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Purpose This study aimed to determine whether continual electronic patient-reported outcome (ePRO) measurements at home can capture the fluctuations in health-related quality of life (HRQOL) scores between visits. Methods We performed a randomized controlled trial to compare the scores obtained by standard practice (paper-based measurements in the hospital) to scores by continuous measurement of ePRO at home. Metastatic cancer patients were randomly assigned to either the paper-based ( n = 50) or the ePRO group ( n = 52). EQ-5D-5L and EORTC QLQ C-30 scores were obtained on 3 different chemotherapy days in the paper-based group. Meanwhile, scores were obtained on the chemotherapy day and on days 3, 7, 10, and 14 in the ePRO group during 2 cycles. The first hypothesis of our study was that both scores at the same time points would be equivalent despite different measurement frequency, place, or mode of measurement. The second hypothesis was that PRO score–adjusted time would be different between the groups. For equivalence, the endpoint was the mean EQ-5D-5L index value on the chemotherapy day before the outpatient treatment. Only if equivalence was shown, quality-adjusted life-days (QALDs) were considered using all the data. Results The adjusted mean difference in the EQ-5D-5L index was determined to be −0.013 (95% confidence interval [CI]: −0.049 to 0.022); the 95% CI did not exceed the equivalence margin. Similarly, the mean difference in global health status (2.28 [95% CI: −2.55 to 7.11]) also showed equivalence. However, the QALD by EQ-5D-5L was significantly lower in the ePRO group by 1.36 per 30 d (95% CI: −2.22 to −0.51; P = 0.0021). Conclusions Continual measurements of the HRQOL at home by ePRO may yield more detailed profiles of the HRQOL.

Objective This study was aimed at establishing population norms of EQ-5D-Y in Japan by a nationwide large sample survey. Methods We performed a door-to-door survey by visiting the homes of children/adolescents aged 8–15 years selected by random sampling. The planned sample size was 3600 from 100 districts in Japan. Children/adolescents were asked to respond to the EQ-5D-Y instrument, and their parents, to background questions on themselves and their children. Summary statistics by age/sex were calculated to obtain the Japanese population norms. A multiple linear regression model was used to examine the relationships between the EQ-5D-Y index and their parents’ demographic factors, the children/adolescents’ diseases/symptoms and the family environment. Results We collected 3636 responses from 100 districts. The overall EQ-5D-Y index values (all sexes, ages) ranged from 0.90 to 0.95. The percentage of respondents reporting full health ranged from 40 to 60%. In regard to the influence of the children/adolescents’ diseases/symptoms on disutility, developmental disability showed the largest disutility values of 0.090. Sleeplessness and body pain were the symptoms that exerted the greatest influence on the EQ-5D-Y index; the effect sizes ranged from − 0.030 to − 0.098 for sleeplessness, and from − 0.023 to − 0.079 for body pain. The EQ-5D-Y index of children/adolescents with parents who reported severe stress was lower by 0.072 (p < 0.001), as compared with that of children/adolescents with parents reporting no stress. Conclusions Population norms of EQ-5D-Y were established for the first time. We also clarified the relationship between the EQ-5D-Y index value and the children/adolescents’ diseases/symptoms and the family environment.

Objectives This study aimed to establish the Japanese population norms of the EQ-5D-5L and Health Utilities Index Mark 3 (HUI3) and estimate the disutility associated with diseases and symptoms. Methods We performed a door-to-door survey of the general population by random sampling. The planned sample size was 10 000 residents (age ≥16 years) of 334 districts in Japan. In addition to the EQ-5D-5L and HUI3 questionnaires, questions regarding demographic factors and self-reported main diseases and symptoms were asked. The EQ-5D-5L and HUI3 responses were converted to index values on the basis of Japanese value sets. Summary values by age and sex were calculated to obtain Japanese normative values. A multiple linear model was used to examine relationships between these values and diseases and symptoms. Results We collected 10 183 responses from 334 districts. The mean EQ-5D-5L index values were 0.821 (male) and 0.774 (female) in the age group of 80 to 89 years, which were lower compared with 0.978 (male) and 0.967 (female) in the age group of 16 to 19 years. Similar trends were observed for the HUI3 values. Age, sex, household income, and education level had a significant influence on the values of both instruments. When measured with the EQ-5D-5L, Parkinson disease, dementia, and stroke were associated with the largest disutility (>0.2), and the disutility for depression was approximately 0.18. In contrast, the HUI3 disutility values for Parkinson disease and dementia were approximately 0.4. Conclusions This study established the Japanese population norms of the EQ-5D-5L and HUI3, which can be used in healthcare decision making and contribute to a more reliable analysis of economic evaluations.

Objectives: A 50–100 mg rectal dose of diclofenac or indomethacin is recommended for prophylaxis of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP); however, limited data are available regarding the appropriate dose to prevent PEP in elderly patients. We aimed to evaluate the efficacy and safety of 25 mg diclofenac in preventing PEP in elderly patients. ......

Introduction. An on-going coronavirus disease 2019 (COVID-19) has become a challenge all over the world. Since an endoscopy unit and its staff are at potentially high risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we conducted a survey for the management of the gastrointestinal endoscopic practice, personal protective equipment (PPE), and risk assessment for COVID-19 during the pandemic at multiple facilities. Methods. The 11-item survey questionnaire was sent to representative respondent of Department of Gastroenterology, Osaka City University Hospital, and its 19 related facilities. Results. A total of 18 facilities submitted valid responses and a total of 373 health care professionals (HCPs) participated. All facilities (18/18: 100%) were screening patients at risk for SARS-CoV-2 infection before endoscopy. During the pandemic, we found that the total volume of endoscopic procedures decreased by 44%. Eleven facilities (11/18: 61%) followed recommendations of the Japan Gastroenterological Endoscopy Society (JGES); consequently, about 35%–50% of esophagogastroduodenoscopy and colonoscopy were canceled. Mask (surgical mask or N95 mask), face shield/goggle, gloves (one or two sets), and gown (with long or short sleeves) were being used by endoscopists, nurses, endoscopy technicians, and endoscope cleaning staff in all the facilities (18/18: 100%). SARS-CoV-2 infection risk assessment of HCPs was conducted daily in all the facilities (18/18: 100%), resulting in no subsequent SARS-CoV-2 infection in HCPs. Conclusion. COVID-19 has had a dramatic impact on the gastrointestinal endoscopic practice. The recommendations of the JGES were appropriate as preventive measures for the SARSCoV-2 infection in the endoscopy unit and its staff.

A new cytotoxic agent designated as 2-epi-anthracimycin (1) was isolated along with anthracimycin and anthracimycin B (2-demethylanthracimycin) from the culture broth of the marine-derived actinomycete Streptomyces sp. OPMA00631. The structure of 1 was elucidated based on spectroscopic analyses (1D and 2D NMR data and ROESY correlations). Compound 1 exhibited cytotoxicity against Jurkat cells with an IC50 value of 50.5 μM in 20 h. The effect of 1 on the cell cycle distribution of Jurkat cells was investigated. Compound 1 (7.80 μM) increased G1 phase cells from 51.1 to 62.0% and conversely, decreased G2 and M phase cells from 30.7 to 19.3 % in 20 h. At a higher concentration, 1 (250 μM) markedly increased subG1 phase cells (1.9% at 0 h to 16.5% at 20 h), while the proportion of G1 phase cells was maintained (62.3%). These results suggest that 1 exhibits cytotoxicity against Jurkat cells by arresting the cell cycle at the G1 phase.

Radical lymph-node dissection along the recurrent laryngeal nerves (RLN) improves the prognosis of patients with esophageal cancer. The RLN is a landmark for achieving adequate lymph-node dissection. However, the right RLN is sometimes covered by the right vertebral veins (VVs), making it undetectable. We investigated the relationship between this anomaly of the right VVs and the challenges of performing lymphadenectomy along the right RLN. Patients with esophageal cancer, who underwent thoracoscopic esophagectomy with radical lymph-node dissection, were registered. The patterns of the right VVs were evaluated by preoperative computed tomography. The time required for identifying the right RLN or completing the lymphadenectomy was determined by reviewing surgical videos. In total, 178 patients were enrolled. Eighty patients (45%) had right VVs passing dorsal to the right subclavian artery (Dorsal group). More time was required to detect the right RLN in these cases (11 vs 9.5 min for the other cases, p = 0.034). In the Dorsal group, there were 15 patients who had specific VV patterns: The right VV converged on the lower portion of the right brachiocephalic vein (BCV), or passed through to the more medial side of the mediastinum. These patients required more time for detecting the right RLN (25 vs 9 min, p

Purpose The prognostic significance of pretreatment serum C-terminus of cytokeratin 19 (CYFRA21-1, CYFRA) status was evaluated in the patients with surgically treated esophageal squamous cell carcinoma. Methods A total of 1047 patients with surgically treated esophageal cancer were enrolled in a multi-institutional study promoted by the Japanese Esophageal Society. This study included an up-front surgery group (n = 412), a neoadjuvant chemotherapy (NAC) group (n = 486), and a neoadjuvant chemoradiation/radiation therapy (NACRT/RT) group (n = 149). The pretreatment CYFRA status was analyzed to assess prognostic significance using multivariate analysis according to treatment modalities. Results The CYFRA-positive group was significantly associated with deep tumor. Univariate analysis showed that the overall survival of the CYFRA-positive group was significantly worse than that of the CYFRA-negative group, but the difference was not significant in the multivariate analysis. CYFRA was an independent risk factor for poor prognosis just in the NACRT/RT group. Conclusions The CYFRA-positive group was associated with deep tumor and poor survival. Pretreatment CYFRA was not an independent risk factor for poor prognosis in the up-front surgery group or NAC group. It was an independent risk factor for poor prognosis just in the NACRT/RT group.

Although previous reports showed clinicopathological and diagnostic significance of serum p53 antibody in esophageal squamous cell carcinoma, all those reports analyzed only 100 to 200 patients at single institute. This study was designed as a multi-institutional study promoted by the Japan Esophageal Society to elucidate the clinical significance of serum p53 antibody in esophageal cancer treatment. Methods A total of 1,487 patients, from 15 hospitals of Japan, with esophageal carcinoma surgically treated between 2008 and 2016 were enrolled in this retrospective study. We used 1.30 U/ml as a cutoff for classifying patients into positive and negative groups. And we attempted to analyze only positive cases. A receiver operating characteristic curve was constructed to assess serum p53 antibody cutoff levels to differentiate poor prognosis. We used 9.82 U/ml as a cutoff for classifying patients into low and high groups. Univariate and multivariate analyses were used to evaluate the clinicopathological and prognostic significance of pretreatment level of serum p53 antibody. Results There were significant relationships between serum p53 antibody level and tumor depth (p = 0.002), nodal status (p = 0.027) and pathological stage (p = 0.002). The positive serum p53 antibody group had a no significantly worse overall survival than that of the negative group (p = 0.699). The high serum p53 antibody group had a significantly worse overall survival than that of the low group (p = 0.024). However, the difference was not significant in the multivariate analysis (p = 0.137). Conclusion Although high level (>9.82 U/ml) of pretreatment serum p53 antibody might be associated with poor prognosis for patients with esophageal cancer, high serum p53 antibody was not an independent risk factor.

Constipation has been considered the key risk factor for diverticulosis occurrence, but the underlying mechanism is unclear. We investigated the factors associated with diverticulosis, focusing on the association of constipation severity with the localization and number of diverticula.We analyzed consecutive patients who underwent colonoscopy between March and December 2019. Chronic constipation was diagnosed as constipation meeting Rome IV criteria or as that requiring laxative therapy for more than 6 months. The degree of constipation was scored using the Constipation Scoring System (CSS).We assessed 1014 patients. Multivariate analysis revealed that age, alcohol consumption, and hypertension were positively associated with diverticulosis, whereas chronic constipation was negatively associated with diverticulosis (odds ratio [OR] = 0.74; 95% confidence interval [CI], 0.55-0.99). When assessed according to the location of diverticula, right-sided diverticula were significantly associated with a lower incidence of constipation (OR = 0.94; 95% CI, 0.89-0.98), whereas neither left-sided nor bilateral diverticula was associated with constipation. This negative association of diverticula with constipation was stronger in patients with a high CSS score. In stratified analysis, the number of diverticula decreased with increasing degree of constipation (Chronic constipation was negatively associated with colonic diverticulosis. The association increased with the degree of constipation and was strong only in cases with right-sided diverticula and those with ≥3 diverticula.

Various lifestyle behaviors have been known to affect health-related quality of life (HRQL) and life expectancy. However, the impact on quality-adjusted life years (QALYs), which can be used for health economics, has not been clarified. The purpose of this study was to estimate the impact of lifestyle behaviors on lifetime QALYs. We first examined the relationship between lifestyle behaviors and HRQL as measured by the EQ-5D-5L among 4000 participants via a web-based survey. The results of multiple regression analysis showed that physical activity and sleep were significantly related to HRQL. Therefore, we used microsimulation to estimate QALYs from physical activity and sleep, which were determined to be significant in the regression analysis. The results showed that there was a difference of 3.6 QALYs between the recommended lifestyle scenario (23.4 QALYs, 95%CI 3.6 to 35.1) and the non-recommended lifestyle scenario (19.8 QALYs, 95%CI 3.1 to 31.6). This difference was greater in the younger age group than in the older age group. The results also indicated a large difference in QALYs between physical activity and sleep. These findings may provide a significant suggestion for future health promotion measures.

A new compound, designated nectriatide (1), was isolated as a potentiator of amphotericin B (AmB) activity against Candida albicans from the culture broth of Nectriaceae sp. BF-0114. This structure was elucidated based on spectroscopic analyses (1D and 2D NMR data), chemical methods, and total synthesis. Compound 1 was a unique cyclotetrapeptide consisting of l-N-methyltyrosine, anthranilic acid, l-alanine, and l-valine. Compound 1 and several synthetic derivatives, including linear peptides, potentiated AmB activity against C. albicans by up to 16-fold (the MIC value of AmB decreased from 0.5 μg/mL to 0.031 μg/mL in combination with test compound).

Background: The purpose of this study was to identify risk factors for intensive nutritional intervention outcomes in elderly undernourished patients to help reduce the number of patients with prolonged hospital stay or without recuperation of previous activities of daily living and quality of life. Methods: In total, 230 patients who received interventions from a nutrition support team (NST) between January 2016 and July 2018 were included. Patients were classified into two groups based on NST intervention outcomes: patients with improved nutritional status were included in the successful group, whereas those whose nutritional status did not improve, as defined by progressive illness or death, were classified into the non-successful group. We assessed patient characteristics, laboratory data, and nutrition support methods. Results: Our multivariate Cox proportional hazard analysis showed that: 1) The presence of peripheral parenteral nutrition (hazard ratio (HR): 1.80; 95% confidence interval (CI): 1.13 - 2.88) was identified as an independent risk factor for NST intervention outcomes; 2) The energy fill rate to total energy expenditure was < 66.0% (HR: 1.61; 95% CI: 0.98 - 2.66); and 3) A geriatric nutritional risk index score < 70.0 (HR: 1.54; 95% CI: 0.92 - 2.56) tended to be negatively associated with NST intervention outcomes. Conclusions: In addition to the nutrition therapy provided by a traditional NST, patients with the risk factors require nutritional intervention. Elderly individuals should also receive nutrition care because they have been recuperating at their home or in long-term care facilities, to prevent experiencing adverse conditions. J Clin Med Res. 2019;11(7):472-479 doi: https://doi.org/10.14740/jocmr3738

Head and neck cancer metastasizing to the small intestine is very rare. Here we report a case of cancer of the mandibular gingiva metastasizing to the small intestine. The patient was an 82-year-old man who had squamous cell carcinoma of the mandibular gingiva staged as T2N2bM0. Two months after surgery, he presented with lower abdominal pain accompanied by signs of peritoneal irritation. Urgent abdominal surgery was performed, during which a crater-shaped perforation was noted on the wall of the ileum. Microscopic findings at this site confirmed a diagnosis of metastatic squamous cell carcinoma in the small intestine from the mandibular gingiva. To our knowledge, this is the first case report of oral cancer metastasizing to the small intestine. If gastrointestinal symptoms appear in a patient with advanced oral cancer, a differential diagnosis of metastasis to the gastrointestinal tract should be kept in mind.

Kinoshita, T., Moriwaki, K., Hanaki, N. et al. Cost-effectiveness of a hybrid emergency room system for severe trauma: a health technology assessment from the perspective of the third-party payer in Japan. World J Emerg Surg 16, 2 (2021). https://doi.org/10.1186/s13017-020-00344-x, Background: Hybrid emergency room (ER) systems, consisting of an angiography-computed tomography (CT) machine in a trauma resuscitation room, are reported to be effective for reducing death from exsanguination in trauma patients. We aimed to investigate the cost-effectiveness of a hybrid ER system in severe trauma patients without severe traumatic brain injury (TBI). Methods: We conducted a cost-utility analysis comparing the hybrid ER system to the conventional ER system from the perspective of the third-party healthcare payer in Japan. A short-term decision tree and a long-term Markov model using a lifetime time horizon were constructed to estimate quality-adjusted life years (QALYs) and associated lifetime healthcare costs. Short-term mortality and healthcare costs were derived from medical records and claims data in a tertiary care hospital with a hybrid ER. Long-term mortality and utilities were extrapolated from the literature. The willingness-to-pay threshold was set at $47,619 per QALY gained and the discount rate was 2%. Deterministic and probabilistic sensitivity analyses were conducted. Results: The hybrid ER system was associated with a gain of 1.03 QALYs and an increment of $33,591 lifetime costs compared to the conventional ER system, resulting in an ICER of $32,522 per QALY gained. The ICER was lower than the willingness-to-pay threshold if the odds ratio of 28-day mortality was < 0.66. Probabilistic sensitivity analysis indicated that the hybrid ER system was cost-effective with a 79.3% probability. Conclusion: The present study suggested that the hybrid ER system is a likely cost-effective strategy for treating severe trauma patients without severe TBI.

BackgroundThe polymerase chain reaction (PCR) is commonly used to detect viral pathogens because of its high sensitivity and specificity. However, conventional PCR methods cannot determine virus infectivity. Virus infectivity is conventionally examined with methods such as the plaque assay, even though such assays require several days. Long-range reverse-transcription quantitative PCR (RT-qPCR) has previously been suggested for the rapid assessment of RNA virus infectivity where the loss of infectivity is attributable to genomic fragmentation.MethodsIAV was irradiated with 253.7 nm ultraviolet (UV) rays to induce genomic strand breaks that were confirmed by a full-length RT-PCR assay. The IAV was then subjected to plaque assay, conventional RT-qPCR and long-range RT-qPCR to examine the relationship between infectious titer and copy number. A simple linear regression analysis was performed to examine the correlation between the results of these assays.ResultsA long-range RT-qPCR assay was developed and validated for influenza A virus (IAV). Although only a few minutes of UV irradiation was required to completely inactivate IAV, genomic RNA remained detectable by the conventional RT-qPCR and the full-length RT-PCR for NS of viral genome following inactivation. A long-range RT-qPCR assay was then designed using RT-priming at the 3′ termini of each genomic segment and subsequent qPCR of the 5′ regions. UV-mediated IAV inactivation was successfully analyzed by the long-range RT-qPCR assay especially when targeting PA of the viral genome. This was also supported by the regression analysis that the long-range RT-qPCR is highly correlated with plaque assay (AdjustedR2 = 0.931,P = 0.000066).ConclusionsThis study suggests that IAV infectivity can be predicted without the infectivity assays. The rapid detection of pathogenic IAV has, therefore, been achieved with this sensing technology.

In this paper, we propose a novel approach to fabricate fluidic chips. The method utilizes molecular cross-diffusion, induced by photopolymerization under ultraviolet (UV) irradiation in a channel pattern, to form the channel structures. During channel structure formation, the photopolymer layer still contains many uncured molecules. Subsequently, a top substrate is attached to the channel structure under adequate pressure, and the entire chip is homogenously irradiated by UV light. Immediately thereafter, a sufficiently sealed fluidic chip is formed. Using this fabrication process, the channel pattern of a chip can be designed quickly by a computer as binary images, and practical chips can be produced on demand at a benchtop, instead of awaiting production in specialized factories.

Objective The aim of this study was to investigate the impact of adverse events (AEs) on health utility and health-related quality of life (HRQOL) in patients with metastatic breast cancer undergoing first-line chemotherapy. Methods We analyzed the data from the SELECT BC study, a multicenter, open-label, randomized, phase III study conducted in Japan, which compared first-line S-1 with taxane therapies. Heath utility and HRQOL were assessed using the EQ-5D-3L and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) at baseline and 3, 6, and 12 months after treatment initiation. Health utility was calculated based on societal preferences, and AEs were reported at each cycle of the study treatment. Linear marginal mean models were used to quantify the impact of the last AEs (with 10 or more incidences) observed before HRQOL assessment on health utility and HRQOL. Results Analysis included 380 patients and 12 (of 15) AEs. Grade 1 nausea and oral mucositis, grade 1 and 2 edema, and grade 2 fatigue, motor and sensory neuropathy, and myalgia were significantly associated with disutility, measured using the EQ-5D-3L. Grade 1 oral mucositis, grade 1 and 2 fatigue, and grade 2 sensory neuropathy were significantly associated with impaired global health status in the EORTC QLQ-C30. AEs associated with decrements in the five functioning scales included fatigue, oral mucositis, nausea, edema, motor and sensory neuropathy, and myalgia. Conclusions We reported disutilities caused by AEs in patients with metastatic breast cancer under chemotherapy. These findings can be applied to future model-based cost-effectiveness analyses. Trial Registration Number C000000416. Electronic supplementary material The online version of this article (doi:10.1007/s40273-017-0580-7) contains supplementary material, which is available to authorized users.

Sodium-glucose co-transporter-2 inhibitors are newly established anti-diabetic agents with a unique glucose-lowering mechanism. In the present study, we investigated the efficacy and safety of the sodium-glucose co-transporter-2 inhibitor ipragliflozin (Ipra) for metabolic markers and cardiovascular parameters in Japanese patients with type 2 diabetes mellitus (T2DM). This study was an investigator-initiated, open-label, single-arm, multicenter prospective study. Patients with T2DM were treated with 50 mg Ipra for 24 and 52 weeks. The primary outcome investigated was the reduction of glycated hemoglobin (HbA1c) level. The secondary outcome was the change in other metabolic and cardiovascular parameters by 24 weeks. Before and after 52 weeks of treatment, carotid intima-media thickening (IMT) was measured by echography. A total of 134 patients were recruited in the study. A 24-week treatment with 50 mg Ipra daily significantly reduced HbA1c level (-0.6%, p < 0.01). Body mass index (BMI), blood pressure and serum C-peptide were reduced significantly (p < 0.05), while serum glucagon level was unchanged. Interestingly, the serum adiponectin and high-density lipoprotein (HDL) cholesterol levels were significantly increased by Ipra. However, 52 weeks of Ipra treatment did not change carotid IMT. Multiple regression analysis revealed that the only significant contributing factor for HbA1c reduction by Ipra was baseline HbA1c level. These data suggest that Ipra decreased not only glucose level but also BMI, blood pressure and serum C-peptide, and the contributing factor for HbA1c reduction by Ipra was baseline HbA1c level. Further, Ipra improved serum adiponectin and HDL cholesterol levels.

Economic evaluation is used for decision-making processes in healthcare technologies in many developed countries. In Japan, no health economic data have been requested for drugs, medical devices, and interventions till date. However, economic evaluation is gradually gaining importance, and a trial implementation of the cost-effectiveness evaluation of drugs and medical devices has begun. Discussions on economic evaluation began in May 2012 within a newly established sub-committee of the Chuikyo, referred to as the "Special Committee on Cost Effectiveness." After four years of discussions, this committee determined that during the trial implementation, the results of the cost-effectiveness evaluation would be used for the re-pricing of drugs and medical devices at the end of fiscal year (FY) 2017. Chuikyo selected 13 products (7 drugs and 6 medical devices) as targets for this evaluation. These products will be evaluated until the end of FY 2017 based on the following process: manufacturers will submit the data of economic evaluation; the National Institute of Public Health will coordinate the review process; academic groups will perform the actual review of the submitted data, and the expert committee will appraise these data. This represents the first step to introducing cost-effectiveness analysis in the Japanese healthcare system. We believe that these efforts will contribute to the efficiency and sustainability of the Japanese healthcare system.

A high-density array of barnacle-like porous structures was fabricated using monolayers of polystyrene spheres and various types of poly(vinyl alcohol). We first prepared the polystyrene sphere monolayer as a close-packed hexagonal array on a glass substrate. The monolayer was then etched using a plasma treatment to isolate each sphere. Next, we spin-coated the isolated spheres with a water solution of poly(vinyl alcohol). After drying, we applied a second short plasma treatment to the substrate before immersing it in a toluene bath, which promoted opening formation due to polystyrene swelling. As a result, a high-density array of barnacle-like porous structures was homogenously formed on the substrate. These porous structures are expected to be used for various applications including functional coatings, protective cell cultures, and sensor chips.

Cervical esophageal cancer (CEC) is an uncommon disease. Thus, the clinical data from CEC patients have not been sufficient to establish a standard treatment. Forty-six CEC patients who received definitive radiotherapy at our center from January 2003 to December 2014 were enrolled in this retrospective study. The stages of the patients according to the UICC 2002 staging system were as follows: stage I, n = 5; stage IIA + IIB, n = 3; and stage III, n = 38. The median radiation dose was 60 Gy. Thirty-nine patients (84.8%) received concurrent chemotherapy. The 3-year overall survival rate of the 46 patients was 45.4%. The 3-year laryngectomy-free survival rates of non-T4 (n = 20) and T4 patients (n = 26) were 57.8 and 23.6%, respectively; there was a significant difference (p = 0.010). Among the 35 patients who survived for >1 year after treatment, 29 (82.8%) had mild or no dysphagia and could eat solid foods. Among the 11 patients who died at more than 2 years after treatment, 6 (54.5%) died from distant metastasis. Although the number of cases is small, the results of the log-rank tests for various factors suggest that the performance status, tumor progression (TNM stage, T factor, and N factor), tumor response to definitive radiotherapy, and tumor response to induction chemotherapy might affect the prognosis. Definitive radiotherapy is a promising organ-preserving treatment for CEC, especially in patients with non-T4 disease. However, new treatment strategies will be required to improve the outcomes of patients with advanced CEC, and confirmatory prospective clinical trials are required.

Objectives In Japan, cost-effectiveness evaluation was implemented on a trial basis from fiscal year 2016. The results will be applied to the future repricing of drugs and medical devices. On the basis of a request from the Central Social Insurance Medical Council ( Chuikyo ), our research team drafted the official methodological guideline for trial implementation. Here, we report the process of developing and the contents of the official guideline for cost-effectiveness evaluation. Methods The guideline reflects discussions at the Chuikyo subcommittee (e.g., the role of quality-adjusted life-year) and incorporates our academic perspective. Team members generated research questions for each section of the guideline and discussions on these questions were carried out. A draft guideline was prepared and submitted to the Ministry of Health, Labour and Welfare (MHLW), and then to the subcommittee. The draft guideline was revised on the basis of the discussions at the subcommitte, if appropriate. Results Although the "public health care payer's perspective" is standard in this guideline, other perspectives can be applied as necessary depending on the objective of analysis. On the basis of the discussions at the subcommittee, quality-adjusted life-year will be used as the basic outcome. A discount rate of 2% per annum for costs and outcomes is recommended. The final guideline was officially approved by the Chuikyo general assembly in February 2016. Conclusions This is the first officially approved guideline for the economic evaluation of drugs and medical devices in Japan. The guideline is expected to improve the quality and comparability of submitted cost-effectiveness data for decision making.

214 Background: Perioperative chemotherapy has been suggested to be beneficial in patients with advanced gastric cancer. Based on the German FLOT-4 study, the FLOT regimen is considered as the new standard perioperative chemotherapy regimen for resectable gastric cancer in Europe. However, most clinical trials have included few or no cases of esophagogastric junction (EGJ) cancer, because of the difference in surgical procedures. The benefit of neoadjuvant chemotherapy in patients with advanced adenocarcinoma of the EGJ thus remains controversial in Japan. Methods: We conducted a phase II study in 13 Japanese institutions. Eligible patients had histopathologically confirmed adenocarcinoma of the EGJ (Siewert type I or II with invasion of the esophagus ≥30 mm) with clinical T3/4a and/or node-positive on imaging findings, who required thoracic surgery to achieve R0 resection. Patients received three cycles of S-1 (80 mg/m2) twice a day on days 1–14 and oxaliplatin (130 mg/m2) (SOX) on day 1 of a 21-day cycle before surgery. The primary endpoint was R0 resection rate and the secondary endpoints were overall response rate, pathological complete response (pCR) rate, 2-year and 3-year disease-free survival, overall survival, and toxicity. The planned sample size was 50 patients based on an expected R0 resection rate of 85% and the threshold was 70%, with a one-sided alpha of 0.1 and power of 80%. Results: Fifty patients were enrolled in this study between June 2016 and April 2020. Totals of 21/29 and 7/4/22/8/8/1 had Siewert type I/II and clinical stage IIA/IIB/IIIA/IIIB/IIIC/IV disease, respectively. The completion rates for preoperative chemotherapy and surgery were 92% and 88%, respectively. Neoadjuvant therapy resulted in downstaging in 46% of patients (95% confidence interval (CI) 31.8%-60.7%). The pCR rate was 18% (95% CI 8.6%-31.4%) and the R0 resection rate was 82.0% (95% CI 68.6%-91.4%, 80% CI 73.1%-88.9%). Adverse events ≥ grade 3 during chemotherapy included thrombocytopenia (10%), neutropenia (8%), anemia (4%), anorexia (4%), nausea(2%), hypocalcemia(2%), hyponatremia(2%) and diarrhea (2%). Surgical morbidity was acceptable (Clavien-Dindo Grade IIIa surgical complications included anastomotic leakage (6.3%), pleural effusion (4.2%), thromboembolism (2.1%), and anastomotic infection (2.1%)). Conclusions: Neoadjuvant SOX met the primary endpoint of R0 resection rate 82% ( > 70%), with acceptable adverse effects and no impression on surgeries, suggesting that neoadjuvant SOX might be a new treatment strategy for patients with EGJ adenocarcinoma in Japan. Clinical trial information: 000020815.

A new cytotoxic agent designated isomethoxyneihumicin (1 and 2), a mixture of lactam-lactim tautomers, was isolated along with methoxyneihumicin (3) from the culture broth of the marine Nocardiopsis alba KM6-1. The structures of 1 and 2 were elucidated in spectroscopic analyses (1D and 2D NMR data, and ROESY correlations). Isomethoxyneihumicin (15.0 μM) and 3 (15.0 μM) arrested the cell cycle of Jurkat cells at the G2/M phase (66 and 67%) in 12 h. Isomethoxyneihumicin and 3 exhibited cytotoxicity against Jurkat cells with IC50 values of 6.98 and 30.5 μM in 20 h, respectively. These results strongly suggest that isomethoxyneihumicin and 3 exhibit cytotoxicity against Jurkat cells by inhibiting the cell cycle at the G2/M phase.

Multi-drug resistance of pathogenic microorganisms is becoming a serious threat, particularly to immunocompromised populations. The high mortality of systematic fungal infections necessitates novel antifungal drugs and therapies. Unfortunately, with traditional drug discovery approaches, only echinocandins was approved by FDA as a new class of antifungals in the past two decades. Drug efflux is one of the major contributors to multi-drug resistance, the modulator of drug efflux pumps is considered as one of the keys to conquer multi-drug resistance. In this study, we combined structure-based virtual screening and whole-cell based mechanism study, identified a natural product, beauvericin (BEA) as a drug efflux pump modulator, which can reverse the multi-drug resistant phenotype of Candida albicans by specifically blocking the ATP-binding cassette (ABC) transporters; meantime, BEA alone has fungicidal activity in vitro by elevating intracellular calcium and reactive oxygen species (ROS). It was further demonstrated by histopathological study that BEA synergizes with a sub-therapeutic dose of ketoconazole (KTC) and could cure the murine model of disseminated candidiasis. Toxicity evaluation of BEA, including acute toxicity test, Ames test, and hERG (human ether-à-go-go-related gene) test promised that BEA can be harnessed for treatment of candidiasis, especially the candidiasis caused by ABC overexpressed multi-drug resistant C. albicans.

Background The valuation study of the five-level version of the EuroQol five-dimensional questionnaire (EQ-5D-5L) involved composite time trade-off (cTTO) and a discrete choice experiment (DCE). The DCE scores must be anchored to the quality-of-life scale from 0 (death) to 1 (full health). Nevertheless, the characteristics of the statistical methods used for converting the EQ-5D-5L DCE results by using TTO information are not yet clearly known. Objectives To present the Japanese DCE value set of the EQ-5D-5L and compare three methods for converting latent DCE values. Methods The survey sampled the general population at five locations in Japan. 1098 respondents were stratified by age and sex. To obtain and compare the value sets of the EQ-5D-5L, the cTTO and DCE data were analyzed by a linear mixed model and conditional logit, respectively. The DCE scores were converted to the quality-of-life scale by anchoring to the worst state using cTTO, mapping DCE onto cTTO, and a hybrid model. Results The data from 1026 respondents were analyzed. All the coefficients in the cTTO and DCE value sets were consistent throughout all the analyses. Compared with the cTTO algorithm, the mapping and hybrid methods yielded very similar scoring coefficients. The hybrid model results, however, produced a lower root mean square error and fewer health states with errors exceeding 0.05 than did the other models. The DCE anchored to the worst state overestimated the cTTO scores of almost all the health states. Conclusions Japanese value sets based on DCE were demonstrated. On comparing the observed cTTO scores, we found that the hybrid model was slightly superior to the simpler methods, including the TTO model.

The Japan National Committee for the Union for International Cancer Control (UICC) and UICC – Asia Regional Office organized an international session as part of the 74th Annual Meeting of the Japanese Cancer Association on the topic “What are the implications of sharing the concept of Universal Health Coverage for cancer in Asia?” Universal Health Coverage (UHC) is included in the United Nations’ Sustainable Development Goals and aims to ensure that all people can receive high‐quality medical services, are protected from public health risks, and are prevented from falling into poverty due to medical costs or loss of income arising from illness. The session discussed the growing cost of cancer and the challenges that this poses to the establishment and deployment of UHC in the Asian region, where countries face budgetary and other systemic constraints in tackling and controlling cancer. It was noted how sharing concepts on UHC will assist mutual learning among Asian countries and help in the formation of guidelines that can be adapted to national and regional realities. Presentations included a status report on UHC for cancer control in Thailand, and a report from the WHO Kobe Centre concerning prospects for collaborative research on UHC. Also discussed were the current status of cancer burden and control in China and Korea and Japan's progress in systemizing cost‐effectiveness evaluation. The final presentation highlighted the importance of gathering social and economic data across Asia in order to build a picture of commonalities and differences in the region., The Japan National Committee for the Union for International Cancer Control (UICC) and UICC‐Asia Regional Office (ARO) organized an international session as part of the official program of the 74th Annual Meeting of the Japanese Cancer Association to discuss the topic “What are the implications of sharing the concept of Universal Health Coverage for cancer in Asia?” The presenters and participants discussed the growing cost of cancer in the Asian region and the challenges that this poses to the establishment and deployment of UHC in the countries of Asia, all of which face budgetary and other systemic constraints in tackling and controlling cancer in the region.

Objective Gastroesophageal reflux disease (GERD) is strongly associated with sleep disturbances; however, the detailed differences in the characteristics of sleep disturbances between GERD and non-GERD patients are unknown. The aim of the present study was to analyze the clinical characteristics as well as health-related quality of life in GERD and non-GERD patients with sleep disturbances. Methods Three hundred and fifty patients, including 124 patients with GERD and 226 patients without GERD, completed a self-administered questionnaire that evaluated clinical information. The Pittsburg Sleep Quality Index (PSQI), Hospital Anxiety and Depression Scale (HADS), Insomnia Severity Index (ISI), Epworth Sleepiness Scale (ESS) and 8-item Short-Form Health Survey (SF-8) were also used. Sleep disturbance was considered to be present if the PSQI was >5.5. Results The prevalence of sleep disturbances was significantly higher in the GERD patients (66/124, 53.9%) than in the non-GERD patients (89/226, 39.3%). Depression and anxiety were significantly more common in the subjects with sleep disturbances than in those without sleep disturbances, although there were no differences between the GERD and non-GERD patients. Among the subjects with sleep disturbances, daytime sleepiness was more common in the GERD patients than in the non-GERD patients. The subjects with sleep disturbances had a poorer health-related quality of life. The physical components of quality of life were impaired, particularly in the GERD patients with sleep disturbances. Conclusion GERD patients with sleep disturbances commonly experience daytime sleepiness and an impaired health-related quality of life, especially in terms of physical components.

Background The population is aging rapidly in many developed countries. Such countries need to respond to the growing demand and expanding costs of healthcare (HC) for the elderly. Therefore, it is important to investigate the factors correlating such HC costs. In Japan, HC is composed of two sections, namely medical care (MC) and long-term care (LTC). While many studies have examined MC and LTC costs on their own, few studies have conducted comprehensive investigations of HC costs. The aim of this study is to examine the risk factors that influence HC costs for the elderly who enroll in the LTC insurance system in Japan. Methods The inclusion criteria in the present study are as follows: being 65 years of age, or older; certified eligibility for, and use of services offered by the LTC insurance system at home or in an institutional setting in December 2009; and being covered by the National Health Insurance (NHI) system. MC and LTC insurance data were obtained from claim records for the elderly in July and December of 2007, 2008, and 2009 (i.e., a total of six survey points). Panel data, per subject, were constructed using MC and LTC claim records. The sample included 810 subjects and 4029 observations. Results We estimated a regression equation with a censored dependent variable using a Tobit model. Significant associations between MC or LTC costs and interaction terms (household composition × seasonal effects) were investigated. MC costs significantly decreased and LTC costs significantly increased among subjects living alone during winter. Income level was also a positive determinant of MC costs, while eligibility level was a positive determinant of LTC costs. Conclusions We recommend that the health policy for the elderly focus more on seasonal effects, household composition, and income level, as well as on eligibility level.

The high prevalence of severe pressure ulcers (PUs) is an important issue that requires to be highlighted in Japan. In a previous study, we devised an advanced PU management protocol to enable early detection of and intervention for deep tissue injury and critical colonization. This protocol was effective for preventing more severe PUs. The present study aimed to compare the cost-effectiveness of the care provided using an advanced PU management protocol, from a medical provider's perspective, implemented by trained wound, ostomy, and continence nurses (WOCNs), with that of conventional care provided by a control group of WOCNs. A Markov model was constructed for a 1-year time horizon to determine the incremental cost-effectiveness ratio of advanced PU management compared with conventional care. The number of quality-adjusted life-years gained, and the cost in Japanese yen (¥) ($US1 = ¥120; 2015) was used as the outcome. Model inputs for clinical probabilities and related costs were based on our previous clinical trial results. Univariate sensitivity analyses were performed. Furthermore, a Bayesian multivariate probability sensitivity analysis was performed using Monte Carlo simulations with advanced PU management. Two different models were created for initial cohort distribution. For both models, the expected effectiveness for the intervention group using advanced PU management techniques was high, with a low expected cost value. The sensitivity analyses suggested that the results were robust. Intervention by WOCNs using advanced PU management techniques was more effective and cost-effective than conventional care.

Purpose The purpose of this study was to measure the population norms for the Japanese versions of preference-based measures (EQ-5D-3L, EQ-5D-5L, and SF-6D). We also considered the relations between QOL score in the general population and socio-demographic factors. Methods A total of 1143 adult respondents (aged ≥ 20 years) were randomly sampled from across Japan using data from the Basic Resident Register. The health status of each respondent was measured using the EQ-5D-3L, EQ-5D-5L, and SF-6D, and responses regarding socio-demographic data as well as subjective diseases and symptoms were obtained. The responses were converted to a QOL score using Japanese value sets. Results The percentages of respondents with full health scores were 68 % (EQ-5D-3L), 55 % (EQ-5D-5L), and 4 % (SF-6D). The QOL score measured using the SF-6D was significantly lower than those measured using either EQ-5D score. The QOL score was significantly lower among respondents over the age of 60 years, those who had a lower income, and those who had a shorter period of education. Intraclass correlation coefficient showed a poor agreement between the EQ-5D and SF-6D scores. The differences in QOL scores between respondents with and those without any disease were 0.064 for the EQ-5D-3L, 0.061 for the EQ-5D-5L, and 0.073 for the SF-6D; these differences are regarded as between-group minimal important differences in the general population. Conclusion The Japanese population norms of three preference-based QOL measures were examined for the first time. Such information is useful for economic evaluations and research examining QOL score.

This study evaluated the cost-effectiveness of replacing standard intravenous therapy (taxane) with oral S-1 therapy for first-line metastatic breast cancer treatment. This cost-effectiveness analysis was based on data from a randomized phase III trial (SELECT BC). As cost-effectiveness was a secondary endpoint of the SELECT BC trial, some of the randomized patients participated in an EQ-5D survey (N = 391) and health economic survey (N = 146). The EQ-5D responses, claims, and prescription data were collected for as long as possible until death. The expected quality-adjusted life years (QALY) obtained from each treatment were calculated using patient-level EQ-5D data, and the expected cost was calculated using patient-level claim data. The analysis was performed from the perspective of public healthcare payers. The estimated EQ-5D least-square means and 95% CI up to 48 months were 0.764 (95% CI, 0.741–0.782) and 0.742 (95% CI, 0.720–0.764) in the S-1 and taxane arms, respectively. The expected QALY was 2.11 for the S-1 arm and 2.04 for the taxane arm, with expected costs of JPY 5.13 million (USD 46,600) and JPY 5.56 million (USD 50,500), respectively. These results show that S-1 is cost-saving. According to probabilistic sensitivity analysis, S-1 was dominant with a probability of 63%. When the willingness to pay (WTP) value was JPY 5 million (USD 45,500) per QALY, the probability of being cost-effective was 92%. Our results show that the introduction of oral S-1 therapy for metastatic breast cancer is highly likely to be cost-effective. UMIN CTR C000000416 . Registered on May 10, 2006.

Objective: To evaluate the effects of S-1, an orally administered 5-FU agent, versus taxane on patient-reported outcomes (PROs) in the SELECT BC trial. Methods: Patients with HER2-negative and endocrine treatment-resistant breast cancer with metastasis or recurrence after surgery were randomly assigned to receive first-line taxane or S-1. PROs (secondary endpoint) were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and Patient Neurotoxicity Questionnaire (PNQ) at baseline and at 3, 6, and 12 months. We conducted a responder analysis for the QLQ-C30 and PNQ and created cumulative distribution function (CDF) plots as a sensitivity analysis. Results: The questionnaire response rates were over 80% from 386 patients, who completed at least one baseline questionnaire. S-1 was significantly superior to taxane with respect to 6 scales (physical functioning [p = 0.03], role functioning [p = 0.04], social functioning [p < 0.01], financial difficulties [p = 0.01], global health status [p = 0.02], and constipation [p < 0.01]) and sensory neuropathy (p = 0.01). The CDF plots partially supported the conclusions and their robustness. Conclusion: First-line S-1 therapy has clinical benefits with respect to many aspects of health-related quality of life for metastatic breast cancer patients.

Objective To compare radical surgery with definitive chemoradiation (CRT) for esophageal squamous cell carcinoma using propensity score (PS) matching at our single institution. Materials and methods A total of 386 consecutive, surgically treated and 243 CRT-treated cases between 2001 and 2014 were analyzed. PS was calculated using multivariable analysis (logistic regression) for pairs of variables such as treatment time, age, sex, primary tumor location, clinical stage, and clinical T- and N-stage for patients after excluding clinical T4 and M1 cases. According to PS, 133 surgically-treated and 134 CRT-treated cases were selected randomly by software. Results The patients’ median age was 68 years in the CRT group and 71 years in the surgery group. Clinical stage II-III, T3, N0 (according to the 7th American Joint Committee on Cancer-2009), and upper plus middle thoracic esophageal disease were seen in 68%, 44%, 54%, and 59%, respectively, in the CRT group and 64%, 47%, 55%, and 64%, respectively, in the surgery group. The 3- and 5-year overall survival was 47.1% and 34.0% in the CRT group and 68.3% and 54.4% in the surgery group (p = 0.0019). The 3- and 5-year progression-free survival was 45.3% and 38.8% in the CRT group and 61.1% and 54.4% in the surgery group (p = 0.022). Conclusion CRT may be inferior to surgery in survival, although a selection bias for patients selected for a non-operative approach cannot be excluded, especially since surgery is the standard of care at this institution. A prospective randomized clinical trial will be necessary to draw a definite conclusion.

Natural products continue to provide vital treatment options for cancer. Although their translation into chemotherapeutics is complex, collaborative programs continue to deliver productive pipelines for cancer chemotherapy. A new natural product, seriniquinone, isolated from a marine bacterium of the genus Serinicoccus, demonstrated potent activity over a select set of tumor cell lines with particular selectivity toward melanoma cell lines. Upon entering the cell, its journey began by localization into the endoplasmic reticulum. Within 3 h, cells treated with seriniquinone underwent cell death marked by activation of autophagocytosis and gradually terminated through a caspase-9 apoptotic pathway. Using an immunoaffinity approach followed by multipoint validation, we identified the target of seriniquinone as the small protein, dermcidin. Combined, these findings revealed a small molecule motif in parallel with its therapeutic target, whose potential in cancer therapy may be significant. This discovery defines a new pharmacophore that displayed selective activity toward a distinct set of cell lines, predominantly melanoma, within the NCI 60 panel. This selectivity, along with the ease in medicinal chemical modification, provides a key opportunity to design and evaluate new treatments for those cancers that rely on dermcidin activity. Further, the use of dermcidin as a patient preselection biomarker may accelerate the development of more effective personalized treatments.

The Japan National Committee for the Union for International Cancer Control (UICC) and UICC-Asia Regional Office (ARO) organized an international session as part of the official program of the 72nd Annual Meeting of the Japanese Cancer Association to discuss the topic "What is cost-effectiveness in cancer treatment? " Healthcare economics are an international concern and a key issue for the UICC. The presenters and participants discussed the question of how limited medical resources can be best used to support life, which is a question that applies to both developing and industrialized countries, given that cancer treatment is putting medical systems under increasing strain. The emergence of advanced yet hugely expensive drugs has prompted discussion on methodologies for Health Technology Assessment (HTA) that seek to quantify cost and effect. The session benefited from the participation of various stakeholders, including representatives of industry, government and academia and three speakers from the Republic of Korea, an Asian country where discussion on HTA methodologies is already advanced. In addition, the session was joined by a representative of National Institute for Health and Care Excellence (NICE) of the United Kingdom, which has pioneered the concept of cost-effectiveness in a medical context. The aim of the session was to advance and deepen understanding of the issue of cost-effectiveness as viewed from medical care systems in different regions.