Search

Direct-acting antivirals (DAAs) have recently been developed to treat hepatitis C virus (HCV) infection, and interferon-free DAA treatment has improved liver function of HCV patients. The risk of hepatocellular carcinoma (HCC) occurrence following HCV eradication has been previously reported, but HCC may have been missed following imaging diagnosis before DAA administration in previous studies. Therefore, the present study aimed to identify definite predictors of HCC occurrence ≥1 year after DAA treatment. Among 956 patients receiving DAAs for HCV infection, 567 patients who achieved sustained virologic response with no history of HCC treatment were enrolled in this study between September 2014 and July 2021. The incidence of HCC in HCV-infected patients ≥1 year following DAA treatment, and the predictors contributing to HCC occurrence were identified using clinical characteristics and blood test results. In the present study, 25 patients developed HCC. The incidence of HCC was 1.4%, 3.2%, 4.9% and 6.8% at 2, 3, 4 and 5 years, respectively, from the end of treatment with DAAs. Multivariate logistic analysis revealed serum α-fetoprotein level at end of treatment (EOT-AFP) >3.8 ng/ml ≥1 year following treatment with DAAs (HR, 9.7; p

Current genome-wide association studies do not yet capture sufficient diversity in populations and scope of phenotypes. To expand an atlas of genetic associations in non-European populations, we conducted 220 deep-phenotype genome-wide association studies (diseases, biomarkers and medication usage) in BioBank Japan (n = 179,000), by incorporating past medical history and text-mining of electronic medical records. Meta-analyses with the UK Biobank and FinnGen (ntotal = 628,000) identified ~5,000 new loci, which improved the resolution of the genomic map of human traits. This atlas elucidated the landscape of pleiotropy as represented by the major histocompatibility complex locus, where we conducted HLA fine-mapping. Finally, we performed statistical decomposition of matrices of phenome-wide summary statistics, and identified latent genetic components, which pinpointed responsible variants and biological mechanisms underlying current disease classifications across populations. The decomposed components enabled genetically informed subtyping of similar diseases (for example, allergic diseases). Our study suggests a potential avenue for hypothesis-free re-investigation of human diseases through genetics.

A 61-year-old man was admitted due to alcoholic liver cirrhosis, portal vein thrombosis, hepatocellular carcinoma, and chronic pancreatitis. The patient's portal vein thrombosis improved with anticoagulant therapy. Serum amylase gradually increased, but there was no abdominal pain. The patient was placed under observation. The pain in both ankle and knee joints appeared on nine days after admission. Multiple osteonecrotic lesions of both elbows, both knees and both ankle joints were examined using

The overwhelming majority of participants in current genetic studies are of European ancestry. To elucidate disease biology in the East Asian population, we conducted a genome-wide association study (GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 320 independent signals in 276 loci for 27 diseases, with 25 novel loci (P < 9.58 × 10-9). East Asian-specific missense variants were identified as candidate causal variants for three novel loci, and we successfully replicated two of them by analyzing independent Japanese cohorts; p.R220W of ATG16L2 (associated with coronary artery disease) and p.V326A of POT1 (associated with lung cancer). We further investigated enrichment of heritability within 2,868 annotations of genome-wide transcription factor occupancy, and identified 378 significant enrichments across nine diseases (false discovery rate < 0.05) (for example, NKX3-1 for prostate cancer). This large-scale GWAS in a Japanese population provides insights into the etiology of complex diseases and highlights the importance of performing GWAS in non-European populations.

Atezolizumab plus bevacizumab therapy has high response rates in patients with advanced hepatocellular carcinoma (HCC). It has been reported that HCC with immune exclusion associated with the signal activation of WNT/β-catenin is resistant to immune checkpoint inhibitors; however, to the best of our knowledge, the effectiveness of atezolizumab plus bevacizumab for HCC with WNT/β-catenin signal activation has not been reported. The present study aimed to analyze the efficacy of atezolizumab plus bevacizumab for HCC with WNT/β-catenin signal activation. A total of 24 patients who underwent liver tumor biopsy for HCC were classified into WNT/β-catenin signal activation and inactivation groups according to the expression levels of β-catenin and glutamine synthetase, which are indicative of WNT/β-catenin signal activation. The differences in the clinical responses to treatment between the groups were analyzed. A total of 15 patients had HCC with WNT/β-catenin signal activation, whereas 9 patients had HCC with WNT/β-catenin signal inactivation. There were no significant differences between both groups regarding objective responses (P=0.519) and disease control (P=0.586). In the WNT/β-catenin signal activation group, the median progression-free survival rate was 6.9 months compared with 6.2 months in the WNT/β-catenin signal inactivation group (P=0.674). Although a small number of patients was included in the present study, the present findings suggested that the efficacy of atezolizumab plus bevacizumab might be unaffected by WNT/β-catenin signal activation.

The risk of hepatocellular carcinoma (HCC) occurrence following hepatitis C virus (HCV) eradication has been previously reported, but the impact of HCV eradication on advanced HCC patient survival remains unclear. Therefore, the present study aimed to evaluate the effect of HCV eradication on the survival outcome of patients with advanced HCC treated with sorafenib. One hundred and three HCV-related advanced HCC patients who were treated with sorafenib were enrolled in this study. Of these, 43 patients were administered antiviral therapy before sorafenib treatment (HCV eradication group), while 60 patients remained HCV-infected (HCV non-eradication group). We analysed the impact of HCV eradication on survival in advanced HCC treated with sorafenib. Median overall survival (OS) was significantly longer in the HCV eradication group than in the HCV non-eradication group (24.0 months vs. 14.1 months; p = 0.001). Although there was no significant difference in the albumin-bilirubin (ALBI) score at the start of treatment between the HCV eradication group and the non-eradication group (p = 0.065), the ALBI score at 2 months after initiation of sorafenib treatment was significantly decreased in the HCV non-eradication group (p 0.001), but not in the HCV eradication group (p = 0.121). Multivariate logistic analysis revealed HCV eradication (hazard ratio [HR], 0.5; p = 0.006) and ALBI score at the start of treatment (HR, 2.47; p = 0.002) as factors that may contribute to OS. HCV eradication may serve an important role in the survival outcome of advanced HCC patients treated with sorafenib.

Previous studies have reported that hepatocellular carcinoma (HCC) harboring WNT/β-catenin mutations exhibits iso-high intensity by gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid-enhanced magnetic resonance imaging (Gd-EOB-DTPA-MRI, i.e. EOB-MRI) during the hepatobiliary phase (HBP), thus indicating that EOB-MRI may help clinicians identify an immune exclusion class, which might not respond to treatment with immune checkpoint inhibitors. The present study analyzed the efficacy of lenvatinib for HCC with iso-high intensity during the HBP of EOB-MRI. Overall, 52 patients who underwent EOB-MRI for 140 HCC nodules were classified into iso-high-intensity and low-intensity groups during the HBP of EOB-MRI. The clinical and histological characteristics, and different responses to treatment of both groups were analyzed. The expression levels of β-catenin and glutamine synthetase, indicative of WNT/β-catenin mutations, were enhanced in the HCC with iso-high-intensity group. Nine patients had iso-high intensity, whereas 43 patients had low intensity. Tumor size was larger, and the levels of antagonist-II or vitamin K absence were higher in the iso-high-intensity group. Furthermore, 3/9 patients in the iso-high-intensity group had objective responses compared with 13/43 patients in the low-intensity group. Disease control was observed in 5/9 patients in the iso-high-intensity group and 26/43 patients in the low-intensity group. Median overall survival was 29.8 months for the iso-high-intensity group compared with 20.8 months for the low-intensity group. In the iso-high-intensity group, the median progression-free survival rate was 6.7 months compared with 5.6 months in the low-intensity group. No differences in best percentage change from baseline tumor size were observed in either group. Although few patients were included in this study, the present findings suggested that the efficacy of lenvatinib was unaffected by signal intensity during the HBP of EOB-MRI.

Here, we report a rare case of intrahepatic sarcomatoid cholangiocarcinoma that expressed granulocyte colony-stimulating factor (G-CSF). An 87-year-old man who presented with a continuous high-grade fever and cough over two weeks, and increased inflammatory response was admitted to our hospital. Laboratory tests revealed marked granulocytosis and high serum levels of G-CSF and interlukin-6. Imaging studies showed a huge liver mass in his right lobe and intrahepatic metastasis. He died of progressive disease. Pathological findings of the primary liver tumor at autopsy showed sarcomatous change; the specimen was positive for cytokeratins (AE1/AE3, cytokeratin-7, cytokeratin-19) and G-CSF. Few cases of G-CSF-producing intrahepatic sarcomatoid cholangiocarcinoma have been reported.

The current genome-wide association studies (GWASs) do not yet capture sufficient diversity in terms of populations and scope of phenotypes. To address an essential need to expand an atlas of genetic associations in non-European populations, we conducted 220 deep-phenotype GWASs (disease endpoints, biomarkers, and medication usage) in BioBank Japan (n = 179,000), by incorporating past medical history and text-mining results of electronic medical records. Meta-analyses with the harmonized phenotypes in the UK Biobank and FinnGen (ntotal = 628,000) identified over 4,000 novel loci, which substantially deepened the resolution of the genomic map of human traits, benefited from East Asian endemic diseases and East Asian specific variants. This atlas elucidated the globally shared landscape of pleiotropy as represented by the MHC locus, where we conducted fine-mapping by HLA imputation. Finally, to intensify the value of deep-phenotype GWASs, we performed statistical decomposition of matrices of phenome-wide summary statistics, and identified the latent genetic components, which pinpointed the responsible variants and shared biological mechanisms underlying current disease classifications across populations. The decomposed components enabled genetically informed subtyping of similar diseases (e.g., allergic diseases). Our study suggests a potential avenue for hypothesis-free re-investigation of human disease classifications through genetics.

Current genome-wide association studies do not yet capture sufficient diversity in populations and scope of phenotypes. To expand an atlas of genetic associations in non-European populations, we conducted 220 deep-phenotype genome-wide association studies (diseases, biomarkers and medication usage) in BioBank Japan (n = 179,000), by incorporating past medical history and text-mining of electronic medical records. Meta-analyses with the UK Biobank and FinnGen (n

AIM To investigate the real-world efficacy and safety of sofosbuvir/ribavirin (SOF/RBV) therapy for Japanese patients with genotype 2 hepatitis C virus (GT2-HCV). METHODS A total of 182 patients with GT2-HCV infection who received SOF/RBV therapy for 12 wk at our hospital were enrolled. The patients comprised 122 men and 60 women (age range: 17-84 years; mean age ± SD: 60.1 ± 12.1 years). Relationships between virological response and clinical data were examined by logistic regression analyses. RESULTS The proportions of patients with liver cirrhosis and history of hepatocellular carcinoma (HCC) were 29.0% and 17.3%, respectively. The proportion of patients with prior interferon (IFN)-based therapy was 25.6%. SOF/RBV therapy rapidly decreased HCV RNA levels. Several patients required RBV dose reduction because of anemia or fatigue. Four patients discontinued the therapy. The rates of sustained virological response at 12 wk after the end of treatment were 87.9% (intention to treat: 160/182) and 94.1% (per protocol: 159/169). Multivariate analyses showed that history of HCC or IFN-based therapy independently reduced the efficacy of SOF/RBV therapy. CONCLUSION SOF/RBV therapy for GT2-HCV is safe, highly tolerated, and effective. History of HCC or IFN-based therapy independently reduces the efficacy of this treatment.

A 49-year-old man with chronic hepatitis B receiving treatment with entecavir visited a hospital with a complaint of abdominal pain. Computed tomography (CT) showed 2 liver tumors, each measuring 1cm in diameter, 1 in segment 7 and 1 in segment 4. Magnetic resonance imaging (MRI) showed a hypervascular tumor in segment 7 that appeared in a site different from that seen on CT. The liver tumor in segment 4 was not detected by MRI. Two months later, MRI showed a new liver tumor in segment 7/6 and that the liver tumor in segment 7 had increased to 2cm in diameter;blood tests showed eosinophilia. Enzyme-linked immunosorbent assay showed a high serum Toxocara antibody. The patient was diagnosed as having hepatic toxocariasis and was treated with albendazole for 8 weeks. After treatment, MRI showed that the liver tumors disappeared. Eosinophilia, multiple lesions, and the disappearance of the tumors were characteristic findings of visceral larva migrans.

INTRODUCTORY PARAGRAPHThe overwhelming majority of participants in current genetic studies are of European ancestry1–3, limiting our genetic understanding of complex disease in non-European populations. To address this, we aimed to elucidate polygenic disease biology in the East Asian population by conducting a genome-wide association study (GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 383 independent signals in 331 loci for 30 diseases, among which 45 loci were novel (P< 5 × 10−8). Compared with known variants, novel variants have lower frequency in European populations but comparable frequency in East Asian populations, suggesting the advantage of this study in discovering these novel variants. Three novel signals were in linkage disequilibrium (r2> 0.6) with missense variants which are monomorphic in European populations (1000 Genomes Project) including rs11235604(p.R220W ofATG16L2, a autophagy-related gene) associated with coronary artery disease. We further investigated enrichment of heritability within 2,868 annotations of genome-wide transcription factor occupancy, andidentified 378 significant enrichments across nine diseases (FDR < 0.05) (e.g. NF-κB for immune-related diseases). This large-scale GWAS in a Japanese population provides insights into the etiology of common complex diseases and highlights the importance of performing GWAS in non-European populations.

Background Prostate cancer is the sixth leading cause of cancer-related deaths in Japan. We aimed to elucidate the clinical and histopathological characteristics of patients with prostate cancer in the BioBank Japan (BBJ) project. Methods Four thousand, seven hundred and ninety-three patients diagnosed with prostate cancer in the BBJ project were included. Clinical and histopathological data, including causes of death, were analyzed. Relative survival (RS) rates of prostate cancer were calculated. Results Four thousand, one hundred and seventy-one prostate cancer patients with available histological data had adenocarcinoma. The mean age of the patients was 72.5 years. The proportion of patients who were non-smokers, non-drinkers, had a normal body mass index, did not exercise, had a normal prostate-specific antigen level, and had a family history of prostate cancer were 30.7%, 28.0%, 66.6%, 58.1%, 67.6%, and 6.5%, respectively. The proportion of patients with Stage II, III, and IV disease were 24.4%, 7.3%, and 4.4%, respectively. After limiting to patients with a time from the initial diagnosis of prostate cancer to entry into the study cohort of ≤90 days (n = 869), the 5- and 10-year RS rates were 96.3% and 100.5%, respectively, although we were unable to consider management strategies due to a plenty of data missing. Conclusions We provide an overview of patients with prostate cancer in the BBJ project. Our findings, coupled with those from various high throughput “omics” technologies, will contribute to the implementation of prevention interventions and medical management of prostate cancer patients., Highlights • Prostate cancer represents the second leading cause of cancer incidence worldwide. • We aimed to provide an overview of patients with prostate cancer. • Based on prostate cancer histology, 99.3% had adenocarcinoma. • The 5- and 10-year relative survival rates were 96.3% and 100.5%. • Future studies will help develop preventive programs for prostate cancer.

Background Liver cancer is the fifth cause of cancer-related deaths in Japan. The BioBank Japan (BBJ) project included 200,000 patients with 47 diseases and samples; their clinical information can be used for further studies. Methods Patients diagnosed with liver cancer (n = 1733; 1316 men, 417 women) were included. Histology, patient characteristics, clinical characteristics, and causes of death were collected. Cumulative and relative survival rates for liver cancer were calculated. Results Of the 1354 patients with available liver cancer histology, 91.9% had hepatocellular carcinoma (HCC). Compared with the National Health and Nutrition Examination Survey, greater proportions of the male patients in this cohort were daily alcohol consumers (26%), and a greater proportion of the men was overweight/obesity (22%). Although Japan is the only Asian country with a predominance of hepatitis C virus (HCV)-related HCC, the prevalence of HCV infection (44%) was lower than that in a previous study. The 3-, 5-, and 10-year cumulative survival rates were 57%, 47%, and 25% in men, respectively, and 49%, 41%, and 27% in women, respectively. Conclusions The present results provide an overview of the patients with liver cancer in the BBJ project. We are planning further analyses combined with various high-throughput ‘omics’ technologies., Highlights • Liver cancer is the second leading cause of death worldwide. • We aimed to provide an overview of patients with liver cancer. • Based on liver cancer histology, 91.9% had hepatocellular carcinoma. • The 10-year relative survival rates were 34% in men and 38% in women. • Future studies will help develop preventive programs for liver cancer.

Background Breast cancer is currently the most common type of cancer in Japanese females. Unlike most other types of cancer, breast cancer develops more frequently in middle-aged females than in elderly females. Methods Of all Japanese female breast cancer patients aged ≥20 years whom the BioBank Japan Project originally enrolled between 2003 and 2008, 2034 were registered within 90 days after their diagnosis. We described the lifestyle and clinical characteristics of these patients at study entry. Furthermore, we examined the effect of these characteristics on all-cause mortality. Results In the female patients registered within 90 days after diagnosis, the frequency of stage 0 or unclassified, stage I, II, III and IV were 11.4%, 47.9%, 37.0%, 2.9% and 0.8%, respectively. The proportion of histological types was 12.9% for non-invasive carcinoma (ductal carcinoma and lobular carcinoma), 81.0% for invasive carcinoma (papillotubular carcinoma, solid tubular carcinoma, scirrhous carcinoma and special types), 0.2% for Paget's diseases and 5.8% for others. Those positive for the estrogen and progesterone receptors accounted for 75.8% and 62.1% of all patients, respectively. Among 1860 female participants registered within 90 days, 218 participants died during 144,54 person-years of follow-up. More advanced stage, elevation of serum carcinoembryonic antigen and carbohydrate antigen 15-3 levels and absence of the estrogen receptor at study entry were crudely associated with an increased risk of all-cause mortality after adjustment for age. Conclusions This study showed the association of several clinical characteristics with all-cause mortality in female breast cancer patients., Highlights • About 1% of Japanese female breast cancer patients were diagnosed as stage IV. • Invasive carcinoma was much more common than non-invasive carcinoma. • Papillotubular carcinoma was the most common type of invasive carcinoma. • About 75% were positive for estrogen receptor and 60% for progesterone receptor. • Some characteristics would affect all-cause mortality in breast cancer patients.

Background Colorectal cancer is the third most common cancer worldwide, and in Japan, it is estimated that about 10% of men and 8% of women will be diagnosed with colorectal cancer during their lifetime. Methods We focused on 5864 participants (3699 men and 2165 women) who had colorectal cancer and were registered with BioBank Japan (BBJ) between April 2003 and March 2008. Characteristics of colon and rectal cancer patients were calculated separately. Among the enrolled patients registered in BBJ within 90 days after diagnosis, we also calculated the 5-year cumulative and relative survival rates, and estimated the effect of lifestyle factors on all-cause mortality. Results Our participants included younger men than those in the Patient Survey and the Cancer Registry Japan. In more than 95% of cases the histological type was adenocarcinoma both in colon and rectal cancer. Rectal cancer patients tended to eat more meat and less green leafy vegetables compared with colon cancer patients. The 5-year cumulative survival rate was 73.0% (95% CI; 70.1%–75.7%) and the 5-year relative survival rate was 80.6% (77.4%–83.6%), respectively, for colon cancer. For rectal cancer, the rates were 73.3% (69.1%–77.0%) and 80.9% (76.3%–85.0%), in the same order. Lifestyle factors such as consuming less green leafy vegetables, being underweight, smoking, not consuming alcoholic beverages and being physically inactive were found to be related to poor survival. Conclusions We described lifestyle characteristics of colorectal cancer patients in BBJ and examined the impacts on subsequent all-cause mortality., Highlights • More than 95% were adenocarcinoma both in colon and rectal cancer. • Rectal cancer patients ate more meat and less green vegetables than colon cancer. • Eating green vegetables and drinking alcohol moderately decreased the mortality risk.

Background The number of patients with diabetes is increasing worldwide. Macrovascular disease, chronic kidney disease, chronic respiratory disease, cancer and smoking frequently accompany type 2 diabetes. Few data are available related to mortality of Asians with diabetes associated with these serious comorbidities. The present study aimed to quantify the excess mortality risks of type 2 diabetic patients with comorbidities. Methods We analysed the available records of 30,834 Japanese patients with type 2 diabetes from the BioBank Japan Project between 2003 and 2007. Men and women were followed up for median 8.03 and 8.30 years, respectively. We applied Cox proportional hazard model and Kaplan–Meier estimates for survival curves to evaluate mortality in diabetic patients with or without macrovascular disease, chronic respiratory disease, chronic kidney disease, cancer and smoking. Results Adjusted hazard ratios (HRs) for mortality were 1.39 (95% CI, 1.09–1.78) for male sex, 2.01 (95% CI, 1.78–2.26) per 10-year increment of age. Adjusted HRs of primary interest were 1.77 (95% CI, 1.42–2.22), macrovascular disease; 1.58 (95% CI, 1.08–2.31), chronic respiratory disease; 2.03 (95% CI, 1.67–2.47), chronic kidney disease; 1.16 (95% CI, 0.86–1.56), cancer; and 1.74 (95% CI, 1.30–2.31), current smoking. Conclusions Diabetic patients with a past or current history of chronic kidney, macrovascular or respiratory diseases or smoking habit have exhibited the highest risk of mortality. Data were limited to those of survivors of comorbidities but we propose the need to improve comorbidities and terminate cigarette smoking for better prognosis in patients with diabetes., Highlights • Fatal diseases frequently accompany diabetes. • Data for survival of Asian patients with diabetes with comorbidities are scarce. • Comorbid chronic kidney disease was associated with the most fatalities. • Current smoking was as fatal as 10 years of ageing in diabetic patients. • Values of 1% HbA1c and 10 mmHg blood pressure confer 11% excess mortality risk.

Background Controlling serum cholesterol is critical to prevent cardiovascular disease in patients with dyslipidaemia. Guidelines emphasise the need to select treatment for dyslipidaemia based on specific patient profiles; however, there is little information about the serum cholesterol levels of patients in each profile in Japan. Therefore, we aimed to describe the serum cholesterol levels and prevalence of uncontrolled cases in Japanese patients with dyslipidaemia. Methods We included data for patients with dyslipidaemia between 2003 and 2007 from the BioBank Japan Project (66 hospitals). Then, we reported their serum cholesterol levels by age, body mass index, glycaemic control (glycated haemoglobin A1c), blood pressure, smoking, drinking, comorbidity and medication profiles. Results We included 22,189 male and 21,545 female patients. The mean serum low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG) and non-HDL-C levels in males were 117.4 mg/dL, 51.0 mg/dL, 187.6 mg/dL and 153.6 mg/dL, respectively; the corresponding levels in females were 129.5 mg/dL, 60.5 mg/dL, 144.9 mg/dL and 157.9 mg/dL, respectively. In both males and females, the LDL-C levels were the highest in the following profiles: age 19–44 years, body mass index 18.5–22 kg/m2, glycated haemoglobin A1c, Highlights • Evidence of serum cholesterol control in Japanese dyslipidaemic patients is scarce. • We analysed data for a large-scale population in hospital settings. • Our findings provide serum cholesterol levels by different risk profiles. • Serum lipid levels were the lowest in the youngest patients. • Data should be carefully applied to patients with mild hyperlipidaemia.

REACH evaluated ramucirumab in the second-line treatment of patients with advanced hepatocellular carcinoma. In the intent-to-treat population (n = 565), a significant improvement in overall survival (OS) was not observed. In patients with an elevated baseline α-fetoprotein (AFP) level (400 ng/mL or greater), an improvement in OS was demonstrated. An analysis of the Japanese patients in REACH was performed.An analysis was performed with the subset of the intent-to-treat population enrolled in Japan (n = 93).The median OS was 12.9 months for the ramucirumab arm (n = 45) and 8.0 months for the placebo arm (n = 48) [hazard ratio (HR) 0.621 (95 % confidence interval (CI) 0.391-0.986); P = 0.0416]. The median progression-free survival was 4.1 months for the ramucirumab arm and 1.7 months for the placebo arm [HR 0.449 (95 % CI 0.285-0.706); P = 0.0004]. The objective response rates were 11 % for the ramucirumab arm and 2 % for the placebo arm (P = 0.0817). The grade 3 or higher treatment-emergent adverse events occurring in more than 5 % of patients with a higher incidence for the ramucirumab arm (n = 44) than for the placebo arm (n = 47) were ascites (7% vs 2 %), hypertension (7 % vs 2 %), and cholangitis (7 % vs 0 %). In patients with a baseline AFP level of 400 ng/mL or greater, the median OS was 12.9 months for the ramucirumab arm (n = 20) and 4.3 months for the placebo arm (n = 22) [HR 0.464 (95 % CI 0.232-0.926); P = 0.0263].In the Japanese patients in REACH, ramucirumab treatment improved OS, including in patients with a baseline AFP level of 400 ng/mL or greater; improvements in progression-free survival and objective response rate were also demonstrated. The safety profile of ramucirumab was acceptable and well tolerated in Japanese patients. ClinicalTrials.gov identifier NCT01140347.

Background: Serum lactate dehydrogenase (LDH) levels could be a prognostic factor for sorafenib-treated patients with several types of solid tumor because it reflects hypoxic circumstances in aggressive tumors. For hepatocellular carcinoma (HCC), however, the prognostic role of LDH has been controversial. Liver fibrosis can potentially cause hypoxia in the liver, which has not been previously studied in the patients with advanced HCC. Thus, we aimed to analyze the prognostic role of LDH based on the degree of fibrosis. Methods: Eighty-nine consecutive patients with HCC (Child-Pugh class A) who were treated using sorafenib were enrolled into this study. Pretreatment characteristics and changes in hepatic functional tests based on early response to sorafenib and serum LDH levels were analyzed. The degree of fibrosis was estimated using the aspartate aminotransferase (AST) to platelet ratio index (APRI), and the tumor response was evaluated after 3 months of sorafenib treatment. Results: Overall, five patients discontinued sorafenib within 4 weeks. For the other 84 patients, those with progressive disease (PD) had significantly high pretreatment LDH levels, which correlated with the APRI score but not with the tumor stage. Multivariate logistic analysis revealed that older age and lower pretreatment LDH levels were independent prognostic factors for a better response to sorafenib. In patients who discontinued sorafenib early, three experienced acute liver failure accompanied with an increase in serum LDH. Conclusions: We demonstrated that baseline serum LDH levels in HCC patients were affected by liver fibrosis but not by the tumor stage, and these LDH levels could be a marker for early response to sorafenib. A marked increase in serum LDH levels during sorafenib administration might also indicate subsequent acute liver failure. Close observation of serum LDH levels before and during sorafenib treatment could be useful in managing treatment of patients receiving this therapy.

Aim We analyzed the 5-year post-treatment response to peginterferon α-2a (PEG IFN-α-2a) in hepatitis B e-antigen (HBeAg) positive and negative chronic hepatitis B patients. Methods One hundred and thirty-seven chronic hepatitis B (CHB) patients receiving 90 μg or 180 μg of PEG IFN-α-2a for 24 or 48 weeks in phase II or III studies were enrolled in the study, including 100 HBeAg positive patients and 37 HBeAg negative patients; 121 patients (88.4%) had genotype C. Results Of the 137 patients, 94 received additional antiviral therapy because of viral reactivation and 43 did not receive any additional antiviral treatment during follow up. Five years upon PEG IFN-α-2a treatment, 32 patients (23.4%) who did not receive any additional antiviral agent after PEG IFN-α-2a therapy achieved a good response (normal serum alanine aminotransferase, low-level hepatitis B virus [HBV] DNA, and HBeAg negativity). Female sex and low HBV DNA levels by the end of treatment were independently associated with favorable 5-year post-treatment responses. Forty-eight-week administration of PEG IFN-α-2a showed a better response (26.4%) than 24-week administration (18.0%). Six patients (4.3%), four males and two females, cleared hepatitis B surface antigen (HBsAg) during the 5-year follow-up period. Conclusion The 48-week administration of PEG IFN-α-2a achieved better biochemical and virological responses than the 24-week administration, particularly in younger females. The 5-year post-treatment response rate was 23.4%; however, more than two-thirds of the patients received additional antiviral therapy because of viral reactivation after PEG IFN-α-2a treatment. HBsAg clearance was noted in six patients (4.3%). PEG IFN-α-2a is effective in young female patients.

Background We established a patient-oriented biobank, BioBank Japan, with information on approximately 200,000 patients, suffering from any of 47 common diseases. This follow-up survey focused on 32 diseases, potentially associated with poor vital prognosis, and collected patient survival information, including cause of death. We performed a survival analysis for all subjects to get an overview of BioBank Japan follow-up data. Methods A total of 141,612 participants were included. The survival data were last updated in 2014. Kaplan–Meier survival analysis was performed after categorizing subjects according to sex, age group, and disease status. Relative survival rates were estimated using a survival-rate table of the Japanese general population. Results Of 141,612 subjects (56.48% male) with 1,087,434 person-years and a 97.0% follow-up rate, 35,482 patients died during follow-up. Mean age at enrollment was 64.24 years for male subjects and 63.98 years for female subjects. The 5-year and 10-year relative survival rates for all subjects were 0.944 and 0.911, respectively, with a median follow-up duration of 8.40 years. Patients with pancreatic cancer had the least favorable prognosis (10-year relative survival: 0.184) and patients with dyslipidemia had the most favorable prognosis (1.013). The most common cause of death was malignant neoplasms. A number of subjects died from diseases other than their registered disease(s). Conclusions This is the first report to perform follow-up survival analysis across various common diseases. Further studies should use detailed clinical and genomic information to identify predictors of mortality in patients with common diseases, contributing to the implementation of personalized medicine., Highlights • 141,612 participants with any of 32 diseases were included in the follow-up survey. • Subject characteristics at enrollment for the follow-up survey were identified. • The relative survival analysis showed the worst prognosis in pancreatic cancer. • The most common cause of death in all subjects was malignant neoplasms.

Background Evidence of characteristics of Japanese patients with diabetes from a large-scale population is necessary. Few studies have compared glycaemic controls, complications and comorbidities between type 1 and 2 diabetic patients. This paper focuses on illustrating a clinical picture of Japanese diabetic patients and comparing glycaemic control and prognoses between type 1 and 2 diabetes using multi-institutional data. Methods The BioBank Japan Project enrolled adult type 1 and 2 diabetic patients between fiscal years 2003 and 2007. We have presented characteristics, controls of serum glucose, cholesterol and blood pressure, prevalence of complications and comorbidities and survival curves. We have also shown glycaemic controls according to various individual profiles of diabetic patients. Results A total of 558 type 1 diabetic patients and 30,834 type 2 diabetic patients participated in this study. The mean glycated haemoglobin A1c was higher in type 1 diabetes than in type 2 diabetes. In the type 1 diabetic patients, the glycated haemoglobin A1c had no consistent trend according to age and body mass index. The Kaplan–Meier estimates represented a longer survival time from baseline with type 1 diabetes than with type 2 diabetes. Compared with type 1 diabetic patients, type 2 diabetic patients had double the prevalence of macrovascular complications. Conclusions This work has revealed detailed plasma glucose levels of type 1 and 2 diabetic patients according to age, body mass index, blood pressure, serum cholesterol levels and smoking and drinking habits. Our data have also shown that the prognosis is worse for type 2 diabetes than for type 1 diabetes in Japan., Highlights • Detailed glycaemic control data of diabetic patients are necessary. • Few studies have compared the survival times between type 1 and 2 diabetes. • Higher glycated HbA1c was observed in type 1 than in type 2 diabetes. • Data showed higher hazard ratio of mortality in type 1 than in type 2 diabetes. • Fewer macrovascular complications accompany type 1 than type 2 diabetes.

Background To implement personalized medicine, we established a large-scale patient cohort, BioBank Japan, in 2003. BioBank Japan contains DNA, serum, and clinical information derived from approximately 200,000 patients with 47 diseases. Serum and clinical information were collected annually until 2012. Methods We analyzed clinical information of participants at enrollment, including age, sex, body mass index, hypertension, and smoking and drinking status, across 47 diseases, and compared the results with the Japanese database on Patient Survey and National Health and Nutrition Survey. We conducted multivariate logistic regression analysis, adjusting for sex and age, to assess the association between family history and disease development. Results Distribution of age at enrollment reflected the typical age of disease onset. Analysis of the clinical information revealed strong associations between smoking and chronic obstructive pulmonary disease, drinking and esophageal cancer, high body mass index and metabolic disease, and hypertension and cardiovascular disease. Logistic regression analysis showed that individuals with a family history of keloid exhibited a higher odds ratio than those without a family history, highlighting the strong impact of host genetic factor(s) on disease onset. Conclusions Cross-sectional analysis of the clinical information of participants at enrollment revealed characteristics of the present cohort. Analysis of family history revealed the impact of host genetic factors on each disease. BioBank Japan, by publicly distributing DNA, serum, and clinical information, could be a fundamental infrastructure for the implementation of personalized medicine., Highlights • The BioBank Japan Project (BBJ) annually collected clinical information. • Analysis of the clinical information at enrollment characterized the BBJ cohort. • Analysis of family history revealed impacts of host genetic factors on the diseases.

Background Statins are the first-line agents used to treat patients with high serum low-density lipoprotein cholesterol levels, thus reducing the risk of death from arterial sclerotic cardiovascular disease; however, little is known about the effects of non-statin pharmacological interventions on mortality as well as about the potential protective effects of statin use against cancer death. This work aimed to compare all-cause and cancer mortality among patients with hyperlipidaemia who did and did not receive statin treatment. Methods Between 2003 and 2007 fiscal years, we recruited Japanese patients diagnosed with hyperlipidaemia from 66 hospitals. Patients in our cohort were followed up for a maximum of 12 years to observe the causes of death. Kaplan–Meier estimates from the baseline were used to compare the mortality of patients based on the administered medicine. All-cause mortality were compared among patients with/without administration of statins and other agents; any-organ and colorectal cancer mortality were compared between patients with/without administration of statins. Results Our cohort included 41,930 patients with mean ages of 64–66 years and mean body mass indices of 24–25 kg/m2. Patients who received statin monotherapy and were treated with lifestyle modification exhibited nearly identical survival curves, whereas statin use represented a non-significant but potentially protective effect against colorectal cancer-related mortality. The lowest mortality in this cohort was associated with resin monotherapy. Conclusions Mortality rate has been similar for patients treated with statin monotherapy and lifestyle modification. Statin monotherapy could potentially reduce any-organ- and colorectal cancer-related mortality., Highlights • Statin-mediated reduction of low-density lipoprotein levels reduces mortality. • Little is known on the effect of non-statin hyperlipidaemia medicines on mortality. • Statin monotherapy is safe in terms of cancer mortality. • Statin use may reduce colorectal cancer-related mortality. • Resin monotherapy was associated with the lowest mortality.

Background Several studies have evaluated associations between the characteristics of patients with esophageal and gastric cancer and survival, but these associations remain unclear. We described the distribution of demographic and lifestyle factors among patients with esophageal and gastric cancer in Japan, and investigated their potential effects on survival. Methods Between 2003 and 2007, 24- to 95-year-old Japanese patients with esophageal and gastric cancer were enrolled in the BioBank Japan Project. The analysis included 365 patients with esophageal squamous cell carcinoma (ESCC) and 1574 patients with gastric cancer. Hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality were estimated using medical institution-stratified Cox proportional hazards models. Results During follow-up, 213 patients with ESCC (median follow-up, 4.4 years) and 603 patients with gastric cancer (median follow-up, 6.1 years) died. Among patients with ESCC, the mortality risk was higher in ever drinkers versus never drinkers (multivariable HR = 2.37, 95% CI: 1.24, 4.53). Among patients with gastric cancer, the mortality risk was higher in underweight patients versus patients of normal weight (multivariable HR = 1.66, 95% CI: 1.34, 2.05). Compared to patients with gastric cancer with no physical exercise habit, those who exercised ≥3 times/week had a lower mortality risk (multivariate HR = 0.75, 95% CI = 0.61, 0.93). However, lack of stage in many cases was a limitation. Conclusions Among patients with ESCC, alcohol drinkers have a poor prognosis. Patients with gastric cancer who are underweight also have a poor prognosis, whereas patients with physical exercise habits have a good prognosis., Highlights • Among ESCC patients, alcohol drinkers had a poor prognosis. • Underweight gastric cancer patients had a poor prognosis. • Gastric cancer patients who exercised had a good prognosis. • No association between esophageal or gastric cancer and smoking was observed.

Background In Japanese males and females, lung cancer is currently the second and fourth most common type of cancer, and the first and second leading cause of cancer-related deaths, respectively. Methods Of all Japanese male and female lung cancer patients aged ≥20 years whom the BioBank Japan Project originally enrolled between 2003 and 2008, 764 males and 415 females were registered within 90 days after their diagnosis. We described the lifestyle and clinical characteristics of these patients at study entry. Furthermore, we examined the effect of these characteristics on all-cause mortality. Results In the lung cancer patients registered within 90 days, the frequencies of occult or stage 0, stage I, II, III and IV were 0.4%, 55.8%, 10.8%, 22.0% and 11.0% for males and 0.3%, 62.4%, 9.9%, 17.1% and 10.2% for females, respectively. The proportions of histological types in males and females were 56.3% and 82.4% for adenocarcinoma, 26.9% and 8.2% for squamous cell carcinoma, 4.5% and 1.5% for large cell carcinoma, 7.7% and 4.1% for small cell carcinoma and 4.6% and 3.8% for others, respectively. Among 1120 participants who registered within 90 days, 572 participants died during 5811 person-years of follow-up. Low body mass index, ever smoker, more advanced stage, squamous cell or small cell carcinoma and high serum carcinoembryonic antigen level at study entry were crudely associated with an increased risk of all-cause mortality after adjustment for age. Conclusions This study showed the association of several lifestyle and clinical characteristics with all-cause mortality in lung cancer patients., Highlights • Nearly one-tenth of Japanese lung cancer patients were diagnosed as stage IV. • Adenocarcinoma was the most common histological type in both males and females. • Some characteristics would affect all-cause mortality in lung cancer patients.

Background Cardiovascular disease (CVD) is a leading cause of death in Japan. The present study aimed to develop new risk prediction models for long-term risks of all-cause and cardiovascular death in patients with chronic phase CVD. Methods Among the subjects registered in the BioBank Japan database, 15,058 patients aged ≥40 years with chronic ischemic CVD (ischemic stroke or myocardial infarction) were divided randomly into a derivation cohort (n = 10,039) and validation cohort (n = 5019). These subjects were followed up for 8.55 years in median. Risk prediction models for all-cause and cardiovascular death were developed using the derivation cohort by Cox proportional hazards regression. Their prediction performances for 5-year risk of mortality were evaluated in the validation cohort. Results During the follow-up, all-cause and cardiovascular death events were observed in 2962 and 962 patients from the derivation cohort and 1536 and 481 from the validation cohort, respectively. Risk prediction models for all-cause and cardiovascular death were developed from the derivation cohort using ten traditional cardiovascular risk factors, namely, age, sex, CVD subtype, hypertension, diabetes, total cholesterol, body mass index, current smoking, current drinking, and physical activity. These models demonstrated modest discrimination (c-statistics, 0.703 for all-cause death; 0.685 for cardiovascular death) and good calibration (Hosmer-Lemeshow χ2-test, P = 0.17 and 0.15, respectively) in the validation cohort. Conclusions We developed and validated risk prediction models of all-cause and cardiovascular death for patients with chronic ischemic CVD. These models would be useful for estimating the long-term risk of mortality in chronic phase CVD., Highlights • We developed risk prediction models for death after cardiovascular disease (CVD). • Performances of these models were validated in an independent cohort. • Our models may be used to estimate mortality risk in chronic CVD patients.

Background The BioBank Japan (BBJ) Project was launched in 2003 with the aim of providing evidence for the implementation of personalized medicine by constructing a large, patient-based biobank (BBJ). This report describes the study design and profile of BBJ participants who were registered during the first 5-year period of the project. Methods The BBJ is a registry of patients diagnosed with any of 47 target common diseases. Patients were enrolled at 12 cooperative medical institutes all over Japan from June 2003 to March 2008. Clinical information was collected annually via interviews and medical record reviews until 2013. We collected DNA from all participants at baseline and collected annual serum samples until 2013. In addition, we followed patients who reported a history of 32 of the 47 target diseases to collect survival data, including cause of death. Results During the 5-year period, 200,000 participants were registered in the study. The total number of cases was 291,274 at baseline. Baseline data for 199,982 participants (53.1% male) were available for analysis. The average age at entry was 62.7 years for men and 61.5 years for women. Follow-up surveys were performed for participants with any of 32 diseases, and survival time data for 141,612 participants were available for analysis. Conclusions The BBJ Project has constructed the infrastructure for genomic research for various common diseases. This clinical information, coupled with genomic data, will provide important clues for the implementation of personalized medicine., Highlights • The BioBank Japan Project (BBJ) enrolled 200,000 patients with 47 target diseases. • The BBJ is one of the largest patient-based biobanks in the world. • The BBJ may allow for personalized medicine in the future.

AIM To determine the prognostic factors associated with mortality in patients with gastric fundal variceal (GFV) bleeding. METHODS In total, 42 patients were endoscopically diagnosed with GFV bleeding from January 2000 to March 2014. We retrospectively reviewed the patients' medical records and assessed their history, etiology of liver cirrhosis, disease conditions, treatment options for GFV bleeding, medications administered before and after onset of GFV bleeding, blood test results (hemoglobin, albumin, and bilirubin concentrations), and imaging results (including computed tomography and abdominal ultrasonography). We also assessed the prognostic factors associated with short-term mortality (up to 90 d) and long-term mortality in all patients. RESULTS Multivariate analysis showed that prophylactic administration of antibiotics was an independent prognostic factor associated with decreases in short-term mortality (OR = 0.08, 95%CI: 0.01-0.52) and long-term mortality (OR = 0.27, 95%CI: 0.08-0.91) in patients with GFV bleeding. In contrast, concurrent hepatocellular carcinoma (HCC) and regular use of proton pump inhibitors (PPI) were independent prognostic factors associated with increases in short-term mortality (HCC: OR = 15.4, 95%CI: 2.08-114.75; PPI: OR = 12.76, 95%CI: 2.13-76.52) and long-term mortality (HCC: OR = 7.89, 95%CI: 1.98-31.58; PPI: OR = 10.91, 95%CI: 2.86-41.65) in patients with GFV bleeding. The long-term overall survival rate was significantly lower in patients who regularly used PPI than in those who did not use PPI (P = 0.0074). CONCLUSION Administration of antibiotics is associated with decreased short- and long-term mortality, while concurrent HCC and regular PPI administration are associated with increased short- and long-term mortality.

症例は34歳男性．職業は獣医．平成21年11月10日頃より微熱，全身倦怠感を自覚し，近医で黄疸を伴う肝障害を指摘され11月20日当科を受診した．初診時AST 215 IU/l ，ALT 465 IU/l ，T-Bil 2.9 mg/dl ，CRP 0.38 mg/dl であり，11月27日入院後，末梢血白血球数，CRP，ALT値が次第に上昇し，発熱と関節痛が著明となった．右背部に紅斑とマダニ刺咬痕を認め，血清ボレリア抗体IgM，IgG陽性の所見からライム病と診断し，Doxycycline，Ceftriaxone投与により軽快した．ライム病による急性肝炎はこれまで本邦に報告がない．

症例は75歳女性．2000年から近医でpravastatinの投与を受けていた．2007年9月AST，ALT値の上昇を指摘されたが自然に低下した．2008年4月，黄疸を伴う肝障害のため当科を紹介され，AST 617 IU/l，ALT 407 IU/l，T-Bil 6.6 mg/dl，Alb 2.9 g/dl，抗核抗体80倍，IgG 1,914 mg/dl，HLA DR4陽性であった．画像所見は肝硬変像を呈しており，肝生検を施行し自己免疫性肝炎（AIH）と診断した．Pravastatin中止とウルソデオキシコール酸投与により肝機能検査値は改善したが，血小板数が徐々に減少し腹水の出現を認め，プレドニゾロン追加投与により寛解した．Pravastatin起因性AIHが潜在性に進行して肝硬変に至った症例と考えられた．

手術的に短絡路閉鎖を行い，門脈大循環短絡症による猪瀬型肝性脳症の改善を認めた症例を経験したので報告する. 患者1, 71歳男性，明らかな肝障害の既往はない．絞扼性イレウス，汎発性腹膜炎を発症し手術を施行したが，術後より繰り返す肝性脳症が出現した．CTにて巨大な脾腎短絡路を認めたため，開胸，開腹下に脾腎短絡路閉鎖術を行った． 患者2, 79歳男性，C型肝炎の既往がある．CTにて上腸間膜静脈と下大静脈間に巨大な短絡路を認め，短絡路閉鎖，摘出術を行った．術後に門脈血栓，上腸間膜静脈血栓症を発症したが，抗凝固療法により血栓は完全に消失した． 患者は二名とも術後肝性脳症の発症はなかった．猪瀬型肝性脳症の治療に短絡路閉鎖術は有効な治療法であるが門脈血栓に対しては注意を要する．

We analyzed the 5-year post-treatment response to peginterferon α-2a (PEG IFN-α-2a) in hepatitis B e-antigen (HBeAg) positive and negative chronic hepatitis B patients.One hundred and thirty-seven chronic hepatitis B (CHB) patients receiving 90 μg or 180 μg of PEG IFN-α-2a for 24 or 48 weeks in phase II or III studies were enrolled in the study, including 100 HBeAg positive patients and 37 HBeAg negative patients; 121 patients (88.4%) had genotype C.Of the 137 patients, 94 received additional antiviral therapy because of viral reactivation and 43 did not receive any additional antiviral treatment during follow up. Five years upon PEG IFN-α-2a treatment, 32 patients (23.4%) who did not receive any additional antiviral agent after PEG IFN-α-2a therapy achieved a good response (normal serum alanine aminotransferase, low-level hepatitis B virus [HBV] DNA, and HBeAg negativity). Female sex and low HBV DNA levels by the end of treatment were independently associated with favorable 5-year post-treatment responses. Forty-eight-week administration of PEG IFN-α-2a showed a better response (26.4%) than 24-week administration (18.0%). Six patients (4.3%), four males and two females, cleared hepatitis B surface antigen (HBsAg) during the 5-year follow-up period.The 48-week administration of PEG IFN-α-2a achieved better biochemical and virological responses than the 24-week administration, particularly in younger females. The 5-year post-treatment response rate was 23.4%; however, more than two-thirds of the patients received additional antiviral therapy because of viral reactivation after PEG IFN-α-2a treatment. HBsAg clearance was noted in six patients (4.3%). PEG IFN-α-2a is effective in young female patients.

症例は38歳，女性．焼酎3∼5合/日15年間の飲酒歴を有する大酒家である．1996年アルコール性肝硬変と診断され，食道静脈瘤破裂のため当科に入院した．1999年，肝両葉に径10-20mmの多発性低エコー腫瘤を認め，S8腫瘤の生検で大酒家肝過形成結節と診断した．2002年，この腫瘤が造影CT早期相で造影効果を呈し，再生検したが同様に過形成結節の組織像であった．また2000年にS4に出現した径5mmの腫瘤が次第に増大して径20mmとなり，2004年7月生検したところ過形成結節の所見であった．この腫瘤はその後CT造影効果の変化を呈し，2005年7月径30mmとなったが再生検の結果同様の組織所見であった．今回，大酒家の肝過形成結節を6年間追跡し，腫瘤径の増大および縮小と画像所見の変化を呈する興味ある経過を観察した．