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).     

T cell receptor vβ repertoire of double-negative α/β t cells in patients with systemic sclerosis

Objective. To analyze the T cell receptor V_β gene on double-negative (DN) α/β T cells, which are increased in number, on peripheral blood lymphocytes (PBL) from patients with systemic sclerosis (SSc). Methods. The DN α/β T cells were sorted by flow cytometry from PBL obtained from 3 patients with SSc. The V_β repertoire was analyzed by polymerase chain reaction. Results. Only 1 or 2 V_β genes (V_β5/7, 5, or 17) were predominantly expressed on DN α/β T cells from these 3 patients. Conclusion. The V_β repertoire on DN α/β T cells in PBL from patients with SSc is rather restricted.     

Phenol-based endoscopic ultrasound-guided celiac plexus neurolysis for East Asian alcohol-intolerant upper gastrointestinal cancer patients:A pilot study

AIM:To investigate the effectiveness of phenol for the relief of cancer pain by endoscopic ultrasound-guided celiac plexus neurolysis(EUS-CPN).METHODS:Twenty-two patients referred to our hospital with cancer pain from August 2009 to July 2011for EUS-CPN were enrolled in this study.Phenol was used for 6 patients with alcohol intolerance and ethanol was used for 16 patients without alcohol intolerance.The primary endpoint was the positive response rate(pain score decreased to≤3)on postoperative day 7.Secondary endpoints included the time to onset of pain relief,duration of pain relief,and complication rates.RESULTS:There was no significant difference in the positive response rate on day 7.The rates were 83%and 69%in the phenol and ethanol groups,respectively.Regarding the time to onset of pain relief,in the phenol group,the median pre-treatment pain score was 5,whereas the post-treatment scores decreased to 1.5,1.5,and 1.5 at 2,8,and 24 h,respectively(P<0.05).In the ethanol group,the median pre-treatment pain score was 5.5,whereas the post-treatment scores significantly decreased to 2.5,2.5,and 2.5 at 2,8,and24 h,respectively(P<0.01).There was no significant difference in the duration of pain relief between the phenol and ethanol groups.No significant difference was found in the rate of complications between the 2groups;however,burning pain and inebriation occurred only in the ethanol group.CONCLUSION:Phenol had similar pain-relieving effects to ethanol in EUS-CPN.Comparing the incidences of inebriation and burning pain,phenol may be superior to ethanol in EUS-CPN procedures.     

One‐year safety and efficacy study of bilastine treatment in Japanese patients with chronic spontaneous urticaria or pruritus associated with skin diseases

A number of second‐generation non‐sedating antihistamines are used in clinical practices over the world. However, long‐term safety and efficacy have not been proved high level evidence based medicine. We have performed an open‐label, multicenter, phase III study to evaluate the long‐term safety and efficacy of bilastine, a novel non‐sedating H₁‐antihistamine for patients with chronic spontaneous urticaria (CSU) or pruritus associated with skin diseases (trial registration no. JapicCTI‐142528). Patients aged 18–74 years were treated with bilastine 20 mg once daily for up to 52 weeks. Safety and tolerability were assessed on the basis of adverse events (AE), bilastine‐related AE, laboratory tests and vital signs. Efficacy was assessed based on rash score, itch score, overall improvement and quality of life. One hundred and ninety‐eight patients enrolled, 122 of whom (61.6%) completed the 52‐week treatment period. AE were reported in 64.5% and bilastine‐related AE in 2.5% of patients throughout the 52‐week treatment period. All AE were mild to moderate in severity. AE associated with the nervous system occurred in 10 patients (5.1%) including seven patients (3.6%) with headache. Somnolence reported in two of these patients (1.0%) was related to bilastine. All efficacy variables improved during treatment with bilastine. In conclusion, long‐term treatment with bilastine 20 mg once daily for 52 weeks is safe and well tolerated in Japanese patients with CSU or pruritus associated with skin diseases. Bilastine improved disease symptoms of both conditions early in treatment, and the efficacy was maintained throughout the treatment.     

Systematised naevus sebaceus resulting from post‐zygotic mutation in HRAS

Naevus sebaceus has recently been shown to result from post‐zygotic mutations in HRAS, KRAS or occasionally NRAS. We present details of a neonate with extensive naevus sebaceus in whom we identified a pathogenic mutation in HRAS (c.37G > C; p.Gly13Arg), but only in lesional skin DNA, consistent with a mosaic RASopathy. This case highlights the clinicopathological and molecular findings of this naevoid disorder as well as the key issues in the clinical assessment and management of such patients.     

Successful treatment for infected aortic aneurysm using endovascular aneurysm repairs as a bridge to delayed open surgery

Management of infected aortic aneurysms, which can be life-threatening, remains challenging. Open surgical treatments, including debridement of the infected aorta and the surrounding tissue and either in situ reconstruction or extra-anatomic bypass covering with omentum or muscle flap, are the mainstay of therapy. However, increasing advances in technology have made endovascular treatment of infected aneurysms feasible. The present study describes the first clinical report of successful treatment of an infected aneurysm using endovascular techniques in the acute phase, followed by delayed open surgery.