RAGE in circulating immune cells is fundamental for hippocampal inflammation and cognitive decline in a mouse model of latent chronic inflammation.

BACKGROUND: Latent chronic inflammation has been proposed as a key mediator of multiple derangements in metabolic syndrome (MetS), which are increasingly becoming recognized as risk factors for age-related cognitive decline. However, the question remains whether latent chronic inflammation indeed induces brain inflammation and cognitive decline. METHODS: A mouse model of latent chronic inflammation was constructed by a chronic subcutaneous infusion of low dose lipopolysaccharide (LPS) for four weeks. A receptor for advanced glycation end products (RAGE) knockout mouse, a chimeric myeloid cell specific RAGE-deficient mouse established by bone marrow transplantation and a human endogenous secretory RAGE (esRAGE) overexpressing adenovirus system were utilized to examine the role of RAGE in vivo. The cognitive function was examined by a Y-maze test, and the expression level of genes was determined by quantitative RT-PCR, western blot, immunohistochemical staining, or ELISA assays. RESULTS: Latent chronic inflammation induced MetS features in C57BL/6J mice, which were associated with cognitive decline and brain inflammation characterized by microgliosis, monocyte infiltration and endothelial inflammation, without significant changes in circulating cytokines including TNF-α and IL-1ß. These changes as well as cognitive impairment were rescued in RAGE knockout mice or chimeric mice lacking RAGE in bone marrow cells. P-selectin glycoprotein ligand-1 (PSGL-1), a critical adhesion molecule, was induced in circulating mononuclear cells in latent chronic inflammation in wild-type but not RAGE knockout mice. These inflammatory changes and cognitive decline induced in the wild-type mice were ameliorated by an adenoviral increase in circulating esRAGE. Meanwhile, chimeric RAGE knockout mice possessing RAGE in myeloid cells were still resistant to cognitive decline and brain inflammation. CONCLUSIONS: These findings indicate that RAGE in inflammatory cells is necessary to mediate stimuli of latent chronic inflammation that cause brain inflammation and cognitive decline, potentially by orchestrating monocyte activation via regulation of PSGL-1 expression. Our results also suggest esRAGE-mediated inflammatory regulation as a potential therapeutic option for cognitive dysfunction in MetS with latent chronic inflammation.

Clinical Efficacy and Safety of Nivolumab in Malignant Non-Pleural Mesothelioma: A Multicenter, Open-Label, Single-Arm, Japanese Phase II Trial (Viola) Protocol.

BACKGROUND: There is no authorized treatment for malignant non-pleural mesothelioma (MNPM) worldwide. In contrast to malignant pleural mesothelioma, MNPM has not been investigated, and no treatment has been established due to its rarity. OBJECTIVES: This multicenter, open-label, single-arm, Japanese phase II trial aims at evaluating the efficacy and safety of nivolumab, an immune checkpoint inhibitor, in advanced or metastatic MNPM treatment. METHODS: This phase II trial commenced in October 2020. Twenty-three patients with advanced or metastatic MNPM who meet the inclusion and exclusion criteria were enrolled from five institutions within 2 years. Regardless of prior therapy, 240 mg of nivolumab will be administered intravenously to MNPM patients every 2 weeks to investigate its efficacy and safety until disease progression or unacceptable toxicities are detected, or the patient's condition meets the withdrawal criteria. RESULTS: The primary endpoint is the objective response rate by central assessment following the Response Evaluation Criteria in Solid Tumors version 1.1. The secondary endpoints include disease control rate, overall survival, progression-free survival, adverse events, and treatment-related adverse events. CONCLUSIONS: This is the first prospective investigator-initiated trial to evaluate the effect of nivolumab monotherapy for MNPM.

Novel nomogram developed for determining suitability of metastatic castration-resistant prostate cancer patients to receive maximum benefit from radium-223 dichloride treatment-Japanese Ra-223 Therapy in Prostate Cancer using Bone Scan Index (J-RAP-BSI) Trial.

PURPOSE: To develop a novel nomogram for determining radium-223 dichloride (Ra-223) treatment suitability for metastatic castration-resistant prostate cancer (mCRPC) patients. METHODS: This Japanese Ra-223 Therapy in Prostate Cancer using Bone Scan Index (J-RAP-BSI) Trial was a retrospective multicenter investigation enrolled 258 mCRPC patients in Japan with Ra-223 treatment between June 2016 and August 2020, with bone scintigraphy findings before treatment, clinical data, and survival outcome available. A nomogram was constructed using prognostic factors for overall survival (OS) based on a least absolute shrinkage and selection operator Cox regression model. A sub-analysis was also conducted for patients meeting European Medicines Agency (EMA) guidelines. RESULTS: Within a median of 17.4 months after initial Ra-223 treatment, 124 patients (48.1%) died from prostate cancer. Predictive factors included (1) sum of prior treatment history (score 0, never prior novel androgen receptor-targeted agents (ARTA) therapy, never prior taxane-based chemotherapy, and ever prior bisphosphonate/denosumab treatment), (2) Eastern Cooperative Oncology Group (ECOG) performance status, (3) prostate-specific antigen doubling time (PSADT), (4) hemoglobin, (5) lactate dehydrogenase (LDH), and (6) alkaline phosphatase (ALP) levels, and (7) automated bone scan index (aBSI) value based on bone scintigraphy. The nomogram using those factors showed good discrimination, with apparent and optimism-corrected Harrell's concordance index values of 0.748 and 0.734, respectively. Time-dependent area under the curve values at 1, 2, and 3 years were 0.771, 0.818, and 0.771, respectively. In 227 patients meeting EMA recommendation, the nomogram with seven factors showed good discrimination, with apparent and optimism-corrected Harrell's concordance index values of 0.722 and 0.704, respectively. Time-dependent area under the curve values at 1, 2, and 3 years were 0.747, 0.790, and 0.759, respectively. CONCLUSION: This novel nomogram including aBSI to select mCRPC patients to receive Ra-223 with significantly prolonged OS possibility was found suitable for assisting therapeutic decision-making, regardless of EMA recommendation.

Risk factors for the postoperative recurrence of ulcerative colitis-associated colorectal cancer.

PURPOSE: Although ulcerative colitis-associated colorectal cancer (UC-CRC) has been described, there are few reports regarding recurrent cases of UC-CRC. In this study, we investigated the risk factors for UC-CRC recurrence. METHODS: Recurrence-free survival (RFS) was determined for 144 stage I to III cancer patients among 210 UC-CRC patients from August 2002 to August 2019. The Kaplan‒Meier method was used to obtain the cumulative RFS rate, and the Cox proportional hazard model was used to extract recurrence risk factors. The interaction term between cancer stage and prognostic factors specific to UC-CRC was evaluated using the Cox model. The Kaplan‒Meier method was applied by cancer stage to the UC-CRC-specific prognostic factors for which interaction effects were indicated. RESULTS: There were 18 cases of recurrence involving patients with stage I to III cancer, and the recurrence rate was 12.5%. The cumulative 5-year RFS rate was 87.5%. Multivariable analysis showed that age at surgery (hazard ratio (HR): 0.95, 95% CI: 0.91-0.99, p = 0.02), undifferentiated carcinoma (HR: 4.42, 95% CI: 1.13-17.24, p = 0.03), lymph node metastasis (HR: 4.11, 95% CI: 1.08-15.69, p = 0.03), and vascular invasion (HR: 8.01, 95% CI: 1.54-41.65, p = 0.01) were significant risk factors for recurrence. Patients with stage III CRC in the young adult (age < 50 years) group had a significantly worse prognosis than those in the adult (age ≥ 50 years) group (p < 0.01). CONCLUSION: Age at surgery was identified as a risk factor for UC-CRC recurrence. Young adult patients with stage III cancer may have a poor prognosis.

Preoperative higher right ventricular stroke work index increases the risk of de novo aortic insufficiency after continuous-flow left ventricular assist device implantation.

During continuous-flow left ventricular assist device (CF-LVAD) support, hemodynamic shear stress causes a burden on aortic valve (AV) leaflets, leading to de novo aortic insufficiency (AI). This study investigated the influence of preoperative hemodynamic parameters on de novo AI in CF-LVAD recipients. We reviewed 125 patients who underwent CF-LVAD implantation without concomitant AV surgery between 2005 and 2018. De novo AI was defined as moderate or severe AI in those with none or trivial preoperative AI. During mean 30 ± 16 months of CF-LVAD support, de novo AI-free rate was 86% and 67% at 1 and 2 years, respectively. Multivariable analysis showed that higher right ventricular stroke work index (RVSWI) (hazard ratio, 1.12 /g/m2/beat; 95% confidence interval, 1.00-1.20; p = 0.047) and trivial grade AI (hazard ratio, 2.8; 95% confidence interval, 1.2-6.4; p = 0.020) were independent preoperative risk factors for de novo AI. The longitudinal analysis using generalized mixed effects model showed that higher RVSWI was associated with continuous AV closure after LVAD implantation (Odd ratio, 1.20/g/m2/beat; 95% confidence interval, 1.00-1.43 /g/m2/beat; p = 0.047). Right heart catheterization revealed that preoperative RVSWI was positively correlated with postoperative pump flow index in patients with continuously closed AV (r = 0.44, p = 0.04, n = 22). Preoperative higher RVSWI was a significant risk factor for de novo AI following CF-LVAD implantation. In patients with preserved right ventricular function, postoperative higher pump flow may affect AI development via hemodynamic stress on the AV.

Blinded sample size re-estimation for comparing over-dispersed count data incorporating follow-up lengths.

Blinded sample size re-estimation (BSSR) is an adaptive design to prevent the power reduction caused by misspecifications of the nuisance parameters in the sample size calculation of comparative clinical trials. However, conventional BSSR methods used for overdispersed count data may not recover the power as expected under the misspecification of the working variance function introduced by the specified analysis model. In this article, we propose a BSSR method that is robust to the misspecification of the working variance function. A weighted estimator of the dispersion parameter for the BSSR is derived, where the weights are introduced to incorporate the difference in the distribution of follow-up length between the interim analysis with BSSR and the final analysis. Simulation studies demonstrated the power of the proposed BSSR method was relatively stable under misspecifications of the working variance function. An application to a hypothetical randomized clinical trial of a treatment to reduce exacerbation rate in patients with chronic obstructive pulmonary disease is provided.

Regulatory issues and the potential use of Bayesian approaches for early drug approval systems in Japan.

Bayesian methods quantify and interpret the therapeutic effects of investigational drugs based on probability statements of the posterior distribution. However, the basic principle underlying the use of Bayesian methods in registration trials for new drug applications in Japan has not been adequately discussed. Motivated by the two drug approval systems for early approval recently enacted in Japan, we present our perspectives on the application of the Bayesian approach in registration trials in Japan. These are based on discussions among academic, industry, and regulatory experts at invited workshops. Based on the aforementioned early approval systems, we discuss putative common regulatory issues related to the use of the Bayesian approach and introduce instances of clinical trials in which the Bayesian approach is expected to be used. This article provides a well-defined premise for the discussion between industry and regulatory agencies on the use of Bayesian approaches for early drug approval in Japan.

Four-quadrant visualization of systemic circulatory equilibrium: right ventricular failure after left ventricular assist device implantation.

Right ventricular failure (RVF) is a serious adverse event after left ventricular assist device (LVAD) implantation but difficult to be characterized. This study aimed to visualize the dynamic circulatory equilibrium of acute RVF after LVAD implantation using a new four-quadrant diagram constructed by 1) cardiac function with central venous pressure (CVP) and cardiac index (CI) axes, 2) arterial vascular resistance with CI and mean blood pressure (mBP) axes, 3) pressure-diuretic function with mBP and net urinary sodium output (net U-Na) axes, and 4) venous compliance with net U-Na and CVP axes. Twenty LVAD patients were stratified into two groups, group S (≤10 days) and group L (>10 days), according to duration of postoperative inotropic support. The preoperative equilibrium loops were small in both groups. In the early postoperative phase, the loop in group S became dramatically enlarged to the left and upward, indicating increased CVP and CI by LVAD support. In group L, however, augmentation of CI was smaller despite similarly increased CVP, and net U-Na was decreased despite increased mBP. In the late postoperative phase, the equilibrium loop in group L recovered as similar to that seen in group S. Thus, acute RVF, as shown in group L, was characterized by the shape of the loop constructed by marked increased CVP, a relatively small increase in CI, and concomitant impairment of pressure natriuresis. In conclusion, the novel four-quadrant presentation of systemic circulatory equilibrium provides clear visualization of RVF after LVAD implantation, thus serving as a useful guide for prompt and optimal management.NEW & NOTEWORTHY Systemic circulatory dynamics are regulated by various negative feedback systems, including cardiac, arterial, venous, and renal functions, as well as autonomic nervous systems. The present novel four-quadrant presentation of their functions allows clear visualization of dynamic organ-to-organ interactions that can lead to a new circulatory equilibrium after therapeutic intervention. This new system physiological framework can serve as a useful guide for prompt and optimal management of circulatory malfunction.

Anastomosis behind the sternoclavicular joint is associated with increased incidence of anastomotic stenosis in retrosternal reconstruction with a gastric conduit after esophagectomy.

Anastomotic stenosis after esophagectomy is a major cause of long-term morbidity because it leads to poor dietary intake and malnutrition that markedly reduces the quality of life. The aim of this study was to test the hypothesis that anastomosis behind the sternoclavicular (SC) joint in retrosternal reconstruction is associated with an increased risk of anastomotic stenosis compared with anastomosis deviated from the joint. Among 226 patients who underwent esophagectomy for esophageal cancer between April 2010 and March 2019, we selected 114 patients who underwent retrosternal reconstruction using a gastric conduit for this study. They were classified into two groups according to the location of the anastomosis as determined by axial sections on postoperative computed tomography scans: anastomosis located behind the SC joint (Group B; n = 71) and anastomosis deviated from the joint (Group D; n = 43). The primary endpoint was the difference in the incidence of anastomotic stenosis between the two groups. Whether the occurrence of anastomotic leak affected the likelihood of anastomotic stenosis was also investigated. The incidence of anastomotic stenosis was significantly higher in Group B than in Group D (71.8% [n = 51] vs. 18.6% [n = 8]; P < 0.0001). The incidence of stenosis in patients who developed an anastomotic leak was significantly higher in Group B than in Group D (88.0% vs. 41.7%; P = 0.0057), although the findings were similar in patients who did not develop anastomotic leak (63.0% and 9.7%, respectively; P < 0.0001). We conclude that anastomosis located behind the SC joint in retrosternal reconstruction with a gastric conduit after esophagectomy is associated with an increased risk of anastomotic stenosis regardless of the development of anastomotic leak.

Statistical testing strategies for assessing treatment efficacy and marker accuracy in phase III trials.

When a candidate predictive marker is available, but evidence on its predictive ability is not sufficiently reliable, all-comers trials with marker stratification are frequently conducted. We propose a framework for planning and evaluating prospective testing strategies in confirmatory, phase III marker-stratified clinical trials based on a natural assumption on heterogeneity of treatment effects across marker-defined subpopulations, where weak rather than strong control is permitted for multiple population tests. For phase III marker-stratified trials, it is expected that treatment efficacy is established in a particular patient population, possibly in a marker-defined subpopulation, and that the marker accuracy is assessed when the marker is used to restrict the indication or labelling of the treatment to a marker-based subpopulation, ie, assessment of the clinical validity of the marker. In this paper, we develop statistical testing strategies based on criteria that are explicitly designated to the marker assessment, including those examining treatment effects in marker-negative patients. As existing and developed statistical testing strategies can assert treatment efficacy for either the overall patient population or the marker-positive subpopulation, we also develop criteria for evaluating the operating characteristics of the statistical testing strategies based on the probabilities of asserting treatment efficacy across marker subpopulations. Numerical evaluations to compare the statistical testing strategies based on the developed criteria are provided.

UGT1A1 polymorphisms in rectal cancer associated with the efficacy and toxicity of preoperative chemoradiotherapy using irinotecan.

The purpose of the present study was to assess the efficacy and toxicity of preoperative chemoradiotherapy using irinotecan against locally advanced lower rectal cancer according to UDP-glucuronosyltransferase 1A1 (UGT1A1) polymorphisms. Between 2009 and 2016, 46 patients with resectable rectal cancer (T3-T4, N0-N2, M0) received preoperative chemoradiotherapy consisting of 80 mg/m2 per day tegafur/gimeracil/oteracil (S-1; days 1-5, 8-12, 22-26, and 29-33), 60 mg/m2 per day irinotecan (days 1, 8, 22, and 29), and 45 Gy radiation (1.8 Gy/day, 5 days per week for 5 weeks). Six to eight weeks after completing chemoradiotherapy, total mesorectal excision was carried out. Patients with UGT1A1 polymorphisms were divided into WT (n = 26), heterozygous (n = 15), and homozygous (n = 5) groups, the latter including double heterozygosities. We evaluated associations between clinical characteristics, including UGT1A1 polymorphisms, and chemoradiotherapy efficacy and toxicity. Incidence rates of grade 3+ neutropenia and diarrhea were 17.0% and 30.4%, respectively. Relative dose intensity was 89.3%. Pathological complete response rate (grade 3) was 26.1%, and the good response (grade 2/3) rate was 84.8%. UGT1A1 polymorphisms were significantly associated with neutropenia and pathological good responses, but not with diarrhea. UGT1A1 polymorphism was the only predictive factor for pathological good responses. Our results indicate that UGT1A1 polymorphism is a predictive factor to determine the clinical efficacy of preoperative chemoradiotherapy and hematological toxicity induced by chemoradiotherapy using irinotecan in locally advanced rectal cancer patients.

Power and sample size calculation incorporating misspecifications of the variance function in comparative clinical trials with over-dispersed count data.

Over-dispersed count data are frequently observed in clinical trials where the primary endpoint is occurrence of clinical events. Sample sizes of comparative clinical trials with these data are typically calculated under negative binomial models or quasi-Poisson models with specified variance functions, or under the assumption that the specified "working" variance functions are correctly specified. In this article, we propose a sample size formula anticipating misspecifications of the working variance function. We derived a method based on the asymptotic distribution of a Wald test statistic with a sandwich-type robust variance estimator under quasi-Poisson models. Under misspecifications of the working variance function, the asymptotic variance of the estimator of the treatment effect is expressed as a form involving both true and working variance functions. Our sample size formula includes several existing formulas as special cases when the working variance function is correctly specified as the true variance function. We also consider a sensitivity analysis for possible misspecifications of the "true" variance function when estimating sample sizes using our formula. A simulation study demonstrated the adequacy of our formulas in finite sample size settings. An application to a clinical trial to evaluate the treatment effect on prevention of COPD exacerbation is provided.

Analysis of splicing abnormalities in the white matter of myotonic dystrophy type 1 brain using RNA sequencing.

Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by the genomic expansion of CTG repeats, in which RNA-binding proteins, such as muscleblind-like protein, are sequestered in the nucleus, and abnormal splicing is observed in various genes. Although abnormal splicing occurs in the brains of patients with DM1, its relation to central nervous system symptoms is unknown. Several imaging studies have indicated substantial white matter defects in patients with DM1. Here, we performed RNA sequencing and analysis of CTG repeat lengths in the frontal lobe of patients with DM1, separating the gray matter and white matter, to investigate splicing abnormalities in the DM1 brain, especially in the white matter. Several genes showed similar levels of splicing abnormalities in both gray and white matter, with an observable trend toward an increased number of repeats in the gray matter. These findings suggest that white matter defects in DM1 stem from aberrant RNA splicing in both gray and white matter. Notably, several of the genes displaying abnormal splicing are recognized as being dominantly expressed in astrocytes and oligodendrocytes, leading us to hypothesize that splicing defects in the white matter may be attributed to abnormal RNA splicing in glial cells.

Risk Factors Causing Hypothyroidism in Patients With Head and Neck Cancer After Radiotherapy Using SIB-VMAT.

BACKGROUND/AIM: We evaluated the incidence of radiation-induced hypothyroidism and its risk factors in patients with head and neck cancer who underwent radiotherapy using simultaneous integrated boost-volumetric-modulated arc therapy (SIB-VMAT). PATIENTS AND METHODS: This retrospective study included 86 patients who received definitive radiotherapy using SIB-VMAT for head and neck cancer. The incidence of ≥ grade 2 hypothyroidism was evaluated. We also evaluated the relationships between hypothyroidism development and clinical factors and thyroid dose-volume parameters. RESULTS: During a median follow-up period of 17 months (range=3-65 months), 31 patients (36.0%, 31/86) developed grade 2 hypothyroidism requiring hormone replacement therapy. No patients experienced ≥ grade 3 hypothyroidism. The cumulative incidences of hypothyroidism at 1 and 2 years after radiation therapy were 24.5% and 38.7%, respectively, with a median onset time of 10.0 months (range=3.0-35.0 months). Thyroid volume (p=0.003), volume of the thyroid spared at 60 Gy (VS60; cut-off value, 5.16 ml; p=0.009), VS70 (cut-off value, 8.0 ml; p=0.007), VS60 equivalent dose in 2 Gy fraction (EQD2; cut-off value, 7.78 ml; p=0.001), and VS70EQD2 (cut-off value, 10.59 ml; p=0.008) were significantly associated with the development of radiation-induced hypothyroidism. CONCLUSION: Radiation-induced hypothyroidism is not rare in patients with head and neck cancer undergoing radiotherapy using SIB-VMAT. Radiation dose-volume parameters detected in this study may be useful indicators to prevent this complication.

The Comprehensive Complication Index in Ulcerative Colitis: A Comparison with the Clavien-Dindo Classification.

Introduction: The comprehensive complication index (CCI), which weights all postoperative complications according to severity and integrates them into a single formula, has been reported as a new evaluation system. We aimed to compare the CCI with the Clavien-Dindo Classification (CDC) to patients with ulcerative colitis (UC). Methods: Patients who underwent initial surgery for UC from April 2012 to March 2020 were included. The patients were classified into a length of stay (LOS) >30 days group or an LOS ≤30 days group. We performed a multivariate analysis of risk factors for LOS >30 days in the model with the factors identified in the univariate analysis plus the CCI (the CCI model) and plus CDC (the CDC model). An ROC curve was used to test the difference in the area under the curve (AUC) between the CCI model and the CDC model. Results: The median LOS was 21 days (IQR: 16-29 days), and the rate of LOS >30 days was 119/588 (20.2%). In the CCI model, age at the time of surgery (odds ratio [OR] = 1.24, 95% confidence interval [CI] 1.07-1.45, p = 0.01), ASA score ≥3 (OR = 1.94, 95% CI:1.00-3.76, p = 0.04), and CCI (OR = 1.07, 95% CI: 1.05-1.09; p < 0.01) were identified as independent risk factors for LOS >30 days. The AUC value of the CCI model (0.86) was significantly better in relation to LOS >30 days than that of the CDC model (0.82) (p = 0.02). Conclusion: The CCI was a better measure of LOS than was the CDC and was found to be a useful indicator in UC.

Nocturnal Hypertension and Left Ventricular Diastolic Dysfunction in Patients With Diabetes With the Absence of Heart Failure: Prospective Cohort HSCAA Study.

BACKGROUND: Diabetes is an important risk factor for heart failure (HF) and is associated with left ventricular (LV) diastolic dysfunction. However, diabetic comorbid conditions, such as nocturnal hypertension, as predictors of diastolic dysfunction are not known in the absence of an HF period. The present study was conducted as the longitudinal examination of the predictive value of nocturnal hypertension profiles on the progression of LV diastolic dysfunction in patients with and without diabetes without HF. METHODS: The subjects (154 diabetes and 268 nondiabetes) in the absence of HF were followed for 36.8±18.2 months. The relationships among the patterns of nocturnal hypertension and the outcome of LV diastolic dysfunction, defined as an increase in E/e'>14, were investigated in the patients with and without diabetes. RESULTS: The interaction effect of the diabetes status and the patterns of nocturnal hypertension on the hazard rate of the occurrence of E/e'>14 was statistically significant (P=0.017). Kaplan-Meier analysis results revealed that patients with diabetes with nondipper (P=0.021 versus dipper) and riser (P=0.006 versus dipper) had a greater risk for a diastolic dysfunction event. Furthermore, multivariable Cox proportional hazards analysis revealed that nondipper (hazard ratio, 4.56 [95% CI, 1.49-13.96]; P=0.007) and riser (hazard ratio, 3.89 [95% CI, 1.31-11.57]; P=0.014) patterns were associated with elevated risk of the outcome of LV diastolic dysfunction. In contrast, no similar significant associations were found in patients without diabetes. CONCLUSIONS: During the absence of HF periods, nocturnal hypertension is an important predictor for the progression of LV diastolic dysfunction in patients with diabetes.

Effect of azilsartan versus candesartan on nocturnal blood pressure variation in Japanese patients with essential hypertension.

BACKGROUND: Abnormal variations in night-time hypertension such as "non-dipping" type (< 10% decrease in nocturnal systolic blood pressure [SBP] from daytime SBP) are a risk factor for cardiovascular events independent of 24-h BP. METHODS: As part of a randomized, double-blind study of azilsartan (20-40 mg once daily) and candesartan (8-12 mg once daily) in Japanese patients with essential hypertension, an exploratory analysis was performed using ambulatory BP monitoring (ABPM) at baseline and Week 14. Effects of study drugs on nocturnal BP variations according to patients' nocturnal SBP dipping status were evaluated. RESULTS: ABPM data were available for 273 patients treated with azilsartan and 275 with candesartan. In the dipping group (≥ 10% decrease from daytime SBP), azilsartan produced a greater reduction from baseline in daytime than in night-time SBP (- 14.1 and - 10.9 mmHg, respectively), and the change in daytime SBP was significantly greater with azilsartan than with candesartan (p = 0.0077). In the non-dipping group, azilsartan produced a greater reduction from baseline in night-time than in daytime SBP (- 20.2 and - 9.9 mmHg, respectively), and reductions in both night-time SBP (p = 0.02) and daytime SBP (p = 0.0042) were significantly greater with azilsartan than with candesartan. CONCLUSIONS: Once-daily azilsartan improved non-dipping night-time SBP to a greater extent than candesartan in Japanese patients with grade I-II essential hypertension.

Long-term survival after surgical or transcatheter aortic valve replacement for low or intermediate surgical risk aortic stenosis: Comparison with general population.

BACKGROUND: Long-term survival after surgery for severe aortic stenosis (AS) provides important information regarding the choice between surgical (SAVR) and transcatheter (TAVR) aortic valve replacement. This study investigated the long-term survival of AS patients with low or intermediate surgical risk who underwent SAVR or TAVR in our institution versus that of the Japanese general population. METHODS: From 2009 to 2019, 1276 consecutive patients underwent SAVR or TAVR for severe AS. Among them, we retrospectively investigated those with low (n = 383) or intermediate (n = 137) surgical risk treated with SAVR and those with low (n = 86) or intermediate (n = 333) surgical risk treated with TAVR. Their post-intervention survival was compared with that of an age- and gender-matched Japanese general population. RESULTS: The overall 5-year survival rate of SAVR for patients with low surgical risk (mean age, 72 ±â€¯9 years) was not significantly different from that of the general population (90 % vs. 89 %, respectively; p = 0.58), whereas that of patients with intermediate surgical risk (77 ±â€¯6 years) was significantly lower than that of the general population (77 % vs. 84 %, respectively; p = 0.03). After TAVR, the 5-year survival of patients with low (78 ±â€¯8 years) or intermediate (83 ±â€¯5 years) surgical risk was significantly lower than that of the general population (low risk, 64 % vs. 81 %, p < 0.01; intermediate risk, 66 % vs. 71 %, respectively, p = 0.01). CONCLUSIONS: Our study demonstrated that long-term survival after SAVR for AS patients with low surgical risk was as good as that of the age- and gender-matched general population, while the long-term survival after SAVR for intermediate-risk or TAVR for low- or intermediate-risk patients was lower than that of the general population. These findings suggest that SAVR is an appropriate option for AS patients with low surgical risk and good life expectancy, especially in Japan, where the life expectancy is the longest worldwide.

Analysis of particle therapy registries based on a unified treatment policy for esophageal cancer.

This study aimed to evaluate the efficacy and safety of particle therapy (proton beam therapy and carbon-ion radiotherapy) for esophageal cancer by analyzing prospective nationwide registry data from particle therapy facilities throughout Japan. Patients diagnosed with esophageal cancer who received particle therapy between May 2016 and June 2018 were recruited from the registries of 12 particle therapy centers in Japan. Eventually, we enrolled 174 patients who met the inclusion criteria. Of the 174 patients, 137 (78.7%) were male, with a median age of 69 years (range: 41-88 years). Clinical stages included I (n = 55; 31.6%), II (n = 31; 17.8%), III (n = 82; 47.1%), IV (n = 3; 1.7%) and unknown (n = 3; 1.7%) (Union for International Cancer Control, seventh edition), and the median follow-up period was 908 days (range: 76-1669 days) for all patients. The 3-year overall survival (OS) rate, the 3-year progression-free survival (PFS) rate and the 3-year local control (LC) rates were 60.5, 53.2 and 72.7%, respectively. For each clinical stage, the 3-year OS rates were I, 84.8%; II, 60.3% and III, 42.9%; the 3-year PFS rates were I, 71.9%; II, 58.3% and III, 37.0% and the 3-year LC were I, 78.4%; II, 79.8% and III, 65.2%, respectively. Notably, four patients (2.3%) with ≥Grade 3 cardiopulmonary toxicities were observed (Common Terminology Criteria for Adverse Events, version 5.0). Our study showed that particle therapy for esophageal cancer has lower rates of adverse cardiopulmonary events than X-ray radiotherapy.

Safety and stable survival of stem-cell-derived retinal organoid for 2 years in patients with retinitis pigmentosa.

Transplantation of induced pluripotent stem cell (iPSC)-derived retinal organoids into retinal disease animal models has yielded promising results, and several clinical trials on iPSC-derived retinal pigment epithelial cell transplantation have confirmed its safety. In this study, we performed allogeneic iPSC-derived retinal organoid sheet transplantation in two subjects with advanced retinitis pigmentosa (jRCTa050200027). The primary endpoint was the survival and safety of the transplanted retinal organoid sheets in the first year post-transplantation. The secondary endpoints were the safety of the transplantation procedure and visual function evaluation. The grafts survived in a stable condition for 2 years, and the retinal thickness increased at the transplant site without serious adverse events in both subjects. Changes in visual function were less progressive than those of the untreated eye during the follow-up. Allogeneic iPSC-derived retinal organoid sheet transplantation is a potential therapeutic approach, and the treatment's safety and efficacy for visual function should be investigated further.