研究等業績 - 原著論文 - 羽渕　友則

Distinct cancer-specific survival in metastatic prostate cancer patients classified by a panel of single nucleotide polymorphisms of cancer-associated genes.

Norihiko Tsuchiya, Shigeyuki Matsui, Shintaro Narita, Tomomi Kamba, Koji Mitsuzuka, Shingo Hatakeyama, Yohei Horikawa, Takamitsu Inoue, Seiichi Saito, Chikara Ohyama, Yoich Arai, Osamu Ogawa, Tomonori Habuchi

Genes & cancer   4 ( 1-2 ) 54 - 60   2013年01月

研究論文（学術雑誌）  

Individual genetic variations may have a significant influence on the survival of metastatic prostate cancer (PCa) patients. We aimed to identify target genes and their variations involved in the survival of PCa patients using a single nucleotide polymorphism (SNP) panel. A total of 185 PCa patients with bone metastasis at the initial diagnosis were analyzed. Germline DNA in each patient was genotyped using a cancer SNP panel that contained 1,421 SNPs in 408 cancer-related genes. SNPs associated with survival were screened by a log-rank test. Fourteen SNPs in 6 genes, XRCC4, PMS1, GATA3, IL13, CASP8, and IGF1, were identified to have a statistically significant association with cancer-specific survival. The cancer-specific survival times of patients grouped according to the number of risk genotypes of 6 SNPs selected from the 14 SNPs differed significantly (0-1 v. 2-3 v. 4-6 risk genotypes; P = 7.20 × 10(-8)). The high-risk group was independently associated with survival in a multivariate analysis that included conventional clinicopathological variables (P = 0.0060). We identified 14 candidate SNPs in 6 cancer-related genes, which were associated with poor survival in patients with metastatic PCa. A panel of SNPs may help predict the survival of those patients.

DOI PubMed

In vivo selection of high-metastatic subline of bladder cancer cell and its characterization.

Naoki Sugiyama, Mihoko Sutoh Yoneyama, Shingo Hatakeyama, Hayato Yamamoto, Akiko Okamoto, Takuya Koie, Hisao Saitoh, Kanemitsu Yamaya, Tomihisa Funyu, Takamitsu Inoue, Tomonori Habuchi, Chikara Ohyama, Shigeru Tsuboi

Oncology research   20 ( 7 ) 289 - 95   2013年

研究論文（学術雑誌）  

The majority of deaths associated with solid tumors are caused by tumor metastasis. To prevent metastasis, it is vital to understand its detailed process. In hematogenous metastasis of bladder cancer, some cancer cells disseminating into blood circulation extravasate into the lung tissues to form metastases. To study the molecular basis of the lung metastasis of bladder cancer, we employed an in vivo selection system that mimics hematogenous metastasis of bladder cancer on a low-metastatic bladder cancer cell line (KK-47). We have successfully isolated a high-metastatic bladder cancer subline, KK-47HM4, from KK-47 cells. We characterized KK-47HM4 in in vitro experimental systems. No significant difference in growth rate and susceptibility to NK cell attack between KK-47 and KK-47HM4 cells was observed. However, KK-47HM4 exhibited the higher capacities of Matrigel Matrix invasion and transendothelial invasion than KK-47. These results suggest that the extravasation of KK-47HM4 cells was enhanced among the multiple steps of the lung metastasis of bladder cancer. Our cDNA microarray analysis identified 67 genes whose expression was up- or downregulated in KK-47HM4 cells compared with KK-47 cells. This analysis data implied that one possible cause for enhanced extravasation of KK-47HM4 is its higher adhesion to extracellular matrix proteins. KK-47HM4 is the first bladder cancer subline with enhanced extravasation potential using the in vivo selection system. The information provided by our cDNA microarray analysis using KK-47HM4 will be useful for further investigation into the molecular basis of extravasation of cancer cells.

DOI PubMed

A high-fat diet enhances proliferation of prostate cancer cells and activates MCP-1/CCR2 signaling.

Mingguo Huang, Shintaro Narita, Kazuyuki Numakura, Hiroshi Tsuruta, Mitsuru Saito, Takamitsu Inoue, Yohei Horikawa, Norihiko Tsuchiya, Tomonori Habuchi

The Prostate   72 ( 16 ) 1779 - 88   2012年12月

研究論文（学術雑誌）  

BACKGROUND: Dietary patterns including high-fat diet (HFD) and high-carbohydrate diet (HCD) play an important role in prostate cancer progression. However, which of these diets have the greatest effect on tumor progression and its underlying mechanisms remains unclear. METHODS: We investigated the effects of different diets on prostate cancer cell growth and the relevant circulating factors including serum insulin, growth factors, and inflammatory cytokines using the in vivo and ex vivo model. RESULTS: The tumor growth of prostate cancer LNCaP xenograft was significantly higher in the HFD group than in the HCD and control diet (CD) groups (P = 0.01; HFD vs. HCD, P = 0.025; HFD vs. CD, P = 0.003). The mean level of the serum monocyte chemoattractant protein-1 (MCP-1) in the HFD group was significantly higher than that in the HCD and CD groups (P = 0.024; HFD vs. HCD, P = 0.033; HFD vs. CD, P = 0.001). The mRNA levels of CC chemokine receptor 2 (CCR2), which is an MCP-1 receptor, and the expression of activated Akt were the highest in the HFD group. Furthermore, serum from HFD-fed mice enhanced the proliferation of two PCa cells and CCR2 knockdown inhibited HFD-induced proliferation of LNCaP cells. CONCLUSIONS: An HFD enhanced prostate cancer cell growth more strongly than an HCD or CD. MCP-1/CCR2 signaling may be involved in an HFD-induced prostate cancer progression.

DOI PubMed

Improvement of continuous-wave terahertz imaging system for cellulose acetate membrane electrophoresis

Hongbing Zhang, Kazutaka Mitobe, Mahmudul Kabir, Masafumi Suzuki, Yoko Mitobe, Tomonori Habuchi, Noboru Yoshimura

IEEJ Transactions on Electrical and Electronic Engineering   7 ( SUPPL. 1 )   2012年12月

研究論文（学術雑誌）  

We have successfully achieved terahertz imaging of cellulose acetate membrane electrophoresis of egg albumin using continuous-wave imaging at 0.189 THz. A sample holder has been devised that can eliminate the membrane crook generated in the drying process after electrophoresis. A probe has been also fabricated, which was assembled with a Schottky barrier diode detector to detect the terahertz signal. A higher spatial resolution of 0.3 mm was achieved, which is 6.83 times the 2.05-mm resolution without using the probe. Terahertz images of cellulose acetate membrane electrophoresis of egg albumin of 2 μl was obtained, in which the positions of protein were perfectly in accordance with the stained images. The technology can be used instead of the staining method for cellulose acetate membrane electrophoresis. © 2012 Institute of Electrical Engineers of Japan.

DOI

Comparison of pharmacokinetics and pharmacogenetics of once- and twice-daily tacrolimus in the early stage after renal transplantation.

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

Transplantation   94 ( 10 ) 1013 - 9   2012年11月

研究論文（学術雑誌）  

BACKGROUND: This study investigated pharmacokinetic and pharmacogenetic differences between a modified-release once-daily formulation of tacrolimus (Tac-QD) and the original formulation requiring twice-daily intake (Tac-BID) in de novo renal transplant recipients. METHODS: Forty-seven and 25 patients who received Tac-BID and Tac-QD, respectively, were enrolled. The pharmacokinetics and CYP3A5 6986A>G and ABCB1 3435C>T pharmacogenetics of each formulation were analyzed on day 28 posttransplantation. RESULTS: The dose-adjusted trough level (C0) and area under the concentration-time curve (AUC0-24) of tacrolimus were approximately 25% lower for Tac-QD than Tac-BID. However, there was a good correlation between the AUC0-24 and C0 in the Tac-BID and Tac-QD groups (r=0.575, P<0.001; and r=0.638, P<0.001, respectively) and a similar coefficient in each regression equation. The dose-adjusted AUC0-24 was approximately 25% lower in carriers of the CYP3A*1 allele (CYP3A5 expressers), but not individuals with the CYP3A*3/*3 genotype (nonexpressers), for TAC-QD than Tac-BID. In the Tac-QD group, the interpatient variability for dose-adjusted parameters was small, and the interquatile ranges of dose-adjusted parameters differed between CYP3A5 expressers and nonexpressers and did not overlap. The ABCB1 polymorphism was not associated with any pharmacokinetic parameters of Tac-QD. CONCLUSIONS: C0-guided monitoring may lead to similar AUC0-24 values for both formulations. However, to maintain the same AUC0-24 value, a higher dose of Tac-QD than Tac-BID may be needed, especially for CYP3A5 expressers, in the early stage posttransplantation. The narrow interindividual variability of Tac-QD pharmacokinetics and its difference between CYP3A5 expressers and nonexpressers might contribute to a dosing strategy based on CYP3A5 genotype.

DOI PubMed

Laparoscopic radical nephrectomy : Standard method

Tomonori Habuchi

Japanese Journal of Clinical Urology   66 ( 12 ) 931 - 940   2012年11月

研究論文（学術雑誌）  

Comparison of the clinical outcome and systemic inflammatory marker levels between retroperitoneal and transperitoneal laparoscopic donor nephrectomy.

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

Journal of endourology   26 ( 8 ) 1038 - 43   2012年08月

研究論文（学術雑誌）  

BACKGROUND AND PURPOSE: Whether the retroperitoneal approach (RA) or the transperitoneal approach (TA) for performing laparoscopic donor nephrectomy (LDN) in kidney transplant donors is less invasive is unclear. In this study, we compared the clinical outcome and systemic inflammatory marker levels between RA and TA to assess surgical invasiveness. PATIENTS AND METHODS: We enrolled 105 donors (RA: 41, TA: 64) who underwent LDN in our hospital. Evaluation of both approaches included comparison of conventional clinical parameters and preoperative, immediate postoperative, and 1-day postoperative levels of the following circulating inflammatory cytokines: Tumor necrosis factor-α, interleukin (IL)-1β, IL-6, IL-8, IL-10, and IL-12p70. RESULTS: The frequency of right nephrectomy being performed was significantly lower in the TA than in the RA group (3/64 vs 12/41, P<0.001). Other clinical parameters in the TA group, including the frequency of surgical complications and incidence of delayed graft function, were comparable to those in the RA group. Immediate and 1-day postoperative mean serum IL-6 levels were significantly higher in the RA than in the TA group (P=0.023 and 0.044, respectively). The 1-day postoperative mean serum IL-10 level was also significantly higher in the RA than in the TA group (P=0.041). Meanwhile, the mean serum IL-6 and IL-10 levels were not associated with surgical duration or estimated intraoperative blood loss. CONCLUSIONS: Conventional clinical parameters related to surgical invasiveness were comparable in both approaches, thus indicating that both LDN approaches were similar and equally effective as minimally invasive procedures. The clinical significance of the higher postoperative mean serum IL-6 and IL-10 levels in the RA group remains to be clarified in a future study.

DOI PubMed

Hyperuricemia at 1 year after renal transplantation, its prevalence, associated factors, and graft survival.

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

Transplantation   94 ( 2 ) 145 - 51   2012年07月

研究論文（学術雑誌）  

BACKGROUND: The present study investigated the prevalence and predictors for the development of hyperuricemia within 1 year after transplantation and their associations with genetic polymorphisms and graft outcome in patients taking tacrolimus and mycophenolate mofetil. METHODS: One hundred twenty-one renal allograft recipients transplanted between January 2001 and March 2009 were studied. Patients with serum uric acid concentrations above 7.0 mg/dL within 1 year after transplantation were defined as having hyperuricemia, and all were treated with allopurinol. Genetic polymorphisms of nitric oxide synthase, angiotensin-converting enzyme, methylenetetrahydrofolate reductase, and 3 uric acid transporters were examined. RESULTS: At 1 year after transplantation, 46 (38%) recipients developed hyperuricemia. Male gender, higher body mass index, long-term pretransplantation dialysis, and hypertension were associated with the development of hyperuricemia. The estimated glomerular filtration rate (eGFR) at 1 year after transplantation was lower in the patients with hyperuricemia than in those without. There were no differences in graft survival between the two groups. The pharmacokinetics of tacrolimus and mycophenolic acid and 6 polymorphisms were not associated with hyperuricemia. In the multivariate analysis, male gender, long-term pretransplantation dialysis (>36 months), and eGFR (<60 mL/min) were independently associated with the development of hyperuricemia. CONCLUSION: The incidence of hyperuricemia in our cohort was 38%. Male gender and long-term pretransplantation dialysis were predictors for the development of hyperuricemia. The eGFR was lower in patients with hyperuricemia, but graft survival did not differ between the patients with hyperuricemia treated with alloprinol and those without hyperuricemia. We could not define the significance of the pharmacokinetics of immunosuppressants and genetic risk factors for hyperuricemia.

DOI PubMed

Evaluation of 2,590 urological laparoscopic surgeries undertaken by urological surgeons accredited by an endoscopic surgical skill qualification system in urological laparoscopy in Japan.

Tomonori Habuchi, Toshiro Terachi, Hiromitsu Mimata, Yukihiro Kondo, Hiroomi Kanayama, Tomohiko Ichikawa, Kikuo Nutahara, Tsuneharu Miki, Yoshinari Ono, Shiro Baba, Seiji Naito, Tadashi Matsuda

Surgical endoscopy   26 ( 6 ) 1656 - 63   2012年06月

研究論文（学術雑誌）  

BACKGROUND: In 2003, the Japanese Urological Association (JUA) and Japanese Society of Endourology (JSE) established a urological laparoscopic skill qualification system, called the Endoscopic Surgical Skill Qualification System in Urological Laparoscopy of JUA and JSE (ESSQSJJ). The main goal of the system is to decrease the prevalence of complications associated with laparoscopic surgery. To validate the qualification system, perioperative outcome and the prevalence of complications in different types of urological laparoscopic surgery performed by accredited surgeons were evaluated. METHODS: One hundred thirty-six surgeons who obtained the qualification in 2004 were prospectively asked to submit intraoperative and postoperative data of their latest 20 cases at the end of 2009, along with the number of laparoscopic urological surgeries performed in each year for a 5-year period (2004-2009). Intraoperative and postoperative complications were graded according to the Satava classification and modified Clavien classification, respectively. RESULTS: Data of 2,590 urological laparoscopic surgeries of 130 surgeons, including 904 laparoscopic radical nephrectomies, 430 laparoscopic nephroureterectomies, 390 laparoscopic adrenalectomies, 320 laparoscopic radical prostatectomies, and 170 laparoscopic partial nephrectomies, were analyzed. Complications were noted in 97 (3.7%) patients. Major intraoperative complications (grade II or III) occurred in 32 (1.2%) patients, and major postoperative complications (grade III or higher) occurred in 24 (0.9%) patients. The prevalence of conversion to open surgery, allogeneic transfusion, and perioperative mortality was 2.5%, 1.6%, and 0%, respectively. The number of surgeries performed by each qualified surgeon or the role of the surgeon (main operator vs. mentor/instructor) in the surgery did not affect the prevalence of intraoperative complications or postoperative complications. The open conversion rate was significantly higher in surgeons with a low surgical volume. CONCLUSIONS: ESSQSJJ can ensure urological laparoscopic surgeons who can perform various types of urological laparoscopic surgeries with a low prevalence of perioperative complications and reasonable outcomes.

DOI PubMed

MUC1 carrying core 2 O-glycans functions as a molecular shield against NK cell attack, promoting bladder tumor metastasis.

Yuichiro Suzuki, Mihoko Sutoh, Shingo Hatakeyama, Kazuyuki Mori, Hayato Yamamoto, Takuya Koie, Hisao Saitoh, Kanemitsu Yamaya, Tomihisa Funyu, Tomonori Habuchi, Yoichi Arai, Minoru Fukuda, Chikara Ohyama, Shigeru Tsuboi

International journal of oncology   40 ( 6 ) 1831 - 8   2012年06月

研究論文（学術雑誌）  

Core 2 β-1,6-N-acetylglucosaminyltransferase (C2GnT) forms an N-acetylglucosamine branch in O-glycans (core 2 O-glycans) of cell surface glycoproteins. C2GnT-expressing bladder tumors acquire highly metastatic phenotypes by surviving longer in host blood circulation. However, the detailed mechanisms underlying this increased survival remain unclear. In this study, we report that the expression of C2GnT in bladder tumors positively correlates with tumor progression and that bladder tumor cell-surface mucin 1 (MUC1) carrying core 2 O-glycans plays an important role in the evasion from natural killer (NK) cell attack. In C2GnT-expressing bladder tumor cells, heavily core 2 O-glycosylated MUC1 carries poly-N-acetyllactosamine in its O-glycans and galectin-3 binds to MUC1 through this poly-N-acetyllactosamine. The binding of galectin-3 to poly-N-acetyllactosamine in MUC1 core 2 O-glycans attenuates the interaction of the tumor cells with NK cells and interferes with the access of tumor necrosis factor-related apoptosis-inducing ligand to the tumor cell surface. These effects of MUC1 carrying core 2 O-glycans on NK cell attack facilitate C2GnT-expressing tumor cells to evade NK cell immunity and survive longer in host blood circulation. We reveal that MUC1 carrying core 2 O-glycans thus functions as a molecular shield against NK cell attack, thereby promoting bladder tumor metastasis.

DOI PubMed

Outcome, clinical prognostic factors and genetic predictors of adverse reactions of intermittent combination chemotherapy with docetaxel, estramustine phosphate and carboplatin for castration-resistant prostate cancer.

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

International journal of clinical oncology   17 ( 3 ) 204 - 11   2012年06月

研究論文（学術雑誌）  

OBJECTIVES: Docetaxel-based chemotherapy is effective in patients with castration-resistant prostate cancer (CRPC). This phase II study assessed the outcome and predictive factors for prognosis and toxicity following intermittent chemotherapy with docetaxel, estramustine phosphate, and carboplatin (DEC) in patients with CRPC. METHODS: Thirty-five patients were treated with a DEC regimen that consisted of a 28-day cycle of drugs as follows: docetaxel (60 mg/m(2) on day 1), carboplatin (AUC 5 on day 1) and estramustine phosphate (560 mg daily). Treatment was continued intermittently. The end point was to test the effect of DEC on the response rate and overall survival (OS). Statistical correlations between the outcomes and predictive factors, including clinical parameters and 8 single-nucleotide polymorphisms (SNPs) related to drug metabolism, were assessed. RESULTS: Prostate-specific antigen levels decreased by more than 30% in 65.7% of the patients. The median OS following DEC was 17.8 months, and the median total time of chemotherapy holiday was 7.7 months (range 1.7-35.8). On multivariate analysis, serum lactate dehydrogenase (LDH) was an independent prognostic factor for OS (p = 0.007). On SNP analysis, patients carrying the TT genotype of the ABCB1 C3435T polymorphism showed a significantly more severe leukocytopenia during the first cycle of DEC therapy compared to patients with the CC + CT genotype (p = 0.036). CONCLUSION: Combination chemotherapy with DEC has a potential effect on CRPC with acceptable toxicity. Serum LDH may be a promising predictor of prognosis, and the ABCB1 C3435T polymorphism may be a genetic predictor of the severity of leukocytopenia in patients with CRPC treated with DEC.

DOI PubMed

Clinical efficacy and prognostic factors for overall survival in Japanese patients with metastatic renal cell cancer treated with sunitinib.

Takeshi Yuasa, Norihiko Tsuchiya, Shinji Urakami, Yohei Horikawa, Shintaro Narita, Takamitsu Inoue, Mitsuru Saito, Shinya Yamamoto, Junji Yonese, Iwao Fukui, Kenji Nakano, Shunji Takahashi, Kiyohiko Hatake, Tomonori Habuchi

BJU international   109 ( 9 ) 1349 - 54   2012年05月

研究論文（学術雑誌）  

UNLABELLED: Study Type--Therapy (case series). Level of Evidence 4. What's known on the subject? and What does the study add? A randomized prospective phase III clinical trial for systemic treatment-naïve metastatic renal cell cancer (RCC) patients demonstrated the superiority of sunitinib over interferon with an acceptable safety profile. However, a commonly asked question is whether patients with RCC in clinical trials are representative of those with this disease being seen in ordinary clinical practice. To our knowledge, this is the first report of sunitinib for the Japanese patients with metastatic RCC in ordinary clinical practice. The estimated median PFS and OS in this study were 9.3 and 32.2 months, respectively. The application of the MSKCC model distinctly separated OS curves (P<0.001), suggesting that MSKCC prognostic factors might be still valid to predict survival in metastatic RCC in the era of molecular targeted therapy. OBJECTIVES: • To report the treatment efficacy and safety profile of sunitinib for patients with metastatic renal cell carcinoma (RCC) in ordinary clinical practice. • In addition, to investigate the prognostic clinicopathological factors in these patients. PATIENTS AND METHODS: • The present study consisted of native Japanese patients with metastatic RCC, comprising 29 pretreated and 34 systemic treatment-naïve patients. • Univariate and multivariate analyses were performed by the log-rank test and the Cox proportional hazards model, respectively. RESULTS: • Estimated median progression-free survival and overall survival (OS) were 9.3 months (95% confidence interval, CI, 5.0-13.7) and 32.2 months (95% CI, 24.4-40.0), respectively. • Among the patients pretreated before sunitinib, two patients were treated with initialized systemic therapy with sorafenib and the remaining 27 were initialized with interferon-α. • The OS from the initial systemic therapy of the patients in pretreated groups was 79.6 months (95% CI, 14.6-144.5). • The application of the Memorial Sloan-Kettering Cancer Center model distinctly separated the OS curves (P < 0.001). • The most common grade 3 adverse events were fatigue (53%), thrombocytopaenia (48%), hand-foot syndrome (16%), anaemia (20%), hypertension (10%) and leucopaenia (9%), although these events were manageable and reversible. CONCLUSIONS: • Sunitinib has a favourable efficacy/safety profile for Japanese metastatic RCC patients in clinical practice. • The estimated median OS was >2 years with acceptable tolerability. • The median OS from the initial systemic therapy of the pretreated patients was >6 years. • Memorial Sloan-Kettering Cancer Center prognostic factors still appear to be valid for predicting survival in metastatic RCC in the era of molecular targeted therapy.

DOI PubMed

Genomic profiling of renal cell carcinoma in patients with end-stage renal disease.

Toru Inoue, Keiko Matsuura, Taichiro Yoshimoto, Lam Tung Nguyen, Yoshiyuki Tsukamoto, Chisato Nakada, Naoki Hijiya, Takahiro Narimatsu, Takeo Nomura, Fuminori Sato, Yoji Nagashima, Kenji Kashima, Shingo Hatakeyama, Chikara Ohyama, Kazuyuki Numakura, Tomonori Habuchi, Masayuki Nakagawa, Masao Seto, Hiromitsu Mimata, Masatsugu Moriyama

Cancer science   103 ( 3 ) 569 - 76   2012年03月

研究論文（学術雑誌）  

The purpose of the present study was to determine the genomic profile of renal cell carcinoma (RCC) in end-stage renal disease (ESRD) by analyzing genomic copy number aberrations. Seventy-nine tumor samples from 63 patients with RCC-ESRD were analyzed by array comparative genomic hybridization using the Agilent Whole Human Genome 4 × 44K Oligo Micro Array (Agilent Technologies Inc., Palo Alto, CA, USA). Unsupervised hierarchical clustering analysis revealed that the 63 cases could be divided into two groups, Clusters A and B. Cluster A was comprised mainly of clear cell RCC (CCRCC), whereas Cluster B was comprised mainly of papillary RCC (PRCC), acquired cystic disease (ACD)-associated RCC, and clear cell papillary RCC. Analysis of the averaged frequencies revealed that the genomic profiles of Clusters A and B resembled those of sporadic CCRCC and sporadic PRCC, respectively. Although it has been proposed on the basis of histopathology that ACD-associated RCC, clear cell papillary RCC and PRCC-ESRD are distinct subtypes, the present data reveal that the genomic profiles of these types, categorized as Cluster B, resemble one another. Furthermore, the genomic profiles of PRCC, ACD-associated RCC and clear cell papillary RCC admixed in one tissue tended to resemble one another. On the basis of genomic profiling of RCC-ESRD, we conclude that the molecular pathogenesis of CCRCC-ESRD resembles that of sporadic CCRCC. Although various histologic subtypes of non-clear cell RCC-ESRD have been proposed, their genomic profiles resemble those of sporadic PRCC, suggesting that the molecular pathogenesis of non-CCRCC-ESRD may be related to that of sporadic PRCC.

DOI PubMed

Antitumor effect of sunitinib against skeletal metastatic renal cell carcinoma through inhibition of osteoclast function.

Shinya Maita, Takeshi Yuasa, Norihiko Tsuchiya, Yoko Mitobe, Shintaro Narita, Yohei Horikawa, Kiyohiko Hatake, Iwao Fukui, Shinya Kimura, Taira Maekawa, Tomonori Habuchi

International journal of cancer   130 ( 3 ) 677 - 84   2012年02月

研究論文（学術雑誌）  

We investigated the inhibitory effect of sunitinib, a newly approved multitargeted tyrosine kinase inhibitor, against the progression of renal cell cancer (RCC) bone metastases in vivo. In vitro cell proliferation was determined using the MTS assay. To investigate the inhibitory effects of sunitinib in vivo, we established luciferase-labeled ACHN(Luc) cells derived from papillary RCC. Mice in which ACHN(Luc) cells had been transplanted into the left ventricle to establish bone metastases were treated orally with 40 mg/kg/day sunitinib or vehicle control for 3 weeks. Growth of the cancer cells was monitored using an in vivo imaging system. In addition, 16 patients with metastatic RCC were treated with sunitinib, and serum and urine levels of amino-terminal telopeptide (NTx) were measured as markers of bone resorption. Sunitinib did not inhibit the growth of RCC cells in vitro at clinically or experimentally achievable serum levels (100 nM-1 μM). To investigate the inhibitory effect of sunitinib in vivo, we established luciferase-labeled human RCC cells (ACHN(Luc) ). Sunitinib prevented the growth of ACHN(Luc) RCC cells in the bone metastatic mouse model. The number of osteoclasts in sunitinib-treated mice was significantly less than that in control mice. Serum and urine levels of NTx in patients with metastatic RCC declined significantly during the first 4 weeks of sunitinib treatment (p = 0.027). Sunitinib is a potent anticancer agent for RCC bone metastases, at least for papillary RCC.

DOI PubMed

Common variants at 11q12, 10q26 and 3p11.2 are associated with prostate cancer susceptibility in Japanese.

Shusuke Akamatsu, Ryo Takata, Christopher A Haiman, Atsushi Takahashi, Takahiro Inoue, Michiaki Kubo, Mutsuo Furihata, Naoyuki Kamatani, Johji Inazawa, Gary K Chen, Loïc Le Marchand, Laurence N Kolonel, Takahiko Katoh, Yuko Yamano, Minoru Yamakado, Hiroyuki Takahashi, Hiroki Yamada, Shin Egawa, Tomoaki Fujioka, Brian E Henderson, Tomonori Habuchi, Osamu Ogawa, Yusuke Nakamura, Hidewaki Nakagawa

Nature genetics   44 ( 4 ) 426 - 9   2012年02月

研究論文（学術雑誌）  

We have previously reported multiple loci associated with prostate cancer susceptibility in a Japanese population using a genome-wide association study (GWAS). To identify additional prostate cancer susceptibility loci, we genotyped nine SNPs that were nominally associated with prostate cancer (P < 1 × 10(-4)) in our previous GWAS in three independent studies of prostate cancer in Japanese men (2,557 individuals with prostate cancer (cases) and 3,003 controls). In a meta-analysis of our previous GWAS and the replication studies, which included a total of 7,141 prostate cancer cases and 11,804 controls from a single ancestry group, three new loci reached genome-wide significance on chromosomes 11q12 (rs1938781; P = 1.10 × 10(-10); FAM111A-FAM111B), 10q26 (rs2252004; P = 1.98 × 10(-8)) and 3p11.2 (rs2055109; P = 3.94 × 10(-8)). We also found suggestive evidence of association at a previously reported prostate cancer susceptibility locus at 2p11 (rs2028898; P = 1.08 × 10(-7)). The identification of three new susceptibility loci should provide additional insight into the pathogenesis of prostate cancer and emphasizes the importance of conducting GWAS in diverse populations.

DOI PubMed

Influence of NAT2 polymorphisms on sulfamethoxazole pharmacokinetics in renal transplant recipients.

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

Antimicrobial agents and chemotherapy   56 ( 2 ) 825 - 9   2012年02月

研究論文（学術雑誌）  

The sulfamethoxazole (SMX)-trimethoprim drug combination is routinely used as prophylaxis against Pneumocystis pneumonia during the first 3 to 6 months after renal transplantation. The objective of this study was to examine the impact of N-acetyltransferase 2 (NAT2) and CYP2C9 polymorphisms on the pharmacokinetics of SMX in 118 renal transplant recipients. Starting on day 14 after renal transplantation, patients were administered 400 mg/day-80 mg/day of SMX-trimethoprim orally once daily. On day 14 after the beginning of SMX therapy, plasma SMX concentrations were determined by a high-performance liquid chromatography method. The SMX area under the concentration-time curve from 0 to 24 h (AUC(0-24)) for 15 recipients with the NAT2 slow acetylator genotype (NAT2 5/ 6, - 6/ 6, - 6/ 7, and - 7/ 7) was significantly greater than that for 56 recipients with the NAT2 rapid acetylator genotype (homozygous for NAT2 4) (766.4 ± 432.3 versus 537.2 ± 257.5 μg-h/ml, respectively; P = 0.0430), whereas there were no significant differences in the SMX AUC(0-24) between the CYP2C9 1/ 1 and - 1/ 3 groups. In a multiple regression analysis, the SMX AUC(0-24) was associated with NAT2 slow acetylator polymorphisms (P = 0.0095) and with creatinine clearance (P = 0.0499). Hepatic dysfunction in NAT2 slow acetylator recipient patients during the 6-month period after SMX administration was not observed. SMX plasma concentrations were affected by NAT2 polymorphisms and renal dysfunction. Although standard SMX administration to patients with NAT2 slow acetylator polymorphisms should be accompanied by monitoring for side effects and drug interaction effects from the inhibition of CYP2C9, SMX administration at a low dose (400 mg) as prophylaxis may not provide drug concentrations that reach the level necessary for the expression of side effects. Further studies with a larger sample size should be able to clarify the relationship between SMX plasma concentration and side effects.

DOI PubMed

Elevated expression of transforming growth factor β3 in carbon tetrachloride-treated rat liver and involvement of retinoid signaling.

Yoshihiro Mezaki, Mayako Morii, Kiwamu Yoshikawa, Noriko Yamaguchi, Kiyofumi Satoyoshi, Mitsutaka Miura, Katsuyuki Imai, Tatsuzo Hebiguchi, Tomonori Habuchi, Haruki Senoo

International journal of molecular medicine   29 ( 1 ) 18 - 24   2012年01月

研究論文（学術雑誌）  

Transforming growth factor (TGF) β is a pro-fibrotic cytokine. While three isoforms (TGF-β1, 2 and 3) are known, the functional differences between them are obscure. To investigate the roles of TGF-β isoforms during liver fibrogenesis, male Wistar rats were administrated carbon tetrachloride (CCl4) subcutaneously twice a week for two months. Livers were excised and sectioned for histochemical examinations. These livers were also used to quantitate the expression of genes associated with fibrogenesis, including TGF-β isoforms, as well as those associated with retinoid metabolism. Expression levels of Tgfb1 and Tgfb3 were up-regulated in CCl4-treated rat livers while that of Tgfb2 was not changed. The mRNAs for lecithin-retinol acyltransferase (Lrat) and retinoic acid hydroxylase, Cyp26a1, were also elevated. By immunohistochemical staining, TGF-β3 protein was found to be localized mainly in liver parenchymal cells (hepatocytes). These results indicate that retinoid mobilization likely takes place within the rat's liver following CCl4 treatment, and suggest the possibility that the expression of Tgfb mRNA is regulated by retinoic acid receptors. Reporter analyses of a region of the Tgfb3 gene were performed using the rat liver parenchymal cell line, RLC-16, and a positively responsive region was identified within its intron.

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Short-term clinicopathological outcome of neoadjuvant chemohormonal therapy comprising complete androgen blockade, followed by treatment with docetaxel and estramustine phosphate before radical prostatectomy in Japanese patients with high-risk localized prostate cancer.

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

World journal of surgical oncology   10   1 - 1   2012年01月

研究論文（学術雑誌）  

BACKGROUND: To assess the outcome of neoadjuvant chemohormonal therapy comprising complete androgen blockade followed by treatment with docetaxel and estramustine phosphate before radical prostatectomy in Japanese patients with a high risk of localized prostate cancer (PCa). METHODS: Complete androgen blockade followed by 6 cycles of docetaxel (30 mg/m2) with estramustine phosphate (560 mg) were given to 18 PCa patients before radical prostatectomy. Subsequently, the clinical and pathological outcomes were analyzed. RESULTS: No patients had severe adverse events during chemohormonal therapy, and hence they were treated with radical prostatectomy. Two patients (11.1%) achieved pathological complete response. Surgical margins were negative in all patients. At a median follow-up of 18 months, 14 patients (77.8%) were disease-free without PSA recurrence. All 4 patients with PSA recurrence had pathologic T3b or T4 disease and 3 of these 4 patients had pathologic N1 disease. CONCLUSION: We found that neoadjuvant chemohormonal therapy with complete androgen blockade followed by treatment with docetaxel and estramustine phosphate before radical prostatectomy was safe, feasible, and associated with favorable pathological outcomes in patients with a high risk of localized PCa.

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Association between various indices of obesity and intraoperative factors in laparoscopic donor nephrectomy.

Teruaki Kumazawa, Norihiko Tsuchiya, Takamitsu Inoue, Takashi Obara, Hiroshi Tsuruta, Mitsuru Saito, Shintaro Narita, Youhei Horikawa, Shigeru Satoh, Tomonori Habuchi

Journal of laparoendoscopic & advanced surgical techniques. Part A   22 ( 6 ) 567 - 71   2012年

研究論文（学術雑誌）  

PURPOSE: Obesity has been considered a potential risk factor for complications during laparoscopic surgery. The purpose of this study is to retrospectively investigate the association of various obesity indices and intraoperative factors in laparoscopic donor nephrectomy. PATIENTS AND METHODS: This study included 70 and 44 patients who underwent laparoscopic donor nephrectomy by a transperitoneal approach and retroperitoneal approach, respectively. We measured fat thickness and fat areas on preoperative computerized tomography (CT) images. The median value of fat thickness or of the subcutaneous fat area, visceral fat area, perirenal fat area, or total fat area among subjects was used as a cutoff to define fatty and non-fatty groups. The operative time and estimated blood loss were then compared between the two groups. RESULTS: In the transperitoneal approach group, there was no statistically significant difference in any of the indices or intraoperative factors between the fatty and non-fatty groups defined using any of the fat parameters. In the retroperitoneal approach group, patients in the fatty group categorized by perirenal fat thickness and visceral fat area had significantly greater estimated blood loss than those in the non-fatty group. Also, in the retroperitoneal approach group, patients in the fatty group categorized by perirenal fat area had significantly greater estimated blood loss and longer operating time than those in the non-fatty group (P=.02 and P=.014, respectively). CONCLUSIONS: The results indicate that the visceral fat, and in particular the perirenal fat area measured using CT scan imaging, influences operating time and estimated blood loss after retroperitoneal approach surgery but not in transperitoneal approach surgery. In donors with a high volume of perirenal fat, the transperitoneal approach may be recommended for laparoscopic nephrectomy.

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Reproducibility, performance, and clinical utility of a genetic risk prediction model for prostate cancer in Japanese.

Shusuke Akamatsu, Atsushi Takahashi, Ryo Takata, Michiaki Kubo, Takahiro Inoue, Takashi Morizono, Tatsuhiko Tsunoda, Naoyuki Kamatani, Christopher A Haiman, Peggy Wan, Gary K Chen, Loic Le Marchand, Laurence N Kolonel, Brian E Henderson, Tomoaki Fujioka, Tomonori Habuchi, Yusuke Nakamura, Osamu Ogawa, Hidewaki Nakagawa

PloS one   7 ( 10 ) e46454   2012年

研究論文（学術雑誌）  

Prostate specific antigen (PSA) is widely used as a diagnostic biomarker for prostate cancer (PC). However, due to its low predictive performance, many patients without PC suffer from the harms of unnecessary prostate needle biopsies. The present study aims to evaluate the reproducibility and performance of a genetic risk prediction model in Japanese and estimate its utility as a diagnostic biomarker in a clinical scenario. We created a logistic regression model incorporating 16 SNPs that were significantly associated with PC in a genome-wide association study of Japanese population using 689 cases and 749 male controls. The model was validated by two independent sets of Japanese samples comprising 3,294 cases and 6,281 male controls. The areas under curve (AUC) of the model were 0.679, 0.655, and 0.661 for the samples used to create the model and those used for validation. The AUCs were not significantly altered in samples with PSA 1-10 ng/ml. 24.2% and 9.7% of the patients had odds ratio <0.5 (low risk) or >2 (high risk) in the model. Assuming the overall positive rate of prostate needle biopsies to be 20%, the positive biopsy rates were 10.7% and 42.4% for the low and high genetic risk groups respectively. Our genetic risk prediction model for PC was highly reproducible, and its predictive performance was not influenced by PSA. The model could have a potential to affect clinical decision when it is applied to patients with gray-zone PSA, which should be confirmed in future clinical studies.

DOI PubMed