Geriatric nutritional risk index as an easy-to-use assessment tool for nutritional status in hepatocellular carcinoma treated with atezolizumab plus bevacizumab.

AIM: The present study focused on Geriatric Nutritional Risk Index (GNRI), which is based on bodyweight and serum albumin, and known as an easy-to-use nutritional assessment tool in clinical settings, to elucidate the prognostic predictive ability of GNRI in patients treated with atezolizumab plus bevacizumab (Atez/Bev) for hepatocellular carcinoma (HCC). METHODS: A total of 525 HCC patients treated with Atez/Bev, based on their classification of unsuitable status for curative treatments and/or transarterial catheter chemoembolization, were enrolled (Child-Pugh A:B:C = 484:40:1, Barcelona Clinic Liver Cancer stage 0:A:B:C:D = 7:25:192:283:18). Prognosis was evaluated retrospectively using GNRI. RESULTS: Atez/Bev was used in 338 of the present cohort as first-line systemic chemotherapy (64.4%). Median progression-free survival based on GNRI indicating normal, mild decline, moderate decline, and severe decline was 8.3, 6.7, 5.3, and 2.4 months, respectively, whereas median overall survival was 21.4, 17.0, 11.5. and 7.3 months, respectively (both p < 0.001). The concordance index (c-index) values of GNRI for predicting prognosis (progression-free survival/overall survival) were superior to those of Child-Pugh class and albumin-bilirubin grade (0.574/0.632 vs. 0.527/0.570 vs. 0.565/0.629). As a subanalysis, muscle volume loss was observed in 37.5% of 256 patients with computed tomography data available. Along with GNRI decline, frequency of muscle volume loss became progressively larger (normal vs. mild vs. moderate vs. severe = 17.6% vs. 29.2% vs. 41.2% vs. 57.9%, p < 0.001), and a GNRI value of 97.8 was predictive of its occurrence (AUC 0.715, 95% CI 0.649-0.781; specificity/sensitivity = 0.644/0.688). CONCLUSION: These findings indicate that GNRI is an effective nutritional prognostic tool for predicting prognosis and muscle volume loss complication in HCC patients treated with Atez/Bev.

Hepatocellular Carcinoma Risk Assessment for Patients With Advanced Fibrosis After Eradication of Hepatitis C Virus.

The identification of patients with advanced fibrosis who do not need any further hepatocellular carcinoma (HCC) surveillance after the eradication of hepatitis C is pivotal. In this study, we developed a simple serum-based risk model that could identify patients with low-risk HCC. This was a nationwide multicenter study involving 16 Hospitals in Japan. Patients with advanced fibrosis (1,325 in a derivation cohort and 508 in a validation cohort) who achieved sustained virological responses at 24 weeks after treatment (SVR24) were enrolled. The HCC risk model at any point after SVR24 and its change were evaluated, and subsequent HCC development was analyzed. Based on the multivariable analysis, patients fulfilling all of the factors (GAF4 criteria: gamma-glutamyl transferase < 28 IU/L, alpha-fetoprotein < 4.0 ng/mL, and Fibrosis-4 Index < 4.28) were classified as low-risk and others were classified as high-risk. When patients were stratified at the SVR24, and 1 year, and 2 years after SVR24, subsequent HCC development was significantly lower in low-risk patients (0.5-1.1 per 100 person-years in the derivation cohort and 0.9-1.1 per 100 person-years in the validation cohort) than in high-risk patients at each point. HCC risk from 1 year after SVR24 decreased in patients whose risk improved from high-risk to low-risk (HCC incidence: 0.6 per 100 person-years [hazard ratio (HR) = 0.163 in the derivation cohort] and 1.3 per 100 person-years [HR = 0.239 in the validation cohort]) than in those with sustained high risk. Conclusion: The HCC risk model based on simple serum markers at any point after SVR and its change can identify patients with advanced fibrosis who are at low HCC risk, and these patients may be able to reduce HCC surveillance.

Association of PM2.5 exposure with hospitalization for cardiovascular disease in elderly individuals in Japan.

Although exposure to particulate matter with aerodynamic diameters ≤ 2.5 µm (PM2.5) influences cardiovascular disease (CVD), its association with CVD-related hospitalizations of super-aged patients in Japan remains uncertain. We investigated the relationship between short-term PM2.5 exposure and CVD-related hospitalizations, lengths of hospital stays, and medical expenses. We analyzed the Japanese national database of patients with CVD (835,405) admitted to acute-care hospitals between 2012 and 2014. Patients with planned hospitalizations and those with missing PM2.5 exposure data were excluded. We classified the included patients into five quintiles based on their PM2.5 exposure: PM-5, -4, -3, -2, and -1 groups, in descending order of concentration. Compared with the PM-1 group, the other groups had higher hospitalization rates. The PM-3, -4, and -5 groups exhibited increased hospitalization durations and medical expenses, compared with the PM-1 group. Interestingly, the hospitalization period was longer for the ≥ 90-year-old group than for the ≤ 64-year-old group, yet the medical expenses were lower for the former group. Short-term PM2.5 exposure is associated with increased CVD-related hospitalizations, hospitalization durations, and medical expenses. The effects of incident CVDs were more marked in elderly than in younger patients. National PM2.5 concentrations should be reduced and the public should be aware of the risks.

Comparative overview of ST-elevation myocardial infarction epidemiology, demographics, management, and outcomes in five Asia-Pacific countries: a meta-analysis.

The aim of this study is to gain insight into the differences in demographics of ST-elevation myocardial infarction (STEMI) patients in Asia-Pacific, as well as inter-country variation in treatment and mortality outcomes. Systematic review of published studies and reports from known registries in Australia, Japan, Korea, Singapore, and Malaysia that began data collection after the year 2000. Supplementary self-report survey questionnaire on public health data answered by representative cardiologists working in these countries. Twenty studies comprising of 158 420 patients were included in the meta-analysis. The mean age was 61.6 years. Chronic kidney disease prevalence was higher in Japan, while dyslipidaemia was low in Korea. Use of aspirin, P2Y12 inhibitors, and statins were high throughout, but ACEi/ARB and ß-blocker prescriptions were lower in Japan and Malaysia. Reperfusion strategies varied greatly, with high rates of primary percutaneous coronary intervention (pPCI) in Korea (91.6%), whilst Malaysia relies far more on fibrinolysis (72.6%) than pPCI (9.6%). Similarly, mortality differed, with 1-year mortality from STEMI was considerably greater in Malaysia (17.9%) and Singapore (11.2%) than in Korea (8.1%), Australia (7.8%), and Japan (6.2%). The countries were broadly similar in development and public health indices. Singapore has the highest gross national income and total healthcare expenditure per capita, whilst Malaysia has the lowest. Primary PCI is available in all countries 24/7/365. Despite broadly comparable public health systems, differences exist in patient profile, in-hospital treatment, and mortality outcomes in these five countries. Our study reveals areas for improvements. The authors advocate further registry-based multi-country comparative studies focused on the Asia-Pacific region.

Diabetes association with self-reported health, resource utilization, and prognosis post-myocardial infarction.

BACKGROUND: Diabetes mellitus (DM) is associated with increased cardiovascular (CV) risk. We compared health-related quality of life (HRQoL), healthcare resource utilization (HRU), and clinical outcomes of stable post-myocardial infarction (MI) patients with and without DM. HYPOTHESIS: In post-MI patients, DM is associated with worse HRQoL, increased HRU, and worse clinical outcomes. METHODS: The prospective, observational long-term risk, clinical management, and healthcare Resource utilization of stable coronary artery disease study obtained data from 8968 patients aged ≥50 years 1 to 3 years post-MI (369 centers; 25 countries). Patients with ≥1 of the following risk factors were included: age ≥65 years, history of a second MI >1 year before enrollment, multivessel coronary artery disease, creatinine clearance ≥15 and <60 mL/min, and DM treated with medication. Self-reported health status was assessed at baseline, 1 and 2 years and converted to EQ-5D scores. The main outcome measures were baseline HRQoL and HRU during follow-up. RESULTS: DM at enrollment was 33% (2959 patients, 869 insulin treated). Mean baseline EQ-5D score (0.86 vs 0.82; P < .0001) was higher; mean number of hospitalizations (0.38 vs 0.50, P < .0001) and mean length of stay (LoS; 9.3 vs 11.5; P = .001) were lower in patients without vs with DM. All-cause death and the composite of CV death, MI, and stroke were significantly higher in DM patients, with adjusted 2-year rate ratios of 1.43 (P < .01) and 1.55 (P < .001), respectively. CONCLUSIONS: Stable post-MI patients with DM (especially insulin treated) had poorer EQ-5D scores, higher hospitalization rates and LoS, and worse clinical outcomes vs those without DM. Strategies focusing specifically on this high-risk population should be developed to improve outcomes. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01866904 (https://clinicaltrials.gov).

Attenuation imaging based on ultrasound technology for assessment of hepatic steatosis: A comparison with magnetic resonance imaging-determined proton density fat fraction.

AIM: A new method has recently been developed for diagnosing hepatic steatosis based on attenuation measurement using ultrasound. We investigated the ability of attenuation imaging (ATI) to detect steatosis that was identified by proton density fat fraction (PDFF) on magnetic resonance imaging (MRI) in patients with chronic liver disease. METHODS: A total of 119 patients with chronic liver disease (non-B, non-C) were analyzed. The relationship between ATI values and steatosis grades determined by PDFF was evaluated. Additionally, the diagnostic ability of ATI was evaluated using receiver operating characteristic curve analysis, and the correlation between ATI values and PDFF values was determined. RESULTS: The ATI values of steatosis grades 0, 1, 2, and 3 were 0.55, 0.61, 0.74, and 0.84 dB/cm/MHz, respectively (P < 0.001). There was a statistically significant trend of higher ATI values with higher steatosis grades (P < 0.001). The correlation coefficient (r) between PDFF values and ATI values was 0.70 (95% confidence interval [CI] 0.59-0.78; P < 0.001), corresponding to a strong relationship. The diagnostic ability of ATI for steatosis grades ≥1, ≥2, and 3, as determined by PDFF, were 0.81 (95% CI 0.73-0.89), 0.87 (95% CI 0.79-0.96), and 0.94 (95% CI 0.89-0.98), respectively. The r between PDFF values and ATI values was 0.49 (95% CI 0.31-0.63; P < 0.001) for patients with mild or no steatosis (grade ≤1), and 0.75 (95% CI 0.57-0.86; P < 0.001) for obese patients (body mass index ≥25 kg/m2 ). CONCLUSION: ATI values had an excellent diagnostic ability to detect hepatic steatosis.

Long-term prognosis of liver disease in patients with eradicated chronic hepatitis C virus: An analysis using a Markov chain model.

AIM: The long-term prognosis of patients with chronic hepatitis C virus (HCV) infection who have received antiviral therapy and who demonstrate HCV eradication remains incompletely characterized. In this study, we investigated the long-term prognosis of liver disease in patients with eradication of HCV. METHODS: A total of 552 patients with chronic HCV infection (6815 person-years) who were treated with interferon-based therapy and who achieved sustained virologic response were included. Yearly transition probabilities for each liver state (chronic hepatitis, cirrhosis, and hepatocellular carcinoma [HCC]) were calculated using a Markov chain model. RESULTS: In the analysis of 1-year liver disease state transition probabilities, progression to cirrhosis occurred in 0.5-2.1% of male patients with chronic hepatitis across all age groups. In male patients with cirrhosis, HCC developed in 0.6-1.9% of patients over the age of 50 years. In female patients with chronic hepatitis, progression to cirrhosis occurred in 0.4-2.1% of patients across all age groups. In addition, in female patients with cirrhosis, HCC developed in those aged 60-69 (0.4%) and 70-79 (0.4%) years. Under the assumption of either a chronic hepatitis or cirrhosis state at age 40 or 60 years as the starting condition for simulation over the next 40 or 20 years, respectively, the probability of HCC gradually increased with age and was higher in male patients. CONCLUSIONS: The development or progression of cirrhosis and the development of HCC are risks in HCV patients despite HCV eradication, not only in those with cirrhosis but also in those with chronic hepatitis.

Correction to: Three-dimensional assessment of coronary high-intensity plaques with T1-weighted cardiovascular magnetic resonance imaging to predict periprocedural myocardial injury after elective percutaneous coronary intervention.

In the original publication of this article [1] the wording of '3Di-PMR' was different between the text and figures.

Three-dimensional assessment of coronary high-intensity plaques with T1-weighted cardiovascular magnetic resonance imaging to predict periprocedural myocardial injury after elective percutaneous coronary intervention.

BACKGROUND: Periprocedural myocardial injury (pMI) is a common complication of elective percutaneous coronary intervention (PCI) that reduces some of the beneficial effects of coronary revascularization and impacts the risk of cardiovascular events. We developed a 3-dimensional volumetric cardiovascular magnetic resonance (CMR) method to evaluate coronary high intensity plaques and investigated their association with pMI after elective PCI. METHODS: Between October 2012 and October 2016, 141 patients with stable coronary artery disease underwent T1-weighted CMR imaging before PCI. A conventional 2-dimensional CMR plaque-to-myocardial signal intensity ratio (2D-PMR) and the newly developed 3-dimensional integral of PMR (3Di-PMR) were measured. 3Di-PMR was determined as the sum of PMRs above a threshold of > 1.0 for voxels in a target plaque. pMI was defined as high-sensitivity cardiac troponin T > 0.07 ng/mL. RESULTS: pMI following PCI was observed in 46 patients (33%). 3Di-PMR was significantly higher in patients with pMI than those without pMI. The optimal 3Di-PMR cutoff value for predicting pMI was 51 PMR*mm3 and the area under the receiver operating characteristic curve (0.753) was significantly greater than that for 2D-PMR (0.683, P = 0.015). 3Di-PMR was positively correlated with lipid volume (r = 0.449, P < 0.001) based on intravascular ultrasound. Stepwise multivariable analysis showed that 3Di-PMR ≥ 51 PMR*mm3 and the presence of a side branch at the PCI target lesion site were significant predictors of pMI (odds ratio [OR], 11.9; 95% confidence interval [CI], 4.6-30.4, P < 0.001; and OR, 4.14; 95% CI, 1.6-11.1, P = 0.005, respectively). CONCLUSIONS: 3Di-PMR coronary assessment facilitates risk stratification for pMI after elective PCI. TRIAL REGISTRATION: retrospectively registered.

Natural history of liver-related disease in patients with chronic hepatitis C virus infection: An analysis using a Markov chain model.

BACKGROUND: Long-term prognosis of patients with chronic hepatitis C infection (HCV) remains incompletely characterized. We investigated the long-term prognosis of liver disease in patients with chronic HCV infection who have not received antiviral therapy. METHODS: A total of 2304 patients with chronic HCV who were not received interferon-based therapy were included. RESULTS: In the assessment of 1-year disease state of liver transition probabilities, progression to chronic hepatitis occurred in 12% to 14% of patients across all age groups in male asymptomatic carriers. In male patients with chronic hepatitis, progression to cirrhosis was observed mostly in the 60 to 69 (7.6%) and ≥70 age groups (9.6%). In addition, in male patients with cirrhosis, HCC development occurred in approximately 5% of patients over the age of 40. In female asymptomatic carriers, progression to chronic hepatitis was observed in 6% to 14% of patients across all age groups. In female patients with chronic hepatitis, progression to cirrhosis was observed mostly in the 60 to 69 (8.7%) and ≥70 (7.4%) age groups. In addition, in female patients with cirrhosis, HCC development occurred in 0.9% to 3.3% of patients over the age of 50. Under assumptions of either chronic hepatitis or asymptomatic carrier state at age 40 as the starting condition for simulation over the following 40 years, the probability of HCC gradually increased with age and was higher in male patients. CONCLUSIONS: There is a risk of cirrhosis or HCC development in HCV patients with not only chronic hepatitis but the asymptomatic carrier state as well.

Long-term prognosis of liver disease in patients with chronic hepatitis B virus infection receiving nucleos(t)ide analogue therapy: an analysis using a Markov chain model.

AIM: Even during nucleos(t)ide analogue therapy, development of hepatocellular carcinoma (HCC) has been observed in patients with chronic hepatitis B virus (HBV) infection. We simulated the long-term prognosis of liver disease in patients with chronic HBV who received nucleos(t)ide analogue therapy. PATIENTS AND METHODS: A total of 254 patients with chronic HBV receiving nucleos(t)ide analogue therapy were enrolled. Yearly transition probabilities between liver disease states [chronic hepatitis, cirrhosis, HCC, and hepatitis B surface antigen (HBsAg)-negative status] were calculated using a Markov chain model. RESULTS: In the analysis of 1-year liver disease state transition probabilities, the development of HCC occurred in men with chronic hepatitis in their 50s (1.8%) and at least 70 years (2.8%) and in patients with cirrhosis in all age groups (40-49, 50-59, 60-69, and ≥ 70 years). HBsAg-negative status was present in patients with chronic hepatitis in their 50s (1.8%) and 60s (2.6%), and in patients with cirrhosis in their 60s (0.6%). In female patients, the development of HCC occurred in patients with cirrhosis during their 50s (0.8%), 60s (0.8%), and older (4.5%). HBsAg-negative status was simulated in patients with cirrhosis in their 50s (0.8%) and 60s (0.8%). Assuming a chronic hepatitis state at age 40 as the starting condition for simulation over the next 40 years, the probability of developing HCC increased gradually with age in male patients and in female patients after the age of 70 years. CONCLUSION: There is a risk of development of HCC in middle-aged men with chronic hepatitis or cirrhosis and older women with cirrhosis even while receiving nucleos(t)ide analogue therapy.

Primary Percutaneous Coronary Intervention in Elderly Patients With Acute Myocardial Infarction　- An Analysis From a Japanese Nationwide Claim-Based Database.

BACKGROUND: Primary percutaneous coronary intervention (pPCI) is strongly recommended by guidelines for patients presenting with acute myocardial infarction (AMI), but its applications in elderly patients are less clear.Methods and Results:The JROAD-DPC is a Japanese nationwide registry for patients with cardiovascular diseases combined with an administrative claim-based database. Among 2,369,165 records from 2012 to 2015, data for 115,407 AMI patients were extracted for this study. Elderly patients (≥75 years) comprised 45,645 subjects (39.6%), and received pPCI less frequently (62.2%) than younger patients (79.2%, P<0.001). Clinical variables such as higher age, female sex, higher Killip class, and renal dysfunction, but not functional status on admission, were predictors of non-application of pPCI. Endpoint 30-day mortality increased with aging, and was significantly higher in elderly patients (10.7%) than in younger patients (3.8%, P<0.001). Indeed, pPCI was independently associated with lower 30-day mortality only in subgroups of patients aged ≥60 years. Propensity score-matching analysis confirmed a similar reduction in endpoint 30-day mortality with pPCI in elderly patients. Duration of hospitalization was significantly shorter and functional ability on discharge was significantly better in elderly patients who underwent pPCI. CONCLUSIONS: Elderly patients with AMI underwent pPCI less frequently, but it was consistently associated with better clinical outcome in these patients. Our findings support the proactive application of pPCI for elderly AMI patients when they are eligible for an invasive strategy.

Hospitalization Costs for Patients With Acute Congestive Heart Failure in Japan.

BACKGROUND: With aging of the population, the economic burden associated with heart failure (HF) is expected to increase. However, little is known about the hospitalization costs associated with HF in Japan. Methods and Results: In this cross-sectional study, using data from The Japanese Registry of All Cardiac and Vascular Diseases (JROAD) and JROAD-Diagnosis Procedure Combination databases between 2012 and 2014, we evaluated hospitalization costs for acute cardiovascular diseases (CVDs), including HF. A total of $1,187 million/year (44% of the hospitalization costs for acute CVDs) was spent on patients with HF. We identified 273,865 patients with HF and the median cost per patient was $8,089 ($5,362-12,787) per episode. The top 1% of spenders accounted for 8% ($80 million/year), and the top 5% of spenders accounted for 22% ($229 million/year) of the entire cost associated with HF. The costs associated with HF for patients over 75 years of age accounted for 68% of the total cost. CONCLUSIONS: The costs associated with HF were higher than the hospitalization cost for any other acute CVD in Japan. Understanding how the total hospitalization cost is distributed may allow health providers to utilize limited resources more effectively for patients with HF.

Multimodality assessment of left ventricular dysfunction in Takayasu arteritis and familial hypercholesterolaemia.

Although left ventricular (LV) systolic dysfunction in patients suffering from Takayasu arteritis (TA) has been reported, little is known regarding the development of heart failure in these patients. We report a novel finding of active TA and familial hypercholesterolaemia presenting with severe LV dysfunction through multimodality assessments of LV systolic dysfunction.

The Current Status of Cardiovascular Medicine in Japan　- Analysis of a Large Number of Health Records From a Nationwide Claim-Based Database, JROAD-DPC.

BACKGROUND: Since cardiovascular disease accounts for one-quarter of deaths in the Japanese population, we developed a nationwide database using the administrative case-mix Diagnostic Procedure Combination (DPC) system (ie, theJapaneseRegistryOfAll cardiac and vascularDiseases (JROAD)-DPC) to reveal the current status of cardiovascular medicine in Japan.Methods and Results:The JROAD-DPC database included 704,593 health records' data of 2012 from 610 certificated hospitals of the Japanese Circulation Society. The 35,824 patients with acute myocardial infarction (AMI) and 108,665 patients with heart failure (HF) were admitted to hospitals. Increased hospital case volume was associated with reduced in-hospital mortality rates for both AMI and HF (P for trend <0.001). Although there was little variation among AMI patients in terms of aspirin use at discharge (median prescription rate, 83.0%; interquartile range [IQR], 76.9-88.0%), there were wide variations in the proportions of patients prescribed ß-blockers (BB) and angiotensin-converting enzyme inhibitors (ACEI)/angiotensin-receptor blockers (ARB) at discharge (BB, 41.4%, IQR 27.6-55.7%; ACEI/ARB, 52.0%, IQR 40.3-62.3%). In patients with HF, there were between-hospital variations in medications at discharge (BB, 38.1%, IQR, 27.8-47.6%; ACEI/ARB, 41.0%, IQR 31.7-49.1%). CONCLUSIONS: A nationwide administrative database of patients with cardiovascular diseases (JROAD-DPC) provided useful information that will contribute to improved quality of medical care, especially in the aging society of Japan, where HF has become an important health problem. (Circ J 2016; 80: 2327-2335).

Application of cell growth analysis to the quality assessment of human cell-processed therapeutic products as a testing method for immortalized cellular impurities.

In human cell-processed therapeutic products (hCTPs) for clinical application, tumorigenic cellular impurities in the manufacturing process are a major concern. Because cellular immortalization is one of the prerequisite steps in tumorigenesis, we tested whether cell growth analysis can be employed to check for immortalized (and potentially tumorigenic) cellular impurities in hCTPs. We monitored the growth of human bone marrow-derived mesenchymal stem cells (BMSCs) mixed with HeLa cells at a ratio of 1/106 or more and compared their growth rates with that of BMSCs alone. The cell growth analysis detected a significant increase in the growth rate of the BMSCs spiked with 0.0001% HeLa within 30 days at a probability of 47%. When human adipose-derived stem cells (ADSCs) were spiked with ASC52telo cells, a human telomerase reverse transcriptase (hTERT)-immortalized adipose-derived mesenchymal stem cell line, at a ratio of 0.001% or more, their growth rates were significantly increased within 15 passages, compared with that of ADSCs alone. These results indicate that cell growth analysis for the detection of immortalized cellular impurities in human somatic stem cells is simple and can be useful for the quality assessment of hCTPs in the manufacturing process.

Tumorigenicity assessment of human cell-processed therapeutic products.

Human pluripotent stem cells (hPSCs) are expected to be sources of various cell types used for cell therapy, although hPSCs are intrinsically tumorigenic and form teratomas in immunodeficient animals after transplant. Despite the urgent need, no detailed guideline for the assessment of tumorigenicity of human cell-processed therapeutic products (hCTPs) has been issued. Here we describe our consideration on tumorigenicity and related tests of hCTPs. The purposes of those tests for hPSC-based products are classified into three categories: 1) quality control of raw materials; 2) quality control of intermediate/final products; and 3) safety assessment of final products. Appropriate types of tests need to be selected, taking the purpose(s) into consideration. In contrast, human somatic (and somatic stem) cells are believed to have little tumorigenicity. Therefore, GMP-compliant quality control is essential to avoid contamination of somatic cell-derived products with tumorigenic cells. Compared with in vivo tumorigenicity tests, in vitro cell proliferation assays may be more useful and reasonable for detecting immortalized cells that have a growth advantage in somatic cell-based products. The results obtained from tumorigenicity and related tests for hCTPs should meet the criteria for decisions on product development, manufacturing processes, and clinical applications.