A multicenter,open‐label,phase II study of tirabrutinib (ONO/GS‐4059) in patients with Waldenström’s macroglobulinemia

Tirabrutinib is a second‐generation Bruton’s tyrosine kinase inhibitor with greater selectivity than ibrutinib. Here, we conducted a multicenter, phase II study of tirabrutinib in patients with treatment‐naïve (Cohort A) or with relapsed/refractory (Cohort B) Waldenström’s macroglobulinemia (WM). Patients were treated with tirabrutinib 480 mg once daily. The primary endpoint was major response rate (MRR; ≥ partial response). Secondary endpoints included overall response rate (ORR; ≥ minor response), time to major response (TTMR), progression‐free survival (PFS), overall survival (OS), and safety. In total, 27 patients (18 in Cohort A; 9 in Cohort B) were enrolled. The median age was 71 y, and the median serum immunoglobulin M level was 3600 mg/dL. Among the patients, 96.2% had the MYD88^L265P mutation. MRR and ORR were 88.9% and 96.3%, respectively (Cohort A: MRR, 88.9%; ORR, 94.4%; Cohort B: MRR, 88.9%; ORR, 100%). Median TTMR was 1.87 mo. PFS and OS were not reached with a median follow‐up of 6.5 and 8.3 mo for Cohorts A and B, respectively. The most common adverse events (AEs) were rash (44.4%), neutropenia (25.9%), and leukopenia (22.2%), with most AEs classified as grade 1 or 2. Grade ≥ 3 AEs included neutropenia (11.1%), lymphopenia (11.1%), and leukopenia (7.4%). No grade 5 AEs were noted. All bleeding events were grade 1; none were associated with drug‐related atrial fibrillation or hypertension. Although the follow‐up duration was relatively short, the study met the primary endpoint. Therefore, tirabrutinib monotherapy is considered to be highly effective for both untreated and relapsed/refractory WM with a manageable safety profile. (JapicCTI‐173646).     

History and Profile of Diagnosis Procedure Combination (DPC): Development of a Real Data Collection System for Acute Inpatient Care in Japan

DPC, which is an acronym for “Diagnosis Procedure Combination,” is a patient classification method developed in Japan for inpatients in the acute phase of illness. It was developed as a measuring tool intended to make acute inpatient care transparent, aiming at standardization of Japanese medical care, as well as evaluation and improvement of its quality. Subsequently, this classification method came to be used in the Japanese medical service reimbursement system for acute inpatient care and appropriate allocation of medical resources. Furthermore, it has recently contributed to the development and maintenance of an appropriate medical care provision system at a regional level, which is accomplished based on DPC data used for patient classification. In this paper, we first provide an overview of DPC. Next, we will look back at over 15 years of DPC history; in particular, we will explore how DPC has been refined to become an appropriate medical service reimbursement system. Finally, we will introduce an outline of DPC-related research, starting with research using DPC data.Key words: Diagnosis Procedure Combination (DPC), DPC-based Per-Diem Payment System (DPC/PDPS), patient classification system, health policy, Japan     

Effects of dietary consistency on the mandible of rats at the growth stage: computed X-ray densitometric and cephalometric analysis

Thirty 3-week-old male Wistar rats were grouped into a hard diet control group, a kneaded-diet group, and a powdered-diet group. After 6 weeks of growth, all rats were killed under deep anesthesia. The effects of dietary physical consistency on the mandible were investigated with respect to morphology and bone mineral content using lateral cephalometric analysis and computed X-ray densitometry. Significant differences between the experimental and control groups were determined by measuring the means and standard deviation of the coordinates and differences between 15 points selected on the mandibles. Gonion (Go), which is a measurement of depth to the X-axis, was significantly less in the powdered-diet group, while the kneaded-diet group showed no significant differences. The most posterior point of the coronoid process (Cr) and the most posterior point of condylar process (Cd), which are measures of height to the Y-axis, were less in the kneaded-diet group than in the control group. In the powdered-diet group, Cr, Cd, Go and Infradentale were significantly less than in the control group. On the other hand, the bone mineral content was significantly lower in the coronoid process and angle of mandible in only the powdered-diet group.     

Differences in the diagnostic value of various criteria of negative T waves for hypertrophic cardiomyopathy based on a molecular genetic diagnosis

Differences in the diagnostic value of a variety of definitions of negative T waves for HCM (hypertrophic cardiomyopathy) have not yet been clarified, resulting in a number of definitions being applied in previous studies. The aim of the present study was to determine the most accurate diagnostic definition of negative T waves for HCM in genotyped populations. Electrocardiographic and echocardiographic findings were analysed in 161 genotyped subjects (97 carriers and 64 non-carriers). We applied three different criteria that have been used in previous studies: Criterion 1, negative T wave >10 mm in depth in any leads; Criterion 2, negative T wave >3 mm in depth in at least two leads; and Criterion 3, negative T wave >1 mm in depth in at least two leads. Of the three criteria, Criterion 3 had the highest sensitivity (43% compared with 5 and 26% in Criterion 1 and Criterion 2 respectively; P<0.0001) and retained a specificity of 95%, resulting in the highest accuracy. In comparison with abnormal Q waves, negative T waves for Criterion 3 had a lower sensitivity in detecting carriers without LVH (left ventricular hypertrophy) (12.9% for negative T waves compared with 22.6% for abnormal Q waves). On the other hand, in detecting carriers with LVH, the sensitivity of negative T waves increased in a stepwise direction with the increasing extent of LVH (P<0.001), whereas there was less association between the sensitivity of abnormal Q waves and the extent of LVH. In conclusion, Criterion 3 for negative T waves may be the most accurate definition of HCM based on genetic diagnoses. Negative T waves may show different diagnostic value according to the different criteria and phenotypes in genotyped populations with HCM.