Neoadjuvant chemotherapy with docetaxel, nedaplatin, and fluorouracil for resectable esophageal cancer : A phase II study

Cisplatin plus 5‐fluorouracil is regarded as standard neoadjuvant chemotherapy for esophageal squamous cell carcinoma (ESCC) in Japan, but the prognosis remains poor. We have previously described how definitive chemoradiotherapy with docetaxel, nedaplatin, and 5‐fluorouracil (DNF) led to a very high response rate and promising survival times. We therefore undertook a phase II trial to evaluate the feasibility and efficacy of neoadjuvant DNF. The study included patients with clinical stage Ib‐III ESCC. Chemotherapy consisted of i.v. docetaxel (30 mg/m2) and nedaplatin (50 mg/m2) on days 1 and 8, and a continuous infusion of 5‐fluorouracil (400 mg/m2/day) on days 1‐5 and 8‐12, every 3 weeks. After three courses of chemotherapy, esophagectomy was carried out. The primary end‐point was the completion rate of the protocol treatment. Twenty‐eight patients were enrolled (cStage Ib/II/III, 2/3/23) and all received at least two cycles of chemotherapy. Twenty‐five patients underwent surgery, all of whom achieved an R0 resection, leading to a completion rate of 89.3%. The overall response rate was 87.0%. A pathological complete response was confirmed in eight (32.0%) cases. Grade 3/4 adverse events included leukopenia (32.1%), neutropenia (39.3%), febrile neutropenia (10.7%), thrombocytopenia (10.7%), and diarrhea (14.3%), but were manageable. Treatment‐related deaths and major surgical complications did not occur. Estimated 2‐year progression‐free and overall survival rates were 70.4% and 77.2%, respectively. Thus, DNF therapy was well tolerated and deemed feasible, with a strong tumor response in a neoadjuvant setting for ESCC. This trial is registered with the University Hospital Medical Information Network (UMIN ID: 000014305)

A Functional SNP in BNC2 Is Associated with Adolescent Idiopathic Scoliosis

Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity. We previously conducted a genome-wide association study (GWAS) and detected two loci associated with AIS. To identify additional loci, we extended our GWAS by increasing the number of cohorts (2,109 affected subjects and 11,140 control subjects in total) and conducting a whole-genome imputation. Through the extended GWAS and replication studies using independent Japanese and Chinese populations, we identified a susceptibility locus on chromosome 9p22.2 (p = 2.46 × 10−13; odds ratio = 1.21). The most significantly associated SNPs were in intron 3 of BNC2, which encodes a zinc finger transcription factor, basonuclin-2. Expression quantitative trait loci data suggested that the associated SNPs have the potential to regulate the BNC2 transcriptional activity and that the susceptibility alleles increase BNC2 expression. We identified a functional SNP, rs10738445 in BNC2, whose susceptibility allele showed both higher binding to a transcription factor, YY1 (yin and yang 1), and higher BNC2 enhancer activity than the non-susceptibility allele. BNC2 overexpression produced body curvature in developing zebrafish in a gene-dosage-dependent manner. Our results suggest that increased BNC2 expression is implicated in the etiology of AIS

Evidence of causality of low body mass index on risk of adolescent idiopathic scoliosis: a Mendelian randomization study

IntroductionAdolescent idiopathic scoliosis (AIS) is a disorder with a three-dimensional spinal deformity and is a common disease affecting 1-5% of adolescents. AIS is also known as a complex disease involved in environmental and genetic factors. A relation between AIS and body mass index (BMI) has been epidemiologically and genetically suggested. However, the causal relationship between AIS and BMI remains to be elucidated.Material and methodsMendelian randomization (MR) analysis was performed using summary statistics from genome-wide association studies (GWASs) of AIS (Japanese cohort, 5,327 cases, 73,884 controls; US cohort: 1,468 cases, 20,158 controls) and BMI (Biobank Japan: 173430 individual; meta-analysis of genetic investigation of anthropometric traits and UK Biobank: 806334 individuals; European Children cohort: 39620 individuals; Population Architecture using Genomics and Epidemiology: 49335 individuals). In MR analyses evaluating the effect of BMI on AIS, the association between BMI and AIS summary statistics was evaluated using the inverse-variance weighted (IVW) method, weighted median method, and Egger regression (MR-Egger) methods in Japanese.ResultsSignificant causality of genetically decreased BMI on risk of AIS was estimated: IVW method (Estimate (beta) [SE] = -0.56 [0.16], p = 1.8 × 10-3), weighted median method (beta = -0.56 [0.18], p = 8.5 × 10-3) and MR-Egger method (beta = -1.50 [0.43], p = 4.7 × 10-3), respectively. Consistent results were also observed when using the US AIS summary statistic in three MR methods; however, no significant causality was observed when evaluating the effect of AIS on BMI.ConclusionsOur Mendelian randomization analysis using large studies of AIS and GWAS for BMI summary statistics revealed that genetic variants contributing to low BMI have a causal effect on the onset of AIS. This result was consistent with those of epidemiological studies and would contribute to the early detection of AIS

Penetration factors and introduction possibility for image diagnostic equipment

Background: This study investigated and analyzed the relationship between medical resources and economic conditions of OECD member countries and extracted factors for introducing imaging diagnostic equipment in each country. We also investigated the possibility of introducing diagnostic imaging equipment. Methods: A principal component analysis was conducted from medical environment indices and economic situation indices; the results were visualized on a graph with the extracted two principal components as axes, and the target nations were categorized according to the possibility of introducing diagnostic imaging equipment. Next, with the number of CTs and MRIs as response variables, we visualized the probability results on a graph by conducting a multiple regression analysis with the indices as explanatory variables and extracting the most influential factors on the number of diagnostic imaging equipment introduced. Results: We classified 29 countries into four groups according to medical environment and economic situation indices. By extracting from the four groups a group with a high possibility for introducing medical equipment then conducting a multiple regression analysis with CT and MRI unit counts as objective variables and other medical environment and economic situation indices as explanatory variables, it became clear that the factor with the greatest influence on CT and MRI unit counts is the number of hospital beds. Conclusion: As topics of future studies, we would like to clarify the factors behind as well as the probability for the introduction of medical equipment in each nation by researching high-growth medical equipment markets. (C) 2018 Fellowship of Postgraduate Medicine. Published by Elsevier Ltd. All rights reserved

Projecting future supply and demand for physical therapists in Japan using system dynamics

Objectives: Japan is the oldest country in the world, and its demand for medical care is expected to increase. Although a clear vision regarding the supply and demand for physical therapy services is necessary, there has been no research that forecasts the supply and demand for physical therapists in Japan. Consensus has not been reached on whether the supply of physical therapists is sufficient. This study projects this supply and demand to provide medical policymakers with basic data. Methods: A system dynamics model was created to predict the number of physical therapists working in hospitals and clinics in Japan from 2014 to 2040. The future demand for physical therapy was estimated using the rehabilitation service utilization data from Open National Database, a publicly available nationwide health claims database. Sufficiency rates (supply/demand) were calculated, and sensitivity analysis was conducted on supply-related parameters. Results: The number of physical therapists was projected to be 1.74 and 2.54 times greater in 2025 and 2040, respectively, than in 2014. The sufficiency rates were 1.72, 2.39, and 3.30 in 2015, 2025, and 2040, respectively. The sensitivity analysis revealed that attrition rates had the greatest effects on sufficiency. Conclusions: Although the current supply appears to be needed, considering the expected increase and uncertainty in medical needs. However, there is a possibility of a future oversupply, especially after 2025, when the rate of increase in demand will lessen. Further studies are required to evaluate the distribution of physical therapists among regions and specialties. (C) 2019 Fellowship of Postgraduate Medicine. Published by Elsevier Ltd. All rights reserved

Forecasting maldistribution of human resources for healthcare and patients in Japan: a utilization-based approach

Background Hokkaido's demographic trend of population decrease with aging population is remarkable even in Japan. Although healthcare policy decision-makers need to appropriately allocate resources while grasping regional demands, not much is available on whether medical demand would increase or not for future. In addition, little is known about what impact will current situation have on future demand-supply balance and equality by regions. This study aims to support decision-making in human resource planning for coping with changing population structure by forecasting future demand, and evaluation those regional maldistributions. Method We set patients with acute myocardial infarction or cerebral stroke, and all medical care as study subjects and analyzed for 2015, 2025, and 2035 in Hokkaido and each Secondary Medical Care Area. We used a utilization-based approach to estimate the healthcare supply-demand balance in the future. Moreover, we evaluated the regional maldistribution of demand-supply balance by calculating Herfindahl-Hirschman Index, Gini Coefficients, the number of physicians/specialists per patient. Moreover, we conducted sensitivity analysis to evaluation impact on aspects of demand-supply balance by uncertainty of utilization for future. Results Our results displayed that concentration of patients will progress, while regional distribution will shrink in all subject. However, from comparison based on all medical care, Gini Coefficients of acute myocardial infarction and cerebral stroke has always been high. This suggest that the resource allocation of them has room for improvement. In addition, our analysis showed the change in this balance will differ in each region in the future. Moreover, demographic change will not consistent with the number of patient change from 2015 to 2035. Conclusion These results suggest policy planners should use the number of patient by disease, by region as indicator of demand, instead of provider-to-population ratios being in use today. The result of our sensitivity analysis show two findings. First, the range of each indicator have possible for future. Second, increase of utilization, for instance lowing barrier in the use by development operation of patient transportation in AMI/CS, would improve maldistribution of opportunity for resident to get emergency medical services

Novel polychrome staining distinguishing osteochondral tissue and bone cells in decalcified paraffin sections

The bone is a dynamic and metabolically active organ in which growth and resorption of the osteochondral matrix is orchestrated by osteoblasts and osteoclasts. For decalcified paraffin-embedded specimens, decalcifying agents alter the staining intensity, and excess decalcification interferes with bone staining. Robust bone staining methods independent of the decalcification conditions and animal species are lacking. In this study, we have developed a novel polychrome staining method, named JFRL staining, which stains the components of osteochondral tissue in different colors. With this staining we could visualize the hyaline cartilage as blue by alcian blue, osteoid as red by picrosirius red, and mineralized bone as green by picro-light green SF or picro-naphthol green B and easily distinguished osteoblasts, osteocytes, and osteoclasts. In mineralized bone, this staining revealed the obvious lamellar structures and woven bone. Notably, this staining was independent of the decalcification conditions and experimental animal species examined. To verify the usefulness of JFRL staining, we observed cotton rat tail which has shorter length and shows a false autotomy. The caudal vertebrae were normally developed via endochondral ossification without a fracture plane. At 6 months of age, the number of chondrocytes declined and the hypertrophic zone was absent at the epiphyseal plate, which might reflect the shorter tail. In conclusion, JFRL staining is the first method to simultaneously distinguish osteochondral matrix and bone cells in one section regardless of decalcifying conditions. This robust staining will provide new information for a wide number of biomedical fields, including bone development, physiology, and pathology