Treatment sequencing after failure to alectinib in patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer.

Alectinib is the first-line therapy for anaplastic lymphoma kinase-positive non-small-cell lung cancer. Although some guidelines have recommended using other anaplastic lymphoma kinase inhibitors after alectinib failure, evidence for such regimens in patients who fail to respond to alectinib is limited. This study involved using administrative claims data from acute care hospitals in Japan. We extracted the data of 634 patients diagnosed with lung cancer between September 1, 2014, and January 31, 2023, who received alectinib treatment before treatment with another anaplastic lymphoma kinase inhibitor. We assessed distributions of patients according to their treatment sequencing and prognosis among three periods defined based on the initial marketing dates of lorlatinib and brigatinib. The type of anaplastic lymphoma kinase inhibitors after alectinib failure changed over time. In the most recent period, lorlatinib (58%) and brigatinib (40%) became predominant. Two-year overall survival improved over time (47%-84%), accompanied by an increased 2-year proportion of patients who continuously used anaplastic lymphoma kinase inhibitors after alectinib failure (13%-44%). The times to treatment discontinuation of the regimen between patients treated with lorlatinib and brigatinib were similar, with a hazard ratio of 1.02 (95% confidence interval, 0.64-1.64) in the period after marketing brigatinib. This study provides insights into the evolving treatment landscape for patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer who experience failed alectinib treatment and highlights the need for further studies and data accumulation to determine the optimal treatment strategy.

Epidemiology and Risk Factors of Eosinophilic Esophagitis in Japan: A Population-Based Study.

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) has been increasingly diagnosed globally. However, there have been few general population-based studies in Asia. The aim of this study was to investigate EoE epidemiology in the Japanese general population. METHODS: We analyzed an employer-based health insurance claim database from January 2005 to September 2022. EoE cases were identified on the basis of the International Statistical Classification of Diseases and Health-related Problems, 10th Revision code, K20.0. We calculated the incidence and prevalence of EoE using Poisson regression and binomial distribution, respectively. Using 10 matched controls for each EoE case, a nested case-control study was performed to identify potential risk factors for EoE. RESULTS: Of 15,200,895 individuals, 1010 EoE cases were identified. The incidence and prevalence of EoE were 2.82 (95% confidence interval [CI], 2.44-3.26) per 100,000 person-years and 10.68 (95% CI, 10.01-11.37) per 100,000 people in 2022, nearly 3 and 8 times as high as those in 2017, respectively. Smoking was associated with decreased risk of EoE (odds ratio [OR], 0.45, 0.36-0.56, P < .001), whereas alcohol consumption (OR, 1.51, 1.21-1.88, P < .001) was associated with increased risk of EoE along with several allergic conditions and psychiatric disorders. EoE was not related to either body mass index or lifestyle-related diseases such as hypertension, diabetes mellitus, hyperuricemia, and dyslipidemia. CONCLUSIONS: The incidence and prevalence of EoE in Japan have steadily increased over the past 2 decades. Nevertheless, EoE remains less common in Japan compared with the United States and Western Europe. Factors contributing to the epidemiology of EoE on a global basis may improve our understanding of the contribution of genetic and environmental risk factors.

Immune Checkpoint Inhibitor Is Associated with Improved Survival in Advanced Non-small Cell Lung Cancer Occurring in Patients with Autoimmune Disease.

The use of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of advanced non-small cell lung cancer (NSCLC). However, clinical trials often exclude those with a history of autoimmune diseases (ADs) because of concerns regarding immune-related adverse events. Therefore, the efficacy of ICIs in advanced NSCLC patients with ADs should be evaluated. This study used administrative claims data from advanced treatment centers in Japan and identified patients with advanced NSCLC who began chemotherapy between December 2016 and January 2023. The patients were divided into four groups based on the presence of ADs and types of chemotherapy received. The association between ICI therapy and overall survival in the subgroups with or without ADs, and the association between the presence of AD and overall survival in patients who received ICI therapy and conventional chemotherapy, were analyzed using Cox proportional hazard regression, including therapy and presence of ADs and their interaction as covariates. These results were obtained using the inverse probability of treatment weighting. ICI therapy had a hazard ratio (95% confidence interval) for death in the subgroup of AD and non-AD patients of 0.88 (0.84-0.92) and 0.83 (0.71-0.97), respectively (p = 0.459 for interaction). For some specific ADs, including type 1 diabetes mellitus, the association between ICI therapy and decreased mortality was not observed. In conclusion, our study showed comparable associations between ICI therapy and reduced mortality in AD and non-AD subgroups of patients with advanced NSCLC. However, therapy strategies tailored to each AD type and thorough discussions regarding the risk-benefit profile are crucial.

Evaluating the association of body mass index with COVID-19 severity and mortality using Japanese administrative claims data.

INTRODUCTION: Obesity is a risk factor for aggravation of and mortality from coronavirus disease 2019 (COVID-19). We aimed to investigate the relationship between COVID-19 and Body Mass Index (BMI) in the Japanese population. METHODS: We used administrative claims data from an advanced treatment hospital in Japan and extracted data from patients hospitalized for COVID-19. The exposure variable was BMI measured at the time of admission, and the study outcomes were progression to critical illness and death. Analyses were performed for each age group. RESULTS: Overall, 58,944 patients met the inclusion criteria. The risk of critical illness increased monotonically with higher BMI. In contrast, the relationship between BMI and mortality follows a J-shaped curve; being underweight and obese are risk factors for mortality. When stratified by age, similar trends were observed for both critical illness and mortality. CONCLUSION: A higher BMI is a risk factor for the progression of COVID-19 severity, whereas both lower and higher BMIs are risk factors for mortality in the Japanese population.

Incidence and Potential Risk Factors of Human Cytomegalovirus Infection in Patients with Severe and Critical Coronavirus disease 2019.

BACKGROUND: Human cytomegalovirus (HCMV) infection occurs in immunosuppressed individuals and is known to increase mortality. Patients with coronavirus disease 2019 (COVID-19) are often treated with steroids, require intensive care unit (ICU) treatment, and may therefore be at risk for HCMV infection. However, which factors predispose severely ill patients with COVID-19 to HCMV infection and the prognostic value of such infections remain largely unexplored. This study aimed to examine the incidence and potential risk factors of HCMV infection in patients with severe or critical COVID-19 and evaluate the relationship between HCMV infection and mortality. METHODS AND FINDINGS: We used administrative claims data from advanced treatment hospitals in Japan to identify and analyze patients with severe or critical COVID-19. We explored potential risk factors for HCMV infection using multivariable regression models and their contribution to mortality in patients with COVID-19. Overall, 33,151 patients who progressed to severe or critical COVID-19 illness were identified. The incidence of HCMV infection was 0.3-1.7% depending on the definition of HCMV infection. Steroids, immunosuppressants, ICU admission, and blood transfusion were strongly associated with HCMV infection. Furthermore, HCMV infection was associated with patient mortality independent of the observed risk factors for death. CONCLUSIONS: HCMV infection is a notable complication in patients with severe or critical COVID-19 who are admitted to the ICU or receive steroids, immunosuppressants, and blood transfusion and can significantly increase mortality risk.

Assessment of patients' characteristics associated with the efficacy and safety of oral valganciclovir treatment for infants with symptomatic congenital cytomegalovirus disease.

INTRODUCTION: Insurance coverage for oral valganciclovir (VGCV) began in Japan in April 2023 on the basis of results, including our clinical trials for symptomatic congenital cytomegalovirus (CMV) disease. The VGCV treatment is available throughout Japan, so clinicians must consider the likelihood of hearing improvement and the possibility of neutropenia before dosing. MATERIALS AND METHODS: We performed a substudy of an investigator-initiated, single-arm, prospective, multicenter, clinical trial in which 24 infants with symptomatic congenital CMV disease were orally administered 16 mg/kg VGCV twice daily for 6 months as an intervention. We examined the infants' baseline characteristics associated with improved hearing impairment or a severely reduced neutrophil count. RESULTS: Of the 24 patients, 4 had normal hearing on assessment of their ear with the best hearing. Hearing impairment improved in 14 patients and did not respond to VGCV treatment in 6 patients at the 6-month hearing assessment. CMV DNA levels in plasma at baseline were higher in patients in whom hearing did not respond to treatment. A neutrophil count <500/mm3 occurred in 5 (21%) patients for the first 6 weeks and in 8 (33%) patients for the first 6 months. A neutrophil count at screening and the lowest neutrophil count over the 6 months showed the highest correlation (r = 0.477, p = 0.019). CONCLUSIONS: Infants with a low plasma viral load at screening tend to have an improvement in hearing impairment. Clinicians should be aware of neutropenia during VGCV treatment particularly in patients with a low neutrophil count during screening.

Lack of impact of ipragliflozin on endothelial function in patients with type 2 diabetes: sub-analysis of the PROTECT study.

BACKGROUND: We assessed the impact of 24 months of treatment with ipragliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on endothelial function in patients with type 2 diabetes as a sub-analysis of the PROTECT study. METHODS: In the PROTECT study, patients were randomized to receive either standard antihyperglycemic treatment (control group, n = 241 ) or add-on ipragliflozin treatment (ipragliflozin group, n = 241) in a 1:1 ratio. Among the 482 patients in the PROTECT study, flow-mediated vasodilation (FMD) was assessed in 32 patients in the control group and 26 patients in the ipragliflozin group before and after 24 months of treatment. RESULTS: HbA1c levels significantly decreased after 24 months of treatment compared to the baseline value in the ipragliflozin group, but not in the control group. However, there was no significant difference between the changes in HbA1c levels in the two groups (7.4 ± 0.8% vs. 7.0 ± 0.9% in the ipragliflozin group and 7.4 ± 0.7% vs. 7.3 ± 0.7% in the control group; P = 0.08). There was no significant difference between FMD values at baseline and after 24 months in both groups (5.2 ± 2.6% vs. 5.2 ± 2.6%, P = 0.98 in the ipragliflozin group; 5.4 ± 2.9% vs. 5.0 ± 3.2%, P = 0.34 in the control group). There was no significant difference in the estimated percentage change in FMD between the two groups (P = 0.77). CONCLUSIONS: Over a 24-month period, the addition of ipragliflozin to standard therapy in patients with type 2 diabetes did not change endothelial function assessed by FMD in the brachial artery. TRIAL REGISTRATION: Registration Number for Clinical Trial: jRCT1071220089 ( https://jrct.niph.go.jp/en-latest-detail/jRCT1071220089 ).

Rationale and design of an investigator-initiated, multicenter, prospective, placebo-controlled, double-blind, randomized trial to evaluate the effects of finerenone on vascular stiffness and cardiorenal biomarkers in type 2 diabetes and chronic kidney disease (FIVE-STAR).

BACKGROUND: The overactivation of mineralocorticoid receptor (MR) plays a key pathological role in the progression of cardiovascular and renal diseases by promoting pro-inflammatory and pro-fibrotic signaling. Recently, it has been found that finerenone, a novel nonsteroidal selective MR antagonist, can robustly improve cardiorenal outcomes in patients with type 2 diabetes (T2D) and a wide spectrum of chronic kidney disease (CKD). However, the mechanisms underlying the cardiorenal benefits of finerenone are poorly understood. Further, whether the clinical benefits are mediated by an improvement in vascular stiffness is not confirmed. Therefore, the current study aims to evaluate the effects of finerenone on vascular stiffness as assessed using cardio ankle vascular index (CAVI) and relevant cardiorenal biomarkers in patients with T2D and CKD. METHODS: The Effects of Finerenone on Vascular Stiffness and Cardiorenal Biomarkers in Type 2 Diabetes and Chronic Kidney Disease (FIVE-STAR) is an ongoing, investigator-initiated, multicenter, prospective, placebo-controlled, double-blind, randomized clinical trial in Japan. Its target sample size is 100 subjects. Recruitment will be performed from September 2023 to July 2024. After obtaining informed consent, eligible participants with T2D and CKD (25 mL/min/1.73 m2 ≤ estimated glomerular filtration ratio [eGFR] < 90 mL/min/1.73 m2 and 30 mg/g Cr ≤ urinary albumin-to-creatinine ratio [UACR] < 3500 mg/g Cr) will be equally randomized to receive 24-week treatment with either finerenone (starting dose at 10 mg once daily in participants with a baseline eGFR < 60 mL/min/1.73 m2 or at 20 mg once daily in those with a baseline eGFR ≥ 60 mL/min/1.73 m2) or dose-matched placebo. The primary endpoint is the change from baseline in CAVI at 24 weeks. The secondary endpoints are changes from baseline in UACR at 12 and 24 weeks and relevant serum and urinary biomarkers at 24 weeks. As an exploratory endpoint, proteomic analysis using the Olink® Target 96 panels will be also performed. DISCUSSION: FIVE-STAR is the first trial evaluating the therapeutic impact of finerenone on vascular stiffness and relevant cardiorenal biomarkers in patients with T2D and CKD. This study will provide mechanistic insights on the clinical benefits of finerenone based on recent cardiovascular and renal outcome trials. Trial registration Unique Trial Number, NCT05887817 ( https://clinicaltrials.gov/ct2/show/NCT05887817 ) and jRCTs021230011 ( https://jrct.niph.go.jp/latest-detail/jRCTs021230011 ).

Canagliflozin reduces proteinuria by targeting hyperinsulinaemia in diabetes patients with heart failure: A post hoc analysis of the CANDLE trial.

AIM: To investigate factors associated with proteinuria regression in patients with type 2 diabetes mellitus (T2DM) treated with canagliflozin. MATERIALS AND METHODS: This study was a post hoc analysis of the CANDLE trial (UMIN000017669), which compared the effect of 24 weeks of treatment with canagliflozin or glimepiride for changes in N-terminal pro-brain natriuretic peptide in patients with T2DM and chronic heart failure (CHF). Factors associated with regression of proteinuria at 24 weeks were evaluated with multivariate logistic models. RESULTS: The rate of regression of proteinuria was higher (28/102, 27.5% vs. 12/112, 10.7%), and that of progression was lower (9/102, 8.8% vs. 26/112, 23.2%), in the canagliflozin versus the glimepiride group (P = .0001). There were no differences in the change in the estimated glomerular filtration rate category between groups. Insulin level, homeostatic model assessment of ß-cell function, homeostatic model assessment for insulin resistance and estimated plasma volume were decreased at 24 weeks in the regression subclass but not in the progression subclass, suggesting that regression of proteinuria is associated with the declines in these values in the canagliflozin group. Higher insulin level at baseline was solely associated with proteinuria regression in the multivariate logistic regression model (baseline insulin, as per a 1-mlU/L increase, odds ratio 1.24 [1.05-1.47], P = .011). CONCLUSIONS: In patients with T2DM and CHF, regression of proteinuria with canagliflozin treatment was associated with the pretreatment insulin level. These results may provide clinicians with novel mechanistic insights into the beneficial effects of canagliflozin on renal outcomes and may warrant discussion for selecting preferred patient profiles, including pretreatment insulin levels.

Employment Status of Patients With Colorectal Cancer After Surgery: A Multicenter Prospective Cohort Study in Japan.

BACKGROUND: Because of improved survival rates, patients with colorectal cancer may try to return to work. Many countries, however, have limited knowledge of the employment status of these patients. OBJECTIVE: To explore the employment status of patients with colorectal cancer after surgery in Japan and the risk factors affecting the same. DESIGN: This is a prospective multicenter cohort study that used self-administered questionnaires. Patients were recruited from June 2019 to August 2020 and were followed up for 12 months after surgery. SETTING: Six community hospitals and 1 university hospital in Japan. PATIENTS: Patients with clinical stages I to III colorectal cancer, employed at the time of diagnosis. INTERVENTIONS: Patients who underwent surgical resection between June 2019 and August 2020. MAIN OUTCOME MEASUREMENTS: The time it takes patients to return to work after surgery and the proportion of working patients 12 months after surgery were collected using self-administered questionnaires. RESULTS: A total of 129 patients were included in the analyses. The median time to return-to-work was 1.1 months, and the proportion of working patients at 12 months after surgery was 79%. Risk factors for delayed return-to-work after surgery were an advanced tumor stage, stoma, severe postoperative complications, shorter years of service at the workplace, and lower willingness to return-to-work. Risk factors for not working 12 months after surgery were stoma, lower willingness to return-to-work, nonregular employee status, lower income, national health insurance, and no private medical insurance. LIMITATIONS: This study is limited by its short-term follow-up and small sample size. CONCLUSIONS: This study revealed that Japanese patients with stages I to III colorectal cancer found favorable employment outcomes in the 12 months after surgery. These results may help health care providers better understand the employment status of patients with colorectal cancer and encourage them to consider returning to work after surgery. SITUACIN LABORAL DE LOS PACIENTES CON CNCER COLORRECTAL DESPUS DE LA CIRUGA UN ESTUDIO DE COHORTE PROSPECTIVO MULTICNTRICO EN JAPN: ANTECEDENTES:Debido a las mejores tasas de supervivencia, los pacientes con cáncer colorrectal pueden intentar volver al trabajo. Muchos países, sin embargo, tienen un conocimiento limitado de su situación laboral.OBJETIVO:Explorar la situación laboral de los pacientes con cáncer colorrectal después de la cirugía en Japón y los factores de riesgo que afectan a la misma.DISEÑO:Este es un estudio prospectivo de cohortes multicéntrico que utiliza cuestionarios autoadministrados. Los pacientes fueron reclutados desde junio de 2019 hasta agosto de 2020 y fueron seguidos durante 12 meses después de la cirugía.ENTORNO CLINICO:Seis hospitales comunitarios y un hospital universitario en Japón.PACIENTES:Pacientes con estadios clínicos I-III de cáncer colorrectal, trabajando en el momento del diagnóstico.INTERVENCIONES:Pacientes que recibieron resección quirúrgica desde junio de 2019 hasta agosto de 2020.PRINCIPALES MEDIDAS DE RESULTADO:El tiempo que tardan los pacientes en volver al trabajo después de la cirugía y la proporción de pacientes que trabajan 12 meses después de la cirugía se recogieron mediante cuestionarios autoadministrados.RESULTADOS:Un total de 129 pacientes fueron incluidos en los análisis. La mediana de tiempo de reincorporación al trabajo fue de 1,1 meses y la proporción de pacientes que trabajaban a los 12 meses de la cirugía fue del 79%. Los factores de riesgo para el retraso en el regreso al trabajo después de la cirugía fueron un estadio avanzado del tumor, estoma, complicaciones postoperatorias graves, menos años de servicio en el lugar de trabajo y menor disposición para volver al trabajo. Los factores de riesgo para no trabajar 12 meses después de la cirugía fueron estoma, menor voluntad de volver al trabajo, condición de empleado no regular, ingresos más bajos, seguro nacional de salud y la falta de seguro médico privado.LIMITACIONES:Este estudio está limitado por su seguimiento a corto plazo y tamaño de muestra pequeño.CONCLUSIONES:Este estudio reveló que los pacientes japoneses con cáncer colorrectal en estadios I-III obtuvieron resultados laborales favorables en los 12 meses posteriores a la cirugía. Estos resultados pueden ayudar a los proveedores de atención médica a comprender mejor la situación laboral de los pacientes con cáncer colorrectal y alentarlos a considerar regresar al trabajo después de la cirugía. (Traducción- Dr. Francisco M. Abarca-Rendon ).

Renin-angiotensin-aldosterone system inhibitors are associated with improved paclitaxel-induced peripheral neuropathy in lung cancer: a study using administrative claims data.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) has been reported to reduce patients' quality of life and impair cancer treatment by causing anticancer drug withdrawal or interruption. However, there are currently no effective methods for the prevention of CIPN. Renin-angiotensin-aldosterone system (RAAS) inhibitors may be associated with a reduced risk of developing oxaliplatin-induced peripheral neuropathy, and it would be valuable to examine whether they have the same effect on CIPN caused by other anticancer drugs. Our study explored the potential preventive effects of RAAS inhibitors on preventing paclitaxel-induced peripheral neuropathy (PIPN). METHODS: An exploratory cohort study was conducted using commercially available administrative claims data on lung cancer patients treated with paclitaxel-based chemotherapy. Cumulative paclitaxel doses, RAAS inhibitor prescriptions, and incidences of PIPN were identified using patient medical records. Fine-Gray analyses with death as a competing risk were performed. A propensity score approach was applied to address the problem of confounding. RESULTS: Patients with lung cancer who received paclitaxel-based chemotherapy were classified into users of RAAS inhibitor (n = 1320) and non-users of RAAS inhibitor (n = 4566). The doses of RAAS inhibitors in our study were similar to those commonly used to treat hypertension. The PIPN incidence was significantly lower in users of RAAS inhibitor than in the non-users of RAAS inhibitor (sub-distribution hazard ratio, 0.842; 95% confidence interval, 0.762-0.929). The result was consistent in various sensitivity analyses and important subgroup analyses. CONCLUSIONS: RAAS inhibitors at doses commonly used for hypertension were associated with a reduced incidence of PIPN in patients with lung cancer.

Antiresorptive Drugs and the Risk of Femoral Shaft Fracture in Men and Women With Osteoporosis: A Cohort Study Using the National Database of Health Insurance Claims of Japan.

BACKGROUND: This cohort study aimed to estimate incidence rates of femoral shaft fracture in patients who were treated with antiresorptive drugs. METHODS: We used data from the National Database of Health Insurance Claims of Japan from April 2009 and October 2016. All patients with new use of an antiresorptive drug, prescription-free period of ≥3 months, and no prior femoral fractures were included. Femoral shaft fractures were identified using a validated definition based on International Classification of Diseases, 10th revision (ICD-10) codes. Incidence rate ratios were estimated using Poisson regression, with adjustment for sex, age, and the Charlson Comorbidity Index. RESULTS: We identified 7,958,655 patients (women: 88.4%; age ≥75 years: 51.2%). Femoral shaft fractures were identified in 22,604 patients. Incidence rates per 100,000 person-years were 74.8 for women, 30.1 for men, 30.1 for patients aged ≤64 years, 47.7 for patients aged 65-74 years, and 99.0 for patients aged ≥75 years. Adjusted incidence rate ratios in patients taking versus not taking each type of antiresorptive drug were 1.00 (95% confidence interval [CI], 0.98-1.03) for bisphosphonates, 0.46 (95% CI, 0.44-0.48) for selective estrogen receptor modulators, 0.24 (95% CI, 0.18-0.32) for estrogens, 0.75 (95% CI, 0.71-0.79) for calcitonins, and 0.93 (95% CI, 0.84-1.03) for denosumab. The adjusted incidence rate ratio for alendronate was 1.18 (95% CI, 1.14-1.22). CONCLUSION: The incidence rates of femoral shaft fracture varied across patients treated with different antiresorptive drugs. Further research on a specific antiresorptive drug can increase understanding of the risk of femoral shaft fracture.

The Evaluation of Sarcopenia before Neoadjuvant Chemotherapy Is Important for Predicting Postoperative Pneumonia in Patients with Esophageal Cancer.

INTRODUCTION: Sarcopenia is often observed in patients with esophageal cancer (EC). However, the influence of sarcopenia during neoadjuvant chemotherapy (NAC) on complications has not been fully investigated. Thus, we aimed to investigate the best way of evaluating sarcopenia for predicting complications, especially postoperative pneumonia (PP), in patients with EC undergoing NAC and esophagectomy. METHODS: We retrospectively reviewed 113 patients. The skeletal muscle mass index (SMI) was evaluated by bioelectrical impedance analysis and/or computed tomography. Patients were diagnosed with sarcopenia at pre-NAC and preoperative timing. Different criteria were compared in terms of the predictability of PP. Next, we evaluated which factors were related to sarcopenia with the best PP predictability. RESULTS: Fifteen (13.2%) patients developed grade III or higher PP. Pre-NAC modified European Working Group on Sarcopenia in Older People (EWGSOP) criteria showed the highest sensitivity (100%) and acceptable specificity (75.8%) for predicting PP. Low pre-NAC body mass index and %VC were significantly associated with sarcopenia by the modified EWGSOP criteria. CONCLUSION: Pre-NAC sarcopenia by modified EWGSOP was a significant predictor of PP after esophagectomy. Appropriate interventions for these patients should be explored to prevent PP.

Association between serum insulin levels and heart failure-related parameters in patients with type 2 diabetes and heart failure treated with canagliflozin: a post-hoc analysis of the randomized CANDLE trial.

BACKGROUND: Insulin resistance and hyperinsulinemia in patients with type 2 diabetes (T2D) are adversely associated with the development and worsening of heart failure (HF). Herein, we sought to investigate the effect of canagliflozin on insulin concentrations and the associations of changes in insulin concentrations with HF-related clinical parameters in patients with T2D and HF. METHODS: This was a post-hoc analysis of the investigator-initiated, multicenter, open-label, randomized, controlled CANDLE trial for patients with T2D and chronic HF (UMIN000017669). The endpoints were the effects of 24 weeks of canagliflozin treatment, relative to glimepiride treatment, on insulin concentrations and the relationship between changes in insulin concentrations and clinical parameters of interest, including New York Heart Association (NYHA) classification. The effects of canagliflozin on those parameters were also analyzed by baseline insulin level. RESULTS: Among the participants in the CANDLE trial, a total of 129 patients (canagliflozin, n = 64; glimepiride, n = 65) who were non-insulin users with available serum insulin data both at baseline and week 24 were included in this analysis. Overall, the mean age was 69.0 ± 9.4 years; 75% were male; the mean HbA1c was 6.8 ± 0.7%; and the mean left ventricular ejection fraction was 59.0 ± 14.1%, with parameters roughly balanced between treatment groups. Canagliflozin treatment significantly reduced insulin concentrations at week 24 (p < 0.001), and the between-group difference (canagliflozin minus glimepiride) in those changes was - 3.52 mU/L (95% confidence interval, - 4.85 to - 2.19; p < 0.001). Decreases in insulin concentrations, irrespective of baseline insulin level, were significantly associated with improvement in NYHA class in patients treated with canagliflozin. CONCLUSION: Our findings suggest that canagliflozin treatment in patients with T2D and HF ameliorated excess insulin overload, contributing to the improvement of clinical HF status. TRIAL REGISTRATION: University Medical Information Network Clinical Trial Registry, number 000017669, Registered on May 25, 2015.

Utility of Mac-2 Binding Protein Glycosylation Isomer to Evaluate Graft Status After Liver Transplantation.

Mac-2 binding protein glycosylation isomer (M2BPGi) is a novel liver fibrosis biomarker, but there are few studies on M2BPGi in liver transplantation (LT) recipients. This study aimed to evaluate the utility of M2BPGi measurement in LT recipients. We collected the clinicopathological data of 233 patients who underwent a liver biopsy at Kyoto University Hospital after LT between August 2015 and June 2019. The median values of M2BPGi in patients with METAVIR fibrosis stages F0, F1, F2, and ≥F3 were 0.61, 0.76, 1.16, and 1.47, respectively, whereas those in patients with METAVIR necroinflammatory indexes A0, A1, and ≥A2 were 0.53, 1.145, and 2.24, respectively. Spearman rank correlation test suggested that the necroinflammatory index had a stronger correlation to the M2BPGi value than the fibrosis stage. The area under the receiver operating characteristic curve of M2BPGi to predict ≥A1 was 0.75, which was significantly higher than that of any other liver fibrosis and inflammation marker. Patients with a rejection activity index (RAI) of ≥3 had a higher M2BPGi value than those with RAI ≤ 2 (P = 0.001). Patients with hepatitis C virus viremia had a higher M2BPGi value than sustained virological responders or those with other etiologies. In conclusion, the present study demonstrated that M2BPGi values are more strongly influenced by necroinflammatory activity and revealed M2BPGi, which has been thought to be a so-called fibrosis marker, as a disease activity marker in transplant recipients. M2BPGi measurement may be useful to detect early stage liver inflammation that cannot be detected by routine blood examination of LT recipients.

Effect of canagliflozin on N-terminal pro-brain natriuretic peptide in patients with type 2 diabetes and chronic heart failure according to baseline use of glucose-lowering agents.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of a deterioration in heart failure (HF) and mortality in patients with a broad range of cardiovascular risks. Recent guidelines recommend considering the use of SGLT2 inhibitors in patients with type 2 diabetes (T2D) and HF, irrespective of their glycemic control status and background use of other glucose-lowering agents including metformin. However, only a small number of studies have investigated whether the effects of SGLT2 inhibitor in these patients differ by the concomitant use of other glucose-lowering agents. METHODS: This was a post-hoc analysis of the CANDLE trial (UMIN000017669), an investigator-initiated, multicenter, open-label, randomized, controlled trial. The primary aim of the analysis was to assess the effect of 24 weeks of treatment with canagliflozin, relative to glimepiride, on N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration in patients with T2D and clinically stable chronic HF. In the present analysis, the effect of canagliflozin on NT-proBNP concentration was assessed in the patients according to their baseline use of other glucose-lowering agents. RESULTS: Almost all patients in the CANDLE trial presented as clinically stable (New York Heart Association class I to II), with about 70% of participants having HF with a preserved ejection fraction phenotype (defined as a left ventricular ejection fraction ≥ 50%) at baseline. Of the 233 patients randomized to either canagliflozin (100 mg daily) or glimepiride (starting dose 0.5 mg daily), 85 (36.5%) had not been taking any glucose-lowering agents at baseline (naïve). Of the 148 patients who had been taking at least one glucose-lowering agent at baseline (non-naïve), 44 (29.7%) and 127 (85.8%) had received metformin or a dipeptidyl dipeptidase-4 (DPP-4) inhibitor, respectively. The group ratio (canagliflozin vs. glimepiride) of proportional changes in the geometric means of NT-proBNP concentration was 0.95 (95% confidence interval [CI] 0.76 to 1.18, p = 0.618) for the naïve subgroup, 0.92 (95% CI 0.79 to1.07, p = 0.288) for the non-naïve subgroup, 0.90 (95% CI 0.68 to 1.20, p = 0.473) for the metformin-user subgroup, and 0.91 (95% CI 0.77 to 1.08, p = 0.271) for the DPP-4 inhibitor-user subgroup. No heterogeneity in the effect of canagliflozin, relative to glimepiride, on NT-proBNP concentration was observed in the non-naïve subgroups compared to that in the naïve subgroup. CONCLUSION: The impact of canagliflozin treatment on NT-proBNP concentration appears to be independent of the background use of diabetes therapy in the patient population examined. Trial registration University Medical Information Network Clinical Trial Registry, number 000017669. Registered on May 25, 2015.

Effects of canagliflozin on NT-proBNP stratified by left ventricular diastolic function in patients with type 2 diabetes and chronic heart failure: a sub analysis of the CANDLE trial.

BACKGROUND: Identification of the effective subtypes of treatment for heart failure (HF) is an essential topic for optimizing treatment of the disorder. We hypothesized that the beneficial effect of SGLT2 inhibitors (SGLT2i) on the levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) might depend on baseline diastolic function. To elucidate the effects of SGLT2i in type 2 diabetes mellitus (T2DM) and chronic HF we investigated, as a post-hoc sub-study of the CANDLE trial, the effects of canagliflozin on NT-proBNP levels from baseline to 24 weeks, with the data stratified by left ventricular (LV) diastolic function at baseline. METHODS: Patients (n = 233) in the CANDLE trial were assigned randomly to either an add-on canagliflozin (n = 113) or glimepiride treatment groups (n = 120). The primary endpoint was a comparison between the two groups of the changes from baseline to 24 weeks in NT-pro BNP levels, stratified according to baseline ventricular diastolic function. RESULTS: The change in the geometric mean of NT-proBNP level from baseline to 24 weeks was 0.98 (95% CI 0.89-1.08) in the canagliflozin group and 1.07 (95% CI 0.97-1.18) in the glimepiride group. The ratio of change with canagliflozin/glimepiride was 0.93 (95% CI 0.82-1.05). Responder analyses were used to investigate the response of an improvement in NT-proBNP levels. Although the subgroup analyses for septal annular velocity (SEP-e') showed no marked heterogeneity in treatment effect, the subgroup with an SEP-e' < 4.7 cm/s indicated there was an association with lower NT-proBNP levels in the canagliflozin group compared with that in the glimepiride group (ratio of change with canagliflozin/glimepiride (0.83, 95% CI 0.66-1.04). CONCLUSIONS: In the subgroup with a lower LV diastolic function, canagliflozin showed a trend of reduced NT-pro BNP levels compared to that observed with glimepiride. This study suggests that the beneficial effects of canagliflozin treatment may be different in subgroups classified by the severity of LV diastolic dysfunction.

Exploratory assessment of treatment-dependent random-effects distribution using gradient functions.

In analyzing repeated measurements from randomized controlled trials with mixed-effects models, it is important to carefully examine the conventional normality assumption regarding the random-effects distribution and its dependence on treatment allocation in order to avoid biased estimation and correctly interpret the estimated random-effects distribution. In this article, we propose the use of a gradient function method in modeling with the different random-effects distributions depending on the treatment allocation. This method can be effective for considering in advance whether a proper fit requires a model that allows dependence of the random-effects distribution on covariates, or for finding the subpopulations in the random effects.

Virological and genomic analysis of SARS-CoV-2 from a favipiravir clinical trial cohort.

INTRODUCTION: Several clinical studies have reported the efficacy of favipiravir in reducing viral load and shortening the duration of symptoms. However, the viability of SARS-CoV-2 in the context of favipiravir therapy and the potential for resistance development is unclear. METHODS: We sequenced SARS-CoV-2 in nasopharyngeal specimens collected from patients who participated in a randomized clinical trial of favipiravir at hospitals across Japan between March and May 2020. Paired genomes were sequenced from those who remained RT-PCR-positive 5-8 days into favipiravir therapy. Daily nasopharyngeal specimens from 69 patients who were RT-PCR-positive at randomization were examined for a cytopathic effect (CPE). RESULTS: Some strains early in the trial belonged to clade 19 B, whereas the majority belonged to clade 20 B. The median time from the disease onset to negative CPE was 9 days. CPE was strongly correlated with the time from disease onset, viral load, age, and male sex. Among 23 patients for whom paired genomes were available, all except one had identical genomes. Two mutations were observed in one patient who received favipiravir, neither in the RdRp gene. CONCLUSIONS: The SARS-CoV-2 genome distribution in this clinical trial conducted in Japan reflected the early influx of strains from China followed by replacement by strains from Europe. CPE was significantly associated with age, male sex, and viral loads but not with favipiravir therapy. There was no evidence of resistance development during favipiravir therapy.

Risk factors for acute kidney injury in vancomycin and piperacillin/tazobactam combination therapy: A retrospective study.

INTRODUCTION: Combined use of vancomycin (VCM) and piperacillin/tazobactam (PIPC/TAZ) has been reported to increase the incidence of acute kidney injury (AKI). However, the risk factors associated with AKI after VCM and PIPC/TAZ (VPT) administration have not yet been identified. Therefore, we retrospectively assessed patients treated with VPT to investigate the risk factors for AKI development. METHODS: The study involved patients who were treated with VPT from January 1, 2016 to March 31, 2020. The patients were divided into the AKI or non-AKI group. The clinical characteristics of patients and antimicrobial therapy were compared between the groups. Their association with AKI risk was evaluated using multivariate logistic regression analysis. RESULTS: In total, 182 patients were included, with 118 in the non-AKI group and 64 in the AKI group. Therefore, the incidence of AKI was 35.2 %. The initiation of VPT combination therapy on the same day and concomitant use of vasopressors were associated with an increased risk of AKI (odds ratio [OR] 2.55, 95 % confidential interval [CI] 1.20-5.44 and OR 3.22, 95 % CI 1.31-7.89, respectively). CONCLUSION: Our findings suggest that the concomitant use of vasopressors and initiating VPT combination therapy on the same day are likely risk factors for AKI development.