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Naoki Morimoto,
Kenichi Yoshimura, Miyuki Niimi,
Tatsuya Ito,
Rino Aya,
Junpei Fujitaka,
Harue Tada,
Satoshi Teramukai,
Toshinori Murayama,
Chikako Toyooka,
Kazumi Miura,
Satoru Takemoto,
Norikazu Kanda,
Katsuya Kawai,
Masayuki Yokode,
Akira Shimizu,
Shigehiko Suzuki
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ABSTRACT: Chronic skin ulcers such as diabetic ulcers and venous leg ulcers are increasing and are a costly problem in healthcare. We have developed a novel artificial dermis, collagen/gelatin sponge (CGS), which is capable of the sustained release of basic fibroblast growth factor (bFGF) for more than 10 days. The objective of this study was to investigate the safety and efficacy of CGS impregnated with bFGF in the treatment of chronic skin ulcers. Patients with chronic skin ulcers that had not healed in at least four weeks were treated with CGS impregnated with bFGF at 7 μg/cm2 or 14 μg/cm2 after debridement, and the wound bed improvement was assessed 14 days after application. Wound bed improvement was defined as a granulated and epithelialized area on Day 14 with a proportion to the baseline wound area after debridement of 50% or higher. The wound area, the wound area on Day 14, and the granulation area on Day 14 were independently measured by blinded reviewers in a central review using digital images of wounds taken with a calibrator. Patients were followed up until 28 days after application to observe the adverse reactions related to the application of CGS. From May 2010 to June 2011, 17 patients were enrolled and, in 16 patients, the wound bed improved. Among the randomized patients in step 2, no significant difference was seen between the low-dose group and the high-dose group. No serious adverse reactions were observed. Adverse reactions with a clear causal relationship to the study treatment were mild and recovered from quickly. This study is the first-in-man clinical trial of CGS and showed the safety and efficacy of CGS impregnated with bFGF in the treatment of chronic skin ulcers. This combination therapy could be a promising therapy for chronic skin ulcers.
Tissue Engineering Part A 03/2013; · 4.64 Impact Factor
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Naoki Morimoto,
Kenichi Yoshimura, Miyuki Niimi,
Tatsuya Ito,
Harue Tada,
Satoshi Teramukai,
Toshinori Murayama,
Chikako Toyooka,
Satoru Takemoto,
Katsuya Kawai,
Masayuki Yokode,
Akira Shimizu,
Shigehiko Suzuki
[show abstract]
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ABSTRACT: Chronic skin ulcers such as diabetic ulcers and venous leg ulcers are increasing and are a costly problem in health care. We have developed a novel artificial dermis, collagen/gelatin sponge (CGS), that is capable of the sustained release of basic fibroblast growth factor (bFGF) for more than 10 days. The objective of this study was to investigate the safety and efficacy of CGS impregnated with bFGF in the treatment of chronic skin ulcers. Methods/
Seventeen patients (≥ 20 years of age) with chronic skin ulcers that have not healed by conventional therapy for at least 4 weeks are being recruited. Patients will be applied with CGS impregnated with bFGF of 7 μg/cm(2) or 14 μg/cm(2) after debridement, and the wound bed improvement will be assessed 14 days after application. "Wound bed improvement" is defined as a granulated and epithelialized area on Day 14 in proportion to the baseline wound area after debridement of 50% or higher. Patients will be followed up until 28 days after application to observe the adverse events related to the application of CGS.
This study has been designed to address the safety and efficacy of CGS impregnated with bFGF. If successful, this intervention may be an alternative to bioengineered skin substitutes and lead to substantial and important changes in the management of chronic skin ulcers such as diabetic ulcers and venous ulcers.
American Journal of Translational Research 01/2012; 4(1):52-9.
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Masashi Kanai,
Kenichi Yoshimura,
Takehiko Tsumura,
Masanori Asada,
Chihiro Suzuki, Miyuki Niimi,
Shigemi Matsumoto,
Takafumi Nishimura,
Takashi Nitta,
Kentaro Yasuchika, [......],
Naoya Inoue,
Shinsuke Tada,
Kazuhiro Yanagihara,
Shujiro Yazumi,
Yukio Osaki,
Tsutomu Chiba,
Iwao Ikai,
Masanori Fukushima,
Shinji Uemoto,
Etsuro Hatano
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ABSTRACT: We aimed to evaluate the efficacy and safety of gemcitabine/S-1 combination chemotherapy for the treatment of patients with advanced biliary tract cancer.
Patients with histologically or cytologically confirmed unresectable or recurrent biliary tract cancer were eligible for inclusion. The primary endpoint was overall survival. Gemcitabine was administered intravenously at a dose of 1,000 mg/m(2) over 30 min on days 1 and 8, and oral S-1 was administered daily at a dose of 60 mg/m(2) on days 1-14. This schedule was repeated every 3 weeks until disease progression or patient refusal.
Twenty-five patients were enrolled between October 2007 and January 2009. Eleven patients (44%) had extrahepatic bile duct cancer, 5 (20%) had intrahepatic bile duct cancer, 8 had gallbladder cancer (32%), and 1 (4%) had ampulla of Vater cancer. The median overall survival time was 12.7 months (95% CI, 8.4-23.5 months), and the 1-year survival rate was 52.0% (95% CI, 31.2-69.2%). Of the 23 patients with evaluable target regions, seven patients experienced a partial response, and an overall response rate was 30.4%. The following grade 3-4 hematological toxicities occurred: neutropenia (56%), leukopenia (24%), anemia (8%) and thrombocytopenia (4%). In spite of the high incidence of grade 3-4 neutropenia, no patients developed febrile neutropenia in the present study. The major grade 3-4 non-hematological toxicities were fatigue (8%), anorexia (8%) and diarrhea (4%).
Gemcitabine/S-1 combination chemotherapy offered a promising survival benefit with acceptable toxicity in patients with advanced biliary tract cancer.
Cancer Chemotherapy and Pharmacology 06/2011; 67(6):1429-34. · 2.83 Impact Factor
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ABSTRACT: Erlotinib is the first epidermal growth factor receptor-tyrosine kinase inhibitor shown to provide a survival benefit for advanced non-small-cell lung cancer (NSCLC) patients. Adverse drug reactions of erlotinib in Japanese, which may be very different from those in Caucasians because of differences in genetic background, have not been fully reported. Therefore, we aimed to clarify the safety profile of erlotinib.
Forty-eight patients with pretreated NSCLC were treated with erlotinib between March 2008 and January 2009 in this historical cohort study at Kyoto University Hospital Outpatients Oncology Unit. Erlotinib 150 mg/day was administered until progressive disease or discontinuation due to adverse events. The primary endpoint was frequency and degree of adverse events, and secondary endpoints were clinical efficacy including response rate, disease control rate, progression-free survival and overall survival.
Of 48 patients, 3 patients experienced erlotinib-induced interstitial pneumonitis, which appeared on day 15 and 70 in 2 patients who recovered and on day 8 in 1 patient who died. The incidences of pruritus, dry skin, diarrhea and stomatitis rapidly increased within 14 days after the start of medication with erlotinib. However, these adverse events were well controllable in outpatients treated with erlotinib. Overall response rate was 10% and disease control rate was 68%. The median progression-free survival was 58 days (95% confidence interval 30-118) and the median overall survival was 229 days (95% confidence interval 135-not available).
Outpatients with NSCLC can be treated with initial administration of erlotinib by careful management.
International Journal of Clinical Oncology 04/2011; 16(5):560-7. · 1.41 Impact Factor
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ABSTRACT: Combination of erlotinib and bevacizumab is a promising regimen in advanced non-squamous non-small-cell lung cancer (NSCLC). We are conducting a single arm phase II trial which aims to evaluate the efficacy and safety of this regime as a second- or third-line chemotherapy.
Key eligibility criteria were histologically or cytologically confirmed non-squamous NSCLC, stage III/IV or recurrent NSCLC not indicated radical chemoradiation, prior one or two regimen of chemotherapy, age 20 years or more, and performance status of two or less. The primary endpoint is objective response rate. The secondary endpoints include overall survival, progression-free survival, disease control rate and incidence of adverse events. This trial plans to accrue 80 patients based on a two-stage design employing a binomial distribution with an alternative hypothesis response rate of 35% and a null hypothesis threshold response rate of 20%. A subset analysis according to EGFR mutation status is planned.
We have presented the design of a single arm phase II trial to evaluate the efficacy and safety of combination of bevacizumab and erlotinib in advanced non-squamous NSCLC patients. In particular we are interested in determining the merit of further development of this regimen and whether prospective patient selection using EGFR gene is necessary in future trials.
This trial was registered at the UMIN Clinical Trials Registry as UMIN000004255 (http://www.umin.ac.jp/ctr/index.htm).
Trials 01/2011; 12:120. · 2.02 Impact Factor
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Kazuhiro Yanagihara,
Kenichi Yoshimura, Miyuki Niimi,
Hiroyasu Yasuda,
Takahiko Sasaki,
Takafumi Nishimura,
Hiroshi Ishiguro,
Shigemi Matsumoto,
Toshiyuki Kitano,
Masashi Kanai,
Akiko Misawa,
Harue Tada,
Satoshi Teramukai,
Tadashi Mio,
Masanori Fukushima
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ABSTRACT: The purpose of the present phase II study was to evaluate both the efficacy and toxicity of the combination of S-1 and docetaxel in previously treated patients with locally advanced or metastatic non-small cell lung cancer.
Thirty-eight previously treated patients with non-small cell lung cancer were treated with S-1 (80 mg/m(2), days 1-14, oral) and docetaxel (40 mg/m(2), day 1, intravenous) every 3 weeks.
No complete response was observed, and seven patients had a partial response, yielding an overall response rate of 18.4% (95% CI, 7.7-34.3%). The median overall survival time and 1-year overall survival rate were 16.1 months and 60%, respectively. The median progression-free survival time was 4.4 months. Myelosuppression was the main toxicity with grade 3 or 4 neutropenia and leukopenia in 50 and 21%, respectively. There was no irreversible toxicity in this study.
The combination of S-1 and docetaxel is well tolerable and has substantial activity for patients with locally advanced or metastatic non-small cell lung cancer. A phase III trial comparing docetaxel with or without S-1 would warrant further investigation.
Cancer Chemotherapy and Pharmacology 10/2010; 66(5):913-8. · 2.83 Impact Factor
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Masashi Kanai,
Akira Yoshioka,
Shiro Tanaka,
Satoshi Nagayama,
Shigemi Matsumoto,
Takafumi Nishimura, Miyuki Niimi,
Satoshi Teramukai,
Ryo Takahashi,
Yukiko Mori,
Toshiyuki Kitano,
Hiroshi Ishiguro,
Kazuhiro Yanagihara,
Tsutomu Chiba,
Masanori Fukushima,
Fumihiko Matsuda
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ABSTRACT: Although the risk of oxaliplatin-induced neuropathy depends on cumulative oxaliplatin dose, susceptibility to this adverse event differs greatly among patients. In this study, we investigated the associations between oxaliplatin-induced neuropathy and the following polymorphisms: glutathione S-transferase pi (GSTP1) Ile(105)Val, and glyoxylate aminotransferase (AGXT) Pro(11)Leu and AGXT Ile(340)Met.
Eighty-two Japanese patients with histologically confirmed colorectal cancer who received at least six cycles of the modified FOLFOX6 (m-FOLFOX6) regimen were enrolled. To minimize differences in cumulative oxaliplatin dose between patients, oxaliplatin-induced neuropathy was evaluated using an oxaliplatin-specific scale during the 2-week period after completion of the sixth cycle of treatment.
Forty-four patients developed grade 2/3 oxaliplatin-induced neuropathy. There were more patients carrying at least one GSTP1(105)Val allele among the group with grade 2/3 neuropathy (18/44, 41%) than among the group with grade 1 neuropathy (9/38, 24%), although the difference was not statistically significant (P=0.098). There were similar numbers of patients carrying at least one AGXT(105)Met allele in the grade 2/3 neuropathy (7/44, 16%) and grade 1 neuropathy groups (5/38, 13%; P=0.725). The AGXT(11)Leu allele was not found in any of our patients or controls.
We found no significant association between oxaliplatin-induced neuropathy and the GSTP1 Ile(105)Val and AGXT Ile(340)Met polymorphisms. Given that no AGXT(11)Leu allele was found among our study population (n=177), evaluating this polymorphism in Japanese patients in future studies is likely to be uninformative.
Cancer epidemiology. 03/2010; 34(2):189-93.
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ABSTRACT: Progression-free survival (PFS) is a common endpoint in cancer clinical trials. This study was undertaken to assess the impact of data errors and data handling on the statistical estimation of PFS.
Data from four trials conducted by the Japan Clinical Oncology Group were examined. Three types of data handling methods were defined: (1) data handling method A (METHOD-A), the collected event data are used as much as possible, (2) METHOD-C, only reliable data with firm evidence are used, and (3) METHOD-B is intermediate between METHOD-A and METHOD-C. To assess the impact of each of the three methods, Kaplan-Meier survival curves, median PFS, proportion of PFS, log-rank p values and hazard ratios were estimated.
In three trials that collected PFS data periodically, no remarkable differences in median PFS and the proportion of PFS were observed. In one trial with non-periodic data cleaning, however, the ratio of median PFS by METHOD-C to that by METHOD-B was 0.85, the maximum difference of proportion of PFS between METHOD-C and METHOD-B was 12.0% and the largest spread in PFS curves amongst the three methods was observed in this trial. In all trials, log-rank p values and hazard ratios for between arm comparisons did not differ between the three methods.
Periodic data management can reduce errors in comparisons of PFS and is a critical requirement when using PFS as a major endpoint. Furthermore, proper data handling is essential in the estimation of patient benefit and caution is needed when making clinical decisions based on PFS.
Japanese Journal of Clinical Oncology 02/2002; 32(1):19-26. · 1.78 Impact Factor
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Masashi Kanai,
Akira Yoshioka,
Shiro Tanaka,
Satoshi Nagayama,
Shigemi Matsumoto,
Takafumi Nishimura, Miyuki Niimi,
Satoshi Teramukai,
Ryo Takahashi,
Yukiko Mori,
Toshiyuki Kitano,
Hiroshi Ishiguro,
Kazuhiro Yanagihara,
Tsutomu Chiba,
Masanori Fukushima,
Fumihiko Matsuda
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ABSTRACT: Purpose: Although the risk of oxaliplatin-induced neuropathy depends on cumulative oxaliplatin dose, susceptibility to this adverse event differs greatly among patients. In this study, we investigated the associations between oxaliplatin-induced neuropathy and the following polymorphisms: glutathione S-transferase π (GSTP1) Ile105Val, and glyoxylate aminotransferase (AGXT) Pro11Leu and AGXT Ile340Met. Experimental design: Eighty-two Japanese patients with histologically confirmed colorectal cancer who received at least six cycles of the modified FOLFOX6 (m-FOLFOX6) regimen were enrolled. To minimize differences in cumulative oxaliplatin dose between patients, oxaliplatin-induced neuropathy was evaluated using an oxaliplatin-specific scale during the 2-week period after completion of the sixth cycle of treatment. Results: Forty-four patients developed grade 2/3 oxaliplatin-induced neuropathy. There were more patients carrying at least one GSTP1105Val allele among the group with grade 2/3 neuropathy (18/44, 41%) than among the group with grade 1 neuropathy (9/38, 24%), although the difference was not statistically significant (P = 0.098). There were similar numbers of patients carrying at least one AGXT105Met allele in the grade 2/3 neuropathy (7/44, 16%) and grade 1 neuropathy groups (5/38, 13%; P = 0.725). The AGXT11Leu allele was not found in any of our patients or controls. Conclusions: We found no significant association between oxaliplatin-induced neuropathy and the GSTP1 Ile105Val and AGXT Ile340Met polymorphisms. Given that no AGXT11Leu allele was found among our study population (n = 177), evaluating this polymorphism in Japanese patients in future studies is likely to be uninformative.
Cancer Epidemiology. 34(2):189-193.
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Mitsuhiro Fujishiro,
Tetsu Shinkai,
Minoru Fukuda,
Tomohide Tamura,
Yuichiro Ohe,
Hideo Kunitoh,
Hiroshi Nishiwaki,
Ikuo Sekine,
Yoshihiro Matsuno, Miyuki Niimi,
Nagahiro Saijo
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ABSTRACT: Background: To determine the maximum-tolerated dose (MTD) and acceptable dose level of CPT-11 in combination with a 14-day continuous infusion of etoposide in patients with refractory advanced lung cancer (LC), especially small cell lung cancer (SCLC). Methods: Etoposide was administered continuously at 25 mg/m2/day for 14 days. The initial dose of CPT-11 was 40 mg/m2 given as a 90-min intravenous infusion on days 1, 8 and 15 and the dose escalation of CPT-11 was planned in increments of 20 mg/m2 until severe or life-threatening toxic effects were observed. Results: Eight refractory advanced LC patients entered this study, of whom two were not assessable for toxicity because of patient’s refusal and progressive disease. One treatment-related death due to pulmonary toxicity and one patient with hypotension who needed catecholamine for more than 48 h were observed at a CPT-11 dose of 40 mg/m2. The MTD of CPT-11 was 40 mg/m2. Therapeutic efficacy could be assessed in six patients, of whom two achieved a partial response. Conclusions: This regimen was too toxic and the recommended dose was outside this study. One has to consider pulmonary toxicity when using CPT-11, especially for patients previously treated with cytotoxic agents for which pulmonary toxicity has been reported.
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Takeaki Takenaka,
Chikara Mikuni,
Akira Miura,
Tsuneo Sasaki,
Hisamitsu Suzuki,
Tomomitsu Hotta,
Masami Hirano,
Shiro Fukuhara,
Haruo Sugiyama,
Kaori Nasu,
Hiroo Dohi,
Mitsuo Kozuru,
Masao Tomonaga,
Kinuko Tajima, Miyuki Niimi,
Haruhiko Fukuda,
Kiyoshi Mukai
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ABSTRACT: Background: The main form of cytotoxic treatment for advanced Hodgkin’s disease (HD) is conventional dose multiagents chemotherapy. As HD is not common in Japan, we conducted a phase II study of the commonly used combination chemotherapy (CCT) regimen established in the West for Japanese patients with advanced HD to confirm the efficacy and safety. Method: Between October 1989 and February 1993, a multicenter phase II study of alternating CCT C-MOPP (cyclophosphamide, vincristine, procarbazine, prednisone) and ABVd (adriamycin, vinblastine, bleomycin, dacarbazine) to evaluate its clinical usefulness for clinical stage (cS) II–IV HD was conducted by the Lymphoma Study Group of the Japan Clinical Oncology Group. Results: Seventy-nine previously untreated patients were enrolled in the study. For 67 eligible patients, the response rate was 92.5% with 83.6% complete response (CR). For 40 cS II and 27 cS III/IV patients the response rate was 95.0% with 90.0% CR and 88.9% with 74.1% CR, respectively. The overall 5-year survival rate was 84.8%. Those of cS II and cS III/IV were 92.5 and 73.1%, respectively. There was no significant difference between cS II and cS III/IV ( p = 0.1025). The progression-free 4-year survival rate was 72.8%. Those of cS II and cS III/IV were 77.5 and 65.7%, respectively. There was no significant difference between cS II and cS III/IV ( p = 0.2483). Grade 4 toxicity by the criteria of the World Health Organization consisted of leukocytopenia in 28.4% of patients. There was GPT elevation in 4.5%, nausea/vomiting in 11.9% and CNS in 1.5% of patients, but there was no treatment-related death. Conclusion: The C-MOPP/ABVd regimen for Japanese patients with advanced HD is considered to be one of the effective CCTs according to the results of the present phase II study.
