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Articles by K Nakagawa
Total Records ( 10 ) for K Nakagawa
  M Ishida , S Mikami , E Kikuchi , T Kosaka , A Miyajima , K Nakagawa , M Mukai , Y Okada and M. Oya
 

Aryl hydrocarbon receptor (AhR) and the activation of the AhR pathway are involved in xenobiotic-induced toxicity and carcinogenesis. Although xenobiotics, such as cigarette smoke, contribute to the development of urothelial carcinoma (UC), the relationship between AhR and UC is unclear. In the present study, we investigated AhR expression in 209 patients with upper urinary tract UC. The nuclear expression of AhR was significantly associated with histological grade, pathological T stage, lymphovascular invasion and lymph node involvement. A multivariate Cox analysis revealed that nuclear AhR expression was a significant and independent predictor for disease-specific survival (hazard ratio = 2.469, P = 0.013). To determine whether the AhR pathway can be activated in the T24 UC cell line, we examined the expression of cytochrome P450 (CYP) 1A1 and CYP1B1, which are target genes of the AhR pathway, following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a ligand of AhR. TCDD treatment upregulated the expression levels of AhR, CYP1A1 and CYP1B1. TCDD enhanced T24 cell invasion associated with the upregulation of matrix metalloproteinase (MMP)-1 and MMP-9. Furthermore, targeting AhR messenger RNA (mRNA) expression in T24 cells with small interfering RNA (siRNA) downregulated the mRNA expression of AhR, CYP1A1, CYP1B1, MMP-1, MMP-2 and MMP-9; furthermore, the cells transfected with siRNA for AhR showed decreased invasion activity in comparison with the cells transfected with a non-targeting siRNA. Our results therefore suggest that AhR plays a role in the invasiveness of UC cells and can serve as a marker for the prognosis of upper urinary tract UC.

  K Ueki , K Nakagawa , K Marukawa , E Yamamoto and N. Takeuchi
 

The purpose of this study was to evaluate changes in stress on the temporomandibular joint (TMJ) in 80 Japanese subjects (21 males and 59 females, mean age 23.7 years) with mandibular prognathism, with and without asymmetry after orthognathic surgery using the rigid bodies spring model (RBSM). The asymmetric group consisted of 40 subjects whose Mx–Md midline was more than 3 degrees. The remaining 40 subjects formed the symmetric group.

The geometry of the stress analysis model was based on frontal cephalograms of the subjects. Menton (Me), the centre point of occlusal force on a line connecting the bilateral buccal cusps of the second molars, and the most lateral, superior, and medial points on the condyle were plotted on a computer display and stress on the condyle was calculated with the two-dimensional RBSM program, Fortran. The degree (force partition) of the resultant force, the direction (angulation), and the displacement (X, Y) of each condyle were calculated and the horizontal displacement (u), the vertical displacement (v), and rotation displacement () of the mandibular body at Me were calculated pre- and post-operatively. The data was analysed using paired and unpaired t-tests.

For the vertical (v) and rotational () displacement, the post-operative value was smaller than the pre-operative value (v: P < 0.001, : P = 0.0063) in the asymmetric group. For angulation and the X-component, the post-operative value was smaller than that pre-operatively on the deviated (angulation: P = 0.0074, X-component: P = 0.0003) and non-deviated (angulation: P = 0.0024, X-component: P = 0.001) side in the asymmetric group. However, there was no significant difference between the pre- and post-operative value for any parameter in the symmetric group.

These findings suggest that surgical correction of mandibular prognathism, with and without asymmetry, could induce an improvement in stress balance on the TMJ in the frontal aspect.

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

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.

Methods

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.

Results

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.

Conclusions

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.

  H Ide , E Kikuchi , H Kono , H Nagata , A Miyajima , K Nakagawa , T Ohigashi , J Nakashima and M. Oya
  Objective

The objective of this study was to evaluate the efficacy and toxicity of docetaxel in combination with prednisolone in Japanese patients with hormone refractory prostate cancer.

Methods

Twenty patients with hormone refractory prostate cancer (HRPC) were administered a treatment regimen consisting of docetaxel 75 mg/m2 once every 3 or 4 weeks and prednisolone 5 mg twice daily at our institution between 2006 and 2008.

Results

The patients received a median of 5.5 cycles of treatment (range, 2–12 cycles). Nine of the 20 patients (45%) had a ≥50% decrease in serum prostate-specific antigen (PSA). The median duration of response was 4 months (range, 1–11 months). The number of cycles performed, the presence of bone metastasis and the extent of disease had statistically significant associations with the response. Three patients had a transient PSA rise among the patients who ultimately had a response. Grade 3/4 leukopenia and neutropenia occurred in 80.0% and 85.0% of the patients, respectively. Interstitial pneumonia occurred in only one patient; however, the patient recovered. Finally, no treatment-related deaths were seen during the observation period.

Conclusions

The combination of docetaxel 75 mg/m2 every 3 weeks and prednisolone 10 mg daily was effective and well tolerated in Japanese patients with HRPC. The results of this study suggest that a decision concerning discontinuation of this treatment should be carefully considered because a transient PSA rise was observed. Although interstitial pneumonia was rare, the potential risk of its development should be taken into consideration.

  I Okamoto , M Munakata , M Miyazaki , T Satoh , T Takahata , Y Takamatsu , O Muto , K Koike , K Ishitani , T Mukaiyama , Y Sakata , K Nakagawa and K. Tamura
  Objective

Hormonal imbalance characterized by excessive production of growth hormone (GH) and a low circulating concentration of insulin-like growth factor (IGF)-1 has been demonstrated in individuals with various serious conditions. However, little is known about changes in the GH–IGF-1 axis in cancer patients.

Methods

We prospectively examined the circulating levels of several hormones in 58 patients with solid tumors who were classified according to Eastern Cooperative Oncology Group performance status (PS): PS 0–1, n = 15; PS 2, n = 15; PS 3, n = 15; and PS 4, n = 13. The relations of hormone concentrations, with a focus on the GH–IGF-1 system, to PS were evaluated by Spearman's rank correlation test and regression analysis.

Results

The circulating levels of IGF-1, IGF-binding protein-3 and thyroid hormones (total T3 and T4) were inversely correlated with PS score. The concentration of GH was increased irrespective of PS but not statistically significant. The ratio of IGF-I to GH was inversely correlated with PS. The levels of GH and IGF-1 in all patients were also inversely correlated.

Conclusions

The present study suggests that the GH–IGF-1 axis is disturbed in patients with cancer.

  S Shirotake , E Kikuchi , K Matsumoto , S Yazawa , T Kosaka , A Miyajima , K Nakagawa and M. Oya
  Objectives

The role of pelvic lymphadenectomy in patients with lymph node-negative bladder cancer at radical cystectomy (RC) has not yet been examined in detail. We retrospectively reviewed patients who underwent RC with pelvic lymphadenectomy for bladder cancer from January 1987 to March 2008.

Methods

We identified consecutive data on 169 patients who underwent RC for bladder cancer. The mean follow-up was 64 months (range: 1–253 months). Node-positive status (pN(+)) was seen in 16 patients and 91 were diagnosed as node-negative (pN(–)). The lymph node status of the remaining 62 patients was unclear (pN(x)). We analysed the association between lymph node status and cancer-specific survival (CSS), and examined the role of the number of retrieved lymph nodes, particularly in pN(–).

Results

The median number of retrieved nodes was 12.9 and 10.2 for stage pN(+) and stage pN(–), respectively. In 91 patients with pN(–), multivariate analysis revealed that pathological T3-4 (P = 0.0276) and less than nine retrieved lymph nodes (P = 0.0108) were independent risk factors for CSS. In a subgroup of 83 patients with pT3-4, Kaplan–Meier curves showed that the 5-year CSS rate in pN(–) patients with less than nine retrieved lymph nodes was 38.8%, which was extremely similar to the 40.8% in pN(+) and 45.1% in pN(x).

Conclusions

Our results demonstrate that at least nine lymph nodes should be removed to improve the survival of pN(–) patients at RC and lymphadenectomy, and would provide information not only on prognosis but also on the therapeutic impact on pT3-4 invasive bladder cancer.

  S Yoshimine , A Miyajima , K Nakagawa , H Ide , E Kikuchi and M. Oya
  Objective

The aim of this study was to determine the incidence and risk factors of postoperative inguinal hernia and to investigate whether the difference of approach could induce postoperative inguinal hernia after laparoscopic radical prostatectomy.

Methods

We reviewed 493 consecutive patients who underwent laparoscopic radical prostatectomy from November 2000 to November 2007, and evaluated various preoperative parameters, specifically age, prostate-specific antigen (ng/ml), body mass index (kg/m2), prostate volume (ml), previous major abdominal surgery, previous appendectomy, previous inguinal hernia repair and laparoscopic approach as risk factors for postoperative inguinal hernia.

Results

Inguinal hernia occurred in 4 (4.9%) of the 81 patients in the transperitoneal approach group, and in 37 (9.0%) of the 412 patients in the extraperitoneal approach group. The overall incidence of inguinal hernia was 8.3% (41 of 493 patients). The median inguinal hernia-free survival time was 35 months and 6 months in the transperitoneal approach and extraperitoneal approach groups, respectively. Inguinal hernia developed within 2 years after surgery in 2 (50%) of 4 patients in the transperitoneal approach group, in 34 (91.9%) of 37 patients in the extraperitoneal approach group, for a total of 36 (87.8%) of 41 patients overall. Multivariate analysis showed that the extraperitoneal approach was a significant risk factor (P = 0.043) for inguinal hernia.

Conclusions

Inguinal hernia is a frequent complication after laparoscopic radical prostatectomy, and the incidence of inguinal hernia is greater with the extraperitoneal approach than with the transperitoneal approach.

  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.

  K Matsumoto , K Nakagawa , A Hashiguchi , H Kono , E Kikuchi , H Nagata , A Miyajima and M. Oya
  Objective

The diagnosis of prostate cancer is based on the results of ultrasonography-guided needle biopsy of the prostate, but cancer foci are often not visible in conventional transrectal ultrasonography. Sonazoid is a new microbubble contrast agent. The purpose of our study was to compare areas of contrast material enhancement in the prostate at ultrasonography with whole-mount radical prostatectomy specimens to determine if the use of Sonazoid improves the detection rate of prostate cancer.

Methods

Fifty patients with biopsy-proven cancer of the prostate who were scheduled to undergo radical prostatectomy were recruited for this study. The day before the operation, each patient was evaluated with ultrasonography at baseline and again during intravenous infusion of Sonazoid. A map of ultrasonography findings was created prospectively at the time of imaging. Following radical prostatectomy, independent mapping of the pathologic results was performed and the maps were compared.

Results

Ultrasonography evaluation at baseline demonstrated that at least one focus of cancer was identified in 20 of the 50 subjects (40.0%). Meanwhile at least one cancer focus was enhanced in 31 of the 50 patients (62.0%) when Sonazoid was used. The combination of baseline grayscale imaging and contrast-enhanced imaging allowed identification of at least one focus of cancer in 40 patients (80.0%). Contrast-enhanced ultrasonography can improve sensitivity, especially for the detection of large cancer, peripheral zone cancer and highly malignant cancer.

Conclusions

Our study has demonstrated significantly improved detection of prostate cancer with the combination of baseline grayscale imaging and contrast-enhanced imaging compared with conventional ultrasonography techniques only, and this technique may be applicable to targeted biopsy.

  M Ito , K Miyado , K Nakagawa , M Muraki , M Imai , N Yamakawa , J Qin , Y Hosoi , H Saito and Y. Takahashi
 

p38 MAPK (p38) plays pivotal roles in aging and reproductive physiology. Nevertheless, involvement of p38 in female reproductive aging is uncertain. To improve knowledge of the role of p38 in age-associated reproductive failure, the expression and subcellular localization of phosphorylated p38 was investigated in human granulosa cells. p38 was 7-fold more activated in cells from older subjects than in those from younger subjects. Similar results were obtained in human granulosa-like KGN cells treated with hydrogen peroxide (H2O2). Interestingly, phosphorylated p38 was detected in the nucleus less frequently in older cells than in younger cells (Younger: 58.6%; Older: 29.8%, P< 0.01). Similarly cytoplasmic localization of phosphorylated p38 in KGN cells was observed after treatment with H2O2. The activation and cytoplasmic localization of p38 in H2O2-treated KGN cells were blocked by N-acetylcysteine and SB203580. Although the p38 activators, FSH and tumor necrosis factor-, induced a similar localization of phosphorylated p38 in KGN cells, the expression and localization patterns of p38 were distinct from those in older granulosa cells and H2O2-treated KGN cells. These results indicate that the characteristic localization of p38 in older granulosa cells is induced by oxidative stress.

 
 
 
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