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There is an ongoing controversy regarding the necessity of single-photon emission computed tomography (SPECT) for patients with ischemic heart diseases after the publication of the results of the ISCHEMIA trial. We aimed to evaluate the association of the extent of myocardial ischemia with outcomes in patients with suspected coronary artery disease in Japan.From the data of 2780 patients with stable angina who were enrolled prospectively between January 2006 and March 2008 in Japan and had undergone physician-referred non-invasive imaging tests (Japanese Coronary-Angiography or Myocardial Imaging for Angina Pectoris Study), 1205 patients managed with SPECT were stratified by 10 % myocardial ischemia. Major adverse cardiac events (MACEs), including death, myocardial infarction, hospitalization for heart failure, and late revascularization, were followed-up for 1 year.Patients with ≥10 % myocardial ischemia (n = 173) were less likely to be women than patients with10 % myocardial ischemia (n = 1032) and had a significantly higher 1-year cumulative incidence of MACEs (6.9 % vs. 1.8 %, p 0.0001). After adjusting for confounders, the risk of ≥10 % myocardial ischemia relative to10 % myocardial ischemia for MACEs remained significant [adjusted hazard ratio (95 % confidence interval), 2.40 (1.09-5.26), p = 0.029]. After adjusting including treatments, the risk of MACEs became insignificant between the ≥10 % myocardial ischemia group and the10 % myocardial ischemia group [adjusted hazard ratio (95 % confidence interval), 1.04 (0.45-2.45), p = 0.92].The presence of ≥10 % myocardial ischemia at diagnosis was significantly associated with the 1-year risk for MACEs in Japanese patients with suspected coronary artery disease.

Purpose To establish minimal important differences (MIDs) for the European Organisation for Research and Treatment for Cancer Quality of life Questionnaire core 30 (EORTC QLQ-C30) in patients with metastatic breast cancer. Methods The dataset was obtained from the SELECT BC-CONFIRM randomized clinical trial. Anchors obtained from patients (transition items) and clinicians (performance status) were used for anchor-based methods. Anchors obtained through 6 months after starting treatment were used for this analysis. Correlation coefficients of anchor and change in QLQ-C30 and effect size were used to qualify for estimating MIDs. Mean change method and generalized estimating equation were applied to estimate MIDs. Distribution-based methods were used for comparison. Results We analyzed a dataset of 154 metastatic breast cancer patients. MIDs were estimated in 8 of 15 scales of QLQ-C30. Estimated MIDs for within-group improvement varied from 7 to 15 and those for deterioration varied from − 7 to − 17. Estimated MIDs for between-group improvement varied from 5 to 11 and those for deterioration varied from − 5 to − 8 across QLQ-C30 scales. Patient-reported anchors were more susceptible to early changes in health status than clinician-reported anchors. Conclusion We provided the MIDs of the QLQ-C30 using both patient- and clinicians-reported anchors measured in a randomized trial of Japanese patients with metastatic breast cancer. We recommend patient-reported anchors for anchor-based estimation of MID. Our results can aid patients and clinicians, as well as researchers, in the interpretation of QLQ-C30.

PURPOSE We report findings on quality of life (QoL) in the RESPECT trial, which compared adjuvant trastuzumab monotherapy with trastuzumab plus chemotherapy in older patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC). PATIENTS AND METHODS Patients age 70-80 years with human epidermal growth factor receptor 2-positive surgically treated breast cancer were randomly assigned to receive trastuzumab (T) or trastuzumab plus chemotherapy (T + C). QoL was assessed using the Functional Assessment of Cancer Therapy-General (FACT-G), Philadelphia Geriatric Center Morale Scale, Hospital Anxiety and Depression Scale, Patient Neurotoxicity Questionnaire, and Tokyo Metropolitan Institute of Gerontology Index of Competence at baseline and after 2, 12, and 36 months. Comparisons were based on individual changes from baseline and were performed by Fisher’s test or mixed-model repeated-measures. RESULTS Among 275 patients in the parent study, 231 (84%) (average age: 74 years) were included in the analysis. At 2, 12, and 36 months, 198, 177, and 178 patients completed surveys, and the mean FACT-G scores at each survey point were 78.9, 80.4, 82.7, and 79.1 in group T and 79.5, 74.5, 78.4, and 78.5 in group T + C. Compared with group T + C, the proportion of patients showing QoL deterioration (≥ 5 points decrease from baseline in FACT-G) was significantly lower at 2 months (31% v 48%; P = .016) and 12 months (19% v 38%; P = .009). In group T, the Hospital Anxiety and Depression Scale score ( P = .003) and the proportion of severe sensory peripheral neuropathy ( P = .001) were significantly lower at 2 months, and Philadelphia Geriatric Center Morale Scale and Tokyo Metropolitan Institute of Gerontology Index of Competence scores were significantly higher ( P = .024, .042) at 12 months. At 36 months, there were no significant differences in any QoL items. CONCLUSION Detrimental effects of adjuvant chemotherapy on global QoL, morale, and activity capacity lasted for at least 12 months but were not observed at 36 months.

To identify predictors for incident fractures in patients on pharmaceutical treatment for osteoporosis by a secondary analysis of the Japanese Osteoporosis Intervention Trial protocol number 4 (JOINT-04), which was a 2-year, randomized, parallel-group, controlled trial of minodronate and raloxifene in women with primary osteoporosis. This was a prospective, observational study using JOINT-04 data, in which biomarkers, such as undercarboxylated osteocalcin (ucOC), N-telopeptide of type 1 collagen, tartrate-resistant acid phosphatase 5b (TRACP-5b), bone alkaline phosphatase, homocysteine, and pentosidine in blood, and physical functions, such as the timed up and go test and one-leg standing test with eyes open (OLST), and the fall risk index, were measured. The relationships of incident morphometric vertebral fractures during the treatment period, as well as prevalent vertebral fractures, and baseline data were analyzed. The full analysis set of the JOINT-04 included 3247 patients (1623 in the minodronate group and 1624 in the raloxifene group). The hazard ratio (95% confidence interval) for incident vertebral fractures over 2 years of pharmacotherapy, adjusted for confounders, was 0.93 (0.90–0.96) for ucOC, 1.15 (1.08–1.23) for TRACP-5b, 1.02 (1.01–1.03) for pentosidine, 0.91 (0.88–0.94) for the OLST, and 1.27 (1.01–1.60) for the fall risk index, which were all independent predictors. Evaluating fracture risk for patients with osteoporosis considering these potential risk factors for fracture in addition to the established risk factors may be useful when starting pharmaceutical treatment.

Cardiovascular complications of coronavirus disease 2019 (COVID-19) are critical for prognosis but have not been elucidated in Japan.Methods and Results:The COVID-19 Registry Japan, which included data from 19,853 individuals at the end of 2020, was analyzed. The incidences of cardiovascular complications were 0.098% for myocarditis/pericarditis/cardiomyopathy, 0.48% for ventricular tachycardia/fibrillation, 0.17% for myocardial ischemia, 0.062% for endocarditis, 0.59% for deep vein thrombosis, 0.19% for pulmonary embolism, and 0.37% for cerebral infarction/hemorrhage. Excluding endocarditis, all complications were associated with increased in-hospital mortality.Cardiovascular complications of COVID-19 were infrequent in Japan but were associated with poor prognosis.

Few studies have evaluated the therapeutic effect of long-term cardiac rehabilitation (CR) and no large-scale survey of cardiovascular outcomes after long-term CR is reported.This cohort study included 9981 patients undergoing CR from 2004 to 2015. Patients who had supervised CR were divided into three groups according to CR duration: up to acute phase (until discharge, Phase I group), up to recovery phase (≤150 days, Phase II group), and up to maintenance phase (150 days, Phase III group). Using propensity score matching, mortality and major adverse cardiovascular events (MACE) were compared among the groups.Follow-up period was 4.9 ± 3.0 years. Adult patients were divided into three groups (Phase I group: n = 4649, Phase II group: n = 3271, and Phase III group: n = 731). After propensity score matching, the risk of death and MACE was extremely lower in Phase III group than in Phase I or Phase II group (death: HR 0.47, P 0.01, HR 0.64, P 0.01, and MACE: HR 0.48, P 0.01, HR 0.70, P 0.01). Most patients in Phase II group had better survival than those in Phase I group. Subpopulations of female patients and those with dyslipidemia, smoking history, coronary artery bypass graft, or heart failure had better survival in Phase III group than in Phase II group.Long-term supervised CR for patients with cardiovascular diseases is more effective than short-term CR.

Background Chemotherapy-induced amenorrhea (CIA) is one of the critical side effects from the chemotherapy in premenopausal patients with breast cancer. The goals of our study are the following: (1) to investigate the factors affecting the incidence of CIA; and (2) to evaluate the prognostic role of CIA in premenopausal patients with breast cancer. Methods We conducted a post hoc retrospective substudy to examine the incidence of the CIA and the relationship between CIA and prognosis in NSAS-BC02 that compared taxane alone to Doxorubicin(A) Cyclophosphamide(C) followed by taxane in postoperative patients with node-positive breast cancer Results Of 395 premenopausal women, 287 (72.7%) had CIA due to protocol treatment. Regarding type of protocol regimen, proportion of CIA was 76.9% in AC Paclitaxel(P), 75.2% in AC Docetaxel(D), 62.8% in PTX, and 75.2% in DTX. Predictive factors of CIA were age increase by 5 years (OR 1.50), ER positivity (OR 2.08), and HER2 3 + ( OR 0.40) according to logistic regression analysis. According to the log rank test and the Cox proportional hazards model, CIA group had significantly better disease-free survival than non-CIA group (P Conclusion Treatment with taxane alone caused high frequency of CIA in premenopausal women with breast cancer. CIA did not turn out to be an independent prognostic factor, taking guarantee-time bias into consideration. Further clinical studies are needed to validate these findings.

Background The effectiveness of a therapeutic strategy that switches chemotherapy, based on Ki-67 tumour expression after initial therapy, relative to that of standard chemotherapy, has not been evaluated. Methods Patients were randomly assigned to the control arm or the Ki-67 response-guided arm (Ki-67 arm). Primary tumour biopsies were obtained before treatment, and after three once-weekly doses of paclitaxel and trastuzumab to assess the interim Ki-67 index. In the control arm, paclitaxel and trastuzumab were continued for a total of 12 doses, regardless of the interim Ki-67 index. In the Ki-67 arm, subsequent treatment was based on the interim Ki-67 index. Ki-67 early responder is defined as the absolute Ki-67 value that was 30% compared with before treatment. Early Ki-67 responders continued to receive the same treatment, while early Ki-67 non-responders were switched to epirubicin plus cyclophosphamide. The primary endpoint was the pathological complete response (pCR) rate. Results A total of 237 patients were randomised. There was almost linear correlation between the Ki-67 reduction rate at interim assessment and the pCR rate. The pCR rate in Ki-67 early non-responders in the Ki-67 arm was inferior to that in the control arm (44.1%; 31.4–56.7; P = 0.025). Conclusions The standard chemotherapy protocol remains as the recommended strategy for patients with HER2-positive breast cancer. Clinical trial registration Clinical Trial Registration: UMIN-CTR as UMIN000007074.

We aimed to evaluate the prognostic impact of pulmonary dysfunctions and their relationships with other possible prognostic factors, especially sarcopenia, in elderly patients with gastric carcinoma (GC). In total, 402 elderly GC patients (≥ 75 years) who underwent radical gastrectomy were retrospectively reviewed. Restrictive and obstructive pulmonary dysfunction were defined as %VC

Assessment of preoperative physiological status is crucial for optimizing clinical outcomes in patients undergoing surgery for esophageal carcinoma (EC). We aimed to evaluate the prognostic impact of pulmonary dysfunctions and their relationships with other physiological factors, especially sarcopenia, in EC patients receiving esophagectomy. In total, 411 EC patients who underwent esophagectomy between 2006 and 2016 were retrospectively reviewed. Preoperative pulmonary functions were evaluated based on %vital capacity (%VC) and forced expiratory volume (FEV) 1.0%. The thresholds were set as the lowest quartile (99% for %VC and 68.6% for FEV1.0%) in this cohort. One hundred and two patients (24.8%) had low %VC (%VC

SUMMARYBackgroundWhile mRNA vaccines against SARS-CoV-2 have been exceedingly effective in preventing symptomatic viral infection, the features of immune response remain to be clarified.MethodsIn the present prospective observational study, 225 healthy individuals in Kumamoto General Hospital, Japan, who received two BNT162b2 doses in February 2021, were enrolled. Correlates of BNT162b2-elicited SARS-CoV-2-neutralizing activity (50% neutralization titer: NT50; assessed using infectious virions and live target cells) with SARS-CoV-2-S1-binding-IgG and -IgM levels, adverse effects (AEs), ages, and genders were examined. The average half-life of neutralizing activity and the average time length for the loss of detectable neutralizing activity were determined and the potency of serums against variants of concerns was also determined.FindingsSignificant rise in NT50s was seen in serums on day 28 post-1st dose. A moderate inverse correlation was seen between NT50s and ages, but no correlation was seen between NT50s and AEs. NT50s and IgG levels on day 28 post-1st dose and pain scores following the 2nd shot were greater in women than in men. The average half-life of neutralizing activity in the vaccinees was approximately 67.8 days and the average time length for their serums to lose the detectable neutralizing activity was 198.3 days. While serums from elite-responders (NT50s>1,500-fold: the top 4% among all participants’ NT50s) potently to moderately blocked the infectivity of variants of concerns, some serums with moderate NT50s failed to block the infectivity of a beta strain.InterpretationBNT162b2-elicited immune response has no significant association with AEs. BNT162b2-efficacy is likely diminished to under detection limit by 6-7 months post-1st shot. High-level neutralizing antibody-containing serums potently to moderately block the infection of SARS-CoV-2 variants; however, a few moderate-level neutralizing antibody-containing serums failed to do so. If BNT162b2-elicited immunity memory is short, an additional vaccine or other protective measures would be needed.Research in contextEvidence before this studyWhile mRNA vaccines against SARS-CoV-2 have been exceedingly effective in preventing symptomatic viral infection, the salient features of immune response including the persistence of protection remain to be clarified. There is a report that anti-SARS-CoV-2 antibodies persist through 6 months after the second dose of mRNA-1273 vaccine (Doria-Roseet al. N Engl J Med. 2021;384:2259-2261); however, more definite immune kinetics following mRNA-vaccine-elicited protection have to be clarified. The mRNA-vaccine-elicited protection against SARS-CoV-2 variants are also to be determined.Added value of this studyIn the present prospective study, 225 twice-BNT162b2-dose-receiving individuals in Japan were enrolled. No significant correlation was seen between 50% neutralizing titers (NT50s), determined by using infectious SARS-CoV-2 virions and live target cells, and adverse effects. Largely, NT50s and IgG levels were greater in women than in men. Following 28 days post-2ndshot, significant reduction was seen in NT50s, IgG, and IgM levels. The average half-life of NT50s was ∼68 days and the average time-length for participants’ serums to lose the detectable activity was ∼198 days. Although serums from elite-responders potently to moderately blocked the infectivity of variants of concerns, some serums with moderate NT50s failed to block the infectivity of a beta strain.Implications of all the available evidenceBNT162b2 efficacy is likely to be diminished to under detection limit by 6-7 months post-1stshot on average. Individuals with moderate NT50s may fail to block beta variants. If BNT162b2-elicited immune memory is lost soon, additional vaccine(s) or other protective means would be needed.

Background Due to the lack of clinical trials on the efficacy of chemotherapy in older patients, an optimal treatment strategy has not been developed. We investigated whether adjuvant chemotherapy could improve the survival of older patients with breast cancer in Japan. Methods We retrospectively analyzed data of patients with breast cancer aged ≥ 70 years who underwent breast cancer surgery in eight hospitals between 2008 and 2013. Clinical treatment and follow-up data were obtained from the patients’ medical electric records. Results A total of 1095 patients were enrolled, of which 905 were included in the initial non-matched analysis. The median age and follow-up period were 75 (range 70–93) and 6.3 years, respectively. Of these patients, 127 (14%) received adjuvant chemotherapy (Chemo group) while the remaining 778 (86%) did not (Control group). The Chemo group was younger (mean age in years 73 vs 76; P P P P = 0.783 and P = 0.558). After matched analyses, DFS was found to be significantly prolonged with adjuvant chemotherapy (P = 0.037); however, OS difference in the matched cohort was not statistically significant (P = 0.333). Conclusion The results showed that adjuvant chemotherapy was associated with a reduced risk of recurrence, but survival benefits were limited.

Japanese postmenopausal women with symptomatic periodontal disease had a significantly smaller increase in the T-score for total hip bone density than those without periodontal disease during medication therapy for osteoporosis. Intervention to treat symptomatic periodontal disease before and/or during osteoporosis therapy could maintain the effect of osteoporosis medications.Women with periodontal disease may be more likely to develop osteoporosis. We evaluated whether the presence of symptomatic periodontal disease can influence changes in skeletal bone mineral density (BMD) during medication therapy for osteoporosis in Japanese postmenopausal women.A total of 4,258 postmenopausal women participated in the Japanese Osteoporosis Intervention Trial protocol number 4 (JOINT-04 trial) and number 5 (JOINT-05 trial), which were multi-center, open-label, randomized controlled trials in Japan. Of these, 3,670 non-edentulous subjects participated in the study. Subjects who had self-reported symptoms of periodontal disease at baseline were defined as having periodontal disease. The study outcome was the difference in BMD changes during the study between subjects with and without periodontal disease. Mixed models for repeated measures after adjusting for covariates were used to investigate the difference in the BMD changes during the study between subjects with and without periodontal disease.Subjects with periodontal disease had significantly lower T-scores for total hip (p = 0.035) and metacarpal (p = 0.048) BMD than those without periodontal disease at baseline. During medication therapy for osteoporosis, subjects with periodontal disease had a significantly smaller increase in T-score for total hip BMD than those without periodontal disease (p = 0.021), although no significant differences were observed in the changes in T-scores for other skeletal BMD measurements between subjects with and without periodontal disease.The presence of self-reported symptoms of periodontal disease may be associated with a decrease in the effect of osteoporosis medications in Japanese postmenopausal women.

Background We have previously demonstrated S-1 is non-inferior to taxane with respect to overall survival as first-line chemotherapy for HER2-negative metastatic breast cancer. We aimed to confirm whether S-1 is also non-inferior to anthracycline-containing regimens in the same setting. Methods We conducted an open-label, non-inferiority, Phase 3 study. Individuals who had HER2-negative metastatic breast cancer, had received no chemotherapy for advanced disease and had endocrine therapy resistance, were randomly assigned to the anthracycline-containing regimens or S-1. The primary endpoint was overall survival. A pre-planned combined analysis of our two Phase 3 studies was also carried out. Results We enrolled 230 patients (anthracycline, n = 115; S-1, n = 115). Median overall survival was 30.1 months (95% CI 24.9-35.8) with the S-1 group and 33.7 months (95% CI 25.5-36.9) with the anthracycline group. The HR for the anthracycline group was 1.09 (95% CI 0.80-1.48). The combined analysis constituted 814 patients (395 assigned to standard treatment (anthracycline or taxane); 419 assigned to S-1). Median overall survival was 36.3 months in the standard treatment group and 32.7 months in the S-1 group. S-1 was non-inferior to standard treatment in terms of overall survival (HR 1.06 (95% CI 0.90-1.25); P non-inferiority = 0.0062). Conclusions S-1 could be considered a new treatment option for first-line chemotherapy for patients with HER2-negative metastatic breast cancer. Clinical trial registration The University Hospital Medical Information Network, Japan: UMIN000005449. This trial was registered on 15 April, 2011.

While some studies show improved outcomes in clinical trial participants as compared to non-participants, existence of such a trial effect has not been proved precisely. This was a prospective cohort study to compare the prognoses for participants in the randomized controlled trial (SELECT BC) and non-participants. SELECT BC compared S-1 and taxane as first-line treatment for metastatic breast cancer. Non-participants were all patients who met the eligibility criteria of SELECT BC and who had been requested to participate in that trial by attending doctors and declined. The study aimed to compare the prognoses between participants and non-participants. The primary endpoint was median overall survival. The median OS in participants was significantly superior to that in non-participants with a statistically significant difference (36.8 months vs. 25.2 months. HR 1.48, p = 0.022). A similar result was obtained when only patients who received the same chemotherapy (S-1 or taxane) used in SELECT BC after declining participation were assumed as non-participants (36.8 months vs. 22.0 months. HR 2.03, p = 0.006). This study may suggest the existence of a trial effect, in which, for a given treatment, participation in a clinical trial is associated with a better outcome.

To investigate the immediate effects of thoracic spine self-mobilization in patients with mechanical neck pain.Randomized, controlled trial.Thoracic spine self-mobilization is performed after thoracic spine thrust manipulation to augment and maintain its effects. To the best of our knowledge, no study has investigated the effects of thoracic spine self-mobilization alone in individuals with mechanical neck pain. The purpose of this randomized, controlled trial was to evaluate the immediate effects of thoracic spine self-mobilization alone without any other intervention on disability, pain, and cervical range of motion in patients with mechanical neck pain.Fifty-two patients (39 females and 13 males) with mechanical neck pain were randomly allocated to either a thoracic spine self-mobilization group that was performing a thoracic spine active flexion and extension activity using two tennis balls fixed by athletic tape or a placebo thoracic spine self-mobilization group. Outcome measures were collected at pre-intervention and immediately after intervention, including the Neck Disability Index, visual analogue scale, and active cervical range of motion (ROM). The immediate effect of the intervention was analyzed using two-way repeated measures analysis of variance (ANOVA). If interactions were found, a simple main effect test was performed to compare the pre-post intra-group results.The results of two-way repeated measures ANOVA indicated that the main effect of time was significant (p 0.05) for all measurement outcomes. The main effect of group was not significant for all measurement outcomes (p 0.05). The group × time interactions for cervical flexion active ROM (p = 0.005) and cervical extension active ROM (p = 0.036) were significant. The tests of simple main effect in cervical flexion active ROM (p 0.0001) and cervical extension active ROM (p 0.0001) showed a significant difference before and after intervention in the thoracic spine self-mobilization group.Patients with mechanical neck pain who carried out thoracic spine self-mobilization showed increases in active cervical flexion and extension ROM.

Chronic kidney disease (CKD) is a public health challenge; however, evidence-based, optimal follow-up intervals for patients with CKD have not been identified. This study aimed to identify appropriate follow-up intervals for different stages of CKD. We studied 2682 patients with CKD. The number of patients experiencing a 50% increase in creatinine and those reaching end-stage renal failure were examined on the basis of their CKD stage. The renal function testing interval was defined as the estimated time for 0.1% of the patients with CKD to have a composite renal outcome, after adjusting for clinical risk factors. Transitions from CKD stage-based subgroups were analyzed using parametric cumulative incidence models. Other sensitivity analyses involved estimation of the time to renal event occurrence for 1% of patients. Of the 913 patients (34%) who had a composite renal event, 29 had stage 3A (10.5%), 151 had stage 3B (16.3%), 429 had stage 4 (41.0%), and 304 had stage 5 CKD (70.9%). The estimated renal function testing intervals for patients with CKD were 6.0 months for stage 3A, 3.4 months for stage 3B, 2.0 months for stage 4, and 1.2 months for stage 5. The optimal follow-up intervals were longer for patients with lower CKD stages. These estimates are longer than those recommended by the current guidelines and serve as a reference for nephrologists in selecting an appropriate follow-up interval for each patient. UMIN clinical trial registry number: UMIN000020038.

To investigate whether postoperative adjuvant trastuzumab plus chemotherapy negatively affected cognitive functioning during the post-chemotherapy period compared with trastuzumab monotherapy in older patients with HER2-positive breast cancer. In the randomized RESPECT trial, women aged between 70 and 80 years with HER2-positive, stage I to IIIA invasive breast cancer who underwent curative operation were randomly assigned to receive either 1-year trastuzumab monotherapy or 1-year trastuzumab plus chemotherapy. Cognitive functioning was assessed using the Mini-Mental State Examination (MMSE) test at enrollment and 1 and 3 years after initiation of the protocol treatment. The primary outcome was change in the MMSE total score from baseline. Secondary outcomes included prevalence of suspected mild cognitive impairment (MMSE total score

Although intranasal oxytocin is expected to be a novel therapy for the core symptoms of autism spectrum disorder, which has currently no approved medication, the efficacy of repeated administrations was inconsistent, suggesting that the optimal dose for a single administration of oxytocin is not optimal for repeated administration. The current double-blind, placebo-controlled, multicentre, crossover trial (ClinicalTrials.gov Identifier: NCT03466671) was aimed to test the effect of TTA-121, a new formulation of intranasal oxytocin spray with an enhanced bioavailability (3.6 times higher than Syntocinon® spray, as assessed by area under the concentration–time curve in rabbit brains), which enabled us to test a wide range of multiple doses, on autism spectrum disorder core symptoms and to determine the dose–response relationship. Four-week administrations of TTA-121, at low dose once per day (3 U/day), low dose twice per day (6 U/day), high dose once per day (10 U/day), or high dose twice per day (20 U/day), and 4-week placebo were administered in a crossover manner. The primary outcome was the mean difference in the reciprocity score (range: 0–14, higher values represent worse outcomes) on the Autism Diagnostic Observation Schedule between the baseline and end point of each administration period. This trial with two administration periods and eight groups was conducted at seven university hospitals in Japan, enrolling adult males with high-functioning autism spectrum disorder. Enrolment began from June 2018 and ended December 2019. Follow-up ended March 2020. Of 109 males with high-functioning autism spectrum disorder who were randomized, 103 completed the trial. The smallest P-value, judged as the dose–response relationship, was the contrast with the peak at TTA-121 6 U/day, with inverted U-shape for both the full analysis set (P = 0.182) and per protocol set (P = 0.073). The Autism Diagnostic Observation Schedule reciprocity score, the primary outcome, was reduced in the TTA-121 6 U/day administration period compared with the placebo (full analysis set: P = 0.118, mean difference = −0.5; 95% CI: −1.1 to 0.1; per protocol set: P = 0.012, mean difference = −0.8; 95% CI: −1.3 to −0.2). The per protocol set was the analysis target population, consisting of all full analysis set participants except those who deviated from the protocol. Most dropouts from the full analysis set to the per protocol set occurred because of poor adherence to the test drug (9 of 12 in the first period and 8 of 15 in the second period). None of the secondary clinical and behavioural outcomes were significantly improved with the TTA-121 compared with the placebo in the full analysis set. A novel intranasal spray of oxytocin with enhanced bioavailability enabled us to test a wide range of multiple doses, revealing an inverted U-shape dose–response curve, with the peak at a dose that was lower than expected from previous studies. The efficacy of TTA-121 shown in the current exploratory study should be verified in a future large-scale, parallel-group trial.

Introduction The previous randomized phase 3 trial (SELECT BC) showed that S-1 as a first-line chemotherapy for metastatic breast cancer (MBC) is non-inferior to taxane with respect to overall survival. This study aimed to identify the usefulness of metabolism-related genes as predictive biomarkers for the response to S-1 compared with taxane using tumor tissue samples from the previous trial. Patients and Methods In this SELECT BC-EURECA study, 147 patients with human epidermal growth factor 2 (HER2)-negative MBC who received either S-1 or taxane were evaluated. Formalin-fixed paraffin-embedded specimens were collected, and 14 genes involved in the pyrimidine metabolic pathway, estrogen receptor, progesterone receptor, HER2, Ki67, and beta-tubulin were measured using reverse transcription polymerase chain reaction in microdissected tumor specimens. The expression of each gene was categorized as low, intermediate, and high by tertile values. Results Interaction tests to identify biomarkers for the response to S-1 compared with taxane, revealed the following as the top 3 biomarkers: RRM1 (P value = 0.24), GGH (P value = 0.25), and MTHFR (P value = 0.28). In the S-1 group, lower GGH and higher MTHFR expression were significantly correlated with better time to treatment failure. In the taxane group, there was no gene that was identified as a significant indicator of treatment failure. Conclusion This biomarker analysis from SELECT BC did not identify any predictive biomarkers for the response to S-1 compared with taxane. Future studies with larger sample size and information on not only mRNA, but also protein and DNA for broad functional analyses are needed.

PURPOSE Adjuvant trastuzumab monotherapy has not been compared with trastuzumab + chemotherapy. We investigated the relative value of trastuzumab monotherapy for older patients with breast cancer. METHODS This study was an open-label, randomized controlled study with a treatment selection design in which a noninferiority criterion was predefined. Patients aged 70-80 years with surgically treated human epidermal growth factor receptor 2–positive invasive breast cancer received trastuzumab monotherapy or trastuzumab + chemotherapy. The primary end point was disease-free survival (DFS) with assessment of prespecified hazard ratio (HR), relapse-free survival (RFS), adverse events (AEs), health-related quality of life (HRQoL), and restricted mean survival time (RMST). RESULTS The study involved 275 patients (mean age, 73.5 years) who were followed up for a mean of 4.1 years (range, 0.3-8.0 years). The percentages of patients by cancer stage were as follows: I (pT > 0.5 cm), 43.6%; IIA, 41.7%; IIB, 13.5%; and IIIA, 1.1%. Three-year DFS was 89.5% with trastuzumab monotherapy versus 93.8% with trastuzumab + chemotherapy (HR, 1.36; 95% CI, 0.72 to 2.58; P = .51). At 3 years, RMST differed by −0.39 months between arms (95% CI, −1.71 to 0.93; P = .56). Three-year RFS was 92.4% with trastuzumab monotherapy versus 95.3% with trastuzumab + chemotherapy (HR, 1.33; 95% CI, 0.63 to 2.79; P = .53). Common AEs were anorexia (7.4% v 44.3%; P < .0001) and alopecia (2.2% v 71.7%; P < .0001), and grade 3/4 nonhematologic AEs occurred in 11.9% versus 29.8% ( P = .0003) for trastuzumab monotherapy versus trastuzumab + chemotherapy, respectively. Clinically meaningful HRQoL deterioration rate showed significant differences at 2 months (31% for trastuzumab monotherapy v 48% for trastuzumab + chemotherapy; P = .016) and at 1 year (19% v 38%; P = .009). CONCLUSION The primary objective of noninferiority for trastuzumab monotherapy was not met. However, the observed loss of survival without chemotherapy was < 1 month at 3 years. Therefore, and in light of the lower toxicity and more favorable HRQoL profile, trastuzumab monotherapy can be considered an adjuvant therapy option for selected older patients.

Backgroud Changes in bone mineral density (BMD) are a potential surrogate marker for fracture endpoints in clinical trials. However little is known whether the increase in BMD in response to combination treatment with alendronate plus alfacalcidol is associated with fracture risk reduction. We aimed to evaluate the impact of BMD on fracture risk in osteoporosis patients, using the data from the randomized clinical trial comparing alendronate plus alfacalcidol with alendronate alone. Methods We selected 412 patients with two or more prevalent vertebral fractures and who had BMD measurements at baseline and after 6, 12, and/or 24 months out of 2022 patients from the database of the Japanese Osteoporosis Intervention Trial. Patients in this subset who received combination treatment with alendronate plus alfacalcidol had shown a lower risk of fracture than patients treated with alendronate alone. We used Poisson regression model analysis to calculate the proportion of treatment effect (PTE) that was attributable to BMD increases in patients receiving combination treatment. Results The highest PTE attributable to changes in BMD was 1.2% in patients with a BMD increase of 3% or more in the lumbar spine. For BMD measurements of the radius, the highest PTE was 2.8% with a BMD increase of 0% or more. For BMD measurements of the metacarpal bone, the highest PTE was 1.2% with a BMD increase of 3% or more. In patients with a BMD greater than or equal to 70% of the young adult mean in the lumbar spine, the PTE attributable to BMD was 0.2%. In patients with a BMD greater than or equal to 70% of the young adult mean in the radius, the PTE attributable to BMD was 0.3%. Conclusions The additional effects of alfacalcidol in reducing fracture risk do not likely result from increased BMD; other mechanisms remain a possibility.

There is no evidence regarding appropriate target hemoglobin levels in chronic kidney disease (CKD) patients with an erythropoiesis-stimulating agent (ESA)-hyporesponsiveness. Therefore, we conducted a randomized controlled study in non-dialysis dependent CKD (NDD-CKD) patients with ESA-hyporesponsiveness, comparing results of intensive versus conservative treatment to maintain hemoglobin levels.This was a multicenter, open-label, randomized, parallel-group study conducted at 89 institutions. Among NDD-CKD patients, those with ESA-hyporesponsive renal anemia were randomly assigned to an intensive treatment group, to which epoetin beta pegol was administered with target hemoglobin level of 11 g/dL or higher, or conservative treatment group, in which the hemoglobin levels at enrollment (within ± 1 g/dL) were maintained. The primary endpoint was the time to the first kidney composite event defined as (1) transition to renal replacement therapy (dialysis or renal transplantation); (2) reduction of estimated glomerular filtration rate (eGFR) to less than 6.0 mL/min/1.73 mBetween August 2012 and December 2015, 385 patients were registered, and 362 patients who met the eligibility criteria were enrolled. There was no significant difference in kidney survival or in CV events between the two groups. However, the incidences of the 3 types of kidney composite events tended to differ.In NDD-CKD patients with ESA-hyporesponsive renal anemia, the aggressive administration of ESA did not clearly extend kidney survival or result in a significant difference in the incidence of CV events.

We conducted a head-to-head randomized trial of minodronate, a bisphosphonate, and raloxifene, a selective estrogen receptor modulator, to obtain clinical evidence and information about their efficacy and safety. The Japanese Osteoporosis Intervention Trial protocol number 4 (JOINT-04) trial is a multi-center, open-labeled, blinded endpoints, head-to-head randomized trial of minodronate and raloxifene. Ambulatory elderly women with osteoporosis (age, >60 years) were randomly allocated to the raloxifene or minodronate group by central registration. The co-primary endpoints included any one of osteoporotic fractures (vertebral, humeral, femoral, and radial fractures), vertebral fractures, and major osteoporotic fractures (clinical vertebral, humeral, femoral, and radial fractures). The biological effects of each drug, patients’ quality of life, and drug safety were assessed based on the secondary outcomes. This study was registered at the University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR) under trial identification number UMIN000005433. A total of 3896 patients were randomized to the minodronate and raloxifene groups, and drug efficacy assessments were performed for 3247 patients (1623 and 1624 patients, respectively). Among these patients, 1176 and 1187 patients received allocated treatment for 2 years. The incidence rate ratios for osteoporotic, vertebral, and major osteoporotic fractures in the minodronate group were 0.94 (95% CI: 0.78–1.13, p = .494), 0.86 (95% CI: 0.70–1.05, p = .147), and 1.22 (95% CI: 0.86–1.74, p = .274), respectively. Compared to the raloxifene group, the minodronate group showed significantly increased bone mineral density of the lumbar spine for each visit (6 months: p = .007, 12 months: p = .0003, 24 months: p Overall, there were no statistical differences in the incidence rates of osteoporotic, vertebral, or major osteoporotic fractures between the two groups. Serious adverse reactions were rare in both groups.

Background Previous randomized-controlled trials have shown that targeting higher hemoglobin (Hb) levels using high dose of ESA in non-dialysis chronic kidney disease (NDCKD) patients resulted in poorer cardiovascular outcome; however, it remains unknown how high Hb levels achieved by ESA in clinical practice dose could affect renal outcome. Methods In a multicenter prospective observational study, Japanese NDCKD patients with an estimated glomerular filtration rate (eGFR) of ≥ 6 mL/min/1.73 m2 and renal anemia (Hb

Ameliorating effect of noisy galvanic vestibular stimulation (nGVS) on posture varies among subjects. In this feasibility study, we investigated the association between original postural instability and the ameliorating effect of nGVS on posture. Data were collected in a previously published study. Thirty healthy elderly were recruited. Two nGVS sessions (30 min or 3 h) were performed in a randomised order. The optimal intensity of nGVS, the most effective intensity for improving posture, was determined before each session. Posture was measured for 30 s during and after nGVS in the eyes-closed/foam rubber condition. The velocity, envelopment area, and root mean square of the centre of pressure movement without nGVS were significantly larger in the group with an optimal intensity than those in the group without an optimal intensity. There was a significant positive correlation between these values and the long-term ameliorating effects. The ratio of the values in the eyes-closed/foam rubber condition to those in the eyes-open condition was significantly larger in the group with an optimal intensity, and had a significant correlation with the long-term ameliorating effects. The ameliorating effects are greater in subjects who were originally unstable and in those whose postural stability was relatively independent of vestibular input.

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.

Background The current eighth tumor node metastasis lymph node category pathologic lymph node staging system for esophageal squamous cell carcinoma is based solely on the number of metastatic nodes and does not consider anatomic distribution. We aimed to assess the prognostic capability of the eighth tumor node metastasis pathologic lymph node staging system (numeric-based) compared with the 11th Japan Esophageal Society (topography-based) pathologic lymph node staging system in patients with esophageal squamous cell carcinoma. Methods We retrospectively reviewed the clinical records of 289 patients with esophageal squamous cell carcinoma who underwent esophagectomy with extended lymph node dissection during the period from January 2006 through June 2016. We compared discrimination abilities for overall survival, recurrence-free survival, and cancer-specific survival between these 2 staging systems using C-statistics. Results The median number of dissected and metastatic nodes was 61 (25% to 75% quartile range, 45 to 79) and 1 (25% to 75% quartile range, 0 to 3), respectively. The eighth tumor node metastasis pathologic lymph node staging system had a greater ability to accurately determine overall survival (C-statistics: tumor node metastasis classification, 0.69, 95% confidence interval, 0.62–0.76; Japan Esophageal Society classification; 0.65, 95% confidence interval, 0.58–0.71; P = .014) and cancer-specific survival (C-statistics: tumor node metastasis classification, 0.78, 95% confidence interval, 0.70–0.87; Japan Esophageal Society classification; 0.72, 95% confidence interval, 0.64–0.80; P = .018). Rates of total recurrence rose as the eighth tumor node metastasis pathologic lymph node stage increased, while stratification of patients according to the topography-based node classification system was not feasible. Conclusion Numeric nodal staging is an essential tool for stratifying the oncologic outcomes of patients with esophageal squamous cell carcinoma even in the cohort in which adequate numbers of lymph nodes were harvested.

To evaluate the efficacy of adjuvant systemic chemotherapy for locally advanced (pT3-4pN0/xM0) upper tract urothelial carcinoma (UTUC). We retrospectively reviewed the medical records of 109 patients with pT3-4pN0/xM0 UTUC who had undergone radical nephroureterectomy between 1996 and 2013 at our four institutions. The patients were divided into two groups: those who received adjuvant chemotherapy (AC group) and those who did not (surgery-alone: SA group). All chemotherapy regimens were cisplatin-based. Cox proportional hazards regression models addressed the associations between clinicopathological factors and recurrence-free survival (RFS) and cancer-specific survival (CSS). Forty-three (39.5%) out of the 109 patients underwent one to four cycles of adjuvant chemotherapy after nephroureterectomy. Median follow-up was 46.5 months. There were no significant differences in the background characteristics of the two groups, except for age. Recurrence developed in 11 (25.6%) and 29 (43.9%) patients in the AC and SA groups, respectively. Ultimately, six (14.0%) and 18 (27.3%) patients in the AC and SA groups, respectively, died of disease progression. On univariate analysis, hydronephrosis, nuclear grade, lymphovascular invasion, and adjuvant chemotherapy were significantly associated with both RFS and CSS. Charlson comorbidity index was associated only with CSS. On multivariate analysis, adjuvant chemotherapy was the only independent factor associated with improved RFS (p = 0.0178, HR = 0.41). Moreover, adjuvant chemotherapy (p = 0.0375, HR = 0.33), lower nuclear grade (p = 0.0070), and the absence of hydronephrosis (p = 0.0493) were independently associated with better CSS. Locally advanced (pT3-4pN0/xM0) UTUC patients who underwent cisplatin-based adjuvant chemotherapy demonstrated better RFS and CSS than those without adjuvant chemotherapy.

BACKGROUND In postoperative patients with breast cancer, the combination of an anthracycline and cyclophosphamide (AC) followed by a taxane is a standard regimen. In the current study, the authors examined whether AC could be safely omitted, and compared the effectiveness of paclitaxel versus docetaxel. METHODS Female postoperative patients with axillary lymph node‐positive breast cancer were eligible for enrollment in this phase 3, open‐label, randomized controlled trial at 84 centers in Japan. Patients were randomized to 4 cycles of doxorubicin at a dose of 60 mg/m2 and cyclophosphamide at a dose of 600 mg/m2 (AC) followed by 4 cycles of paclitaxel at a dose of 175 mg/m2 (ACpT) or AC followed by 4 cycles of docetaxel at a dose of 75 mg/m2 (ACdT), or 8 cycles of paclitaxel (PTx) or docetaxel (DTx) every 3 weeks. The primary endpoint was disease‐free survival (DFS). Secondary endpoints included overall survival adverse events. The authors adopted a 2 × 2 factorial design to examine the AC containing‐regimens (ACpT and ACdT) versus the AC free‐regimens (PTx and DTx), and the paclitaxel‐containing regimens (ACpT and PTx) versus the docetaxel‐containing regimens (ACdT and DTx). RESULTS Of 1060 patients, 1049 were treated and included in the intention‐to‐treat population. The DFS results did not demonstrate noninferiority between the AC‐containing and the AC‐free regimens (hazard ratio [HR], 1.19; 95% confidence interval [95% CI], 0.982‐1.448 [P noninferiority = .30]). Better outcomes were noted in patients treated with the docetaxel‐containing regimens compared with the paclitaxel‐containing regimens with respect to DFS (HR, 0.72; 95% CI, 0.589‐0.875 [P = .0008]) and overall survival (HR, 0.75; 95% CI, 0.574‐0.980 [P = .035]). Neutropenia, nausea, and vomiting were found to occur more often in the AC‐containing arms, whereas the incidence of edema was greater in the docetaxel‐containing treatment arms. CONCLUSIONS Noninferiority in DFS was not demonstrated between the AC‐containing and AC‐free regimens. Compared with a similar regimen of paclitaxel, docetaxel appeared to increase the DFS. Cancer 2017;123:759–68. © 2016 American Cancer Society., In postoperative patients with breast cancer, the combination of an anthracycline and cyclophosphamide followed by a taxane is a standard regimen. The results of the current phase 3 study demonstrate that noninferiority in disease‐free survival is not shown between regimens containing the combination of doxorubicin plus cyclophosphamide and those that do not, and that compared with a similar regimen of paclitaxel, docetaxel increased disease‐free survival.

As Japan has one of the most rapidly aging populations in the world, transcatheter aortic valve implantation (TAVI) is likely to be performed in increasing numbers of older people. There is little information on either the efficacy or the safety of TAVI in nonagenarians in Asia.From October 2013 to June 2015, 112 consecutive patients underwent TAVI with Edwards SAPIEN XT valves in our institution. We compared 25 patients aged at least 90 years (mean 91.6 ± 1.7 years) with 87 patients aged under 90 years (mean 82.5 ± 6.0 years) at the time of TAVI. All definitions of clinical endpoints and adverse events were based on the Valve Academic Research Consortium 2 definitions.The median follow-up interval was 561.5 days (the first and third quarters, 405.0 and 735.8 days). Nonagenarians had a higher logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE), Euro II score, and the Society of Thoracic Surgeons predictive risk of mortality (STS) score, and a prevalence of clinical frailty scale ≥ 4. The rate of device success, and the 30-day and 6-month mortalities were not different between patients aged ≥ 90 years and < 90 years (96.0% versus 92.0%, P = 0.68; both 0%, P = 1.00; 4.0% versus 3.5%, P = 0.32, respectively). At six months, clinical efficacy and time-related valve safety were also similar in the two groups (12.5% versus 13.4%, P = 1.00; 4.5% versus 10.3%, P = 0.68, respectively). The cumulative 1-year mortalities were not significantly different between the two groups (8.4% versus 9.4%, P = 0.94, respectively).TAVI can contribute to acceptable clinical results and benefits in a carefully selected group of nonagenarians in Asia.

Although both sarcopenia and systemic inflammation reportedly affect long-term outcomes of esophageal carcinoma (EC) patients, their reciprocal associations with survival outcomes have yet to be investigated. This study aimed to evaluate the survival impact of sarcopenia combined with the neutrophil-to-lymphocyte ratio (NLR) in EC patients undergoing esophagectomy.In total, 378 EC patients were retrospectively reviewed. The cutoff value for NLR was set at the NLR median of the cohort. Sarcopenia was determined based on decreased skeletal muscle index calculated from computed tomography obtained before surgery. Univariate and multivariate Cox hazards models were applied to determine independent predictors of poor overall survival and cancer-specific survival.Sarcopenia was more common in the high-NLR group (2.57 or greater) than in the low-NLR group (less than 2.57; P = .01). In the high-NLR group, patients with sarcopenia had significantly poorer overall and cancer-specific survival than those without sarcopenia (P.001). In contrast, there was no survival impact of sarcopenia in the low-NLR group. Patients with both high NLR and sarcopenia exhibited poor overall and cancer-specific survival (5-year overall survival = 44.4%, 5-year cancer-specific survival = 57.0%). Sarcopenia was independently associated with poor overall survival (hazard ratio = 1.95; P = .007) and poor cancer-specific survival (hazard ratio = 2.66; P = .002) as well as pathological stage III disease and noncurative resection in the high-NLR group.The survival and oncological impact of sarcopenia was noteworthy only when present with elevated NLR. The combination of 2 factors is rational for identifying EC patients likely to have poor survival outcomes.

IntroductionTumour localisation is important for successful resection of lung nodules with optimal resection margins in sublobar resection. Virtual-assisted bronchoscopic localisation technique combined with dye marking and microcoil placement (VAL-MAP 2.0) is a minimally invasive, virtual-assisted, bronchoscopic technique that combines dye marking and microcoil implementation. As indwelling microcoils can provide information on the depth from the lung surface, they can be applied for deeply located small lung tumours that are barely identifiable by surface dye marking. This proposed study will examine the effectiveness of VAL-MAP 2.0 in patients with small pulmonary nodules.Methods and analysisThis is a multicentre, prospective, single-arm, clinical trial. A total of 65 patients will be registered to undergo VAL-MAP 2.0 followed by thoracoscopic surgery. The primary outcome is successful resection, defined as resection of the lesion with optimal resection margins. The goal of the study is the achievement of a successful resection rate of 80%.Ethics and disseminationThe study was approved by the Clinical Research Review Boards of the University of Tokyo (approval number 218 003SP) for all institutes, and the Technical Review Board for Advanced Medicine Category B of the Ministry of Health, Labour and Welfare. Results of the primary and secondary endpoints will be submitted for publication in a peer-reviewed journal.Trial registration numberjRCTs031180099

We investigated the interaction between the prognostic impact of a decrease in eGFR and the choice of initial diagnostic imaging modality for coronary artery disease. Out of 2878 patients who enrolled in the J-COMPASS study, 2780 patients underwent single photon emission computed tomography (SPECT), coronary computed tomography (CT) angiography, or coronary angiography (CAG) as an initial diagnostic test. After excluding patients with routine hemodialysis or lacked serum creatinine levels, 2096 patients in the non-decreased eGFR group (eGFR ≥ 60 ml/min/1.73 m2) and 557 patients in the decreased eGFR group (eGFR 2) were analyzed in this study. Major adverse cardiac events, including death, myocardial infarction, heart failure hospitalization, and late revascularization, were followed, with a median follow-up duration of 472 days. SPECT or CAG was preferable to CT in patients in the decreased eGFR group (p

We developed an HPV16 E7-expressing Lactobacillus-based therapeutic vaccine, IGMKK16E7, to elicit mucosal E7-specific TH1 cellular immune responses. This study aims to examine the safety and clinical efficacy of IGMKK16E7 on HPV16-positive high-grade squamous intraepithelial lesion (HSIL). This is a multicenter, placebo-controlled, double-blind randomized phase I/II trial to test the safety and efficacy of IGMKK16E7 against HPV16-positive HSIL. The groups will include placebo, low-dose (0.5 g/day), middle-dose (1 g/day), and high-dose (1.5 g/day) IGMKK16E7. The target sample size will be 41 patients per group, and our data on our former agent, GLBL101c, were used to calculate sample size for 70% power and an α level = 0.05. The primary endpoint is IGMKK16E7 safety and pathological regression at week 16, and the secondary endpoints are cytological regression and HPV16 E7 immunological response. This study protocol has been approved by the Japanese Pharmaceuticals and Medical Devices Agency. Patient enrollment will begin in May 2019.

Ex vivo lung perfusion (EVLP) is reportedly a useful strategy that permits marginal donor lungs to be evaluated and reconditioned for successful lung transplantation (LTx). This systematic review and meta-analysis was performed to evaluate the outcomes of EVLP conducted for marginal donor lungs.We searched PubMed, the Cochrane Library, and Embase to select studies describing the results of LTx following EVLP for marginal donor lungs compared with standard LTx without EVLP. We performed a meta-analysis to examine donor baseline characteristics, recipient baseline characteristics, and postoperative outcomes.Of 1380 studies, 8 studies involving 1191 patients met the inclusion criteria. Compared with the non-EVLP group (ie, standard LTx without EVLP), the EVLP group (ie, EVLP of marginal donors following LTx) had similar donor age and sex and recipient baseline age, sex, body mass index, bridge by ventilator/extracorporeal life support/extracorporeal membrane oxygenation, and rate of double LTx but more abnormal donor lung radiographs (P = .0002), a higher smoking history rate (P = .03), and worse donor arterial oxygen tension/inspired oxygen fraction (P .00001). However, there were no significant differences in outcomes between the EVLP and non-EVLP groups with respect to the length of postoperative intubation, postoperative extracorporeal life support/extracorporeal membrane oxygenation use, length of intensive care unit stay, length of hospital stay, 72-hour primary graft dysfunction of grade 3, 30-day survival, or 1-year survival (all P values .05).Posttransplant outcomes were similar between EVLP-treated LTx and standard LTx without EVLP, although the quality of donor lungs was worse with EVLP-treated LTx.

This post hoc subanalysis of the randomized Japanese Primary Prevention Project investigated whether once-daily low-dose aspirin versus no aspirin reduced the risk of cardiovascular events (CVEs) in patients aged ≥ 70 years with atherosclerotic risk factors. Patients aged

Background There is limited data showing that early treatment for anemia could prolong renal survival in non-dialysis chronic kidney disease (CKD) patients. We therefore investigated the relationship between hemoglobin (Hb) levels at initiation of epoetin beta therapy and renal outcome in non-dialysis CKD patients with anemia. Methods In this prospective, multi-center, observational study, non-dialysis CKD patients with anemia who were naïve to erythropoiesis-stimulating agents (ESAs) were divided into three groups based on their Hb levels at initiation of epoetin beta therapy (Group I: 10 ≤ Hb

BACKGROUND Previous trials have found that low low-density lipoprotein-cholesterol (LDL-C) on admission was associated with increased mortality in patients with acute myocardial infarction (AMI). There are few reports, however, on the effect of low LDL-C with or without in-hospital statin treatment on short-term prognosis in AMI patients. METHODS AND RESULTS A total of 9,032 AMI patients underwent primary PCI in 68 centers in the Tokyo CCU Network Registry during 2009-2012, in whom LDL-C was measured in 6,486. We divided them into 4 groups: statin-treated/LDL-C

BACKGROUND The long-term outcomes of complete revascularization (CR) in patients with left ventricular (LV) dysfunction undergoing coronary artery bypass grafting (CABG) remain unclear. Methods and Results: We evaluated a consecutive series of 111 patients with LV ejection fraction ≤35% who underwent isolated first-time CABG: 63 underwent CR and 48 underwent incomplete revascularization (IR). At a median follow-up of 10.1 years, the rates of death from any cause, cardiac death, and major adverse cardiac and cerebrovascular events (MACCE) were significantly greater in the IR group. After adjusting for propensity score, no significant difference was found between the CR and IR groups regarding death from any cause (hazard ratio [HR], 1.45; 95% CI: 0.75-2.81; P=0.271) and cardiac death (HR, 1.45; 95% CI: 0.68-3.10; P=0.337). In contrast, IR increased the risk of MACCE (HR, 1.92; 95% CI: 1.08-3.41; P=0.027), which was principally attributed to an increased risk of repeat revascularization (HR, 3.92; 95% CI: 1.34-11.44; P=0.013). CONCLUSIONS Although IR was not significantly associated with an increased risk of long-term mortality in patients with LV dysfunction who underwent CABG, CR might reduce the risks of repeat revascularization and subsequent MACCE.

Transcatheter aortic valve implantation (TAVI) often causes intraventricular conduction abnormalities (ICA), particularly left bundle branch block (LBBB) and advanced atrioventricular block, requiring pacemaker implantation (PMI). However, the relation between ICA and clinical outcomes after TAVI with balloon-expandable valves remains unclear, particularly in the Asian population. This retrospective study included all patients who underwent TAVI with balloon-expandable valves from October 2013 to September 2016. We defined ICA as new onset of complete LBBB (CLBBB) or PMI within 2 weeks after TAVI. We divided the patients into 2 groups: those with and without ICA (new-ICA and no-ICA groups) and we assessed 1-year outcome. Two hundred one consecutive patients underwent TAVI using balloon-expandable valves (mean age, 84.8 ± 5.7 years; women, 64%). ICA occurred in 47 patients (23%), 37 patients (18%) developed CLBBB, and 34 patients recovered from CLBBB within 1 year after TAVI. Ten patients (5%) who developed symptomatic bradycardia required PMI within 2 weeks after TAVI. At 30 days after PMI, 7 patients already had a very low ventricular pacing rate, and 6 patients who recovered from bradycardia needed pacing at 1 year. Patients with ICA tended to have high 1-year all-cause mortality, but there was no significant difference between the 2 groups (12% vs 7%, p = 0.15). In conclusion, ICA occurred in 23% of patients after TAVI with balloon-expandable valves, and approximately 90% of them recovered from ICA during the follow-up. There was no significant difference in 1-year all-cause mortality between the new-ICA and no-ICA groups.

Salvage esophagectomy (SALV) is potentially beneficial for patients with residual or relapsed esophageal carcinoma after definitive chemoradiotherapy (dCRT), although preoperatively identifying good candidates for SALV remains difficult. We investigated the prognostic impacts of inflammatory and nutritional status in patients undergoing SALV after dCRT. Forty-seven SALV patients were retrospectively reviewed, of whom 46 (98%) had squamous cell carcinoma and 1 (2%) adenocarcinoma. Possible prognostic factors included patients' demographic data, physical status, blood chemistry profiles, and clinical/pathological tumor features. The Glasgow prognostic score (GPS) was derived from preoperative C-reactive protein (CRP) and albumin values. Thirty (64%), 11 (23%), and 6 (13%) patients were classified into the GPS 0, 1, and 2, respectively, groups. None of the possible prognostic factors showed significant correlations with GPS. Patients with GPS 0 had better outcomes than those with GPS 1 or GPS 2 (Median survivals: 37.8, 15.9, and 5.1 months, respectively, P < 0.001). In the multivariable Cox proportional hazards model, GPS 1 (HR 5.62, 95% CI 1.94-16.4, P = 0.002), GPS 2 (HR 9.10, 95% CI 2.60-31.8, P < 0.001), R1/2 resection (HR 16.3, 95% CI 3.62-86.7, P < 0.001) and incomplete response to dCRT (HR 3.53, 95% CI 1.12-12.5, P = 0.03) were all independent risk factors for a poor outcome. Preoperative GPS is potentially useful for predicting outcomes in esophageal cancer patients undergoing SALV.

The effects of initial tests on long-term events have been unknown.In this observational retrospective study, we analyzed the effects of initial noninvasive tests by myocardial perfusion imaging (MPI) and computed tomography angiography (CTA) on long-term major adverse cardiac events (MACEs) among patients with suspected coronary artery disease during a median follow-up of 8.1 years (interquartile range: 7.7-8.9).Sex difference in the rate of abnormal findings on initial tests was observed in both the MPI (female vs. male: 32.6 vs. 55.5%; P0.0001) and CTA groups (30.6 vs. 47.9%; P0.0001). Early revascularization in the MPI was significantly lower than that in the CTA (16 vs. 23%; P=0.0005). A total of 109 MACEs (39 of 1830 patients during the original follow-up period and 70 of 616 patients during the extended follow-up period) occurred: 77 MACEs (6.4%) in the MPI group and 32 (5.1%) in the CTA group (adjusted hazard ratio for MPI: 0.78; 95% confidence interval: 0.50-1.23; P=0.29). In the total cohort, the risk-adjusted MACE rate in the females was ∼50% of the males.The long-term MACE rates did not differ between physician-referred initial tests of MPI and CTA despite a higher frequency of early revascularization in the CTA group. In this extended cohort, female sex was associated with a lower rate of positive findings and a lower MACE rate compared with the male sex.

BACKGROUND The present study was performed to clarify whether the preoperative clinical symptoms for endovascular therapy (EVT) can predict post-EVT death and cardiovascular prognosis in Japanese patients with peripheral artery disease (PAD), including acute disease.Methods and Results:The TOkyo taMA peripheral vascular intervention research COmraDE (Toma-Code) Registry is a Japanese prospective cohort of 2,321 consecutive patients with PAD treated with EVT, in 34 hospitals in the Kanto and Kōshin'etsu regions, from August 2014 to August 2016. In total, 2,173 symptomatic patients were followed up for a median of 10.4 months, including 1,370 with claudication, 719 with critical limb ischemia (CLI), and 84 with acute limb ischemia (ALI) for EVT. The all-cause death rates per 100 person-years for claudication, CLI and ALI were 3.5, 26.2, and 24.5, respectively. Similarly, major adverse cardiac and cerebrovascular events (MACCE) rates per 100 person-years for claudication, CLI, ALI, and others were 5.2, 31.2, and 29.7, respectively. After adjusting for the predictors of all-cause death and MACCE, namely, age, body mass index

Background Virtually no reports on the effects of exercise in patients with a small abdominal aortic aneurysm ( AAA ) exist. Methods and Results We conducted a retrospective cohort study on 1515 patients with a small AAA before surgery at 2 high‐volume hospitals in Tokyo, Japan, from April 2004 to September 2015. A carefully modified cardiac rehabilitation program without excessive blood pressure elevation during exercise was prescribed to 50 patients with an AAA . Using propensity score matching, mortality and clinical outcomes, including AAA expansion rate, were compared between 2 groups: rehabilitation group and nonrehabilitation group. The background characteristics of the rehabilitation group (n=49) and the nonrehabilitation group (n=163) were almost identical. The risk for AAA repair was much lower in the rehabilitation group after matching (before matching: hazard ratio, 0.43; 95% confidence interval, 0.25–0.72; P =0.001; and after matching: hazard ratio, 0.19; 95% confidence interval, 0.07–0.50; P AAA expansion rate was slower in the rehabilitation group (before matching: rehabilitation versus nonrehabilitation group, 2.3±3.7 versus 3.8±3.4 mm/y [ P =0.008]; after matching: rehabilitation versus nonrehabilitation group, 2.1±3.0 versus 4.5±4.0 mm/y [ P AAA expansion rate after the rehabilitation program ( r =0.569, P Conclusions Cardiac rehabilitation protects against the expansion of small AAA s and mitigates the risk associated with AAA repair, possibly because of the decreased elevation of blood pressure during exercise. Clinical Trial Registration URL: upload.umin.ac.jp . Unique identifier: UMIN 000028237.

Acute kidney injury (AKI) is relatively common after cardiothoracic surgery for type A acute aortic dissection (TA-AAD) and increases mortality. We investigated the incidence and risk factors for AKI in patients with TA-AAD and its impact on their outcomes. The records of 375 consecutive patients who underwent surgical treatment for TA-AAD from October 2007 to March 2013 were analyzed retrospectively. We defined AKI using the Kidney Disease Improving Global Outcomes criteria, which are based on serum creatinine concentration or glomerular filtration rate. We used Kaplan-Meier methods and multivariate Cox proportional hazards regression to assess the impact of AKI on both mortality and major adverse cardiovascular and cerebrovascular events. We also examined the association between risk factors and AKI using logistic regression modeling. Postoperative AKI was observed in 165 patients (44.0%). The overall 30-day and mid- to long-term mortality was 1.6% and 8.8%, respectively. Mortality and major adverse cardiovascular and cerebrovascular events correlated significantly with the severity of AKI, and multivariate analysis showed that AKI stage 3 (the most sever stage) was an independent risk factor for mortality (hazard ratio 6.83, 95% confidence interval 2.52 to 18.52) after adjustment for important confounding factors. Extracorporeal circulation time, body mass index, perioperative peak serum C-reactive protein concentration, renal malperfusion, and perioperative sepsis were found to be risk factors for AKI. In conclusion, AKI was common in patients who underwent surgery for type A acute aortic dissection. The severity of AKI strongly influences patient outcomes, so it should be recognized promptly and treated aggressively when possible.

Several prognostic models predicting survival of patients with metastatic urothelial carcinoma (UC) have been developed; however, of them, the first model by Bajorin in 1999 is still the most representative and widely used, and validations of newer models are lacking. This study aimed to validate three major prognostic models for metastatic UC constructed based on clinical trials.We reviewed 200 patients with metastatic UC who received first-line chemotherapy at our five affiliate institutions between 2003 and 2011. Using this multi-institutional cohort, we validated the following models: the "Bajorin model," a model consisting of visceral metastasis and performance status; the "Apolo model," a nomogram including visceral metastasis, performance status, albumin and hemoglobin; and the "Galsky model," a nomogram including leukocyte count, number of sites of visceral metastases, site of primary tumor, performance status and lymph node metastasis. Harrell's c-index was calculated for each model. Cox proportional hazards regression model was used for multivariate analysis.Among 200 patients, 171 (85.5%) died during the follow-up, with a median survival of 12.0 months. Multivariate analysis demonstrated ECOG performance status, visceral metastasis and leukocyte count to be independent predictors of overall survival. C-index results (95% confidence interval) were Bajorin: 0.86 (0.74-0.95); Apolo: 0.89 (0.78-0.98); and Galsky: 0.82 (0.69-0.93).All models were demonstrated to have high external validities in real-world patients, and of them, the "Apolo model" achieved the highest c-index in the present population. Further studies with larger populations are needed for establishment of the next standard model.

Background Fermented milk products containing Bifidobacterium breve strain Yakult (BFM) may improve clinical status in ulcerative colitis (UC) patients. Aims To assess efficacy of BFM in maintaining remission in Japanese patients with quiescent UC. Methods This double-blind study (B-FLORA) enrolled 195 patients with quiescent UC, randomized to receive one pack of BFM fermented milk per day [Bifidobacterium breve strain Yakult (10 billion bacteria) and Lactobacillus acidophilus (1 billion bacteria)] (n = 98) or matching placebo (n = 97) for 48 weeks. The primary efficacy endpoint was relapse-free survival (relapse: rectal bleeding score ≥ 2 on Sutherland disease activity index scale for 3 consecutive days and/or initiation of remission induction therapy for worsening of UC). Results An interim analysis was conducted after inclusion and follow-up of one-third of patients for the first phase of the study (n = 195). Relapse-free survival was not significantly different between the BFM and placebo groups (P = 0.643; hazard ratio 1.16; 95% CI 0.63–2.14, log-rank test), nor was the incidence of relapse. Therefore, the study was discontinued for lack of efficacy. An exploratory analysis of fecal samples from a subgroup of patients revealed no effects of either study beverage on intestinal microbiota, but there was a significant decrease in Bifidobacterium species before relapse, regardless of treatment group. Three mild adverse events occurred for which a causal relationship with the study beverage could not be ruled out (placebo: abdominal bloating and stress in one patient; BFM: body odor in one patient). Conclusions BFM had no effect on time to relapse in UC patients compared with placebo. Study Registration UMIN000007593. Electronic supplementary material The online version of this article (10.1007/s10620-018-4946-2) contains supplementary material, which is available to authorized users.

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.

BackgroundDeteriorated quality of life (QOL) is a major problem in osteoporotic women. However, little is known regarding the determinants of QOL in patients with osteoporosis.ObjectiveOur aim was to explore the role of vitamin D status on QOL score in osteoporosis with high fracture risk.MethodsPatients were osteoporotic women aged ≥70 years and with ≥1 risk factor for incident fracture, namely prevalent osteoporotic fracture, bone mineral density (BMD) >–3.0 SD of young adult mean, or high bone turnover marker. Health-related QOL was assessed using the Japanese Osteoporosis Quality of Life Questionnaire (JOQOL). When patients were classified into quartiles by total QOL score). Serum 25-hydroxyvitamin D (25[OH]D) level was measured by immunoassay.ResultsA total of 1585 osteoporotic women were included in the study (age range, 70–95 years). Age, body mass index, serum 25(OH)D status (low, normal, or high), bone mineral density, number of prevalent vertebral fractures, presence of hypertension, presence of osteoarthritis, and history of falls were significantly correlated with QOL quartile. Multivariate liner regression analysis indicated that low serum 25(OH)D level (20 ng/mL may be required to maintain patients’ QOL in osteoporosis.