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).     

Regional fractional ventilation mapping in spontaneously breathing mice using hyperpolarized 129Xe MRI

The feasibility of ventilation imaging with hyperpolarized (HP) ¹²⁹Xe MRI has been investigated for quantitative and regional assessment of ventilation in spontaneously breathing mice. The multiple breath ventilation imaging technique was modified to the protocol of spontaneous inhalation of HP ¹²⁹Xe delivered continuously from a ¹²⁹Xe polarizer. A series of ¹²⁹Xe ventilation images was obtained by varying the number of breaths before the ¹²⁹Xe lung imaging. The fractional ventilation, r, was successfully evaluated for spontaneously breathing mice. An attempt was made to detect ventilation dysfunction in the emphysematous mouse lung induced by intratracheal administration of porcine pancreatic elastase (PPE). As a result, the distribution of fractional ventilation could be visualized by the r map. Significant dysfunction of ventilation was quantitatively identified in the PPE‐treated group. The whole‐lung r value of 0.34 ± 0.01 for control mice (N = 4) was significantly reduced, to 0.25 ± 0.07, in PPE‐treated mice (N = 4) (p = 0.038). This study is the first application of multiple breath ventilation imaging to spontaneously breathing mice, and shows that this methodology is sensitive to differences in the pulmonary ventilation. This methodology is expected to improve simplicity as well as noninvasiveness when assessing regional ventilation in small rodents. Copyright © 2014 John Wiley & Sons, Ltd.     

Tongue function is important for masticatory performance in the healthy elderly: a cross-sectional survey of community-dwelling elderly

Purpose

The aim of this study was to determine the influences of oral motor function such as tongue function and bite force on masticatory performance in the elderly.

Analysis of muscle atrophy after hip fracture in the elderly

Ogawa H, Oshita H, Ishimaru D, Yamada K, Shimizu T, Koyama Y, Akaike A, Hori H. Analysis of muscle atrophy after hip fracture in the elderly.

Objectives

To examine the relationship between muscle atrophy, ambulatory ability, and fracture type, and to make a specific rehabilitation regimen for each fracture type.

Design

Observational study.

Setting

Public hospital.

Participants

Consecutive patients (N=53) with hip fracture (mean age, 83.6y) who underwent operative treatment.

Interventions

Not applicable.

Main Outcome Measures

The ambulatory ability score and the cross-sectional areas of lower-limb muscles as measured on computed tomography scans.

Results

Muscle atrophy was not related to fracture type. Although the mean ambulatory ability score decreased significantly from 4.5±0.3 points prior to injury to 3.0±0.6 points 1 month postadmission, the degree of muscle atrophy was not associated with the decrease in ambulatory ability.

Conclusions

It seems likely that other factors are more important than muscle atrophy and fracture type in determining recovery after surgical repair of a fracture and that there is no need for rehabilitation regimens based on fracture types.     

Clinical significance of MRI/18F-FDG PET fusion imaging of the spinal cord in patients with cervical compressive myelopathy

Purpose

¹⁸F-FDG PET is used to investigate the metabolic activity of neural tissue. MRI is used to visualize morphological changes, but the relationship between intramedullary signal changes and clinical outcome remains controversial. The present study was designed to evaluate the use of 3-D MRI/¹⁸F-FDG PET fusion imaging for defining intramedullary signal changes on MRI scans and local glucose metabolic rate measured on ¹⁸F-FDG PET scans in relation to clinical outcome and prognosis.

Methods

We studied 24 patients undergoing decompressive surgery for cervical compressive myelopathy. All patients underwent 3-D MRI and ¹⁸F-FDG PET before surgery. Quantitative analysis of intramedullary signal changes on MRI scans included calculation of the signal intensity ratio (SIR) as the ratio between the increased lesional signal intensity and the signal intensity at the level of the C7/T1 disc. Using an Advantage workstation, the same slices of cervical 3-D MRI and ¹⁸F-FDG PET images were fused. On the fused images, the maximal count of the lesion was adopted as the standardized uptake value (SUV_max). In a similar manner to SIR, the SUV ratio (SUVR) was also calculated. Neurological assessment was conducted using the Japanese Orthopedic Association (JOA) scoring system for cervical myelopathy.

Results

The SIR on T1-weighted (T1-W) images, but not SIR on T2-W images, was significantly correlated with preoperative JOA score and postoperative neurological improvement. Lesion SUV_max was significantly correlated with SIR on T1-W images, but not with SIR on T2-W images, and also with postoperative neurological outcome. The SUVR correlated better than SIR on T1-W images and lesion SUV_max with neurological improvement. Longer symptom duration was correlated negatively with SIR on T1-W images, positively with SIR on T2-W images, and negatively with SUV_max.

Conclusion

Our results suggest that low-intensity signal on T1-W images, but not on T2-W images, is correlated with a poor postoperative neurological outcome. SUV_max of lesions showing increased signal intensity and SUVR measured on fusion MRI/PET scans are more sensitive parameters for predicting clinical outcome than signal intensity on the MRI scan.     

T‐bet regulates differentiation of forkhead box protein 3+ regulatory T cells in programmed cell death‐1‐deficient mice

Programmed cell death‐1 (PD‐1) plays an important role in peripheral T cell tolerance, but whether or not it affects the differentiation of helper T cell subsets remains elusive. Here we describe the importance of PD‐1 in the control of T helper type 1 (Th1) cell activation and development of forkhead box protein 3 (FoxP3⁺) regulatory T cells (T_regs). PD‐1‐deficient T cell‐specific T‐bet transgenic (P/T) mice showed growth retardation, and the majority died within 10 weeks. P/T mice showed T‐bet over‐expression, increased interferon (IFN)‐γ production by CD4⁺ T cells and significantly low FoxP3⁺ T_reg cell percentage. P/T mice developed systemic inflammation, which was probably induced by augmented Th1 response and low FoxP3⁺ T_reg count. The study identified a unique, previously undescribed role for PD‐1 in Th1 and T_reg differentiation, with potential implication in the development of Th1 cell‐targeted therapy.     

Endonasal flap suture-dacryocystorhinostomy (eFS-DCR): a new surgical technique for nasolacrimal duct obstruction (NLDO)

Conclusion: Endonasal flap suture-dacryocystorhinostomy (eFS- DCR) is a new and valuable technique for the treatment of nasolacrimal duct obstruction (NLDO). This technique could improve the success rate of endonasal DCR in comparison to external DCR. Objective: The standard procedure for NLDO is DCR. DCR can be performed via either an external or endonasal approach. External DCR is now regarded as the gold standard in the treatment of NLDO because of its higher success rate. However, we report a new endonasal surgical technique, eFS-DCR, and assess its efficacy by comparison with the standard endonasal DCR. Methods: We prospectively investigated a series of 62 consecutive patients with NLDO undergoing endonasal DCR. There were two surgical intervention groups: group 1 (24 patients, 28 sites) undergoing endonasal DCR without eFS; and group 2 (38 patients, 47 sites) undergoing eFS-DCR. Study end points were success rate, the ostium diameter (OD) of the lacrimal sac after DCR, and the duration of stent placement. We compared the two groups on these three points. Results: The success rate was 78.6% (22 of 28 sites) for group 1 (DCR without eFS) and 97.9% (46 of 47 sites) for group 2 (eFS-DCR). The ostium size in patients in group 2 was larger than that in group 1. The median time for the duration of stent placement was 42.5 days for group 1 and 31.5 days for group 2. There was a statistical difference (p < 0.01) in all these parameters between the two groups.