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Articles by T Fujii
Total Records ( 7 ) for T Fujii
  T Kake , H Kitamura , Y Adachi , T Yoshioka , T Watanabe , H Matsushita , T Fujii , E Kondo , T Tachibe , Y Kawase , K. i Jishage , A Yasoda , M Mukoyama and K. Nakao
 

C-type natriuretic peptide (CNP) plays a critical role in endochondral ossification through guanylyl cyclase-B (GC-B), a natriuretic peptide receptor subtype. Cartilage-specific overexpression of CNP enhances skeletal growth and rescues the dwarfism in a transgenic achondroplasia model with constitutive active mutation of fibroblast growth factor receptor-3. For future clinical application, the efficacy of CNP administration on skeletal growth must be evaluated. Due to the high clearance of CNP, maintaining a high concentration is technically difficult. However, to model high blood CNP concentration, we established a liver-targeted CNP-overexpressing transgenic mouse (SAP-CNP tgm). SAP-CNP tgm exhibited skeletal overgrowth in proportion to the blood CNP concentration and revealed phenotypes of systemic stimulation of cartilage bones, including limbs, paws, costal bones, spine, and skull. Furthermore, in SAP-CNP tgm, the size of the foramen magnum, the insufficient formation of which results in cervico-medullary compression in achondroplasia, also showed significant increase. CNP primarily activates GC-B, but under high concentrations it cross-reacts with guanylyl cyclase-A (GC-A), a natriuretic peptide receptor subtype of atrial natriuretic peptides (ANP) and brain natriuretic peptides (BNP). Although activation of GC-A could alter cardiovascular homeostasis, leading to hypotension and heart weight reduction, the skeletal overgrowth phenotype in the line of SAP-CNP tgm with mild overexpression of CNP did not accompany decrease of systolic blood pressure or heart weight. These results suggest that CNP administration stimulates skeletal growth without adverse cardiovascular effect, and thus CNP could be a promising remedy targeting achondroplasia.

  A Yasoda , H Kitamura , T Fujii , E Kondo , N Murao , M Miura , N Kanamoto , Y Komatsu , H Arai and K. Nakao
 

Skeletal dysplasias are a group of genetic disorders characterized by severe impairment of bone growth. Various forms of them add to produce a significant morbidity and mortality, yet no efficient drug therapy has been developed to date. We previously demonstrated that C-type natriuretic peptide (CNP), a member of the natriuretic peptide family, is a potent stimulator of endochondral bone growth. Furthermore, we exhibited that targeted overexpression of a CNP transgene in the growth plate rescued the impaired bone growth observed in a mouse model of achondroplasia (Ach), the most frequent form of human skeletal dysplasias, leading us to propose that CNP may prove to be an effective treatment for this disorder. In the present study, to elucidate whether or not the systemic administration of CNP is a novel drug therapy for skeletal dysplasias, we have investigated the effects of plasma CNP on impaired bone growth in Ach mice that specifically overexpress CNP in the liver under the control of human serum amyloid P component promoter or in those treated with a continuous CNP infusion system. Our results demonstrated that increased plasma CNP from the liver or by iv administration of synthetic CNP-22 rescued the impaired bone growth phenotype of Ach mice without significant adverse effects. These results indicate that treatment with systemic CNP is a potential therapeutic strategy for skeletal dysplasias, including Ach, in humans.

  T Matsuda , T Fujii , Y Sano , S. e Kudo , Y Oda , M Igarashi , H Iishi , Y Murakami , H Ishikawa , T Shimoda , K Kaneko and S. Yoshida
  Objective

The National Polyp Study is used as the basis of recommendations for colonoscopic surveillance after polypectomy, establishing an interval of 3 years after removal of newly diagnosed adenomas. The aim of this retrospective cohort study was to estimate the incidence of advanced neoplasia after initial colonoscopy and compare the differences among risk groups.

Methods

Patients over 40 years who were referred for initial colonoscopy at six institutes were selected. They were classified into four groups based on the initial colonoscopy: A, patients without any adenoma; B, with adenomas of <6 mm only; C, with adenomas of ≥6 mm; D, with any intramucosal cancer. The index lesion (IL) at follow-up colonoscopy was defined as large adenoma ≥10 mm, intramucosal/invasive cancer.

Results

A total of 5309 patients were enrolled in this study. Overall, median follow-up period was 5.1 years. The numbers of eligible patients in the various subgroups were A, 2006; B, 1655; C, 1123; D, 525. A total of 379 ILs were newly diagnosed during follow-up colonoscopy. The cumulative incidence of ILs in each group was A, 2.6%; B, 6.7%; C, 13.4%; and D, 12.6%.

Conclusions

Patients with any adenomas >6 mm or intramucosal cancer at the initial colonoscopy have a higher risk of advanced neoplasia during follow-up colonoscopy.

  K Naoki , H Kunikane , T Fujii , S Tsujimura , N Hida , H Okamoto and K. Watanabe
  Objective

Combined paclitaxel and carboplatin is a standard regimen for inoperable non-small cell lung cancer (NSCLC). Although an every-3-week schedule is common, weekly paclitaxel is clinically effective for various cancers. A Phase I clinical trial was conducted to determine maximum-tolerated doses (MTDs) for weekly combined paclitaxel and carboplatin, and to evaluate anti-tumor response, toxicity and pharmacokinetics of paclitaxel in patients with inoperable NSCLC.

Methods

Twenty patients with inoperable NSCLC received weekly carboplatin at area under the curve (AUC) = 2 mg/ml min and paclitaxel. Paclitaxel was escalated if MTD was not reached. Three patients each were entered at levels 1 and 2 (level 1, paclitaxel 50 mg/m2 and carboplatin AUC = 2 mg/ml min; level 2, 60/2), six at level 3 (70/2), five at level 4 (80/2) and three at level 5 (90/2).

Results

One patient had grade 4 (G4) neutropenia at level 2, one had G3 hepatic toxicity at level 3 and one had G3 cardiac toxicity at level 4. MTD was not reached for all dose levels. Response rate (RR) was 35% (7/20) and median survival was 11.1 months. Severe neutropenia (G3 and G4) was seen in seven patients associated with greater AUC, peak concentration (Cmax) and the duration of plasma concentration >50 ng/ml of paclitaxel.

Conclusions

Weekly combined paclitaxel (up to 90 mg/m2) and carboplatin (AUC = 2 mg/ml min) was well tolerated. A higher dose intensity of paclitaxel can be given, and RR and survival are not less than the every-3-week protocol. The weekly regimen is an alternative for untreated inoperable NSCLC patients.

  T Fujii , H Kunikane , H Okamoto , K Watanabe , H Kunitoh , K Mori , A Yokoyama , H Fukuda , T Tamura and N. Saijo
  Objective

It is important to find optimal regimens of cisplatin (CDDP)-based third-generation chemotherapy and radiotherapy for patients with unresectable Stage III non-small cell lung cancer (NSCLC).

Methods

This Phase II study was designed to determine the toxicity and efficacy of two courses of chemotherapy (CDDP 80 mg/m2 on day 1 and irinotecan 60 mg/m2 on days 1 and 8) followed by accelerated hyperfractionated thoracic radiotherapy (60 Gy/40 fractions in 4 weeks) combined with daily carboplatin (CBDCA) administration. CBDCA was administered at a target area under the plasma level–time curve of 0.4 x (24 h creatinine clearance + 25), according to Calvert's formula.

Results

Twenty-six patients were enrolled in the study. The patients' median age was 63 years (range 40–74 years) and included 22 males and 4 females. Seven patients were Stage IIIA and 19 were Stage IIIB. Twenty had a performance status (PS) of 1 versus six with a PS of 0. There was one treatment-related death due to sepsis and pneumonia associated with Grade 4 neutropenia and diarrhea during chemotherapy. Grade 3 or 4 neutropenia and diarrhea were observed in 14 and 5 patients, respectively. Toxicity of the radiotherapy was mild. There were 0 complete response and 13 partial responses, giving a response rate of 50.0%. Median survival time and 2-year survival were 16.4 months and 21.5%, respectively. This study was designed with Simon's two-stage design, and the response rate did not meet the criteria to proceed to the second stage and the study was terminated early.

Conclusions

This regimen might be inactive for patients with unresectable Stage III NSCLC.

  M Morimoto , K Nishiyama , S Nakamura , O Suzuki , Y Kawaguchi , A Nakajima , A Imai , R Ishihara , H Uemura , T Fujii , K Yoshino and Y. Tomita
  Objective

The efficacy of endoscopic screening for esophageal cancer in patients with hypopharyngeal cancer remains controversial and its impact on prognosis has not been adequately discussed. We studied the use of endoscopic screening to detect esophageal cancer in hypopharyngeal cancer patients by analyzing the incidence, stage and prognosis.

Methods

We included 64 patients with hypopharyngeal cancer who received radical radiotherapy at our institute. Chromoendoscopic esophageal examinations with Lugol dye solution were routinely performed at and after treatment for hypopharyngeal cancer.

Results

Twenty-eight esophageal cancers were detected in 28 (41%) patients (18 synchronous and 10 metachronous cancers). Of the 28 cancers, 23 were stage 0 or I cancer and 15 of these were treated with endoscopic resection. Local control was achieved in all of these 23 stage 0 or I cancers. The 5-year overall survival rates with esophageal cancer were 83% in stage 0, 47% in stage I and 0% in stage IIA–IVB.

Conclusions

This study showed a strikingly high incidence of esophageal cancer in hypopharyngeal cancer patients. We suppose that the combination of early detection by chromoendoscopic examination and endoscopic resection for associated esophageal cancer in hypopharyngeal cancer patients improve prognosis and maintain quality of life.

  K Kuriyama , T Soshi , T Fujii and Y. Kim
 

The interaction between amygdala-driven and hippocampus-driven activities is expected to explain why emotion enhances episodic memory recognition. However, overwhelming behavioral evidence regarding the emotion-induced enhancement of immediate and delayed episodic memory recognition has not been obtained in humans. We found that the recognition performance for event memory differs from that for emotional memory. Although event recognition deteriorated equally for episodes that were or were not emotionally salient, emotional recognition remained high for only stimuli related to emotional episodes. Recognition performance pertaining to delayed emotional memory is an accurate predictor of the context of past episodes.

 
 
 
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