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The learning curve of laparoendoscopic single-site adrenalectomy

Fukumoto Keishiro, Miyajima Akira, Hattori Seiya, Matsumoto Kazuhiro, Abe Takayuki, Kurihara Isao, Jinzaki Masahiro, Kikuchi Eiji, Oya Mototsugu

Surgical Endoscopy and Other Interventional Techniques 1 - 8 2016年05月

ISSN 0930-2794

Background: Recently, laparoendoscopic single-site adrenalectomy (LESS-A) has been developed as an alternative treatment for adrenal tumors. Although LESS-A is more technically complex than conventional laparoscopic adrenalectomy, its learning curve and the factors associated with poor surgical outcomes are poorly understood. We analyzed the learning curve of LESS-A and attempted to identify risk factors associated with worse surgical outcomes. Methods: We identified 103 patients who underwent LESS-A [performed by the same surgeon (A.M.)] from 2009 to 2015. The learning curve was analyzed using the moving average method (the 10-case moving average), and we assessed potential risk factors for a prolonged pneumoperitoneum time. Results: The learning curve stabilized at 30 cases. The cases were divided into two groups, the learning stage (LS) (cases 1–29) and master stage (MS) (cases 30–103) groups. The percentage of females and the frequency of previous abdominal surgery were higher in the LS group (p = 0.022 and 0.001, respectively). In the LS group, the mean pneumoperitoneum time was 92 ± 35 min, which was significantly longer than the equivalent value for the MS group (55 ± 18 min, p <0.001). In the LS group, univariate analysis revealed that tumor size (≥50 mm) and the visceral fat area (VFA)/total fat area (TFA) ratio (≥0.49) were significantly associated with a prolonged pneumoperitoneum time (p = 0.046 and 0.046, respectively). In the multivariate analysis, tumor size and the VFA/TFA ratio were confirmed to be associated with a prolonged pneumoperitoneum time (p = 0.029 and 0.029, odds ratio 20.83 and 20.83, respectively). On the other hand, none of the examined factors were found to be associated with a prolonged pneumoperitoneum time in the MS group. Conclusions: LESS-A was performed safely in most cases. However, surgeons who are learning the LESS-A procedure need to pay attention to tumor size and visceral obesity.

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Little impact on renal function in advanced renal cell carcinoma patients treated with sorafenib-analyses of postmarketing surveillance in Japan in over 3, 200 consecutive cases

Oya Mototsugu, Tatsugami Katsunori, Kabu Koki, Adachi Masatoshi, Ito Yuichiro, Akaza Hideyuki

Japanese Journal of Cancer and Chemotherapy 43 （ 5 ） 559 - 569 2016年05月

ISSN 0385-0684

Background: To assess the effect of sorafenib on renal function in patients with advanced renal cell carcinoma (RCC) included in a postmarketing surveillance. Methods: All patients in Japan with advanced RCC treated with sorafenib between February 2008 and September 2009 were followed for 12 months. Baseline characteristics, renal function, survival, safety, and dosage were stratified according to baseline estimated glomerular filtration rate (eGFR):G1 (eGFR≥90), G2 (eGFR≥60- <90), G3a (eGFR≥45-<60), G3b (eGFR≥30-<45), G4 (eGFR≥15-<30), and G5 (eGFR<15). A total of 3, 255 and 3, 171 patients were included in this analysis for safety and efficacy, respectively. Results: The mean eGFRs (mL/min/1.73 m²) were not substantially changed for each group at baseline and 12 months, respectively. Median daily doses of sorafenib were 726mg (G1), 522mg (G2), 524mg (G3a), 517mg (G3b), 483mg (G4), and 400mg (G5). Renal failure, reported as an adverse event, occurred more frequently in the G4and G5 groups (9% and 3%, respectively) than in other groups. Objective response rates for each subgroup were as follows: G1, 23%; G2, 28%; G3a, 29%; G3b, 26%; G4, 24%; and G5, 18%. Oneyear survival was higher in the G3a and G3b groups (82% and 78%, respectively) and lower in the G1 group (50%). Conclusions: This study demonstrated little impact of sorafenib on renal function in advanced RCC patients during the observational period. Patients showed sufficient clinical response and safety irrespective of baseline eGFR value.

Little Impact on Renal Function in Advanced Renal Cell Carcinoma Patients Treated with Sorafenib--Analyses of Postmarketing Surveillance in Japan in over 3,200 Consecutive Cases

Oya Mototsugu, Tatsugami Katsunori, Kabu Koki, Adachi Masatoshi, Ito Yuichiro, Akaza Hideyuki

Gan to kagaku ryoho. Cancer & chemotherapy 43 （ 5 ） 559 - 569 2016年05月

ISSN 0385-0684

BACKGROUND: To assess the effect of sorafenib on renal function in patients with advanced renal cell carcinoma (RCC) included in a postmarketing surveillance.METHODS: All patients in Japan with advanced RCC treated with sorafenib between February 2008 and September 2009 were followed for 12 months. Baseline characteristics, renal function, survival, safety, and dosage were stratified according to baseline estimated glomerular filtration rate (eGFR): G1 (eGFR≥90), G2 (eGFR≥60-RESULTS: The mean eGFRs (mL/min/1.73 m2) were not substantially changed for each group at baseline and 12 months, respectively. Median daily doses of sorafenib were 726 mg (G1), 522 mg (G2), 524 mg (G3a), 517 mg (G3b), 483 mg (G4), and 400 mg (G5). Renal failure, reported as an adverse event, occurred more frequently in the G4 and G5 groups (9%and 3%, respectively) than in other groups. Objective response rates for each subgroup were as follows: G1, 23%; G2, 28%; G3a, 29%; G3b, 26%; G4, 24%; and G5, 18%. One-year survival was higher in the G3a and G3b groups (82% and 78%, respectively) and lower in the G1 group (50%).CONCLUSIONS: This study demonstrated little impact of sorafenib on renal function in advanced RCC patients during the observational period. Patients showed sufficient clinical response and safety irrespective of baseline eGFR value.

The prognostic significance of OCT4 expression in patients with prostate cancer

大家基嗣

HUMAN PATHOLOGY 51 1 - 8 2016年05月

研究論文（学術雑誌）, ISSN 0046-8177

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Role of computed tomography urography in the clinical evaluation of upper tract urothelial carcinoma

Jinzaki Masahiro, Kikuchi Eiji, Akita Hirotaka, Sugiura Hiroaki, Shinmoto Hiroshi, Oya Mototsugu

International Journal of Urology 23 （ 4 ） 284 - 298 2016年04月

ISSN 0919-8172

Intravenous urography has been widely used for the evaluation of upper tract urothelial carcinoma. However, computed tomography urography presently has a higher diagnostic accuracy for upper tract urothelial carcinoma (94.2-99.6%) than intravenous urography (80.8-84.9%), and has replaced intravenous urography as the first-line imaging test for investigating patients with a high risk of upper tract urothelial carcinoma. Although the detection rate for bladder tumors using standard computed tomography urography is not yet high enough to replace cystoscopy, the addition of a 60- to 80-s delayed scan after the administration of contrast material for the whole pelvis improves the detection rate. A drawback to computed tomography urography is the higher radiation dose of 15-35 mSv, compared with a mean effective dose of 5-10 mSv for intravenous urography. Among several approaches to reducing the radiation dose, the use of an iterative reconstruction algorithm is most likely to become an effective solution because of its simplicity. One advantage of computed tomography urography over intravenous urography is its ability to reliably differentiate between upper tract urothelial carcinoma and calculi or blood clots. Computed tomography urography also shows characteristic findings of other benign conditions. These findings, in combination with negative cytology, are very important diagnostic clues for avoiding an unnecessary nephroureterectomy. For the clinical staging, a recent study has reported the high diagnostic accuracy of computed tomography urography with respect to ≥pT3 tumors. The present review shows the current status of computed tomography urography for the evaluation of upper tract urothelial carcinoma.

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Spontaneous Regression of Epstein-Barr Virus-Positive Primary Diffuse Large Cell B-Cell Lymphoma of the Urinary Bladder after the Cessation of Enzalutamide

Ogihara Koichiro, Kosaka Takeo, Kikuchi Eiji, Hongo Hiroshi, Mikami Shuji, Oya Mototsugu

Clinical Genitourinary Cancer 14 （ 2 ） e215 - e218 2016年04月

ISSN 1558-7673

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Placebo-Induced Severe Diarrhea in a Patient with Metastatic Castration-Resistant Prostate Cancer Participating in a Double-Blind, Randomized, Phase III International Trial

Niwa Naoya, Kosaka Takeo, Oya Mototsugu

Clinical Genitourinary Cancer 14 （ 2 ） e219 - e220 2016年04月

ISSN 1558-7673

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A prospective longitudinal survey of erectile function status in symptomatic benign prostatic hyperplasia patients treated with dutasteride

Maeda Takahiro, Kikuchi Eiji, Hasegawa Masanori, Ando Toshiyuki, Matsushima Masashi, Yuge Kazuyuki, Ito Yujiro, Miyajima Akira, Oya Mototsugu

Aging Male 1 - 6 2016年03月

ISSN 1368-5538

We prospectively evaluated erectile function (EF) using the Sexual Health Inventory for Men (SHIM) and the erectile hardness score (EHS) as well as urinary statuses using the International Prostate Symptom Score (IPSS) and Overactive Bladder Symptom Score (OABSS) before and 3, 6, and 12 months after a daily treatment with 0.5 mg dutasteride (DUT). Significant improvements were observed in IPSS and OABSS in 98 patients with the DUT treatment, and the effects were similar between 28 patients with potency with baseline SHIM of 8 or greater and 70 severe erectile dysfunction (ED) patients at baseline. In the 28 patients with potency, significant decreases were observed in SHIM and EHS after 3, 6, and 12 months of the DUT treatment, with the severity of ED according to SHIM deteriorating in half of these patients after 12 months of the DUT treatment. Eighteen out of 28 patients (64.3%) with potency at baseline had awareness of the occurrence of ED before the DUT treatment, were younger, and had higher SHIM and EHS just before the DUT treatment than their counterparts. Regular assessments of EF may be needed, especially in younger patients and those with higher levels of EF before the administration of DUT.

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Erectile function status is highly associated with prostate-specific antigen bounce in localized prostate cancer patients treated with permanent prostate brachytherapy

Matsushima Masashi, Kikuchi Eiji, Matsumoto Kazuhiro, Kosaka Takeo, Mizuno Ryuichi, Ohashi Toshio, Mikami Shuji, Miyajima Akira, Shigematsu Naoyuki, Oya Mototsugu

International Journal of Urology 23 （ 3 ） 247 - 252 2016年03月

ISSN 0919-8172

Objectives: To examine the relationship between erectile function status and prostate-specific antigen bounce after prostate brachytherapy for localized prostate cancer. Methods: We identified 154 patients who were followed up for at least 24 months after brachytherapy. Erectile function status was assessed prospectively before brachytherapy (baseline), and 3, 6, 12, 18, 24 and 36 months postoperatively using the International Index of Erectile Function-15 questionnaire. Prostate-specific antigen bounce was defined as an increase of at least 0.4 ng/mL from a previous prostate-specific antigen level with a subsequent decline equal to, or less than, the initial nadir without treatment. A logistic regression analysis was used to identify a significant set of independent predictors of prostate-specific antigen bounce after brachytherapy. Results: Prostate-specific antigen bounce was observed in 38 (24.7%) men. The prostate-specific antigen bounce group had a higher erectile function domain score, higher orgasmic function domain score, and higher total International Index of Erectile Function-15 score before (at baseline) and after brachytherapy (3, 6, 12, 18, 24 and 36 months after brachytherapy) than their counterparts (P <0.05). Of the 77 patients who completed the International Index of Erectile Function-15 questionnaire 18 months after brachytherapy (the median time of prostate-specific antigen bounce), sexual desire and intercourse satisfaction domain scores, and total International Index of Erectile Function scores 18 months after brachytherapy correlated with the occurrence of prostate-specific antigen bounce. A multivariate analysis identified the intercourse satisfaction domain score 18 months after brachytherapy as an independent indicator for the occurrence of prostate-specific antigen bounce (P = 0.008). Conclusions: International Index of Erectile Function-15 score seems to be correlated with the prostate-specific antigen bounce in prostate cancer patients undergoing brachytherapy, and an occurrence of prostate-specific antigen bounce seems to be more likely in those who are more sexually active.

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Syndrome of inappropriate antidiuretic hormone secretion in a patient with castration-resistant prostate cancer treated with enzalutamide

大家基嗣

ACTA ONCOLOGICA 55 （ 3 ） 399 - 400 2016年03月

研究論文（学術雑誌）, ISSN 0284-186X

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Impact of novel techniques on minimally invasive adrenal surgery

Pavan Nicola, Autorino Riccardo, Lee Hak, Porpiglia Francesco, Sun Yinghao, Greco Francesco, Jeff Chueh S., Han Deok Hyun, Cindolo Luca, Ferro Matteo, Chen Xiang, Branco Anibal, Fornara Paolo, Liao Chun Hou, Miyajima Akira, Kyriazis Iason, Puglisi Marco, Fiori Cristian, Yang Bo, Fei Guo, Altieri Vincenzo, Jeong Byong Chang, Berardinelli Francesco, Schips Luigi, de Cobelli Ottavio, Chen Zhi, Haber Georges Pascal, He Yao, Oya Mototsugu, Liatsikos Evangelos, Brandao Luis, Challacombe Benjamin, Kaouk Jihad, Darweesh Ithaar

World Journal of Urology 1 - 7 2016年02月

ISSN 0724-4983

Objective: To evaluate contemporary international trends in the implementation of minimally invasive adrenalectomy and to assess contemporary outcomes of different minimally invasive techniques performed at urologic centers worldwide. Methods: A retrospective multinational multicenter study of patients who underwent minimally invasive adrenalectomy from 2008 to 2013 at 14 urology institutions worldwide was included in the analysis. Cases were categorized based on the minimally invasive adrenalectomy technique: conventional laparoscopy (CL), robot-assisted laparoscopy (RAL), laparoendoscopic single-site surgery (LESS), and mini-laparoscopy (ML). The rates of the four treatment modalities were determined according to the year of surgery, and a regression analysis was performed for trends in all surgical modalities. Results: Overall, a total of 737 adrenalectomies were performed across participating institutions and included in this analysis: 337 CL (46 % of cases), 57 ML (8 %), 263 LESS (36 %), and 80 RA (11 %). Overall, 204 (28 %) operations were performed with a retroperitoneal approach. The overall number of adrenalectomies increased from 2008 to 2013 (p = 0.05). A transperitoneal approach was preferred in all but the ML group (p <0.001). European centers mostly adopted CL and ML techniques, whereas those from Asia and South America reported the highest rate in LESS procedures, and RAL was adopted to larger extent in the USA. LESS had the fastest increase in utilization at 6 %/year. The rate of RAL procedures increased at slower rates (2.2 %/year), similar to ML (1.7 %/year). Limitations of this study are the retrospective design and the lack of a cost analysis. Conclusions: Several minimally invasive surgical techniques for the management of adrenal masses are successfully implemented in urology institutions worldwide. CL and LESS seem to represent the most commonly adopted techniques, whereas ML and RAL are growing at a slower rate. All the MIS techniques can be safely and effectively performed for a variety of adrenal disease.

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Asia prostate cancer study (A-CaP Study) launch symposium

Akaza Hideyuki, Hirao Yoshihiko, Kim Choung Soo, Oya Mototsugu, Ozono Seiichiro, Ye Dingwei, Cooperberg Matthew, Hinotsu Shiro, Lee Ji Youl, Zhu Gang, Namiki Mikio, Horie Shigeo, Chung Byung Ha, Chen Chung Hsin, Fai Ng Chi, Hakim Lukman, Chiong Edmund, Letran Jason, Umbas Rainy, Suzuki Kazuhiro, Nishimura Kazuo, Ong Teng Aik, Lojanapiwat Bannakij, Wu Tong lin, Kim Wun Jae, Murphy Declan, Ogawa Osamu, Carroll Peter, Naito Seiji, Tsukamoto Taiji

Prostate International 2016年02月

ISSN 2287-8882

The Asian Prostate Cancer (A-CaP) Study is an Asia-wide initiative that has been developed over the course of 2 years. The A-CaP Study is scheduled to begin in 2016, when each participating country or region will begin registration of newly diagnosed prostate cancer patients and conduct prognosis investigations. From the data gathered, common research themes will be identified, such as comparisons among Asian countries of background factors in newly diagnosed prostate cancer patients. This is the first Asia-wide study of prostate cancer and has developed from single country research efforts in this field, including in Japan and Korea. The inaugural Board Meeting of A-CaP was held on December 11, 2015 at the Research Center for Advanced Science and Technology, The University of Tokyo, attended by representatives of all participating countries and regions, who signed a memorandum of understanding concerning registration for A-CaP. Following the Board Meeting an A-CaP Launch Symposium was held. The symposium was attended by representatives of countries and regions participating in A-CaP, who gave presentations. Presentations and a keynote address were also delivered by representatives of the University of California San Francisco, USA, and the Peter MacCallum Cancer Centre, Australia, who provided insight and experience on similar databases compiled in their respective countries.

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Relationship Between Increased Expression of the Axl/Gas6 Signal Cascade and Prognosis of Patients with Upper Tract Urothelial Carcinoma

Hattori Seiya, Kikuchi Eiji, Kosaka Takeo, Miyazaki Yasumasa, Tanaka Nobuyuki, Miyajima Akira, Mikami Shuji, Oya Mototsugu

Annals of Surgical Oncology 23 （ 2 ） 663 - 670 2016年02月

ISSN 1068-9265

Purpose: Axl, which is in the TAM family of receptor tyrosine kinases, and its ligand, growth arrest-specific gene 6 (Gas6), have been associated with worse prognoses after the surgical treatment of some types of cancers. We herein investigated the biological significance of the protein expression of Axl and Gas6 on the outcomes of patients with upper tract urothelial carcinoma (UTUC). Methods: The protein expression of Axl and Gas6 was evaluated by immunohistochemistry, and their relationships with clinicopathological features were investigated in surgical specimens obtained from 161 patients who had been surgically treated for UTUC. Results: Axl labeling was strong in 67 of 161 (42 %) cases, while Gas6 labeling was strong in 72 of 161 (45 %) cases. The strong expression of Axl correlated with that of Gas6. A high pathological stage (p = 0.009), strong expression of Gas6 (p = 0.038), and strong expression of Axl (p = 0.016) were independent factors for predicting worse cancer-specific survival (CSS). In a subgroup analysis of patients with pT

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Lysophosphatidic acid activates Arf6 to promote the mesenchymal malignancy of renal cancer

大家基嗣

NATURE COMMUNICATIONS 7 399 - 400 2016年02月

研究論文（学術雑誌）, ISSN 2041-1723

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Impact of Second-Line Targeted Therapy Dose Intensity on Patients With Metastatic Renal Cell Carcinoma

Shirotake Suguru, Yasumizu Yota, Ito Keiichi, Masunaga Ayako, Ito Yujiro, Miyazaki Yasumasa, Hagiwara Masayuki, Kanao Kent, Mikami Shuji, Nakagawa Ken, Momma Tetsuo, Masuda Takeshi, Asano Tomohiko, Oyama Masafumi, Tanaka Nobuyuki, Mizuno Ryuichi, Oya Mototsugu

Clinical Genitourinary Cancer 2016年01月

ISSN 1558-7673

Background: Relative dose intensity (RDI) is a simple index for evaluation of the amount of drug administered per unit time. We retrospectively investigated the prognostic impact of RDI for patients with metastatic renal cell carcinoma (mRCC) treated with second-line targeted therapy. Methods: We enrolled 168 patients with mRCC. We assessed RDI at 4 weeks after second-line targeted therapy induction. Results: The median follow-up after second-line targeted therapy was 18.1 months. The median time-to-treatment-failure (TTF) and overall survival (OS) were 4.9 and 25.4 months, respectively. In the Kaplan-Meier analysis, the median OS of patients with second-line RDI <0.7 was significantly shorter than those with RDI ≥ 0.7 (12.1 vs. 31.3 months; P = .030). In the subgroup analysis, second-line RDI was definitely prognostic in the poor-risk group of the International Metastatic Renal Cell Carcinoma Database Consortium criteria, showing second-line RDI was an independent predictor for both TTF (hazard ratio [HR], 3.6; 95% confidence interval [CI], 1.6-8.0; P = .002) and OS (HR, 3.1; 95% CI, 1.1-8.4; P = .026). Also, assessing the type of second-line regimen, the multivariate analysis showed that second-line RDI was an independent prognostic indicator of TTF (HR, 1.7; 95% CI, 1.0-2.9; P = .040) and OS (HR, 2.7; 95% CI, 1.3-5.7; P = .009) in patients treated with everolimus. In this group, the median TTF and OS of patients with RDI <0.7 were 2.4 and 11.1 months, and those with RDI ≥ 0.7 were 5.3 and 25.9 months, respectively. Conclusion: The results suggest that second-line RDI may be a prognostic predictor for patients with mRCC treated with second-line targeted therapy, particularly in both the International Metastatic Renal Cell Carcinoma Database Consortium poor-risk group and everolimus-treated group.

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Should We Try Antiandrogen Withdrawal in Castration-Resistant Prostate Cancer Patients? Insights From a Retrospective Study

Hongo Hiroshi, Kosaka Takeo, Mizuno Ryuichi, Ezaki Taisuke, Matsumoto Kazuhiro, Morita Shinya, Shinoda Kazunobu, Shinojima Toshiaki, Kikuchi Eiji, Miyajima Akira, Oya Mototsugu

Clinical Genitourinary Cancer 2016年01月

ISSN 1558-7673

Background: It remains uncertain whether those with response to antiandrogen withdrawal (AAW) have a better prognosis. We investigated the predictors of a better response to AAW and overall survival after acquiring resistance to first-line androgen deprivation therapy inpatients with castration-resistant prostate cancer (CRPC). Patients and Methods: We retrospectively reviewed the medical records of 87 CRPC patients treated at Keio University Hospital. Sixty-seven of 87 CRPC patients underwent AAW. We analyzed clinicopathologic parameters to identify predictors of survival in CRPC patients and investigated predictors of good response to AAW. Results: Younger age, longer duration of androgen deprivation therapy before CRPC development, and better response to AAW were independent favorable prognostic factors for overall survival. Although better response to AAW was a favorable prognostic factor in this study, trying AAW was not significantly related to overall survival. Duration of hormone therapy was significantly longer in those whose disease responded to AAW (69.9 ± 11.0 months) than those with no response (45.3 ± 5.2 months). Conclusion: The prognostic benefit of AAW was not clearly determined in this study. However, AAW might be beneficial in patients who have favorable prognostic factors for a response to AAW-that is, those who have received hormone therapy for a long period. However, AAW should not be done in patients who do not have favorable factors and who had a high prostate-specific antigen level at the time of their prostate cancer diagnosis.

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A multicenter phase I/II study of enzalutamide in Japanese patients with castration-resistant prostate cancer

Akaza Hideyuki, Uemura Hirotsugu, Tsukamoto Taiji, Ozono Seiichiro, Ogawa Osamu, Sakai Hideki, Oya Mototsugu, Namiki Mikio, Fukasawa Satoshi, Yamaguchi Akito, Uemura Hiroji, Ohashi Yasuo, Maeda Hideki, Saito Atsushi, Takeda Kentaro, Naito Seiji

International Journal of Clinical Oncology 1 - 10 2016年01月

ISSN 1341-9625

Background: The safety, tolerability, pharmacokinetics (PK) and anti-tumor activity of enzalutamide were investigated in patients with castration-resistant prostate cancer (CRPC) in Japan through a multicenter phase I/II study. Methods: In phase I, patients with progressive metastatic CRPC received single, then multiple, ascending doses of enzalutamide 80, 160 or 240 mg/day. After assessment of tolerability at multiple doses of 160 mg/day for 4 weeks, post-docetaxel patients with CRPC and measurable disease were enrolled into phase II; receiving long-term administration of enzalutamide 160 mg/day. Results: Nine and 38 patients were enrolled in phase I and II, respectively. During phase I, enzalutamide was well tolerated in each cohort; PK parameters were similar to those of non-Japanese populations in other studies. By week 12, overall response rate was 5.3 % and clinical benefit rate was 47.4 %. Prostate-specific antigen response rate (≥50 % reduction from baseline) was 28.9 %. Treatment-emergent adverse events reported in >20 % of patients in phase II were decreased weight, decreased appetite and constipation. No seizures were observed. Conclusion: Enzalutamide at 160 mg/day was well tolerated, with PK and safety profiles similar to the non-Japanese population. Anti-tumor activity was observed in post-docetaxel Japanese patients with metastatic CRPC. Apparent differences in anti-tumor activity compared with the AFFIRM study (a phase III trial in a diverse population of patients with CRPC post-docetaxel) may be attributed to differences in treatment history prior to starting enzalutamide. Particularly in Japan, the influence of sequence in hormone treatments, including combined androgen blockade therapy, should be considered. Trial registration: ClinicalTrials.gov NCT01284920.

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Lymphovascular invasion status at transurethral resection of bladder tumors may predict subsequent poor response of T1 tumors to bacillus Calmette-Guérin

Fukumoto Keishiro, Kikuchi Eiji, Mikami Shuji, Miyajima Akira, Oya Mototsugu

BMC Urology 16 （ 1 ） 2016年01月

ISSN 1471-2490

Background: Lymphovascular invasion (LVI) is an important step in the process of tumor dissemination and metastasis outside the primary organ, but the relationship between LVI and the prognosis of T1 non-muscle invasive bladder cancer (NMIBC) has not been fully evaluated. Accordingly, the present study was performed to evaluate whether LVI had an impact on the clinical outcome in patients with T1 NMIBC. Methods: A total of 116 consecutive patients were diagnosed with T1 NMIBC from 1994 to 2013 at Keio University Hospital. All cases were reviewed by a single uro-pathologist. The prognostic significance of LVI was assessed in relation to recurrence and stage progression. Results: The median follow-up period was 53 months. LVI was histologically confirmed in 30 patients (25.9%). There were no significant differences of clinical features between the patients with and without LVI. In T1 patients, univariate analysis demonstrated that LVI positivity was associated with stage progression (p = 0.003), but not with tumor recurrence (p = 0.192). Multivariate analysis confirmed that LVI was independently associated with stage progression (p = 0.006, hazard ratio = 4.00). In 85 patients who received BCG instillation, LVI was independently associated with both tumor recurrence and stage progression (p = 0.036 and 0.024, hazard ratio = 2.19 and 3.76). Conclusions: LVI is a strong indicator of an increased risk of recurrence and progression in BCG-treated patients with T1 NMIBC. This information might assist clinicians to develop appropriate management and counseling strategies for these patients.

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Variant isoforms of CD44 expression in upper tract urothelial cancer as a predictive marker for recurrence and mortality

Hagiwara Masayuki, Kikuchi Eiji, Kosaka Takeo, Mikami Shuji, Saya Hideyuki, Oya Mototsugu

Urologic Oncology: Seminars and Original Investigations 2016年01月

ISSN 1078-1439

Purpose: The variant isoforms of CD44 (CD44v), which has been associated with treatment resistance and tumor recurrence, are contributed to the feature of some of the new cell surface markers for cancer stem cells. The aim of this study is to address the prognostic significant of CD44v expression in upper tract urothelial cancer (UTUC). Materials and methods: We retrospectively analyzed the medical records of 110 patients treated surgically for≥pT2 UTUC. To determine the biological significance of CD44v in UTUC, we examined the immunohistochemical expression of CD44v9 and its association with clinical features and oncological outcomes. Results: During the mean follow-up of 4.8 years, tumor recurrence, including local and distant metastasis, was observed in 57 patients (51.8%), and 42 patients (38.2%) died of the disease. The incidence of ureter cancers was significantly higher in patients expressing CD44v9. In this series, 37 patients in the CD44v9-positive group (45.1%) and 5 (17.9%) in the CD44v9-negative group died of the disease. Kaplan-Meier curves revealed that cancer-specific survival and recurrence-free survival rates were significantly lower in the CD44v9-positive group than in the CD44v9-negative group (P = 0.032 and P = 0.038, respectively). A multivariate analysis identified the expression of CD44v9 as one of the independent risk factors for cancer-specific survival (P = 0.040, hazard ratio = 2.67) in addition to tumor grade G3, and also for recurrence-free survival (P = 0.028, hazard ratio = 2.33), in addition to tumor grade G3 and lymphovascular invasion. Conclusions: The expression of CD44v9 may be a new biomarker of malignant potential in muscle invasive UTUC and provide additional prognostic information in patients with UTUC.

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Prostate cancer stem cell and drug resistance

Kosaka Takeo, Oya Mototsugu

Nihon rinsho. Japanese journal of clinical medicine 74 （ 1 ） 45 - 49 2016年01月

ISSN 0047-1852

Cancer tissues are comprised of cell population including a variety of cells, such as stem cell-like cancer cells, upon which a hierarchical society is constructed. This hypothesis has been applied not only to leukemia, in which the hypothesis was first experimentally confirmed, but also to solid cancers. Recent topics shed light on the modified heterogeneity by various treatments which evolve disease progression. In prostate cancer, the identification of cancer stem cells using surface markers and the relationship with prostate origin are of current interest. This article reviews studies related to the development of prostate cancer and introduce recent progress of our project, focusing on cancer stemness and drug resistance.

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