.8 years (range: 0.5-11.6 years). All patients had been identified as having HCC during screening, which included 12 patients assessed by ultrasound, four patients assessed with computerized tomography, two patients that underwent serum des-γ-carboxy prothrombin testing and one patient that underwent serum α-fetoprotein testing. The median diameter of HCC tumors was 1.8 cm (range: 0.8-3.0 cm). The majority of patients (n = 13; 68%) presented with only one HCC tumor. The stage of liver fibrosis was significantly more advanced at the time of diagnosis of HCC than at the time of initial diagnosis of NASH, whereas there were no significant differences in the degree of steatosis. CONCLUSION: Screening for HCC with imaging is necessary not only in NASH patients with advanced fibrosis, but also in those with less advanced forms of fibrosis, particularly if they are old men. Liver fibrosis progresses to a more advanced stage during the development of HCC in NASH patients.

Data mining reveals complex interactions of risk factors and clinical feature profiling associated with the staging of non-hepatitis B virus/non-hepatitis C virus-related hepatocellular carcinoma.

AIM: Non-hepatitis B virus/non-hepatitis C virus-related hepatocellular carcinoma (NBNC-HCC) is often detected at an advanced stage, and the pathology associated with the staging of NBNC-HCC remains unclear. Data mining is a set of statistical techniques which uncovers interactions and meaningful patterns of factors from a large data collection. The aims of this study were to reveal complex interactions of the risk factors and clinical feature profiling associated with the staging of NBNC-HCC using data mining techniques. METHODS: A database was created from 663 patients with NBNC-HCC at 20 institutions. The Milan criteria were used as staging of HCC. Complex associations of variables and clinical feature profiling with the Milan criteria were analyzed by graphical modeling and decision tree algorithm methods, respectively. RESULTS: Graphical modeling identified six factors independently associated with the Milan criteria: diagnostic year of HCC; diagnosis of liver cirrhosis; serum aspartate aminotransferase (AST); alanine aminotransferase (ALT); α-fetoprotein (AFP); and des-γ-carboxy prothrombin (DCP) levels. The decision trees were created with five variables to classify six groups of patients. Sixty-nine percent of the patients were within the Milan criteria, when patients showed an AFP level of 200 ng/mL or less, diagnosis of liver cirrhosis and an AST level of less than 93 IU/mL. On the other hand, 18% of the patients were within the Milan criteria, when patients showed an AFP level of more than 200 ng/mL and ALT level of 20 IU/mL or more. CONCLUSION: Data mining disclosed complex interactions of the risk factors and clinical feature profiling associated with the staging of NBNC-HCC.

Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma.

BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) can progress to hepatocellular carcinoma (HCC). We aimed to characterize the clinical features of NASH patients with HCC. METHODS: In a cross-sectional multicenter study in Japan, we examined 87 patients (median age, 72 years; 62% male) with histologically proven NASH who developed HCC. The clinical data were collected at the time HCC was diagnosed. RESULTS: Obesity (body mass index ≥25 kg/m(2)), diabetes, dyslipidemia, and hypertension were present in 54 (62%), 51 (59%), 24 (28%), and 47 (55%) patients, respectively. In nontumor liver tissues, the degree of fibrosis was stage 1 in 10 patients (11%), stage 2 in 15 (17%), stage 3 in 18 (21%), and stage 4 (ie, liver cirrhosis) in 44 (51%). The prevalence of cirrhosis was significantly lower among male patients (21 of 54, 39%) compared with female patients (23 of 33, 70%) (P = .008). CONCLUSIONS: Most patients with NASH who develop HCC are men; the patients have high rates of obesity, diabetes, and hypertension. Male patients appear to develop HCC at a less advanced stage of liver fibrosis than female patients.

The incidence of hepatocellular carcinoma associated with hepatitis C infection decreased in Kyushu area.

BACKGROUND: The incidence of hepatocellular carcinoma (HCC) in Japan has still been increasing. The aim of the present study was to analyze the epidemiological trend of HCC in the western area of Japan, Kyushu. MATERIAL/METHODS: A total of 10,010 patients with HCC diagnosed between 1996 and 2008 in the Liver Cancer study group of Kyushu (LCSK), were recruited for this study. Cohorts of patients with HCC were categorized into five year intervals. The etiology of HCC was categorized to four groups as follows; B: HBsAg positive, HCV-RNA negative, C: HCV-RNA positive, HBsAg negative, B+C: both of HBsAg and HCV-RNA positive, nonBC: both of HBsAg and HCV-RNA negative. RESULTS: B was 14.8% (1,485 of 10,010), whereas 68.1% (6,819 of 10,010) had C, and 1.4% (140 of 10,010) had HCC associated with both viruses. The remaining 1,566 patients (15.6%) did not associate with both viruses.
Cohorts of patients with HCC were divided into six-year intervals (1996-2001 and 2002-2007). The ratio of C cases decreased from 73.1% in 1996-2001 to 64.9% in 2002-2007. On the other hand, B and -nonBC cases increased significantly from 13.9% and 11.3% in 1996-2001 to 16.2% and 17.6% in 2002-2007, respectively. CONCLUSIONS: The incidence of hepatocellular carcinoma associated with hepatitis C infection decreased after 2001 in Kyushu area. This change was due to the increase in the number and proportion of the HCC not only nonBC patients but also B patients.

Peginterferon-alpha-2b plus ribavirin therapy in patients with chronic hepatitis C as assessed by a multi-institutional questionnaire in Japan.

BACKGROUND AND AIM: There has so far been no questionnaire report on patients who were treated with peginterferon plus ribavirin (PEG IFN+RBV) therapy. The purpose of this study was to investigate the problems of this therapy by a questionnaire survey. PATIENTS AND METHODS: A survey of 681 patients with chronic hepatitis C who received treatment with PEG IFN+RBV was conducted in the Kyushu region of Japan. Using an original questionnaire, the survey was conducted prior to the treatment, during the third month of treatment, at the completion of treatment or the discontinuation of treatment, and at 6 months after the completion of treatment. RESULTS: It was indicated that the patients had a high level of comprehension and understanding of chronic hepatitis C and PEG IFN+RBV treatment. However, the results also indicated that patients had a high level of anxiety. Side effects were adequately dealt with by physicians. However, dermatological symptoms were not adequately explained to the patients, although they were the second most severe side-effect. It was also revealed that side-effects were most distressing during the first and second months after the start of treatment. CONCLUSION: The questionnaire survey provided new information that has never been reported. It is believed that understanding this information is important for future treatment.

Comparison of survival rates between patients treated with transcatheter arterial chemoembolization and hepatic resection for solitary hepatocellular carcinoma.

The present study aimed to retrospectively compare the survival rates between patients treated with transcatheter arterial chemoembolization and hepatic resection for solitary hepatocellular carcinoma (HCC). According to our database, derived from three affiliated hospitals, the inclusion criteria for this study were: solitary HCC [Child-Pugh class A and International Union Against Cancer (UICC) stage T1-3N0M0] treated between July 1990 and October 2001. Subsequently, hepatic resection (149 patients) as well as chemoembolization (102 patients) groups were selected. Following stratification according to tumor stage [UICC, Cancer of the Liver Italian Program (CLIP) and Milan criteria], survival rates were compared between the treatment groups. Survival rates were calculated using the Kaplan-Meier method. Age, gender and size of the HCC did not differ significantly between the groups. Moreover, no significant difference in the survival rates (average hepatic resection, 58.9 months; average chemoembolization, 45 months; P=0.1697) was observed between the groups. In the subgroup analysis, according to tumor stage, the survival rate was significantly higher for the hepatic resection group than for the chemoembolization group in the UICC T3N0M0 (P=0.017) subgroup. However, no significant differences in survival rates were observed between the hepatic resection and chemoembolization groups for UICC T1 (P=0.7329), T2N0M0 (P=0.5741), CLIP0 (P=0.3593), CLIP1-2 (P=0.3287) and within (>5 cm; P=0.4429) and beyond Milan criteria (≤5 cm; P=0.4003) subgroups. Chemoembolization is as effective as hepatic resection in treating solitary HCC in subpopulations with UICC T1-2N0M0 or CLIP 0-2 HCC or Milan criteria and adequate liver function. In the subgroup with UICC T3N0M0 HCC, hepatic resection is superior to chemoembolization.

Adult T-cell leukemia in a liver transplant recipient that did not progress after onset of graft rejection.

A liver allograft recipient developed acute-type adult T-cell leukemia (ATL) during tacrolimus treatment, 2 years after undergoing transplantation for subacute fulminant hepatitis. Both donor and recipient were asymptomatic carriers of human T-cell lymphotropic virus type I (HTLV-I), but the ATL cells originated from the recipient. Tacrolimus treatment was discontinued, and combination chemotherapy was administered. The patient achieved complete remission, but the transplanted liver was acutely and chronically rejected. The patient did not respond to rescue therapy with tacrolimus, prednisolone, and mycophenolate mofetil and died of hepatic failure. Liver biopsies showed CD4+ ATL cell infiltration at the onset of ATL but not at the terminal stage. Moreover, Southern blotting revealed clonal integration of HTLV-I into the host genome of lymphoma cells at onset but not at the terminal stage. ATL after liver transplantation has not been previously described. The clinical course of the posttransplantational ATL was atypical, because it did not progress after the onset of rejection.

[Optimal phase of dynamic CT for detecting hypervascular hepatocellular carcinoma: evaluation of double arterial phases].

PURPOSE: To investigate the appropriate time of arterial phase for the detection of hypervascular hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Fifty-two hypervascular HCCs of 36 patients were evaluated on double arterial-phase images of the liver. The first and second arterial-phase images were obtained 10 sec after aortic peak enhancement time as determined by test bolus injection. Patients received a low or high concentration of contrast medium, according to their body weight, that was administered intravenously at a rate of 4 mL/sec and injection duration of 23 sec. Three radiologists evaluated the images separately. RESULTS: Sensitivity in detecting hypervascular HCCs was higher in the first arterial phase than in the second arterial phase (p = 0.039). HCCs were not detected as hypervascular nodules in one of 20 cases during 31 or fewer sec, or in 8 of 19 cases during 48 or more sec after the initiation of contrast medium injection. All nodules were detected as hypervascular lesions between 32 and 47 sec after the initiation of contrast medium injection. CONCLUSION: When a single arterial phase is obtained to detect hypervascular HCCs with a 23-sec injection time and an injection rate of 4 mL/sec, a protocol is recommended in which scanning is started at 35 sec and ended within 47 sec after initiating the injection of contrast medium.

Outcome of patients with hepatitis C virus-related single, small hepatocellular carcinoma.

To clarify the cumulative recurrence-free interval and survival rate with hepatitis C virus (HCV)-related single, small hepatocellular carcinoma (HCC), we studied 32 patients with surgical resection, 61 with ablation therapy and 28 with transcatheter chemoembolization (TACE). A log-rank test revealed that there were no significant differences in the recurrence-free interval (p = 0.08) and survival (p = 0.279) between the resection and the ablation groups. Univariate analysis using the Cox proportional hazards regression model showed initial treatment (p = 0.0051) was associated with recurrence-free interval. Platelet count (p = 0.009), indocianine green retention rate at 15 minutes (p = 0.003), Child-Pugh classification (p = 0.001), serum albumin level (p = 0.0012) and serum total bililubin (p = 0.015) were associated with survival. Hence patients with HCV-related single, small HCC should be treated according to their hepatic reserve.

Systemic combined chemotherapy with low dose of 5-fluorouracil, cisplatin, and interferon-alpha for advanced hepatocellular carcinoma: a pilot study.

The purpose of this pilot study was to evaluate the efficacy and adverse events of systemic combined chemotherapy with low dose of 5-fluorouracil (250 mg/m2, 5 days), cisplatin (10 mg/m2, 5 days), and interferon-alpha (2.5 million units, three times weekly) for advanced hepatocellular carcinoma (HCC) underlying liver cirrhosis. Six patients who had advanced HCC with tumor thrombi in the main portal trunk were enrolled in this study. Partial response was achieved in 2, stable disease in 1, and disease progressed in 3. Objective responses were achieved in 2 (33%), however, marked decreases of alpha-fetoprotein protein and protein-induced vitamin K antagonist or absence (PIVKAII) levels were also seen in one patient (stable disease). Four patients showed hematologic or renal toxicity, which were well tolerated and managed. Our systemic combined chemotherapy resulted in favorable response and was well tolerated in those with advanced HCC underlying liver cirrhosis, complicated by leukocytopenia and thromobocytopenia.

Risk factors for local recurrence of small hepatocellular carcinoma tumors after a single session, single application of percutaneous radiofrequency ablation.

BACKGROUND: The objectives of this study were to clarify risk factors for local tumor recurrence and to determine which patients with hepatocellular carcinoma (HCC) are most suitable for a single session, single application of percutaneous radiofrequency (RF) ablation. METHODS: Fifty-six consecutive patients with 65 HCC tumors measuring 2 cm (risk ratio [RR], 4.9; 95%CI, 1.3-16.4; P = 0.019) and subcapsular location (RR, 5.2; 95%CI, 1.7-16.6; P = 0.005) were associated independently with local recurrence. The other four factors were not associated with local recurrence in this study. CONCLUSIONS: A single session, single application of RF ablation produced favorable local control. Patients who have nonsubcapsular HCC tumors measuring