Japanese Clinical Setting Research Articles

First detection of VEB-1 extended-spectrum β-lactamase-producing Escherichia coli clinical isolate in Japan.

ESBLs are plasmid-mediated enzymes that confer resistance to clinically significant antimicrobial agents, such as broad-spectrum cephalosporins. Recently, the rapid spread of CTX-M-type ESBL-producing E. coli has become a global issue, including in Japan, where ESBL production in human pathogenic E. coli, such as the ExPEC and UPEC lineages, which typically harbor several virulence genes, is a severe public health concern. To date, VEB (Vietnamese extended-spectrum β-lactamase) producers have been found only in hospital wastewater and rivers in Japan. Thus, we describe the first detection of a very rare human-derived blaVEB-1 gene in the E. coli B2-ST95 pandemic clonal lineage that is highly associated with ExPEC and UPEC in a Japanese clinical setting. Furthermore, we characterized the genomic features of plasmids harboring the class 1 integron-borne blaVEB-1. Our findings highlight the significance of closely monitoring ESBL-producing E. coli isolates to prevent the potential dissemination of this resistance determinant in Japan.

Population characteristics and diagnosis rate of chronic kidney disease by eGFR and proteinuria in Japanese clinical practice: an observational database study

Chronic kidney disease (CKD) guidelines recommend early identification and intervention to delay the progression of CKD. The Kidney Disease: Improving Global Outcomes (KDIGO) heatmap is widely used for risk evaluation in CKD management; however, real-world evidence on clinical characteristics based on the KDIGO heatmap remains limited worldwide including Japan. In order to understand the management of CKD including its diagnostic rates in a Japanese clinical setting on the basis of KDIGO heatmap, we utilized a medical record database that contains estimated glomerular filtration rate (eGFR) and urine protein data. Adult individuals (≥ 18 years) with two eGFR results of < 90 mL/min/1.73 m2, 90–360 days apart, were included. Approximately half of patients (452,996/788,059) had proteinuria test results and 6.9% (54,073) had quantitative results. CKD diagnosis rate in patients without proteinuria data was 5.9%, with a lower rate (2.9%) in stage G2; the corresponding rates with quantitative test results were 43.5% and 31.3%, respectively. The most frequent comorbidities were hypertension, diabetes, and cardiovascular disease, and their prevalence increased as the eGFR and proteinuria stages progressed. This study revealed a low rate of proteinuria assessment, especially using quantitative methods, and diagnosis in individuals with suspected CKD. With emerging treatment options to prevent CKD progression and complication onset, there is a need for early evaluation and diagnosis of CKD.

Psychotherapeutic drug-induced life-threatening arrhythmias: A retrospective analysis using the Japanese adverse drug eventreport database.

Drug-induced life-threatening ventricular arrhythmias including torsade de pointes (TdP), ventricular tachycardia (VT), and ventricular fibrillation (VF) are serious cardiac side effects. Psychotherapeutic drugs are known to be risk factors for arrhythmias. The aim of this study was to evaluate psychotherapeutic drugs associated with life-threatening ventricular arrhythmias using the Japanese Adverse Drug Event Report (JADER) database. From the JADER database (April 2004 to September 2022), cases of TdP, VT, VF, and QT prolongation in patients taking psychotherapeutic drugs as 'suspected drugs' were extracted. The adjusted reported odds ratio (aROR) was calculated to identify potential drugs involved in combined TdP/VF/VT or combined QT prolongation/TdP. Of the 4,530,772 cases reported, life-threatening arrhythmia-related adverse events were reported in 1760 cases (QT prolongation 1261, TdP 192, VF 108, VT 199) among 909 patients; 58.9% of patients were female, and the highest incidence was among patients aged 80-89 years (18.6%), followed by patients aged 70-79 years (15.4%). The highest aROR for TdP/VF/VT was found for trazodone (17.1), followed by sulpiride (10.8), haloperidol (9.8), donepezil (9.1), and fluvoxamine (7.9). The highest aROR for QT prolongation/TdP was found for guanfacine (87.8), followed by sultopride (60.1), escitalopram (21.0), trazodone (12.8), and donepezil (9.3). This study showed that typical antipsychotics, antidepressants, and antidementia drugs were associated with life-threatening arrhythmia-related adverse events in a Japanese clinical setting. These events were more frequent in women and elderly individuals.

RWD150 Cost of Illness: Estimating Direct Healthcare Costs Related to Obesity in a Japanese Clinical Setting

Obesity or overweight is associated with diabetes, cardiovascular complications, cancer, and knee replacement surgery. This study aimed to estimate direct healthcare costs of obesity-related complications in Japanese patients.

Perioperative Analgesics and Anesthesia as Risk Factors for Postoperative Chronic Opioid Use in Patients Undergoing Total Knee Arthroplasty: A Retrospective Cohort Study Using Japanese Hospital Claims Data.

Patients with chronic postsurgical pain are commonly prescribed opioids chronically because of refractory pain although chronic opioid use can cause various severe problems. We aimed to investigate postoperative chronic opioid use and its association with perioperative pain management in patients who underwent a total knee arthroplasty in a Japanese real-world clinical setting. We conducted a retrospective cohort study using an administrative claims database. We used a multivariate logistic regression analysis to examine the association between perioperative analgesic and anesthesia prescriptions and postoperative chronic opioid use. We calculated all-cause medication and medical costs for each patient. Of the 23,537,431 patient records, 14,325 patients met the criteria and were included in the analyses. There were 5.4% of patients with postoperative chronic opioid use. Perioperative prescriptions of weak opioids, strong and weak opioids, and the α2δ ligand were significantly associated with postoperative chronic opioid use (adjusted odds ratio [95% confidence interval], 7.22 [3.89, 13.41], 7.97 [5.07, 12.50], and 1.45 [1.13, 1.88], respectively). Perioperative combined prescriptions of general and local anesthesia were also significantly associated with postoperative chronic opioid use (3.37 [2.23, 5.08]). These medications and local anesthesia were more commonly prescribed on the day following surgery, after routinely used medications and general anesthesia were prescribed. The median total direct costs were approximately 1.3-fold higher among patients with postoperative chronic opioid use than those without postoperative chronic opioid use. Patients who require supplementary prescription of analgesics for acute postsurgical pain are at high risk of postoperative chronic opioid use and these prescriptions should be given careful consideration to mitigate the patient burden.

Final analysis of a post-marketing surveillance study of dabrafenib and trametinib combination therapy in Japanese patients with unresectable malignant melanoma with BRAF V600 mutation.

Targeted therapy with a combination of dabrafenib and trametinib has been developed and widely used for treatment of melanoma. However, data regarding its safety and efficacy in Japanese patients with malignant melanoma are limited. A post-marketing surveillance (PMS) study was conducted to investigate the safety and efficacy of combination therapy in a Japanese clinical setting with a surveillance period of June 2016 to March 2022; 326 patients with unresectable malignant melanoma with BRAF mutation were enrolled. The interim results were published in July 2020. Herein, we report the results of the final analysis based on the data collected until the completion of the PMS study. The safety analysis population included 326 patients, the majority of whom had stage IV disease (79.14%) and Eastern Cooperative Oncology Group performance status 0 or 1 (85.28%). All patients were treated with the approved dose of dabrafenib, while 99.08% were treated with the approved dose of trametinib. Adverse events (AEs) occurred in 282 patients (86.50%) and the major AEs (incidence ≥5%) were pyrexia (47.85%), malignant melanoma (33.44%), hepatic function abnormal (9.82%), rash and blood creatine phosphokinase increased (8.59% each), malaise (6.44%), nausea (5.52%), and diarrhea and rhabdomyolysis (5.21% each). The incidences rates of adverse drug reactions of safety specifications were 45.71% for pyrexia, 15.95% for hepatic impairment, 12.58% for rhabdomyolysis, 4.60% for cardiac disorders, and 3.07% for eye disorders. In the efficacy analysis population of 318 patients, the objective response rate was 58.18% (95% confidence interval [CI] 52.54%-63.66%). The progression-free survival rates at 90, 180, and 360 days were 88.14% (95% CI 84.00%-91.26%), 69.53% (63.85%-74.50%), and 52.07% (45.71%-58.03%), respectively. Consistent with previous interim results, no new safety or efficacy concerns were observed in this final analysis of a PMS study conducted in a Japanese real-world clinical setting.

Feasibility, acceptability, and preliminary efficacy of cognitive processing therapy in Japanese patients with posttraumatic stress disorder.

Cognitive processing therapy (CPT) is one of the most widely tested evidence-based treatments for posttraumatic stress disorder (PTSD). However, most studies on CPT have been conducted in Western cultural settings. This open-label, single-arm trial investigated the feasibility, acceptability, and preliminary efficacy of CPT for treating Japanese patients with PTSD. A total of 25 outpatients underwent 12 CPT sessions. The primary outcome was the assessment of PTSD symptoms using the Clinician-Administered PTSD Scale for DSM-IV (CAPS-IV); secondary outcomes included the assessment of subjective PTSD severity, depressive and anxiety symptoms, trauma-related cognitions, and subjective quality of life. All outcomes were evaluated at pretreatment (i.e., baseline), posttreatment, and 6- and 12-month follow-ups. On average, participants attended 13 sessions of CPT (SD = 1.38), with a completion rate of 96.0%. One serious adverse event (hospitalization) occurred. Significant within-subjects standardized mean differences in CAPS-IV scores were found from baseline to treatment completion, g = -2.28, 95% CI [-3.00, -1.56]; 6-month follow-up, g = -2.95, 95% CI [-3.79, -2.12]; and 12-month follow-up, g = -2.15, 95% CI [-2.89, -1.41]. Moderate-to-large effects, gs = -0.77 to -2.45, were found on secondary outcomes. These findings support the feasibility, acceptability, and preliminary efficacy of CPT in a Japanese clinical setting.

Skills Training in Affective and Interpersonal Regulation Narrative Therapy for women with ICD-11 complex PTSD related to childhood abuse in Japan: a pilot study

ABSTRACT Background: Skills Training in Affective and Interpersonal Regulation (STAIR) Narrative Therapy (SNT) has shown efficacy in alleviating symptoms of posttraumatic stress disorder (PTSD) and improving emotion regulation and interpersonal skills among individuals with complex trauma, such as childhood abuse. Although this therapy is expected to be effective for patients with complex PTSD (CPTSD), no study has directly assessed diagnostic and symptom outcomes. Moreover, the potential of therapy to achieve good outcomes in non-Western countries remains unclear. Objective: This pilot study examined the feasibility, safety, and outcomes of SNT for CPTSD among women with a history of childhood abuse in a Japanese clinical setting. Methods: Ten women aged 21–54 years (M = 29.1 years) with childhood-abuse-related ICD-11 CPTSD were enrolled in this study. The International Trauma Interview and International Trauma Questionnaire were administered to diagnose CPTSD and assess its severity. Symptoms of dissociation and depression, difficulties in emotion regulation and interpersonal relationships, quality of life, and negative cognitions were assessed pretreatment, midtreatment (after the STAIR phase), and immediately posttreatment (after the Narrative Therapy phase), in addition to 3 months after treatment. Results: Seven of the 10 participants completed the treatment. The therapists’ adherence to the therapy protocol was 96.4%, ranging from 93.6% to 100% across therapists. Serious adverse events were not observed. Among the seven completers, six at posttreatment and all at follow-up no longer met CPTSD diagnosis. Exploratory analyses using the linear mixed-effects model showed significant improvements at posttreatment and follow-up for almost all the variables. Conclusions: The results provide preliminary evidence for the feasibility and safety of SNT for CPTSD in a Japanese clinical setting. This study is the first to report the use of SNT for individuals diagnosed with ICD-11 CPTSD using reliable clinician and self-report measures. HIGHLIGHTS This study examined the feasibility and safety of STAIR Narrative Therapy for women with ICD-11 CPTSD related to childhood abuse in a Japanese clinical setting. High therapy adherence was observed. No serious adverse events occurred.

Cost-effectiveness analysis of lemborexant for treating insomnia in Japan: a model-based projection, incorporating the risk of falls, motor vehicle collisions, and workplace accidents.

Lemborexant has demonstrated statistically significant improvements in sleep onset and sleep maintenance compared with placebo and zolpidem tartrate extended release, measured both objectively using polysomnography and subjectively using sleep diaries, in the phase 3 clinical trial SUNRISE 1. This study evaluated the cost-effectiveness of lemborexant compared with suvorexant, zolpidem immediate release (IR), and untreated insomnia. A decision-tree model was developed for falls, motor vehicle collisions, and workplace accidents associated with insomnia and insomnia treatments from a Japanese healthcare perspective and with a 6-month time horizon. The model extracted subjective sleep onset latency treatment responses and disutility values for non-responders from SUNRISE 1. Cost-effectiveness was assessed using incremental cost per quality-adjusted life year (QALY) gained. One-way and probabilistic sensitivity analyses were conducted to evaluate the impact of parameter uncertainty on the results. In the base-case analysis, the mean estimated QALYs for lemborexant, suvorexant, zolpidem-IR, and untreated insomnia were 0.4220, 0.4204, 0.4113, and 0.4163, and expected medical costs were JPY 34 034, JPY 38 371, JPY 38 139, and JPY 15 383, respectively. Lemborexant saved JPY 4337 and JPY 4105 compared with suvorexant or zolpidem-IR, respectively, while conferring QALY benefits. The incremental cost-effectiveness ratio (ICER) of lemborexant compared with that of untreated insomnia was JPY 3 220 975 /QALY. Lemborexant was dominant over suvorexant and zolpidem-IR and was cost-effective when compared with untreated insomnia. Sensitivity analyses supported the results' robustness. In a Japanese clinical practice setting, lemborexant may represent a better investment for treating insomnia in the healthcare system in Japan.

Transdiagnostic Behavioural Intervention for Children with Anxiety and Depressive Disorders: A Feasibility Study

AbstractThere is increasing support for the efficacy of transdiagnostic cognitive behavioural interventions for anxiety and depression. However, little is known about the applicability of transdiagnostic behavioural interventions for children younger than 12 years old. This study was conducted to examine the feasibility and potential efficacy of Streamlined Transdiagnostic Intervention for Anxiety and Depression (STREAM) for children with anxiety and/or depressive disorders using a randomised controlled design with a wait-list control (WLC) condition and blind-assessments. Of the 22 potential participants, 16 Japanese children (M = 9.81; SD = 0.75; range 9–12 years) with principal anxiety or depressive disorder were eligible and enrolled. Then, the participants were randomly assigned to the STREAM or WLC condition. The dropout rates were 0% for both the conditions at post-assessment. Mixed model analyses showed that, although there were no significant interactions at post-assessment between both the conditions, both anxiety and depressive disorders significantly improved at 3 months compared with pre-assessment for the combined condition (the STREAM and WLC conditions). Therefore, this study demonstrated the feasibility of the STREAM in the Japanese clinical setting and potentially supported its efficacy for children with anxiety and depressive disorders at the follow-up assessment.

Are Fatigue and Pain Overlooked in Subjects with Stable Chronic Obstructive Pulmonary Disease?

Although there have been many published reports on fatigue and pain in patients with chronic obstructive pulmonary disease (COPD), it is considered that these symptoms are seldom, if ever, asked about during consultations in Japanese clinical practice. To bridge this gap between the literature and daily clinical experience, the authors attempted to gain a better understanding of fatigue and pain in Japanese subjects with COPD. The Brief Fatigue Inventory (BFI) to analyse and quantify the degree of fatigue, the revised Short–Form McGill Pain Questionnaire 2 (SF-MPQ-2) for measuring pain and the Kihon Checklist to judge whether a participant is frail and elderly were administered to 89 subjects with stable COPD. The median BFI and SF-MPQ-2 Total scores were 1.00 [IQR: 0.11–2.78] and 0.00 [IQR: 0.00–0.27], respectively. They were all skewed toward the milder end of the respective scales. A floor effect was noted in around a quarter on the BFI and over half on the SF-MPQ-2. The BFI scores were significantly different between groups regarding frailty determined by the Kihon Checklist but not between groups classified by the severity of airflow limitation. Compared to the literature, neither fatigue nor pain are considered to be frequent, important problems in a real-world Japanese clinical setting, especially among subjects with mild to moderate COPD. In addition, our results might suggest that fatigue is more closely related to frailty than COPD.

Abstract 1122‐000146: A Survey of Current Status and Roles of Interventional Neurologists in Japan

Introduction : In Japan, there are more board‐certified neurosurgeons than board‐certified neurologists, and a significant part of stroke practice is provided by neurosurgeons. In neuroendovascular therapy practice, the trend of neurosurgeons to be in majority is more pronounced. The most of neuroendovascular therapy specialists (n = 1,586) certified by the Japanese Society for Neuroendovascular Therapy (JSNET) consists of neurosurgeons, and the proportion of neurologists/internists is only 8% (n = 128) as of April 2021. The aim of this study is to investigate the current status and roles of interventional neurologists, the minority providing neuroendovascular therapy, in Japanese clinical setting. Methods : Between 16th and 28th February 2021, the Japan Society of Vascular and Interventional Neurology (JSVIN) conducted a survey for society‐member neurologists and internists using questionnaires on Google Forms. The questionnaires consisted of 11 items regarding years after graduation, facility location, department, work style (full‐time or concurrent interventionalist), diseases for which respondents were engaged, disease/procedure preferences which respondents would treat by themselves, respondents’ roles in their own neuroendovascular therapy team, and others. Results : Replies were obtained from 112 (67.1%) out of all JSVIN‐member neurologists and internists (n = 167). The respondents included 71 JSNET‐certified specialists and they consisted of 56.3% of all the JSNET‐certified neurologists/internists. The departments to where the respondents belonged were Neurology in 66%, Cerebrovascular medicine in 25%, Neuroendovascular therapy in 4%, and Neurosurgery in 3%. The median years after graduation was 15 years (interquartile range, 10 – 21 years) and the proportion of respondents who have graduated 10 years or less was 30%. Respondents’ facilities were distributed around 27 prefectures of all 47 Japanese prefectures and a significant proportion of those was located in urban area; 20% in Osaka and 13% in Tokyo. The number of full‐time interventionalist was only 1. Sixty‐three (56%) were concurrently engaged in general neurology practice, and 33 (30%) in stroke neurology practice. The proportions of diseases for which the respondents were engaged were ischemic cerebrovascular diseases (acute large vessel occlusion strokes, carotid stenoses, and others) in 100%, hemorrhagic cerebrovascular diseases (cerebral aneurysms, arteriovenous shunts, and others) in 44%, and other diseases (tumors, spinal vascular disorders, and others) in 28%. The proportions of disease/procedure preferences which respondents would treat by themselves were acute stroke thrombectomy in 90%, carotid/intracranial stenoses in 87%, ruptured cerebral aneurysms in 38%, unruptured cerebral aneurysms in 31%, cerebral arteriovenous shunts in 33%, brain tumors in 29%, spinal vascular disorders in 13%, and pediatric diseases in 3%. Respondents’ roles in their own neuroendovascular therapy team were diagnostic performances based on neurologist’s skills in 89%, comorbidity assessment and management based on internist’s skills in 88%, precise neurological evaluation in 77%, neurosonological evaluation in 75%, and establishments of in‐hospital workflow/multi‐disciplinary collaboration in 71%. Conclusions : Most of interventional neurologists in Japan were engaged in neuroendovascular therapy mainly for ischemic cerebrovascular diseases in parallel with general neurology and/or stroke neurology practices. Interventional neurologists’ skill set developed in neurology/internist trainings and practices might contribute to the quality improvement of neuroendovascular therapy in Japan.

Is Blood Eosinophil Count a Biomarker for Chronic Obstructive Pulmonary Disease in a Real-World Clinical Setting? Predictive Property and Longitudinal Stability in Japanese Patients.

The authors examined predictive properties and the longitudinal stability of blood eosinophil count (BEC) or three strata (<100 cells/mm3, 100–299 cells/mm3 and ≥300 cells/mm3) in patients with chronic obstructive pulmonary disease (COPD) for up to six and a half years as part of a hospital-based cohort study. Of the 135 patients enrolled, 21 (15.6%) were confirmed to have died during the follow-up period. Episodes of acute exacerbation of COPD (AECOPD) were identified in 74 out of 130 available patients (56.9%), and admission due to AECOPD in 35 out of 132 (26.5%). Univariate Cox proportional hazards analyses revealed that almost all the age, forced expiratory volume in 1 s (FEV1) and health status measures using St. George’s Respiratory Questionnaire (SGRQ) Total and COPD Assessment Test (CAT) Score were significantly related to these types of events, but the relationship between age and AECOPD did not reach statistical significance (p = 0.05). Neither BEC nor the three different groups stratified by BEC were significant predictors of any subsequent events. There were no significant differences in the BEC between Visits 1–3 (p = 0.127, Friedman test). The ICC value was 0.755 using log-transformed data, indicating excellent repeatability. In the case of assigning to strata, Fleiss’ kappa was calculated to be 0.464, indicating moderate agreement. The predictive properties of BEC may be limited in a real-world Japanese clinical setting. Attention must be paid to the fact that the longitudinal stability of the three strata is regarded as moderate.

Evaluation of azacitidine in patients with transplant-ineligible myelodysplastic syndromes and acute myeloid leukemia with myelodysplasia-related changes in a Japanese clinical setting.

Patients with high-risk myelodysplastic syndromes (MDS) treated with azacitidine (AZA) have exhibited improved overall survival. However, information on AZA in real-world settings is limited. The present study retrospectively analyzed 85 patients with MDS treated with AZA. Complete response was achieved in 24% of cases and hematologic improvement in 29%. Severe adverse events (grade ≥3) included neutropenia and infection. Multivariate analysis identified higher revised international prognostic scoring system (IPSS-R) and male sex as significant factors affecting survival. However, the present study did not identify any significant associations between patient characteristics and response to AZA. In conclusion, AZA could produce a hematologic response in ~53% of patients with MDS. Furthermore, IPSS-R may reflect MDS prognosis. Further studies are required to establish the criteria for identifying patients likely to obtain maximum benefit from AZA treatment.

A Direct Aspiration First Pass Technique in Japanese Real-World Clinical Setting.

It is debatable whether mechanical thrombectomy has benefits in a real-world setting outside the more rigid and selective clinical trial environment. To evaluate clinical outcomes, efficacy, and safety of mechanical thrombectomy in single-center retrospective cohort case series. We reviewed prospectively collected data from our large-vessel occlusion stroke database to identify patients undergoing mechanical thrombectomy using Penumbra catheters (Penumbra, Almeida, California) as first-line devices. The primary outcomes were the modified Rankin Scale score at 90 d and recanalization rate. The secondary outcomes included the rates of hemorrhagic complications and mortality. The entire study population included 298 patients. Thrombolysis in Cerebral Infarction Scale ≥2b was achieved in 86.6% of patients. Fifty-five patients (18.5%) were outside the 6 hr time window and 82 patients (27.5%) were over 80-yr old. The posterior circulation thrombectomy rate was 12.4%. At 90 d from onset, 49.3% of patients had favorable outcomes. The parenchymal hemorrhage type 2 (PH2) and subarachnoid hemorrhage rates were 2.3% and 11.7%, respectively. In multivariate analyses, cerebral blood flow/cerebral blood volume mismatch (odds ratio [OR]=9.418; 95% confidence interval [CI], 3.680-27.726; P<.0001), onset to recanalization time (OR=0.995; 95% CI, 0.991-0.998; P=.0003), and hemorrhagic complications including PH2 and subarachnoid hemorrhage (OR=0.186; 95% CI, 0.070-0.455; P=.0002) were associated with favorable outcomes. A direct aspiration first pass technique with an adjunctive device demonstrated high recanalization rates in old Japanese patients. Our patient cohort may reflect the application of endovascular techniques in acute ischemic stroke treatment in a real-world setting.

Commentary: A Direct Aspiration First Pass Technique in Japanese Real-world Clinical Setting.

Commentary: A Direct Aspiration First Pass Technique in Japanese Real-world Clinical Setting.

Clinical pharmacokinetic and pharmacodynamic analysis of daptomycin and the necessity of high-dose regimen in Japanese adult patients

The objective of this study was to explore the optimal dosage regimen of daptomycin and to determine the necessity and validity of a high-dose regimen from the perspectives of PK/PD parameters using Monte Carlo Simulation (MCS) and therapeutic drug monitoring (TDM) in a Japanese clinical setting. The volume of distribution (0.13 ± 0.012 L/kg) in this study was greater than that in healthy volunteers reported in Japan. The range of half-lives was between 8.9 and 34.9 h, which were gradually prolonged as creatinine clearance decreased. In MCS, the cumulative fractions of response (CFR) of the peak/MIC ≧ 60 and the AUC/MIC ≧ 666 at the 6 mg/kg q 24 h were 72.0% and 78.8% but at the 10 mg/kg q 24 h, the CFRs improved to both 99%. In TDM with 6 mg/kg q 24 h regimen, the patients who reached the peak and AUC target were 40% (2 out of 5 patients), respectively. The intraindividual variability in daptomycin PK may indicate the necessity of TDM and high-dose regimen, such as over 8 mg/kg, may be needed to ensure the effectiveness especially on Japanese patients with normal renal function.

Evaluation of the Revised International Staging System in 400 Patients with Symptomatic Myeloma in a Japanese Clinical Setting

Background:In 2015, the International Myeloma Working Group (IMWG) developed the Revised International Staging System (R-ISS), which combined the ISS with the status of high-risk cytogenetic abnormalities (CAs) and serum levels of lactate dehydrogenase to identify three multiple myeloma (MM) entities with clearly different outcomes. However, although MM tends to affect older adults, the original and validation studies of the R-ISS included relatively younger patients. Furthermore, although studies report that bortezomib-containing therapies can reverse the unfavorable prognostic impact of the t(4;14) CA,most original and validation studies of the R-ISS included few patients who had been treated with bortezomib. Therefore, the results of these studies are less applicable to patients in the era of novel targeted agents.Methods: This study retrospectively analyzed the data of 400 consecutive patients who were newly diagnosed with MM and treated with chemotherapy between January 2006 and December 2017 at Kameda Medical Center, Kamogowa-shi, Japan; Keiju Kanazawa Hospital, Ishikawa, Japan and National Hospital Organization Okayama Medical Center, Okayama, Japan. We included only patients who had been treated with novel agents (e.g., immunomodulatory agents or proteasome inhibitors) to reduce the prognostic impact of heterogeneity in chemotherapy.Results: The 400 included patients had a median age of 72 years (interquartile range [IQR]: 64-79 years). The median observation period was 37.9 months (IQR: 16.4-67.9 months). Ninety-eight (24.5%), 121 (30.2%) and 181 (45.2%) patients were classified as ISS stages I, II, and III, respectively, while 66 (16.5%), 243 (60.8%), and 91 (22.8%) patients were classified as R-ISS stages I, II, and III, respectively. Additionally, 384 (96.0%) patients were treated with bortezomib. R-ISS stages II and III differed significantly in terms of age, with the former including significantly older patients than the latter (median age: 74 and 70 years, respectively; P=0.001). The Kaplan-Meier overall survival (OS) curves according to the ISS and R-ISS stages are shown in Figure 1A and 1B, respectively. The three groups of patients categorized by ISS stage differed significantly in terms of survival duration. By contrast, no significant differences in OS were observed between R-ISS stages II and III (median OS: 63.4 and 54.7 months, respectively; P=0.32).Furthermore, receiver operating characteristic (ROC) curves were developed tocompare the prognostic performances of the ISS and R-ISS. Notably, the area under curve (AUC) was significantly greater for the ISS than for the R-ISS (0.659 vs. 0.608, respectively; P=0.029, Figure 2A). ISS stage III patients recategorized to R-ISS stage III were significantly younger than those recategorized to R-ISS stage II (median age, 70 vs. 77 years; P<0.001) and had a relatively more favorable OS (Figure 3). Patients with high-risk cytogenetic abnormality t(4;14) were significantly younger than the others and also had an improved OS (Figure 4), which was attributed to young age and bortezomib therapy.We again divided the patients into three groups using a modified R-ISS (mR-ISS) categorization in which only t(14;16) and del(17p) were included as high-risk CAs.The three groups categorized by mR-ISS stage exhibited significant differences in survival (Figure 1C).We additionally developed a ROC curve for the mR-ISS, and the resulting AUC value was significantly greater than that obtained for the R-ISS (0.657 vs. 0.608, respectively; P=0.001, Figure 2B).Conclusions: Our study is the first to suggest that the performance of the R-ISS may be somewhat limited when applied to patients with MM who are treated with novel agents in ageing societies. Furthermore, we suggest that this limitation may be attributed to the inclusion of t(4;14) as a high-risk CA in the R-ISS categorization strategy. This potential limitation suggests that the R-ISS should be carefully interpreted on an individual basis when applied to patients in a real-world setting. Our findings are of particular interest because many developed countries, including Western countries, are approaching a period of super-ageing such as that observed currently in Japan. [Display omitted] DisclosuresSunami:Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Merck Sharp and Dohme: Research Funding; Takeda: Research Funding; AbbVie: Research Funding; Sanofi: Research Funding. Takamatsu:Janssen: Honoraria; Bristol-Myers Squibb: Research Funding; Ono: Research Funding; Celgene: Honoraria, Research Funding.

Feasibility of the imatinib stop study in the Japanese clinical setting: delightedly overcome CML expert stop TKI trial (DOMEST Trial)

BackgroundTreatment-free remission (TFR), the ability to maintain a molecular response (MR), occurs in approximately 50% of patients with chronic myelogenous leukemia (CML) treated with tyrosine kinase inhibitors (TKIs).MethodsA multicenter phase 2 trial (Delightedly Overcome CML Expert Stop TKI Trial: DOMEST Trial) was conducted to test the safety and efficacy of discontinuing imatinib. Patients with CML with a sustained MR of 4.0 or MR4.0-equivalent for at least 2 years and confirmed MR4.0 at the beginning of the study were enrolled. In the TFR phase, the international scale (IS) was regularly monitored by IS-PCR testing. Molecular recurrence was defined as the loss of MR4.0. Recurrent patients were immediately treated with dasatinib or other TKIs including imatinib.ResultsOf 110 enrolled patients, 99 were evaluable. The median time from diagnosis to discontinuation of imatinib was 103 months, and the median duration of imatinib therapy was 100 months. Molecular recurrence-free survival rates were 69.6%, 68.6% and 64.3% at 6, 12, and 24 months, respectively. After discontinuation of imatinib therapy, 26 patients showed molecular recurrence, and 25 re-achieved deep MR after dasatinib treatment. Molecular response MR4.0 was achieved in 23 patients within 6 months and 25 patients within 12 months. Multivariate analysis revealed that a longer time from diagnosis to discontinuation of imatinib therapy (p = 0.0002) and long duration of imatinib therapy (p = 0.0029) predicted a favorable prognosis.ConclusionsThis DOMEST Trial showed the feasibility of TKI discontinuation in a Japanese clinical setting.

Nurse-led group cognitive behavioral therapy for major depressive disorder among adults in Japan: A preliminary single-group study

ObjectivesThe prevalence and burden of disease of depression necessitates effective and accessible treatment options worldwide. Since April 2016, Japanese national health insurance has covered nurse-administered cognitive behavioral therapy (CBT) for mood disorders. However, empirical support for nurse-led CBT for depression in Asian countries, especially in Japan, is still lacking. This preliminary study aimed to examine the feasibility and acceptability of nurse-led group CBT for Japanese patients with depression. MethodsIn this single-arm study, we evaluated the effects of a 6-week group CBT, led by trained nurses, on patients with major depression. The primary outcome was the Beck Depression Inventory-II (BDI-II). Assessments were conducted at the beginning and end of the intervention. ResultsOf 25 participants screened, 23 were eligible for the study (of these, three dropped out during the trial but were included in the analysis). Nurse-led group CBT led to significant improvements in the severity of depression (BDI-II, P < 0.001). The mean total BDI-II score improved from 23.1 (SD = 7.56) to 12.4 (SD = 8.57), and the pre-to post-effect size was large (Cohen's d = 1.33). After CBT, 45% of the participants were judged to be treatment responders, and 34% met the remission criteria. ConclusionsOur preliminary findings indicate that 6 weeks of nurse-led group CBT produced a favorable treatment outcome for individuals with major depression in a Japanese clinical setting. The results of this study might encourage more Asian nurses to provide CBT as a part of their nursing practice. Further controlled trials that address the limitations of this study are required.