研究等業績 - 原著論文 - 羽渕　友則

Vimentin intermediate filament and plectin provide a scaffold for invadopodia, facilitating cancer cell invasion and extravasation for metastasis.

Mihoko Sutoh Yoneyama, Shingo Hatakeyama, Tomonori Habuchi, Takamitsu Inoue, Toshiya Nakamura, Tomihisa Funyu, Gerhard Wiche, Chikara Ohyama, Shigeru Tsuboi

European journal of cell biology   93 ( 4 ) 157 - 69   2014年04月

研究論文（学術雑誌）  

To investigate the molecular mechanisms of cancer metastasis, we have isolated a high-metastatic bladder cancer cell subpopulation from a low-metastatic cell line by using an in vivo selection system. Cells in the subpopulation showed a high ability to form invadopodia, the filamentous actin (F-actin)-based membrane protrusions that play an essential role in cancer cell invasion. Analysis of the gene expression profile revealed that the expression of an intermediate filament (IF) protein, vimentin and a cytoskeletal linker protein, plectin was up-regulated in the high-metastatic subpopulation compared with the low metastatic cell line. Here we report a novel role of vimentin IF and plectin in metastasis. In invasive bladder cancer cells, the vimentin IF-plectin-invadopodia F-actin link was formed. Disruption of this link severely impaired invadopodia formation, reducing the capacities of extracellular matrix degradation, transendothelial migration and metastasis. In addition, the vimentin assembly into the filaments was required for invadopodia formation. Our results suggest that plectin anchoring invadopodia to vimentin IF scaffolds and stabilizes invadopodia, which is a critical molecular process for cancer cell invasion and extravasation for metastasis.

DOI PubMed

Functional mononucleotide repeat polymorphism in the promoter region of HGF is associated with risk and malignant aggressiveness of bladder cancer.

Syuji Chiba, Norihiko Tsuchiya, Yohei Horikawa, Shintaro Narita, Takamitsu Inoue, Susumu Akihama, Mitsuru Saito, Kazuyuki Numakura, Hiroshi Tsuruta, Mingguo Huang, Shigeru Satoh, Tomonori Habuchi

International journal of oncology   44 ( 3 ) 678 - 84   2014年03月

研究論文（学術雑誌）  

Increased expression of hepatocyte growth factor (HGF) has been shown to be associated with aggressiveness in several types of cancer. Shorter variants of deoxyadenosine tract element (DATE) located in the HGF promoter region have been reported to enhance the expression of HGF. In this study, we investigated the role of HGF DATE variants in bladder cancer risk, HGF expression and clinicopathological features. The frequency of individuals with a short DATE (<28 repeats) in peripheral blood lymphocytes (PBLs) was significantly higher in bladder cancer patients compared to controls (p<0.001). Somatic mutations were observed in 37 of 70 bladder tumor (BT) tissues and the frequency of mutation to long DATE was significantly higher than that to short DATE (p=0.047). The presence of the short DATE in BT tissue was significantly associated with higher tumor grade (p=0.015). HGF mRNA levels were significantly higher in pT2 tumors than pTa or pT1 tumors (p=0.019), and in grade 3 tumors than grade 1 or 2 tumors (p=0.020). Furthermore, BT tissues with the short DATE showed significantly higher levels of HGF mRNA (p<0.001). In patients who underwent radical cystectomy, those with higher HGF expression had a significantly shorter overall survival than those with lower HGF expression (p=0.012). In conclusion, HGF may be associated with the prognosis of patients who undergo radical cystectomy, and the HGF DATE may affect the risk and aggressiveness of bladder cancer by altering HGF expression.

DOI PubMed

Organ-specific and tumor-size-dependent responses to sunitinib in clear cell renal cell carcinoma.

Norihiko Tsuchiya, Takeshi Yuasa, Shinya Maita, Shintaro Narita, Takamitsu Inoue, Kazuyuki Numakura, Mitsuru Saito, Shigeru Satoh, Junji Yonese, Tomonori Habuchi

BMC urology   14 ( 1 ) 26 - 26   2014年03月

研究論文（学術雑誌）  

BACKGROUND: Tyrosine kinase inhibitors (TKIs) have been used as standard therapy for patients with advanced renal cell carcinoma (RCC). However, information on factors predicting response to treatment with TKIs is lacking. This study aimed to assess the association between initial tumor size, involved organs, pre-treatment C-reactive protein (CRP) levels, and reduction in tumor size in patients with clear cell RCC (CCRCC) treated with sunitinib. METHODS: Patients with advanced CCRCC with target lesions with a maximum diameter ≥ 10 mm treated with sunitinib were evaluated. The tumor diameter representing the best overall response was designated as the post-treatment tumor diameter. RESULTS: A total of 179 lesions in 38 patients were analyzed. Organ-specific analysis demonstrated that pre-treatment diameter of lung metastatic lesions had a moderate inverse association with percent reduction in post-treatment tumor diameter (R = 0.341). Lung lesions showed significantly greater percent reductions in diameter than liver and kidney lesions (P = 0.007 and 0.002, respectively). Furthermore, based on a CRP cut-off level of 2.0 mg/dl, mean tumor size reduction was significantly greater in patients with low CRP levels than in patients with high CRP levels in lesions with diameters < 20 mm (P = 0.002). CRP level had no effect on mean size reduction in lesions with a diameter ≥ 20 mm. CONCLUSIONS: Patients with CCRCC with smaller lung metastatic lesions and lower CRP levels may achieve greater percent reductions in tumor size with sunitinib therapy than patients with extra-pulmonary lesions, large lung lesions, and/or higher CRP levels.

DOI PubMed

Serum N-glycan alteration associated with renal cell carcinoma detected by high throughput glycan analysis.

Shingo Hatakeyama, Maho Amano, Yuki Tobisawa, Tohru Yoneyama, Norihiko Tsuchiya, Tomonori Habuchi, Shin-Ichiro Nishimura, Chikara Ohyama

The Journal of urology   191 ( 3 ) 805 - 13   2014年03月

研究論文（学術雑誌）  

PURPOSE: Biomarkers for the early detection and prediction of survival in patients with renal cell carcinoma have not been established. We developed what is to our knowledge a novel glycoblotting method that allows high throughput, comprehensive, quantitative analysis of glycans in human serum. In this study we identified alterations in serum N-glycans associated with renal cell carcinoma. MATERIALS AND METHODS: We performed a comprehensive N-glycan structural analysis of serum from 64 patients with renal cell carcinoma and 34 age matched, healthy volunteers using glycoblotting methods and matrix-assisted laser desorption/ionization-time of flight mass spectrometry. The peak intensity of N-glycan was analyzed using logistic regression analysis and ROCs were used to select candidate N-glycans. Candidate N-glycans with a statistically significant relationship to renal cell carcinoma or overall survival were independently evaluated using a Cox regression model to determine superiority compared to other conventional renal cell carcinoma biomarkers. RESULTS: We identified 56 types of N-glycans in serum from healthy volunteers and patients with renal cell carcinoma. Peaks 40 and 43 were significantly more intense in patients than in volunteers. Peak 19 intensity was significantly higher and peak 49 intensity was significantly lower in patients with renal cell carcinoma who survived for a longer period. Multivariate analysis revealed that peaks 19 and 49 were independent predictors of overall survival. CONCLUSIONS: Serum N-glycan analysis is a promising approach to discovering new biomarkers for renal cell carcinoma. Further study is warranted to validate our results.

DOI PubMed

[An intravesical foreign body by migration of remnant gauze into the bladder: a case report].

Soki Kashima, Ryohei Yamamoto, Yoshiko Miura, Akihiko Abe, Hisafumi Togashi, Toshiya Ishida, Shigeki Matsuo, Kazuyuki Numakura, Tomonori Habuchi

Hinyokika kiyo. Acta urologica Japonica   60 ( 2 ) 83 - 6   2014年02月

研究論文（学術雑誌）  

A 35-year-old female, who had undergone Caesarean sections in 2000 and 2001, presented with repeated candida vaginitis and cystitis. She reported that a piece of gauze was excreted through the urethra in 2005. The patient visited an outpatient clinic, but no foreign body was identified by cystoscopy. She again visited the clinic in 2012 complaining of miction pain, and a calcified mass was identified in the bladder. The patient was then referred to our hospital. During a transurethral operation, crushed stones, which included the gauze, were removed from the bladder. We concluded that remnant gauze left in the abdominal cavity during the previous pelvic surgery, had migrated into the bladder and formed a calcified mass.

PubMed

Diet-induced macrophage inhibitory cytokine 1 promotes prostate cancer progression.

Mingguo Huang, Shintaro Narita, Takamitsu Inoue, Norihiko Tsuchiya, Shigeru Satoh, Hiroshi Nanjo, Takehiko Sasaki, Tomonori Habuchi

Endocrine-related cancer   21 ( 1 ) 39 - 50   2014年02月

研究論文（学術雑誌）  

Recent studies have indicated that a high-fat diet (HFD) plays an important role in prostate cancer (PCa) progression. Palmitic acid (PA) is one of the most abundant saturated free fatty acids (FAs) and is associated with carcinogenesis. In this study, we investigated the mechanism underlying the association of dietary fat, including PA, with PCa progression. In four PCa cell lines, in vitro PA administration stimulated the expression of macrophage inhibitory cytokine 1 (MIC1), which is a divergent member of the transforming growth factor-β family. In vivo, LNCaP xenograft tumor growth, serum MIC1 levels, and FA levels in xenograft tumors were significantly higher in mice receiving an HFD containing high amounts of PA than in those receiving a low-fat diet (LFD). In addition, tumor cells with high MIC1 expression invaded to venules and lymph vessels in the LNCaP xenograft. In vitro studies showed that proliferation and invasive capacity were significantly higher in PCa cells cultured with serum from HFD-fed mice than in those cultured with the serum from LFD-fed mice. This effect was attenuated by the addition of neutralizing antibodies against MIC1, but not by isotype control antibodies. Clinically, serum MIC1 levels were significantly higher in PCa patients than in healthy controls, and higher levels were associated with higher pathological grade and obesity. In conclusion, our results indicate that an HFD containing PA may promote growth and invasiveness of PCa cells through the upregulation of MIC1 expression.

DOI PubMed

Pathological and oncological outcomes of elderly men with clinically localized prostate cancer.

Koji Mitsuzuka, Takuya Koie, Shintaro Narita, Yasuhiro Kaiho, Takahiro Yoneyama, Norihiko Tsuchiya, Narihiko Kakoi, Sadafumi Kawamura, Tatsuo Tochigi, Chikara Ohyama, Tomonori Habuchi, Yoichi Arai

Japanese journal of clinical oncology   43 ( 12 ) 1238 - 42   2013年12月

研究論文（学術雑誌）  

OBJECTIVE: The aim of the study was to characterize pathological and oncological outcomes of elderly men with clinically localized prostate cancer treated with radical prostatectomy. METHODS: Data from 1268 patients undergoing radical prostatectomy between 2000 and 2009 were retrospectively reviewed. Patients were classified according to whether they were of age <70 or ≥70 years at radical prostatectomy. Patient characteristics, pathological and oncological outcomes were compared among the groups. RESULTS: Of the total population, 31.4% (398 of 1268) of patients were ≥70 years of age. The median age in patients <70 and ≥70 years of age was 64 (45-69) and 72 (70-83) years. The proportion of low-risk disease was significantly lower among those ≥70 years of age than in those <70 years, while the proportion of high-risk disease was significantly higher among those ≥70 years of age than in those <70 years (P < 0.001). The proportions of pathological high-risk disease (≥T3b, GS ≥8, positive surgical margin or lymph node invasion) in patients <70 and ≥70 years of age were 42.0 and 50.0%, respectively (P = 0.008). The proportions of organ-confined disease in patients <70 and ≥70 years of age were 69.9 and 65.1%, respectively (P = 0.09). With a median follow-up of 50 months, 5-year biochemical recurrence-free and cancer-specific survival rates were not significantly different among the groups. CONCLUSIONS: Radical prostatectomy was more likely to be performed in those with higher-risk disease among patients ≥70 years of age. About half of the patients ≥70 years of age had pathological, high-risk disease. Radical prostatectomy could be considered for patients with expected long-term life expectancy, even in the setting of advanced age.

DOI PubMed

Is pelvic lymph node dissection required at radical prostatectomy for low-risk prostate cancer?

Koji Mitsuzuka, Takuya Koie, Shintaro Narita, Yasuhiro Kaiho, Takahiro Yoneyama, Sadafumi Kawamura, Tatsuo Tochigi, Chikara Ohyama, Tomonori Habuchi, Yoichi Arai

International journal of urology : official journal of the Japanese Urological Association   20 ( 11 ) 1092 - 6   2013年11月

研究論文（学術雑誌）  

OBJECTIVES: To determine the necessity of pelvic lymph node dissection for low-risk prostate cancer, we analyzed the incidence of lymph node invasion and the therapeutic value of pelvic lymph node dissection in low-risk prostate cancer patients. METHODS: Medical records for 1268 patients undergoing open radical prostatectomy between January 2000 and December 2009 who had not undergone neoadjuvant therapy were retrospectively reviewed. Patients with low-risk disease (n = 222; prostate-specific antigen <10 ng/mL, biopsy Gleason score ≤6, clinical T1c or T2a) were classified according to whether they underwent pelvic lymph node dissection (pelvic lymph node dissection group, n = 147) or did not (no pelvic lymph node dissection group, n = 75). Pelvic lymph node dissection was carried out in a limited style, which included the external iliac vein and the obturator fossa. The incidence of lymph node invasion was determined and referred to the preoperative nomogram developed for Japanese patients (Japanese nomogram), Partin and Kattan nomograms. The 5-year biochemical recurrence-free survivals in both groups were analyzed. RESULTS: Lymph node invasion in low-, intermediate- and high-risk disease was 0.7% (1/147), 1.2% (7/595) and 6.1% (23/374). The 5-year biochemical recurrence-free survival rates for patients with low-risk disease were 87.6% in the pelvic lymph node dissection group and 87.1% in the no pelvic lymph node dissection group (P = 0.65, log-rank). No patients in the pelvic lymph node dissection group exceeded 2% of lymph node invasion risk with Japanese and Partin nomograms. With the Kattan nomogram, 22.4% (33/147) of the pelvic lymph node dissection group exceeded 2% of lymph node invasion risk, and one patient had documented lymph node invasion, but none exceeded 2.5%. CONCLUSIONS: Pelvic lymph node dissection can be spared at radical prostatectomy for low-risk disease, as its diagnostic and therapeutic value is poor.

DOI PubMed

Impact of body mass index on clinicopathological outcome and biochemical recurrence after radical prostatectomy

S. Narita, K. Mitsuzuka, T. Yoneyama, N. Tsuchiya, T. Koie, N. Kakoi, S. Kawamura, Y. Kaiho, C. Ohyama, T. Tochigi, T. Yamaguchi, T. Habuchi, Y. Arai

Prostate Cancer and Prostatic Diseases   16 ( 3 ) 271 - 276   2013年09月

研究論文（学術雑誌）  

Background:Accumulating evidence suggests that obesity is associated with tumor progression in prostate cancer (PCa) patients after radical prostatectomy (RP). We conducted a retrospective multicenter study to determine the effect of body mass index (BMI) on the clinicopathological characteristics and biochemical recurrence of PCa in Japanese men who underwent RP.Methods:The medical records of 1257 men with PCa treated by RP without neoadjuvant therapy at four medical institutes between 2001 and 2009 were retrospectively reviewed. Patients were categorized into four groups using the World Health Organization (WHO) BMI classification and BMI quartiles. Associations of the various BMI categories with clinicopathological characteristics and biochemical recurrences were statistically evaluated. Biochemical recurrence was defined as a PSA level of >0.2 ng ml -1.Results:Of the 1257 patients, 230 (18.3%) experienced biochemical recurrence during the median follow-up period of 49 months. The median BMI was 23.8 kg m -2, and 1.4% patients were underweight, 65.4% were of normal weight, 30.9% were overweight and 2.4% were obese (WHO classification). Preoperative PSA levels and PSA density (PSAD) tended to decrease as BMI increased. Pathological characteristics did not differ significantly among BMI categories. As per the WHO classification and quartile categories, biochemical recurrence rate was comparable among the BMI groups. After adjusting for other pre- and postoperative covariables, multivariate Cox proportional hazards analysis revealed that a high BMI did not have an independent impact on biochemical recurrence-free survival.Conclusions:Underweight Japanese PCa patients treated by RP had higher preoperative PSA levels and PSAD. High BMI was not associated with adverse pathological findings or increased biochemical recurrence rate in Japanese PCa patients treated with RP. Racial differences may exist in the relationship between obesity and outcomes of RP in PCa patients.© 2013 Macmillan Publishers Limited All rights reserved.

DOI PubMed

Pharmaceutical and genetic determinants for interindividual differences of tacrolimus bioavailability in renal transplant recipients.

Takenori Niioka, Hideaki Kagaya, Masatomo Miura, Kazuyuki Numakura, Mitsuru Saito, Takamitsu Inoue, Tomonori Habuchi, Shigeru Satoh

European journal of clinical pharmacology   69 ( 9 ) 1659 - 65   2013年09月

研究論文（学術雑誌）  

PURPOSE: The pharmacokinetics of orally administered immediate-release, twice-daily (BID) and modified-release, once-daily (QD) formulations of tacrolimus have high interindividual variability. We investigated factors affecting interindividual variability of tacrolimus bioavailability in renal transplant patients. METHODS: Ninety-seven Japanese renal transplant patients (47 patients on tacrolimus BID and 50 patients on tacrolimus QD) were enrolled in this study. The tacrolimus absolute bioavailability was calculated using the area under the concentration-time curve from 0 to 24 h (AUC0-24) after continuous intravenous infusion and oral formulations of tacrolimus in the same recipient. RESULTS: The median (quartile 1-quartile 3) tacrolimus relative bioavailability for recipients with the CYP3A5*1 or CYP3A5*3/*3 alleles was significantly lower for the tacrolimus QD group [9.1 % (6.3-10.7 %) and 15.4 % (11.5-18.7 %), respectively] than for the tacrolimus BID group [12.6 % (9.9-14.2 %) and 19.3 % (16.5-24.8 %), respectively] (P = 0.004 and 0.028, respectively). Consequently, tacrolimus absolute bioavailability was lowest for recipients with the CYP3A5*1 allele taking tacrolimus QD. The CYP3A5 polymorphism had no impact on the dose-adjusted AUC0-24 of tacrolimus in patients on continuous intravenous infusion (P = 0.906). CONCLUSION: The larger interindividual variability of tacrolimus bioavailability for oral formulations appears to be due to the effects of the CYP3A5 polymorphism and the tacrolimus oral formulation. These factors should therefore be taken into account when determining individualized tacrolimus dosing.

DOI PubMed

Changes in indications and oncological outcomes of radical prostatectomy after 2000--data from 1268 Japanese patients treated with radical prostatectomy between 2000 and 2009.

Koji Mitsuzuka, Takuya Koie, Shintaro Narita, Yasuhiro Kaiho, Takahiro Yoneyama, Norihiko Tsuchiya, Narihiko Kakoi, Sadafumi Kawamura, Tatsuo Tochigi, Chikara Ohyama, Tomonori Habuchi, Takuhiro Yamaguchi, Yoichi Arai

Japanese journal of clinical oncology   43 ( 8 ) 821 - 6   2013年08月

研究論文（学術雑誌）  

OBJECTIVE: The aim of the study was to characterize trends in indications for and oncological outcomes of radical prostatectomy after 2000. METHODS: Data from 1268 patients undergoing radical prostatectomy without neoadjuvant therapy between 2000 and 2009 at four urological centers in Japan were retrospectively reviewed. Changes in age at radical prostatectomy, prostate-specific antigen level, biopsy Gleason score, clinical T stage, D'Amico risk classification, organ-confined disease and tumor volume in surgical specimens were analyzed over time. RESULTS: The median age at radical prostatectomy decreased from 68 years in 2000-2 to 65 years in 2009 (P < 0.001). Approximately 63.3% of patients were ≥65 years old, and 31.4% of patients were ≥70 years old during the whole study period. The median prostate-specific antigen level decreased from 8.61 ng/ml in 2000-2 to 6.90 ng/ml in 2009 (P < 0.001). The rate of organ-confined disease increased from 52.8% in 2000-2 to 72.5% in 2009 (P = 0.004). The median tumor volume decreased from 1.70 cc in 2000-2 to 1.28 cc in 2009 (P = 0.017). The proportion of biopsy Gleason score 7 increased from 40.6% in 2000-2 to 60.1% in 2009 (P < 0.001), and the proportion of the intermediate-risk group increased from 39.5% in 2000-2 to 59.5% in 2009 (P < 0.001). CONCLUSIONS: Age at radical prostatectomy for men with localized prostate cancer was higher in Japan than in the USA or Europe. Prostate-specific antigen, non-organ-confined disease and tumor volume decreased during the study period, whereas Gleason score 7 and intermediate-risk disease increased during the study period. This information enables comparison of outcomes between various treatments, between various geographic regions and between various time periods.

DOI PubMed

Laparoscopic donor nephrectomy in living kidney transplantation

Norihiko Tsuchiya, Tomonori Habuchi

Japanese Journal of Clinical Urology   67 ( 8 ) 579 - 587   2013年07月

研究論文（学術雑誌）  

Pathological and biochemical outcomes after radical prostatectomy in men with low-risk prostate cancer meeting the Prostate Cancer International: Active Surveillance criteria.

Koji Mitsuzuka, Shintaro Narita, Takuya Koie, Yasuhiro Kaiho, Norihiko Tsuchiya, Takahiro Yoneyama, Narihiko Kakoi, Sadafumi Kawamura, Tatsuo Tochigi, Tomonori Habuchi, Chikara Ohyama, Yoichi Arai

BJU international   111 ( 6 ) 914 - 20   2013年05月

研究論文（学術雑誌）  

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Active surveillance has been widely accepted as a treatment tool for low-risk prostate cancer, and use of the Prostate Cancer Research International: Active Surveillance (PRIAS) criteria can select smaller and less aggressive tumours in low-risk disease. The study shows the pathological outcomes of radical prostatectomy for patients with low-risk disease who met the PRIAS criteria. It found that ~20% had unfavourable pathological features and only 30% satisfied insignificant cancer criteria with pT2 stage, a Gleason score ≤6 and tumour volume <2.5 mL. It concludes that close follow-up including repeat biopsy or MRI is necessary to minimize unexpected progression of disease. OBJECTIVE: To assess the effectiveness of the Prostate Cancer Research International Active Surveillance (PRIAS) criteria in identifying indolent cancer. PATIENTS AND METHODS: Data from 1268 patients undergoing radical prostatectomy without neoadjuvant therapy were retrospectively reviewed. Within this cohort, patients with low-risk disease (n = 211) were classified according to whether they met (Group A, n = 87) or did not meet (Group B, n = 124) the PRIAS criteria. Pathological upstaging, upgrading, tumour volume and 5-year prostate-specific antigen (PSA) recurrence-free survival were compared between the two groups, and factors that predicted upstaging, upgrading and PSA recurrence were analysed by univariate and multivariate methods. RESULTS: Pathological T3 stage was present in 10.3% of patients in Group A and in 18.5% of patients in Group B (P = 0.08). Gleason score upgrading to 4+3 or greater was seen in 19.5% of Group A and in 29.9% of Group B (P = 0.01). The mean (range) tumour volume was 0.81 (0.03-5.09) mL in Group A and 1.40 (0.04-8.21) mL in Group B (P < 0.01). The rates of insignificant cancer with total tumour volume <2.5 mL, Gleason score ≤6 and stage pT2 were 30.6% in Group A and 15.4% in Group B (P = 0.07). With a median follow-up of 44 months, the 5-year PSA recurrence-free survival rates were 91.2% in Group A and 86.4% in Group B (P = 0.47). In multivariate analysis, PSA density and the PRIAS criteria were independent factors that predicted upstaging. CONCLUSIONS: Although use of the PRIAS criteria could select more favourable tumours even in low-risk prostate cancer, about one in five men had unfavourable pathological outcomes and only three in ten had insignificant cancer. Close and careful follow-up is necessary to avoid misclassification or progression of disease, especially during the first few years of active surveillance.

DOI PubMed

A limited sampling strategy to estimate the area under the concentration-time curve of tacrolimus modified-release once-daily preparation in renal transplant recipients.

Takenori Niioka, Masatomo Miura, Hideaki Kagaya, Mitsuru Saito, Kazuyuki Numakura, Tomonori Habuchi, Shigeru Satoh

Therapeutic drug monitoring   35 ( 2 ) 228 - 32   2013年04月

研究論文（学術雑誌）  

OBJECTIVES: The aim of this study was to develop a limited sampling strategy to estimate the area under the concentration-time curve (AUC) of a modified-release, once-daily formulation of tacrolimus (Advagraf, Japanese trade name Graceptor) with Japanese renal transplant patients. METHODS: Among the 43 enrolled patients, 23 patients continued to take Graceptor for 1 year. A total of 66 profiles on day 28 and day 365 from the 43 patients were randomly divided into a training group (N = 33) and a validation group (N = 33) without any overlap. RESULTS: The prediction formula for the AUC 0-24 using the single C 12h time point gave the highest correlation with the observed AUC 0-24 (r2 = 0.9057). When 2 sampling times were used, C 0h-C 12h were the best time points for the estimation of the AUC 0-24 (AUC 0-24 = 26.8 + 8.0C 0h + 17.8C 12h, r2 = 0.9221, P < 0.0001). There was no significant difference in the prediction error for the prediction formulas with the C 0h-C 12h combination between CYP3A5 genotypes. The % mean prediction error, % mean absolute error, and % root mean squared prediction error of the prediction formula using C 0h-C 12h were 0.1%, 7.6%, and 8.8%, respectively. CONCLUSIONS: In a hospital setting, a limited sampling strategy using C 0h-C 12h would be applicable to estimating the AUC 0-24 of tacrolimus once daily.

DOI PubMed

Risk factors for intravesical recurrence in patients with high-grade T1 bladder cancer in the second TUR era.

Ei-ichiro Takaoka, Yoshiyuki Matsui, Takamitsu Inoue, Jun Miyazaki, Masakazu Nakashima, Tomokazu Kimura, Takehiro Oikawa, Koji Kawai, Koji Yoshimura, Tomonori Habuchi, Osamu Ogawa, Hiroyuki Nishiyama

Japanese journal of clinical oncology   43 ( 4 ) 404 - 9   2013年04月

研究論文（学術雑誌）  

OBJECTIVE: We aimed to elucidate risk factors for intravesical recurrence of high-grade T1 bladder cancer in the second transurethral resection era. METHODS: The analysis included 73 patients with high-grade T1 bladder cancer on initial transurethral resection. The median follow-up period was 49.2 months. Recurrence-free survival, progression-free survival and risk factors related to the presence of residual tumors or recurrence-free survival were statistically analyzed. RESULTS: The pathological findings for second transurethral resection were pT0 36 (49%), pTis/a 21 (29%), pT1 13 (18%) and pT2 3 (4%), respectively. The risk factor for residual tumors at second transurethral resection was the presence of concomitant carcinoma in situ at the initial transurethral resection (P < 0.01). The bladder was preserved in all 57 patients with pT0/is/a tumors on second transurethral resection, and 43 patients (75%) received intravesical BCG therapy. Of these patients, 3-year recurrence-free survival and 3-year progression-free survival rates were 81 and 96%, respectively. In addition, the presence of pTis/a residual tumors on second transurethral resection had a significant impact on the recurrence. Five of the 13 patients with pT1 on second transurethral resection were immediately treated by radical cystectomy or radiation therapy combined with chemotherapy, and two (25%) of the eight who were treated by intravesical BCG therapy had progression including distant metastasis. CONCLUSIONS: High recurrence-free survival and progression-free survival were achieved by a second transurethral resection and intravesical BCG therapy in the patients with pT0/is/a on the second transurethral resection. In this group, the residual tumors at second transurethral resection are risk factors for intravesical recurrence.

DOI PubMed

Insulin-like growth factor-1 genotypes and haplotypes influence the survival of prostate cancer patients with bone metastasis at initial diagnosis.

Norihiko Tsuchiya, Shintaro Narita, Takamitsu Inoue, Mitsuru Saito, Kazuyuki Numakura, Mingguo Huang, Shingo Hatakeyama, Shigeru Satoh, Seiichi Saito, Chikara Ohyama, Yoichi Arai, Osamu Ogawa, Tomonori Habuchi

BMC cancer   13   150 - 150   2013年03月

研究論文（学術雑誌）  

BACKGROUND: The insulin-like growth factor-1 (IGF-1) plays an important role in growth of prostate cancer (PCa) cells and facilitating the development and progression of PCa. This study aimed to evaluate the association of polymorphisms in three linkage disequilibrium (LD) blocks of the IGF-1 on the survival of metastatic PCa patients. METHODS: A total of 215 patients with bone metastases at initial presentation were included in this study. The cytosine-adenine (CA) repeat polymorphism and rs12423791 were selected as representative polymorphisms in the LD blocks 1 and 2, respectively. Haplotype in the LD block 3 was analyzed using two tag single nucleotide polymorphisms (SNPs), rs6220 and rs7136446. Cancer-specific survival rate was estimated from the Kaplan-Meier curve, and the survival data were compared using the log-rank test. RESULTS: Cancer-specific survival was significantly associated with the CA repeat polymorphism, rs12423791, and rs6220 (P = 0.013, 0.014, and 0.014, respectively). Although rs7136446 had no significant association with survival, the haplotype in the LD block 3 was significantly associated with cancer-specific survival (P = 0.0003). When the sum of the risk genetic factors in each LD block (19-repeat allele, C allele of rs12423791, or C-T haplotype) was considered, patients with all the risk factors had significantly shorter cancer specific-survival than those with 0-2 risk factors (P = 0.0003). CONCLUSIONS: Polymorphisms in the IGF-1, especially a haplotype in the LD block 3, are assumed to be genetic markers predicting the outcome of metastatic PCa.

DOI PubMed

Risk factors for sorafenib-induced high-grade skin rash in Japanese patients with advanced renal cell carcinoma.

Norihiko Tsuchiya, Shintaro Narita, Takamitsu Inoue, Naoko Hasunuma, Kazuyuki Numakura, Yohei Horikawa, Shigeru Satoh, Takeshi Notoya, Naohito Fujishima, Shingo Hatakeyama, Chikara Ohyama, Tomonori Habuchi

Anti-cancer drugs   24 ( 3 ) 310 - 4   2013年03月

研究論文（学術雑誌）  

The aim of this study was to evaluate the clinical factors, drug-related genetic polymorphisms, and human leukocyte antigen (HLA) types to determine the association with sorafenib-induced high-grade skin rash (HGSR) in Japanese patients with advanced renal cell carcinoma (RCC). A total of 55 patients with advanced RCC treated with sorafenib were analyzed retrospectively. Of these, 33 patients were subjected to HLA typing and polymorphism analyses of CYP3A5, ABCB1, ABCC2, and UGT1A1, which are involved in the metabolism and membrane transport of sorafenib. Grade 3 or higher SR developed in 12 (22%), and a higher incidence was observed in female patients than in male patients (40 vs. 15%, P=0.046). The initial dose, initial dose per body weight, and initial dose per body surface area in patients with HGSR were significantly higher than those in patients without HGSR. Patients with the ABCC2 -24CC genotype were at a significantly higher risk of SR than those with the CT genotype (35 vs. 0%, P=0.032). HLA-A*24 was significantly associated with the occurrence of HGSR (P=0.049). Our finding suggested that women, higher initial dose per body weight or body surface area, the ABCC2 -24CC genotype, and HLA-A*24 are associated with the risk of sorafenib-induced HGSR in Japanese RCC patients.

DOI PubMed

Laparoendoscopic single-site plus one trocar donor nephrectomy using the GelPort: initial clinical experience.

Takamitsu Inoue, Norihiko Tsuchiya, Shintaro Narita, Mitsuru Saito, Shinya Maita, Kazuyuki Numakura, Takashi Obara, Hiroshi Tsuruta, Yohei Horikawa, Shigeru Satoh, Tomonori Habuchi

Urology   81 ( 2 ) 308 - 12   2013年02月

研究論文（学術雑誌）  

OBJECTIVE: To achieve better cosmesis, less invasiveness, and less morbidity in donor nephrectomy without using specialized instruments, which is usually required in the laparoendoscopic single-site (LESS) procedure, we performed laparoendoscopic plus one trocar donor nephrectomy (LEPODN). METHODS: From October 2010 to December 2011, 20 living renal transplantation donors underwent the LEPODN procedure. Their mean age, body mass index (BMI), and preoperative creatinine clearance were 55.7 years, 23.2, and 118.4 mg/min, respectively. The GelPort laparoscopic system was inserted through a 5-6 cm pararectal incision at the umbilicus level. A subcostal 5-mm right-hand working trocar was placed under the left costal arch. The graft kidney was extracted using a retrieval bag. A 5-mm diameter drain was placed via a right-hand working trocar. Operative data of LEPODN were retrospectively compared to those of standard laparoscopic donor nephrectomy (standard-LDN, n = 27) previously performed at our hospital. RESULTS: The procedure was technically successful in all 20 patients. The mean operative time in the LEPODN group was significantly shorter than that in the standard-LDN group (229.1 vs 249.8 minutes, P = .033). Mean blood loss and warm ischemic time in the LEPODN group were 39.4 mL and 272.4 seconds, respectively. The mean serum creatinine concentrations of the recipients 7 and 30 days after operation were 1.57 and 1.13 mg/dL, respectively. These results were not significantly different from those in the standard-LDN group. CONCLUSION: The LEPODN procedure was feasible and performed without specialized instruments by surgeons experienced in only standard laparoscopic nephrectomy.

DOI PubMed

A meta-analysis of genome-wide association studies to identify prostate cancer susceptibility loci associated with aggressive and non-aggressive disease.

Ali Amin Al Olama, Zsofia Kote-Jarai, Fredrick R Schumacher, Fredrik Wiklund, Sonja I Berndt, Sara Benlloch, Graham G Giles, Gianluca Severi, David E Neal, Freddie C Hamdy, Jenny L Donovan, David J Hunter, Brian E Henderson, Michael J Thun, Michael Gaziano, Edward L Giovannucci, Afshan Siddiq, Ruth C Travis, David G Cox, Federico Canzian, Elio Riboli, Timothy J Key, Gerald Andriole, Demetrius Albanes, Richard B Hayes, Johanna Schleutker, Anssi Auvinen, Teuvo L J Tammela, Maren Weischer, Janet L Stanford, Elaine A Ostrander, Cezary Cybulski, Jan Lubinski, Stephen N Thibodeau, Daniel J Schaid, Karina D Sorensen, Jyotsna Batra, Judith A Clements, Suzanne Chambers, Joanne Aitken, Robert A Gardiner, Christiane Maier, Walther Vogel, Thilo Dörk, Hermann Brenner, Tomonori Habuchi, Sue Ingles, Esther M John, Joanne L Dickinson, Lisa Cannon-Albright, Manuel R Teixeira, Radka Kaneva, Hong-Wei Zhang, Yong-Jie Lu, Jong Y Park, Kathleen A Cooney, Kenneth R Muir, Daniel A Leongamornlert, Edward Saunders, Malgorzata Tymrakiewicz, Nadiya Mahmud, Michelle Guy, Koveela Govindasami, Lynne T O'Brien, Rosemary A Wilkinson, Amanda L Hall, Emma J Sawyer, Tokhir Dadaev, Jonathan Morrison, David P Dearnaley, Alan Horwich, Robert A Huddart, Vincent S Khoo, Christopher C Parker, Nicholas Van As, Christopher J Woodhouse, Alan Thompson, Tim Dudderidge, Chris Ogden, Colin S Cooper, Artitaya Lophatonanon, Melissa C Southey, John L Hopper, Dallas English, Jarmo Virtamo, Loic Le Marchand, Daniele Campa, Rudolf Kaaks, Sara Lindstrom, W Ryan Diver, Susan Gapstur, Meredith Yeager, Angela Cox, Mariana C Stern, Roman Corral, Markus Aly, William Isaacs, Jan Adolfsson, Jianfeng Xu, S Lilly Zheng, Tiina Wahlfors, Kimmo Taari, Paula Kujala, Peter Klarskov, Børge G Nordestgaard, M Andreas Røder, Ruth Frikke-Schmidt, Stig E Bojesen, Liesel M FitzGerald, Suzanne Kolb, Erika M Kwon, Danielle M Karyadi, Torben Falck Orntoft, Michael Borre, Antje Rinckleb, Manuel Luedeke, Kathleen Herkommer, Andreas Meyer, Jürgen Serth, James R Marthick, Briony Patterson, Dominika Wokolorczyk, Amanda Spurdle, Felicity Lose, Shannon K McDonnell, Amit D Joshi, Ahva Shahabi, Pedro Pinto, Joana Santos, Ana Ray, Thomas A Sellers, Hui-Yi Lin, Robert A Stephenson, Craig Teerlink, Heiko Muller, Dietrich Rothenbacher, Norihiko Tsuchiya, Shintaro Narita, Guang-Wen Cao, Chavdar Slavov, Vanio Mitev, Stephen Chanock, Henrik Gronberg, Christopher A Haiman, Peter Kraft, Douglas F Easton, Rosalind A Eeles

Human molecular genetics   22 ( 2 ) 408 - 15   2013年01月

研究論文（学術雑誌）  

Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one-third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four GWAS including 5953 cases of aggressive PrCa and 11 463 controls (men without PrCa). We computed association tests for approximately 2.6 million SNPs and followed up the most significant SNPs by genotyping 49 121 samples in 29 studies through the international PRACTICAL and BPC3 consortia. We not only confirmed the association of a PrCa susceptibility locus, rs11672691 on chromosome 19, but also showed an association with aggressive PrCa [odds ratio = 1.12 (95% confidence interval 1.03-1.21), P = 1.4 × 10(-8)]. This report describes a genetic variant which is associated with aggressive PrCa, which is a type of PrCa associated with a poorer prognosis.

DOI PubMed

Comparison of surgical stress in patients undergoing open versus laparoscopic radical prostatectomy by measuring perioperative serum cytokine levels.

Shintaro Narita, Norihiko Tsuchiya, Teruaki Kumazawa, Shinya Maita, Kazuyuki Numakura, Takashi Obara, Hiroshi Tsuruta, Mitsuru Saito, Takamitsu Inoue, Yohei Horikawa, Shigeru Satoh, Tomonori Habuchi

Journal of laparoendoscopic & advanced surgical techniques. Part A   23 ( 1 ) 33 - 7   2013年01月

研究論文（学術雑誌）  

PURPOSE: We evaluated the perioperative serum levels of inflammatory cytokines in patients with prostate cancer (PCa) treated with open or laparoscopic radical prostatectomy (RP) and assessed the surgical stress based on the cytokine levels in addition to conventional clinical stress markers after surgery. PATIENTS AND METHODS: One hundred sixty-five patients who received RP for clinically localized PCa were enrolled. Serum levels of interleukin (IL)-10, IL-6, tumor necrosis factor-α, IL-1β, IL-8, and IL-12p70 were quantitatively measured using a multiplex bead array at three time points (i.e., before the operation [pre-OP], immediately after the operation [post-OP], and on postoperative Day 1 [POD1]). The perioperative changes in serum stress markers, including cytokines, were compared between patients who underwent open and laparoscopic RP, and the predictors for high levels of postoperative cytokines were assessed. RESULTS: The median age and estimated blood loss were significantly lower in the laparoscopic RP group than in the open RP group (P=.003 and P<.01, respectively). In all patients, body temperature, white blood cell count, and serum IL-10 and IL-6 levels were significantly higher at post-OP and POD1 than at pre-OP. Patients who underwent laparoscopic RP had significantly lower levels of serum IL-10, IL-6, and IL-1β at post-OP and POD1 than those who underwent open RP. Multivariate regression analyses showed that the surgical group (open versus laparoscopic) was an independent influencing factor on the levels of serum IL-6 and IL-10 at POD1 (P=.031 and P<.004, respectively) among various clinical perioperative parameters. CONCLUSIONS: Several inflammatory cytokines, particularly IL-6 and IL-10, are potential surgical stress markers in patients with PCa treated with RP. Based on cytokine production, our data support the view that laparoscopic RP is less invasive than open RP.

DOI PubMed