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Articles by N Yamamoto
Total Records ( 8 ) for N Yamamoto
  T Matsumoto , S Terai , T Oishi , S Kuwashiro , K Fujisawa , N Yamamoto , Y Fujita , Y Hamamoto , M Furutani Seiki , H Nishina and I. Sakaida
  Toshihiko Matsumoto, Shuji Terai, Toshiyuki Oishi, Shinya Kuwashiro, Koichi Fujisawa, Naoki Yamamoto, Yusuke Fujita, Yoshihiko Hamamoto, Makoto Furutani-Seiki, Hiroshi Nishina, and Isao Sakaida

The global incidence of nonalcoholic steatohepatitis (NASH) is increasing and current mammalian models of NASH are imperfect. We have developed a NASH model in the ricefish medaka (Oryzias latipes), which is based on feeding the fish a high-fat diet (HFD). Medaka that are fed a HFD (HFD-medaka) exhibited hyperlipidemia and hyperglycemia, and histological examination of the liver revealed ballooning degeneration. The expression of lipogenic genes (SREBP-1c, FAS and ACC1) was increased, whereas the expression of lipolytic genes (PPARA and CPT1) was decreased. With respect to liver fatty acid composition, the concentrations of n-3 polyunsaturated fatty acids (PUFAs) and n-6 PUFAs had declined and the n-3:n-6 ratio was reduced. Treatment of HFD-medaka with the n-3 PUFA eicosapentaenoic acid (EPA) mitigated disease, as judged by the restoration of normal liver fatty acid composition and normal expression levels of lipogenic and lipolytic genes. Moreover, medaka that were fed a diet deficient in n-3 PUFAs developed NASH features. Thus, NASH can be induced in medaka by a HFD, and the proportion of n-3 PUFAs in the liver influences the progress of NASH pathology in these fish. Our model should prove helpful for the dissection of the causes of human NASH and for the design of new and effective therapies.

  N Yamamoto , I Sekine , K Nakagawa , M Takada , M Fukuoka , Y Tanigawara and N. Saijo

The aim of this study was to investigate the safety, pharmacokinetic and pharmacodynamic profiles of pegfilgrastim (KRN125), a long-acting granulocyte colony-stimulating factor, in lung cancer patients with chemotherapy-induced neutropenia.


Eighteen Japanese lung cancer patients who had experienced severe neutropenia (absolute neutrophil counts <0.5 x 109 cells/l) were enrolled. Six patients were sequentially enrolled in each pegfilgrastim dose cohort (dose levels of 30, 60 or 100 µg/kg). Patients received the same chemotherapy regimen as in their previous cycle and pegfilgrastim was injected subcutaneously the day after chemotherapy ended in each treatment cycle. Pharmacokinetic, pharmacodynamic and safety analyses were performed.


Dose-limiting toxicity and serious adverse events related to pegfilgrastim were not observed in any patients. Pegfilgrastim antibodies were not detected. Maximum serum concentrations and area under the serum concentration–time curves of pegfilgrastim were dependent on the pegfilgrastim dose in a non-linear manner. Of the 18 patients, severe neutropenia occurred in 4 (22.2%), and, of these, 1 patient (5.5%) required rescue treatment by filgrastim.


A single dose of pegfilgrastim increases the serum concentration of pegfilgrastim for several days in a dose-dependent manner and is not associated with significant toxicity. Good efficacy of pegfilgrastim for the prevention of severe neutropenia was observed at all dose levels. Based on these data, further studies are warranted to determine the recommended dose of pegfilgrastim for Japanese patients with chemotherapy-induced neutropenia.

  I Sekine , M Sumi , Y Ito , C Tanai , H Nokihara , N Yamamoto , H Kunitoh , Y Ohe and T. Tamura

To identify any gender differences in the outcomes of concurrent platinum-based chemotherapy and thoracic radiotherapy for unresectable stage III non-small cell lung cancer (NSCLC).


A comparative retrospective review of the clinical characteristics and treatment outcomes between female and male NSCLC patients receiving chemoradiotherapy.


Of a total of 204 patients, 44 (22%) were females and 160 (78%) were males. There was no difference in age, body weight loss, performance status or disease stage between the sexes, whereas never-smokers and adenocarcinoma were more common in female patients (55% vs. 3%, P < 0.001, and 73% vs. 55%, P = 0.034, respectively). Full cycles of chemotherapy and radiotherapy at a total dose of 60 Gy were administered to ~70% and >80% of the patients, respectively, of both sexes. Grade 3–4 neutropenia was observed in 64% of the female patients and 63% of the male patients. Severe esophagitis was encountered in <10% of the patients, irrespective of the sex. The response rate was higher in the female than in the male patients (93% vs. 79%, P = 0.028), but the median progression-free survival did not differ between the sexes. The median survival time in the female and male patients was 22.3 and 24.3 months, respectively (P = 0.64).


This study failed to show any gender differences in the survival or toxicity among patients treated by concurrent chemoradiotherapy. These results contrast with the better survival in female patients undergoing surgery for localized disease or chemotherapy for metastatic disease.

  K Yamada , N Yamamoto , Y Yamada , T Mukohara , H Minami and T. Tamura

ABI-007 is a novel Cremophor® EL-free nanoparticle albumin-bound paclitaxel. This Phase I study was designed to evaluate tolerability and determine recommended dose for Japanese patients when ABI-007 was administered in every-3-week schedule. Pharmacokinetics of paclitaxel was also assessed.


Patients with advanced solid tumors refractory to standard therapy received a 30 min intravenous infusion of ABI-007 every 3 weeks without pre-medications at 200, 260 or 300 mg/m2, respectively. Tolerability and recommended dose were determined by the standard ‘3 + 3’ rule.


No dose-limiting toxicity was observed, despite the dose escalation. In another cohort, 260 mg/m2 was re-evaluated and resulted in no dose-limiting toxicity. Grade 3 or 4 neutropenia was reported for the majority of patients (n = 8) but no incidence of febrile neutropenia. Non-hematological toxicities were generally mild except for Grade 3 sensory neuropathy (n = 3). Pharmacokinetic study demonstrated the area under the curve of paclitaxel increased with increasing the dosage, and comparable pharmacokinetic parameters to the western population. Partial response was observed in three non-small cell lung cancer patients. Two of whom had received docetaxel-containing chemotherapy prior to the study.


ABI-007 administered in every-3-week schedule was well tolerated up to 300 mg/m2, and recommended dose was determined at 260 mg/m2 in consideration of efficacy, toxicities and similarity of pharmacokinetic profile in western studies. Additional studies of single-agent ABI-007 as well as platinum-based combinations, particularly in patients with non-small cell lung cancer, are warranted.

  Y Fujisaka , Y Yamada , N Yamamoto , A Horiike and T. Tamura

Temsirolimus (CCI-779) is a novel inhibitor of the mammalian target of rapamycin. This Phase 1 study was aimed at investigating the maximum-tolerated dose, toxicity, pharmacokinetics and antitumor activity in Japanese patients with advanced solid tumors.


Temsirolimus was given as a 30 min intravenous infusion once a week. Patients with solid tumors not amenable to standard forms of treatment were eligible. Dose escalation of temsirolimus was planned from 15, 45, 80 to 165 mg/m2. The pharmacokinetics of temsirolimus and sirolimus in whole blood were examined for cycles 1, 2, 4 and 5 of treatment.


Ten patients (median age 60.5 years; range 41–69 years) with advanced solid tumors were enrolled. Their primary cancers were renal cell carcinoma (five patients), lung cancer (three patients) and colorectal cancer (two patients). The major toxicities were hypophosphatemia diarrhea, hyperglycemia, stomatitis, pyrexia, elevated aspartate aminotransferase, rash, reduced neutrophil count, elevated alanine aminotransferase, anorexia, hypertriglyceridemia and somnolence. Two of three patients who received temsirolimus 45 mg/m2 developed dose-limiting toxicities of Grade 3 stomatitis (one patient) and Grade 3 diarrhea (two patients). The maximum-tolerated dose was 15 mg/m2. The peak blood concentrations of temsirolimus and sirolimus, a major active metabolite, increased in a dose-dependent manner. The area under the concentration-versus-time curve of sirolimus, but not temsirolimus, increased in a dose-dependent manner.


The recommended dose for Phase 2 clinical studies of temsirolimus in Japanese patients with advanced solid tumors is 15 mg/m2 intravenously once a week.

  T Kurata , N Yamamoto , T Komiya , J Tsurutani , M Miyazaki , K Tamura , K Takeda , K Nakagawa and M. Fukuoka

A combination Phase I study of gemcitabine and irinotecan in patients with previously untreated advanced non-small-cell lung cancer was conducted. Patients received gemcitabine and irinotecan on Days 1 and 8 every 3 weeks. A total of 11 patients were enrolled. Three of six patients who received the starting dose (gemcitabine, 800 mg/m2; irinotecan, 80 mg/m2) experienced dose-limiting toxicities (Grade 4 neutropenia, Grade 3 elevation of transaminase and Grade 5 interstitial pneumonia). At the reduced dose level (gemcitabine, 800 mg/m2; irinotecan, 60 mg/m2), all two assessable patients could not meet the administration criteria of Day 8 (one, Grade 2 elevation of transaminase; the other, Grade 1 diarrhea). No objective response was observed in eight evaluable patients. We could not determine the recommended dose of this combination because of intolerable toxicities and no efficacy. Therefore, it is difficult to forward this combination chemotherapy toward further studies.

  A Fukumura , H Tsujii , T Kamada , M Baba , H Tsuji , H Kato , S Kato , S Yamada , S Yasuda , T Yanagi , R Hara , N Yamamoto , J Mizoe , K Akahane , S Fukuda , Y Furusawa , Y Iwata , T Kanai , N Kanematsu , A Kitagawa , N Matsufuji , S Minohara , N Miyahara , H Mizuno , T Murakami , K Nishizawa , K Noda , E Takada and S. Yonai

The features of relativistic carbon-ion beams are attractive from the viewpoint of radiotherapy. They exhibit not only a superior physical dose distribution but also an increase in biological efficiency with depth, because energy loss of the beams increases as they penetrate the body. This paper reviews clinical aspects of carbon-beam radiotherapy using the experience at the National Institute of Radiological Sciences. The paper also outlines the dosimetry related to carbon-beam radiotherapy, including absolute dosimetry of the carbon beam, neutron measurements and radiation protection measurements.

  T Muraki , N Yamamoto , K. D Zhao , J. W Sperling , S. P Steinmann , R. H Cofield and K. N. An

Tightness of the posteroinferior capsule is assumed to be the cause of internal rotation loss in baseball pitchers. Although the relationship between posterior capsule and subacromial impingement has been recognized, this relationship during the baseball-pitching motion is unclear.


Contact pressure during baseball-pitching motion increases with posterior capsule tightness.

Study Design

Controlled laboratory study.


Eight fresh-frozen shoulders were used. The peak contact pressure and area on the coracoacromial arch were measured on a custom-designed shoulder experimental device capable of 6 degrees of freedom motion. Simultaneously, the sites of peak pressure on the coracoacromial arch and humerus were observed from various angles. The posteroinferior capsule tightness was simulated by plicating the capsule in the region from 6 to 8 o’clock. The static testing positions correlated to the early cocking, late cocking, acceleration, deceleration, and follow-through phases of the pitching motion.


The peak contact pressure during the follow-through phase (0.63 ± 0.50 MPa) significantly increased with posteroinferior capsule tightness (1.00 ± 0.65 MPa) (P = .014). Additionally, the contact area on the coracoacromial ligament during the follow-through phase (0.98 ± 0.67 cm2) significantly increased with posteroinferior capsule tightness (1.47 ± 0.91 cm2) (P < .001). The site of the peak contact pressure did not change between the 2 conditions.


Our findings demonstrate that posteroinferior capsule tightness leads to higher contact pressure under the subacromial arch and increased contact area, particularly on the coracoacromial ligament during the follow-through phase.

Clinical Relevance

This tightness may affect risk of injury of the rotator cuff and its surrounding tissues by increasing subacromial contact during pitching.

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