Japan Association Research Articles

COVID-19 pandemic modifies temperature and heat-related illness ambulance transport association in Japan: a nationwide observational study

BackgroundDuring the COVID-19 pandemic, several illnesses were reduced. In Japan, heat-related illnesses were reduced by 22% compared to pre-pandemic period. However, it is uncertain as to what has led to this reduction. Here, we model the association of maximum temperature and heat-related illnesses in the 47 Japanese prefectures. We specifically examined how the exposure and lag associations varied before and during the pandemic.MethodsWe obtained the summer-specific, daily heat-related illness ambulance transport (HIAT), exposure variable (maximum temperature) and covariate data from relevant data sources. We utilized a stratified (pre-pandemic and pandemic), two-stage approach. In each stratified group, we estimated the 1) prefecture-level association using a quasi-Poisson regression coupled with a distributed lag non-linear model, which was 2) pooled using a random-effects meta-analysis. The difference between pooled pre-pandemic and pandemic associations was examined across the exposure and the lag dimensions.ResultsA total of 321,655 HIAT cases was recorded in Japan from 2016 to 2020. We found an overall reduction of heat-related risks for HIAT during the pandemic, with a wide range of reduction (10.85 to 57.47%) in the HIAT risk, across exposure levels ranging from 21.69 °C to 36.31 °C. On the contrary, we found an increment in the delayed heat-related risks during the pandemic at Lag 2 (16.33%; 95% CI: 1.00, 33.98%).ConclusionThis study provides evidence of the impact of COVID-19, particularly on the possible roles of physical interventions and behavioral changes, in modifying the temperature-health association. These findings would have implications on subsequent policies or heat-related warning strategies in light of ongoing or future pandemics.

Open access, closed systems: independent online journalism in Japan

ABSTRACT This article is part of an ethnography of Japan’s ‘independent’ journalism movement, with a focus on the establishment and dissolution of the Free Press Association of Japan (FPAJ). Based on 13 months of fieldwork within this organization and other internet news broadcasters (i.e., the Independent Web Journal, Our Planet TV), I argue that the conventional taxonomies applied to journalists and journalistic praxis do not easily apply to Japan. Even in the period of heightened political activism following the March 2011 earthquake and nuclear disaster, the country’s stalwart kisha (press) club infrastructure proved too great an obstacle for comparatively informal challengers such as the FPAJ. While resistance movements and protest groups have made much use of the internet here, as in other parts of the world, the FPAJ’s attempt to provide direct streaming access to official sources of information largely failed to attract official sources to its press conferences and to generate consistently newsworthy material. The FPAJ attempted to argue that anyone in Japan could be a journalist, but its eventual bankruptcy and dissolution ultimately wound up serving the argument for a professional and official journalistic class put forward by the colleagues whose monopoly over the information they were fighting against.

Genotype frequency of ATP7A and ATP7B mutation-related copper-associated hepatitis in a Japanese guide dog Labrador retriever population.

The incidence of copper-associated hepatitis in Labrador retriever in Japan has not been examined. This study examined the genotype frequencies of ATP7B:c.4358G>A, a mutation responsible for copper-associated hepatitis, and ATP7A:c.980C>T, a modifier of this disease, in Labrador retrievers of guide dog associations in Japan. Genetic material was collected by buccal swabs from 253 Labrador retrievers and genotyping was performed for the ATP7B and ATP7A mutations. The gene frequency was 0.107 for ATP7B:c.4358A. For ATP7A:c.980C, the gene frequencies were 0.703 in females and 0.368 in males. In this study, we established genotyping methods for the ATP7B:c.4358G>A and ATP7A:c.980C>T mutations. Based on the genotyping results, the risk of copper-associated hepatitis in the study population was 0.80% in males and 1.05% in females.

Was India Right in Not Joining RCEP? A Cost–Benefit Analysis

India dropped out of the Regional Comprehensive Economic Partnership (RCEP)—which included the Association of Southeast Asian Nations (ASEAN) countries, China, South Korea, New Zealand, Japan and Australia—after negotiating for almost seven years in November 2018 on the grounds of national interest and also that free trade agreements (FTAs) did not amount to free trade and led to more trade diversion than trade creation. The cost and benefit of a regional agreement depend on the amount of trade creation with respect to trade diversion (Panagriya, 2000). This study tries to examine India’s concerns and, at the same time, highlights the cost of not joining RCEP. India’s trade deficit with 11 out of the 15 RCEP nations has been a major cause of concern. Unfavourable trade balance, concerns about the impact on dairy sector, economic slowdown, past experience with FTA’s, China factor, data localisation, rules of origin and the experience of ASEAN countries with Sino-FTA have been some of the reasons behind India’s decision to opt out of this mega multilateral agreement. Also, bilateral trade agreements with some RCEP countries such as Japan, Malaysia, Singapore, Thailand and South Korea were operational. A multilateral trade agreement with ASEAN countries was very much in place. So, trade between India and 12 of the RCEP member countries would not have changed much after India’s inclusion in the RCEP. The impact of lower tariffs would have been evident for the remaining three countries: China, Australia and New Zealand. Furthermore, there was fear of a massive surge in imports of manufactures from China and dairy imports from Australia and New Zealand. This study also examines the long-term impact of this decision and if India has missed out on becoming a part of the global value chain and gaining greater market access in the Asia-Pacific region. India’s policy of import substitution and protectionism did not capitulate desired results in the past. Hence, a critical evaluation of India’s decision and some validation on her concerns and fears have been done.

Transitioning from paediatric to adult rheumatological healthcare: English summary of the Japanese Transition Support Guide.

Issues related to transitioning from paediatric to adult healthcare are currently receiving international attention. In Japan, 1000 patients with childhood-onset chronic rheumatological diseases reach adulthood every year and require transition from care by paediatric to care by adult rheumatologists. Here, we propose a guide for the latter, wherein the adult caregiver poses the clinical questions about transitional support that they need to have answered, and the paediatric caregiver mainly compiles the plans for the transition. To formulate the guide, we sought comments from both the Japan College of Rheumatology and the Pediatric Rheumatology Association of Japan and obtained their approval. Here, we present the outcome of this consultation in the form of a Guide for Supporting Transitional Care, aiming to provide essential knowledge to physicians in the fields of adult internal medicine and orthopaedics who may be involved in treating patients with rheumatic disease during the transition from paediatric to adult care. The features of transitional support that are common for patients with various different rheumatic diseases are presented in this guide, with the aim of informing policy and strategies to deliver optimal outcomes in transitional care by non-paediatric rheumatologists.

Clinical practice guidance for childhood-onset systemic lupus erythematosus-secondary publication.

Childhood-onset systemic lupus erythematosus (cSLE) has been recognised as a more acute and severe autoimmune disease than adult-onset SLE. With the development of medications for the disease and supportive therapy, the mortality rate associated with cSLE has drastically improved; the 10-year survival rate among patients with cSLE between 1995 and 2006 in Japan was 98.3%. However, the 10-year survival rate without any permanent functional impairment remained low at 66.1%. Therefore, the current treatment goal for cSLE is to ensure that they can perform normal daily activities throughout their lives by preventing the occurrence and/or progression of organ damage. For this purpose, appropriate treatments and evaluations are required according to the severity and risk of organ damage; however, there are no established guidelines for cSLE. Therefore, the Pediatric Rheumatology Association of Japan and the Pediatric Rheumatology Subcommittee in the Japan College of Rheumatology developed a comprehensive guidance for clinical practice based on cSLE-related data collected from Japanese national surveys and relevant articles from both domestic and international sources. However, due to the lack of indications for defined and objective evidence quality levels, this guidance should be used on the basis of the judgement of the attending physicians for individual patients.

Utility of B-Mode, Color Doppler and Elastography in the Diagnosis of Breast Cancer: Results of the CD-CONFIRM Multicenter Study of 1351 Breast Solid Masses

The usefulness of color Doppler ultrasound (CD) in distinguishing between benign and malignant breast lesions remains controversial. Our prior study, the Japan Association of Breast and Thyroid Sonology (JABTS) BC-04 study (malignant: 839, benign: 569), found CD was useful in breast cancer diagnosis, and we developed CD diagnostic criteria. The first aim of the current study (the CD-CONFIRM study) was to evaluate the usefulness of the CD diagnostic criteria. The second aim was to evaluate the relationship between CD and elastography. We evaluated ultrasound images of breast masses from 13 institutions (malignant: 639, benign: 712). While the sensitivity of B-mode alone was very high and was not significantly improved with CD, the specificity was significantly improved with CD (61.2%–69.2%, p < 0.0001). Furthermore, the specificity of the combination of B-mode and CD improved significantly with the addition of elastography (72.8%–79.0%, p < 0.0001). This study found that the CD criteria are useful, and CD and elastography are independent.

日本衣料管理協会、50年の歩みに思うこと

日本衣料管理協会、50年の歩みに思うこと

Maternal occupation and infant mortality in Japan: Insights from the Vital Statistics (Occupational and Industrial Aspects)

Objectives The proportion of Japanese women who maintain their employment during pregnancy and after delivery has been increasing. Previous studies from Western countries showed an association between the mother's occupation and birth outcomes; however, to the best of our knowledge, no epidemiological study has analyzed this association in Japan. Therefore, data from the national Vital Statistics: Occupational and Industrial Aspects were used to examine the association between the mother's occupation and (1) the risk of stillbirth at or after 12 weeks of gestation, and (2) the risk of infant death under 1 year of age after livebirth.Methods Data from the Vital Statistics: Occupational and Industrial Aspects (Live Birth Form, and Foetal Death Form) for fiscal years (FYs) 1995, 2000, 2005, 2010, and 2015 and Vital Statistics data files (Death Form) from FYs 1995-96, 2000-01, 2005-06, 2010-11, and 2015-16 were analyzed. The study population consisted of (1) 5,355,881 infants who were born during the survey period, with (2) 5,290,808 live birth excluding still birth during the same period. The odds ratios (ORs) were estimated for (1) stillbirth (without stillbirth = livebirth) and (2) infant death (without infant death = alive at 1 year of age) by mother's occupation (managers/specialist/technical workers, clerical workers, sales workers, service workers, blue collar workers, and not employed) using logistic regression. Blue collar workers included workers in security, agriculture/forestry/fishing, manufacturing process, transport, and machine operation. The population attributable risk (PAR) for stillbirth attributed to mother's occupation among employed mothers was also calculated.Results There were 61,179 (1.1%) stillbirths in the study population and 12,789 (0.2%) infant deaths among 5,290,808 live birth. Compared to managers/specialist/technical workers, the adjusted ORs (95% confidence interval) for stillbirth among clerical workers, sales workers, service workers, blue collar workers and not employed women were 1.24 (1.20-1.29), 1.48 (1.41-1.56), 1.76 (1.69-1.83), 1.54 (1.46-1.61), and 0.95 (0.92-0.98), respectively. There was no association between the mother's occupation and infant deaths. The PAR values for stillbirth among mothers employed as clerical workers and service workers were 7.4% and 12.3%.Conclusion The risk of stillbirth differed according to the mother's occupation in our study. The OR and PAR of stillbirth were the highest for service workers. Mother's occupation was not associated with the risk of infant death; therefore, the mothers' occupation is likely to affect the children's condition only during pregnancy. Our study suggests the importance of understanding the causal linkage between pregnant women's occupation and birth outcomes.

Assessment of Critical Care Surge Capacity During the COVID-19 Pandemic in Japan.

Japan has the highest proportion of older adults worldwide but has fewer critical care beds than most high-income countries. Although the COVID-19 infection rate in Japan is low compared with Europe and the United States, by the end of 2020, several infected people died in ambulances because they could not find hospitals to accept them. Our study aimed to examine the Japanese healthcare system's capacity to accommodate critically ill COVID-19 patients during the pandemic. We created a model to estimate bed and staff capacity at 3 levels of pandemic response (conventional, contingency, and crisis), as defined by the US National Academy of Medicine, and the function of Japan's healthcare system at each level. We then compared our estimates of the number of COVID-19 patients requiring intensive care at peak times with the national health system capacity using expert panel data. Our findings suggest that Japan's healthcare system currently can accommodate only a limited number of critically ill COVID-19 patients. It could accommodate the surge of pandemic demands by converting nonintensive care unit beds to critical care beds and using nonintensive care unit staff for critical care. However, bed and staff capacity should not be expanded uniformly, so that the limited number of physicians and nurses are allocated efficiently and so staffing does not become the bottleneck of the expansion. Training and deploying physicians and nurses to provide immediate intensive care is essential. The key is to introduce and implement the concept and mechanism of tiered staffing in the Japanese healthcare system. More importantly, most intensive care facilities in Japanese hospitals are small-scaled and thinly distributed in each region. The government needs to introduce an efficient system for smooth dispatching of medical personnel among hospitals regardless of their founding institutions.

Effects of physician's diabetes self-management education using Japan Association of Diabetes Education and Care Diabetes Education Card System Program and a self-monitoring of blood glucose readings analyzer in individuals with type 2 diabetes: An exploratory, open-labeled, prospective randomized clinical trial.

Aims/IntroductionThis 6‐month, single‐center, prospective, open‐labeled, randomized trial was designed to investigate whether physicians’ diabetes self‐management education using an education tool developed by the Japan Association of Diabetes Education and Care and a self‐monitoring of blood glucose (SMBG) analyzer improves glycemic control in individuals with type 2 diabetes receiving insulin and SMBG.Materials and MethodsParticipants were randomized into intervention (I) and control (C) groups. Both groups received physicians’ diabetes self‐management education at each hospital visit, whereas the Japan Association of Diabetes Education and Care education tool and the SMBG readings analyzer was used in group I, but not group C. All participants filled out a diabetes treatment‐related quality of life form and an original questionnaire on SMBG use with five questions (Q1–Q5) before and after the study period.ResultsA total of 76 individuals were recruited and randomized. Glycated hemoglobin (HbA1c) was significantly improved during the study period in group I, whereas no significant change was observed in group C. The change in HbA1c was greater in group I, although it did not reach statistical significance. The diabetes treatment‐related quality of life total score was not changed in either group. Interestingly, the score of Q1 (“How important is SMBG to you?”) in the SMBG questionnaire was unchanged in group I, whereas it was significantly decreased in group C. HbA1c change was independently associated with changes in insulin dose and SMBG Q1 score.ConclusionGreater HbA1c‐lowering by physicians’ diabetes self‐management education using the Japan Association of Diabetes Education and Care education tool and SMBG analyzer in individuals with type 2 diabetes receiving insulin and SMBG was suggested, but not confirmed.

Maternal Death Related to Sudden Unexpected Death in Epilepsy: A Nationwide Survey in Japan.

Sudden unexpected death in epilepsy (SUDEP) is defined as the sudden death of a patient with epilepsy in the absence of an anatomic or toxicologic cause. Whether pregnancy is a risk factor for SUDEP is unclear. Using data submitted to the Japan Association of Obstetricians and Gynecologists (JAOG), which has been collating information regarding all maternal deaths in Japan since 2000, this study evaluated maternal mortality data from 2010 to 2019 to evaluate the current circumstances of maternal death related to SUDEP in Japan. Six women died due to SUDEP during this period; the maternal mortality rate related to SUDEP was 0.066/100,000 individuals. Two women each died during the second trimester, third trimester, and postpartum period. Four and two women were receiving monotherapy and no therapy with anti-epileptic drugs, respectively. The duration of epilepsy was ≤15 years in three women, >15 years in one woman, and unknown in two women. This study furthers our understanding of the prevalence of maternal deaths due to SUDEP in Japan. Further studies are needed to confirm whether pregnancy is a risk factor for SUDEP.

Checklist for rapid assessment of independence in children with pediatric rheumatic diseases in transition to adult medical care

Objectives The Committee for Support of Transition to Adult Medical Care, Pediatric Rheumatology Association of Japan, has developed a checklist for patients with pediatric rheumatologic diseases to evaluate readiness for transition to adult medical care. Methods Using checklists for general pediatric chronic diseases developed by researchers at the Ministry of Health, Labour and Welfare, committee members discussed points for modification or addition specific to pediatric rheumatic diseases and pediatric rheumatism clinical practice. Results Three patient-assessment checklists based on patient age and understanding level and a parent-assessment checklist were developed. The checklist for junior high school students and above included a ‘Health Education in Adolescence and Young Adulthood’ section with items related to sexual knowledge and concerns. Also, items on oral medications and subcutaneous injections management in the ‘Self-management of Daily Medical Care,’ domain and next medical visits management were added. The checklist for junior high school students included 30 items in seven domains and can be completed within 10 minutes. The checklist was given to 28 children with pediatric rheumatic diseases aged 10 years and older and their mothers. Conclusion The checklist was developed to share the challenges of independence during transition with patients and parents.

“Ship Carbon Recycling Working Group” inside Japan Association of Carbon Capture &amp; Reuse Launches Initiative for Zero-emission Ship Fuels

“Ship Carbon Recycling Working Group” inside Japan Association of Carbon Capture &amp; Reuse Launches Initiative for Zero-emission Ship Fuels

Knowledge Co-Creation Roadmapping for Future Industrial Visions: Case Study on Smart Infrastructure

This paper proposes a knowledge co-creation roadmapping tool for knowledge creation in future-oriented discussions for members of competing firms with the aim of co-creatively envisioning the future of the industry. This approach adapts the roadmapping method to knowledge creation, thus building a communication infrastructure for discussing future plans beyond an organization (i.e., participants are from competing companies). Knowledge co-creation roadmapping could be commissioned to an open industry organization consisting of members sent by individual companies interested in overcoming obstacles to development. We put our method into practice with the subcommittee of the Engineering Advancement Association of Japan and set the subject as “The Future of Smart Social Infrastructure”, a theme involving multiple stakeholders. We were able to draw up a vision of smart technology on the basis of the insights gained through the roadmapping activities. These results demonstrate the effectiveness of our method in terms of acquiring knowledge that could not be obtained by our own company or a single industry organization alone.

Low Incidence of Osteonecrosis in Childhood Acute Lymphoblastic Leukemia Treated with ALL-97 and ALL-02 Study of Japan Association of Childhood Leukemia Study Group

Purpose: Osteonecrosis (ON) is a serious complication of the treatment of childhood acute lymphoblastic leukemia (ALL). The incidence of ON varies (range, 2.0-18.0%) according to treatment strategy. Previous studies reported older age, female sex, dosage of corticosteroid, use of dexamethasone (DEX), combination therapy with DEX and L-asparaginase (L-Asp), and ethnicity were putative risk factors. However, most of these studies were mainly conducted in U.S.A. or European countries. Thus, the data relating to ON in Asian ALL patients are scarce. Herein, we performed a retrospective analysis of Japanese ALL patient cohorts uniformly treated with consecutive two clinical trials (ALL-97 and ALL-02) to clarify the incidence, clinical characteristics and risk factors of ON.Methods: In the ALL-97 study, various data on adverse events, including ON, were collected prospectively; however, in the ALL-02 study, there was no prospective collection of ON data. Thus, a questionnaire targeting ON was administered to all JACLS investigators in 2016. A total 1662 patients (635 patients treated with ALL-97, 1027 with ALL-02 protocol) were analyzed in this study. The total numbers of patients enrolled in the ALL-97 and ALL-02 studies were 635 and 1192 patients, respectively, and the majority of patients enrolled in both studies (100% in ALL-97 and 86.2% in ALL-02) were included in these analyses. The numbers of patients aged >10 years were 167/635 (26.3%) and 209/1027 (20.4%) in the ALL-97 and ALL-02 study, respectively. Clinical diagnosis of ON was defined as a symptomatic patient and positive findings on at least one imaging study, including plain bone X-ray, CT, or magnetic resonance imaging (MRI). Patients with ON diagnosed after hematopoietic stem cell transplantation were excluded. Patients with ON identified thorough these investigations were further examined for time of onset, sites involved, severity of symptoms, treatment, and outcome by questionnaire.Results: In total, 24 of 1662 patients suffered from ON, of which 12/635 (1.9%) and 12/1027 (1.2%) patients were treated with ALL-97 and ALL-02 protocols, respectively. Of these 24 patients, the median age at diagnosis of ALL was 13.0 ± 1.4 and 12.5 ± 3.0 in ALL-97 and ALL-02 study, respectively. Of patients with ON, only one patient was <10 years old, with the remaining 23 patients aged >10 years at onset of ALL. Most patients were diagnosed with ON by MRI, and the femoral head was the most frequent site of ON (10/12 patients in ALL-97; 7/12 patients in ALL-02). In 13 patients, ON became apparent during chemotherapy (seven patients in ALL-97; six patients in ALL-02), while nine patients (five patients in ALL-97; four patients in ALL-02) developed ON after completion of chemotherapy. On multivariate analysis, only age >10 years was a significant factor associated with ON development (hazard ratio = 27.8, 95% = CI 5.99-129.0, p < 0.001). Separate evaluation of patients >10 years indicated incidence rates of ON of 12/167 (7.2%) and 11/209 (5.3%) in the ALL-97 and ALL-02 protocols, respectively, which was lower than previous reports, despite total administration of dexamethasone (DEX) similar to that in comparable studies; however, concomitant administration of DEX and L-Asp was reduced in JACLS protocols. In JACLS ALL-97 and ALL-02, combined use of DEX and L-Asp was performed in induction therapy. DEX was administered on days 8 to 14 and L-Asp three times per week after day 15 of induction therapy in the JACLS protocol; thus we did not administer DEX and L-Asp simultaneously in any treatment period. By contrast, all previous studies administered DEX and L-Asp/Peg-Asp simultaneously during several treatment phases. Hence, only JACLS studies lacked simultaneous administration of DEX and L-Asp. In addition, the cumulative dosage of DEX in the treatment phases including both DEX and L-Asp was lower in the JACLS ALL-97 and -02 protocols than in those in other studies.Conclusions: We identified a low frequency of ON in the JACLS ALL-97 and -02 studies. Although the sole risk factor for ON was age (>10 years), even among high-risk patients, ON incidence was significantly lower than that reported in previous studies. These results suggest that, not only the total amount of DEX, but also how DEX and L-Asp are administered, which affects the clearance of DEX, may be associated with ON incidence in ALL patients. DisclosuresHiramatsu:Novartis Pharmaceuticals Corporation: Other: Clinical trials .

The Outcome of Childhood B-Cell Precursor ALL with ETV6-RUNX1 Treated with Japan Association of Childhood Leukemia Study (JACLS) ALL-02 Trial

Background: It is well known that ETV6-RUNX1 positive pediatric B cell precursor acute lymphoblastic leukemia (B-ALL) shows excellent outcome when they are treated with contemporary chemotherapeutic regimens. However, the prognosis of ETV6-RUNX1 positive B-ALL wasn't determined in Japanese pediatric cohort which was uniformly treated. Japan Association of Childhood Leukemia Study (JACLS) ALL-02 protocol achieved 83.7±1.1% of 4-year event free survival of pediatric B-ALL (Hasegawa et al. 58th ASH annual meeting) which was comparable to that in major recent pediatric ALL clinical trials, although risk stratification based on minimal residual disease (MRD) was not employed. Herein, we report the outcome and analyze the prognostic factors of ETV6-RUNX1 positive B-ALL treated with JACLS ALL-02 protocol.Patients and treatment: Between April 2002 and March 2008, newly diagnosed de novo ETV6-RUNX1 positive ALL with 1-18 years of age were enrolled to JACLS ALL-02 trial. Patients were stratified into 3 groups: standard-risk (SR), high-risk (HR), extremely high-risk (ER), based on initial prednisolone (PSL) response and the modified National Cancer Institute(NCI) workshop criteria. Prednisolone poor response (PPR) was determined after 7 days of monotherapy with prednisone and one intrathecal dose of methotrexate. PSL good responders (PGR; < 1,000 blasts/μL) were divided into SR and HR according to the modified NCI workshop criteria by WBC 10K and age 10, and received conventional therapy. BCP-ALL with PPR (≥ 1,000 blasts/μL) were assigned to ER and received intensified post-induction therapy. Estimation of event free survival (EFS) and overall survival (OS) was performed using the Kaplan-Meier method and the differences were compared using the log-rank test. Multivariate analysis was performed using a Cox regression model.Results: 205 newly diagnosed ETV6-RUNX1 positive ALL patients were enrolled in JACLS ALL-02 clinical trial, which included 108 patients in SR group (52.7%), 89 in HR group (43.3%) and 8 in ER group (3.9%). The median age at diagnosis was 4.3 years (range, 1.0 to 15.0 years) and the median WBC count was 6,800/μL (range, 370 to 384,700 /μL). The median follow-up time was 6 year and 6 months. 4y/8y EFS and OS (±SE) are 92.5±2.6/ 89.8±2.5% and 96.5±1.5/ 95.5±1.6%, respectively. 4y / 8y EFS of the patients of NCI-SR (n=167) and NCI-HR (n=38) are 95.6±1.6% / 91.3±2.7% and 89.5±5.0% / 83.0±6.4%, respectively (log rank p=0.04). 4y / 8y OS of the patients with PSL good response (n=197) was 97.9±1.1% / 97.0±1.3%, while those of the patients with PPR (n=8) was 87.5±11.7% / 58.3±18.6% (log rank p<0.001). Eighteen of 205 (8.8%) patients experienced relapse. According to BFM risk stratification of relapsed ALL (S1 to S4), 13 of 18 patients were in S2 and ten of them were rescued by salvage therapy. However, 5 patients in S3 or S4 group died of disease progression. Although two patients showing PPR belonged to S2, all of them died of disease progression. Multivariate analysis identifies NCI-HR (HR=2.92, p=0.05) as a predictor of poor prognosis in EFS, and PPR (HR=12.0, p<0.01) as predictor of poor prognosis in OS.Discussion: Although JACLS ALL-02 protocol didn't employ MRD based risk stratification, good outcome of the 4y EFS and OS (92.5±2.6 % and 96.5±1.5 %) was achieved for ETV6-RUNX1 positive B-ALL patients. Because NCI-SR and PGR were predictors of excellent outcome for ETV6-RUNX1 positive B-ALL, less intensive treatment should be explored for this group. On the other hand, NCI-HR and PPR indicated poor outcome. We hope that MRD based monitoring might improve outcome of this subgroup in our next clinical trial. DisclosuresNo relevant conflicts of interest to declare.

The Epigenetic and Genetic Landscapes of Pediatric T-Cell Acute Lymphoblastic Leukemia (T-ALL)

IntroductionAlthough genetic basis of pediatric T-cell acute lymphoblastic leukemia (T-ALL) has been well characterized and we reported recurrent SPI1 fusion cases exhibiting uniformly dismal outcome, no comprehensive studies have yet explored the epigenetic profiles and their potential contribution to clinicopathological features of T-ALL.MethodsA total of 79 cases with pediatric T-ALL samples from Tokyo Children's Cancer Study Group (TCCSG) and Japan Association of childhood Leukemia Study (JACLS) including 7 cases of SPI1 fusions were analyzed in this study. To describe epigenetic landscape of T-ALL, we performed methylation array analysis using Illumina HumanMethylation EPIC array, and conducted combined analysis of methylation data with our previous data of whole transcriptome sequencing (WTS) and targeted-capture sequencing for 158 ALL-related genes.ResultsAfter normalization, 939 probes were selected to identify the most variable methylated probes, when a standard deviation of the beta-values across the samples was above 0.38. Unsupervised consensus clustering clearly identified 4 distinct sample clusters. Combined analyses with WTS data revealed that these 4 clusters were characterized by TAL1 fusions/high expression with intermediate methylation (M1 cluster; n=39), high TLX/HOX expression with intermediate methylation (M2 cluster; n=20), high TLX//HOX expression with high methylation (M3 cluster; n=11), and SPI1 fusions/high expression with low methylation (M4 cluster; n=9), respectively. Interestingly, these methylation clusters were well correlated with genetic features, expression status, and clinical outcomes. In M1 cluster, PTEN abnormalities and UPS7 mutations were especially enriched, and these aberrations were observed mutually exclusive. Furthermore, promoter regions in TAL1 and its target ALDH1A2, important for retinoic acid synthesis, were significantly hypomethylated and highly expressed in this cluster. In M2 cluster, genes related to chromatin remodeling and JAK-STAT were frequently mutated. PRR5L and DEPTOR, both related to AKT1 activation, were differentially methylated and expressed, suggesting an important role of PI3K-AKT1 pathway. M3 cluster was characterized by frequent mutations of epigenetic regulators related genes, such as PHF6, EZH2, and DNM2 . In contrast, mutations in JAK-STAT and PI3K-AKT1 pathways were less frequent. Since the methylation profile of M3 cluster was similar to normal T cells, abnormal DNA methylation status may be not crucial for the leukemogenesis in this group. Intriguingly, all SPI1 fusion cases were classified into M4 cluster, and remaining 2 cases without SPI1 fusions in this cluster showed very high SPI1 expression. Importantly, M4 cluster was characterized by high expression of RASGRP4, a family of Ras guanine nucleotide exchange factors, and low methylation of RASGRP4 promoter. In addition, FGFR1 expression was uniformly repressed and abnormalities of CDKN2A (89%) and KRAS/NRAS (44%) were frequently observed in this group. Furthermore, it should be noted that patients in M4 cluster showed significantly poor prognosis compared to other clusters; eight out of nine cases were died (Log-rank p =4.4×10-7). SPI1 fusion cases exhibited not only unique cytological and gene expression profiles but also distinctive methylation status.ConclusionsBased on DNA methylation profiles, pediatric T-ALL is clustered into 4 distinct subtypes, which exhibited remarkable correlation with genetic signatures, expression features, and clinical outcomes. PI3K-AKT pathway may be essential in M1/M2 cluster, whereas genetic abnormalities of epigenetic regulators were characteristics in M2/M3 clusters. In addition, the involvement of JAK-STAT pathway would be unique in M2 cluster. Given that cases with M4 cluster showed a catastrophic prognosis and very high expression of RASGRP4 with high frequency of RAS mutation, our findings implicate that targeting therapy of RAS may improve the prognosis of the patients in this group. Although our cohort is limited, our results suggested that the biological phenotype of T-ALL is mediated by both genetic and epigenetic regulations, and explorations for aberrant DNA methylation along with genetic alterations might be helpful for a new therapeutic strategy for T-ALL. DisclosuresNo relevant conflicts of interest to declare.

Clinical Effect of Genetic Alterations in Pediatric Patients with B-Progenitor Acute Lymphoblastic Leukemia

▪BackgroundRecent genetic studies using high-throughput sequencing have substantially revealed genetic alterations in pediatric patients with B-progenitor acute lymphoblastic leukemia (B-ALL). However, their clinical relevance of these alterations has not been fully investigated.MethodsWe performed targeted-capture sequencing of 149 known or putative driver genes for B-ALL in 525 pediatric patients who were uniformly treated according to the Japan Association of Childhood Leukemia Study ALL-02 protocol. In addition, we performed whole transcriptome sequencing in 63 of 118 patients who were not categorized into any genetic subgroup defined by RT-PCR status or targeted-capture sequencing results.ResultsIn total, 647 focal deletions (median 1 per patient; range, 0-7) and 993 mutations (median 2 per patient; range, 0-10) were detected in 491 (94%) cases. Some of these alterations were closely associated with disease subtypes. We identified recurrent PHF6 mutations, which were almost exclusively detected in the TCF3 - PBX1- positive ALL genotype. Furthermore, frequent involvement of PAX5 and KMT2D (mutations) and IKZF3 (deletions) were characteristic of TCF3 - PBX1 -positive ALL genotype. To identify genetic alterations associated with a poor prognosis, we analyzed 20 genes that were mutated in at least 20 patients in our study cohort. Univariate analyses revealed genetic alterations in TP53 , KMT2D , and IKZF1 to be associated with a significantly shorter overall survival. Mutations and deletions in IKZF1 were also strongly associated with induction failure (Odds ratio, 12; 95% CI, 2.7-55). This led to death in 80% (n = 4/5) of the patients with IKZF1 alterations. Most patients with TP53 and KMT2D mutations and with disease relapse had fatal disease progression [94% mortality rate (n = 17/18)]. Multivariate analysis, together with the NCI criteria, revealed that two genetic lesions, TP53 and KMT2D , retained prognostic impacts for overall survival. Prediction of 5-year OS improved in each NCI-risk group when patients in each risk group were stratified according to the presence or absence of mutations in TP53 or KMT2D lesions: 69% [with alteration (n = 26)] vs. 85% [without alteration (n = 138)] for the NCI-HR group (P = 0.03) and 85% [with alteration (n = 42)] vs. 97% [without alteration (n = 319)] for the NCI-SR group (P = 0.004). Additionally, the four less frequently mutated genes also had an independent prognostic impact before and after adjustment for risk factors: IKZF2 (n = 6; HR for death, 7.4; 95% CI, 2.3-24), SH2B3 (n = 4; HR for death, 7.0; 95% CI, 1.7-29), JAK2 (n = 7; HR for events, 4.6; 95% CI, 1.7-12), and PTEN (n = 9; HR for death, 3.8; 95% CI, 1.2-12). Notably, mutations in three genes present potentially druggable targets: ruxolitinib for mutations in JAK2 or SH2B3 and poly (ADP-ribose) polymerase inhibitor formutations in PTEN . Finally, based on a gene expression profile, 20 of 63 patients were categorized into discrete subgroups characterized by Ph-like profiles (n = 7), ZNF384 (n = 7), and MEF2D (n = 6) fusions. Ph-like and MEF2D fusion-positive ALLs were associated with a dismal prognosis, whereas all patients with a ZNF384 fusion survived with complete remission. No mutations were associated with a poor prognosis in the 43 remaining patients. Further analysis, such as whole genome sequencing, is warranted for these patients.ConclusionsTargeted-capture sequencing improves the prediction of clinical outcomes and helps detect prognostic and druggable biomarkers. Our results can facilitate the clinical applications of next-generation sequencing to select optimal therapy for pediatric patients with B-ALL. DisclosuresMakishima:Yasuda Medical Foundation: Research Funding.

PM2.5 and Diabetes in the Japanese Population.

Growing evidence suggests that PM2.5 is associated with diabetes mellitus (DM). Although DM is a major public health concern, there has not yet been a study of this association in Japan. We used health examination data from 66,885 individuals in Tokyo, Japan 2005–2019. Cox proportional hazards models were used to evaluate an association between annual exposure to PM2.5 and glycated hemoglobin A1c (HbA1c), or fasting plasma glucose (FPG). An increase of 1 μg/m3 in the annual average of PM2.5 concentration was associated (HR = 1.029; 95% CI = 1.004–1.055) with an increase in diabetes (incident + prevalent). For incident DM, a greater PM2.5 level was associated with more DM (HR = 1.029; 95% CI, 1.003–1.055). Compared to HbA1c, FPG showed a stronger association with the annual exposure to PM2.5 (HR = 1.065; 95% CI, 1.040–1.091). We found that greater exposure to PM2.5 in the long-term was associated with an increased risk of diabetes, and that the magnitude of association became stronger as the exposure duration increased. Omorogieva Ojo