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.     

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.     

Easy Diagnosis of Aortic Invasion in Patients with Lung Cancer Using Cine Magnetic Resonance Imaging

Selecting the proper treatment strategy for locally advanced lung cancer, such as T4 tumors, is difficult. Therefore, obtaining an accurate diagnosis of T4 tumors is required. It can be difficult to determine whether the tumor invades adjacent structures. We describe the case of a patient easily diagnosed to be without aortic invasion using cine magnetic resonance imaging (MRI). We herein report the case of an 80-year-old male who presented a lung tumor. The transbronchial lung washing cytology findings were consistent with those of adenocarcinoma. In addition, the computed tomography findings indicated suspected aortic invasion of the lung tumor, as the mass girdled the descending aorta beyond 120° adjoining at a length of 10 cm. However, cine MRI display clearly demonstrated a clear area of isolation between the aorta and lung tissue based on differences in the heart rhythm from the patient''s respiratory movements. Therefore, the lesion was clinically diagnosed as a stage IIB (T3N0M0) tumor. Radiation was administered due to the patient''s advanced age and comorbidities such as chronic obstructive pulmonary disease. He remains alive without disease progression 6 months after the therapy. Our findings, therefore, indicate the usefulness of easily diagnosing the absence of aortic invasion in patients with lung cancer using cine MRI without the need for a special software program.Key Words: Cine magnetic resonance imaging, Diagnosis, Aorta, Invasion, Lung cancer     

Robust arterial transit time and cerebral blood flow estimation using combined acquisition of Hadamard‐encoded multi‐delay and long‐labeled long‐delay pseudo‐continuous arterial spin labeling: a simulation and in vivo study

Arterial transit time (ATT) prolongation causes an error of cerebral blood flow (CBF) measurement during arterial spin labeling (ASL). To improve the accuracy of ATT and CBF in patients with prolonged ATT, we propose a robust ATT and CBF estimation method for clinical practice. The proposed method consists of a three‐delay Hadamard‐encoded pseudo‐continuous ASL (H‐pCASL) with an additional‐encoding and single‐delay with long‐labeled long‐delay (1dLLLD) acquisition. The additional‐encoding allows for the reconstruction of a single‐delay image with long‐labeled short‐delay (1dLLSD) in addition to the normal Hadamard sub‐bolus images. Five different images (normal Hadamard 3 delay, 1dLLSD, 1dLLLD) were reconstructed to calculate ATT and CBF. A Monte Carlo simulation and an in vivo study were performed to access the accuracy of the proposed method in comparison to normal 7‐delay (7d) H‐pCASL with equally divided sub‐bolus labeling duration (LD). The simulation showed that the accuracy of CBF is strongly affected by ATT. It was also demonstrated that underestimation of ATT and CBF by 7d H‐pCASL was higher with longer ATT than with the proposed method. Consistent with the simulation, the 7d H‐pCASL significantly underestimated the ATT compared to that of the proposed method. This underestimation was evident in the distal anterior cerebral artery (ACA; P = 0.0394) and the distal posterior cerebral artery (PCA; 2 P = 0.0255). Similar to the ATT, the CBF was underestimated with 7d H‐pCASL in the distal ACA (P = 0.0099), distal middle cerebral artery (P = 0.0109), and distal PCA (P = 0.0319) compared to the proposed method. Improving the SNR of each delay image (even though the number of delays is small) is crucial for ATT estimation. This is opposed to acquiring many delays with short LD. The proposed method confers accurate ATT and CBF estimation within a practical acquisition time in a clinical setting.