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Articles by T Doi
Total Records ( 5 ) for T Doi
  F Sanada , Y Taniyama , K Iekushi , J Azuma , K Okayama , H Kusunoki , N Koibuchi , T Doi , Y Aizawa and R. Morishita
 

Rationale: Neointimal hyperplasia contributes to atherosclerosis and restenosis after percutaneous coronary intervention. Vascular injury in each of these conditions results in the release of mitogenic growth factors and hormones that contribute to pathological vascular smooth muscle cell growth and inflammation. Hepatocyte growth factor (HGF) is known as an antiinflammatory growth factor, although it is downregulated in injured tissue. However, the precise mechanism how HGF reduces inflammation is unclear.

Objective: To elucidate the mechanism how HGF and its receptor c-Met reduces angiotensin II (Ang II)–induced inflammation.

Methods and Results: HGF reduced Ang II–induced vascular smooth muscle cell growth and inflammation by controlling translocation of SHIP2 (Src homology domain 2–containing inositol 5'-phosphatase 2), which led to Ang II–dependent degradation of epithelial growth factor receptor. Moreover, the present study also revealed a preventive effect of HGF on atherosclerotic change in an Ang II infusion and cuff HGF transgenic mouse model.

Conclusions: These data suggest that the HGF/c-Met system might regulate extrinsic factor signaling that maintains the homeostasis of organs.

  I Okamoto , T Doi , A Ohtsu , M Miyazaki , A Tsuya , K Kurei , K Kobayashi and K. Nakagawa
  Objective

To determine the pharmacokinetics and safety of RAD001 (everolimus) in Japanese patients with advanced solid tumors.

Methods

An open-label, non-randomized, dose-escalation Phase I study of RAD001 administered continuously once daily in a 28-day cycle was performed. The study had a ‘3 + 3’ design, with three patients recruited to each of three successive cohorts treated with RAD001 at 2.5, 5.0 or 10.0 mg/day.

Results

The pharmacokinetics of RAD001 in Japanese patients were similar to those previously determined in Caucasians. The drug safety profile was consistent with that of a mammalian target of rapamycin inhibitor. No dose-limiting toxicities were observed. One patient with esophageal cancer and one with gastric cancer treated with RAD001 at 10 mg/day showed marked tumor responses.

Conclusions

Treatment of Japanese cancer patients with RAD001 may be undertaken with the expectation that previously determined pharmacokinetic and safety profiles apply. The drug may hold promise for treatment of esophageal and gastric cancer.

  T Doi , N Boku , K Kato , Y Komatsu , K Yamaguchi , K Muro , Y Hamamoto , A Sato , W Koizumi , N Mizunuma and H. Takiuchi
  Objective

The addition of bevacizumab to fluoropyrimidine-based combination chemotherapy as first-line therapy for metastatic colorectal cancer results in clinically significant improvements in patient outcome. However, clinical trials have been conducted primarily in Caucasian patients with only a small proportion of Asian patients. This Phase I/II study was designed to evaluate the efficacy and safety of XELOX (capecitabine plus oxaliplatin) plus bevacizumab in Japanese patients with metastatic colorectal cancer.

Methods

Patients with previously untreated, measurable metastatic colorectal cancer received bevacizumab 7.5 mg/kg and oxaliplatin 130 mg/m2 on day 1, plus capecitabine 1000 mg/m2 twice daily on days 1–14, every 3 weeks. A three-step design evaluated in: step 1, initial safety of XELOX in six patients; step 2, initial safety of XELOX plus bevacizumab in six patients; and step 3, efficacy and safety in a further 48 patients. The primary study endpoints were safety and response rate.

Results

No dose-limiting toxicity occurred during Steps 1 and 2. Fifty-eight patients were enrolled in Steps 2 and 3 and received XELOX plus bevacizumab. In the 57 patients assessed for response, the overall response rate was 72% (95% confidence interval, 58.5–83.0). Median progression-free survival was 11.0 months (95% confidence interval, 9.6–12.5) and median overall survival was 27.4 months (95% confidence interval, 22.0–not calculated). Eight patients (14%) underwent surgery with curative intent. The most common grade 3/4 adverse events were neurosensory toxicity (17%) and neutropenia (16%).

Conclusions

XELOX plus bevacizumab is effective and has a manageable tolerability profile when given to Japanese patients with metastatic colorectal cancer.

  S Mochizuki , T Yoshino , T Kojima , N Fuse , H Ikematsu , K Minashi , T Yano , M Tahara , K Kaneko , T Doi , K Koike and A. Ohtsu
  Objective

The risk of venous thromboembolism has been reported to increase when receiving bevacizumab. Many cancer patients are reported to have elevated D-dimer levels. It is not clear what D-dimer level might indicate an increased risk of venous thromboembolism in the colorectal cancer patients treated with bevacizumab-containing chemotherapy.

Methods

The D-dimer levels and any event concurrent with an elevated D-dimer level were evaluated in patients receiving bevacizumab. The D-dimer cut-off level was determined using the receiver-operating characteristic analysis. The selection criteria were as follows: histologically proven metastatic and unresectable colorectal adenocarcinoma; no prior chemotherapy containing bevacizumab; D-dimer test performed repetitively on the baseline and during bevacizumab administration; no venous thromboembolism identified at the baseline; and enhanced computed tomographic scan performed every 2 months.

Results

Sixty-nine patients were included. The chemotherapy regimens with bevacizumab included the regimen of 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX), the regimen of 5-fluorouracil, leucovorin and irinotecan (FOLFIRI), and leucovorin-modulated 5-fluorouracil. The median baseline D-dimer level was 1.2 µg/ml. The appropriate D-dimer cut-off level was 3 µg/ml with the negative predictive value of 98% and relative risk of 6.9. Twenty-one of 69 patients showed elevated D-dimer levels of >3 µg/ml, with 11 patients for unknown reasons, 6 with tumor progression, 3 with venous thromboembolism and 1 with sepsis. In the remaining 48 patients whose D-dimer levels were ≤3 µg/ml, only one patient developed a venous thromboembolism.

Conclusions

A D-dimer cut-off level of 3 µg/ml might be a useful indicator level to exclude venous thromboembolism or show an increased risk for venous thromboembolism in colorectal cancer patients treated with bevacizumab-containing chemotherapy.

  K Nishiyama , M Horiguchi , S Shizuta , T Doi , N Ehara , R Tanuguchi , Y Haruna , Y Nakagawa , Y Furukawa , M Fukushima , T Kita and T. Kimura
  Background

The incidence of strokes has not decreased after coronary artery bypass graft surgery (CABG). The purpose of this study is to identify incidence, risk factors, and temporal pattern of strokes after on-pump and off-pump CABG.

Methods

We analyzed 2,516 consecutive patients who underwent first elective isolated CABG. The primary endpoint was strokes within 30 days. The temporal onset of the deficits was classified by consensus as either an "early stroke," which is present just after emergence from anesthesia, or a "delayed stroke," which is present after first awaking from surgery without a neurologic deficit.

Results

More than half of strokes (29 of 46; 63%) were delayed strokes. Patients undergoing off-pump CABG had significantly lower risk of early stroke (0.1% versus 1.1%, p = 0.0009), whereas the incidence of delayed strokes was not different significantly (0.9% versus 1.4%, p = 0.3484) between patients undergoing on-pump and off-pump CABG. In multivariate analyses, undergoing off-pump CABG was an independent protective factor for all strokes (relative risk 0.29, 95% confidence interval: 0.14 to 0.56, p = 0.0005) and early strokes (relative risk 0.05, 95% confidence interval: 0.003 to 0.24, p < 0.0001), but it was not an independent protective factor for delayed strokes (relative risk 0.54, 95% confidence interval: 0.24 to 1.17, p = 0.1210).

Conclusions

Undergoing off-pump CABG reduces the incidence of perioperative stroke mainly by minimizing early strokes; however, the risk of delayed strokes is not different between patients undergoing on-pump and off-pump CABG.

 
 
 
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