Ōsaka, Japan
Ōsaka, Japan

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Purpose: The purpose of this study was to monitor anti-vascular endothelial growth factor (anti-VEGF) treatment regimens for wet age-related macular degeneration (wAMD) in clinical practice and to determine how they impact the physician, patient, and caregiver treatment experience. Materials and methods: This was a qualitative analysis based on semistructured interviews with 20 ophthalmologists who had practiced both pro re nata (PRN) and treat-and-extend (T&E) anti-VEGF regimens for wAMD. Interview questions were constructed to assess how the different regimens affected patient and caregiver experiences (in the opinion of the ophthalmologist) in addition to the ophthalmologist’s own experience. The interview included questions relating to 1) issues and benefits of PRN and T&E; 2) logistical and operational issues of introducing proactive therapy, especially T&E, to PRN practice; and 3) actions taken to handle the issues raised in 2). Results: A total of 18 interview results were eligible for analysis. The study demonstrated that the benefits of T&E compared with PRN included decreased burden of patient consultations, decreased patient and caregiver emotional burden, and a sustained period of macular dryness. The issues associated with T&E were increased number of injections and financial burden from prolonged treatment duration. The ophthalmologists also experienced difficulty explaining the significance of proactive injections to patients. Countermeasures to operational issues experienced by ophthalmologists varied by practice. Conclusion: Patients, caregivers, and the practicing ophthalmologists experienced benefits associated with a T&E regimen. However, in order to encourage better understanding of the T&E regimen, including its smooth implementation and significance for patients, a formal T&E treatment guideline providing standard practice should be considered. © 2016 Iida and Ishii.

Hori M.,Hiroshima University | Matsumoto M.,Hiroshima University | Tanahashi N.,International University of Japan | Momomura S.,Jichi Medical University | And 9 more authors.
Circulation Journal | Year: 2012

Background: The global ROCKET AF study evaluated once-daily rivaroxaban vs. warfarin for stroke and systemic embolism prevention in patients with atrial fibrillation (AF). A separate trial, J-ROCKET AF, compared the safety of a Japanspecific rivaroxaban dose with warfarin administered according to Japanese guidelines in Japanese patients with AF. Methods and Results: J-ROCKET AF was a prospective, randomized, double-blind, phase III trial. Patients (n=1,280) with non-valvular AF at increased risk for stroke were randomized to receive 15 mg once-daily rivaroxaban or warfarin dose-adjusted according to Japanese guidelines. The primary objective was to determine non-inferiority of rivaroxaban against warfarin for the principal safety outcome of major and non-major clinically relevant bleeding, in the on-treatment safety population. The primary efficacy endpoint was the composite of stroke and systemic embolism. Non-inferiority of rivaroxaban to warfarin was confirmed; the rate of the principal safety outcome was 18.04% per year in rivaroxaban-treated patients and 16.42% per year in warfarin-treated patients (hazard ratio [HR] 1.11; 95% confidence interval 0.87-1.42; P<0.001 [non-inferiority]). Intracranial hemorrhage rates were 0.8% with rivaroxaban and 1.6% with warfarin. There was a strong trend for a reduction in the rate of stroke/systemic embolism with rivaroxaban vs. warfarin (HR, 0.49; P=0.050). Conclusions: J-ROCKET AF demonstrated the safety of a Japan-specific rivaroxaban dose and supports bridging the global ROCKET AF results into Japanese clinical practice.

Jothi M.,Roswell Park Cancer Institute | Nishijo K.,University of Texas Health Science Center at San Antonio | Nishijo K.,Bayer Yakuhin Ltd. | Keller C.,Oregon Health And Science University | Mal A.K.,Roswell Park Cancer Institute
Cell Cycle | Year: 2012

The chimeric PAX3-FKHR transcription factor is present in a majority of alveolar rhabdomyosarcoma (ARMS), an aggressive skeletal muscle cancer of childhood. PAX3-FKHR-mediated aberrant myogenic gene expression resulting in escape from terminal differentiation program is believed to contribute in ARMS development. In skeletal muscle differentiation, activation of AKT pathway leads to myogenic gene activation and terminal differentiation. Here, we report that AKT acts, in part, by modulating PAX3-FKHR transcriptional activity via phosphorylation in the maintenance of the myogenic differentiation blockade in established mouse models of ARMS cells. We observed that low levels of AKT activity are associated with elevated levels of PAX3-FKHR transcriptional activity, and AKT hyperactivation results in PAX3-FKHR phosphorylation coupled with decreased activity once cells are under differentiation-permissible conditions. Subsequent data shows that attenuated AKT activity-associated PAX3-FKHR activity is required to suppress the function of MyoD, a key myogenic regulator of muscle differentiation. Conversely, decreased PAX3-FKHR activity results in the eradication of MyoD expression and subsequent suppression of the myogenic differentiation. Thus, AKT regulation of the PAX3-FKHR suppresses myogenic gene expression in ARMS cells, causing a failure in differentiation. Evidence is presented that provides a novel molecular link between AKT and PAX3-FKHR in maintaining myogenic differentiation blockade in ARMS. © 2012 Landes Bioscience.

Naito S.,Kyushu University | Tsukamoto T.,Sapporo Medical University | Murai M.,International Goodwill Hospital | Fukino K.,Bayer Yakuhin Ltd | Akaza H.,University of Tsukuba
BJU International | Year: 2011

Study Type - Therapy (Phase II non-randomized trial) Level of Evidence 2b What's known on the subject? and What does the study add? Interim result of this study had shown promising efficacy, with response rate of 14.7% and median PFS of 7.4 months, and good tolerability of sorafenib in previously-treated Japanese patients with metastatic RCC. Final result of the study adds: (1) the median overall survival of 25.3 months, which is longer than that in the global phase III study TARGET; (2) the response rate which elevated to 19.4% because of 6 late responders achieved after 9.2 months or longer of SD period; (3) lack of either unknown adverse events nor cumulative toxicity in the long-term use of sorafenib. OBJECTIVE • To explore the long-term efficacy and safety of sorafenib in Japanese patients with metastatic renal cell carcinoma (RCC) in a phase II trial. PATIENTS AND METHODS • In all, 131 Japanese patients with metastatic RCC who had received nephrectomy and failed at least one cytokine-containing systemic therapy received continuous sorafenib 400 mg twice daily, and the efficacy and safety parameters were evaluated in these patients, including objective response rate, progression-free survival and overall survival. RESULTS • Of the total, 129 patients were valid for intention-to-treat analyses and 131 patients were valid for safety analyses. • Twenty-five patients (19.4%) had confirmed partial response and 87 patients (67.4%) had stable disease as best overall response. The 25 patients included six late-responders who achieved response after 9.2 months or longer of stable disease. The objective response rate and disease control rate were 19.4% and 73.6%, respectively. • The median overall survival and median progression-free survival were 25.3 and 7.9 months, respectively. • Safety profile was consistent with those previously reported, with hand-foot skin reaction (58.0%), lipase elevation (57.3%) and diarrhoea (42.7%) as the most frequently observed drug-related adverse events. Neither unknown adverse event nor cumulative toxicity was observed over the long-term use of sorafenib. • Despite the dose discontinuation/interruption/reduction, the mean and median relative dose intensities were 86.4% and 97.4%, respectively. CONCLUSION • The final results of this trial showed that long-term use of sorafenib after cytokine treatment was well tolerated and provided new efficacy data, including late-response events and favourable overall survival in Japanese patients with metastatic RCC. © 2011 BAYER YAKUHIN, LTD. BJU INTERNATIONAL © 2011 BJU INTERNATIONAL.

Purpose: Quantification of vascular endothelial cell damage induced by iodinated contrast media using an in situ perfused rat vena cava model. Materials and methods: The institutional review board approved this study protocol prior to the commencement of all studies. A laparotomy was performed in 90 rats divided into 18 groups of five, and an 18G-catheter was inserted into the abdominal vena cava (mean length: ca 8 mm). After sacrificing, a thoracotomy was done and the outflow perfusate was emitted via a polyethylene tube inserted into the thoracic vena cava through the right atrium for an open system. Iopamidol (300 or 370 mg I/mL, 50 or 100 mL) was injected via the abdominal vena cava at a rate of 1, 4, or 8 mL/s. The abdominal vena cava was removed for histological analysis (n = 5). Physiological saline was injected as a negative control. The detachment percentage of endothelial cells was calculated by measuring the circumference and detachment section of the endothelium. The difference of the detachment percentage and circumference between each group was compared with Tukey's range test. Results: In contrast media groups, the severity of damage to the vascular endothelial cell was direct proportional to the increase of injection rate. The detachment percentage at 4 or 8 mL/s was significantly higher than that at 1 mL/s. As a result, the correlation between the injection rate and severity of cell damage was significant; however, the detachment percentage among contrast media groups was not significant at any injection rate. Conclusion: The in situ vena cava model was able to quantify contrast media injection related endothelial damage based on histopathological endpoints. Moreover, our results indicate that mechanical shear stress besides physico-chemical properties such as osmolality or viscosity cause endothelial damage. © 2011 Elsevier Ireland Ltd. All rights reserved.

Tsuda N.,Bayer Yakuhin Ltd. | Harada K.,Kanazawa University | Matsui O.,Kanazawa University
Journal of Gastroenterology and Hepatology (Australia) | Year: 2011

Background and Aims: To analyze the difference in signal intensity on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) among various hepatocellular nodules during hepatocarcinogenesis as correlated with the expressions of the transporters of Gd-EOB-DTPA. Methods: We received institutional animal review board approval prior to the commencement of all studies. Forty rats were divided into three groups. The rats in the tumor groups received N-nitrosomorpholine solution (n=16), and rats in the cirrhosis group (thioacetamide [TAA] group) received thioacetamide solution (n=12). As a control, the remaining 12 rats were fed normal water. Each group was divided into two sub-groups: Group 1 for Gd-EOB-DTPA-enhanced MRI (0.025mmolGd/kg, n=7) and Group 2 for reverse transcription-polymerase chain reaction to compare transporter (oatp1 and mrp2) expressions (n=5 for control and TAA groups, n=9 for tumor groups). Results: Signal enhancement of tumors decreased according to the progress of hepatocarcinogenesis. Although the relative enhancement of each tumor group was significantly lower than that of the control group (P<0.01), and there was no significant difference between TAA, hyperplastic nodules (HPN), and HCCwell groups. The relative enhancement of the HCCmod group was significantly lower than the other groups (P<0.01). The oatp1 expression of HPN tended to be higher than those of HCCwell and HCCmod. The mrp2 expression of TAA was significantly higher than those of HCCwell, HCCmod, HPN and control (P<0.01). The mrp2 expression of HPN tended to be higher than those of HCCwelland HCCmod. Conclusion: It was suggested that the signal enhancement on Gd-EOB-DTPA-enhanced MRI would correlate with the transporter expression in various hepatocellular nodules during hepatocarcinogenesis. © 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

Objectives: To compare the transporter expression and signal profile on Gd-EOB-DTPA-enhanced MRI between non-alcoholic steatohepatitis (NASH) and cirrhotic liver induced in rats, and investigate the correlation of the transporter expression and fibrosis rate in both diseases. Methods: Forty-eight rats were divided into four groups of 12: TAA (cirrhosis), NASH 7- and 10-week, and control groups. Each group was divided into two subgroups: Group 1 for MRI and Group 2 for transporter examinations. Results: The relative enhancement of the TAA group was significantly lower than those of other groups (p∈<∈0.01). The T max and T 1/2 of the NASH 10-week group was significantly prolonged in comparison with the TAA group (p∈<∈0.01). There was no significant difference in the oatp1 expression, whereas the mrp2 expression of the TAA group was significantly higher than those of other groups (p∈<∈0.01). There was no significant correlation between the fibrosis rate and oatp1 expression, whereas a paradoxical correlation was found between the fibrosis rate and mrp2 expression (NASH: negative correlation, r∈=∈0.91, p∈<∈0. 01; TAA: positive correlation, r∈=∈0.85, p∈<∈0.01). Conclusions: Our findings showed that the mrp2 expression in cirrhosis increases in comparison with NASH, and there was a paradoxical correlation between the fibrosis rate and mrp2 expression. © 2011 European Society of Radiology.

Takahara Y.,Bayer Yakuhin Ltd. | Matsuda Y.,Bayer Yakuhin Ltd. | Takahashi S.,Bayer Yakuhin Ltd. | Shigematsu T.,Wakayama Medical University
Clinical Nephrology | Year: 2014

Background: Lanthanum carbonate (LC), an effective non-calcium phosphate binder is widely used to manage hyperphosphatemia in patients with chronic kidney disease (CKD) on dialysis. Recently, the additional indication for control of hyperphosphatemia in CKD patients not on dialysis has been approved. Methods: A multicenter, randomized, double-blind, placebo-controlled trial to confirm the efficacy and safety of LC in Japanese hyperphosphatemic stage 4 - 5 CKD patients not on dialysis. After a 4-week run-in period, 143 eligible subjects with serum phosphate levels of 5.6 - 11.0 mg/dL were randomized (2: 1) to receive LC or placebo (88 vs. 55) for 8 weeks; 119 subjects completed the study (76 vs. 43). The starting LC dose was 750 mg/day, which was then up-titrated to 2,250 mg/day as needed while tolerated. Primary efficacy analysis was performed on the intent-to-treat (ITT) population of 141 patients (86 vs. 55). Results: LC produced a significantly greater reduction in serum phosphate level compared with placebo after 8 weeks of treatment (difference, 0.97 (95% CI: 0.58, 1.37) mg/ dL; p < 0.0001). The cumulative proportion of subjects with controlled phosphate levels ≤ 4.6 mg/dL was higher in the LC group than the placebo group (59.56% vs. 10.46%). LC caused significantly greater reductions in serum Ca × P product and urinary phosphate excretion compared with placebo. The safety profile of LC was similar to that of placebo. Conclusions: This study demonstrated the effectiveness of LC to control hyperphosphatemia in pre-dialysis CKD patients. © 2014 Dustri-Verlag Dr. K. Feistle.

Tsuda N.,Bayer Yakuhin Ltd. | Okada M.,Kinki University | Murakami T.,Kinki University
European Journal of Radiology | Year: 2010

Purpose: We investigated whether the gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI was useful for nonalcoholic steatohepatitis (NASH) staging based on the severity of liver fibrosis. Materials and methods: Twenty-one male Sprague-Dawley rats aged 7 weeks, weighing about 150 g in NASH group were fed a choline-deficient diet for 4, 7 or 10 weeks, and seven rats in the control group were fed a standard diet (n = 7). After the feeding period, the rats were subjected to contrast-enhanced MRI (2D-FLASH; TR/TE = 101/2.9 ms, flip angle 90°). Gd-DTPA (0.1 mmol Gd/kg) and Gd-EOB-DTPA (0.025 mmol Gd/kg) were injected at 24-h intervals, and the speed of contrast injection was 1 mL/s. Signal intensities of the liver were measured and the relative enhancement (RE), the time of maximum RE (Tmax) and elimination half-life of RE (T1/2) in the liver were compared. The fibrosis rate (%) was calculated with the following formula: fibrosis/whole area × 100. Results: The fibrosis rates of each group were as follows: 0.52, 0.79, 2.84, and 0.50% (4, 7, 10 weeks and control groups). The fibrosis rate of the 10 weeks group was significantly higher than the control and 4 or 7 weeks groups. Although there was no difference between the Tmax and T1/2 of each group after Gd-DTPA injection, the Tmax and T1/2 of the 10 weeks group were significantly prolonged in comparison with the control and 4 or 7 weeks groups after Gd-EOB-DTPA injection (p < 0.01). There was a significant correlation between the fibrosis rate and Tmax or T1/2 after Gd-EOB-DTPA injection (r = 0.90 or 0.97). Conclusion: It was possible to assess the progress of liver fibrosis in NASH by evaluating the signal intensity-time course on Gd-EOB-DTPA-enhanced MRI. © 2008 Elsevier Ireland Ltd. All rights reserved.

Yamada Y.,National Cancer Center Hospital | Kiyota N.,Kobe University | Fuse N.,National Cancer Hospital East | Kato K.,National Cancer Center Hospital | And 5 more authors.
Gastric Cancer | Year: 2014

Background: Sorafenib inhibits several receptor tyrosine kinases involved in tumor progression and angiogenesis. S-1, an oral fluorouracil antitumor drug, plus cisplatin (CDDP) is the standard regimen for advanced gastric adenocarcinoma (AGC) in Japan. The purpose of this phase I study was to evaluate the safety, pharmacokinetics, and preliminary efficacy of sorafenib in combination with S-1 plus CDDP. Methods: Patients with histologically confirmed previously untreated AGC were evaluated for eligibility and treated with sorafenib (400 mg bid, days 1-35), S-1 (40 mg/m2 bid, days 1-21), and CDDP (60 mg/m2, day 8). Treatment was continued until disease progression or unacceptable toxicity. Pharmacokinetics for sorafenib, 5-FU, and CDDP were investigated in cycle 1. Results: Thirteen patients were enrolled and received at least one dose of the study treatment. No specific or serious adverse event was newly reported in this study. Five patients had partial response and 8 had stable disease as the best response. Pharmacokinetic analysis showed no significant differences in the exposures of sorafenib when administered alone or in combination with S-1 and CDDP. Conclusions: The present phase I study demonstrates the acceptable toxicity and preliminary efficacy of combined treatment with S-1, CDDP, and sorafenib. © 2013 The International Gastric Cancer Association and The Japanese Gastric Cancer Association.

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