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).     

Dopamine agonists and valvular heart disease in Japanese patients with Parkinson's disease

Journal of Neurology - A high incidence of valvular heart disease in Parkinson's disease (PD) patients treated with ergot-derived dopamine agonists, such as cabergoline and pergolide, has been...     

Characteristics and course of bone mineral densities among fast bone losers in a rural Japanese community: the Miyama Study

The aim of this study was to clarify and compare the temporal course of bone mineral density (BMD) between fast bone losers and normal residents in Miyama Village, a rural Japanese community. BMD was measured over a 10-year period in a cohort study in Miyama Village, Wakayama Prefecture, Japan, to provide information on rate of bone loss in the mature and elderly population. Subjects (n=400) were selected by sex and age stratum from the full list of residents born in 1910–1949, with 50 men and 50 women in each age decade. Baseline BMD of the lumbar spine and proximal femur was measured using dual energy X-ray absorptiometry in 1990, 1993, 1997 and 2000. In the cohort, 171 men and 189 women completed the follow-up survey performed in 1993. After calculating the rate of bone loss between 1990 and 1993, the greatest tertile from the distribution of bone loss was categorized as fast bone losers, with the remainder considered as normal subjects. Changes in BMD were compared between normal subjects and fast bone losers over the 10-year period. Mean rate of change for BMD at both lumbar spine and femoral neck in fast bone losers recovered to levels similar to those in normal subjects over 7 years of observation. By contrast, BMD at the lumbar spine and femoral neck decreased steeply over the 10-year period in both groups, and mean BMD for fast bone losers was significantly lower than that of normal subjects (P<0.05). These differences were apparent only at the lumbar spine in both men and women, even after adjusting for age. These results indicate that fast bone loss is a transient phenomenon rather than a fixed status, although individuals who have been categorized as fast bone losers at some stage continue to display low BMD in the lumbar spine.     

Permanent prostate brachytherapy for Japanese men: Results from initial 100 patients with prostate cancer

OBJECTIVE: To evaluate the initial results of brachytherapy for prostate cancer with permanent iodine-125 implant in Japan. METHODS: The results obtained with brachytherapy in the initial 100 Japanese patients treated at Nagano Municipal Hospital were reviewed. Patients with a prostate-specific antigen (PSA) level of less than 10 ng/mL and a Gleason's scores of 5, 6, 3 + 4 were classified as having a low risk of recurrence. Patients with a PSA level of 10-20 ng/mL and/or a Gleason's score of 4 + 3 were classified as having an intermediate risk for recurrence. Seventy-eight of the low-risk patients and 19 of the intermediate-risk patients were treated by seed implants alone, or seed implants combined with preceding external radiation, respectively. A total of 53 patients received neoadjuvant hormone therapy. The efficacy and morbidity of brachytherapy were investigated using the serum PSA, International Prostate Symptom Score, quality of life score and uroflowmetry data. RESULTS: The average V100 and D90 obtained by post-implant dosimetry was 94.3 and 113.7%, respectively. Serum PSA decreased gradually after treatment, although it had still not reached a nadir after 1 year. There was little difference of the PSA level between the patients with and without neoadjuvant hormone therapy even at 1 year after seed implantation. There were no PSA biochemical failure or clinical recurrence during the follow-up period. Voiding symptoms worsened until 3 months after treatment, and then gradually improved. Acute urinary retention occurred transiently in one patient (1%). Rectal bleeding and severe diarrhea did not occur. CONCLUSION: Brachytherapy is a feasible and effective option for the treatment of prostate cancer in Japanese men. Brachytherapy may have a different effect in Japanese patients with respect to voiding symptoms. Urinary retention was rare, but voiding symptoms were persistent in Japanese patients. Neoadjuvant hormone therapy deserves investigation to determine whether it can achieve better results, especially in patients with an intermediate risk.     

Production of the first offspring from oocytes derived from fresh and cryopreserved pre-antral follicles of adult mice

Although mammalian ovaries contain hundreds of thousands of pre-antral follicles, fewer than 1% of these reach maturity and ovulation. Obtaining immature eggs from the pre-antral follicles of ovarian tissue could increase the possibility of preserving fertility in women undergoing anti-cancer treatment, and in women who wish to delay pregnancy and child raising until they are older. This study reports the birth of 10 healthy mouse pups derived from oocytes obtained from pre-antral follicles after adult ovary tissue cryopreservation and allotransplantation. High in-vitro maturation (55.1%), fertilization (76.3%) and cleavage (98.3%) rates were achieved using these oocytes, and there was no significant difference between the vitrified and control samples except in maturation rate (55.1 versus 72.8%, P < 0.05). After an ultra-rapid vitrification procedure, the warmed tissue fragments were transplanted beneath the kidney capsule of severe combined immunodeficient mice for onward in-vivo culture. Within 10 days of culture, 138 full size oocytes developed from the 456 transplanted pre-antral follicles. In-vivo growth of follicles was followed by in-vitro oocyte maturation, in-vitro fertilization and subsequent embryo transfer, leading to the birth of 10 healthy pups. These results may lead to increasing the possibility of preserving fertility by cryopreservation of ovarian tissue.     

Preoperative chemotherapy increases cytokine production after lung cancer surgery.

OBJECTIVE: Many phase II trials have shown that preoperative chemotherapy for lung cancer is feasible but associated with postoperative morbidity and mortality. However, little is known about the effect of preoperative chemotherapy on surgical stress and postoperative complications associated with surgical intervention. We evaluated the effect of preoperative chemotherapy on perioperative inflammatory cytokine production as a surgical stress marker. METHODS: The study group comprised 38 patients undergoing anatomical lung resection and mediastinal nodal dissection for clinical stage IB/II non-small cell lung cancer during the period October 2001-December 2003. Nineteen patients received a single cycle of cisplatin (80 mg/m(2)) and docetaxel (60 mg/m(2)) chemotherapy prior to surgery (neoadjuvant group), and 19 patients underwent surgery without any previous chemotherapy (control group). White blood cell and neutrophil counts and serum concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), and granulocyte colony-stimulating factor (GCSF) were determined before surgery and on postoperative days 1 and 3. Postoperative complications were reviewed. Differences were assessed by repeated analysis of variance. RESULTS: Serum concentrations of IL-6 and GCSF rose significantly on postoperative days 1 and 3 in the neoadjuvant group in comparison to concentrations in the control group, but white blood cell count, neutrophil count, and CRP did not differ between the groups. No major complication occurred in either group. CONCLUSIONS: A single cycle of cisplatin and docetaxel chemotherapy followed by surgery can exacerbate overproduction of inflammatory cytokines during the perioperative period in lung cancer patients.