研究等業績 - 原著論文 - 羽渕　友則

Real clinical outcomes of nivolumab plus ipilimumab for renal cell carcinoma in patients over 75 years old

Kobayashi M.

International Journal of Clinical Oncology ( International Journal of Clinical Oncology )  28 ( 11 ) 1530 - 1537   2023年11月

研究論文（学術雑誌）  

BACKGROUND: Although nivolumab plus ipilimumab is the standard treatment for metastatic renal cell carcinoma (RCC), its efficacy and safety in older patients remain unclear. Therefore, this study aimed to assess the clinical outcomes of nivolumab plus ipilimumab for metastatic RCC in patients aged ≥ 75 years. METHODS: We enrolled 120 patients with metastatic RCC treated with nivolumab plus ipilimumab from August 2015 to January 2023. Objective response rates (ORRs) were compared between patients aged < 75 and ≥ 75 years. Progression-free survival (PFS), overall survival (OS), and adverse events were compared between the groups. Adverse events were evaluated according to the Response Evaluation Criteria in Solid Tumors 1.1. RESULTS: Among the patients, 57 and 63 were classified as intermediate and poor risk, respectively, and one could not be classified. The median follow-up duration after the initiation of treatment was 16 months. The patient characteristics between the groups, except for age, were not significantly different. Intergroup differences in ORR (42% vs. 40%; p = 0.818), PFS (HR: 0.820, 95% CI 0.455-1.479; p = 0.510), and median OS (HR: 1.492, 95% CI 0.737-3.020; p = 0.267) were not significant. The incidence of adverse events (50% vs. 67%; p = 0.111) and nivolumab plus ipilimumab discontinuation due to adverse events was not significantly different between the groups (14% vs. 13%; p = 0.877). CONCLUSIONS: The effectiveness of nivolumab plus ipilimumab was comparable between patients with metastatic RCC aged < 75 and those ≥ 75 years with respect to their ORRs, PFS, OS, and adverse event rates.

DOI PubMed

The Current Trend of Radiation Therapy for Patients with Localized Prostate Cancer

Numakura K.

Current Oncology ( Current Oncology )  30 ( 9 ) 8092 - 8110   2023年09月

研究論文（学術雑誌）  

A recent approach to radiotherapy for prostate cancer is the administration of high doses of radiation to the prostate while minimizing the risk of side effects. Thus, image-guided radiotherapy utilizes advanced imaging techniques and is a feasible strategy for increasing the radiation dose. New radioactive particles are another approach to achieving high doses and safe procedures. Prostate brachytherapy is currently considered as a combination therapy. Spacers are useful to protect adjacent organs, specifically the rectum, from excessive radiation exposure.

DOI PubMed

Primary resistance to nivolumab plus ipilimumab therapy in patients with metastatic renal cell carcinoma

Numakura K.

Cancer Medicine ( Cancer Medicine )  12 ( 16 ) 16837 - 16845   2023年08月

研究論文（学術雑誌）  

BACKGROUND: Nivolumab plus ipilimumab (NIVO+IPI) is the first-line treatment for patients with metastatic renal cell carcinoma (mRCC). Approximately 40% of patients achieve a durable response; however, 20% develop primary resistant disease (PRD) to NIVO+IPI, about which little is known in patients with mRCC. Therefore, this investigation aimed to evaluate the clinical implication of PRD in patients with mRCC to select better candidates in whom NIVO+IPI can be initiated as first-line therapy. METHODS: This multi-institutional retrospective cohort study used data collected between August 2015 and January 2023. In total, 120 patients with mRCC treated with NIVO+IPI were eligible. Associations between immune-related adverse events and progression-free survival, overall survival (OS), and objective response rate were analyzed. The relationship between other clinical factors and outcomes was also evaluated. RESULTS: The median observation period was 16 months (interquartile range, 5-27). The median age at NIVO+IPI initiation was 68 years in the male-dominant population (n = 86, 71.7%), and most patients had clear cell histology (n = 104, 86.7%). PRD was recorded in 26 (23.4%) of 111 investigated patients during NIVO+IPI therapy. Patients who experienced PRD showed worse OS (hazard ratio: 4.525, 95% confidence interval [CI]: 2.315-8.850, p < 0.001). Multivariable analysis showed that lymph node metastasis (LNM) (odds ratio: 4.274, 95% CI: 1.075-16.949, p = 0.039) was an independent risk factor for PRD. CONCLUSIONS: PRD was strongly correlated with worse survival rates. LNM was independently associated with PRD in patients with mRCC receiving NIVO+IPI as first-line therapy and might indicate that a candidate will not benefit from NIVO+IPI.

DOI PubMed

Subsequent Upper Urinary Tract Carcinoma Related to Worse Survival in Patients Treated with BCG

Numakura K.

Cancers ( Cancers )  15 ( 7 )   2023年04月

研究論文（学術雑誌）  

Upper urinary tract urothelial carcinoma (UTUC) after intravesical bacillus Calmette-Guerin (BCG) therapy is rare, and its incidence, clinical impact, and risk factors are not fully understood. To elucidate the clinical implications of UTUC after intravesical BCG therapy, this retrospective cohort study used data collected between January 2000 and December 2019. A total of 3226 patients diagnosed with non-muscle-invasive bladder cancer (NMIBC) and treated with intravesical BCG therapy were enrolled (JUOG-UC 1901). UTUC impact was evaluated by comparing intravesical recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) rates. The predictors of UTUC after BCG treatment were assessed. Of these patients, 2873 with a medical history that checked UTUC were analyzed. UTUC was detected in 175 patients (6.1%) during the follow-up period. Patients with UTUC had worse survival rates than those without UTUC. Multivariate analyses revealed that tumor multiplicity (odds ratio [OR], 1.681; 95% confidence interval [CI], 1.005-2.812; p = 0.048), Connaught strain (OR, 2.211; 95% CI, 1.380-3.543; p = 0.001), and intravesical recurrence (OR, 5.097; 95% CI, 3.225-8.056; p < 0.001) were associated with UTUC after BCG therapy. In conclusion, patients with subsequent UTUC had worse RFS, CSS, and OS than those without UTUC. Multiple bladder tumors, treatment for Connaught strain, and intravesical recurrence after BCG therapy may be predictive factors for subsequent UTUC diagnosis.

DOI PubMed

Comparison of efficacy and medical costs between upfront docetaxel and abiraterone treatments of metastatic hormone-sensitive prostate cancer patients in real-world practice: a multicenter retrospective study

Ozaki K.

World Journal of Urology ( World Journal of Urology )  41 ( 1 ) 67 - 75   2023年01月

研究論文（学術雑誌）  

PURPOSE: We compared the real-world efficacy and medical costs for treatment with upfront docetaxel (DOC) and abiraterone acetate (ABI) up to progression-free survival 2 (PFS2) in patients with metastatic hormone-sensitive prostate cancer (mHSPC). METHODS: This multicenter retrospective study included 340 patients with mHSPC treated with either upfront DOC or upfront ABI between October 2015 and December 2021. We compared PFS2 and medical costs between the two treatment groups. PFS2 was defined as the time from first-line therapy to progression on second-line therapy. Medical costs were estimated using the National Health Insurance drug prices in 2022 in Japan. RESULTS: The upfront DOC and ABI groups included 107 and 233 patients, respectively. The incidence of metastatic castration-resistant PC progression was significantly higher in the upfront DOC group compared with the incidence in the upfront ABI group. However, no significant differences in PFS2 were observed between the two treatment groups. Monthly medical costs per patient were significantly higher in the upfront ABI group ($3453) compared with the costs in the upfront DOC group ($1239, P < 0.001). The cost differences were significantly influenced by differences in the length of androgen deprivation therapy monotherapy (DOC group, 13.4 months vs. ABI group, 0.0 months). CONCLUSIONS: We observed a significant cost benefit in the upfront DOC group in Japanese real-world practice, while the PFS2 rates were similar between the groups. Upfront DOC was a more cost-effective option for men with mHSPC who were eligible for toxic chemotherapy.

DOI PubMed

Prognostic impact of proton pump inhibitors for immunotherapy in advanced urothelial carcinoma.

Yoshiharu Okuyama, Shingo Hatakeyama, Kazuyuki Numakura, Takuma Narita, Toshikazu Tanaka, Yuki Miura, Daichi Sasaki, Daisuke Noro, Noriko Tokui, Teppei Okamoto, Hayato Yamamoto, Shintaro Narita, Takahiro Yoneyama, Yasuhiro Hashimoto, Tomonori Habuchi, Chikara Ohyama

BJUI compass ( BJUI Compass )  3 ( 2 ) 154 - 161   2022年03月

研究論文（学術雑誌）  

OBJECTIVE: To evaluate the effects of the concomitant use of proton pump inhibitors (PPIs) and/or antibiotics (Abs) on oncological outcomes in patients with advanced urothelial carcinoma. PATIENTS AND METHODS: We retrospectively evaluated 155 patients with advanced urothelial carcinoma who were treated with immune checkpoint inhibitors (ICIs) between August 2015 and April 2021. The concomitant use of PPI or Abs was defined as any PPI or Abs administered within 30 days before ICI initiation and during ICI therapy. The primary outcomes were the effect of PPI and/or Abs use on the objective response rate (ORR) and immune-related adverse events (irAEs). The secondary outcomes were the effects of PPI and/or Abs use on progression-free survival (PFS) and overall survival (OS) after ICI therapy analyzed using the inverse probability of treatment weighting-adjusted Cox regression analysis. RESULTS: Of the 155 patients enrolled in the study, 99 (64%) were PPI users and 56 (36%) Abs users. PPI users were associated with a significantly poorer ORR than non-PPI users (41% vs. 20%, respectively), whereas Abs use was not significantly associated with changes in ORR. The rate of irAEs was not significantly associated with the use of PPIs or Abs. Multivariate inverse probability of treatment weighting-adjusted Cox regression analysis revealed significantly poorer PFS and OS in PPI users than in non-PPI users, whereas Abs use was not associated with poorer outcomes. CONCLUSION: The concomitant use of PPI may adversely affect oncological outcomes in patients with locally advanced or metastatic urothelial carcinoma treated with ICI therapy.

DOI PubMed

Hands on training in the laparoscopic living-donor nephrectomy

Mitsuru Saito, Shintaro Narita, Tomonori Habuchi

Japanese Journal of Clinical Urology   75 ( 10 ) 730 - 735   2021年

研究論文（学術雑誌）  

Robotic-assisted laparoscopic partial nephrectomy for renal cell carcinoma in horseshoe kidney: a hybrid technique with conventional laparoscopic surgery.

Kazuyuki Numakura, Yumina Muto, Ryohei Yamamoto, Atsushi Koizumi, Taketoshi Nara, Sohei Kanda, Mitsuru Saito, Shintaro Narita, Takamitsu Inoue, Tomonori Habuchi

International cancer conference journal   9 ( 4 ) 199 - 202   2020年10月

研究論文（学術雑誌）  

Robotic-assisted laparoscopic partial nephrectomies (RAPN) have come up to standard treatment for small renal tumors, with a growing indication to accomplish this procedure. Although a horseshoe kidney is one of the most common congenital renal fusion anomalies, surgical planning for tumors is considered difficult because of its poor mobility and abnormal vascular supply. We showed our experience of RAPN in combination with conventional laparoscopic kidney mobilization and dissection for a patient with renal cell carcinoma in a horseshoe kidney. The patient was an otherwise healthy 66-year-old man with 26 mm right renal mass on the lower pole of the horseshoe kidney. Robotic assistance allows for proper tissue dissection, easy to aware unconfirmed vasculatures, and meticulous fine suturing and would overcome the potential challenges involved in the minimally invasive management of such complex anomalies as shown in the patient.

DOI PubMed

Follow-up of patients with bladder cancer

Shintaro Narita, Tomonori Habuchi, Yoshiyuki Matsui, Toyonori Tsuzuki

Japanese Journal of Clinical Urology   74 ( 5 ) 320 - 325   2020年

研究論文（学術雑誌）  

Diagnosis of oligometastatic prostate cancer

Shintaro Narita, Takamitsu Inoue, Tomonori Habuchi

Japanese Journal of Clinical Urology   73 ( 8 ) 530 - 534   2019年

研究論文（学術雑誌）  

[A Case of Giant Prostate Carcinoma Effectively Treated with External-Beam Radiation Therapy].

Sohei Kanda, Shintaro Narita, Naoki Komine, Seiichi Kitajima, Misa Yamauchi, Akihiro Sugita, Yutaka Saito, Tomonori Habuchi

Hinyokika kiyo. Acta urologica Japonica   62 ( 12 ) 647 - 650   2016年12月

研究論文（学術雑誌）  

We present a case of gigantic prostate tumor in a patient with castration-resistant prostate cancer with successful local control by external-beam radiation therapy. A 71-year-old man was shown to have a prostate specific antigen (PSA)level of 24.5 ng/ml, Gleason 9, cT2N1M1a, prostate adenocarcinoma with an estimated prostate volume of 26.9 g. He achieved a PSA nadir at 4 months after the initial androgen deprivation therapy and was diagnosed with castration-resistant prostate cancer three years later. Eight months after the diagnosis of castration-resistant prostate cancer, he visited our hospital due to urinary retention. Abdominal computed tomography scan showed a gigantic prostatic mass occupying the whole pelvic cavity along with multiple lymph node, bone and liver metastases. The estimated volume of the prostate was 878 g. A tumor needle biopsy revealed a histological finding similar to the initial prostate biopsy which was adenocarcinoma with Gleason 9. He underwent external beam radiation therapy (60 Gy) to the prostate, which brought about excellent local control with a 96.7% shrinkage of tumor at 2 months after radiation therapy. He had no complaints of urinary symptoms and no need for urethral catheterization until he died of prostate cancer metastases.

DOI PubMed

[Two Cases of Urinary Retention with Prostatic Abscess Drained by Transurethral Resection].

Yoshinori Matsuda, Takamitsu Inoue, Shuji Chiba, Takehiro Suzuki, Tomonori Habuchi

Hinyokika kiyo. Acta urologica Japonica   62 ( 12 ) 651 - 655   2016年12月

研究論文（学術雑誌）  

A 58-year-old male with alcoholic liver cirrhosis and a 58-year-old male with diabetes mellitus presented with high fever and urinary retention. Prostatic abscess was diagnosed by a computed tomography scan, which showed fluid collection in the prostate in both patients. Despite systematic antibiotic therapies, urinary retention persisted even after fever diminished. They underwent prostatic abscess drainage by transurethral resection (TUR). Urinary retention was released, and the recurrence of prostatic abscess has not been observed after TUR.

DOI PubMed

Altered miRNA expression in high-fat diet-induced prostate cancer progression.

Taketoshi Nara, Shintaro Narita, Huang Mingguo, Toshiaki Yoshioka, Atsushi Koizumi, Kazuyuki Numakura, Hiroshi Tsuruta, Atsushi Maeno, Mitsuru Saito, Takamitsu Inoue, Norihiko Tsuchiya, Shigeru Satoh, Tomonori Habuchi

Carcinogenesis   37 ( 12 ) 1129 - 1137   2016年12月

研究論文（学術雑誌）  

Recent evidence suggests that a high-fat diet (HFD) plays an important role in prostate carcinogenesis; however, underlying mechanisms largely remain unknown. Here, we investigated microRNA (miRNA) expression changes in murine prostate cancer (PCa) xenografts using two different diets: HFD and control diet. We then assessed the roles and targets of altered miRNAs in HFD-induced PCa progression. We identified 38 up- and 21 downregulated miRNAs in xenografts under HFD conditions using the miRCURY LNA™ microRNA array. The differences in 10 candidate miRNAs were validated using quantitative RT-PCR. We focused on miR-130a because the expression levels were significantly lower in the three PCa cell lines in comparison with benign prostate PINT1B cells. PCa cells cultured in a medium containing HFD mouse serum were associated with significantly higher cell proliferation rates and lower miR-130a expression levels. Further, miR-130a modulated MET expression in PCa cells, and MET was overexpressed in in vitro and in vivo HFD-induced PCa progression models. Moreover, ectopic miR-130a downregulated AR in LNCaP cells and DICER1 in PC-3 and DU145 cells, respectively. In human tissues, as elucidated using laser capture microdissection, the mean miR-130a expression level in cancer epithelium was significantly lower than that in normal epithelium. Furthermore, cytoplasmic MET in PCa tissues was overexpressed in patients with higher body mass index. In conclusion, a substantial number of miRNAs was altered in HFD-induced PCa growth. Specifically, miR-130a was attenuated in HFD-induced PCa progression with MET overexpression. miRNAs thus have implications in the mechanism, prevention and treatment of HFD-induced PCa progression.

DOI PubMed

Efficacy and safety of bladder hydrodistension for decreased bladder capacity induced by intravesical BCG therapy.

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

Scandinavian journal of urology   50 ( 6 ) 429 - 432   2016年12月

研究論文（学術雑誌）  

OBJECTIVE: Intravesical BCG therapy is widely used for the treatment of high-risk, non-muscle-invasive bladder cancer. Among various reported side-effects, decreased bladder capacity is a serious side-effect that significantly worsens patients' quality of life. This article reports the efficacy and safety of bladder hydrodistension (BHD) in six patients with seriously decreased bladder capacity caused by BCG treatment. METHODS: Six patients with low bladder capacity (<100 ml in voiding diaries) and complaint of grade 3 irritative symptoms were diagnosed with decreased bladder capacity and treated with BHD. Alleviation of symptoms was defined as medication being discontinued or reduced after BHD. RESULTS: Five patients were male and one was female, and the mean age was 67.7 years. The mean interval between the last transurethral resection and BCG therapy was 26.0 days. Before BHD, all patients had been treated with antibiotics, anticholinergics and non-steroidal anti-inflammatory drugs (NSAIDs). The median bladder capacity before treatment was 40 ml (range 30-100 ml), and the median capacity increased to 200 ml (175-250 ml) within 2 weeks following BHD therapy. Four patients stopped NSAID use and three patients stopped anticholinergic use. One patient needed total cystectomy for recurrent symptoms. With a median follow-up period of 32 months, the bladder capacity remained stable without symptomatic deterioration in the remaining five patients. There was neither tumor spread nor disseminated tuberculosis infection. CONCLUSIONS: BHD appears to be an effective treatment option in patients with severely decreased bladder capacity. Its efficacy and safety were acceptable.

DOI PubMed

Key predictive factors for efficacy of axitinib in first-line metastatic renal cell carcinoma: subgroup analysis in Japanese patients from a randomized, double-blind phase II study.

Yoshihiko Tomita, Satoshi Fukasawa, Mototsugu Oya, Hirotsugu Uemura, Nobuo Shinohara, Tomonori Habuchi, Brian I Rini, Ying Chen, Angel H Bair, Seiichiro Ozono, Seiji Naito, Hideyuki Akaza

Japanese journal of clinical oncology   46 ( 11 ) 1031 - 1041   2016年11月

研究論文（学術雑誌）  

OBJECTIVES: To conduct Japanese subgroup analyses of a randomized, global Phase II study of axitinib with and without dose titration in first-line metastatic renal cell carcinoma and to explore predictive factors for axitinib efficacy in first-line metastatic renal cell carcinoma. METHODS: The data included 44 Japanese and 169 non-Japanese treatment-naïve patients with metastatic renal cell carcinoma. Patients received twice-daily axitinib 5 mg during a 4-week lead-in period. Patients who met the pre-defined randomization criteria were stratified by Eastern Cooperative Oncology Group performance status and randomly assigned (1:1) to axitinib or placebo titration. The primary endpoint was objective response rate; secondary endpoints included progression-free survival and safety. Predictive factors were analyzed using data from all patients. RESULTS: The objective response rate (95% confidence interval) was 66% (50-80%) vs. 44% (36-52%) in Japanese and non-Japanese patients, respectively. At the primary analysis, median progression-free survival could not be estimated for Japanese patients, and was 27.6 months (95% confidence interval: 16.6-33.2) in an updated analysis. Hypertension, diarrhea, hand-foot syndrome, dysphonia, hypothyroidism and proteinuria were common adverse events in Japanese patients. Due to a small number of randomized patients, effects of axitinib dose titration could not sufficiently be confirmed among Japanese patients. The multivariate analysis identified time from histopathological diagnosis to treatment and sum of the longest diameter for target lesion at baseline as independent predictive factors for progression-free survival. CONCLUSIONS: Axitinib is effective and well tolerated as first-line metastatic renal cell carcinoma therapy in Japanese patients. Predictive factors for axitinib efficacy endpoints identified in this setting warrant further investigation.

DOI PubMed

Secondary bladder amyloidosis with familial Mediterranean fever in a living donor kidney transplant recipient: a case report.

Sentaro Imamura, Shintaro Narita, Ryuta Nishikomori, Hiroshi Tsuruta, Kazuyuki Numakura, Atsushi Maeno, Mitsuru Saito, Takamitsu Inoue, Norihiko Tsuchiya, Hiroshi Nanjo, Toshio Heike, Shigeru Satoh, Tomonori Habuchi

BMC research notes   9 ( 1 ) 473 - 473   2016年10月

研究論文（学術雑誌）  

BACKGROUND: Secondary bladder amyloidosis is an extremely rare disease, resulting from a chronic systematic inflammatory disorder associated with amyloid deposits. Although uncommon in Japan, familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease characterized by recurrent episodes of fever of short duration and serositis and is frequently associated with systemic amyloidosis. Here, we present a case of a Japanese patient complaining of fever and macroscopic hematuria after a living donor renal transplantation. Consequently, he was diagnosed with secondary bladder amyloidosis with FMF. CASE PRESENTATION: A 64-year-old Japanese male received a living ABO-incompatible kidney transplant from his wife. The postoperative clinical course was normal, and the patient was discharged 21 days after the transplantation with a serum creatinine level of 0.78 mg/dl. The patient frequently complained of general fatigue and fever of unknown origin. Six months later, the patient presented with continuous general fatigue, macroscopic hematuria, and fever. Cystoscopic examination of the bladder showed an edematous region with bleeding, and a transurethral biopsy revealed amyloid deposits. His wife stated that the patient had a recurrent high fever since the age of 40 years and that his younger brother was suspected to have a familial autoinflammatory syndrome; thus, the patient was also suspected to have a familial autoinflammatory syndrome. Based on his brother's medical history and the genetic tests, which showed a homozygous mutation (M694V/M694V) for the Mediterranean fever protein, he was diagnosed with FMF. Although colchicine treatment for FMF was planned, the patient had an untimely death due to heart failure. We re-evaluated the pathological findings of the various tissue biopsies obtained during the treatment after the renal transplantation. Immunohistochemistry revealed amyloid deposits in the bladder region, renal allograft, and myocardium and the condition was diagnosed as AA amyloidosis associated with FMF. CONCLUSION: We presented a case of systemic amyloidosis with FMF, involving the bladder region, myocardium, and renal allograft, diagnosed after renal transplantation. Bladder amyloidosis should be considered in patients with macroscopic hematuria, particularly in the kidney transplant recipients with idiopathic chronic renal disease. Diagnosis of secondary bladder amyloidosis may result in the early detection of underlying diseases, which may contribute to patient prognosis.

DOI PubMed

Cystometric evaluation of recovery in hypocompliant defunctionalized bladder as a result of long-term dialysis after kidney transplantation.

Takamitsu Inoue, Shigeru Satoh, Takashi Obara, Mitsuru Saito, Kazuyuki Numakura, Shintaro Narita, Norihiko Tsuchiya, Tomonori Habuchi

International journal of urology : official journal of the Japanese Urological Association   23 ( 8 ) 694 - 700   2016年08月

研究論文（学術雑誌）  

OBJECTIVES: To evaluate the functional recovery of a pretransplant hypocompliant bladder in patients without neurological disorders, and to determine its relationship with ureteral complications, including vesicoureteral reflux. METHODS: A total of 61 patients without neurogenic disorders, who underwent video water cystometry pre- and 1 year post-transplantation, were enrolled. Cystometric bladder capacity and maximum intravesical pressure were measured, and compliance was calculated by the elevation in intravesical pressure as a result of an increase in volume. The frequencies of urinary complications, including urinary leakage, pyelonephritis and vesicoureteral reflux, were also evaluated. RESULTS: Pretransplant dialysis duration correlated with pretransplant bladder capacity and compliance (R(2) = 0.421, P < 0.001 and R(2) = 0.418, P < 0.001, respectively). A total of 16 (26.2%) patients had hypocompliant bladders <10 mL/cmH2 O, whereas 10 of the 12 patients (83.3%) with pretransplant dialysis duration of more than 5 years had a pretransplant hypocompliant bladder. Bladder compliance significantly recovered to >20 mL/cmH2 O (21.1-286.0) at 1 year post-transplantation in all 16 patients with a pretransplant hypocompliant bladder. No significant differences were observed for urinary leakage, pyelonephritis or vesicoureteral reflux between patients with and without a pretransplant hypocompliant bladder. CONCLUSIONS: Bladder compliance decreases logarithmically pretransplantation according to dialysis duration. Although the ability of the patients to recover varies, dysfunctions associated with a pretransplant hypocompliant bladder recover to normal ranges after renal transplantation. A pretransplant hypocompliant bladder seems not to be associated with the post-transplant prevalence of urinary complications or vesicoureteral reflux.

DOI PubMed

Essential content of evidence-based clinical practice guidelines for bladder cancer: The Japanese Urological Association 2015 update

Yoshinobu Kubota, Noboru Nakaigawa, Hiroyuki Nishiyama, Shiro Hinotsu, Osamu Ogawa, Keiji Inoue, Seiichiro Ozono, Eiji Kikuchi, Tsuneharu Miki, Hideyasu Matsuyama, Tomoaki Fujioka, Chikara Ohyama, Hiroyuki Fujimoto, Haruhito Azuma, Tomonori Habuchi, Masayuki Nakagawa, Takashi Mizowaki, Yoshiyuki Matsui, Takashi Kobayashi, Kimito Osaka, Hiroshi Furuse, Yoshio Naya, Wataru Obara, Takuya Koike, Takahiro Yoneyama, Yasuhiro Hashimoto, Shingo Hatakeyama, Atsushi Imai, Hiroyuki Nakanishi, Tomohiko Hara, Norihiko Tsuchiya, Takamitsu Inoue, Junichi Ohta, Kotaro Suzuki, Atsushi Fujikawa, Susumu Umemoto, Koji Izumi, Sumio Noguchi

International Journal of Urology   23 ( 8 ) 640 - 645   2016年08月

研究論文（学術雑誌）  

The Japanese Urological Association revised the clinical practice guidelines for bladder cancer in April 2015. This was the first update carried out in the 6 years since the development of the initial clinical practice guidelines for bladder cancer in 2009. The descriptive content was revised, and additions were made with a focus on new-found evidence and advances in the latest medical practices, and on the basis of the increasingly aging population observed in the underlying social context in Japan. An algorithm for the treatment of bladder cancer has been presented as a new trial. In the present article, we will introduce the essential contents and clinical questions that address the present revisions.

DOI PubMed

[Extrarenal Retroperitoneal Angiomyolipoma Masquerading as Retroperitoneal Liposarcoma : A Report of Two Cases].

Ryohei Yamamoto, Takamitsu Inoue, Kazuyuki Numakura, Hiroshi Tsuruta, Atsushi Maeno, Mitsuru Saito, Shintaro Narita, Norihiko Tsuchiya, Shigeru Satoh, Tomonori Habuchi

Hinyokika kiyo. Acta urologica Japonica   62 ( 6 ) 317 - 22   2016年06月

研究論文（学術雑誌）  

We report two patients with extrarenal retroperitoneal angiomyolipoma masquerading as perinephric liposarcoma. Patient 1 : A 66-year-old man was diagnosed with a retroperitoneal tumor near the right renal hilum on an abdominal computed tomography (CT) performed before surgery for gastric cancer. A diagnosis of extrarenal retroperitoneal angiomyolipoma was made on the basis of negative uptake of fluorine- 18 2-deoxy-2-fluoro-D-glucose positron emission tomography (18F-FDG PET)/CT. However, because the tumor was found to have gradually enlarged at 18 months afterward, he underwent resection of the extrarenal fat tissue together with the right kidney. Patient 2 : A 56-year-old man underwent abdominal ultrasound during a periodic medical examination, which revealed a right retroperitoneal tumor. Because of the findings in the contrast-enhanced CT and positive uptake of 18F-FDG PET/CT, he underwent resection of the extrarenal fat tissue together with the right kidney. The pathological examination of the two tumors confirmed extrarenal angiomyolipoma. The differential diagnosis of extrarenal retroperitoneal angiomyolipoma from retroperitoneal liposarcoma is difficult even with the use of 18F-FDG PET/CT.

PubMed

[Outcome of Resection of Inferior Vena Cava Superior to the Renal Vein in Renal Cell Carcinoma with Vena Caval Tumor Thrombus].

Soki Kashima, Shintaro Narita, Mitsuru Saito, Makoto Takahashi, Shinya Maita, Hiroshi Tsuruta, Kazuyuki Numakura, Atsushi Maeno, Takamitsu Inoue, Norihiko Tsuchiya, Shigeru Satoh, Hiroshi Yamamoto, Yuzo Yamamoto, Tomonori Habuchi

Hinyokika kiyo. Acta urologica Japonica   62 ( 6 ) 287 - 94   2016年06月

研究論文（学術雑誌）  

Surgical management with radical nephrectomy and thrombectomy has often been performed in renal cell carcinoma (RCC) with tumor thrombus infiltrating the inferior vena cava (IVC). We retrospectively reviewed the outcomes of IVC resection without venous reconstruction in patients with RCC and IVC thrombus at our institution. Eight patients with right RCC underwent radical nephrectomy and IVC resection superior to the level of the renal vein without venous reconstruction from August 2005 to February 2015. Thoracotomy, liver mobilization, and extracorporeal circulation were performed based on the IVC thrombus level. We assessed surgical outcomes, perioperative complications, and survival. At presentation, four patients had level IIIa IVC thrombus, three had level IIIb IVC thrombus, and one had level IV IVC thrombus. Perioperative imaging showed that three of the four patients who underwent neoadjuvant molecular targeting therapy achieved down-staging of the tumor thrombus level. The median operative time was 406 min, and the median estimated blood loss was 3,135 ml. With regard to IVC resectionassociated perioperative complications, one patient needed extracorporeal circulation with IVC ligation and Pringle maneuver owing to low blood pressure. Another patient underwent temporary hemodialysis for 8 days after surgery. There were no perioperative deaths, and none of the patients required permanent hemodialysis. Three patients survived the mean observation period of 25 months, including one patient with no recurrence. Three patients achieved long-term survival of more than 2 years. IVC resection without venous reconstruction may be a feasible option for patients with RCC and IVC tumor thrombus. Further study is needed to determine the most appropriate candidates for this procedure.

PubMed

A prospective multicenter study of intermittent chemotherapy with docetaxel and prednisolone for castration-resistant prostate cancer.

Shintaro Narita, Takuya Koie, Shigeyuki Yamada, Kazuhiko Orikasa, Shigeki Matsuo, Hiroshi Aoki, Shigeto Ishidoya, Senji Hoshi, Norihiko Tsuchiya, Chikara Ohyama, Yoichi Arai, Tomonori Habuchi

Japanese journal of clinical oncology   46 ( 6 ) 547 - 553   2016年06月

研究論文（学術雑誌）  

OBJECTIVE: The optimal schedule of docetaxel chemotherapy for castration-resistant prostate cancer is unknown, although continuous administration is accepted as the standard. We conducted a Phase II trial to evaluate the outcome of intermittent docetaxel and prednisolone therapy in castration-resistant prostate cancer. METHODS: The patients were treated using a 28-day cycle of docetaxel (70 mg/m2 on Day 1) and oral prednisolone (10 mg/day). After three consecutive administrations of docetaxel, a holiday was taken until prostate specific antigen levels returned to the baseline. The therapy was continued intermittently until the disease progressed, drug toxicity occurred, or the patients refused further treatment. The primary endpoint was overall survival. Time to treatment failure, adverse events, the duration of chemotherapy holiday and quality of life were also evaluated. RESULTS: A total of 120 patients were enrolled. The median age and pretreatment prostate specific antigen level were 72 years and 37.5 ng/ml, respectively. Sixty (50.0%) patients resumed chemotherapy after the first holiday, and a maximum of six courses were administered to four patients. The median period of the first, second and third-to-fifth holiday was 18.6, 11.0 and 4.9 weeks, respectively. Toxicity was moderate, except for two fatal adverse events. The median time to treatment failure and overall survival from the initiation of docetaxel and prednisolone therapy in all patients were 17.5 and 35.0 months, respectively. All quality-of-life scores were unchanged statistically from the start of docetaxel and prednisolone therapy to the beginning of the second course. CONCLUSIONS: Intermittent docetaxel and prednisolone therapy might be a feasible treatment option for castration-resistant prostate cancer with comparable outcome and successful chemotherapy holidays.

DOI PubMed

Influence of everolimus on the pharmacokinetics of tacrolimus in Japanese renal transplant patients.

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

International journal of urology : official journal of the Japanese Urological Association   23 ( 6 ) 484 - 90   2016年06月

研究論文（学術雑誌）  

OBJECTIVES: To examine whether a trough concentration of everolimus in the therapeutic range of 3-5 ng/mL affects the pharmacokinetics of tacrolimus in renal transplant patients. METHODS: A total of 52 Japanese renal transplant patients receiving tacrolimus were enrolled in this study. In 28 of them, everolimus was co-administered on day 14 after surgery. Changes in the dose-adjusted blood trough concentration of tacrolimus from day 14 to 28 after surgery were investigated. RESULTS: The dose-adjusted blood trough concentration of tacrolimus on day 28 was affected by CYP3A5*3/*3 and hemoglobin level (P < 0.001 and P = 0.007), but not by everolimus (P = 0.171). In addition, there was no change in the dose-adjusted blood trough concentration of tacrolimus in patients before or after everolimus coadministration (P = 0.165). On day 28, there was no correlation between the rate of change in the dose-adjusted blood trough concentration of tacrolimus and the blood trough concentration or area under the plasma concentration-time curve from 0 to 12 h for everolimus after initiation of combination therapy (r = 0.341, P = 0.076 and r = 0.234, P = 0.231). CONCLUSIONS: A pharmacokinetic interaction between tacrolimus and everolimus was not observed clinically in renal transplant patients. Safe and reliable immunosuppressive therapy in renal transplant patients might be achieved using a combination of tacrolimus and everolimus.

DOI PubMed

[Recent trend in the development of novel treatments based on the mechanisms of prostate cancer progression].

Takamitsu Inoue, Shintaro Narita, Tomonori Habuchi

Nihon rinsho. Japanese journal of clinical medicine   74 Suppl 3   211 - 20   2016年05月

研究論文（学術雑誌）  

PubMed

[Treatment strategy for high-risk localized prostate cancer].

Shintaro Narita, Takamitsu Inoue, Tomonori Habuchi

Nihon rinsho. Japanese journal of clinical medicine   74 Suppl 3   693 - 700   2016年05月

研究論文（学術雑誌）  

PubMed

Influence of 1 year of androgen deprivation therapy on lipid and glucose metabolism and fat accumulation in Japanese patients with prostate cancer

K. Mitsuzuka, A. Kyan, T. Sato, K. Orikasa, M. Miyazato, H. Aoki, N. Kakoi, S. Narita, T. Koie, T. Namima, S. Toyoda, Y. Fukushi, T. Habuchi, C. Ohyama, Y. Arai

Prostate Cancer and Prostatic Diseases   19 ( 1 ) 57 - 62   2016年03月

研究論文（学術雑誌）  

We prospectively examined influence of androgen deprivation therapy (ADT) on lipid and glucose metabolisms in Japanese patients with prostate cancer.Methods:Patients with prostate cancer who were hormone-naive and scheduled to receive long-term ADT were recruited between 2011 and 2013. Body weight, abdominal circumference and blood testing associated with lipid and glucose metabolism were recorded every 3 months during 1 year of ADT. Computed tomography (CT) was performed to measure areas of subcutaneous and visceral fat before and after 1 year of ADT. ADT was limited to a luteinizing hormone-releasing hormone (LHRH) agonist with or without bicalutamide.Results:Of 218 patients registered, data were available from 177 patients who completed 1 year of ADT. Of these, CT was performed before and after 1 year of ADT in 88 patients. Median age was 75 years (range, 49-85 years). Median PSA before ADT was 16.7 ng ml-1 (range, 0.3-3316). Clinical stage was B (54.2%), C (23.2%) and D (20.9%). Mean increases in body weight and abdominal circumference after 1 year of ADT were 2.9 and 3.0%, respectively. Mean increases in total, low-density lipoprotein and high-density lipoprotein cholesterol and triglycerides were 10.6, 14.3, 7.8 and 16.2%, respectively. Mean increases in fasting blood sugar and hemoglobin A1c (HbA1c) were 3.9 and 2.7%, respectively. Lipid alterations were noted in patients without comorbidities, whereas changes in HbA1c were noted in patients with diabetes mellitus at baseline. These lipid and glucose alterations were prominent in the early ADT period. Both visceral and subcutaneous fat, as measured by CT, increased by >20%. The increase in subcutaneous fat was significantly greater than that in visceral fat (P=0.028).Conclusions:One year of ADT significantly changed lipid and glucose metabolism in Japanese patients with prostate cancer. Patient characteristics or comorbidities at baseline may be associated with ADT-induced metabolic changes.

DOI PubMed

Diet-induced alteration of fatty acid synthase in prostate cancer progression

M. Huang, A. Koizumi, S. Narita, T. Inoue, N. Tsuchiya, H. Nakanishi, K. Numakura, H. Tsuruta, M. Saito, S. Satoh, H. Nanjo, T. Sasaki, T. Habuchi

Oncogenesis   5   2016年02月

研究論文（学術雑誌）  

Fatty acid synthase (FASN) is a cytosolic metabolic enzyme that catalyzes de novo fatty acid synthesis. A high-fat diet (HFD) is attributed to prostate cancer (PCa) progression, but the role FASN on HFD-mediated PCa progression remains unclear. We investigated the role of FASN on PCa progression in LNCaP xenograft mice fed with HFD or low-fat diet (LFD), in PCa cells, and in clinical PCa. The HFD promoted tumour growth and FASN expression in the LNCaP xenograft mice. HFD resulted in AKT and extracellular signal-regulated kinase (ERK) activation and 5' adenosine monophosphate-activated protein kinase (AMPK) inactivation. Serum FASN levels were significantly lower in the HFD group (P=0.026) and correlated inversely with tumour volume (P=0.022). Extracellular FASN release was enhanced in the PCa cells with phosphatidylinositol 3-kinase (PI3K)/mitogen-activated protein kinase (MAPK) inhibition and AMPK signalling activation. FASN inhibition resulted in decrease of PCa cell proliferation through PI3K/MAPK downregulation and AMPK activation. Furthermore, AMPK activation was associated with FASN downregulation and PI3K/MAPK inactivation. Clinically, high FASN expression was significantly associated with high Gleason scores and advanced pathological T stage. Moreover, FASN expression was markedly decreased in the PCa response to androgen deprivation therapy and chemotherapy. HFD modulates FASN expression, which may be an important mechanism in HFD-associated PCa progression. Furthermore, a critical stimulatory loop exists between FASN and the PI3K/MAPK system, whereas AMPK signalling was associated with suppression. These may offer appropriate targets for chemoprevention and cancer therapy in HFD-induced PCa.

DOI

[Current status of castration-resistant prostate cancer translational research].

Atsushi Maeno, Tomonori Habuchi

Nihon rinsho. Japanese journal of clinical medicine   74 ( 1 ) 40 - 4   2016年01月

研究論文（学術雑誌）  

Recently, new drugs including abiraterone and enzalutamide have been able to be used for castration resistant prostate cancer(CRPC) patients. However, a subset of these patients who receive the new drugs does not response to the therapies. Furthermore, most patients who initially response to the drugs, progress to secondary resistance eventually. Therefore, it is important to investigate a novel therapeutic target and a novel treatment-selection marker for CRPC. In this review, we focused on AR-V7, TMPRSS2-ERG fusion gene and EP4 antagonist as representative translational researches.

PubMed

Development of RNA-FISH Assay for Detection of Oncogenic FGFR3-TACC3 Fusion Genes in FFPE Samples.

Masahiro Kurobe, Takahiro Kojima, Kouichi Nishimura, Shuya Kandori, Takashi Kawahara, Takayuki Yoshino, Satoshi Ueno, Yuichi Iizumi, Koji Mitsuzuka, Yoichi Arai, Hiroshi Tsuruta, Tomonori Habuchi, Takashi Kobayashi, Yoshiyuki Matsui, Osamu Ogawa, Mikio Sugimoto, Yoshiyuki Kakehi, Yoshiyuki Nagumo, Masakazu Tsutsumi, Takehiro Oikawa, Koji Kikuchi, Hiroyuki Nishiyama

PloS one   11 ( 12 ) e0165109   2016年

研究論文（学術雑誌）  

INTRODUCTION AND OBJECTIVES: Oncogenic FGFR3-TACC3 fusions and FGFR3 mutations are target candidates for small molecule inhibitors in bladder cancer (BC). Because FGFR3 and TACC3 genes are located very closely on chromosome 4p16.3, detection of the fusion by DNA-FISH (fluorescent in situ hybridization) is not a feasible option. In this study, we developed a novel RNA-FISH assay using branched DNA probe to detect FGFR3-TACC3 fusions in formaldehyde-fixed paraffin-embedded (FFPE) human BC samples. MATERIALS AND METHODS: The RNA-FISH assay was developed and validated using a mouse xenograft model with human BC cell lines. Next, we assessed the consistency of the RNA-FISH assay using 104 human BC samples. In this study, primary BC tissues were stored as frozen and FFPE tissues. FGFR3-TACC3 fusions were independently detected in FFPE sections by the RNA-FISH assay and in frozen tissues by RT-PCR. We also analyzed the presence of FGFR3 mutations by targeted sequencing of genomic DNA extracted from deparaffinized FFPE sections. RESULTS: FGFR3-TACC3 fusion transcripts were identified by RNA-FISH and RT-PCR in mouse xenograft FFPE tissues using the human BC cell lines RT112 and RT4. These cell lines have been reported to be fusion-positive. Signals for FGFR3-TACC3 fusions by RNA-FISH were positive in 2/60 (3%) of non-muscle-invasive BC (NMIBC) and 2/44 (5%) muscle-invasive BC (MIBC) patients. The results of RT-PCR of all 104 patients were identical to those of RNA-FISH. FGFR3 mutations were detected in 27/60 (45%) NMIBC and 8/44 (18%) MIBC patients. Except for one NMIBC patient, FGFR3 mutation and FGFR3-TACC3 fusion were mutually exclusive. CONCLUSIONS: We developed an RNA-FISH assay for detection of the FGFR3-TACC3 fusion in FFPE samples of human BC tissues. Screening for not only FGFR3 mutations, but also for FGFR3-TACC3 fusion transcripts has the potential to identify additional patients that can be treated with FGFR inhibitors.

DOI PubMed

Immunosuppressive protocol for the recipients with donor specific antibodies

Mitsuru Saito, Tomonori Habuchi, Shigeru Satoh, Ryohei Yamamoto, Hiroshi Tsuruta, Takamitsu Inoue, Shintaro Narita, Norihiko Tsuchiya

Japanese Journal of Clinical Urology   69 ( 13 ) 1138 - 1143   2015年12月

研究論文（学術雑誌）  

Laparoendoscopic single-site donor nephrectomy : the present status and perspectives

Takamitsu Inoue, Shintaro Narita, Norihiko Tsuchiya, Kazuyuki Numakura, Atsushi Maeno, Mitsuru Saito, Tomonori Habuchi, Shigeru Satoh

Japanese Journal of Clinical Urology   69 ( 13 ) 1102 - 1109   2015年12月

研究論文（学術雑誌）  

Reassessment of the risk factors for biochemical recurrence in D'Amico intermediate-risk prostate cancer treated using radical prostatectomy.

Shintaro Narita, Koji Mitsuzuka, Norihiko Tsuchiya, Takuya Koie, Sadafumi Kawamura, Chikara Ohyama, Tatsuo Tochigi, Takuhiro Yamaguchi, Yoichi Arai, Tomonori Habuchi

International journal of urology : official journal of the Japanese Urological Association   22 ( 11 ) 1029 - 35   2015年11月

研究論文（学術雑誌）  

OBJECTIVES: To assess the risk factors for biochemical recurrence in D'Amico intermediate-risk prostate cancer patients treated using radical prostatectomy. METHODS: We retrospectively reviewed the medical records of 1268 men with prostate cancer treated using radical prostatectomy without neoadjuvant therapy. The association between various risk factors and biochemical recurrence was then statistically evaluated. The Kaplan-Meier method, log-rank tests and Cox proportional hazards models were used for statistical analysis. RESULTS: In the intermediate-risk group, 96 patients (14.5%) experienced biochemical recurrence during a median follow up of 41 months. In the intermediate-risk group, preoperative prostate-specific antigen level, prostate volume and prostate-specific antigen density were significant preoperative risk factors for biochemical recurrence, whereas other factors including age, primary Gleason 4, clinical stage >T2 and percentage of positive biopsies were not. In multivariate analysis, higher preoperative prostate-specific antigen level and density, and a smaller prostate volume were independent risk factors for biochemical recurrence in the intermediate-risk group. Biochemical recurrence-free survival of patients in the intermediate-risk group with a higher prostate-specific antigen level and density (≥15 ng/mL, ≥0.6 ng/mL/cm(3), respectively), and lower prostate volume (≤10 mL) was comparable with that of high-risk group individuals (P = 0.632, 0.494 and 0.961, respectively). CONCLUSIONS: Preoperative prostate-specific antigen, prostate volume and prostate-specific antigen density are significant risk factors for biochemical recurrence in D'Amico intermediate-risk prostate cancer patients treated using radical prostatectomy. Using these variables, a subset of the intermediate-risk patients can be identified as having equivalent outcomes to high-risk patients.

DOI PubMed

Identification of a subgroup with worse prognosis among patients with poor-risk testicular germ cell tumor.

Takahiro Kojima, Koji Kawai, Kunihiko Tsuchiya, Takashige Abe, Nobuo Shinohara, Toshiaki Tanaka, Naoya Masumori, Shigeyuki Yamada, Yoichi Arai, Shintaro Narita, Norihiko Tsuchiya, Tomonori Habuchi, Hiroyuki Nishiyama

International journal of urology : official journal of the Japanese Urological Association   22 ( 10 ) 923 - 7   2015年10月

研究論文（学術雑誌）  

OBJECTIVES: To clarify the significance of the International Germ Cell Cancer Collaborative Group classification in the 2000s, especially in intermediate- and poor-prognosis testicular germ cell tumor in Japan. METHODS: We retrospectively analyzed 117 patients with intermediate- and poor-prognosis testicular non-seminomatous germ cell tumor treated at five university hospitals in Japan between 2000 and 2010. Data collected included age, levels of tumor markers, spread to non-pulmonary visceral metastases, treatment details and survival. RESULTS: The median follow-up period of all patients was 57 months. A total of 50 patients (43%) were classified as having intermediate prognosis, and 67 patients (57%) as poor prognosis according to the International Germ Cell Cancer Collaborative Group classification. As first-line chemotherapy, 92 patients (79%) received bleomycin, etoposide and cisplatin. Of all patients, 74 patients (63%) received second-line chemotherapy. The most commonly used second-line chemotherapy regimens were a combination of taxanes, ifosfamide and platinum in 49 cases (66%). Overall, 33 patients (28%) received third-line chemotherapy. A total of 88 patients (75%) underwent post-chemotherapy surgery. The 5-year overall survival for intermediate (n = 50) and poor prognosis (n = 67) was 89% and 83% (P = 0.21), respectively. In poor prognosis patients, patients with two or more risk factors (any of high lactic dehydrogenase, alpha-fetoprotein and human chorionic gonadotropin levels, and presence of non-pulmonary visceral metastases) had significantly worse survival than those with only one risk factor (71% and 91%, respectively, P = 0.01). CONCLUSIONS: The 5-year overall survivals of poor-prognosis testicular non-seminomatous germ cell tumor patients reached 83%. Further stratification of poor-prognosis patients based on a number of risk factors has the potential to further identify those with poorer prognosis.

DOI PubMed

Lymph node dissection

Norihiko Tsuchiya, Hiroshi Tsuruta, Mitsuru Saito, Takamitsu Inoue, Shintaro Narita, Tomonori Habuchi

Japanese Journal of Clinical Urology   69 ( 11 ) 918 - 923   2015年10月

研究論文（学術雑誌）  

Neoadjuvant luteinizing-hormone-releasing hormone agonist plus low-dose estramustine phosphate improves prostate-specific antigen-free survival in high-risk prostate cancer patients: a propensity score-matched analysis.

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

International journal of clinical oncology   20 ( 5 ) 1018 - 25   2015年10月

研究論文（学術雑誌）  

BACKGROUND: The optimal treatment for high-risk prostate cancer (Pca) remains to be established. We previously reported favorable biochemical recurrence-free survival (BRFS) in high-risk Pca patients treated with a neoadjuvant therapy comprising a luteinizing-hormone-releasing hormone (LHRH) agonist plus low dose estramustine phosphate (EMP) (LHRH+EMP) followed by radical prostatectomy (RP). In the present study, we used a retrospective design via propensity score matching to elucidate the clinical benefit of neoadjuvant LHRH+EMP for high-risk Pca. METHODS: The Michinoku Urological Cancer Study Group database contained data for 1,268 consecutive Pca patients treated with RP alone at 4 institutions between April 2000 and March 2011 (RP alone group). In the RP alone group, we identified 386 high-risk Pca patients. The neoadjuvant LHRH+EMP group included 274 patients with high-risk Pca treated between September 2005 and November 2013 at Hirosaki University. Neoadjuvant LHRH+EMP therapy included LHRH and EMP administration at a dose of 280 mg/day for 6 months before RP. The outcome measures were overall survival (OS) and BRFS. RESULTS: The propensity score-matched analysis indicated 210 matched pairs from both groups. The 5-year BRFS rates were 90.4 and 65.8 % for the neoadjuvant LHRH+EMP and RP alone groups, respectively (P < 0.0001). The 5-year OS rates were 100 and 96.1 % for the neoadjuvant LHRH+EMP and RP alone groups, respectively (P = 0.110). CONCLUSIONS: Although the present study was not randomized, neoadjuvant LHRH+EMP therapy followed by RP appeared to reduce the risk of biochemical recurrence. A prospective randomized study is warranted to determine the clinical implications of the neoadjuvant therapy described here.

DOI PubMed

[PRIMARY MEDIASTINAL GERM CELL TUMOR ARISING IN A PATIENT WITH NEUROFIBROMATOSIS TYPE 1].

Soki Kashima, Mitsuru Saito, Norihiko Tsuchiya, Hajime Saito, Hiroshi Nanjo, Kazuyuki Numakura, Hiroshi Tsuruta, Susumu Akihama, Takamitsu Inoue, Shintaro Narita, Yoshihiro Minamiya, Shigeru Satoh, Tomonori Habuchi

Nihon Hinyokika Gakkai zasshi. The japanese journal of urology   106 ( 3 ) 178 - 84   2015年07月

研究論文（学術雑誌）  

Neurofibromatosis type 1 (NF1) is a distinct genetic disorder due to the NF1 gene mutation which induces the aberrant activation of the RAS-signaling. Because RAS-related proteins function as oncogenic factors, NF1 patients frequently develop malignant tumors, especially of neural crest origin, such as peripheral nerve sheath. In addition, malignant tumors of the pancreas, colorectum, and lung have been reported to frequently arise in NF1 patients. However, the association between germ cell tumor and NF1 has not been clarified yet. A 29-year-old male with dyspnea was referred to our hospital because of the large mass in the anterior mediastinum and cervical lymph node swelling. The diagnosis was extragonadal germ cell tumor with cervical lymph node metastasis, and complete remission was obtained by multidisciplinary treatment consisted of combination chemotherapy and surgical resection. To our acknowledgement, this is the first case of extragonadal germ cell tumor in NF1 patients. We discuss the relevance between activation of the RAS-signaling and the development of germ cell tumor.

DOI PubMed

INPP4B Is a PtdIns(3,4,5)P3 Phosphatase That Can Act as a Tumor Suppressor.

Satoshi Kofuji, Hirotaka Kimura, Hiroki Nakanishi, Hiroshi Nanjo, Shunsuke Takasuga, Hui Liu, Satoshi Eguchi, Ryotaro Nakamura, Reietsu Itoh, Noriko Ueno, Ken Asanuma, Mingguo Huang, Atsushi Koizumi, Tomonori Habuchi, Masakazu Yamazaki, Akira Suzuki, Junko Sasaki, Takehiko Sasaki

Cancer discovery   5 ( 7 ) 730 - 9   2015年07月

研究論文（学術雑誌）  

UNLABELLED: Inositol polyphosphate 4-phosphatase B (INPP4B) has been identified as a tumor suppressor mutated in human breast, ovary, and prostate cancers. The molecular mechanism underlying INPP4B's tumor-suppressive role is currently unknown. Here, we demonstrate that INPP4B restrains tumor development by dephosphorylating the PtdIns(3,4,5)P3 that accumulates in situations of PTEN deficiency. In vitro, INPP4B directly dephosphorylates PtdIns(3,4,5)P3. In vivo, neither inactivation of Inpp4b (Inpp4b(Δ/Δ)) nor heterozygous deletion of Pten (Pten(+/-)) in mice causes thyroid abnormalities, but a combination of these mutations induces malignant thyroid cancers with lung metastases. At the molecular level, simultaneous deletion of Inpp4b and Pten synergistically increases PtdIns(3,4,5)P3 levels and activates AKT downstream signaling proteins in thyroid cells. We propose that the PtdIns(3,4,5)P3 phosphatase activity of INPP4B can function as a "back-up" mechanism when PTEN is deficient, making INPP4B a potential novel therapeutic target for PTEN-deficient or PIK3CA-activated cancers. SIGNIFICANCE: Although INPP4B expression is reduced in several types of human cancers, our work on Inpp4B-deficient mice provides the first evidence that INPP4B is a bona fide tumor suppressor whose function is particularly important in situations of PTEN deficiency. Our biochemical data demonstrate that INPP4B directly dephosphorylates PtdIns(3,4,5)P3.

DOI PubMed

Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci.

Ali Amin Al Olama, Sara Benlloch, Antonis C Antoniou, Graham G Giles, Gianluca Severi, David E Neal, Freddie C Hamdy, Jenny L Donovan, Kenneth Muir, Johanna Schleutker, Brian E Henderson, Christopher A Haiman, Fredrick R Schumacher, Nora Pashayan, Paul D P Pharoah, Elaine A Ostrander, Janet L Stanford, Jyotsna Batra, Judith A Clements, Suzanne K Chambers, Maren Weischer, Børge G Nordestgaard, Sue A Ingles, Karina D Sorensen, Torben F Orntoft, Jong Y Park, Cezary Cybulski, Christiane Maier, Thilo Doerk, Joanne L Dickinson, Lisa Cannon-Albright, Hermann Brenner, Timothy R Rebbeck, Charnita Zeigler-Johnson, Tomonori Habuchi, Stephen N Thibodeau, Kathleen A Cooney, Pierre O Chappuis, Pierre Hutter, Radka P Kaneva, William D Foulkes, Maurice P Zeegers, Yong-Jie Lu, Hong-Wei Zhang, Robert Stephenson, Angela Cox, Melissa C Southey, Amanda B Spurdle, Liesel FitzGerald, Daniel Leongamornlert, Edward Saunders, Malgorzata Tymrakiewicz, Michelle Guy, Tokhir Dadaev, Sarah J Little, Koveela Govindasami, Emma Sawyer, Rosemary Wilkinson, Kathleen Herkommer, John L Hopper, Aritaya Lophatonanon, Antje E Rinckleb, Zsofia Kote-Jarai, Rosalind A Eeles, Douglas F Easton

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology   24 ( 7 ) 1121 - 9   2015年07月

研究論文（学術雑誌）  

BACKGROUND: Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of prostate cancer. METHODS: We genotyped 25 prostate cancer susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS). We estimated empirical odds ratios (OR) for prostate cancer associated with different risk strata defined by PRS and derived age-specific absolute risks of developing prostate cancer by PRS stratum and family history. RESULTS: The prostate cancer risk for men in the top 1% of the PRS distribution was 30.6 (95% CI, 16.4-57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI, 3.2-5.5) fold compared with the median risk. The absolute risk of prostate cancer by age of 85 years was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation = 0.09). CONCLUSIONS: Risk profiling can identify men at substantially increased or reduced risk of prostate cancer. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of prostate cancer. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles. IMPACT: We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs.

DOI PubMed

[Pazopanib for three patients with recurrence of retroperitoneal liposarcoma : initial clinical experience].

Atsushi Koizumi, Takamitsu Inoue, Koichiro Takayama, Makoto Takahashi, Kazuyuki Numakura, Hiroshi Tsuruta, Susumu Akihama, Mitsuru Saito, Shintaro Narita, Norihiko Tsuchiya, Shigeru Satoh, Tomonori Habuchi

Hinyokika kiyo. Acta urologica Japonica   61 ( 4 ) 153 - 8   2015年04月

研究論文（学術雑誌）  

Pazopanib, a novel tyrosine kinase inhibitor, is an effective therapeutic agent for patients with advanced soft tissue sarcoma. Here we report three patients with recurrent retroperitoneal liposarcoma who were treated with pazopanib. Case 1: A 54-year-old male received three courses of combined chemotherapy consisting of doxorubicin and ifosfamide for recurrent left retroperitoneal dedifferentiated liposarcoma and liver metastasis following tumor excision. Because of the lack of response to chemotherapy, 400 mg/day of pazopanib was subsequently administered for two weeks. The patient died 3 weeks after the initiation of pazopznib therapy. Case 2: A 78-year-old male with right retroperitoneal dedifferentiated liposarcoma underwent irradiation for a recurrent tumor 16 months after the initial tumor excision. Pazopanib (600 mg/day) was partially effective for 2 months. Pazopanib was administered for 7 months, but the patient died 8 months after the initiation of pazopanib therapy. Case 3 : An 80-year-old male with locally recurrent right retroperitoneal myxoid liposacroma was treated with 600 mg/day of pazopanib from 5 months after tumor excision. He remains alive and has had stable disease for 17 months to date. In conclusion, pazopanib may be effective in a subset of patients with recurrent retroperitoneal liposarcoma.

PubMed

A solitary positive prostate cancer biopsy does not predict a unilateral lesion in radical prostatectomy specimens.

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

Scandinavian journal of urology   49 ( 2 ) 103 - 7   2015年04月

研究論文（学術雑誌）  

OBJECTIVE: Prostate cancer (PCa) may be a multifocal and bilateral disease. Patients with low-risk PCa and a low number of positive biopsy cores may choose to undergo active surveillance or focal therapy. The aim of this study was to determine the correlation between a solitary positive prostate biopsy core and the pathological outcome after radical prostatectomy (RP). MATERIAL AND METHODS: The Michinoku Japan Urological Cancer Study Group database contains data, including preoperative and postoperative information, on 1268 consecutive patients with PCa treated with RP alone at four institutions. This study focused on 151 patients with a single positive biopsy core, preoperative prostate-specific antigen (PSA) level less than 10 ng/ml, biopsy Gleason score less than 8, and clinical stage T1c/T2a/T2b disease. Potential preoperative predictors of unilateral PCa were age, preoperative PSA level, biopsy Gleason score and clinical T stage. RESULTS: The median age and preoperative PSA level were 65 years (range 47-76 years) and 6.00 ng/ml (range 0.50-9.80 ng/ml), respectively. Unilateral PCa was identified in 41% of the patients. Extraprostatic extension or seminal vesicle invasion was observed in 26% of all patients. CONCLUSION: Serum PSA levels were significantly higher in the bilateral PCa group than in the unilateral PCa group in the current study. For patients with PCa having a solitary positive prostate biopsy core, definitive therapy such as RP should be considered.

DOI PubMed

Successful introduction of laparoendoscopic single-site donor nephrectomy after experience with laparoscopic single-site plus-one trocar donor nephrectomy.

Takamitsu Inoue, Norihiko Tsuchiya, Shintaro Narita, Hiroshi Tsuruta, Susumu Akihama, Mitsuru Saito, Shigeru Satoh, Tomonori Habuchi

Journal of endourology   29 ( 4 ) 435 - 42   2015年04月

研究論文（学術雑誌）  

PURPOSE: To assess the feasibility, safety, and efficacy of the laparoendoscopic single-site (LESS) donor nephrectomy (LESSDN) procedure after experience with the LESS-plus-one-trocar donor nephrectomy (LEPODN) procedure. PATIENTS AND METHODS: From 2009 to 2014, 126 left laparoscopic donor nephrectomies (LDNs) were performed, including 59 Standard (Std)-LDN, 30 LEPODN, and 37 LESSDN. In the LEPODN procedure, a 5-mm trocar was added as a right-hand working trocar to the LESSDN procedure. A GelPOINT(®) platform was applied on a pararectal single incision in both LEPODN and LESSDN procedures. After performing the LEPODN procedure several times, each surgeon performed the LESSDN procedure. RESULTS: Std-LDN, LEPODN, and LESSDN procedures were performed by 10, 10, and 7 surgeons, respectively. The mean operative time, estimated blood loss, warm ischemia time, time to ambulation, and length of postoperative hospital stay were the shortest for the LESSDN procedure (P<0.012, P=0.007, P<0.001, P=0.027, and P=0.001, respectively). No significant difference in the complication rate, delayed graft function rate, and mean 7-day post-transplant serum creatinine levels was observed among the three procedures. Individual results of the operative time and estimated blood loss for the LESSDN procedure were not significantly inferior to those of Std-LDN and LEPODN procedures for each surgeon. CONCLUSIONS: The LESSDN procedure can be introduced safely and effectively without compromising the operative time, complication rate, and graft function after experience with the LEPODN procedure among multiple surgeons. The LEPODN procedure may be an effective bridge from standard multiport LDN to LESSDN.

DOI PubMed

Lymphovascular invasion is significantly associated with biochemical relapse after radical prostatectomy even in patients with pT2N0 negative resection margin

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

Prostate Cancer and Prostatic Diseases   18 ( 1 ) 25 - 30   2015年03月

研究論文（学術雑誌）  

BACKGROUND: The significance of lymphovascular invasion (LVI) remains controversial, and the association of LVI with biochemical relapse was investigated in men treated with radical prostatectomy according to pathological results. METHODS: Data from 1268 patients undergoing radical prostatectomy between 2000 and 2009 were retrospectively reviewed. Clinicopathological variables were compared between LVI-negative and LVI-positive patients. Multivariate analyses by Cox proportional hazard model and Kaplan-Meier method were performed to identify risk factors for biochemical relapse in all patients, patients with pT2N0 and pT2N0 negative resection margin (RM). RESULTS: LVI information was available in 1160 cases, and LVI was seen in 121 cases (10.4%). Clinicopathological variables were significantly worse in LVI-positive patients than in LVI-negative patients. On multivariate analyses, PSA ≥ 10 ng ml-1, pathological Gleason score ≥ 8, pathological T stage ≥ 3, lymph node metastasis, positive RM and LVI were independent predictors for biochemical relapse in all patients. In patients with pT2N0, PSA ≥ 10 ng ml-1, pathological Gleason score ≥ 8, positive RM and LVI were independent predictors for biochemical relapse. In patients with pT2N0 negative RM, LVI and pathological Gleason score ≥ 8 were independent predictors for biochemical relapse (LVI; hazard ratio 3.809, 95% confidence interval 1.900-7.635, P-value < 0.001, Gleason score ≥ 8; hazard ratio 2.189, 95% confidence interval 1.199-3.999, P-value = 0.011). With a median follow-up of 50 months, 5-year biochemical relapse-free survival in patients with pT2N0 negative RM was 95.7% in those with negative LVI in comparison to 85.3% in those with positive LVI (P < 0.001, log rank). CONCLUSIONS: LVI was consistently a significant predictor for biochemical relapse after radical prostatectomy in not only all patients but also in patients with pT2N0 and pT2N0 negative RM. These results strongly support the significance of LVI as a predictor for biochemical relapse.

DOI PubMed

Prostate-specific antigen density predicts extracapsular extension and increased risk of biochemical recurrence in patients with high-risk prostate cancer who underwent radical prostatectomy.

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

International journal of clinical oncology   20 ( 1 ) 176 - 81   2015年02月

研究論文（学術雑誌）  

BACKGROUND: Patients with advanced local-stage, high-grade prostate cancer (Pca) and high pretreatment prostate-specific antigen (PSA) levels have inferior outcomes compared to their counterparts with more favorable clinical characteristics. However, some patients exhibit favorable pathological features or experience long-term PSA-free survival after radical prostatectomy (RP). We retrospectively examined the ability of preoperative characteristics to predict pathological and oncological outcomes in high-risk Pca patients who underwent RP. METHODS: We examined data of 1,268 consecutive Pca patients treated with RP alone at 4 hospitals from the Michinoku Urological Cancer Study Group database. Preoperative predictors included age, PSA level, biopsy Gleason score, clinical T stage, and PSA density (PSAD). The outcome measures pathological T stage and PSA-free survival were evaluated by multivariate analysis. RESULTS: We identified 380 high-risk Pca patients, of which 44 % patients had extracapsular extension. Logistic regression analysis indicated that PSAD was an independent predictor of adverse pathologic stage. The 5-year PSA-free survival rates were 82.9 % for patients with PSAD ≤0.468 ng mL(-1) cm(-2) and 50.7 % for those with PSAD >0.468 ng mL(-1) cm(-2) (P < 0.0001). Multivariate analyses revealed that PSAD, cT, and the number of preoperative high-risk Pca criteria were independent predictors of PSA-free survival. CONCLUSIONS: PSAD may be an independent predictor of advanced pathological features and biochemical recurrence in high-risk Pca patients treated with RP alone. PSAD may be used for further risk stratification of high-risk Pca patients.

DOI PubMed

Capability of utilizing CYP3A5 polymorphisms to predict therapeutic dosage of tacrolimus at early stage post-renal transplantation.

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

International journal of molecular sciences   16 ( 1 ) 1840 - 54   2015年01月

研究論文（学術雑誌）  

While CYP3A5 polymorphisms are used to predict the initial dosage of tacrolimus therapy, the predictive capability of genetic information for dosing at early stage post-renal transplantation is unknown. We investigated the influence of polymorphisms over time. An initial oral dose of modified-release once-daily tacrolimus formulation (0.20 mg/kg) was administered to 50 Japanese renal transplant patients every 24 h. Stepwise multiple linear regression analysis for tacrolimus dosing was performed each week to determine the effect of patient clinical characteristics. The dose-adjusted trough concentration was approximately 70% higher for patients with the CYP3A5*3/*3 than patients with the CYP3A5*1 allele before the second pre-transplantation tacrolimus dose (0.97 (0.78-1.17) vs. 0.59 (0.45-0.87) ng/mL/mg; p < 0.001). The contribution of genetic factors (CYP3A5*1 or *3) for tacrolimus dosing showed increased variation from Day 14 to Day 28 after transplantation: 7.2%, 18.4% and 19.5% on Days 14, 21 and 28, respectively. The influence of CYP3A5 polymorphisms on the tacrolimus maintenance dosage became evident after Day 14 post-transplantation, although the tacrolimus dosage was determined based only on patient body weight for the first three days after surgery. Tacrolimus dosage starting with the initial administration should be individualized using the CYP3A5 genotype information.

DOI PubMed

Effects of functional genetic polymorphisms in the CYP19A1 gene on prostate cancer risk and survival.

Sohei Kanda, Norihiko Tsuchiya, Shintaro Narita, Takamitsu Inoue, Mingguo Huang, Syuji Chiba, Susumu Akihama, Mitsuru Saito, Kazuyuki Numakura, Hiroshi Tsuruta, Shigeru Satoh, Seiichi Saito, Chikara Ohyama, Yoichi Arai, Osamu Ogawa, Tomonori Habuchi

International journal of cancer   136 ( 1 ) 74 - 82   2015年01月

研究論文（学術雑誌）  

CYP19 catalyzes the conversion of androgens to estrogens and is a critical enzyme affecting the sex hormone milieu. In this study, we investigated the functions of CYP19A1 polymorphisms and their associations with prostate cancer risk and clinical outcome. This case-control study evaluated the effects of three single nucleotide polymorphisms (SNPs) in CYP19A1 on the risk of prostate cancer in 330 prostate cancer patients and 354 normal controls. The associations between each SNP and sex hormone levels were evaluated in 164 healthy male patients. The functions of the SNPs were determined by reporter gene assays in PC3 and DU145 cell lines. Prostate-specific antigen nadir was evaluated in 142 patients with metastatic prostate cancer treated with androgen deprivation therapy. Cancer-specific survival (CSS) was determined in 166 patients with metastatic prostate cancer, to evaluate the influence of the three SNPs. Each variant allele of the three SNPs significantly decreased the risk of prostate cancer. Haplotype analysis showed that the T-A-G haplotype (corresponding to rs2470152-rs10459592-rs4775936) increased the risk of prostate cancer, while the C-C-A haplotype decreased the risk. The estrone/androstenedione ratio was significantly higher in men with the C allele of rs2470152, the C allele of rs10459592, and the A allele of rs4775936 in a gene-dosage-dependent manner. Patients with the variant allele at rs4775936 had significantly shorter CSS. These results indicate that CYP19A1 polymorphisms may influence prostate cancer risk and survival by modifying promoter activity, with subsequent effects on the sex hormone milieu.

DOI PubMed

Efficiency of pretreatment risk stratification systems for prostate cancer in a Japanese population treated with radical prostatectomy.

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

International journal of urology : official journal of the Japanese Urological Association   22 ( 1 ) 70 - 3   2015年01月

研究論文（学術雑誌）  

OBJECTIVE: To determine whether the currently available pretreatment risk classification systems are applicable in Japanese prostate cancer patients. METHODS: Using data obtained from 1264 consecutive patients with prostate cancer treated with radical prostatectomy at four hospitals in Japan, biochemical recurrence-free survival rates were estimated and compared between the D'Amico, the National Institute for Health and Clinical Excellence, the Cancer of the Prostate Strategic Urological Research Endeavor, the National Comprehensive Cancer Network, and the European Society of Medical Oncology risk groups by using the Kaplan-Meier method and log-rank test. RESULTS: The 5-year biochemical recurrence-free survival rates in the D'Amico low-, intermediate-, and high-risk groups were 88.3%, 84.7% and 66.9%, respectively (low and intermediate risk vs high risk, P < 0.001). The 5-year biochemical recurrence-free survival rates in the National Institute for Health and Clinical Excellence, National Comprehensive Cancer Network, and European Society of Medical Oncology low-, intermediate- and high-risk groups were 88.3%, 84.3%, and 60.3%, respectively (low and intermediate risk vs high risk, P < 0.001). The 5-year biochemical recurrence-free survival rates in the Cancer of the Prostate Strategic Urological Research Endeavor low-, intermediate-, and high-risk groups were 90%, 83.5% and 60.3%, respectively (low and intermediate risk vs high risk, P < 0.001). Low- and intermediate-risk groups according to any of the risk stratification systems did not show significant differences in biochemical recurrence-free survival. CONCLUSION: Current risk stratification systems do not discriminate between low- and intermediate-risk groups in the Japanese population. A novel, pretreatment risk stratification system including other prognostic factors is necessary for an adequate prostate cancer risk assessment in the Japanese population.

DOI PubMed

Characterization of clinical and genetic risk factors associated with dyslipidemia after kidney transplantation.

Kazuyuki Numakura, Hideaki Kagaya, Ryohei Yamamoto, Naoki Komine, Mitsuru Saito, Tsuruta Hiroshi, Susumu Akihama, Takamitsu Inoue, Shintaro Narita, Norihiko Tsuchiya, Tomonori Habuchi, Takenori Niioka, Masatomo Miura, Shigeru Satoh

Disease markers   2015   179434 - 179434   2015年

研究論文（学術雑誌）  

We determined the prevalence of dyslipidemia in a Japanese cohort of renal allograft recipients and investigated clinical and genetic characteristics associated with having the disease. In total, 126 patients that received renal allograft transplants between February 2002 and August 2011 were studied, of which 44 recipients (34.9%) were diagnosed with dyslipidemia at 1 year after transplantation. Three clinical factors were associated with a risk of having dyslipidemia: a higher prevalence of disease observed among female than male patients (P = 0.021) and treatment with high mycophenolate mofetil (P = 0.012) and prednisolone (P = 0.023) doses per body weight at 28 days after transplantation. The genetic association between dyslipidemia and 60 previously described genetic polymorphisms in 38 putative disease-associated genes was analyzed. The frequency of dyslipidemia was significantly higher in patients with the glucocorticoid receptor (NR3C1) Bcl1 G allele than in those with the CC genotype (P = 0.001). A multivariate analysis revealed that the NR3C1 Bcl1 G allele was a significant risk factor for the prevalence of dyslipidemia (odds ratio = 4.6; 95% confidence interval = 1.8-12.2). These findings may aid in predicting a patient's risk of developing dyslipidemia.

DOI PubMed

Clinical benefits of tubeless umbilical cutaneous ureterostomy.

Kazuyuki Numakura, Norihiko Tsuchiya, Makoto Takahashi, Hiroshi Tsuruta, Susumu Akihama, Mitsuru Saito, Takamitsu Inoue, Shintaro Narita, Mingguo Huang, Shigeru Satoh, Tomonori Habuchi

Canadian Urological Association journal = Journal de l'Association des urologues du Canada   9 ( 5-6 ) E379-83 - E383   2015年

研究論文（学術雑誌）  

INTRODUCTION: We assess a novel technique of tubeless bilateral cutaneous ureterostomy, with a single umbilical stoma, for bladder cancer patients with short ureters after cystectomy. The benefit of cutaneous ureterostomy is equal to other incontinent urinary diversions, when the tubeless procedure is successfully achieved. This simple technique makes it easy to monitor the upper urinary tract (UUT) and is beneficial to patients with a high risk of UUT recurrence. METHODS: This old and new surgical technique was used to perform total cystectomy and urinary diversion on three patients with bladder cancer at a high risk of UUT recurrence. RESULTS: Two men and one woman (mean age: 73 years) underwent this surgery and the mean follow-up period was 8.3 years. The surgical approaches were laparotomy (n = 2) and laparoscopy (n = 1). One case developed para-stomal erosion, whereas another developed ureteral stenosis requiring catheter reinsertion. Although postoperative hydronephrosis was observed in all cases, the mean preoperative and postoperative serum creatinine levels were 0.70 and 0.76, respectively. UUT recurrence was not observed during the follow-up period. CONCLUSION: This tubeless umbilical cutaneous ureterostomy procedure greatly improves the outcome of urinary diversion for cancer patients with short ureters at a high risk of UUT recurrence. The benefits are equivalent to other urinary diversions when the tubeless procedure is successfully achieved.

DOI PubMed

[Treatment for high-risk localized prostate cancer].

Shintaro Narita, Norihiko Tsuchiya, Tomonori Habuchi

Nihon rinsho. Japanese journal of clinical medicine   72 ( 12 ) 2212 - 6   2014年12月

研究論文（学術雑誌）  

High-risk localized prostate cancer encompasses a significant heterogeneity and the treatment strategy for this group of prostate cancer patients remains controversial. The definition of high-risk localized prostate cancer is not consistent in that which clinicopathological parameters are included as risk factors. Therefore, we need to be careful in comparing the treatment outcome of each report. Recently, there have been significant improvements in the radiotherapeutic and surgical management. High radiation dose levels, long-term androgen deprivation therapy, and the combination of brachytherapy may contribute to the improvement of radiation-based treatment. Although some patients can be cured by standard surgical approach, extended lymph node dissection and multimodal treatment with radiation and chemohormonal therapy may improve surgical outcome. This review focuses on the recent treatment strategy for high-risk localized prostate cancer.

PubMed

De novo renal cell carcinoma in an allograft kidney treated with nephron-sparing surgery: a case report.

Kazuyuki Numakura, Shigeru Satoh, Norihiko Tsuchiya, Mitsuru Saito, Taketoshi Nara, Mingguo Huang, Hiroshi Tsuruta, Susumu Akihama, Takamitsu Inoue, Shintaro Narita, Tomonori Habuchi

Progress in transplantation (Aliso Viejo, Calif.)   24 ( 4 ) 328 - 31   2014年12月

研究論文（学術雑誌）  

The development of primary malignant tumors is a distressing complication of organ transplant. However, the emergence of de novo renal cell carcinoma from a kidney allograft is rare. A 60-year-old man underwent living kidney transplant from a spousal donor. Six years after the transplant surgery, computed tomographic evaluation confirmed the presence of a 2.8-cm-diameter solid mass in the lower pole of the allograft. Partial allograft nephrectomy was performed, and the margin surrounding the normal parenchyma was resected. The serum level of creatinine did not decrease. Here, we report a case of renal cell carcinoma in an allograft kidney that was successfully treated with nephron-sparing surgery.

DOI PubMed

Progress in cancer diagnosis and therapy using new imaging technologies

Tomonori Habuchi

Drug Delivery System   29 ( 4 ) 271   2014年12月

研究論文（学術雑誌）  

DOI

Reliability of laparoscopic skills assessment on video: 8-year results of the endoscopic surgical skill qualification system in Japan.

Tadashi Matsuda, Hiroomi Kanayama, Yoshinari Ono, Akihiro Kawauchi, Hiroaki Mizoguchi, Ken Nakagawa, Masatsugu Iwamura, Masanobu Shigeta, Tomonori Habuchi, Toshiro Terachi

Journal of endourology   28 ( 11 ) 1374 - 8   2014年11月

研究論文（学術雑誌）  

BACKGROUND AND PURPOSE: The Japanese Urological Association and Japanese Society of Endourology established a urologic laparoscopic skills qualification system called the Endoscopic Surgical Skill Qualification (ESSQ) System in Urological Laparoscopy in 2004. The reliability of video assessments by referees was evaluated. MATERIALS AND METHODS: Videos of nephrectomies or adrenalectomies performed by the applicants were assessed by two referees selected among a pool of 42 referees. From 2004 to 2011, 1308 urologists applied and 60.2% were qualified after video assessments. The results of skills assessments on 1220 videos that had fixed points by two referees were analyzed statistically. RESULTS: The average number of videos that each referee assessed was 58.1, with a range of 16 to 87. The accordance rate of the results of the video assessment, pass or fail, by the two referees was 68.9%. The scores of the video assessment by each referee averaged 62.7±2.4 (standard deviation) (full score was set at 75 points and ≥60 points was needed to pass). There was a statistically significant difference in the average video assessment score among the referees (P<0.001), and five referees showed significantly higher or lower average scores than the other referees. The percentage qualification of the final decision made by the Referee Committee on the videos originally assessed by each referee showed no significant differences among the 42 referees. The accordance rate of the results from the video assessment by each referee with the final decision by the committee showed a statistically significant positive correlation with the number of videos assessed by each referee (r=0.404, P=0.0080). CONCLUSIONS: The ESSQ system showed moderate reliability for the video assessments by the referees. It was concluded that the video assessments by the referees were fair for all applicants, because the final qualification rates showed no significant differences among the referees.

DOI PubMed

Renal subcapsular fluid collection caused by penetration of a pancreatic pseudocyst.

Soki Kashima, Takamitsu Inoue, Mitsuru Chiba, Naoki Komine, Ryuichi Ito, Kazuyuki Numakura, Hiroshi Tsuruta, Mitsuru Saito, Susumu Akihama, Shintaro Narita, Norihiko Tsuchiya, Shigeru Satoh, Hirohide Onishi, Tomonori Habuchi

Urology   84 ( 5 ) e23-4 - e24   2014年11月

研究論文（学術雑誌）  

A 63-year-old man presented with left flank pain and spiked fever. Computed tomography revealed a pancreatic cyst and left renal subcapsular fluid collection that appeared to be connected to the cyst. High levels of amylase and lipase were observed in a test puncture of renal fluid collection. The cause of the fluid collection was diagnosed as penetration of the pancreatic pseudocyst. Endoscopic nasobiliary drainage was used to drain the pancreatic pseudocyst and renal subcapsular fluid collection. The present case demonstrated that renal subcapsular fluid collection may be caused by penetration of a pancreatic pseudocyst.

DOI PubMed

Serum tri- and tetra-antennary N-glycan is a potential predictive biomarker for castration-resistant prostate cancer.

Yusuke Ishibashi, Yuki Tobisawa, Shingo Hatakeyama, Tetsu Ohashi, Masakazu Tanaka, Shintaro Narita, Takuya Koie, Tomonori Habuchi, Shin-Ichiro Nishimura, Chikara Ohyama, Tohru Yoneyama

The Prostate   74 ( 15 ) 1521 - 9   2014年11月

研究論文（学術雑誌）  

BACKGROUND: The U.S. FDA has approved several novel systemic agents including abiraterone acetate and taxoid cabazitaxel for metastatic castration-resistant prostate cancer (CRPC) result in a complicated decision-making while selecting an appropriate treatment. Therefore, a predictive biomarker for CRPC would provide useful information to physicians. The aim of this study is to evaluate the diagnostic potential of serum N-glycan profiling in CRPC. METHODS: Serum N-glycomics was performed in 80 healthy volunteers and 286 benign prostatic hyperplasia, 258 early-stage PC, 46 PC with androgen deprivation therapy (ADT), and 68 CRPC patients using the glycoblotting method. A total of 36 types of N-glycan levels in each patient were analyzed using logistic regression analysis and receiver operating characteristic curves. We also examined the expression of N-glycan branching enzyme genes in PC cell lines using quantitative RT-PCR. RESULTS: We observed that tri- and tetra-antennary N-glycans were significantly higher in CRPC patients than in any other groups. The longitudinal follow-up of tri- and tetra- antennary N-glycan levels revealed that one PC with ADT patient showed an increase that was more than the cut-off level and two consecutive increases in tri- and tetra-antennary N-glycan levels 3 months apart; resulted in biochemical recurrence despite the castrate level of testosterone, and the patient was defined as CRPC. Expression of N-glycan branching enzyme genes were significantly upregulated in CRPC cell lines. CONCLUSIONS: These results suggest that the overexpression of tri- and tetra-antennary N-glycan may be associated with the castration-resistant status in PC and may be a potential predictive biomarker for CRPC.

DOI PubMed

Reassessment of prognostic heterogeneity of pT3 renal pelvic urothelial carcinoma: analysis in terms of proposed pT3 subclassification systems.

Jinsung Park, Tomonori Habuchi, Youichi Arai, Chikara Ohyama, Takamitsu Inoue, Shingo Hatakeyama, Seong Soo Jeon, Ghee Young Kwon, Cheol Kwak, Kyung Chul Moon, Choung-Soo Kim, Hanjong Ahn

The Journal of urology   192 ( 4 ) 1064 - 71   2014年10月

研究論文（学術雑誌）  

PURPOSE: We determined whether the 3 pT3 subclassification systems reported by the Asan, Cornell and Nagoya groups provide an accurate estimation of patient prognosis. We also determined which subclassification is most predictive of the heterogeneous oncological outcomes of pT3 renal pelvic urothelial carcinoma. MATERIALS AND METHODS: Using a Korea-Japan multi-institutional, retrospective database 250 pT3 renal pelvic urothelial carcinomas treated with radical nephroureterectomy were assigned to the 3 pT3 subcategories by tumor location and depth of parenchymal invasion after pathological reevaluation. Recurrence-free and cancer specific survival was assessed according to the 3 pT3 subclassifications. Predictive accuracy for survival in 4 models (baseline and each of the 3 pT3 subclassifications) was quantified and predictive accuracy increments for each model were compared. RESULTS: In the baseline multivariate Cox regression model nodal metastasis and high grade were significant for survival. On multivariate analysis including the pT3 subclassifications the 3 subclassifications remained significantly associated with survival rates. Of the 3 pT3 subclassification systems the Cornell subclassification had the highest predictive accuracy for discriminating the heterogeneous prognosis of pT3 renal pelvic urothelial carcinoma, followed by the Nagoya subclassification. Compared with the baseline model adding the Cornell subclassification significantly increased predictive accuracy for recurrence-free survival from 0.687 to 0.742 (p = 0.029) and for cancer specific survival from 0.713 to 0.758 (p = 0.047). CONCLUSIONS: The criteria of microscopic vs macroscopic parenchymal invasion and/or peripelvic fat invasion provide the most accurate differential classification of the prognostic heterogeneity of pT3 renal pelvic urothelial carcinoma. Further studies should be performed to determine the need to modify the current pT3 renal pelvic urothelial carcinoma staging system.

DOI PubMed

Antiemetic efficacy and safety of a combination of palonosetron, aprepitant, and dexamethasone in patients with testicular germ cell tumor receiving 5-day cisplatin-based combination chemotherapy.

Shota Hamada, Shiro Hinotsu, Koji Kawai, Shigeyuki Yamada, Shintaro Narita, Tomomi Kamba, Hiroyuki Nishiyama, Yoichi Arai, Tomonori Habuchi, Osamu Ogawa, Koji Kawakami

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer   22 ( 8 ) 2161 - 6   2014年08月

研究論文（学術雑誌）  

PURPOSE: This study aimed to determine the antiemetic efficacy and safety of a combination of palonosetron, aprepitant, and dexamethasone in patients with testicular germ cell tumor (TGCT) receiving 5-day cisplatin-based combination chemotherapy. METHODS: An open-label, single-arm, multicenter study was performed in patients with TGCT who were scheduled to receive 5-day cisplatin-based combination chemotherapy. The antiemetic therapy consisted of palonosetron 0.75 mg on day 1, aprepitant 125 mg on day 1 and 80 mg on days 2 to 5, and dexamethasone 9.9 mg on day 1 and 6.6 mg on days 2 to 8. The primary endpoint was complete response (CR) rate, which was defined as no vomiting and no rescue medication, in the overall period (0 to 216 h) in the first chemotherapy course. Incidence and severity of nausea were assessed based on the Common Terminology Criteria for Adverse Events (CTCAE) and a subjective rating scale completed by patients. RESULTS: Thirty patients were included in the analysis. CR was achieved in 90.0% of the patients in the first chemotherapy course, and high CR rates were also observed in the second and third courses (82.1 and 78.3%, respectively). The incidence of nausea peaked on days 4 to 6 in about 50% of the patients. The reported adverse drug reactions were hiccups (13.3%), anorexia (3.3%), and stomach pain (3.3%). None of these were unexpected and none were grade 3 or 4. CONCLUSIONS: The combination antiemetic therapy examined in this study was highly effective and well-tolerated in patients with TGCT receiving 5-day cisplatin-based combination chemotherapy.

DOI PubMed

Pharmacokinetic and CYP3A5 pharmacogenetic differences between once- and twice-daily tacrolimus from the first dosing day to 1 year after renal transplantation.

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

Pharmacogenomics   15 ( 11 ) 1495 - 506   2014年08月

研究論文（学術雑誌）  

UNLABELLED: Aim & patients & methods: This study investigated 24-h pharmacokinetic and CYP3A5 pharmacogenetic differences between once-daily tacrolimus (Tac-q.d.) versus twice-daily tacrolimus (Tac-b.i.d.) pretransplantation and at 1 month and 1 year post-transplantaion. RESULTS: The dose-adjusted trough level (Cmin) and area under the blood concentration-time curve from 0 to 24 h (AUC₀₋₂₄) increased twofold within 1 year post-transplantation with both formulations and the two genotypes. Good correlations were observed between the AUC₀₋₂₄ and Cmin for both formulations. However, the dose-adjusted Cmin, but not dose-adjusted AUC₀₋₂₄, was approximately 30% lower for Tac-q.d. than for Tac-b.i.d. Although the dose-adjusted Cmin was lower for Tac-q.d. than for Tac-b.i.d. in both genotypes, the dose-adjusted AUC₀₋₂₄ was approximately 25% lower for Tac-q.d. than for Tac-b.i.d. in CYP3A5 expressers, but not in nonexpressers during the study period. CONCLUSION: These results suggested that the approximately 30% lower Cmin for Tac-q.d. than for Tac-b.i.d. may have achieved the same AUC₀₋₂₄ with both formulations and may be associated with CYP3A5 pharmacogenomic differences, especially in CYP3A5 expressers, between Tac-b.i.d. and Tac-q.d.

DOI PubMed

Successful mammalian target of rapamycin inhibitor maintenance therapy following induction chemotherapy with gemcitabine and doxorubicin for metastatic sarcomatoid renal cell carcinoma.

Kazuyuki Numakura, Norihiko Tsuchiya, Susumu Akihama, Takamitsu Inoue, Shintaro Narita, Mingguo Huang, Shigeru Satoh, Tomonori Habuchi

Oncology letters   8 ( 1 ) 464 - 466   2014年07月

研究論文（学術雑誌）  

This study presents a case of metastatic sarcomatoid renal cell carcinoma (RCC) treated with systemic chemotherapy followed by mammalian target of rapamycin inhibitor maintenance therapy. A 63-year-old male presented with lumbago, and lumbar vertebral tumors were detected by magnetic resonance imaging. Subsequent computed tomography (CT) revealed a right renal tumor and CT-guided biopsy of the right renal and left sacroiliac tumors determined pure sarcomatoid carcinoma without a clear cell component. Two cycles of combination chemotherapy comprising of gemcitabine (1,500 mg/m2 on day one) and doxorubicin (50 mg/m2 on day one) resulted in a 20% reduction in the longest diameter of the right renal tumor. However, due to grade 3 neutropenia, the chemotherapy was discontinued and temsirolimus (25 mg once weekly), which binds to the cytoplasmic protein, FKBP-12, and inhibits mTOR, was administered. Stable disease was maintained for 19 months with temsirolimus and no major adverse events, with the exception of grade 2 nausea, were observed. The patient succumbed to their disease at 30 months following the initiation of treatment. These results suggested that systemic chemotherapy followed by temsirolimus maintenance is a feasible treatment option for patients with metastatic sarcomatoid RCC.

DOI PubMed

Are pathological and oncological outcomes of elderly men treated with radical prostatectomy worse than those of younger men? Matched-pair analysis between patients aged <70 and ≥70 years.

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   44 ( 6 ) 587 - 92   2014年06月

研究論文（学術雑誌）  

OBJECTIVE: To compare oncological outcomes of patients aged ≥70 years treated with radical prostatectomy with those of a clinically matched younger cohort. METHODS: Data from 1268 patients undergoing radical prostatectomy between 2000 and 2009 were retrospectively reviewed. Patients were classified according to age (<70 or ≥70 years) at the time of prostatectomy. After matching pre-operative factors (i.e. prostate specific antigen, positive biopsy cores, Gleason score, clinical stage and D'Amico risk group), 333 patients were chosen from each group. RESULTS: The percentage of pathological stage ≥T3 in those of age <70 and ≥70 years was 30.3 and 33.0%, respectively (P = 0.51). The percentage of pathological Gleason score ≤6, 7 and ≥8 was not significantly different between the two age groups (P = 0.08). The percentage of organ-confined disease in those of age <70 and ≥70 years was 69.4 and 67.0%, respectively (P = 0.56). With a median follow-up of 50 months, 5-year prostate specific antigen recurrence-free survival in those of age <70 and ≥70 years was 83.4 and 80.1%, respectively (log rank, P = 0.199). Five-year cancer-specific survival in those of age <70 and ≥70 years was 100 and 99.4%, respectively (log rank, P = 0.317). Five-year overall survival in those of age <70 and ≥70 years was 98.4 and 96.4%, respectively (log rank, P = 0.228). CONCLUSIONS: Pathological and oncological outcomes in elderly patients (age ≥70 years) treated with radical prostatectomy were not significantly different from those of younger patients (age <70 years). This information will help refine the indications for definitive treatment for localized prostate cancer in elderly men.

DOI PubMed

Measurement of aberrant glycosylation of prostate specific antigen can improve specificity in early detection of prostate cancer.

Tohru Yoneyama, Chikara Ohyama, Shingo Hatakeyama, Shintaro Narita, Tomonori Habuchi, Takuya Koie, Kazuyuki Mori, Kazuya I P J Hidari, Maho Yamaguchi, Takashi Suzuki, Yuki Tobisawa

Biochemical and biophysical research communications   448 ( 4 ) 390 - 6   2014年06月

研究論文（学術雑誌）  

INTRODUCTION: We previously identified prostate cancer (PCa)-associated aberrant glycosylation of PSA, where α2,3-linked sialylation is an additional terminal N-glycan on free PSA (S2,3PSA). We then developed a new assay system measuring S2,3PSA using a magnetic microbead-based immunoassay. We compared the diagnostic accuracy of conventional PSA and percent-free PSA (%fPSA) tests. METHODS: We used MagPlex beads to measure serum S2,3PSA levels using anti-human fPSA monoclonal antibody (8A6) for capture and anti-α2,3-linked sialic acid monoclonal antibody (HYB4) for detection. We determined the cutoff values in a training test and measured serum S2,3PSA levels in 314 patients who underwent biopsy, including 138 PCa and 176 non-PCa patients with PSA of <10.0 ng/ml. Serum S2,3PSA levels were presented as mean fluorescence intensity (MFI). Receiver operating characteristic curves were used to evaluate the diagnostic accuracy of total PSA, %fPSA, and S2,3PSA. RESULTS: We determined an MFI cutoff value of 1130 with a sensitivity of 95.0% and specificity of 72.0% for the diagnosis of PCa in the training test. In the validation study, the area under the curve for the detection of PCa with S2,3PSA was 0.84, which was significantly higher than that with PSA or %fPSA. CONCLUSIONS: Although the present study is small and preliminary, these results suggest that the measurement of serum S2,3PSA using a magnetic microbead-based immunoassay may improve the accuracy of early detection of PCa and reduce unnecessary prostate biopsy.

DOI PubMed

Successful local control of recurrent penile cancer treated with a combination of systemic chemotherapy, irradiation, and mohs' paste: a case report.

Naoki Komine, Shintaro Narita, Teruaki Kigure, Hiroshi Tsuruta, Kazuyuki Numakura, Susumu Akihama, Mitsuru Saito, Takamitsu Inoue, Norihiko Tsuchiya, Shigeru Satoh, Hiroshi Nanjo, Tomonori Habuchi

Case reports in oncology   7 ( 2 ) 522 - 7   2014年05月

研究論文（学術雑誌）  

Penile squamous cell carcinoma (pSCC) is a rare disease, making it difficult to establish a standard of care, particularly in the advanced stage. We report a case of pSCC with advanced lymph node metastasis treated with multimodal therapy consisting of combination chemotherapy, irradiation, and chemosurgery using Mohs' zinc chloride-containing paste. An 80-year-old male with a past history of local treatment for penile cancer presented with a large painful inguinal mass with an ulcer and exudates. The patient underwent multimodal treatment with combination chemotherapy, irradiation, and Mohs' paste. The combination chemotherapy consisted of cisplatin, 5-fluorouracil, and docetaxel. The patient received 50-Gy external-beam radiation therapy to the left inguinal region along with daily local treatment with Mohs' paste. After the initiation of treatment, the pain and bleeding in the inguinal region considerably ameliorated. The wound became dry and flattened 20 days after the initiation of chemotherapy. A CT scan showed that the tumor had decreased 70% in diameter 1 month after the initiation of chemotherapy. After the first course of chemotherapy, the patient and his family decided not to continue treatment because of socio-economic reasons. The patient underwent no additional treatments; nevertheless, he had no local progression of the inguinal tumors for 8 months. We report a case of successful local control of recurrent inguinal pSCC treated with multimodal therapy. Combination treatment with taxane-based chemotherapy, external-beam radiation therapy, and Mohs' paste is an option for the management of recurrent pSCC.

DOI PubMed

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

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.

DOI PubMed

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.

DOI PubMed

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.

DOI PubMed

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

[Primary retroperitoneal carcinoid tumor associated with multiple endcrine neoplasia (men) type 1: a case report].

Syuji Chiba, Kazuyuki Numakura, Kiyofumi Satoyoshi, Mitsuru Saito, Yohei Horikawa, Koichiro Takayama, Taketoshi Nara, Sohei Kanda, Yoshiko Miura, Shinya Maita, Hiroshi Tsuruta, Takashi Obara, Teruaki Kumazawa, Shintaro Narita, Norihiko Tsuchiya, Shigeru Satoh, Tomonori Habuchi

Nihon Hinyokika Gakkai zasshi. The japanese journal of urology   102 ( 6 ) 735 - 9   2011年11月

研究論文（学術雑誌）  

We report an extremely rare case of a 69-year-old man having a retroperitoneal carcinoid tumor associated with multiple endocrine neoplasia (MEN) type 1. The patient whose son and daughter were previously diagnosed with MEN type 1 was admitted to the Department of Endocrinology at our hospital for evaluation of this disorder. Computed tomography (CT) and ultrasonography revealed a parathyroid and retroperitoneal tumor (43 mm x 34 mm). The patient did not consent to surgical management of the tumor; however three years later, a follow-up CT revealed tumor enlargement (55 mm x 50 mm). We were unable to rule out a malignancy, and subsequently resected the tumor. A pathological diagnosis of retroperitoneal carcinoid was made. No local recurrence or metastasis have been observed for 21 months.

DOI PubMed

Overexpression of Fn14 promotes androgen-independent prostate cancer progression through MMP-9 and correlates with poor treatment outcome.

Mingguo Huang, Shintaro Narita, Norihiko Tsuchiya, Zhiyong Ma, Kazuyuki Numakura, Takashi Obara, Hiroshi Tsuruta, Mitsuru Saito, Takamitsu Inoue, Yohei Horikawa, Shigeru Satoh, Tomonori Habuchi

Carcinogenesis   32 ( 11 ) 1589 - 96   2011年11月

研究論文（学術雑誌）  

Fibroblast growth factor-inducible 14 (Fn14), a transmembrane receptor binding to the multifunctional cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK), is known to modulate many cellular activities including cancer progression. Here, we demonstrated the significant role of Fn14 in invasion, migration and proliferation of androgen-independent prostate cancer (AIPC) cells. Fn14 and its ligand TWEAK were highly expressed in two AIPC cell lines, DU 145 and PC-3, whereas expression was weak in androgen-sensitive LNCaP cells. Fn14 knockdown using small-interfering RNAs attenuated migration, invasion and proliferation and enhanced apoptosis in the AIPC cell lines. Both forced overexpression of Fn14 by stable Fn14 complementary DNA transfection to PC-3 cells (PC-3/Fn14) and ligand activation by recombinant TWEAK in PC-3 cells enhanced invasion. Fn14 was shown to modulate expression of matrix metalloproteinase (MMP)-9, and MMP-9 mediated the invasive potential influenced by Fn14 in PC-3 cells. In vivo, subcutaneous xenografts of PC-3/Fn14 grew significantly faster than xenograft of PC-3/Mock, and the invasive capacity in PC-3/Fn14 was found to be higher than that of PC-3/Mock as evaluated in an invasion model of the diaphragm. Furthermore, the messenger RNA expressions of MMP-9 in PC-3/Fn14 xenografts were significantly higher than those in PC-3/Mock xenografts. Clinically, high expression of Fn14 was significantly associated with higher prostate-specific antigen recurrence rate in patients who underwent radical prostatectomy. In conclusion, the overexpression of Fn14 may contribute to multiple malignant cellular phenotypes associated with prostate cancer (PCa) progression, in part via MMP-9. TWEAK-Fn14 signaling may be a novel therapeutic target of PCa.

DOI PubMed

The clinical research office of the endourological society audit committee.

Glenn M Preminger, Peter Alken, Tomonori Habuchi, Hessel Wijkstra, Andreas Skolarikos, Chan-Jun Yin

Journal of endourology   25 ( 11 ) 1811 - 3   2011年11月

研究論文（学術雑誌）  

The Clinical Research Office of the Endourological Society (CROES) conducts large-scale, international, multicenter clinical trials in the field of endourology. One of the major challenges that these trials pose is to ensure that data collected remotely and online within a very short time frame are valid and reliable. This editorial describes a formal process for auditing the data by the CROES Audit Committee. The audit process presented is largely based on an automatic scoring system, which takes into consideration several parameters to determine the quality of the data and of the participating institution. This process is dynamic in nature and offers live monitoring of both patient data and study centers.

DOI PubMed

A case study of metastatic Xp11.2 translocation renal cell carcinoma effectively treated with sunitinib.

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

International journal of clinical oncology   16 ( 5 ) 577 - 80   2011年10月

研究論文（学術雑誌）  

We report a case of Xp11.2 translocation renal cell carcinoma (RCC) whose lung metastases were effectively treated with sunitinib. A 43-year-old woman presenting with upper abdominal pain was diagnosed with a left renal tumor. Laparoscopic left radical nephrectomy was performed. Histopathological examination of the surgical specimen revealed a clear-cell carcinoma of the left kidney. Two years later, multiple lung metastases were detected and the patient was treated daily with 50 mg sunitinib. A computed tomography scan performed after 2 cycles of sunitinib treatment revealed partial regression of these metastases. The partial regression has been maintained for >3 years. In retrospective evaluation of the primary RCC, tumor cells showed strong nuclear staining for transcription factor E3 (TFE3) protein and TFE3 split-fluorescence in-situ hybridization revealed translocation involving the TFE3 gene. These findings strongly support diagnosis of Xp11.2 translocation RCC.

DOI PubMed

Combination therapy consisting of gemcitabine, carboplatin, and docetaxel as an active treatment for advanced urothelial carcinoma.

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

International journal of clinical oncology   16 ( 5 ) 533 - 8   2011年10月

研究論文（学術雑誌）  

BACKGROUND: To evaluate the efficacy and toxicity of a combination chemotherapy consisting of gemcitabine, carboplatin, and docetaxel (GCD) in patients with advanced urothelial carcinoma (UC) as a phase II trial. MATERIALS AND METHODS: Patients with metastatic or locally advanced unresectable UC were eligible for this trial. All enrolled patients were considered to be "unfit" for cisplatin-based chemotherapy, or to have methotrexate, vinblastine, doxorubicin, cisplatin (MVAC)-refractory UC. The chemotherapy regimen consisted of gemcitabine 1000 mg/m(2) on days 1 and 8, and carboplatin (with a target area under the curve of 5) and docetaxel 70 mg/m(2) on day 1; this was repeated every 21 days. RESULTS: Thirty-five patients were enrolled, with a median age of 68 years. A total of 89 cycles were administered (median, 2 cycles). Major toxicities were Grade 3/4 neutropenia in 28 (80.0%) patients and Grade 3/4 thrombocytopenia in 18 (51.5%). An objective response rate (ORR) was 11 of 21 patients (52.4%), including a complete response in 1 (4.8%). The median overall survival (OS) was 13.1 months (1-year survival rate, 60%) and the median progression-free survival (PFS) was 5.0 months. Among 16 patients who had previously received MVAC, the ORR, the median PFS, the median OS and 1-year survival rate was 56.3%, 5.0 months, 12.6 months and 54%, respectively. CONCLUSIONS: GCD chemotherapy is active and well tolerated as a first- or second-line therapy for patients with advanced UC. Response rate, duration and survival did not differ between those with and without a history of MVAC treatment.

DOI PubMed

Two survivin polymorphisms are cooperatively associated with bladder cancer susceptibility.

Naoko Kawata, Norihiko Tsuchiya, Yohei Horikawa, Takamitsu Inoue, Hiroshi Tsuruta, Shinya Maita, Shigeru Satoh, Yoko Mitobe, Shintaro Narita, Tomonori Habuchi

International journal of cancer   129 ( 8 ) 1872 - 80   2011年10月

研究論文（学術雑誌）  

Abnormal survivin expression has been reported to be involved in many types of cancer. A single-nucleotide polymorphism (SNP), C-31G, located in the promoter region of survivin reportedly may alter the mRNA level, while the significance of the nonsynonymous SNP A9194G in exon 4 has not yet been clarified. Here, the association between the two survivin SNPs and bladder cancer susceptibility and progression was investigated in 235 patients with bladder cancer and 346 healthy controls. Regarding the C-31G SNP, subjects with the CC genotype had a significantly higher risk of bladder cancer compared to those with the GG + CG genotype [odds ratio (OR) = 1.85, p = 0.001]. Regarding the A9194G SNP, the presence of the G allele was associated with a significantly reduced risk with a gene dosage effect (OR = 0.69, p = 0.002). Using the C-A haplotype as a reference, the G-G haplotype was associated with a significantly lower risk (OR = 0.11, p = 0.00006), indicating the cooperative effect of the two SNPs. Immunohistological evaluation of surgical specimens showed that cancer cells of the C-31G CC genotype had significantly higher nuclear survivin expression than those of the C-31G GG + CG genotype. With reverse transcriptase-polymerase chain reaction analysis, a significantly higher survivin mRNA expression level was observed in surgical specimens with an increase in the number of the C-31G C allele (p = 0.016). These results indicate that the two SNPs have a significant and cooperative influence on bladder cancer susceptibility.

DOI PubMed

Correlations between pretransplant dialysis duration, bladder capacity, and prevalence of vesicoureteral reflux to the graft.

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

Transplantation   92 ( 3 ) 311 - 5   2011年08月

研究論文（学術雑誌）  

BACKGROUND: Urinary bladder capacity is reduced in patients undergoing long-term dialysis, which may increase the risk of vesicoureteral reflux (VUR) to a transplanted kidney. This study investigated the correlations between dialysis duration, pretransplant and posttransplant bladder capacity, and prevalence of VUR to the graft. METHODS: Voiding cystography was performed in 101 adult renal transplant recipients without neurogenic disorders immediately before and 1 year after transplantation to evaluate bladder capacity and VUR. Nonstented extravesical antireflux ureteroneocystostomy was performed in all patients. RESULTS: The median dialysis duration and pretransplant bladder capacity were 32 months (range 1-426 months) and 120 mL (range 15-450 mL), and 21 patients (20.8%) underwent dialysis for more than 120 months, and 30 patients (29.7%) had a pretransplant bladder capacity of less than 80 mL. Dialysis duration was correlated with pretransplant bladder capacity (R=0.466, P<0.001). Bladder capacity expanded more than 6-fold from pretransplantation to posttransplantation, and all recipients had a bladder capacity greater than 150 mL at 1 year posttransplantation. Thirty patients had VUR to the graft. Dialysis duration longer than 60 months (P=0.021) and pretransplant bladder capacity of less than 130 mL (P=0.024) were associated with VUR. VUR was associated with lower graft function. CONCLUSIONS: Although bladder capacity decreased because of long-term dialysis, it exceeded 150 mL at 1 year posttransplantation. A small bladder can be used in renal transplantation, but it may increase the risk of VUR.

DOI PubMed

[Granulocyte colony stimulating factor-producing spindle cell renal cell carcinoma successfully treated by chemotherapy consisting of gemcitabine and doxorubicin].

Souhei Kanda, Takamitsu Inoue, Hiroshi Tsuruta, Shuji Chiba, Takashi Obara, Mitsuru Saito, Teruaki Kumazawa, Norihiko Tsuchiya, Shigeru Satoh, Tomonori Habuchi

Hinyokika kiyo. Acta urologica Japonica   57 ( 7 ) 385 - 9   2011年07月

研究論文（学術雑誌）  

A 62-year-old female patient with a chief complaint of back pain and continuous fever was referred to our hospital. A computed tomography scan revealed a left renal tumor (76×54×67 mm) without a metastatic lesion. Laboratory examination showed an elevated white blood cell count of 23,200/μl. The patient underwent left radical nephrectomy and the histopathological diagnosis was spindle cell renal cell carcinoma (G3-4, pT4, pN2) with positive staining for granulocyte colony-stimulating factor. One month later, a computed tomography scan showed an enlarged locally recurrent tumor mass. Three cycles of combination chemotherapy consisting of gemcitabine (1,500 mg/m2, day 1) and doxorubicine (50 mg/m2, day 1) resulted in an 83% reduction of the tumor mass. A follow-up computed tomography scan after 2 weeks revealed rapid regrowth of the recurrent tumor. The patient died 199 days after the surgery. Combination chemotherapy consisting of gemcitabine and doxorubicin is a treatment option for patients with spindle cell renal cell carcinoma.

PubMed

Impact of the CYP3A4*1G polymorphism and its combination with CYP3A5 genotypes on tacrolimus pharmacokinetics in renal transplant patients.

Masatomo Miura, Shigeru Satoh, Hideaki Kagaya, Mitsuru Saito, Kazuyuki Numakura, Norihiko Tsuchiya, Tomonori Habuchi

Pharmacogenomics   12 ( 7 ) 977 - 84   2011年07月

研究論文（学術雑誌）  

AIM: Tacrolimus is a substrate of CYP3A4 and CYP3A5. The present study investigated the impact of the CYP3A4*1/*1G polymorphism compared with CYP3A5 genotypes on the dose-adjusted pharmacokinetics of tacrolimus. The effects of the polymorphism on the variability in tacrolimus pharmacokinetics among patients with the CYP3A5*1 allele (CYP3A5 expresser) and among those with CYP3A5*3/*3 genotype (nonexpresser) were also studied. MATERIALS & METHODS: A total of 136 renal allograft recipients were given repeated doses of tacrolimus every 12 h. On day 28 after the renal transplantation, blood tacrolimus concentrations were measured, and dose-adjusted pharmacokinetics were determined and compared with the corresponding genotype. RESULTS: The dose-adjusted AUC₀₋₁₂ and C₀ of tacrolimus were significantly lower in patients with the CYP3A4*1G allele and CYP3A5 expressers than those with the CYP3A4*1/*1 genotype and nonexpressers, respectively. In a multiple regression analysis, the dose-adjusted AUC₀₋₁₂ and C₀ values were associated with CYP3A4*1/*1 (p = 0.018 and 0.040, respectively) and CYP3A5*3/*3 (p < 0.001 each). The standardized regression coefficient for the AUC₀₋₁₂ of tacrolimus was approximately twofold less for CYP3A4*1/*1 than CYP3A5*3/*3. The lowest dose-adjusted AUC₀₋₁₂ was found in CYP3A5 expressers with the CYP3A4*1G allele. CONCLUSION: The CYP3A4*1/*1G polymorphism was associated with the pharmacokinetics of tacrolimus, however, its contribution to dose-adjusted pharmacokinetics was approximately twofold less than that of the CYP3A5*1/*3 polymorphism. Although its effect on CYP3A4 activity is not clear, CYP3A4*1/*1G may be a candidate for a polymorphism affecting the interindividual variability in tacrolimus pharmacokinetics among CYP3A5 expressers.

DOI PubMed

Seven prostate cancer susceptibility loci identified by a multi-stage genome-wide association study.

Zsofia Kote-Jarai, Ali Amin Al Olama, Graham G Giles, Gianluca Severi, Johanna Schleutker, Maren Weischer, Daniele Campa, Elio Riboli, Tim Key, Henrik Gronberg, David J Hunter, Peter Kraft, Michael J Thun, Sue Ingles, Stephen Chanock, Demetrius Albanes, Richard B Hayes, David E Neal, Freddie C Hamdy, Jenny L Donovan, Paul Pharoah, Fredrick Schumacher, Brian E Henderson, Janet L Stanford, Elaine A Ostrander, Karina Dalsgaard Sorensen, Thilo Dörk, Gerald Andriole, Joanne L Dickinson, Cezary Cybulski, Jan Lubinski, Amanda Spurdle, Judith A Clements, Suzanne Chambers, Joanne Aitken, R A Frank Gardiner, Stephen N Thibodeau, Dan Schaid, Esther M John, Christiane Maier, Walther Vogel, Kathleen A Cooney, Jong Y Park, Lisa Cannon-Albright, Hermann Brenner, Tomonori Habuchi, Hong-Wei Zhang, Yong-Jie Lu, Radka Kaneva, Ken Muir, Sara Benlloch, Daniel A Leongamornlert, Edward J Saunders, Malgorzata Tymrakiewicz, Nadiya Mahmud, Michelle Guy, 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 Christmas, Chris Ogden, Colin S Cooper, Aritaya Lophatonanon, Melissa C Southey, John L Hopper, Dallas R English, Tiina Wahlfors, Teuvo L J Tammela, Peter Klarskov, Børge G Nordestgaard, M Andreas Røder, Anne Tybjærg-Hansen, Stig E Bojesen, Ruth Travis, Federico Canzian, Rudolf Kaaks, Fredrik Wiklund, Markus Aly, Sara Lindstrom, W Ryan Diver, Susan Gapstur, Mariana C Stern, Roman Corral, Jarmo Virtamo, Angela Cox, Christopher A Haiman, Loic Le Marchand, Liesel Fitzgerald, Suzanne Kolb, Erika M Kwon, Danielle M Karyadi, Torben Falck Orntoft, Michael Borre, Andreas Meyer, Jürgen Serth, Meredith Yeager, Sonja I Berndt, James R Marthick, Briony Patterson, Dominika Wokolorczyk, Jyotsna Batra, Felicity Lose, Shannon K McDonnell, Amit D Joshi, Ahva Shahabi, Antje E Rinckleb, Ana Ray, Thomas A Sellers, Hui-Yi Lin, Robert A Stephenson, James Farnham, Heiko Muller, Dietrich Rothenbacher, Norihiko Tsuchiya, Shintaro Narita, Guang-Wen Cao, Chavdar Slavov, Vanio Mitev, Douglas F Easton, Rosalind A Eeles

Nature genetics   43 ( 8 ) 785 - 91   2011年07月

研究論文（学術雑誌）  

Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. We conducted a multi-stage genome-wide association study for PrCa and previously reported the results of the first two stages, which identified 16 PrCa susceptibility loci. We report here the results of stage 3, in which we evaluated 1,536 SNPs in 4,574 individuals with prostate cancer (cases) and 4,164 controls. We followed up ten new association signals through genotyping in 51,311 samples in 30 studies from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. In addition to replicating previously reported loci, we identified seven new prostate cancer susceptibility loci on chromosomes 2p11, 3q23, 3q26, 5p12, 6p21, 12q13 and Xq12 (P = 4.0 × 10(-8) to P = 2.7 × 10(-24)). We also identified a SNP in TERT more strongly associated with PrCa than that previously reported. More than 40 PrCa susceptibility loci, explaining ∼25% of the familial risk in this disease, have now been identified.

DOI PubMed

[Genetic polymorphisms in prostate cancer].

Norihiko Tsuchiya, Tomonori Habuchi

Nihon rinsho. Japanese journal of clinical medicine   69 Suppl 5   79 - 86   2011年06月

研究論文（学術雑誌）  

PubMed

A novel strategy for evasion of NK cell immunity by tumours expressing core2 O-glycans.

Shigeru Tsuboi, Mihoko Sutoh, Shingo Hatakeyama, Nobuyoshi Hiraoka, Tomonori Habuchi, Yohei Horikawa, Yasuhiro Hashimoto, Takahiro Yoneyama, Kazuyuki Mori, Takuya Koie, Toshiya Nakamura, Hisao Saitoh, Kanemitsu Yamaya, Tomihisa Funyu, Minoru Fukuda, Chikara Ohyama

The EMBO journal   30 ( 15 ) 3173 - 85   2011年06月

研究論文（学術雑誌）  

The O-glycan branching enzyme, core2 β-1,6-N-acetylglucosaminyltransferase (C2GnT), forms O-glycans containing an N-acetylglucosamine branch connected to N-acetylgalactosamine (core2 O-glycans) on cell-surface glycoproteins. Here, we report that upregulation of C2GnT is closely correlated with progression of bladder tumours and that C2GnT-expressing bladder tumours use a novel strategy to increase their metastatic potential. Our results showed that C2GnT-expressing bladder tumour cells are highly metastatic due to their high ability to evade NK cell immunity and revealed the molecular mechanism of the immune evasion by C2GnT expression. Engagement of an NK-activating receptor, NKG2D, by its tumour-associated ligand, Major histocompatibility complex class I-related chain A (MICA), is critical to tumour rejection by NK cells. In C2GnT-expressing bladder tumour cells, poly-N-acetyllactosamine was present on core2 O-glycans on MICA, and galectin-3 bound the NKG2D-binding site of MICA through this poly-N-acetyllactosamine. Galectin-3 reduced the affinity of MICA for NKG2D, thereby severely impairing NK cell activation and silencing the NK cells. This new mode of NK cell silencing promotes immune evasion of C2GnT-expressing bladder tumour cells, resulting in tumour metastasis.

DOI PubMed

Monitoring of mycophenolic acid predose concentrations in the maintenance phase more than one year after renal transplantation.

Masatomo Miura, Takenori Niioka, Shoutaro Kato, Hideaki Kagaya, Mitsuru Saito, Tomonori Habuchi, Shigeru Satoh

Therapeutic drug monitoring   33 ( 3 ) 295 - 302   2011年06月

研究論文（学術雑誌）  

BACKGROUND: Routine therapeutic drug monitoring of mycophenolic acid (MPA) is generally performed using the area under the concentration-time curve from 0 to 12 hours (AUC0-12) with recommended values between 30 and 60 μg·h/mL. OBJECTIVE: The aim of this study was to examine whether the monitoring of the MPA predose concentration (C0) in patients who are stable for >1 year after renal transplantation was practical and to determine factors that cause MPA C0 variability among patients. METHODS: Eighty-six Japanese patients who had undergone renal transplantation and were taking tacrolimus and who had their MPA C0 analyzed >6 times by high-performance liquid chromatography for >1 year posttransplantation were enrolled. RESULTS: Recipients with MPA AUC0-12 levels<30 μg·h/mL on day 28 and 1 year after transplantation had an MPA C0 of <2.0 μg/mL, with a sensitivity of 90.9% and a specificity of 70.7%. There was no significant difference in the mean dose-adjusted MPA C0>1 year after transplantation between subjects with either the UGT (1A1, 1A9, and 2B7) or drug transporter (SLCO1B3, ABCC2, and ABCG2) genotypes. However, in a multiple regression analysis, the dose-adjusted mean MPA C0>1 year after transplantation was significantly associated with age (P=0.0035), creatinine clearance (P=0.0001), and the dose-adjusted MPA AUC0-12 at 1 year (P=0.0147). CONCLUSIONS: To keep the MPA AUC0-12>30 μg·h/mL, the plasma threshold for maintaining the MPA C0 with tacrolimus should be set >2.0 μg/mL as determined by high-performance liquid chromatography. For patients who are stable for >1 year after transplantation, continued monitoring of the MPA C0 using the same samples used to monitor the tacrolimus C0 and the additional assessment of the MPA AUC0-12 at the 1-year time point seem to be a viable option. If a change of the mycophenolate mofetil dose seems necessary based on the routine MPA C0 information, the determination of MPA AUC0-12 using a limited sampling strategy is recommended.

DOI PubMed

Role of lymph node dissection in managing urologic cancers.

Tomonori Habuchi

International journal of clinical oncology   16 ( 3 ) 169 - 169   2011年06月

研究論文（学術雑誌）  

DOI PubMed

A case of intratesticular endometrioid papillary cystadenocarcinoma.

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

Japanese journal of clinical oncology   41 ( 5 ) 674 - 6   2011年05月

研究論文（学術雑誌）  

We report a case of intratesticular endometrioid papillary cystadenocarcinoma. A 73-year-old man was admitted for a painless right scrotal swelling. Ultrasonography and computed tomography revealed a large cystic mass in the right testis. Right scrotum puncture revealed xanthochromic fluid with negative cytology. Three months later, follow-up computed tomography showed enlargement of the cystic mass. Right high orchiectomy was performed because a testicular malignancy was suspected. The pathological diagnosis was endometrioid papillary cystadenocarcinoma, and the cells were strongly positive for the estrogen and progesterone receptors. Testicular neoplasms resembling common ovarian-type epithelial tumors are very rare. This is the first report of endometrioid papillary cystadenocarcinoma of the testis.

DOI PubMed

Pharmacogenetic determinants for interindividual difference of tacrolimus pharmacokinetics 1 year after renal transplantation

M. Miura, T. Niioka, H. Kagaya, M. Saito, M. Hayakari, T. Habuchi, S. Satoh

Journal of Clinical Pharmacy and Therapeutics   36 ( 2 ) 208 - 216   2011年04月

研究論文（学術雑誌）  

What is known and objective: Tacrolimus, a widely used immunosuppressive agent in organ transplantation, has a narrow therapeutic window. It has been suggested that its interaction with lansoprazole could be dependent on polymorphisms of CYP3A5 and CYP2C19. The objective of this study was to investigate how, 1 year after renal transplantation, CYP3A5 and CYP2C19 polymorphisms, biochemical parameters and coadministration with lansoprazole, influenced tacrolimus pharmacokinetics. Methods: The pharmacokinetics of tacrolimus was studied 1 year after renal transplantation, in 75 recipients who were all receiving continuation treatment with 12-hourly oral tacrolimus, and 30 mg lansoprazole daily (Group 1; n = 20) or, 10 mg rabeprazole daily or no proton pump inhibitor (Group 2; n = 55). Results: There were no significant differences in the dose-adjusted area under the plasma concentration-time curve (AUC0-12) and maximum plasma concentration (Cmax) of tacrolimus between CYP2C19 genotype groups, but there were significant differences between CYP3A5 genotypes groups (*1/*1 +*1/*3 vs.*3/*3 = 45·2 ± 20·0 vs. 71·0 ± 34·1 ng·h/mL/mg, P < 0·0001 and 6·3 ± 2·6 vs. 9·3 ± 7·0 ng/mL/mg, P = 0·0017, respectively) and between co-administration with and without lansoprazole (74·5 ± 34·0 vs. 52·4 ± 27·4 ng·h/mL/mg, P = 0·0054 and 10·9 ± 8·8 vs. 6·7 ± 3·0 ng/mL/mg, P = 0·0024, respectively). In a multiple regression analysis, the dose-adjusted AUC 0-12 and Cmax of tacrolimus were associated with CYP3A5*3/*3 and co-administration with lansoprazole. What is new and conclusion: CYP2C19 does not seem to contribute to the interaction between tacrolimus and lansoprazole. The long-term combination of tacrolimus and lansoprazole requires careful monitoring of patients with the CYP3A5*3/*3 genotype. © 2010 The Authors. JCPT © 2010 Blackwell Publishing Ltd.

DOI

A case of ureteral malignant lymphoma diagnosed by laparoscopic needle biopsy.

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

Japanese journal of clinical oncology   41 ( 3 ) 440 - 2   2011年03月

研究論文（学術雑誌）  

A pathological diagnosis of a lesion in the ureteral wall is often attended with a difficulty. We report a case of a 54-year-old man who presented a thickening of the ureteral wall and diffuse swelling of paraaortic lymph nodes diagnosed as a non-Hodgkin lymphoma by a laparoscopic needle biopsy. This is a safe and useful technique by which target tissues can be surely obtained.

DOI PubMed

Factors increasing quantitative interstitial fibrosis from 0 hr to 1 year in living kidney transplant patients receiving tacrolimus.

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

Transplantation   91 ( 1 ) 78 - 85   2011年01月

研究論文（学術雑誌）  

BACKGROUND: This study investigated the increase in interstitial fibrosis (IF) from 0 hr to 1 month and 1 year posttransplantation in biopsy sections and assessed the risk of developing IF in 118 living kidney recipients. METHODS: A quantitative analysis of IF was performed using computer-assisted imaging. The percent IF (%IF) in the cortical region at 0 hr was defined as the baseline, and the increases in %IF at 1 month and 1 year were calculated. Demographics, higher (regimen 1) and lower (regimen 2) target trough concentrations of tacrolimus, and the cytochrome P450 (CYP) 3A5 polymorphism were tested as risk factors. RESULTS: The mean %IF at 0 hr, 1 month, and 1 year was 10.3%+/-4.2%, 15.0%+/-5.8%, and 19.0%+/-7.7%, respectively. %IF increased 1.7- and 2.2-fold from 0 hr to 1 month and 1 year posttransplantation, respectively. At 1 year, the increase was higher in patients with the CYP3A5*3/*3 genotype (nonexpressers), those treated with regimen 1, and those with a lower estimated glomerular filtration rate and higher body mass index. In a multivariate analysis, CYP3A5 nonexpression correlated with the development of IF (odds ratio 2.63, P=0.018). Tacrolimus blood levels in the early stage posttransplantation were higher in nonexpressers than CYP3A5 expressers in both regimens 1 and 2, despite therapeutic drug monitoring. CONCLUSIONS: The higher concentrations of tacrolimus, especially in the nonexpressers treated with regimen 1, might influence the development of IF. This study suggested that a new regimen with lower and narrow target trough levels of tacrolimus or a dosing strategy based on the CYP3A5 genotype is needed to reduce the risk of developing IF.

DOI PubMed

Clearance and safety of the radiocontrast medium iopamidol in peritoneal dialysis patients.

Shingo Hatakeyama, Akihiko Abe, Takehiro Suzuki, Yasuhiro Hashimoto, Takuya Koie, Tomihisa Funyu, Shigeru Satoh, Tomonori Habuchi, Chikara Ohyama, Shigeki Matsuo

International journal of nephrology   2011   657051 - 657051   2011年

研究論文（学術雑誌）  

Although the characteristics and safety of radiocontrast media in peritoneal dialysis (PD) patients are not yet well defined, their use in PD patients is considered generally safe. In this study, we evaluated clearance and adverse events of iopamidol in PD patients. We measured the iopamidol concentration in the plasma, dialysate, and urine of 11 patients. Iopamidol clearance from patient plasma was delayed with a half-life of 33.3 h, and the elimination ratio was 83.6% for 96 h. We retrospectively investigated adverse events occurring in a total of 50 stable PD patients who underwent a total of 64 angiographic computed tomography (CT) scans. In 64 angiographic CT scans, two cases of adverse events were observed. Our results suggest that iopamidol can be eliminated by regular PD and careful observation for adverse events are necessary for the safe use of radiocontrast media.

DOI PubMed

What is the most preferred wound site for laparoscopic donor nephrectomy?: a questionnaire assessment.

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

Journal of laparoendoscopic & advanced surgical techniques. Part A   21 ( 6 ) 511 - 5   2011年

研究論文（学術雑誌）  

INTRODUCTION: Although specimen extraction site selection for laparoscopic donor nephrectomy (LDN) is relatively flexible and is mostly selected by surgeons from the patient's standpoint, the patient's request may differ from the medical worker's recommendation. The cosmetic aspect may also differ with age, gender, and the extent of medical knowledge. We performed an unsigned questionnaire assessment of individual preferences for LDN wound sites. MATERIALS AND METHODS: Between August 2007 and October 2008, we surveyed LDN wound site preferences among 148 physicians, 263 nurses, and 266 outpatients of urology at Akita University Hospital. They were questioned for their age, gender, occupation (medical worker or not), and for the most preferred surgical wound site among the following: A, lower vertical midline: B, upper vertical midline: C, anterior subcostal: D, Pfannenstiel: E, Gibson: and F, subcostal flank. The valid response rate was 93.5% (677/724). RESULTS: Wound sites preferred (ranked in descending order) were F (48.3%), D (25.6%), E (10.5%), A (9.0%), C (5.2%), and B (1.4%). The subcostal flank incision was the most preferred in almost all the categories. Second preferences were Pfannenstiel incisions in women and incisions on the lower abdomen in men. Overall, flank and lower abdominal incisions tended to be preferred, and mid and upper abdominal incisions tended to be avoided. Medical workers selected the subcostal flank and Pfannenstiel incisions more frequently than outpatients. With increasing age, the selection rates of the Gibson and the lower vertical midline incisions increased, whereas the subcostal flank and the Pfannenstiel incisions decreased. CONCLUSIONS: The subcostal flank was the most preferred LDN sites. Age, gender, and the extent of medical knowledge may influence the individual preferences for LDN wound sites.

DOI PubMed

Clinical significance of polymorphism and expression of chromogranin a and endothelin-1 in prostate cancer.

Zhiyong Ma, Norihiko Tsuchiya, Takeshi Yuasa, Mingguo Huang, Takashi Obara, Shintaro Narita, Yohei Horikawa, Hiroshi Tsuruta, Mitsuru Saito, Shigeru Satoh, Osamu Ogawa, Tomonori Habuchi

The Journal of urology   184 ( 3 ) 1182 - 8   2010年09月

研究論文（学術雑誌）  

PURPOSE: We investigated the clinical significance of chromogranin A and endothelin-1 polymorphism and expression in prostate cancer. MATERIALS AND METHODS: We analyzed 2 CHGA polymorphisms by polymerase chain reaction-restriction fragment length polymorphism in DNA samples of 435 patients with prostate cancer and 316 age matched male controls. Chromogranin A and endothelin-1 expression was evaluated by immunohistochemistry in prostate specimens of 114 men with prostate cancer who underwent radical retropubic prostatectomy and in 27 with bladder cancer who underwent radical cystectomy and served as controls. RESULTS: For the CHGA Glu264Asp polymorphism men with the GG genotype were at 2.05 times higher risk for prostate cancer than men with the CC genotype (p = 0.014). In men with prostate cancer higher chromogranin A immunohistochemistry grade was associated with higher stage and higher Gleason score (p = 0.011 and 0.044, respectively). Multivariate analysis showed that chromogranin A immunohistochemistry grade was an independent variable for predicting biochemical failure after radical prostatectomy (p = 0.023). Higher endothelin-1 expression was observed in prostate cancers (p = 0.011), especially those with a higher Gleason score (p = 0.042). There was no significant relationship between chromogranin A polymorphisms, and chromogranin A and endothelin-1 expression. CONCLUSIONS: Polymorphism and expression of chromogranin A and endothelin-1 have clinical significance in prostate cancer. Chromogranin A expression was an independent predictor of biochemical failure after prostatectomy in patients with localized prostate cancer.

DOI PubMed

Correlation of IMPDH1 gene polymorphisms with subclinical acute rejection and mycophenolic acid exposure parameters on day 28 after renal transplantation.

Hideaki Kagaya, Masatomo Miura, Mitsuru Saito, Tomonori Habuchi, Shigeru Satoh

Basic & clinical pharmacology & toxicology   107 ( 2 ) 631 - 6   2010年08月

研究論文（学術雑誌）  

The risk of acute rejection in patients with higher exposure to mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), might be due to inosine 5'-monophosphate dehydrogenase (IMPDH) polymorphisms. The correlations with subclinical acute rejection, IMPDH1 polymorphisms and MPA exposure on day 28 post-transplantation were investigated in 82 Japanese recipients. Renal transplant recipients were given combination immunosuppressive therapy consisting of tacrolimus and 1.0, 1.5 or 2.0 g/day of MMF in equally divided doses every 12 hr at designated times. There were no significant differences in the incidence of subclinical acute rejection between IMPDH1 rs2278293 or rs2278294 polymorphisms (p = 0.243 and 0.735, respectively). However, in the high MPA night-time exposure range (AUC > 60 microg x h/ml and C(0 )> or = 1.9 microg/ml), there was a significant difference in the incidence of subclinical acute rejection between IMPDH1 rs2278293 A/A, A/G and G/G genotypes (each p = 0.019), but not the IMPDH1 rs2278294 genotype. In the higher daytime MPA exposure range, patients with the IMPDH1 rs2278293 G/G genotype also tended to develop subclinical acute rejection. In patients with the IMPDH rs2278293 A/A genotype, the risk of subclinical acute rejection episode tends to be low and the administration of MMF was effective. The risk of subclinical acute rejection for recipients who cannot adapt in therapeutic drug monitoring (TDM) of MPA seems to be influenced by IMPDH1 rs2278293 polymorphism. The prospective analysis of IMPDH1 rs2278293 polymorphism as well as monitoring of MPA plasma concentration after transplantation might help to improve MMF therapy.

DOI PubMed

Medical mushrooms used for biochemical failure after radical treatment for prostate cancer: an open-label study.

Koji Yoshimura, Toshiyuki Kamoto, Osamu Ogawa, Shigeyuki Matsui, Norihiko Tsuchiya, Harue Tada, Keiko Murata, Kenichi Yoshimura, Tomonori Habuchi, Masanori Fukushima

International journal of urology : official journal of the Japanese Urological Association   17 ( 6 ) 548 - 54   2010年06月

研究論文（学術雑誌）  

OBJECTIVE: The aim of this study was to assess the efficacy and safety of two different types of medical mushrooms in patients with prostate cancer in Japan. METHODS: Patients with biochemical failure after radical treatment for non-metastasized prostate cancer were enrolled in this open-label study. For 6 months they ingested one of the two following supplements: Senseiro, containing extracts from the Agaricus blazei Murill mushroom; and Rokkaku Reishi, containing the Ganoderma lucidum mushroom. Levels of serum prostate-specific antigen (PSA) level and PSA doubling time were examined before and after study entry to assess the impact of these supplements on disease progression. The primary end-point of this study was partial response rate (50% or more decrease of serum PSA). Hormonal status, represented by serum testosterone levels, and toxicity were also assessed. RESULTS: A total of 51 patients were enrolled following radical prostatectomy. Forty-seven completed the protocol and could be assessed. Thirty-two patients received Senseiro and the remaining 15 received Rokkaku Reishi. No partial response in terms of PSA was observed. Alteration of PSA doubling time did not correlate with that of serum testosterone levels. Serious adverse effects were not observed. CONCLUSIONS: No significant anticancer effects were observed with the intake of these two medical mushrooms.

DOI PubMed

Post-transplant lymphoproliferative disorder involving the ovary as an initial manifestation: a case report.

Takamitsu Inoue, Shigeru Satoh, Mitsuru Saito, Yohei Horikawa, Norihiko Tsuchiya, Tomonori Habuchi

Journal of medical case reports   4   184 - 184   2010年06月

研究論文（学術雑誌）  

INTRODUCTION: Because the normal ovary is assumed to be devoid of lymphoid tissue, it is unusual for it to be an initial manifestation of malignant lymphoma. This case is the first report, to our knowledge, of post-transplant lymphoproliferative disorder involving the ovary as an initial manifestation. CASE PRESENTATION: Twenty-nine weeks after a living renal transplantation, a 38-year-old Japanese female, whose ethnic origin was Asian, presented with abdominal pain and a chronic high fever. Computed tomography revealed a right ovarian tumor and liver metastases. The patient underwent oophrectomy based on the clinical diagnosis of liver metastasis from the primary ovarian tumor. The pathological diagnosis was Epstein-Barr Virus-associated post-transplant lymphoproliferative disorder. While ovarian malignant lymphoma has a poor prognosis, complete remission of liver involvement in this case was achieved only with a reduction of immunosuppressants. CONCLUSION: Clinicians should remember that malignant lymphoma could initially involve the ovary, especially if the patient is immunosuppressed after transplantation therapy.

DOI PubMed

Relationship between bone mineral density and androgen-deprivation therapy in Japanese prostate cancer patients.

Takeshi Yuasa, Shinya Maita, Norihiko Tsuchiya, Zhiyong Ma, Shintaro Narita, Yohei Horikawa, Shinya Yamamoto, Junji Yonese, Iwao Fukui, Shunji Takahashi, Kiyohiko Hatake, Tomonori Habuchi

Urology   75 ( 5 ) 1131 - 7   2010年05月

研究論文（学術雑誌）  

OBJECTIVES: To examine Japanese patients who had received androgen-deprivation therapy (ADT) for longer periods, as it is known that ADT of patients with prostate cancer reduces their bone mineral density (BMD). However, our previous cross-sectional study revealed that short-term ADT (average, 23.5 months) does not significantly increase the prevalence of osteoporosis in Japanese patients. METHODS: The subjects consisted of 201 native Japanese patients with prostate cancer. They comprised 113 ADT-treated and 88 hormone-naive patients. Lumbar spine, total hip, and femoral neck BMDs were measured by dual-energy x-ray absorptiometry and expressed in standard deviation units relative to the scores of young adult men (T-score) or age-matched men (Z-score). Serum levels of bone metabolism markers were also measured. RESULTS: The ADT-treated patients had significantly lower BMD values, T-scores, and even Z-scores than the hormone-naive patients (P <.001). For patients who were hormone-naive, ADT-treated for less than 2 years, and ADT-treated for more than 2 years, the osteoporosis prevalence was 4.5% (4/88), 12.1% (4/33), and 10.8% (4/37), respectively. The ADT-treated patients had significantly higher serum amino-terminal telopeptide levels than the hormone-naive patients (P = .014), but significantly lower serum carboxy-terminal telopeptide of type-I collagen levels than the ADT-treated patients with bone metastasis (P <.001). CONCLUSIONS: Our cross-sectional study confirmed that both ADT-treated and hormone-naive Japanese patients with prostate cancer have low rates of osteoporosis. These findings are different from those of studies in western countries. Genetic and hormonal or other environmental factors may result in population differences in the characteristics of prostate cancer and BMD.

DOI PubMed

Current status and future issue of molecular targeted agents in solid tumors: Lessons learned from renal cell carcinoma

Norihiko Tsuchiya, Tomonori Habuchi

Drug Delivery System   25 ( 2 ) 134 - 142   2010年

研究論文（学術雑誌）  

We are facing a dramatic shift from cytokine therapy to molecular targeted agents in the therapeutic strategy for advanced renal cell carcinoma. Molecular targeted agents used in renal cell carcinoma, tyrosin kinase inhibitors, mTOR inhibitors, and anti-VEGF antibody, inhibit tumor growth mainly though anti-angiogenic activity. Those agents have different profiles of adverse events and sometimes induce unexpected serious events, although having a strong anti-tumor growth. To ensure maximum therapeutic effect, a team approach involving multi-disciplinary staffs becomes more important than ever.

DOI

Mass screening of prostate cancer and its impact on inhabitants in akita prefecture, Japan

T. Kato, T. Habuchi, N. Tsuchiya, K. Sato, S. Kitajima, S. Kato

Aktuelle Urologie   41 ( SUPPL. 1 )   2010年

研究論文（学術雑誌）  

In 2001, the Akita Medical Association started a prostate cancer (PC) mass screening project for ≥50-year-old male inhabitants in individual municipalities of Akita Prefecture, utilizing serum prostate-specific antigen. The number of examinees increased from 4321 in 2001 to 29936 in 2006, while the annual rate of examinees per target inhabitants remained at 11.6 to 16.8% and the fraction of repeat examinees increased up to 77% in 2006. A total of 944PCs were screened with a stageB tumor incidence of 84.1% (range: 82.2 to 86.6%). The annual PC detection rate was 0.95 to 1.11% for the first 4 years, but then declined to 0.54% in 2006 mainly due to the increase of repeat examinees. PSA mass screening is effective for the detection of early stage PC, but a further promotion is needed to mobilize the sleeping inhabitants. Indeed, the number of new PC patients in 17 major hospitals in Akita Prefecture rapidly increased after the mass screening started (3.2-fold), suggesting an enlightenment effect of the screening project on both the inhabitants and general physicians. © Georg Thieme Verlag KG.

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