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Purpose: A significant number of women with serous ovarian cancer are intrinsically refractory to platinum-based treatment. We analyzed somatic DNA copy number variation and gene expression data to identify key mechanisms associated with primary resistance in advanced-stage serous cancers.Experimental Design: Genome-wide copy number variation was measured in 118 ovarian tumors using high-resolution oligonucleotide microarrays. A well-defined subset of 85 advanced-stage serous tumors was then used to relate copy number variation to primary resistance to treatment. The discovery-based approach was complemented by quantitative-PCR copy number analysis of 12 candidate genes as independent validation of previously reported associations with clinical outcome. Likely copy number variation targets and tumor molecular subtypes were further characterized by gene expression profiling.Results: Amplification of 19q12, containing cyclin E (CCNE1), and 20q11.22-q13.12, mapping immediately adjacent to the steroid receptor coactivator NCOA3, was significantly associated with poor response to primary treatment. Other genes previously associated with copy number variation and clinical outcome in ovarian cancer were not associated with primary treatment resistance. Chemoresistant tumors with high CCNE1 copy number and protein expression were associated with increased cellular proliferation but so too was a subset of treatment-responsive patients, suggesting a cell-cycle independent role for CCNE1 in modulating chemoresponse. Patients with a poor clinical outcome without CCNE1 amplification overexpressed genes involved in extracellular matrix deposition.Conclusions: We have identified two distinct mechanisms of primary treatment failure in serous ovarian cancer, involving CCNE1 amplification and enhanced extracellular matrix deposition. CCNE1 copy number is validated as a dominant marker of patient outcome in ovarian cancer.

To evaluate the effect of vitamin D(3) supplementation on cancer mortality in the general population and on prognosis in cancer patients, a systematic review and meta-analysis of randomised, placebo-controlled trials (RCTs) and individual patient data (IPD) was conducted. Overall, 14 RCTs with a total of 104,727 participants (2015 cancer deaths) were identified and 7 RCTs, including 90 % of all study participants (n = 94,068), could be included in the IPD meta-analyses. The main meta-analysis of the 14 RCTs yielded a statistically non-significant reduction in cancer mortality by 6 % (risk ratio (RR) [95%-confidence interval (95%CI)]: 0.94 [0.86–1.02]). Subgroup analyses revealed a 12 % lower cancer mortality in the vitamin D(3) group compared with the placebo group in 10 trials with a daily dosing regimen (RR [95%CI]: 0.88 [0.78–0.98]), whereas no mortality reduction was seen in 4 trials using a bolus regimen (RR [95%CI]: 1.07 [0.91–1.24]; p-value for interaction: 0.042). The IPD meta-analysis (RR [95%CI]: 0.93 [0.84; 1.02]) confirmed the finding of all trials. The IPD were used to test effect modification by age, sex, body mass index, ethnicity, baseline serum 25-hydroxyvitamin D concentration, adherence and cancer-related factors but no statistically significant findings were obtained in meta-analyses of all trials. When restricted to trials with daily dosing in a post-hoc analysis, adults aged ≥ 70 years (RR [95%CI]: 0.83 [0.77; 0.98]) and subjects with vitamin D(3) therapy initiation before cancer diagnosis (RR [95%CI]: 0.87 [0.69; 0.99]) appeared to benefit most from daily vitamin D(3) supplementation. Measurements of baseline 25-hydroxyvitamin D levels and inclusion of other than non-Hispanic White adults were too sparse in the trials to draw conclusions. Results for all-cause and cancer-specific survival of participants with cancer were comparable to those obtained in the general population for cancer mortality. In conclusion, vitamin D(3) did not reduce cancer mortality in the main meta-analysis of all RCTs because the observed risk reduction by 6 % was not statistically significant. However, a subgroup analysis revealed that vitamin D(3) administered daily, in contrast to bolus supplementation, reduced cancer mortality by 12 %.

Purpose: Higher serum 25-hydroxyvitamin D (25(OH)D) levels are reportedly associated with better survival in early-stage non–small cell lung cancer (NSCLC). Therefore, whether vitamin D supplementation can improve the prognosis of patients with NSCLC was examined (UMIN000001869).Patients and Methods: A randomized, double-blind trial comparing vitamin D supplements (1,200 IU/day) with placebo for 1 year after operation was conducted. The primary and secondary outcomes were relapse-free survival (RFS) and overall survival (OS), respectively. Prespecified subgroup analyses were performed with stratification by stage (early vs. advanced), pathology (adenocarcinoma vs. others), and 25(OH)D levels (low, Results: Patients with NSCLC (n = 155) were randomly assigned to receive vitamin D (n = 77) or placebo (n = 78) and followed for a median of 3.3 years. Relapse and death occurred in 40 (28%) and 24 (17%) patients, respectively. In the total study population, no significant difference in either RFS or OS was seen with vitamin D compared with the placebo group. However, by restricting the analysis to the subgroup with early-stage adenocarcinoma with low 25(OH)D, the vitamin D group showed significantly better 5-year RFS (86% vs. 50%, P = 0.04) and OS (91% vs. 48%, P = 0.02) than the placebo group. Among the examined polymorphisms, DBP1 (rs7041) TT and CDX2 (rs11568820) AA/AG genotypes were markers of better prognosis, even with multivariate adjustment.Conclusions: In patients with NSCLC, vitamin D supplementation may improve survival of patients with early-stage lung adenocarcinoma with lower 25(OH)D levels. Clin Cancer Res; 24(17); 4089–97. ©2018 AACR.

Supplementary Data from Integrated Genome-Wide DNA Copy Number and Expression Analysis Identifies Distinct Mechanisms of Primary Chemoresistance in Ovarian Carcinomas

Figure S1. Relapse-free survival curves (A) and overall survival curves (B) of patients stratified by 25(OH)D equal to or greater than 30 ng/mL. Figure S2. Kaplan-Meier curves of patients restricted only to adenocarcinoma, or both early stages (IA - IIB) and adenocarcinoma. Figure S3. Relapse-free survival curves (A) and overall survival curves (B) of patients stratified by SNPs of FokI. Mean (SD) of 25(OH)D in each genotype are as follows; FokI CC, 19.9 (6.2) ng/ml; CT, 21.8 (6.6) ng/ml; TT 21.4 (7.9) ng/ml. Figure S4. Relapse-free survival curves (A) and overall survival curves (B) of patients stratified by SNPs of BsmI. Mean (SD) of 25(OH)D in each genotype are as follows: BsmI AA, 15 (-) ng/ml; AG, 20.2 (6.4) ng/ml; GG 21.7 (6.8) ng/ml. Figure S6. Relapse-free survival curves (A) and overall survival curves (B) of patients stratified by SNPs of ApaI. Mean (SD) of 25(OH)D in each genotype are as follows: ApaI GG, 21.2 (7.2) ng/ml; GT, 21.4 (6.3) ng/ml; TT, 21.5 (7.7) ng/ml. Figure S7. Relapse-free survival curves (A) and overall survival curves (B) of patients stratified by SNPs of TaqI. Mean (SD) of 25(OH)D in each genotype are as follows: TaqI TT, 21.7 (6.7) ng/ml; TG, 20.4 (6.9) ng/ml; GG, - (-) ng/ml. Figure S8. Relapse-free survival curves (A) and overall survival curves (B) of patients stratified by SNPs of DBP1. Mean (SD) of 25(OH)D in each genotype are as follows: DBP1 TT, 21.3 (7.0) ng/ml; TG, 20.8 (6.0) ng/ml; GG, 23.6 (7.9) ng/ml. Figure S9. Relapse-free survival curves (A) and overall survival curves (B) of patients stratified by SNPs of DBP2. Mean (SD) of 25(OH)D in each genotype are as follows: DBP2 CC, 22.7 (6.6) ng/ml; CA, 20.0 (6.3) ng/ml; AA, 12.8 (1.5) ng/ml.

This cross-sectional study investigates the association between life expectancy before COVID-19 and excess mortality during the pandemic in aging countries.

Objective Just before the Tokyo 2020 Olympic and Paralympic Games in Japan, the number of people infected with coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), started to increase at an unprecedented rate. This study investigated the effectiveness of vaccines in large-scale sporting events under difficult circumstances, such as during adherence to a bubble system and confinement inside the Olympic/Paralympic Village. Methods In collaboration with medical clinics inside and outside the Village, a prospective cohort study was conducted among overseas participants using the results of polymerase chain reaction (PCR) tests for SARS-CoV-2 upon leaving Japan. Results A total of 12,072 foreign participants were enrolled, 13 (0.11%) of whom had a positive PCR test result. None of these cases were broadcasters or members of the press, were tested outside the Olympic Village, or had a history of COVID-19 infection. The effectiveness of full vaccination and vaccination at least once (≥14 days ago) was 74% (95% confidence interval [CI]: 6-93%) and 81% (95% CI: 30-95%), respectively. Three breakthrough infections with the Delta variant were observed in 6,485 fully vaccinated participants (0.05%). The positivity rate was 0.09% among adherents to the bubble system and 0.28% among non-adherents, but this difference was not significant. Conclusion These findings indicate that even huge sporting events such as the Olympic and Paralympic Games can proceed while pandemics are ongoing in the host country by combining countermeasures such as vaccination, frequent testing, social distancing, and adherence to a bubble system.

Background: A 2017 meta-analysis of data from 25 randomised controlled trials (RCTs) of vitamin D supplementation for the prevention of acute respiratory infections (ARIs) revealed a protective effect of this intervention. We aimed to examine the link between vitamin D supplementation and prevention of ARIs in an updated meta-analysis. Methods: For this systematic review and meta-analysis, we searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and the ClinicalTrials.gov registry for studies listed from database inception to May 1, 2020. Double-blind RCTs of vitamin D3, vitamin D2, or 25-hydroxyvitamin D (25[OH]D) supplementation for any duration, with a placebo or low-dose vitamin D control, were eligible if they had been approved by a research ethics committee, and if ARI incidence was collected prospectively and prespecified as an efficacy outcome. Studies reporting results of long-term follow-up of primary RCTs were excluded. Aggregated study-level data, stratified by baseline 25(OH)D concentration and age, were obtained from study authors. Using the proportion of participants in each trial who had one or more ARIs, we did a random-effects meta-analysis to obtain pooled odds ratios (ORs) and 95% CIs to estimate the effect of vitamin D supplementation on the risk of having one or more ARIs (primary outcome) compared with placebo. Subgroup analyses were done to estimate whether the effects of vitamin D supplementation on the risk of ARI varied according to baseline 25(OH)D concentration (vs 25·0–49·9 nmol/L vs 50·0–74·9 nmol/L vs >75·0 nmol/L), vitamin D dose (daily equivalent of vs 400–1000 IU vs 1001–2000 IU vs >2000 IU), dosing frequency (daily vs weekly vs once per month to once every 3 months), trial duration (≤12 months vs >12 months), age at enrolment (vs 1·00–15·99 years vs 16·00–64·99 years vs ≥65·00 years), and presence versus absence of airway disease (ie, asthma only, COPD only, or unrestricted). Risk of bias was assessed with the Cochrane Collaboration Risk of Bias Tool. The study was registered with PROSPERO, CRD42020190633. Findings: We identified 1528 articles, of which 46 RCTs (75 541 participants) were eligible. Data for the primary outcome were obtained for 48 488 (98·1%) of 49 419 participants (aged 0–95 years) in 43 studies. A significantly lower proportion of participants in the vitamin D supplementation group had one or more ARIs (14 332 [61·3%] of 23 364 participants) than in the placebo group (14 217 [62·3%] of 22 802 participants), with an OR of 0·92 (95% CI 0·86–0·99; 37 studies; I2=35·6%, pheterogeneity=0·018). No significant effect of vitamin D supplementation on the risk of having one or more ARIs was observed for any of the subgroups defined by baseline 25(OH)D concentration. However, protective effects of supplementation were observed in trials in which vitamin D was given in a daily dosing regimen (OR 0·78 [95% CI 0·65–0·94]; 19 studies; I2=53·5%, pheterogeneity=0·003), at daily dose equivalents of 400–1000 IU (0·70 [0·55–0·89]; ten studies; I2=31·2%, pheterogeneity=0·16), for a duration of 12 months or less (0·82 [0·72–0·93]; 29 studies; I2=38·1%, pheterogeneity=0·021), and to participants aged 1·00–15·99 years at enrolment (0·71 [0·57–0·90]; 15 studies; I2=46·0%, pheterogeneity=0·027). No significant interaction between allocation to the vitamin D supplementation group versus the placebo group and dose, dose frequency, study duration, or age was observed. In addition, no significant difference in the proportion of participants who had at least one serious adverse event in the vitamin supplementation group compared with the placebo group was observed (0·97 [0·86–1·07]; 36 studies; I2=0·0%, pheterogeneity=0·99). Risk of bias within individual studies was assessed as being low for all but three trials. Interpretation: Despite evidence of significant heterogeneity across trials, vitamin D supplementation was safe and overall reduced the risk of ARI compared with placebo, although the risk reduction was small. Protection was associated with administration of daily doses of 400–1000 IU for up to 12 months, and age at enrolment of 1·00–15·99 years. The relevance of these findings to COVID-19 is not known and requires further investigation. Funding: None.

Background Coil embolization of aneurysms of the ophthalmic segment of the internal carotid artery (ICA-OphA ANs) has potential risks of visual complications. We analyzed this risk and focused on the relationship of the ophthalmic artery (OphA) origin with the aneurysm neck. Methods From January 2003 to April 2018, 179 unruptured ICA-OphA ANs were treated with endovascular surgery in our institution. Two ruptured and four aneurysms with missing data were excluded. Finally, 173 unruptured aneurysms were included in this study. The aneurysms were classified into three groups according to the location of the OphA origin: Separate, Shared, and Dome type. We retrospectively assessed visual complications based on the relationship between types of aneurysm and postoperative angiographic findings for the OphA. Results Visual deficits remained permanent in eleven cases (6.4%). In the Dome type, visual complications were significantly more frequent compared to the Separate type. Change in the OphA flow was significantly associated with a higher complication rate of 2.9%, but patients with changed OphA flow had a significant rate of 7.5% ( p = 0.020). We found no significant difference in the incidence of visual complications concerning the use of perioperative antithrombotic therapy. Conclusions The location of OphA origin regarding the aneurysmal neck and postoperative OphA flow were significantly correlated with the visual outcome after coil embolization for ICA-OphA ANs. Post-procedural flow in the OphA was an important factor affecting the rate of ischemic retinal complications. Retinal embolic events occurred with preserved flow in the OphA, albeit at a lower rate.

Some controversy remains on thresholds for deficiency or sufficiency of serum 25-hydroxyvitamin D (25(OH)D) levels. Moreover, 25(OH)D levels sufficient for bone health might differ from those required for cancer survival. This study aimed to explore these 25(OH)D threshold levels by applying the machine learning method of multivariable adaptive regression splines (MARS) in post hoc analyses using data from the AMATERASU trial, which randomly assigned Japanese patients with digestive tract cancer to receive vitamin D or placebo supplementation. Using MARS, threshold 25(OH)D levels were estimated as 17 ng/mL for calcium and 29 ng/mL for parathyroid hormone (PTH). Vitamin D supplementation increased calcium levels in patients with baseline 25(OH)D levels ≤17 ng/mL, suggesting deficiency for bone health, but not in those >17 ng/mL. Vitamin D supplementation improved 5-year relapse-free survival (RFS) compared with placebo in patients with intermediate 25(OH)D levels (18–28 ng/mL): vitamin D, 84% vs. placebo, 71%; hazard ratio, 0.49; 95% confidence interval, 0.25–0.96; p = 0.04. In contrast, vitamin D supplementation did not improve 5-year RFS among patients with low (≤17 ng/mL) or with high (≥29 ng/mL) 25(OH)D levels. MARS might be a reliable method with the potential to eliminate guesswork in the estimation of threshold values of biomarkers.

Background: The AMATERASU randomized trial of vitamin D3 supplementation (2,000 IU/day; UMIN000001977) showed the potential benefit of vitamin D in a subgroup of patients with digestive tract cancer. By conducting post hoc analyses of this trial, we further explored whether subgroups stratified by expression levels of p53, vitamin D receptor (VDR), and Ki-67 modify the effect of vitamin D supplementation. Methods: The primary outcome was relapse-free survival (RFS). On IHC using pathologic specimens, the degree of p53 protein expression parallel with TP53 missense mutations was classified as p53 positive (>10%) and p53 negative (≤10%). In addition, VDR and Ki-67 expression levels were divided into quartiles. Results: The p53 status of 372 patients' pathologic specimens was evaluated. In a subgroup of patients with p53-positive cancer (n = 226), 5-year RFS was 79% in the vitamin D group, which was significantly higher than the 57% in the placebo group (HR, 0.52; 95% confidence interval, 0.31–0.88; P = 0.02). In the subgroup of patients with p53-negative cancer, 5-year RFS in the vitamin D group versus placebo group was 72% versus 84% (not significantly different), respectively. Effect modification by p53 positivity was significant (Pinteraction = 0.02). However, no significant effect modification by either VDR or Ki-67 was observed. Conclusions: These results generate a hypothesis that vitamin D supplementation may improve RFS in patients with p53-positive digestive tract cancer. Impact: The results are still preliminary, but potentially important, because TP53 is the most frequently mutated gene across cancers at all sites.

BackgroundAngiotensin-converting enzyme 2 (ACE2) works as an endogenous counter-regulator of the renin-angiotensin system, which has pivotal roles in preventing both cardiovascular disease (CVD) and inflammation. In general populations, higher plasma soluble ACE2 levels were reported to be associated with increased risks of all-cause death and major CVD. Because infections are fatal in patients on maintenance hemodialysis, we aimed to explore whether soluble ACE2 levels are associated with an increased risk of infection-related hospitalization in these patients.MethodsUsing data from a prospective, multicenter, cohort study conducted in Tokyo, Japan, we performed a post-hoc analyses of 724 clinically stable patients on maintenance hemodialysis. We measured baseline serum soluble ACE2 levels and assessed potential determinants of its with infection-related hospitalization as a primary outcome as well as all-cause death and CVD as secondary outcomes using a Cox proportional hazards model.ResultsThe soluble ACE2 level (median, 0.16 ng/ml; interquartile range, 0.07–0.57 ng/ml) showed a weak negative association with age. During a median follow-up of 39 months, 106 patients (14.6%) were hospitalized with infectious diseases. Compared with the lower half of soluble ACE2 levels, the higher half was associated with an increased risk of infection-related hospitalization (hazard ratio, 1.57; 95% confidence interval, 1.02–2.41) with adjustment by other risk factors. On the other hand, there were no significant associations between soluble ACE2 and risks of all-cause death and CVD.ConclusionHigher soluble ACE2 levels may associate with an increased risk of infection-related hospitalization in patients on maintenance hemodialysis.

The aim was to examine whether vitamin D supplementation (2000 IU/day) reduces the risk of relapse in a subgroup of patients with digestive tract cancer, showing a sufficient immune response in tumor stroma by conducting secondary subgroup analyses of the AMATERASU randomized, double-blind, placebo-controlled trial (UMIN000001977). A total of 372 patients were divided into two subgroups stratified by the median density of immune cells infiltrating in tumor stroma into higher and lower halves. In the higher-half subgroup of CD56+ cells, the relapse ratio was significantly lower in the vitamin D group (7.4%) than in the placebo group (20.5%) (subdistribution hazard ratio (SHR), 0.35, 95% confidence interval (CI), 0.15–0.82), but it was equivalent (25.2% vs. 22.7%) in the lower-half subgroup of CD56+ cells (SHR, 1.21, 95% CI, 0.68–2.19) with a significant interaction (Pinteraction = 0.02). Although there were no significant differences, the risk of relapse was lower in the vitamin D group than in the placebo group in the higher half of CD45RO+ memory T cells (8.9% vs. 19.2%), and of CD8+ cytotoxic T cells (11.3% vs. 22.5%). In patients with digestive tract cancer, vitamin D supplementation was hypothesized to reduce the risk of relapse in the subgroup of patients who already have an adequate infiltration of immune cells in their tumor stroma.

The first coronavirus 2019 (COVID-19) patients were reported in China on December 12, 2019, and the first COVID-19 patients were reported in Japan on January 16, 2020. Here, we investigated the number of patients in Emergency Departments (EDs) in three major hospitals in Tokyo, and also briefly discussed about the relationship between the number of patients in EDs and health system’s capacity. We compared the number of patients in 2020 to the average number of patients from 2016 to 2019. Numbers were compared in three periods: before the first COVID-19 patient was reported in Japan (January 1 to January 16), after the government encouraged social distancing (February 26 to March 10), and the interval between them (January 17 to February 25). The average number of daily patients in 2020 (n = 122) decreased by 17% compared to the average number of patients from 2016 to 2019 (n = 144) (Mann-Whitney test,p

Propolis is a natural product collected from several plants by honeybees and mixed with beeswax and salivary enzymes. In animal models, propolis suppressed IgE-mediated allergies. However, there is no clinical evidence that propolis prevents human atopic sensitization, to the best of our knowledge. Therefore, a randomized, double-blind, placebo-controlled trial was conducted to assess whether propolis supplementation for lactating women increases or decreases the level of total IgE and antigen-specific IgE in the serum of their offspring (i.e., atopic sensitization) at the time of their first birthday. In addition, whether propolis supplementation improves or worsens nonspecific symptoms (e.g., eczema) in the lactating women and their offspring was also investigated. This trial is registered with UMIN000020794. Eligible pairs of mothers and their offspring (n=80) were randomized to two groups: propolis (n=40) and placebo (n=40). Participants were evaluated every month, and 31 (78%) of the propolis group and 23 (58%) of the placebo group underwent blood tests at the first birthday of the offspring. Total IgE ≥ 10 UA/ml was seen in 26 (84%) infants whose mothers were given propolis, which was not significantly different from the 19 (86%) given placebo (P=0.80). Total IgE as a continuous variable was not significantly different between the propolis and placebo groups (P=0.70). Antigen-specific IgE levels for mites, egg white, cow’s milk, and wheat, as both dichotomous and continuous variables, were not significantly different between the two groups. Both in mothers and their offspring, there were no significant differences in the subjective improvements of nonspecific symptoms between the two groups. Except for one mother who had transient and mild nausea, none of the other mothers or their offspring developed severe adverse events during the follow-up period. In conclusion, compared with placebo, Brazilian propolis supplementation did not influence the risk of atopic sensitization in infants and neither did it improve nor worsen nonspecific symptoms in either mothers or their infants.

Background and Aims Many patients with sigmoid volvulus are old with co-morbidities, making elective surgery prohibitive. Colonoscopic management is often successful but volvulus often recurs. We devised a method of colonoscopy-assisted percutaneous sigmoidopexy as an alternative method to prevent recurrence of sigmoid volvulus. This study aimed to assess its safety and effectiveness. Methods Patients with sigmoid volvulus American Society of Anesthesiologists physical status classification ≥3 or Barthel index Results Eight patients received colonoscopy-assisted sigmoidopexy, and no sigmoid volvulus recurred during the 12-month follow-up period. One case of postoperative subcutaneous emphysema was successfully managed with conservative therapy. Conclusion Colonoscopy-assisted sigmoidopexy was an effective, safe alternative method to prevent the recurrence of sigmoid volvulus.

BackgroundPosttransplant anemia (PTA) is associated with the progression of kidney disease and mortality in kidney transplant recipients. Although the main causes of PTA are recipient factors, donor factors have not been fully investigated. In this study we investigated the association of donor pathological findings with the incidence of PTA in kidney transplant recipients after 3 years of transplantation.MethodsWe conducted a retrospective cohort study at a single university hospital. A total of 50 consecutive adult recipients and donors were enrolled. To assess the structure of interstitial lesions, immunohistochemical staining of interstitial fibrosis and fibroblasts were assessed in 0-h biopsies for quantitative analysis.ResultsThe incidence of PTA in this cohort was 30%. The mean hemoglobin (Hb) was 11.6 ± 0.8 g/dL in patients with PTA and 14.3 ± 1.5 g/dL in patients without PTA. An inverse association was observed in biopsies between interstitial fibrosis area and interstitial fibroblast area (P ConclusionsThe presence of interstitial fibroblasts in donor kidneys may play an important role in predicting the incidence of PTA.

BACKGROUND Acute respiratory events (ARE) occasionally occur during induction chemotherapy as a complication in patients with advanced neuroblastoma. AIMS The present study aimed to identify the predictive factors of ARE, defined as severe hypoxia, during initial induction chemotherapy in patients with newly diagnosed advanced neuroblastoma. METHODS AND RESULTS The medical records of 75 consecutive patients in whom stage III or IV neuroblastoma was newly diagnosed between January 2003 and December 2018 at two medical institutions were retrospectively reviewed. The outcome was ARE, which were assessed by measuring oxygen saturation between days 1 and 14 of initial induction chemotherapy. Severe hypoxia was defined as grade 3 or higher according to the Common Terminology Criteria for Adverse Events version 4 (CTCAE v4.0) or decreased oxygen saturation at rest (e.g., pulse oximeter

Marked differences in COVID-19 mortalities have been observed among 47 prefectures in Japan. Here, we explored associations between COVID-19 mortalities and medical and public health capacities in individual prefectures. The following data by prefecture were abstracted from open resources provided by the Ministry of Health, Labour and Welfare in Japan as of May 24, 2020: total number of COVID-19 deaths; polymerase chain reaction (PCR)-positive ratio (i.e., number of patients with PCR-positive results/number of patients aiming diagnosis of COVID-19 or individuals in close contacted with COVID-19 patients); number of call centers, outpatient centers, and hospital beds specifically for patients diagnosed with COVID-19; and others. The primary outcome was COVID-19 mortality per million population. Multiple and simple linear regression models were applied. Two variables were significantly associated with COVID-19 mortality: PCR-positive ratio (P P = 0.001). PCR-positive ratio was positively associated with COVID-19 mortality (aR-sqr = 0.522). Low PCR-positive ratio, especially ≤ 4%, was associated with low COVID-19 mortality. Critical care medical centers may also play an important role in reducing the risk of COVID-19 death.

Supplemental Digital Content is available in the text., Objectives: It is still not known why cases of coronavirus disease 2019 during the first wave in Tokyo have fallen without lockdown restrictions. People with low socioeconomic status are not dominant among coronavirus disease 2019 patients in Tokyo in contrast with New York, where the opposite demographics have been in play. Thus, we set out to examine the association between socioeconomic status and the rate of coronavirus disease 2019 infections using public data from Tokyo. Design: We obtained data from each of the 23 wards of Tokyo, showing population size, density, age, sex, number of graduates, income, and hospital attendance numbers. Coronavirus disease 2019 infections were gathered for 2 separate days: April 9, 2020, when new daily coronavirus disease 2019 infections were at their peak during the first wave in Japan; and May 9, 2020, to observe any changes in incidence over the preceding month. Setting: The primary outcome was set as the number of coronavirus disease 2019 infections per 100,000 population. Interventions: None. Measurements and Main Results: By conducting simple linear regression modeling, the incidence of cases on April 9 was associated significantly with four variables: population age greater than 65 years (%), university rate, hospital, and income. Using these four variables, multivariate linear regression analyses demonstrated that only income remained significant (p = 0.006 at April 9 and p = 0.03 at May 9). This indicates that the highest case numbers were dominant in high-income areas, and affected fewer patients in districts in the low-income areas. Conclusions: The result of the current study is exactly opposite to the data from New York. This may be considered one of the main reasons why the rate of death and new patients of coronavirus disease 2019 has been so low in Tokyo. That is, appropriate hygienic status, free access to hospital by ambulance, and universal health insurance system may contribute to the outcome in such low-income areas.

Ecological studies have suggested fewer COVID-19 morbidities and mortalities in Bacillus Calmette&ndash, Gu&eacute, rin (BCG)-vaccinated countries than BCG-non-vaccinated countries. However, these studies obtained data during the early phase of the pandemic and did not adjust for potential confounders, including PCR-test numbers per population (PCR-tests). Currently&mdash, more than four months after declaration of the pandemic&mdash, the BCG-hypothesis needs reexamining. An ecological study was conducted by obtaining data of 61 factors in 173 countries, including BCG vaccine coverage (%), using morbidity and mortality as outcomes, obtained from open resources. &lsquo, Urban population (%)&rsquo, and &lsquo, insufficient physical activity (%)&rsquo, in each country was positively associated with morbidity, but not mortality, after adjustment for PCR-tests. On the other hand, recent BCG vaccine coverage (%) was negatively associated with mortality, but not morbidity, even with adjustment for percentage of the population &ge, 60 years of age, morbidity, PCR-tests and other factors. The results of this study generated a hypothesis that a national BCG vaccination program seems to be associated with reduced mortality of COVID-19, although this needs to be further examined and proved by randomized clinical trials.

BackgroundA 2017 meta-analysis of data from 25 randomised controlled trials of vitamin D supplementation for the prevention of acute respiratory infections revealed a protective effect of the intervention. Since then, 20 new RCTs have been completed.MethodsSystematic review and meta-analysis of data from randomised controlled trials (RCTs) of vitamin D for ARI prevention using a random effects model. Pre-specified sub-group analyses were done to determine whether effects of vitamin D on risk of ARI varied according to baseline 25-hydroxyvitamin D (25[OH]D) concentration or dosing regimen. We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science and the ClinicalTrials.gov registry from inception to 1st May 2020. Double-blind RCTs of supplementation with vitamin D or calcidiol, of any duration, were eligible if they were approved by a Research Ethics Committee and if ARI incidence was collected prospectively and pre-specified as an efficacy outcome. Aggregate data, stratified by baseline 25(OH)D concentration, were obtained from study authors. The study was registered with PROSPERO (no. CRD42020190633).FindingsWe identified 45 eligible RCTs (total 73,384 participants). Data were obtained for 46,331 (98.0%) of 47,262 participants in 42 studies, aged 0 to 95 years. For the primary comparison of vitamin D supplementation vs. placebo, the intervention reduced risk of ARI overall (Odds Ratio [OR] 0.91, 95% CI 0.84 to 0.99; P for heterogeneity 0.01). No statistically significant effect of vitamin D was seen for any of the sub-groups defined by baseline 25(OH)D concentration. However, protective effects were seen for trials in which vitamin D was given using a daily dosing regimen (OR 0.75, 95% CI 0.61 to 0.93); at daily dose equivalents of 400-1000 IU (OR 0.70, 95% CI 0.55 to 0.89); and for a duration of ≤12 months (OR 0.82, 95% CI 0.72 to 0.93). No significant interaction was seen between allocation to vitamin D vs. placebo and dose frequency, dose size, or study duration. Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (OR 0.97, 95% CI 0.86 to 1.09). Risk of bias within individual studies was assessed as being low for all but three trials. A funnel plot showed left-sided asymmetry (P=0.008, Egger’s test).InterpretationVitamin D supplementation was safe and reduced risk of ARI, despite evidence of significant heterogeneity across trials. Protection was associated with administration of daily doses of 400-1000 IU vitamin D for up to 12 months. The relevance of these findings to COVID-19 is not known and requires investigation.FundingNone

In high-risk neuroblastoma, the presence of an MYCN gain/amplification (MYCN-GA) is not always a risk factor of cancer-specific death. We herein examined the effect modification of high-dose chemotherapy with autologous hematopoietic stem cell rescue (HDC-autoSCR) in terms of the interaction between MYCN status and remission status (complete remission or very good partial remission [CR/VGPR] vs. partial remission or less [≤PR]). The present study recruited patient data from 1992 to 2017 in the Japan Society of Hematopoietic Cell Transplantation’s national registry. The MYCN status was known in 586 of 950 patients with a single course of HDC-autoSCR. Cumulative hazard curves for neuroblastoma-specific death showed that a subgroup with MYCN-GA and ≤PR had a significantly poorer prognosis than three other subgroups, namely, the MYCN-NGA/ ≤ PR, MYCN-NGA/CR/VGPR, and MYCN-GA/CR/VGPR subgroups even after adjusting for non-infants and stage IV disease (hazard ratio: 2.79; 95% confidence interval: 1.91–4.09; P

Background Placement of feeding jejunostomy (PFJ) during esophagectomy is an effective method to maintain adequate nutrition, but is associated with serious complications such as bowel obstruction and jejunal torsion. The purpose of the current study was to analyze the incidence, clinical features, and risk factors of bowel obstruction associated with feeding jejunostomy (BOFJ) after PFJ. Methods This was a retrospective cohort study of 70 patients who underwent esophagectomy with three-field lymph node dissection for esophageal cancer and treated with PFJ between March 2013 and December 2019 in our hospital. Abdominal dissection was performed under hand-assisted laparoscopic surgery (HALS) from March 2013 to March 2015, and was changed to complete laparoscopic surgery in April 2015. We compared patients with and without BOFJ, and the incidence of BOFJ was evaluated. The primary endpoint was incidence of BOFJ after PFJ. Results Six patients (8.5%) were diagnosed with BOFJ, all of whom were symptomatic and in the HALS group. In addition, 3 cases displayed histories of recurrent BOFJ (3, 3, and 5 times). Laparotomy was performed in all cases. Subgroup analysis of the HALS group showed a significant difference only in straight-line distance between the jejunostomy and navel as a significant pre- and perioperative factor (117 mm [101–130 mm] vs. 89 mm [51–150 mm], p p = 0.010), not HD (48 mm [40–59 mm] vs. 46 mm [22–60 mm], p = 0.199). Conclusions VD between the jejunostomy and navel was associated with BOFJ after PFJ with HALS esophagectomy. PFJ

Clinical evidence suggesting the beneficial effects of vitamin D on survival of patients with cancer has been accumulating. Recent articles were thoroughly reviewed to determine if there is enough evidence to conclude that vitamin D supplementation improves survival of patients with cancer. Meta-analyses of observational studies showed that higher blood 25-hydroxyvitamin D levels in patients with cancer at a variety of sites were associated with lower cancer-specific and overall mortalities. Moreover, meta-analyses of randomized clinical trials (RCTs) also suggested that vitamin D supplementation improved the survival of patients with cancer. However, each RCT used in these meta-analyses, as well as very recent RCTs, e.g., the SUNSHINE and the AMATERASU trial, did not show statistical significance in the primary results. For now, compelling evidence that vitamin D supplementation effectively improves survival of patients with cancer is lacking. Thus, confirmatory RCTs are still obligatory for the future.