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Clarification by means of sensory tests whether taste, aroma, or texture is the dominant contributor to people's ability to identify the animal species of meat is discussed. The result reveals that animal species of meat pieces, patties, and soups prepared from beef, pork and chicken support the hypothesis that aroma is most important contributor to the identification of animal species of meat and texture is the second most important contributor.

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/m 2 /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/m 2 /beat; 95% confidence interval, 1.00-1.43 /g/m 2 /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., (© 2023. The Author(s).)

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., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

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., Competing Interests: Declarations of interest None., (Copyright © 2023 Elsevier Ltd and Japan Neuroscience Society. All rights reserved.)

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-1β. 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

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., Competing Interests: Disclosures None.

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., Competing Interests: Declaration of interests Y.H. reports that Kobe City Eye Hospital received a research grant from the Japan Agency for Medical Research and Development (AMED) (grant number: JP19bk0104082) and financial support from Sumitomo Pharma Co. Ltd. for this study. S.S., T.M., M.Y., and M.T. are employed by Vision Care, Inc. T.H., A.N., K.U., K.O., H.O., M. Fujiwara, S. Yamasaki, K.W., K.B., K.K., A.I., and A.K. are employed by Sumitomo Pharma Co. Ltd. T.K. is a board member of Sumitomo Pharma Co. Ltd. The authors are co-inventors on patent applications., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

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., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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 ± 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 ± 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 ± 8 years) or intermediate (83 ± 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., Competing Interests: Declaration of competing interest None to declare., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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., (© 2022 John Wiley & Sons Ltd.)

Background/aim: This study was conducted to ascertain the optimal combination of non-contrast magnetic resonance (MR) imaging sequences for the differential diagnosis between small angiomyolipoma (AML) with minimal fat and clear cell renal cell carcinoma (CCRCC)., Patients and Methods: Thirty-nine patients with pathologically proven AML with minimal fat (n=6) or CCRCC (n=33) measuring 4 cm or less were included. All underwent MR imaging before partial nephrectomy or percutaneous biopsy. Four quantitative parameters of tumors were evaluated: signal intensity (SI) index of T1W- gradient-echo imaging, SI index of T2- fat suppression imaging (T2-SI index), apparent diffusion coefficient (ADC) value, and standard deviation (SD) of ADC. These quantitative parameters were compared using Wilcoxon rank-sum test and receiver operating characteristic (ROC) curve analyses. The optimal combination of quantitative parameters was sought using logistic regression analysis., Results: Comparison of quantitative parameters showed that the T2-SI index (median, AML with minimal fat vs. CCRCC; 0.74 vs. 1.27, p<0.001), ADC value (1.12 vs. 1.75, p=0.005), and SD of ADC (104 vs. 233, p<0.001) were significantly lower in AML with minimal fat than CCRCC. From the ROC curve analysis, the highest area under the curve (1.000; 100% sensitivity; 100% specificity) was obtained using the logistic regression model with the SD of ADC and T2-SI index or ADC value as explanatory variables., Conclusion: SD of ADC combined with T2-SI index or ADC value exhibited the highest diagnostic performance for differentiating small AML with minimal fat from CCRCC., (Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Statins have been shown to prevent microvascular dysfunction that may cause periprocedural myocardial infarction after percutaneous coronary intervention (PCI). Evolocumab has more potent lipid-lowering properties than statins.  Aims: The aims of this study were to investigate whether evolocumab pretreatment on top of statin therapy could prevent periprocedural microvascular dysfunction.  Methods: This study included 100 patients with stable coronary artery disease who were scheduled to undergo PCI and had high low-density lipoprotein cholesterol (LDL-C) under statin therapy. Patients were randomised to receive evolocumab 140 mg every 2 weeks for 2 to 6 weeks before PCI (evolocumab group: N=54) or not (control group: N=46). The primary endpoint was the index of microvascular resistance (IMR) after PCI. Troponin T was measured before and 24 hours after PCI.  Results: Geometric mean LDL-C was 94.1 (95% confidence interval [CI]: 86.8-102.1) mg/dl and 89.4 (95% CI: 83.5-95.7) mg/dl at baseline, and 25.6 (95% CI: 21.9-30.0) mg/dl and 79.8 (95% CI: 73.9-86.3) mg/dl before PCI, in the evolocumab group and in the control group, respectively. PCI was performed 22.1±8.5 days after allocation. Geometric mean IMR was 20.6 (95% CI: 17.2-24.6) in the evolocumab group and 20.6 (95% CI: 17.0-25.0) in the control group (p=0.98). There was no significant difference in the geometric mean of post-PCI troponin T (0.054, 95% CI: 0.041-0.071 ng/ml vs 0.054, 95% CI: 0.038-0.077 ng/ml; p=0.99) and in the incidence of major periprocedural myocardial infarction between the 2 groups (44.4% vs 44.2%; p=1.00).  Conclusions: Evolocumab pretreatment did not prevent periprocedural microvascular dysfunction in patients on modern medical management with statins.

Laparoscopic total gastrectomy (LTG) is a highly technical surgery that can lead to postoperative complications. Whether the recently introduced robotic surgery overcomes the drawbacks of laparoscopic surgery in total gastrectomy remains controversial. Therefore, we aimed to elucidate the potential benefits of robotic total gastrectomy (RTG) and compare the short-term outcomes of RTG and LTG. We retrospectively analyzed 56 patients with primary gastric or esophagogastric junction cancer who underwent RTG or LTG between June 2017 and July 2021. The groups were compared in terms of operative outcomes and postoperative complications. Potential risk factors associated with postoperative complications were assessed by performing multivariable analysis using logistic regression models via the exact method. Operation time was significantly longer, and postoperative hospital stay was significantly shorter in the robotic group (550 vs. 466 min, P < 0.001; 13 vs. 18 days, P = 0.013, respectively). The incidence of overall postoperative complications of Clavien-Dindo grade ≥ II was 18.5% and 24.1% in the RTG and LTG groups, respectively. Pancreatic fistulas were not observed, but other local complications were observed in 0% and 17.2% of the RTG and LTG groups, respectively (P = 0.052). In the multivariable analysis, the independent risk factors for local complications were laparoscopic surgery (odds ratio [95% confidence interval] 8.542 [1.065-∞], P = 0.045) and esophagogastric junction cancer (16.646 [2.559-∞], P = 0.005). Compared with LTG, RTG was associated with fewer local complications (mainly anastomotic leakage), especially in cases of esophagogastric junction cancer with high anastomotic sites., (© 2021. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

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., (© 2022 John Wiley & Sons Ltd.)

Percutaneous coronary intervention (PCI) is a standard treatment in patients with stable coronary artery disease (CAD); however, periprocedural myocardial infarction (PMI) remains a common complication of PCI. Aggressive lipid-lowering therapy with statin has shown to reduce the incidence of PMI by preventing coronary microvascular dysfunction. It is unclear whether evolocumab, a potent lipid-lowering agent, could diminish microvascular damage after PCI. The EVOCATION trial (jRCTs051180022) is a multicenter, randomized, open-label, active-controlled, parallel-group, exploratory, investigator-initiated clinical study to evaluate whether pretreatment with evolocumab could decrease the index of microvascular resistance (IMR) after PCI in patients with stable CAD. This study population consists of 100 patients with stable CAD who will undergo PCI and have high low-density lipoprotein cholesterol levels despite administration of maximum tolerated dose of statins for at least 2 weeks. Eligible patients are randomized in a 1:1 ratio to receive either evolocumab 140 mg every 2 weeks in addition to standard of care treatment or standard of care treatment only for 2-6 weeks before PCI. The primary endpoint is IMR after PCI. The EVOCATION trial will evaluate whether pretreatment with evolocumab reduces periprocedural microvascular damage in patients with stable CAD undergoing PCI., (Copyright © 2021. Published by Elsevier Ltd.)

Background/aim: To evaluate the incidence and grade of radiation pneumonitis after volumetric modulated arc therapy (VMAT) performed for the treatment of non-small cell cancer (NSCLC)., Patients and Methods: Fifty consecutive non-surgical candidates with NSCLC underwent VMAT. Thirty-five patients had stage-III tumors and 15 had recurrent tumors. The prescribed radiation dose for the gross tumor and the elective nodal area was 69 Gy in 30 fractions and 51 Gy in 30 fractions, respectively., Results: Radiation pneumonitis developed in 38 patients (76%, 38/50), and grade ≥2 radiation pneumonitis developed in 11 patients (22%, 11/50). The percentage of lung volume that received a dose in excess of 5 Gy (V5), V10, V20, V30, and the mean lung dose (MLD) in the bilateral and ipsilateral lung were significantly associated with the development of grade ≥2 radiation pneumonitis., Conclusion: The incidence and degree of radiation pneumonitis are acceptable following treatment of NSCLC with VMAT., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: To develop and evaluate the accuracy of augmented reality (AR)-based patient positioning systems in radiotherapy., Materials and Methods: AR head-mounted displays (AR-HMDs), which virtually superimpose a three-dimensional (3D) image generated by the digital imaging and communications in medicine (DICOM) data, have been developed. The AR-based positioning feasibility was evaluated. Then, the setup errors of three translational axes directions and rotation angles between the AR and the conventional laser-based positioning were compared., Results: The AR-based pelvic phantom positioning was feasible. The setup errors of AR-based positioning were comparable to laser-based positioning in all translational axis directions and rotation angles. The time necessary for AR-based positioning was significantly longer than that for laser-based positioning (171.0 s vs. 47.5 s, p<0.001)., Conclusion: AR-based positioning for radiotherapy was feasible, and showed comparable positioning errors to those of conventional line-based positioning; however, a markedly longer setup time was necessary., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

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.

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., (© The Author(s) 2020. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Immune attacks are key issues for cell transplantation. To assess the safety and the immune reactions after iPS cells-derived retinal pigment epithelium (iPS-RPE) transplantation, we transplanted HLA homozygote iPS-RPE cells established at an iPS bank in HLA-matched patients with exudative age-related macular degeneration. In addition, local steroids without immunosuppressive medications were administered. We monitored immune rejections by routine ocular examinations as well as by lymphocytes-graft cells immune reaction (LGIR) tests using graft RPE and the patient's blood cells. In all five of the cases that underwent iPS-RPE transplantation, the presence of graft cells was indicated by clumps or an area of increased pigmentation at 6 months, which became stable with no further abnormal growth in the graft during the 1-year observation period. Adverse events observed included corneal erosion, epiretinal membrane, retinal edema due to epiretinal membrane, elevated intraocular pressure, endophthalmitis, and mild immune rejection in the eye. In the one case exhibiting positive LGIR tests along with a slight fluid recurrence, we administrated local steroid therapy that subsequently resolved the suspected immune attacks. Although the cell delivery strategy must be further optimized, the present results suggest that it is possible to achieve stable survival and safety of iPS-RPE cell transplantation for a year.

Tumour-Node-Metastasis (TNM) staging of colorectal cancer (CRC) needs further classification for better treatment because of disease heterogeneity. Although molecular classifications which are expensive and laborious are under study, cost and labour efficient subtyping is desirable. We assessed the combinations of preoperative tumour marker (TM) elevation and tumour lymphovascular invasion (LVI) as a solution. We used the pooled data of 7151 colon cancer (CC) patients and 4620 rectal cancer (RC) patients who received curative surgery between 2004 and 2008 in Japan. The best-matched subtyping for predicting relapse-free survival (RFS) was statistically selected using the c-index and Akaike's information criterion. This subtyping (TM-LVI), which consisted of three categories by TM elevation status and severity of LVI status, was an independent prognostic factor for RFS of CC (stage IIa, IIIb, and IIIc) and RC (stage I, IIa, IIb, IIIa, and IIIb) and also for disease specific survival of CC (stage IIa, IIb, IIIb, and IIIc) and RC (all stage except for IIc). Although TM-LVI classified CRC patients into low and high recurrence risk groups, the application of adjuvant therapy was not accordance with the TM-LVI status. TM-LVI may be a cost and labour efficient subtyping of colorectal cancer for better treatment strategy.

Myotonic dystrophy type 1 (DM1) is a multi-system disorder caused by CTG repeats in the myotonic dystrophy protein kinase (DMPK) gene. This leads to the sequestration of splicing factors such as muscleblind-like 1/2 (MBNL1/2) and aberrant splicing in the central nervous system. We investigated the splicing patterns of MBNL1/2 and genes controlled by MBNL2 in several regions of the brain and between the grey matter (GM) and white matter (WM) in DM1 patients using RT-PCR. Compared with amyotrophic lateral sclerosis (ALS, as disease controls), the percentage of spliced-in parameter (PSI) for most of the examined exons were significantly altered in most of the brain regions of DM1 patients, except for the cerebellum. The splicing of many genes was differently regulated between the GM and WM in both DM1 and ALS. In 7 out of the 15 examined splicing events, the level of PSI change between DM1 and ALS was significantly higher in the GM than in the WM. The differences in alternative splicing between the GM and WM may be related to the effect of DM1 on the WM of the brain., Competing Interests: The authors have declared that no competing interests exist.

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., (© 2019 John Wiley & Sons, Ltd.)

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/m 2 per day tegafur/gimeracil/oteracil (S-1; days 1-5, 8-12, 22-26, and 29-33), 60 mg/m 2 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., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

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., (© 2018, The International Biometric Society.)

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.