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Cushing's syndrome

Miyajima Akira, Hattori Seiya, Oya Mototsugu

Japanese Journal of Clinical Urology 68 （ 8 ） 600 - 606 2014年

ISSN 0385-2393

Renal cell carcinoma in patients with acquired cystic disease of the kidney

Akita Hirotaka, Jinzaki Masahiro, Akita Ayano, Mikami Shuji, Oya Mototsugu, Kuribayashi Sachio

Journal of Magnetic Resonance Imaging 39 （ 4 ） 924 - 930 2014年

ISSN 1053-1807

Purpose To evaluate the MRI findings of renal cell carcinoma (RCC), including findings on diffusion-weighted images (DWIs) and chemical shift images (CSIs), in patients with acquired cystic disease of the kidney (ACDK) in relation to the histopathologic findings. Materials and Methods Two radiologists retrospectively reviewed the MRI findings of 10 RCCs in seven consecutive patients with ACDK. They evaluated the signal intensities (SIs) and signal homogeneity of the lesions on T2-weighted images, DWIs, and T1-weighted images. Thereafter, they evaluated the cytoplasmic fat in the lesions by CSIs. After image analyses, the MRI findings were correlated with the histopathologic findings. Results The RCCs tended to show heterogeneous high SIs on T2-weighted images and DWIs. The high SIs on DWIs were mainly attributable to the viable parts, and the heterogeneity was due to the various SIs arising from the intratumoral degenerative components. Unlike the reported findings for hemorrhagic cysts, the RCCs did not show homogeneous high SIs or fluid-iron levels on T1-weighted images. The four lesions, in which the presence of cytoplasmic fat was suggested on CSIs, were clear cell RCCs. Conclusion The MRI findings, including findings on DWIs and CSIs, well reflected the histopathologic findings of RCC in patients with ACDK.

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Development of a novel interferon-α2b gene construct with a repetitive hypoxia-inducible factor binding site and its suppressive effects on human renal cell carcinoma cell lines in vitro

Fukui Naotaka, Kageyama Yukio, Higashi Yotsuo, Kihara Kazunori, Kizaka-Kondoh Shinae, Hiraoka Masahiro, Shinojima Toshiaki, Suzuki Kenjiro, Oya Mototsugu

International Journal of Clinical Oncology 19 （ 3 ） 497 - 504 2014年

ISSN 1341-9625

Background: Despite the advent of targeted therapies, interferon-alpha (IFN-α) remains a therapeutic option for advanced renal cell carcinoma (RCC), especially in Japan, with a treatment response rate of 15-20 %. To improve the efficacy of IFN-α-based therapies, we evaluated a novel treatment strategy for RCC using an IFN-α2b gene construct with a repetitive hypoxia-inducible factor binding site. Methods: We constructed an expression plasmid designated 5HREp-IFN-α2b containing the coding region of the IFN-α2b gene. Five copies of the hypoxia-response element (HRE) sequences were inserted upstream of the IFN-α2b gene, and the construct was transfected into human RCC cell lines ACHN, 786-O and KU19-20. The concentrations of IFN-α2b in the conditioned media were measured by enzyme-linked immunosorbent assay. Cell viabilities were determined by MTS assays. Results: Construct-induced IFN-α secretion was confirmed in all three cell lines. IFN-α production was significantly enhanced by the hypoxia-mimicking agent deferoxamine mesylate in cell lines expressing the wild-type von Hippel-Lindau (VHL) gene (KU19-20 and ACHN) compared with cells expressing the mutant VHL gene (786-O). The construct exerted significant suppressive effects on the viabilities of all RCC cell lines. Conclusion: This is the first study to report on the construction of a cytokine gene with a repetitive hypoxia-inducible factor binding site and its application in the suppression of human cancer cells. Gene therapy using this IFN-α2b gene construct with HREs may represent a novel treatment modality for advanced RCC.

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Complete response to bicalutamide withdrawal prolonged for almost 2 years in patients with metastatic prostate cancer

Hongo Hiroshi, Kosaka Takeo, Oya Mototsugu

Urology Case Reports 2 （ 5 ） 150 - 151 2014年

ISSN 2214-4420

This is the first case report describing a complete response to bicalutamide withdrawal that lasted for almost 2years in a patient with metastatic prostate cancer. An 80-year-old man who had prostate-specific antigen (PSA) level elevation (168.1ng/mL) visited our hospital in February 2010. Bone scintigraphy showed pelvic metastases. We started hormonal therapy with leuprorelin and bicalutamide. The PSA concentration decreased to <0.1ng/mL but started increasing again and reached 1.64ng/mL in October 2012, at which time bicalutamide administration was discontinued. The PSA concentration decreased again and has remained below the limit of sensitivity for almost 2years.

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Independent predictors for bladder outcomes after treatment of intravesical recurrence following radical nephroureterectomy in patients with primary upper tract urothelial carcinoma

Tanaka Nobuyuki, Kikuchi Eiji, Kanao Kent, Matsumoto Kazuhiro, Shirotake Suguru, Kobayashi Hiroaki, Miyazaki Yasumasa, Ide Hiroki, Obata Jun, Hoshino Katsura, Hayakawa Nozomi, Hagiwara Masayuki, Kosaka Takeo, Oyama Masafumi, Miyajima Akira, Momma Tetsuo, Nakagawa Ken, Jinzaki Masahiro, Hasegawa Shintaro, Nakajima Yosuke, Oya Mototsugu

Annals of Surgical Oncology 21 （ 9 ） 3151 - 3158 2014年

ISSN 1068-9265

Background. Few studies have described the clinical courses and outcomes in the bladder after treatment of intravesical recurrence after radical nephroureterectomy (RNU) in patients with primary upper tract urothelial carcinoma (UTUC). We investigated the indicators for predicting subsequent bladder outcomes after treatment of intravesical recurrence after RNU. Methods. A total of 241 patients with primary UTUC (pTa-4N0M0) who experienced intravesical recurrence after RNU were included. Of these patients, 101 (41.9 %) underwent Bacillus Calmette-Guérin treatments, whereas 49 (20.3 %) underwent intravesical chemotherapy. The median follow-up period after initial transurethral resection of the bladder tumor was 33 months. Relationships with bladder outcomes were analyzed by using multivariable analysis. Results. Ninety-six patients experienced intravesical recurrence, and bladder progression was observed in 13. Cumulative incidence rates of intravesical recurrence at 1 and 5 years after treatment of the first intravesical recurrence were 31.0 and 48.4 %, whereas those of bladder progression at 1 and 5 years thereafter were 2.4 and 8.0 %. Multivariate analysis showed that the number of recurrent tumors and pT1 tumors at the time of the first intravesical relapse were independent risk factors for subsequent intravesical recurrence. With respect to bladder progression, multivariate analysis showed that pT1 tumors, the appearance of concomitant carcinoma-in situ at the time of the first intravesical relapse, and the absence of the Bacillus Calmette-Guérin treatment were independent risk factors. Conclusions. This retrospective study presents a detailed picture of further bladder outcomes after intravesical recurrence after RNU in primary UTUC patients. The results may assist physicians to develop a more rational protocol in bladder surveillance.

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Age at diagnosis on prostate cancer survival undergoing androgen deprivation therapy as primary treatment in daily practice

Inamoto Teruo, Azuma Haruhito, Hinotsu Shiro, Tsukamoto Taiji, Oya Mototsugu, Ogawa Osamu, Kitamura Tadaichi, Kazuhiro Suzuki, Naito Seiji, Namiki Mikio, Nishimura Kazuo, Hirao Yoshihiko, Usami Michiyuki, Murai Masaru, Akaza Hideyuki

Journal of Cancer Research and Clinical Oncology 140 （ 7 ） 1197 - 1204 2014年

ISSN 0171-5216

Objectives: Primary androgen deprivation therapy (PADT) had been used extensively in Japan than in the USA and European countries regardless of the disease risk or patient's age. To illustrate the consequence of PADT from daily clinical practice, we evaluated the relationship among age, disease risk, and survival of patients with prostate cancer treated by PADT in largest Asian cohort. Patients and methods: The 19,246 men subjected to PADT enrolled in the Japan Study Group of Prostate Cancer were enrolled for the present analysis. Patients were divided into four groups based on age at diagnosis: age <66, 66-70, 71-75, and >75. Risk was stratified according to the Japan Cancer of the Prostate Risk Assessment (J-CAPRA). Multivariate competing risks regression analysis was performed for OS and PFS. Results: There was downward stage migration over age. Among men aged >75 years, 34.1 % had nodal or distant metastatic disease. In contrast, 56.0 % of patients aged <66 years presented with advanced disease. The modality of hormonal therapy varied with age across risk groups; the younger age group showed a higher proportion of maximal androgen blockade, while the proportion of monotherapy use was higher in older men. The likelihood of low-risk disease by J-CAPRA classification increased significantly with increasing age (p < 0.0001 by Pearson's chi-square test). The same as OS, the PFS rate increased with age until after the age of 75. Men aged 71-75 had better survival rates even after adjustments for treatment modality alone, or for treatment modality plus disease risk. Conclusions: Age cohorts do affect orientation toward favorable disease course after PADT with men aged 71-75 being benefiting more from PADT than other age groups.

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Ureteral metastasis from prostate cancer

Hongo Hiroshi, Kosaka Takeo, Yoshimine Shunsuke, Oya Mototsugu

BMJ Case Reports 2014 2014年

A 59-year-old man had an elevated prostate-specific antigen (PSA) concentration (439 ng/mL) in December 2008. We diagnosed prostatic adenocarcinoma by prostate needle biopsy. CT and MRI showed a prostatic tumour with bone and lymph node metastases. Combined androgen blockade therapy reduced the PSA level temporarily. After the PSA level gradually started to increase again and reached 27.27 ng/mL in October 2010, the patient was diagnosed with castration-resistant prostate cancer and treated with docetaxel chemotherapy. Radiological examination detected left hydronephrosis and a tumour in the left lower ureter in March 2011. Retrograde pyelography and urine cytology of class 3 from the left ureter indicated that the ureteral mass was a urothelial carcinoma. A left nephroureterectomy was performed. After the operation, the pathological examination showed a metastatic prostate carcinoma, accompanied by a decrease in the serum PSA level from 59.56 to 45.33 ng/mL.

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Laparoendoscopic single-site adrenalectomy versus conventional laparoscopic adrenalectomy

Hirasawa Yosuke, Miyajima Akira, Hattori Seiya, Miyashita Kazutoshi, Kurihara Isao, Shibata Hirotaka, Kikuchi Eiji, Nakagawa Ken, Oya Mototsugu

Surgical Endoscopy and Other Interventional Techniques 28 （ 10 ） 2911 - 2919 2014年

ISSN 0930-2794

Background: Conventional laparoscopic adrenalectomy (LA) is the gold standard procedure for benign adrenal tumors. Laparoendoscopic single-site adrenalectomy (LESS-A) has been developed as an extension of standard laparoscopic minimally invasive procedures.Methods: This retrospective study compared the first experience of one surgeon with 70 LESS-A to 140 LA cases with respect to evaluating the influence of the inexperience on surgical outcomes and to assess this surgeon’s learning curve for LESS-A.Results: Age, gender, BMI, percentage of patients with prior abdominal surgery, tumor laterality, and tumor size were all comparable between the two groups. There were no statistically significant differences in any surgical outcomes, including mean operative time, pneumoperitoneum time, estimated blood loss, transfusion requirements, hemoglobin decrease at postoperative day 1, analgesic requirements, postoperative day of oral intake, conversion rate, or morbidity between the two groups. The one exception was hospital stay. There were no mortalities or reoperations in either group. The morbidity rates in the LESS-A group and LA group were 4.2 and 6.4 %, respectively (p = 0.528). LESS-A appears to have a steep learning curve and the operative time of the initial 70 cases decreased markedly and remained stable when the experience level exceeded 12 cases. There was no morbidity or conversion in these first 12 LESS-A cases. Multiple regression analysis revealed that surgeon experience (p = 0.008) and tumor size (p = 0.001) were independent predictors of prolonged operative time.Conclusions: Surgical outcomes of LESS-A were equivalent to those of LA without compromising safety. The introduction of LESS-A at our hospital was smooth and safe. While the indication for LESS-A has been controversial, LESS-A was a useful procedure, especially for cases in which cosmesis is of paramount importance.

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Is DHT production by 5a-reductase friend or foe in prostate cancer?

Kosaka Takeo, Miyajima Akira, Oya Mototsugu

Frontiers in Oncology 4 （ SEP ） 2014年

ISSN 2234-943X

The first advance in the history of studies on prostate cancer (PCa) and androgens was the development of treatment with castration and administration of estrogen by Charles B. Huggins, who won the Nobel Prize in Physiology and Medicine. Since then, and for 70 years, androgen deprivation therapy has been the standard therapy for advanced PCa and the center of studies on PCa. However, recent advances have shed light on the relationship between androgens and the development or the progression of PCa. The use of 5AR inhibitors to prevent progression of PCa continues to be widely discussed. Discussion has been fueled by the findings of two large randomized, placebo-controlled trials: the Prostate Cancer Prevention Trial with finasteride and the Reduction by Dutasteride of Prostate Cancer Events trial. Does the development of PCa or progression to castration-resistant PCa depend on dihydrotestosterone (DHT)? Here, we summarize and discuss recent topics of local androgen production of DHT in PCa.

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Occurrence of infection following prostate biopsy procedures in Japan Japanese Research Group for Urinary Tract Infection (JRGU)-A multi-center retrospective study

Togo Yoshikazu, Kubo Tatsuhiko, Taoka Rikiya, Hiyama Yoshiki, Uehara Teruhisa, Hashimoto Jiroh, Kurimura Yuichiro, Takahashi Satoshi, Tsukamoto Taiji, Miyazaki Jun, Nishiyama Hiroyuki, Kira Shinichiro, Kiyota Hiroshi, Yazawa Satoshi, Niwa Naoya, Hongo Hiroshi, Oya Mototsugu, Kato Taku, Yasuda Mitsuru, Deguchi Takashi, Ishikawa Kiyohito, Hoshinaga Kiyotaka, Matsumoto Minori, Shigemura Katsumi, Tanaka Kazushi, Arakawa Soichi, Fujisawa Masato, Wada Koichiro, Uehara Shinya, Watanabe Toyohiko, Kumon Hiromi, Kobayashi Kanao, Matsubara Akio, Matsumoto Masahiro, Sho Takehiko, Hamasuna Ryoichi, Matsumoto Tetsuro, Hayami Hiroshi, Nakagawa Masayuki, Yamamoto Shingo

Journal of Infection and Chemotherapy 20 （ 4 ） 232 - 237 2014年

ISSN 1341-321X

We retrospectively investigated the incidence of genitourinary tract infection in 5895 patients who underwent transrectal and/or transperineal prostate biopsy procedure between January and December 2011 at 46 institutions belonging to Japanese Research Group for Urinary Tract Infection (JRGU). The total rate of genitourinary tract infection after prostate biopsy was 0.76%, while that following transrectal procedure was 0.83% and following transperineal procedure was 0.57%, which were not significantly different. In contrast, febrile infection associated with a fever (≥38 °C) occurred significantly more frequently after transrectal (0.71%) than transperineal (0.16%) approach (P = 0.04). Notably, in infectious cases, Escherichia coli was most frequently isolated. Of the 9 E. coli strains isolated by urine culture, 6 (66.7%) produced extended spectrum β-lactamase (ESBL) and 7 (77.8%) showed levofloxacin resistance. Similarly, of 6 E. coli strains isolated by blood culture, 4 (66.7%) produced ESBL and 6 (100%) showed levofloxacin resistance. When the efficacy of antimicrobial prophylaxis (AMP) with levofloxacin for the patients undergoing transrectal or transperineal biopsy was compared between a single dose (500 mg) and that given for 2 or more days, no significant difference was observed for the rate of infection (transrectal: 0.82% vs. 1.04%, p = 0.94; transperineal: 0.30% vs. 0.46%, p = 0.68).

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Visceral fat is correlated with prolonged operative time in laparoendoscopic single-site adrenalectomy and laparoscopic adrenalectomy

Hasegawa Masanori, Miyajima Akira, Jinzaki Masahiro, Maeda Takahiro, Takeda Toshikazu, Kikuchi Eiji, Shibata Hirotaka, Oya Mototsugu

Urology 82 （ 6 ） 1312 - 1318 2013年12月

ISSN 0090-4295

Objective To investigate the effect of visceral fat on operative time and discuss whether the measurement of adipose accumulation could be used as a sensitive predictor of technical difficulty in performing laparoendoscopic single-site adrenalectomy (LESS-A) and laparoscopic adrenalectomy (LA). Methods We reviewed the medical records of 106 patients undergoing LA or LESS-A at our institution. Total fat area (TFA) and visceral fat area (VFA) were measured at the level of the L4 vertebra by computed tomography. To categorize the type of obesity, the VFA/TFA ratio was calculated. Multiple logistic regression analyses were performed to identify independent predictors of prolonged operative time. Results The VFA/TFA ratio does not always coincide with body mass index (BMI, r = 0.415), and a higher correlation coefficient was observed between operative time and the VFA/TFA ratio (r = 0.359) than with that of BMI (r = 0.189). Multivariate analysis revealed that pheochromocytoma, tumor size ≥5 cm, and the VFA/TFA ratio ≥0.35, defined as the visceral type of adipose accumulation, were independent predictive factors for prolonged operative time in LA and LESS-A. We were able to stratify patients into short, intermediate, and long operative times using these preoperative variables. Conclusion This study revealed that the visceral type of adipose accumulation increases operative complexity in LA and LESS-A as measured by operative time. The VFA/TFA ratio might be a more sensitive indicator of technical difficulty than that of BMI.

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Periprostatic fat area is an independent factor that prolonged operative time in laparoscopic radical prostatectomy

Kaneko Gou, Miyajima Akira, Yuge Kazuyuki, Hasegawa Masanori, Takeda Toshikazu, Jinzaki Masahiro, Kikuchi Eiji, Nakagawa Ken, Oya Mototsugu

Urology 82 （ 6 ） 1304 - 1309 2013年12月

ISSN 0090-4295

Objective To evaluate the effect of visceral obesity on surgical outcomes in laparoscopic radical prostatectomy (LRP). Methods Visceral fat area (VFA) and periprostatic fat area (PPFA) were used as index of visceral obesity. In addition to VFA and PPFA, age, body mass index (BMI), prostate weight, cross-section area of Retzius space, history of previous abdominal surgery, repeated transrectal needle biopsy, and neoadjuvant hormone therapy were recorded. LRP was separated into 7 steps (1: port insertion and lymph node dissection, 2: endopelvic fascia incision, 3: dorsal vein complex ligation, 4: prostate dissection from bladder neck, 5: dissection of seminal vesicle and vas deferens, 6: prostate dissection from rectum, and 7: vesicourethral anastomosis). Potential factors that prolonged total operative time (OT), pneumoperitoneum time, and duration of each step were assessed by multivariate logistic regression analysis. The association between visceral obesity and other surgical outcomes was also evaluated. Results One hundred sixteen LRPs were performed by a single experienced surgeon. High PPFA and prostate weight were independent factors that prolonged total OT and pneumoperitoneum time. High BMI was not a factor. PPFA affected steps 1, 4, 5, and 6, and prostate weight affected prolonged steps 5 and 6. Estimated blood loss, duration of urethral catheterization, postoperative hospital stay, perioperative complications, and margin status were not affected by visceral obesity. Conclusion PPFA was more useful to accurately predict prolonged OT than VFA or BMI. Safety and margin status were not compromised even in high PPFA group when operations were performed by an experienced surgeon.

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Radiolucent circular line in pelvis on plain X-rays

Niwa Naoya, Yazawa Satoshi, Oya Mototsugu

Journal of Emergency Medicine 45 （ 6 ） 2013年12月

ISSN 0736-4679

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Epithelioid angiomyolipoma of the kidney

Tsukada Jitsuro, Jinzaki Masahiro, Yao Masahiro, Nagashima Yoji, Mikami Shuji, Yashiro Hideki, Nozaki Miwako, Mizuno Ryuichi, Oya Mototsugu, Kuribayashi Sachio

International Journal of Urology 20 （ 11 ） 1105 - 1111 2013年11月

ISSN 0919-8172

Objectives: To review the imaging findings of renal epithelioid angiomyolipomas. Methods: Eight patients treated at two institutions were pathologically diagnosed as having epithelioid angiomyolipoma. All of them underwent computed tomography, and four underwent magnetic resonance imaging. The tumor size, existence of fat, heterogeneity, computed tomography attenuation, degree of enhancement, enhancement pattern and magnetic resonance imaging signal intensity were evaluated. Results: Intratumoral fat was not detected in any of the cases. On unenhanced computed tomography, the intratumoral attenuation was hyperattenuating in six of the seven patients who were examined using this modality. On T2-weighted images, the signal intensity of the solid component, cyst wall or septum was low in three of the four cases. Four of the eight cases were heterogeneous solid-type accompanied by hemorrhage, necrosis or hyalinization. One homogeneous solid-type lesion was large in size and was pathologically accompanied by neither hemorrhage nor necrosis. All three multilocular cystic types were pathologically accompanied by massive hemorrhage in the cystic component. One was accompanied by spontaneous perirenal hematoma. Conclusions: The radiological appearance of most epithelioid angiomyolipomas has a tendency to be hyperattenuating on unenhanced computed tomography images, with low intensities on T2-weighted images. They can be heterogeneously solid, homogeneously solid or a multilocular cystic lesion with massive hemorrhage.

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Effect of a Novel Nuclear Factor-kappa B Activation Inhibitor on Renal Ischemia-Reperfusion Injury

Kono Hidaka, Nakagawa Ken, Morita Shinya, Shinoda Kazunobu, Mizuno Ryuichi, Kikuchi Eiji, Miyajima Akira, Umezawa Kazuo, Oya Mototsugu

TRANSPLANTATION 96 （ 10 ） 863 - 870 2013年11月

研究論文（学術雑誌）, 共著, ISSN 0041-1337

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C-reactive protein

Obata Jun, Kikuchi Eiji, Tanaka Nobuyuki, Matsumoto Kazuhiro, Hayakawa Nozomi, Ide Hiroki, Miyajima Akira, Nakagawa Ken, Oya Mototsugu

Urologic Oncology: Seminars and Original Investigations 31 （ 8 ） 1725 - 1730 2013年11月

ISSN 1078-1439

Background and objective: Serum C-reactive protein (CRP) is one particular marker of systemic inflammation, and an elevated CRP level is associated with poor outcome in various malignancies. While the clinical value of CRP levels in upper tract urothelial carcinoma (UTUC) has not yet been fully evaluated, we investigated the impact of CRP elevation as a biomarker of patient prognosis in UTUC. Materials and methods: A total of 183 patients who underwent radical nephroureterectomy (RNU) for localized UTUC (pTa-4N0M0) were identified between 1993 and 2009. The associations between the levels of serum CRP and patient outcome were analyzed. Results: Thirty-three patients experienced disease recurrence, and 28 died of the disease during the median follow-up period of 39 months. Using the defined cutoff level of CRP >0.5 mg/dl as elevated, preoperative CRP (pre-CRP) levels were elevated in 42 patients (23.0%). Kaplan-Meier curves revealed that subsequent tumor recurrences and worse cancer-specific survival could be significantly predicted in the elevated pre-CRP group. The 5-year recurrence-free survival rate was 63.6% in the elevated pre-CRP group and 83.4% in their counterparts (P < 0.001), and the 5-year cancer-specific survival rate was 64.7% in the elevated pre-CRP group and 84.3% in their counterparts (P = 0.001). Multivariate analysis revealed that elevated pre-CRP, in addition to pathologic T stage, was an independent risk factor for subsequent disease recurrence (P = 0.003, hazard ration (HR) = 2.83), and the decrease in cancer-specific survival (P = 0.012, HR = 2.65). In subgroup analysis using patients with pT3 tumors or greater, multivariate analysis also showed that elevated pre-CRP was an independent risk factor for a decrease in both recurrence-free and cancer-specific survival. Conclusions: Pre-CRP level was an independent predictor of patient survival in localized advanced UTUC. Patients with pre-CRP >0.5 mg/dl were strongly predicted to have worse prognostic outcomes following RNU. Due to its low cost and easy accessibility, CRP may be a useful biomarker for localized UTUC.

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Differential diagnosis of upper urinary tract disorders

Yazawa Satoshi, Kikuchi Eiji, Oya Mototsugu, Jinzaki Masahiro

Japanese Journal of Clinical Urology 67 （ 11 ） 863 - 870 2013年10月

ISSN 0385-2393

Identification of drug candidate against prostate cancer from the aspect of somatic cell reprogramming

Kosaka Takeo, Nagamatsu Go, Saito Shigeru, Oya Mototsugu, Suda Toshio, Horimoto Katsuhisa

Cancer Science 104 （ 8 ） 1017 - 1026 2013年08月

ISSN 1347-9032

Considering the similarities between the transcriptional programming involved in cancer progression and somatic cell reprogramming, we tried to identify drugs that would be effective against malignant cancers. We used the early transposon Oct4 and Sox2 enhancer (EOS) system to select human prostate cancer (PCA) cells expressing high levels of OCT4. Patients with metastatic castration-resistant PCA that does not respond to treatment with docetaxel have few therapeutic options. The OCT4-expressing PCA cells selected using the EOS system showed increased tumorigenicity and high resistance to docetaxel, both in vitro and in vivo. By using their gene expression data, expression signature-based prediction for compound candidates identified an antiviral drug, ribavirin, as a conversion modulator from drug resistance to sensitivity. Treatment of PCA cells with ribavirin decreased their resistance against treatment with docetaxel. This indicated that ribavirin reversed the gene expression, including that of humoral factors, in the OCT4-expressing PCA cells selected using the EOS system. Thereby, ribavirin increased the efficacy of docetaxel for cancer cells. We propose a novel cell reprogramming approach, named drug efficacy reprogramming, as a new model for identifying candidate antitumor drugs.

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Therapeutic enhancement of S-1 with CPT-11 through down-regulation of thymidylate synthase in bladder cancer

Ide Hiroki, Kikuchi Eiji, Hasegawa Masanori, Hattori Seiya, Yasumizu Yota, Miyajima Akira, Oya Mototsugu

CANCER MEDICINE 2 （ 4 ） 488 - 495 2013年08月

研究論文（学術雑誌）, 共著, ISSN 2045-7634

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Patient characteristics and outcomes in metastatic upper tract urothelial carcinoma after radical nephroureterectomy

Tanaka Nobuyuki, Kikuchi Eiji, Kanao Kent, Matsumoto Kazuhiro, Kobayashi Hiroaki, Miyazaki Yasumasa, Ide Hiroki, Obata Jun, Hoshino Katsura, Shirotake Suguru, Hayakawa Nozomi, Kosaka Takeo, Miyajima Akira, Momma Tetsuo, Nakagawa Ken, Hasegawa Shintaro, Nakajima Yosuke, Oya Mototsugu

BJU International 112 （ 2 ） 2013年07月

ISSN 1464-4096

Objectives To investigate oncological outcomes and prognostic factors in patients with upper tract urothelial carcinoma (UTUC) who experienced disease recurrence after radical nephroureterectomy (RNU). Few studies have focused on the clinical courses of patients who experienced disease recurrence after RNU. Patients and Methods A total of 204 UTUC patients who experienced disease recurrence from a retrospective multi-institutional cohort were included in the present study. Associated patient outcomes were analyzed using multivariate analysis. Results The mean time from RNU to first disease recurrence was 15.0 months and ≈90% of patients experienced disease recurrence within the first 3 years after RNU. During a median follow-up of 8.1 month after disease recurrence, 165 patients died from UTUC and five patients died from other causes. In the 204 cohorts, 1- and 3-year cancer-specific survival rates were 40.2% and 9.7%, respectively, and 1- and 3-year overall survival rates were 39.5% and 9.4%, respectively. After disease recurrence, 132 patients underwent systemic chemotherapy, and a subgroup analysis of patients who underwent systemic chemotherapy multivariate analysis showed that performance status, the presence of liver metastasis and the number of recurrence sites were independently prognostic of cancer-specific and overall survival after relapsing. According to three significant variables, 1- and 3-year cancer-specific survival rates were 72.7% and 20.8% in patients with no risk factors, 46.5% and 7.5% in patients with one risk factor, and 26.4% and 4.4% in patients with two or three risk factors, respectively (P < 0.001). Conclusions Most patients died from UTUC within 3 years, even though systemic chemotherapies were administered after relapsing. Multivariate analysis showed that performance status, the presence of liver metastasis and the number of recurrence sites were independently related to poor survival after systemic chemotherapy.

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