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Summary Background Systemic sclerosis is a connective tissue disease characterised by multiorgan fibrosis with an autoimmune background and poor prognosis. Although a few drugs have shown some efficacy in treating the disease, there remains a great unmet medical need. We aimed to investigate the efficacy and safety of rituximab in patients with systemic sclerosis. Methods We did a double-blind, investigator-initiated, randomised, placebo-controlled trial at four hospitals in Japan. Patients aged 20–79 years, who fulfilled the 2013 American College of Rheumatology and European League Against Rheumatism classification criteria for systemic sclerosis, with a modified Rodnan Skin Score (mRSS) of 10 or greater, and an expected survival of at least 6 months were randomly assigned (1:1) to receive intravenous rituximab (375 mg/m2) or placebo once per week for 4 weeks. Patients and investigators were masked to treatment allocation. The primary endpoint was the absolute change in mRSS 24 weeks after initiation of study treatment, measured in all patients who received at least one dose of study treatment and had one endpoint assessment. This study is registered with ClinicalTrials.gov, NCT04274257, and UMIN-CTR, UMIN000030139. Findings Between Nov 28, 2017, and Nov 6, 2018, 80 individuals were screened and 56 (70%) were enrolled and randomly assigned; 51 (91%) were women and five (9%) were men. 27 (96%) of 28 patients in the rituximab group and 22 (79%) of 28 patients in the placebo group received at least one dose of their allocated treatment and completed 24 weeks of follow-up. The absolute change in mRSS 24 weeks after initiation of study treatment was lower in the rituximab group than in the placebo group (−6·30 in the rituximab group vs 2·14 in the placebo group; difference −8·44 [95% CI −11·00 to −5·88]; p Interpretation Rituximab appears to be an effective and safe treatment for systemic sclerosis. Although this study has some limitations, this is the first clinical trial to show efficacy of rituximab with skin sclerosis as the primary endpoint. Funding Japan Agency for Medical Research and Development (AMED), Zenyaku Kogyo. Translation For the Japanese translation of the abstract see Supplementary Materials section.

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.

This study was performed to compare the outcome of lung transplantation (LT) for idiopathic pleuroparenchymal fibroelastosis (IPPFE) with that of LT for idiopathic pulmonary fibrosis (IPF). We reviewed, retrospectively, all adult patients who underwent LT for IPPFE or IPF in Japan between 1998 and 2018. There were 100 patients eligible for this study (31 with IPPFE and 69 with IPF). Patients with IPPFE tended to have a significantly lower body mass index (BMI) than those with IPF (median, 16.7 vs. 22.6 kg/m2, respectively; P

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 m2; or (3) reduction of eGFR by 30% or more. Secondary endpoints were kidney function (change rate in eGFR), cardiovascular (CV) events, and safety. Between 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.

For the past decade, sarcopenia has been actively investigated in various cancers, including urothelial carcinoma (UC). Although skeletal muscle index (SMI) is the main parameter used to evaluate sarcopenia in oncology, the optimal definition of SMI-based sarcopenia is not entirely standardized. We recently highlighted the potential limitations of current definitions of SMI-based sarcopenia in another journal. In this study, we reviewed studies that assessed sarcopenia in UC patients. We then performed a comparative validation of three major SMI-based definitions of sarcopenia, including Prado's, the international and Martin's definitions in metastatic UC patients. We believe that the standardization of the sarcopenia definition is an urgent issue in oncology, and this paper discusses a possible new direction to address this issue.

Background There is limited understanding of the characteristics of patients with coronavirus disease 2019 (COVID-19) requiring hospitalization in Japan. Methods This study included 2638 cases enrolled from 227 healthcare facilities that participated in the COVID-19 Registry Japan (COVIREGI-JP). The inclusion criteria for enrollment of a case in COVIREGI-JP are both (1) a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test and (2) inpatient treatment at a healthcare facility. Results The median age of hospitalized patients with COVID-19 was 56 years (interquartile range [IQR], 40–71 years). More than half of cases were male (58.9%, 1542/2619). Nearly 60% of the cases had close contact to confirmed or suspected cases of COVID-19. The median duration of symptoms before admission was 7 days (IQR, 4–10 days). The most common comorbidities were hypertension (15%, 396/2638) and diabetes without complications (14.2%, 374/2638). The number of nonsevere cases (68.2%, n = 1798) was twice the number of severe cases (31.8%, n = 840) at admission. The respiratory support during hospitalization includes those who received no oxygen support (61.6%, 1623/2636) followed by those who received supplemental oxygen (29.9%, 788/2636) and invasive mechanical ventilation/extracorporeal membrane oxygenation (8.5%, 225/2636). Overall, 66.9% (1762/2634) of patients were discharged home, while 7.5% (197/2634) died. Conclusions We identified the clinical epidemiological features of COVID-19 in hospitalized patients in Japan. When compared with existing inpatient studies in other countries, these results demonstrated fewer comorbidities and a trend towards lower mortality.

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

Background: Patient reported outcomes (PROs) have been increasingly important in breast cancer treatment. The questionnaires to evaluate PROs require high response compliance, simplicity, and friendliness. Recently, the communication with Emojis has become friendliness because of the development of social networking services and electronic devices. Therefore, we developed the Emoji scale, a novel indicator to evaluate PROs. Furthermore, two-step validation pilot studies were planned to examine the reliability of the Emoji scale for breast cancer patients at a single center. Pilot 1(Step 1) Aims: To evaluate the content validity (the primary endpoint), concurrent validity and test retest reliability of the Emoji scales (secondary endpoints). Eligibility criteria: (1) Patients with stage 0-III breast cancer. (2) Patients who have been over 1 year since the end of the initial treatment such as surgery, chemotherapy, and radiation therapy or (3) hormone receptor positive patients who have been over 1 year from the start of the endocrine therapy. (4) Patients aged >20 years who understand Japanese. Methods: The participants will complete the PRO Common Terminology Criteria for Adverse Events (PRO-CTCAE) and Emoji scale questionnaires regarding 18 cancer related symptoms twice. First, both questionnaires will be completed in a consulting room while the staff will track the time required for completion of each questionnaire. Thereafter, the patients will be asked if there are any difficult or confused items. Second, both questionnaires will be completed again at home 7 days later. The number of planned participants is 100. Statistical analyses: Content validity will be evaluated by categorizing the comments from participants, and the nature of problems will be determined. The correlation coefficient between the PRO-CTCAE and Emoji scale scores will evaluate the concurrent validity. For the test-retest reliability, the kappa statistic between each scale at different time will be used. We will compare the time required for completion with using the t-test. Pilot 2(Step2) Aims: To evaluate the responsiveness (the primary endpoint), the effect size, the concurrent validity and comparison of the average score between participants with high and low Performance Status. (the secondary endpoints). Eligibility criteria: (1) Patients with stage 0-IV breast cancer who are scheduled to start chemotherapy or endocrine therapy. (2) Patients aged >20 years who understand Japanese. Methods: The participants will complete both the PRO-CTCAE and Emoji scales before they start a new breast cancer treatment (T1). Those will comprise chemotherapy (Cohort A: anthracycline based regimens, Cohort B: docetaxel based regimens, Cohort C: paclitaxel based regimens, Cohort E: eribulin based regimens, and Cohort F: capecitabine/S1 based regimens) or endocrine therapy (Cohort D: tamoxifen/aromatase inhibitor). After several weeks, the participants will complete the same questionnaires again (T2). This time interval will depend on the therapy, and some participants will be complete once again the questionnaires (T3) a few weeks after T2. The number of planned participants is 30 in each cohort. Statistical analyses: Responsiveness will be evaluated by the correlation coefficient between the change from the baseline to second or third score of each scale. The effect size of the Emoji scale will be determined by the difference between the average score of the second or third and that of the baseline divided by the standard deviation of the baseline score. The correlation coefficient for each scale at each time will evaluate the concurrent validity at each time. A comparison of the average scores between PS will be performed using the t-test. Citation Format: Yoko Suzuki, Naruto Taira, Yukiko Kajiwara, Mariko Kochi, Takayuki Iwamoto, Hirokuni Ikeda, Tadahiko Shien, Hiroyoshi Doihara, Yuichiro Kikawa, Yukari Uemura. Validation study of the Emoji scale in evaluating patient reported outcomes for breast cancer patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-19-01.

Background: The randomized controlled trial (RCT) is accepted as the standard clinical trial to decide a standard therapy, but it remains unclear whether or not elderly patients benefit as much as other patients from participation in an RCT. In the RESPECT study (NCT01104935), the relative value of trastuzumab (H) monotherapy as an adjuvant treatment was compared in an RCT with the standard combination treatment with chemotherapy (H+CT) in patients over 70 years old with HER2-positive invasive breast cancer (BC) who received curative surgery. This cohort study was aimed at comparing prognoses between RCT participants (RCT group) and non-participants (Cohort group). Methods: Patients were divided into RCT participants, and those who did not agree to participate in the RCT despite meeting the eligibility criteria and receiving the explanation given by the investigator. In the RCT group patients were randomized to H or H+CT; in the Cohort group treatment was selected for each patient based on the discretion of the treating physician and the patient's wishes without intervention. Treatment categories were divided into three groups: (1) trastuzumab monotherapy group (cH group), (2) trastuzumab plus chemotherapy group (cH+CT group), and (3) those who received either no therapy at all, or any other anticancer therapies without H (cOther group). The primary endpoint was disease-free survival (DFS). Secondary endpoints were overall survival (OS), relapse-free survival, safety, health-related quality of life (HRQOL) and comprehensive geriatric assessment. Results: A total of 275 patients in the RCT group and 123 patients in the Cohort group, in total 398 patients, were enrolled in this study between October 2009 and October 2014. The median age was 74.0 years in the RCT group, 74.5 years in the Cohort group and the median follow-up time was 4.1 years and 3.2 years, respectively. Patients were classified as Stage I: 41.8%, 42.5%; IIA: 41.5 %, 40.8%; IIB: 13.5%, 13.3%; and IIIA: 1.5%. 3.3%, respectively (P = 0.51), there were no significant differences between the two groups. Treatment categories in the Cohort group were: (1) cH group; 43% (n = 52), (2) cH+CT group; 30% (n = 36), cOther group; 27% (n = 32). The planned analysis showed that DFS at 3 years was 91.4% in the RCT group vs 89.3% in the Cohort group (adjusted hazard ratio (HR) = 1.30; 95%CI, 0.72-2.35, P = 0.38). In patients in the cH+CT, cH and cOther group, DFS at 3 years was 92.3%, 89.2% and 82.5%, respectively. DFS in patients in the cH+CT and the cH group was significantly better than that of the cOther group (adjusted HR = 3.79; 95%CI = 1.35-10.64, P = 0.01). DFS in the cH group showed a better tendency compared with cOther (adjusted HR = 2.59; 95%CI, 0.87-7.73, P = 0.08). The incidence of grade 3/4 non-hematological adverse events in the RCT group was relatively higher compared with the Cohort group (18.5% vs 10.8 %, P = 0.05). Conclusion: The prognosis did not vary between the RCT and Cohort groups. H-containing regimens are often chosen for elderly patients with HER2-positive breast cancer. The prognosis of patients who received any H-containing regimen, even H monotherapy, was better than those who were not treated with H. Citation Format: Shinichi Baba, Masataka Sawaki, Yukari Uemura, Tsuyoshi Saito, Kokoro Kobayashi, Hiroaki Kawashima, Michiko Tsuneizumi, Noriko Sagawa, Hiroko Bando, Masato Takahashi, Miki Yamaguchi, Tsutomu Takashima, Takahiro Nakayama, Masahiro Kashiwaba, Toshiro Mizuno, Yutaka Yamamoto, Naruto Taira, Hiroji Iwata, Tatsuya Toyama, Koichiro Tsugawa, Yasuo Ohashi, Hirofumi Mukai. A cohort study to evaluate the efficacy and safety of postoperative adjuvant therapy in HER2-positive elderly breast cancer patients (RESPECT-cohort study) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-14-02.

Background 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. Purpose We aimed to evaluate the association of the extent of myocardial ischemia with outcomes in patients with suspected coronary artery disease in Japan. Methods 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, 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. Results Patients with ≥10% myocardial ischemia (n=173) were older than patients with Conclusion The presence of ≥10% myocardial ischemia was significantly associated with the 1-year risk for MACEs in Japanese patients with suspected coronary artery disease. Funding Acknowledgement Type of funding sources: None. Study flowchartOutcomes

Objective Viral pneumonia is not rare in community-acquired pneumonia (CAP). Mixed or secondary pneumonia (coinfection) can be seen in viral pneumonia; however, its frequency in coronavirus disease 2019 (COVID-19) has only been investigated in a few studies of short duration, and its significance has not been fully elucidated. We investigated the frequency and significance of co-infection in patients with COVID-19 over a 1-year study period. Methods Coinfection was investigated via multiplex polymerase chain reaction (PCR), culture of respiratory samples, rapid diagnostic tests, and paired sera. We used logistic regression analysis to analyze the effect of coinfection on severity at admission and Cox proportional-hazards model analysis to analyze the effect of coinfection on need for high-flow nasal cannula, invasive mandatory ventilation use, and death, respectively. Patients We retrospectively investigated 298 patients who suffered CAP due to severe acute respiratory syndrome coronavirus-2 infection diagnosed by PCR and were admitted to our institution from February 2020 to January 2021. Results Primary viral pneumonia, and mixed viral and bacterial pneumonia, accounted for 90.3% and 9.7%, respectively, of COVID-19-associated CAP, with viral coinfection found in 30.5% of patients with primary viral pneumonia. Influenza virus was the most common (9.4%). Multivariable analysis showed coinfection not to be an independent factor of severity on admission, need for high-flow nasal cannula or invasive mandatory ventilation, and mortality. Conclusion Viral coinfection was common in COVID-19-associated CAP. Severity on admission, need for high-flow oxygen therapy or invasive mandatory ventilation, and mortality were not affected by coinfection.

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.

Visual Abstract, Highlights • Patients with dilated cardiomyopathy who achieved LVRR have a favorable prognosis, but it is still difficult to precisely predict LVRR in the clinical setting. • Immunostaining of DNA damage markers such as PAR in biopsy specimens from patients with dilated cardiomyopathy revealed that patients with LVRR showed a significantly smaller proportion of PAR-positive nuclei compared with those without LVRR. • The high proportion of PAR-positive nuclei was an independent prognostic factor for LVRR. Besides, it can predict clinical prognosis (death, heart transplantation, and ventricular assist device implantation) with good sensitivity and specificity., Summary This study evaluated myocardial nuclear staining for the DNA damage markers poly(ADP-ribose) (PAR) and γ-H2A.X in 58 patients with dilated cardiomyopathy. Patients with left ventricular reverse remodeling (LVRR) showed a significantly smaller proportion of PAR-positive nuclei and γ-H2A.X–positive nuclei in biopsy specimens compared with those without LVRR. Propensity analysis showed that the proportion of both PAR-positive and γ-H2A.X–positive nuclei were independent prognostic factors for LVRR. In conclusion, we showed the utility of DNA damage-marker staining to predict the probability of LVRR, thus revealing a novel prognostic predictor of medical therapy for dilated cardiomyopathy.

OBJECTIVE We examined whether the efficacy of low-dose acetylsalicylic acid (aspirin) for primary prevention of cardiovascular events is influenced by blood pressure (BP) using data from patients aged 60-85 years with hypertension, dyslipidemia, and/or diabetes, but without cardiovascular disease of the Japanese Primary Prevention Project. METHODS All patients had received aspirin (100 mg/day) or no aspirin. BP subgroups were defined as low (average SBP from the baseline to the year of the events

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.

Discrepancies in efficacy between single-dose and repeated administration of oxytocin for autism spectrum disorder have led researchers to hypothesize that time-course changes in efficacy are induced by repeated administrations of the peptide hormone. However, repeatable, objective, and quantitative measurement of autism spectrum disorder’s core symptoms are lacking, making it difficult to examine potential time-course changes in efficacy. We tested this hypothesis using repeatable, objective, and quantitative measurement of the core symptoms of autism spectrum disorder. We examined videos recorded during semi-structured social interaction administered as the primary outcome in single-site exploratory (n = 18, crossover within-subjects design) and multisite confirmatory (n = 106, parallel-group design), double-blind, placebo-controlled 6-week trials of repeated intranasal administrations of oxytocin (48 IU/day) in adult males with autism spectrum disorder. The main outcomes were statistical representative values of objectively quantified facial expression intensity in a repeatable part of the Autism Diagnostic Observation Schedule: the maximum probability (i.e. mode) and the natural logarithm of mode on the probability density function of neutral facial expression and the natural logarithm of mode on the probability density function of happy expression. Our recent study revealed that increases in these indices characterize autistic facial expression, compared with neurotypical individuals. The current results revealed that oxytocin consistently and significantly decreased the increased natural logarithm of mode on the probability density function of neutral facial expression compared with placebo in exploratory (effect-size, −0.57; 95% CI, −1.27 to 0.13; P = 0.023) and confirmatory trials (−0.41; −0.62 to −0.20; P < 0.001). A significant interaction between time-course (at baseline, 2, 4, 6, and 8 weeks) and the efficacy of oxytocin on the natural logarithm of mode on the probability density function of neutral facial expression was found in confirmatory trial (P < 0.001). Post hoc analyses revealed maximum efficacy at 2 weeks (P < 0.001, Cohen’s d = −0.78; 95% CI, −1.21 to −0.35) and deterioration of efficacy at 4 weeks (P = 0.042, Cohen’s d = −0.46; 95% CI, −0.90 to −0.01) and 6 weeks (P = 0.10, Cohen’s d = −0.35; 95% CI, −0.77 to 0.08), while efficacy was preserved at 2 weeks post-treatment (i.e. 8 weeks) (P < 0.001, Cohen’s d = −1.24; 95% CI, −1.71 to −0.78). Quantitative facial expression analyses successfully verified the positive effects of repeated oxytocin on autistic individuals’ facial expressions and demonstrated a time-course change in efficacy. The current findings support further development of an optimized regimen of oxytocin treatment.

Background: Anthracycline-containing regimens and taxane have been standard as the first-line chemotherapy for metastatic breast cancer (MBC). We conducted SELECT BC (randomized phase 3 study of taxane versus S-1 as first-line treatment for MBC) for evaluating the efficacy of S-1 for patients with HER2-negative MBC from 2006 to 2010 in Japan. This study demonstrated non-inferiority of S-1 in overall survival (OS) (median OS was 37.2 months in taxes group and 35.0 months in S-1 group (HR 1.05, 95% CI 0.86–1.27, p=0.015)), and superiority in health-related quality of life (HRQOL) to taxanes. S-1 was also shown as less toxic than taxane (Lancet Oncol 2016; 17: 90-98). S-1 might provide clinical benefit as first-line treatment for patients with HER2-negative MBC. To confirm this suggestion, we have conducted further study (randomized phase 3 study of anthracycline-containing regimens versus S-1 as first-line treatment for HER2-negative MBC: SELECT BC-CONFIRM) from 2011 to present, and a combined analysis of two randomized studies (SELECT-BC CONFIRM and SELECT-BC). Methods: In SELECT BC-CONFIRM, 230 patients receiving first-line treatment for MBC were randomly assigned to either anthracycline group (n=115) or S-1 group (n=115). Anthracycline group patients received anthracycline-containing regimens (AC, EC, FAC, FEC, q3w) at the discretion of the treating physician. S-1 group patients received S-1 40–60 mg twice daily based on the patient's body surface area for 28 days on, 14-day off. The primary endpoint was OS, and secondary endpoints were progression-free survival (PFS), time to treatment failure (TTF), adverse events, HRQOL, and cost-effectiveness. The results were combined with SELECT-BC, to confirm the hypothesis that S-1 treatment is not inferior to the standard therapy (taxanes / anthracycline) for HER2-negative MBC. Results: A combined analysis of the two studies showed that HR was 1.06, 95%CI 0.90-1.253, and p=0.0071 between the standard therapy group and S-1 group. In addition, the Bayesian posterior probability for which HR would be less than 1.333 was about 99.6%. Conclusions: A combined analysis of SELECT BC-CONFIRM and SELECT BC clearly demonstrated that OS with S-1 was not inferior to that with the standard therapy in patients receiving first-line treatment for HER2-negative MBC. S-1 could become a standard therapy for this patient population. Citation Format: Park Y, Akabane H, Watanabe T, Takahashi M, Sagara Y, Nishimura R, Tsurutani J, Takashima T, Fujisawa T, Hozumi Y, Uemura Y, Mukai H. Randomized phase 3 study of anthracycline-containing regimens versus S-1 as first-line treatment for metastatic breast cancer (SELECT BC-CONFIRM)–A combined analysis of two randomized phase 3 studies (SELECT BC-CONFIRM and SELECT BC)– [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-14-07.

OBJECTIVE: The RESPECT trial compared 1-year trastuzumab monotherapy with trastuzumab plus standard chemotherapy as a postoperative adjuvant therapy in HER2-positive elderly breast cancer patients. Primary objective of this study was to verify the noninferiority of 1-year trastuzumab monotherapy to trastuzumab plus chemotherapy in terms of disease free survival, and the planned analysis showed that the difference of restricted mean survival time between two groups at 3 years was 0.45 months (reported by Sawaki at ASCO2018). This report assesses the patients-reported outcomes and health-related quality of life (HRQoL). PATIENTS AND METHODS: The study was done at 99 hospitals in Japan. Elderly women (70 to 80 years old) with HER2-positive, stageI-IIIA invasive breast cancer treated by surgery with clear resection margins were randomly assigned to receive either 1-year trastuzumab or 1-year trastuzumab plus standard chemotherapy, stratified by age, hormone-receptor status, pathological lymph node metastasis and institution. Patients completed questionnaires at baseline, 2 months, 1year, and 3 years after protocol treatment started. The primary outcome was global HRQoL assessed using Functional Assessment of Cancer Therapy-General (FACT-G) total score, and secondary outcomes were chemotherapy-induced peripheral neuropathy (CIPN), instrumental activities of daily living (IADL), anxiety, depression, and subjective happiness. We did the analyses by intention to treat, including patients who completed questionnaires at baseline before start of protocol treatment, and 5point or more change is meaningful in FACT-G total score. This study is registered with ClinicalTrials.gov, NCT01104935. RESULTS: Between Oct 2009 and Oct 2014, 275 patients were enrolled in the study, of whom 9 patients were excluded: 135 assigned to trastuzumab monotherapy and 131 assigned to trastuzumab plus chemotherapy. We detected significant difference between treatment groups for: clinically meaningful HRQoL deterioration rate at 2 months (31% for trastuzumab monotherapy vs 48% for trastuzumab plus chemotherapy; p=0.016) and at 1year (19% vs 38%; p=0.009), clinically meaningful HRQoL improvement rate at 2 months (38% for trastuzumab monotherapy vs 15% for trastuzumab plus chemotherapy; p CONCLUSION: Given the small advantage of adjuvant trastuzumab plus chemotherapy compared to trastuzumab monotherapy for elderly HER-2 positive breast cancer women, decisions about treatment should be informed by the risk for adverse health effects associated with chemotherapy. Citation Format: Kobayashi K, Taira N, Sawaki M, Sagawa N, Baba S, Saito T, Kawahara T, Hagiwara Y, Uemura Y, Shimozuma K, Ohashi Y, Mukai H. Patient-reported outcomes with trastuzumab monotherapy versus trastuzumab plus standard chemotherapy as a postoperative adjuvant therapy in HER2-positive elderly breast cancer patients (RESPECT): A randomized, open-label, phase 3 clinical trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-13-02.

OBJECTIVE: The effect of trastuzumab(Tmab) or chemotherapy on cognitive function has not been fully understood, especially in elderly breast cancer patients. The RESPECT trial compared 1-year(yr) Tmab monotherapy with Tmab plus standard chemotherapy as adjuvant therapy in elderly patients with HER2-positive breast cancer. The primary objective was to verify the noninferiority of 1-yr Tmab monotherapy compared to Tmab plus chemotherapy in terms of disease-free survival, and the planned analysis showed that the difference of restricted mean survival time between two groups at 3 yrs was 0.45 months (Sawaki at ASCO2018). The goal of this report was to assess the impact of the treatment groups on longitudinal cognitive function. PATIENTS AND METHODS: The study was performed with patients from 99 hospitals in Japan. Elderly women with HER2-positive, stage I-IIIA invasive breast cancer surgery treated with clear resection margins were randomly assigned to either receive 1-yr Tmab or 1-yr Tmab plus standard chemotherapy. 15 institutions participated in the cognitive sub-study. Cognitive function was assessed using the Mini-Mental State Examination (MMSE) at baseline and at 1 and 3 yrs after treatment. The primary outcome was the amount of change in the MMSE score from the baseline. A linear mixed-effects model was used for comparisons of change in the MMSE score between groups, controlling for time and baseline score. Secondary outcomes were the proportion of both suspected mild dementia (MMSE≤27) and dementia (MMSE≤23) at each time point. RESULTS: Between October 2009 and October 2014, 275 patients were enrolled in the RESPECT trial, and 57 patients were enrolled in the cognitive function sub-study with 2 patients subsequently excluded. The 55-patient sub-study comprised 29 patients assigned to the Tmab monotherapy group and 26 patients assigned to the Tmab plus chemotherapy group. Primary analysis revealed that change in the MMSE score was not significantly different between the two groups (difference −0.6 at 1 yr and −0.9 at 3 yrs; p=0.136), whereas the baseline score was the only significant factor that had an effect on the amount of change in the MMSE score (p CONCLUSION: Postoperative chemotherapy for elderly breast cancer patients was considered to have little effect on the onset of dementia during the follow-up period of 3 yrs. Further long-term observation is necessary to obtain a significant conclusion. Citation Format: Takahashi M, Sawaki M, Hagiwara Y, Uemura Y, Kawahara T, Shimozuma K, Ohashi Y, Saito T, Baba S, Kobayashi K, Mukai H, Taira N. Analysis of cognitive function in elderly HER2-positive breast cancer patients receiving either trastuzumab monotherapy or trastuzumab plus chemotherapy as a postoperative adjuvant treatment: A cognitive function sub-study of a randomized, open-label, phase 3 clinical trial (RESPECT trial) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-11-21.

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

Cervical intraepithelial neoplasia (CIN), a precursor lesion to cervical cancer, is caused by high-risk human papillomavirus (HPV), high-grade CIN lesions (CIN2-3) are precancerous and require treatment. No globally approved therapy is available for CIN2-3 treatment. This study is a placebo-controlled randomized clinical trial of GLBL101c treatment for CIN2 in 40 patients with HPV16-positive CIN2 who were 1:1 randomized to receive GLBL101c (1 g/daily) or placebo for 5 days at 1, 2, 4, and 8 weeks. No differences were noted between the GLBL101c and placebo groups for patient background and adverse events. Moreover, no statistically significant difference was noted between the two groups at the primary endpoint, pathological regression after 16 weeks of the first oral dose, however, only in the GLBL101c group, two patients had complete regression (CR, regression to normal within 16 weeks). IFNγ production was significantly correlated with the number of spots identified by the interferon gamma enzyme-linked immunospot (IFNγ-ELISPOT) assay using cervical lymphocytes (CxLs) or peripheral blood mononuclear cells. In the two cases of CR, E7-specific Th1 immune responses were observed at week 16. Therefore, we concluded as a novel Lactobacillus-based vaccine with stronger immunogenicity than GLBL101c should be developed.

Background: 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.Methods: 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, 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. Results: Patients with ≥10% myocardial ischemia (n=173) were older than patients with Conclusion: The presence of ≥10% myocardial ischemia was significantly associated with the 1-year risk for MACEs in Japanese patients with suspected coronary artery disease.

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.

ObjectiveWe aimed to evaluate the association of the prognostic impact of coronary revascularisation with physician-referred non-invasive diagnostic imaging tests (single photon emission CT (SPECT) vs coronary CT angiography) for coronary artery disease.DesignA post hoc analysis of a subgroup from the patient cohort recruited for the Japanese Coronary-Angiography or Myocardial Imaging for Angina Pectoris Study.SettingMultiple centres in Japan.ParticipantsFrom the data of 2780 patients with stable angina, enrolled prospectively between January 2006 and March 2008 in Japan, who had undergone physician-referred non-invasive imaging tests, 1205 patients with SPECT as an initial strategy and 625 with CT as an initial strategy were analysed. We assessed the effect of revascularisation (within 90 days) in each diagnostic imaging stratum and the interaction between the two strata.Primary and secondary outcome measuresMajor adverse cardiac events (MACEs), including death, myocardial infarction, hospitalisation for heart failure and late revascularisation, were followed up for 1 year. The χ2 test, Student’s t-test, Kaplan-Meier analysis, log-rank test and multivariable Cox proportional hazard model were used in data analysis.ResultsA total of 210 (17.4%) patients in the SPECT stratum and 149 (23.8%) in the CT stratum underwent revascularisation. Although in each stratum, the cumulative 1 year incidence of MACEs was significantly higher in patients who underwent revascularisation than in those who did not (SPECT stratum: 9.1 vs 1.2%, log-rank pConclusionThe association of revascularisation with the outcomes of patients with suspected coronary artery disease was not different between SPECT-first and CT-first strategies in a physician-referred fashion.

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.

Background While the new Gleason grade grouping (GGG), which started in 2016, has been widely validated in prostate cancer, it does not incorporate the concept of tertiary Gleason pattern 5. Furthermore, no study has “quantified” the individual risk of each Gleason pattern, including tertiary Gleason pattern 5, after radical prostatectomy. Methods We reviewed 1022 men with adjuvant-treatment-naïve prostate cancer who underwent radical prostatectomy between 2005 and 2017. The primary endpoint was biochemical recurrence-free survival, defined as two consecutive prostate-specific antigen measurements ≥0.2 ng/ml after surgery. The individual quantitative risk score (IQRS) of each amount (primary/secondary/tertiary) of each Gleason pattern (3/4/5) was calculated using the Cox regression model. On the basis of the IQRS, the modified Gleason grade grouping (mGGG) model was developed. As a robustness analysis of the mGGG model, salvage treatment-free survival was also assessed. Results During a median follow-up of 45 months, 229 of 1022 (22.4%) patients developed biochemical recurrence. The IQRS of each Gleason pattern was as follows: primary 5, 1.81 points (hazard ratio [HR] 6.13); secondary 5, 1.37 points (HR 3.92); tertiary 5, 0.87 points (HR 2.39); primary 4, 1.07 points (HR 2.91); secondary 4, 0.79 points (HR 2.21); and any Gleason pattern 3, 0 points (HR 1). Based on the IQRS, the mGGG model was developed, which classified patients into the following five groups: I (3 + 3 or less); II (3 + 4); III (4 + 3); IV (3 + 4 + t5, 4 + 3 + t5, 3 + 5, 5 + 3, and 4 + 4); V (4 + 4 + t5, 4 + 5, 5 + 4, and 5 + 5). The c-index for biochemical recurrence-free survival was significantly improved from 0.655 of the original GGG model to 0.672 of the mGGG model (P P Conclusions The quantitative risk of tertiary (

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.

Frailty was associated with delayed extubation on protocol‐based weaning from mechanical ventilation., Aim Frailty has been shown to be associated with prolonged mechanical ventilation (MV). However, due to limited physiological data, it has been unclear how frailty affects weaning from MV in septic patients subjected to a specific weaning protocol. Methods This was a single‐center retrospective cohort study. The study included patients with sepsis on MV who underwent protocol‐based weaning between August 2015 and December 2018. Frailty was defined as a Clinical Frailty Scale score 4 or more. The association between frailty and weaning was evaluated. Results Ninety‐nine eligible patients were identified and categorized as frail (n = 67) or not frail (n = 32). The duration of MV was significantly longer in the frail group (8 days versus 5 days, P

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

Although small-scale studies have described the effects of oxytocin on social deficits in autism spectrum disorder (ASD), no large-scale study has been conducted. In this randomized, parallel-group, multicenter, placebo-controlled, double-blind trial in Japan, 106 ASD individuals (18–48 y.o.) were enrolled between Jan 2015 and March 2016. Participants were randomly assigned to a 6-week intranasal oxytocin (48IU/day, n = 53) or placebo (n = 53) group. One-hundred-three participants were analyzed. Since oxytocin reduced the primary endpoint, Autism Diagnostic Observation Schedule (ADOS) reciprocity, (from 8.5 to 7.7; P

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.

Tatsunori Shimoi,1 Akihiko Shimomura,1 Tadahiko Shien,2 Yukari Uemura,3 Hiroaki Kato,4 Masahiro Kitada,5 Tatsuya Toyama,6 Tomohiko Aihara,7 Hirofumi Mukai8 1Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan; 2Department of Breast and Endocrine Surgery, Okayama University Hospital, Okayama, Japan; 3Division of Biostatistics, Clinical Research Support Center, Tokyo University Hospital, Tokyo, Japan; 4Department of Thoracic Surgery, Teine Keijinkai Hospital, Sapporo, Japan; 5Department of Surgery, Asahikawa Medical University, Asahikawa, Japan; 6Department of Oncology, Immunology and Surgery, Nagoya City University, Graduate School of Medical Science, Nagoya, Japan; 7Department of Breast Surgery, Keimeikai-Aihara Hospital, Osaka, Japan; 8Department of Breast and Medical Oncology, National Cancer Center Hospital East, Chiba, Japan Background: This is a randomized, multicenter, open-label, Phase II study designed to evaluate the efficacy of everolimus added to continuous aromatase inhibitor (AI) administration in patients who had maintained stable disease or a better response for at least 5 months.Patients and methods: Patients will be randomized to everolimus and standard therapy groups (1:1 ratio). In the everolimus group, patients will receive everolimus in addition to the AI agent. The standard therapy group will continue AI alone treatment. The primary endpoint is progression-free survival. Target accrual is 130 patients with a two-sided type I error rate of 10% and 80% power to detect 35% risk reduction.Conclusion: The Chloe trial will provide important information about the efficacy and safety of adding everolimus to AI in patients with estrogen receptor-positive and human epidermal growth factor 2-negative metastatic breast cancer. Keywords: hormone receptor-positive, breast cancer, aromatase inhibitor, everolimus

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.

Progression of anemia in patients with chronic kidney disease (CKD) is associated with an increased risk of death and hospitalization. It is not sufficiently clear whether treating renal anemia with recombinant human erythropoietin (rHuEPO) has a beneficial effect on early survival after hemodialysis (HD) initiation in patients with CKD. The study was an open-label multicenter retrospective cohort study to evaluate the relationship between rHuEPO treatment and early survival after HD initiation in patients with CKD. Predialysis patients with CKD were divided into two groups: an rHuEPO-treated group (rHuEPO group) and a non-treatment group. The primary endpoint was all-cause mortality in the year after HD initiation. A total of 3261 patients were enrolled (2275 in the rHuEPO group and 986 in the non-treatment group). One-year survival was 95.36% in the rHuEPO group and 90.36% in the non-treatment group. The survival rate was significantly higher in the rHuEPO group (P < 0.0001). The results of multivariate analysis confirmed that predialysis treatment with rHuEPO is a predictor for reduced mortality risk (hazard ratio = 0.61, 95% confidence interval: 0.42-0.87, P = 0.006). Risk for the composite event of death/hospitalization was also lower in the rHuEPO group (hazard ratio = 0.88, 95% confidence interval: 0.78-0.98, P = 0.026). The results of this study suggest that treatment with rHuEPO can decrease early mortality risk after initiation of HD in patients with CKD. A prospective study is needed to further investigate early survival after HD initiation.

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.

The survival impact of the preoperative prognostic nutritional index (PNI) has been investigated in older patients with gastric carcinoma (GC), while that of the postoperative PNI has yet to be addressed. We evaluated the significance of PNI before and after surgery in older GC patients (≥75 years).In total, 309 older GC patients undergoing radical gastrectomy between 2006 and 2016 were retrospectively reviewed. The PNI was evaluated before and at six months after gastrectomy. Patients were divided into low (45) and high (≥45) PNI groups. The impact of low PNI on overall survival (OS), cancer-specific survival (CSS), and non-GC-related death were investigated.Low PNI was present in 134 patients (43.4%) preoperatively and 121 (39.2%) postoperatively. Low pre-PNI was independently associated with poor overall survival (P .001). Similarly, OS was significantly stratified by post-PNI (P .001). The significant survival difference according to post-PNI was present only in pStage I disease (P .001). Low post-PNI independently increased the risk of non-GC-related death in a multivariable analysis (P = .002). In contrast, CSS was not stratified by post-PNI (P = .45). In the high pre-PNI group, total gastrectomy and super-older age (≥80 years) independently increased the risk of low post-PNI, which was significantly associated with poor survival outcomes.Pre- and post-operative PNI are useful for predicting long-term outcomes in older patients with GC. Low postoperative PNI is a powerful determinant of mortality due to other diseases. Optimal perioperative management is required for those at high risk of malnutrition postoperatively.

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.

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 and aims Clinical data regarding alendronate jelly are limited. We compared the efficacy and safety of once‐weekly alendronate oral jelly with once‐weekly alendronate tablet formulations in the context of primary osteoporosis. Methods In this 6‐month, open‐label, prospective, observational study, Japanese patients aged ≥60 years with primary osteoporosis were included from 14 primary care centres in Japan. The effects of once‐weekly alendronate oral jelly and tablet formulations on bone mineral density (BMD), bone turnover markers, and quality of life related to gastrointestinal symptoms were assessed at baseline and 6 months. Treatment was allocated by patient preference. This potentially confounding factor was adjusted for statistically. Results In total, 170 patients were enrolled (jelly, n = 97; tablet, n = 73). Mean percent changes in radius, lumbar spine, femoral neck, and hip BMD were similar in both treatment groups at 6 months. Both formulations decreased tartrate‐resistant acid phosphatase 5b (TRACP‐5b) and procollagen 1 N‐terminal peptide (P1NP) between baseline and 6 months (by about 50% and 60%, respectively); no significant differences in mean changes were noted in these markers between groups. At 6 months, no significant differences were noted in visual analogue scale or EuroQOL five‐dimension questionnaire scores between groups. The jelly group had significantly lower scores than the tablet group in the Izumo scale domains of heartburn (−0.81, P = 0.0040), epigastralgia (−0.94, P = 0.0003), and epigastric fullness (−0.49, P = 0.044). During treatment, more patients discontinued for upper gastrointestinal symptoms in the tablet group (n = 4) than the jelly group (n = 1). Conclusions Once‐weekly alendronate oral jelly 35 mg may be a suitable alternative therapeutic agent for primary osteoporosis in Japan.

Background Currently, there are no specific effective treatments for SARS-CoV-2 infection; however, various COVID-19 treatment options are under investigation. It is vital to continue investigating the landscape of SARS-CoV-2–induced pneumonia and therapeutic interventions. Objective This paper presents the protocol for a randomized controlled trial that aims to compare the pneumonia exacerbation rate between ciclesonide (ALVESCO; Teijin Pharma Limited) administration and symptomatic treatment in patients with COVID-19 and to determine the efficacy of ciclesonide. The secondary objectives are to investigate the safety of ciclesonide administration, changes in clinical and laboratory findings, and the number of viral genome copies of SARS-CoV-2 over time between the 2 groups. Methods In this investigator-initiated, exploratory, prospective, multicenter, parallel-group, open-label, randomized controlled trial, a total of 90 patients diagnosed with COVID-19 will be recruited from 21 hospitals in Japan based on specific inclusion and exclusion criteria. Participants will be randomized either to the ciclesonide group, which will receive a 400-µg dose of ciclesonide 3 times per day over a 7-day period, or to the symptomatic treatment group. Both groups will receive antitussives and antipyretics as required. Data collection for various parameters will be conducted on days 1, 2, 4, 8, 22, and 29 to record baseline assessments and the findings over an extended period. Computed tomography images taken prior to drug administration and 1 week following treatment will be compared, and efficacy will be confirmed by checking for pneumonia exacerbation. Primary endpoint analysis will be performed using the Fisher exact test to determine statistically significant differences in the pneumonia exacerbation rate between the ciclesonide and symptomatic treatment groups. Results The first trial participant was enrolled on April 3, 2020. Recruitment is expected to be completed on September 30, 2020, while follow-up assessments of all participants are expected to be completed by October 31, 2020. The study results will be published in a peer-reviewed scientific journal. Conclusions The RACCO (Randomized Ciclesonid COVID-19) study will provide definitive comparative effectiveness data and important clinical outcomes data between the ciclesonide and symptomatic treatment groups. If the hypotheses that pneumonia exacerbation rate reduction is more significant in the ciclesonide treatment group than in the symptomatic treatment group and that ciclesonide is safe for use are valid, ciclesonide will serve as an important therapeutic option for patients with COVID-19. Trial Registration Japan Registry of Clinical Trials jRCTs031190269; https://jrct.niph.go.jp/en-latest-detail/jRCTs031190269 International Registered Report Identifier (IRRID) DERR1-10.2196/23830