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論文 - 大家　基嗣

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Can random bladder biopsies be eliminated after bacillus Calmette-Guérin therapy against carcinoma in situ?

Takamatsu K, Matsumoto K, Kikuchi E, Ogihara K, Hayakawa N, Tanaka N, Takeda T, Morita S, Kosaka T, Mizuno R, Asanuma H, Mikami S, Oyama M, Oya M

International urology and nephrology （International Urology and Nephrology） 53 （ 3 ） 465 - 469 2020年10月

研究論文（学術雑誌）, 共著, ISSN 0301-1623

© 2020, Springer Nature B.V. Purpose: Intravesical bacillus Calmette–Guérin (BCG) is the standard of care for bladder carcinoma in situ (CIS). The response to BCG therapy against CIS is generally assessed by random bladder biopsy (RBB). In this study, we examined the necessity of routine RBB after BCG therapy. Methods: We retrospectively identified 102 patients who were initially diagnosed with CIS with or without papillary tumor and received subsequent 6–8-week BCG therapy. Thereafter, all patients underwent voiding cytology analysis, cystoscopy, and RBB to evaluate the effects of BCG therapy. We evaluated the association between clinical parameters (voiding cytology and cystoscopy findings) and the final pathological results by RBB specimens. Results: According to the pathological results of RBB, 30 (29%) patients had BCG-unresponsive disease (remaining urothelial carcinoma was confirmed pathologically) and 20 were diagnosed with CIS. Positive/suspicious voiding cytology and positive cystoscopy findings were well observed in patients who had BCG-unresponsive disease compared with their counterparts (p = 0.116, and p < 0.001, respectively). The sensitivity (Sen.), specificity (Spe.), positive predictive value (PPV), and negative predictive value (NPV) of voiding cytology were 50%, 68%, 39%, and 77%, respectively. The values for cystoscopy findings were as follows: Sen.: 87%, Spe.: 57%, PPV: 46%, and NPV: 91%. The values for their combination (having either of them) were as follows: Sen.: 100%, Spe.: 44%, PPV: 43%, and NPV: 100%. Conclusion: RBB after BCG therapy for patients with negative voiding cytology and negative cystoscopy may be omitted because their risk of BCG-unresponsive disease is significantly low (NPV: 100%).

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Factors affecting renal function preservation among patients not achieving trifecta after laparoscopic partial nephrectomy for clinical T1a renal masses.

Takeda T, Komatsuda A, Yanai Y, Tanaka N, Matsumoto K, Morita S, Kosaka T, Mizuno R, Shinojima T, Asanuma H, Oya M

Asian journal of endoscopic surgery （Asian journal of endoscopic surgery） 13 （ 4 ） 526 - 531 2020年10月

研究論文（学術雑誌）, 共著, ISSN 1758-5902

© 2019 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and John Wiley & Sons Australia, Ltd. INTRODUCTION: The goal of partial nephrectomy for renal tumors is complete tumor removal with the preservation of renal function and no complications. Trifecta (total ischemia time < 25 minutes, negative surgical margins, and no surgical complications) is widely used to evaluate success after partial nephrectomy. We investigated factors affecting renal function preservation among patients not achieving trifecta after laparoscopic partial nephrectomy. METHODS: Sixty-six patients who underwent laparoscopic partial nephrectomy for clinical T1a renal masses between December 2006 and March 2016 were examined. We defined preserved renal function as the preservation of an estimated glomerular filtration rate ≥ 90% 1 year after surgery. We examined factors affecting renal function preservation among patients not achieving trifecta after laparoscopic partial nephrectomy. RESULTS: Thirty out of 66 patients (45%) did not achieve trifecta. In an evaluation of 66 patients, a multivariate analysis identified tumor size (P = .04) as an independent predictor affecting the achievement of trifecta. Tumor size was significantly smaller in the trifecta achievement group (1.9 ± 0.1 cm) than in the non-achievement group (2.2 ± 0.6 cm) (P = .04). We found that renal function was preserved 1 year after surgery in 14 out of the 30 patients not achieving trifecta. In univariate analysis, age (P = .01) was significantly associated with affecting the preservation of renal function among these patients. Patients with preserved renal function were significantly younger (47.8 ± 2.5 years) than those without (58.5 ± 2.9 years) (P = .01). CONCLUSION: Renal function may be preserved in younger patients even if they do not achieve trifecta after partial nephrectomy for small renal masses.

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Significance of tumor microenvironment in acquiring resistance to vascular endothelial growth factor-tyrosine kinase inhibitor and recent advance of systemic treatment of clear cell renal cell carcinoma.

Mikami S, Mizuno R, Kosaka T, Tanaka N, Kuroda N, Nagashima Y, Okada Y, Oya M

Pathology international （Pathology International） 70 （ 10 ） 712 - 723 2020年10月

研究論文（学術雑誌）, 共著, ISSN 1320-5463

© 2020 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd The development of systemic therapies, including vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKI) and mammalian target of rapamycin (mTOR) inhibitors, represents a major breakthrough in the treatment of patients with renal cell carcinoma (RCC). However, inherent resistance is observed in some patients and acquired resistance commonly develops in many patients within several months of the initiation of systemic therapies. Since these treatments rarely cure patients, their aim is to suppress tumor progression and prolong survival. Therefore, the establishment of dependable criteria that predict responses and resistance to systemic therapies is clinically important, and the underlying molecular mechanisms also need to be elucidated for the future development of more effective therapies. We herein review recent advances in research on the molecular mechanisms underlying resistance, with a focus on morphological characteristics, tumor angiogenesis, and the tumor immune microenvironment in RCC and their relationships with VEGF-TKI treatments. Recent therapies using immune checkpoint inhibitors (ICI) and newly developed VEGF-TKI also appear to be effective for advanced RCC, with stable and durable responses to ICI being observed in some RCC patients. These new drugs and their outcomes have been briefly described.

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尿路上皮癌細胞のおける細胞内代謝リプログラミング機構と抗癌剤耐性機序との関連

茂田啓介, 長谷川政徳, 菊地栄次, 小坂威雄, 水野隆一, 大家基嗣

日本癌学会総会記事（(一社)日本癌学会） 79回 OJ1 - 3 2020年10月

共著, ISSN 0546-0476

Prioritising Urological Surgery in the COVID-19 Era: A Global Reflection on Guidelines.

Gravas S, Fournier G, Oya M, Summerton D, Scarpa RM, Chlosta P, Gkialas I, Xie LP, Rasyid N, Bolton D, Gomez R, Klotz L, Kulkarni S, Tanguay S, de la Rosette J, SIU Board of Directors.

European urology focus （European Urology Focus） 6 （ 5 ） 1104 - 1110 2020年09月

研究論文（学術雑誌）, 共著

© 2020 European Association of Urology Background: Determining whether members follow guidelines, including guidelines prepared to help direct practice management during the coronavirus disease 2019 (COVID-19) pandemic, is an important goal for medical associations. Objective: To determine whether practice of urologists is in line with guidelines for the management of common urological conditions during the COVID-19 pandemic produced by leading (inter)national urological associations. Design, setting, and participants: Self-selected urologists completed a voluntary survey available online from March 27 to April 11, 2020 and distributed globally by the Société Internationale d'Urologie. Outcome measurements and statistical analysis: Responses to two survey questions on the (1) management of 14 common urological procedures and (2) priority scoring of 10 common urological procedures were evaluated by practice setting and geographical region using chi-square and one-way analysis of variance analyses, respectively. Results and limitations: There were 2494 respondents from 76 countries. Oncological conditions were prioritised over benign conditions, and benign conditions were deferred when feasible and safe. Oncological conditions with the greatest malignant potential were prioritised over less aggressive cancers. Respondents from Europe were least likely to postpone and most likely to prioritise conditions identified by guidelines as being of the highest priority. Respondents’ priority scoring of urological procedures closely matched the priorities assigned by guidelines. The main limitation of this study is that respondents were self-selected, and access to the survey was limited by language and technology barriers. Conclusions: Prioritisation and management of urological procedures during the COVID-19 pandemic are in line with current guidelines. The greatest agreement was reported in Europe. Observed differences may be related to limited resources in some settings. Patient summary: When deciding how best to treat patients during the coronavirus disease 2019 (COVID-19) pandemic, urologists are taking into account both expert recommendations and the availability of important local resources. Urologists worldwide have a high level of knowledge of coronavirus disease 2019 (COVID-19) guidelines for the management of urological conditions during the pandemic but may need to adapt their practices based on regional resource availability.

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Significance of prophylactic urethrectomy at the time of radical cystectomy for bladder cancer.

Hakozaki K, Kikuchi E, Ogihara K, Shigeta K, Abe T, Miyazaki Y, Kaneko G, Maeda T, Yoshimine S, Kanai K, Ide H, Shirotake S, Oyama M, Mizuno R, Oya M

Japanese journal of clinical oncology （Japanese journal of clinical oncology） 51 （ 2 ） 287 - 295 2020年09月

研究論文（学術雑誌）, 共著, ISSN 0368-2811

BACKGROUND: Prophylactic urethrectomy at the time of radical cystectomy is frequently recommended for patients with bladder cancer at a high risk of urethral recurrence without definitive evidence. The present study attempted to clarify the survival benefits of performing prophylactic urethrectomy. METHODS: We identified 214 male patients who were treated by radical cystectomy with an incontinent urinary diversion in our seven institutions between 2004 and 2017. We used propensity score matching and ultimately identified 114 patients, 57 of whom underwent prophylactic urethrectomy (prophylactic urethrectomy group) and 57 who did not (non-prophylactic urethrectomy group). RESULTS: No significant differences were observed in the 5-year overall survival rate between the prophylactic urethrectomy and non-prophylactic urethrectomy groups in the overall. However, the local recurrence rate was significantly lower in the prophylactic urethrectomy group than in the non-prophylactic urethrectomy group (P = 0.015). In the subgroup of 58 patients with multiple tumours and/or concomitant carcinoma in situ at the time of transurethral resection of bladder tumour, the 5-year overall survival rate was significantly higher in the prophylactic urethrectomy group than in the non-prophylactic urethrectomy group (P = 0.021). A multivariate analysis revealed that performing prophylactic urethrectomy was the only independent predictor of the overall survival rate (P = 0.016). In those patients who were treated without neoadjuvant chemotherapy (n = 38), the 5-year overall survival rate was significantly higher in the prophylactic urethrectomy group than in the non-prophylactic urethrectomy group (P = 0.007). CONCLUSIONS: Prophylactic urethrectomy at the time of radical cystectomy may have a survival benefit in patients with multiple tumours and/or concomitant carcinoma in situ, particularly those who do not receive neoadjuvant chemotherapy.

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Relationship between radiation doses and erectile function deterioration in patients with localized prostate cancer treated with permanent prostate brachytherapy.

Shigeta K, Kikuchi E, Matsushima M, Ogihara K, Kosaka T, Mizuno R, Tanaka T, Shigematsu N, Oya M

International journal of urology : official journal of the Japanese Urological Association （International Journal of Urology） 27 （ 12 ） 1087 - 1093 2020年09月

研究論文（学術雑誌）, 共著, ISSN 0919-8172

© 2020 The Japanese Urological Association Objectives: To investigate the relationship between radiation doses in prostate brachytherapy and deterioration of erectile function in patients with localized prostate cancer. Methods: A longitudinal survey study was carried out among 261 prostate cancer patients who received prostate brachytherapy. A total of 48 patients were potent at baseline and they did not receive any supplemental therapy preoperatively. Dosimetry parameters of the whole prostate gland, prostate apex, urethra and rectum were collected using the VariSeed 8.0 treatment planning system (Varian Medical Systems, Palo Alto, CA, USA). We carried out a logistic regression analysis to clarify the relationship between radiation doses and erectile function deterioration, which was assessed using the International Index of Erectile Function-15 questionnaire. Results: The median patient age was 66 years (range 53–70 years) with a median follow-up time of 44 months (36–71 months). The mean total International Index of Erectile Function-15 score decreased from 49.9 at baseline to 34.7 after 12 months (P < 0.001), but gradually plateaued within 36 months. Erectile function deterioration was noted in 32 (66.7%) patients 36 months after prostate brachytherapy. In an analysis of risk factors for erectile function deterioration after prostate brachytherapy, age ≥70 years (P = 0.029), prostate V100 ≥95% (P = 0.024), apex V100 ≥95% (P = 0.024), apex V150 ≥70% (P = 0.009) and apex D90 ≥150 Gy (P = 0.011) correlated with erectile function deterioration. A multivariate analysis identified an age of ≥70 years (odds ratio 7.91, P = 0.024) and apex V150 ≥70% (odds ratio 7.75, P = 0.007) as independent risk factors for erectile function deterioration after prostate brachytherapy. Conclusions: An excessive radiation dose, particularly to the prostate apex area, and an advanced age might have a negative impact on the preservation of potency after prostate brachytherapy.

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Influence of chemoradiotherapy on nutritional status in locally advanced rectal cancer: Prospective multicenter study

Yamano Tomoki, Tomita Naohiro, Sato Takeo, Hayakawa Kazushige, Kamikonya Norihiko, Matoba Shuichiro, Uki Akiyoshi, Baba Hideo, Oya Natsuo, Hasegawa Hirotoshi, Shigematsu Naoyuki, Hiraoka Masahiro, Shimada Mitsuo, Noda Masafumi, Sakai Yoshiharu, Sato Hirohiko, Saegusa Makoto, Takeuchi Masahiro, Oguchi Masahiko, Oya Masatoshi, Watanabe Masahiko

NUTRITION 77 2020年09月

ISSN 0899-9007

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Three-dimensional single-cell imaging for the analysis of RNA and protein expression in intact tumour biopsies.

Tanaka N, Kanatani S, Kaczynska D, Fukumoto K, Louhivuori L, Mizutani T, Kopper O, Kronqvist P, Robertson S, Lindh C, Kis L, Pronk R, Niwa N, Matsumoto K, Oya M, Miyakawa A, Falk A, Hartman J, Sahlgren C, Clevers H, Uhlén P

Nature biomedical engineering （Nature Biomedical Engineering） 4 （ 9 ） 875 - 888 2020年09月

研究論文（学術雑誌）, 共著, ISSN 2157-846X

© 2020, The Author(s), under exclusive licence to Springer Nature Limited. Microscopy analysis of tumour samples is commonly performed on fixed, thinly sectioned and protein-labelled tissues. However, these examinations do not reveal the intricate three-dimensional structures of tumours, nor enable the detection of aberrant transcripts. Here, we report a method, which we name DIIFCO (for diagnosing in situ immunofluorescence-labelled cleared oncosamples), for the multimodal volumetric imaging of RNAs and proteins in intact tumour volumes and organoids. We used DIIFCO to spatially profile the expression of diverse coding RNAs and non-coding RNAs at the single-cell resolution in a variety of cancer tissues. Quantitative single-cell analysis revealed spatial niches of cancer stem-like cells, and showed that the niches were present at a higher density in triple-negative breast cancer tissue. The improved molecular phenotyping and histopathological diagnosis of cancers may lead to new insights into the biology of tumours of patients.

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Pyometra in a hemodialysis patient with severe constipation.

Morimoto K, Yoshida T, Oya M

Clinical and experimental nephrology （Clinical and Experimental Nephrology） 24 （ 9 ） 849 - 849 2020年09月

研究論文（学術雑誌）, 共著, ISSN 1342-1751

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Evaluating the Oncological Outcomes of Pure Laparoscopic Radical Nephroureterectomy Performed for Upper-Tract Urothelial Carcinoma Patients: A Multicenter Cohort Study Adjusted by Propensity Score Matching.

Shigeta K, Matsumoto K, Takeda T, Hattori S, Kaneko G, Matsushima M, Abe T, Tanaka N, Mizuno R, Asanuma H, Kikuchi E, Oya M

Annals of surgical oncology （Annals of Surgical Oncology） 28 （ 1 ） 465 - 473 2020年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1068-9265

© 2020, Society of Surgical Oncology. Purpose: To evaluate the oncological feasibility of pure laparoscopic radical nephroureterectomy (p-LRNU) for upper tract urothelial carcinoma (UTUC) compared with conventional LRNU (c-LRNU) using a propensity-adjusted multi-institutional collaboration dataset. Methods: Among the 503 UTUC patients who underwent RNU, we identified 219 who underwent c-LRNU (laparoscopic nephrectomy with open bladder cuff resection) and 72 who underwent p-LRNU (dissecting the kidney, ureter, and bladder cuff under complete laparoscopy). We adopted a propensity score (PS) matching method to achieve homogeneity with respect to patient backgrounds. PS matching-adjusted Cox-regression analysis was performed to evaluate the risk factors that influenced oncological outcomes. Results: Sixty-eight p-LRNU and 68 c-LRNU patients were matched. Overall, 51 (37.0%) developed intravesical recurrence (IVR), 21 (15.4%) had disease recurrence, and 20 (14.7%) died. Patients who underwent p-LRNU had a significantly shorter operation time and less blood loss than those who underwent c-LRNU. Although no significant differences in 3-year recurrence-free survival were found between the two methods, atypical recurrence sites were observed in the p-LRNU group, including the brain, sigmoid colon, vagina, and peritoneum. Regarding IVR, the 3-year IVR-free survival rate was 41.8% in the p-LRNU group, which was significantly lower than that in the c-LRNU group (66.6%, p = 0.004). Multivariate analysis demonstrated that a history of bladder cancer, ureteral cancer, and p-LRNU were independent risk factors for subsequent IVR. Conclusion: Although p-LRNU is less invasive, the current technique may increase the incidence of atypical disease recurrence and subsequent IVR due to extravesical and intravesical tumor dissemination.

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Clinical utility of the Vesical Imaging-Reporting and Data System for muscle-invasive bladder cancer between radiologists and urologists based on multiparametric MRI including 3D FSE T2-weighted acquisitions.

Arita Y, Shigeta K, Akita H, Suzuki T, Kufukihara R, Kwee TC, Ishii R, Mikami S, Okuda S, Kikuchi E, Oya M, Jinzaki M

European radiology （European Radiology） 31 （ 2 ） 875 - 883 2020年08月

研究論文（学術雑誌）, 共著, ISSN 0938-7994

© 2020, European Society of Radiology. Objectives: To investigate the clinical utility of the Vesical Imaging-Reporting and Data System (VI-RADS) by comparing its diagnostic performance for muscle-invasive bladder cancer (MIBC) between radiologists and urologists based on multiparametric MRI, including three-dimensional (3D) fast spin-echo (FSE) T2-weighted acquisitions. Methods: This study included 66 treatment-naïve patients (60 men, 6 women; mean age 74.0 years) with pathologically proven bladder cancer who underwent multiparametric MRI, including 3D FSE T2-weighted imaging, before transurethral bladder tumour resection between January 2010 and November 2018. The MRI scans were categorised according to the five-point VI-RADS score by four independent readers (two board-certified radiologists and board-certified urologists each), blinded to the histopathological findings. The VI-RADS scores were compared with the postoperative histopathological diagnosis. Interobserver agreement was assessed using weighted kappa coefficients. ROC analysis and generalised estimating equations were used to evaluate the diagnostic performance. Results: Forty-nine (74.2%) and 17 (25.8%) tumours were confirmed to be non-MIBC and MIBC, respectively, based on pathological examination. The interobserver agreement was good-to-excellent between all pairs of readers (range, 0.73–0.91). The urologists’ sensitivity/specificity values for DCE-MRI VI-RADS scores were significantly lower than those of radiologists. No significant differences were observed for the overall VI-RADS score. The AUC for the overall VI-RADS score was 0.94, 0.92, 0.89, and 0.87 for radiologists 1 and 2 and urologists 1 and 2, respectively. Conclusions: The VI-RADS score, based on multiparametric MRI including 3D FSE T2-weighted acquisitions, can be useful for radiologists and urologists to determine the bladder cancer muscle invasion status preoperatively. Key Points: • VI-RADS (using multiparametric MRI including 3D FSE T2-weighted acquisitions) achieves good to excellent interobserver agreement and has similar diagnostic performance for detecting muscle invasion by both radiologists and urologists. • The diagnostic performance of the overall VI-RADS score is high for both radiologists and urologists, particularly due to the dominant effect of diffusion-weighted imaging on the overall VI-RADS score. • The sensitivity and specificity values of the T2WI VI-RADS scores for four readers in our study (using 3D FSE T2-weighted acquisitions) were similar (with slightly higher specificity values) to previously published results (using 2D FSE T2-weighted acquisitions).

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ASO Author Reflections: Discussing the Oncological Feasibility of Performing Pure Laparoscopic Radical Nephroureterectomy for Upper-Tract Urothelial Carcinoma Patients: Results from a Multi-institution Collaborative Study Adjusted by Propensity Score Matching.

Shigeta K, Matsumoto K, Oya M

Annals of surgical oncology （Annals of Surgical Oncology） 28 （ 1 ） 474 - 475 2020年08月

研究論文（学術雑誌）, 共著, ISSN 1068-9265

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Reduced recurrence of low-risk non-muscle-invasive bladder cancer is associated with low urine-specific gravity.

Iwasawa T, Niwa N, Matsumoto K, Komatsuda A, Ide H, Oya M

International journal of urology : official journal of the Japanese Urological Association （International Journal of Urology） 27 （ 11 ） 1019 - 1023 2020年08月

研究論文（学術雑誌）, 共著, ISSN 0919-8172

© 2020 The Japanese Urological Association Objective: To investigate the association between urine-specific gravity and oncological outcomes in patients with non-muscle-invasive bladder cancer. Methods: We identified 433 primary non-muscle-invasive bladder cancer patients who underwent transurethral resection between 2002 and 2016. The association between urine-specific gravity and tumor recurrence was statistically evaluated. Results: A total of 211 (48.7%) patients received adjuvant bacillus Calmette–Guérin therapy. During the median follow-up period of 60 months, 155 (35.8%) patients experienced at least one tumor recurrence. Of them all, 95 (21.9%) and 338 (78.1%) patients had high (>1.020) and low (≤1.020) urine-specific gravity, respectively. The Kaplan–Meier curve suggested that recurrence-free survival was significantly lower in patients with a high urine-specific gravity; however, the multivariate analysis failed to show that urine-specific gravity is significantly associated with tumor recurrence. In 222 (51.3%) patients who had not received bacillus Calmette–Guérin therapy, the Kaplan–Meier curve also suggested that recurrence-free survival was significantly lower in patients with a high urine-specific gravity. Multivariate analysis showed that age >70 years (hazard ratio 1.69, P = 0.02), grade 3 tumor (hazard ratio 1.81, P = 0.03) and high urine-specific gravity (hazard ratio 1.87, P < 0.01) were independent risk factors for tumor recurrence. Conclusion: High urine-specific gravity is an independent risk factor for tumor recurrence in non-muscle-invasive bladder cancer patients who have not received bacillus Calmette–Guérin therapy. Our results suggest that hydration status might have some clinical impacts on bladder tumor recurrence.

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Cabozantinib in advanced renal cell carcinoma: A phase II, open-label, single-arm study of Japanese patients.

Tomita Y, Tatsugami K, Nakaigawa N, Osawa T, Oya M, Kanayama H, Nakayama Kondoh C, Sassa N, Nishimura K, Nozawa M, Masumori N, Miyoshi Y, Kuroda S, Tanaka S, Kimura A, Tamada S

International journal of urology : official journal of the Japanese Urological Association （International Journal of Urology） 27 （ 11 ） 952 - 959 2020年08月

研究論文（学術雑誌）, 共著, ISSN 0919-8172

© 2020 The Authors. International Journal of Urology published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Urological Association Objectives: To evaluate the efficacy and safety of cabozantinib, through a bridging study to METEOR, in Japanese patients with advanced renal cell carcinoma who had progressed after prior tyrosine kinase inhibitor therapy. Methods: This phase II, open-label, single-arm study (ClinicalTrials.gov registration number: NCT03339219) included adult Japanese patients with advanced renal cell carcinoma and measurable disease who had received one or more tyrosine kinase inhibitors. Patients received cabozantinib 60 mg orally once daily while there was clinical benefit, or until unacceptable toxicity or disease progression. The primary end-point was objective response rate per Response Evaluation Criteria in Solid Tumors Version 1.1. Secondary end-points included clinical benefit rate (complete or partial response, or ≥8-week stable disease), progression-free survival, overall survival and safety. Results: Of the 35 patients enrolled, 68.6%, 22.9% and 8.6% had previously received one, two and three prior tyrosine kinase inhibitors, respectively. The median duration of cabozantinib exposure was 27.0 weeks (range 5.1–43.0 weeks). The objective response rate was 20.0% (90% confidence interval 9.8–34.3%), and the clinical benefit rate was 85.7% (95% confidence interval 69.7–95.2%). The 6-month estimated progression-free survival was 72.3% (95% confidence interval 53.3–84.6%); the median progression-free survival and overall survival were not reached. All patients reported adverse events, which were manageable by supportive treatment or dose modification; two patients (5.7%) discontinued therapy due to adverse events. Conclusions: The results showed that findings from METEOR can be extrapolated, and that cabozantinib 60 mg/day is a viable treatment option in Japanese patients with advanced renal cell carcinoma who had progressed after prior tyrosine kinase inhibitor therapy.

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Dehydroxymethylepoxyquinomicin, a novel nuclear factor-κB inhibitor, prevents the development of cyclosporine A nephrotoxicity in a rat model.

Morita S, Shinoda K, Yoshida T, Shimoda M, Kanno Y, Mizuno R, Kono H, Asanuma H, Nakagawa K, Umezawa K, Oya M

BMC pharmacology & toxicology （BMC Pharmacology and Toxicology） 21 （ 1 ） 60 - 60 2020年08月

研究論文（学術雑誌）, 共著

© 2020 The Author(s). Background: Cyclosporine A (CsA) is an essential immunosuppressant in organ transplantation. However, its chronic nephrotoxicity is an obstacle to long allograft survival that has not been overcome. Nuclear factor-κB (NF-κB) is activated in the renal tissue in CsA nephropathy. In this study, we aimed to investigate the effect of the specific NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), in a rat model of CsA nephrotoxicity. Methods: We administered CsA (15 mg/kg) daily for 28 days to Sprague-Dawley rats that underwent 5/6 nephrectomy under a low-salt diet. We administered DHMEQ (8 mg/kg) simultaneously with CsA to the treatment group, daily for 28 days and evaluated its effect on CsA nephrotoxicity. Results: DHMEQ significantly inhibited NF-κB activation and nuclear translocation due to CsA treatment. Elevated serum urea nitrogen and creatinine levels due to repeated CsA administration were significantly decreased by DHMEQ treatment (serum urea nitrogen in CsA + DHMEQ vs CsA vs control, 69 ± 6.4 vs 113.5 ± 8.8 vs 43.1 ± 1.1 mg/dL, respectively, p < 0.0001; serum creatinine in CsA + DHMEQ vs CsA vs control, 0.75 ± 0.02 vs 0.91 ± 0.02 vs 0.49 ± 0.02 mg/dL, respectively, p < 0.0001), and creatinine clearance was restored in the treatment group (CsA + DHMEQ vs CsA vs control, 2.57 ± 0.09 vs 1.94 ± 0.12 vs 4.61 ± 0.18 ml/min/kg, respectively, p < 0.0001). However, DHMEQ treatment did not alter the inhibitory effect of CsA on urinary protein secretion. The development of renal fibrosis due to chronic CsA nephrotoxicity was significantly inhibited by DHMEQ treatment (CsA + DHMEQ vs CsA vs control, 13.4 ± 7.1 vs 35.6 ± 18.4 vs 9.4 ± 5.4%, respectively, p < 0.0001), and these results reflected the results of renal functional assessment. DHMEQ treatment also had an inhibitory effect on the increased expression of chemokines, monocyte chemoattractant protein-1, and chemokine (c-c motif) ligand 5 due to repeated CsA administration, which inhibited the infiltration of macrophages and neutrophils into the renal tissue. Conclusions: These findings suggest that DHMEQ treatment in combination therapy with CsA-based immunosuppression is beneficial to prevent the development of CsA-induced nephrotoxicity.

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Evaluation of Gleason Grade Group 5 in a Contemporary Prostate Cancer Grading System and Literature Review.

Kamitani R, Matsumoto K, Kosaka T, Takeda T, Hashiguchi A, Tanaka N, Morita S, Mizuno R, Shinojima T, Asanuma H, Oya M

Clinical genitourinary cancer （Clinical Genitourinary Cancer） 19 （ 1 ） 69 - 75.e5 2020年08月

研究論文（学術雑誌）, 共著, ISSN 1558-7673

© 2020 Elsevier Inc. Introduction: The aim of this study was to validate contemporary grading systems, in particular, the Gleason grade group (GGG) 5. Patients and Methods: We retrospectively reviewed the clinicopathologic data of 176 patients who underwent radical prostatectomy and whose pathologic results were GGG 4 or 5. The endpoints were biochemical recurrence (BCR) and castration-resistant prostate cancer (CRPC). Results: The GGG 4 group was composed of 69 patients. The GGG 5 group consisted of 78 patients with GS 4+5 and 29 patients with GS 5+4 or higher. The 5-year BCR-free survival rates for men with GGG 4, GS 4+5, and GS 5+4 or higher were 59%, 54%, and 20%, respectively, and the 5-year CRPC-free survival rates were 98%, 100%, and 88%, respectively. Both the BCR- and CRPC-free survival rates were significantly higher in GS 4+5 than in GS 5+4 or higher (P < .001 and P = .002, respectively), but there were no significant differences between GGG 4 and GS 4+5 (P = .702 and P = .803, respectively). The multivariate analysis demonstrated that GS 5+4 or higher (hazard ratio, 3.4; P = .002) and lymphovascular invasion (hazard ratio, 3.4; P < .001) greatly affected BCR. Conclusion: Our follow-up study revealed that men with GS 4+5 and those with GGG 4 had a similar prognosis. However, there was a significant discrepancy in prognosis between GS 4+5 and GS 5+4 or higher. This suggested that GGG 4 and 5 in the contemporary prostate cancer grading system should be reviewed. Furthermore, lymphovascular invasion may be useful to subgroup these pathologically high-risk patients.

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A Japanese patient with ductal carcinoma of the prostate carrying an adenomatosis polyposis coli gene mutation: a case report.

Umeda K, Kosaka T, Nakamura K, Takeda T, Mikami S, Nishihara H, Oya M

Diagnostic pathology （Diagnostic Pathology） 15 （ 1 ） 102 - 102 2020年08月

研究論文（学術雑誌）, 共著

© 2020 The Author(s). Background: Ductal carcinoma of the prostate is a histological subtype with a higher mortality than acinar adenocarcinoma. The number of cases is small and there are no treatment guidelines. We believe that this is the first report of ductal carcinoma of the prostate with an adenomatosis polyposis coli (APC) gene mutation in Japan. Case presentation: An 85-year-old man presented with gross hematuria, and a papillary tumor in the prostatic urethra that was diagnosed as ductal carcinoma of the prostate following transurethral resection. Genetic analysis found an APC mutation with loss of heterozygosity. Immunostaining revealed focal nuclear translocation of β-catenin. APC mutations associated with loss of β-catenin degradation in the Wnt signaling pathway and result in over accumulation of β-catenin are thought to increase mortality. In this patient, β-catenin migrated into tumor cell nuclei. Conclusion: To the best of our knowledge, this is the first report of ductal carcinoma of the prostate with an APC mutation in Japan. The development of a therapeutic Wnt inhibitor is discussed.

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Real-world use of temsirolimus in Japanese patients with unresectable or metastatic renal cell carcinoma: recent consideration based on the results of a post-marketing, all-case surveillance study.

Sugiyama S, Sato K, Shibasaki Y, Endo Y, Uryu T, Toyoshima Y, Oya M, Miyanaga N, Saijo N, Gemma A, Akaza H

Japanese journal of clinical oncology （Japanese Journal of Clinical Oncology） 50 （ 8 ） 940 - 947 2020年08月

研究論文（学術雑誌）, 共著, ISSN 0368-2811

© The Author(s) 2020. Published by Oxford University Press. All rights reserved. Objective: A prospective, observational, post-marketing surveillance was conducted to assess the safety and effectiveness of temsirolimus in patients with renal cell carcinoma in Japan. Methods: Patients prescribed temsirolimus for advanced renal cell carcinoma were registered and received temsirolimus (25 mg weekly, intravenous infusion for 30-60 minutes) in routine clinical settings (observation period: 96 weeks). Results: Among 1001 patients included in the safety analysis data set (median age, 65.0 years; men, 74.8%; Eastern Cooperative Oncology Group performance status 0 or 1, 69.6%), 778 (77.7%) reported adverse drug reactions. The most common (≥10%) all-grade adverse drug reactions were stomatitis (26.7%), interstitial lung disease (17.3%) and platelet count decreased (11.1%). The incidence rate of grade ≥3 interstitial lung disease was 4.5%. The onset of interstitial lung disease was more frequent after 4-8 weeks of treatment or in patients with lower Eastern Cooperative Oncology Group performance status (21.6% for score 0 vs 8.3% for score 4, P < 0.001). Among 654 patients in the effectiveness analysis data set, the response and clinical benefit rates were 6.7% (95% confidence interval 4.9-8.9) and 53.2% (95% confidence interval 49.3-57.1), respectively. The median progression-free survival was 18.3 weeks (95% confidence interval 16.9-21.1). Conclusions: The safety and effectiveness profile of temsirolimus observed in this study was similar to that observed in the multinational phase 3 study. The results are generalizable to the real-world scenario at the time of this research, and safety and effectiveness of temsirolimus as a subsequent anticancer therapy for renal cell carcinoma warrants further investigation.

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A comparison of laparoendoscopic single-site surgery versus conventional procedures for laparoscopic donor nephrectomy: a Japanese multi-institutional retrospective study.

Inoue T, Miura M, Yanishi M, Furukawa J, Sato F, Nitta M, Yoshimura K, Hagiuda J, Shinoda K, Kobayashi T, Miyajima A, Nakagawa K, Oya M, Ogawa O, Mimata H, Kanayama HO, Fujisawa M, Terachi T, Matsuda T, Habuchi T, LESS and RPS Research Group in Japanese Society of Endourology.

Surgical endoscopy （Surgical Endoscopy） 34 （ 8 ） 3424 - 3434 2020年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0930-2794

© 2019, Springer Science+Business Media, LLC, part of Springer Nature. Purpose: Laparoendoscopic single-site donor nephrectomy (LESSDN) is a feasible and effective procedure because of its non-invasiveness and better cosmetic outcomes. However, there have been few multi-institutional studies conducted by multiple surgeons on LESSDN. We retrospectively compared the clinical data and outcomes between LESSDN and conventional laparoscopic donor nephrectomy (LDN) at multiple institutes in Japan. Materials and methods: From 2009 to 2015, the clinical data of 223 donors who underwent LESSDN and 151 donors who underwent LDN were collected from 10 institutes. All LESSDNs were performed transperitoneally, whereas LDNs were performed transperitoneally (P-LDN) in 75 patients and retroperitoneally (R-LDN) in 76 patients. Results: In the LESSDN group, the single-incision site was pararectal in 155 (69.5%) patients and umbilical in 65 (29.1%) patients. Multiple surgeons (one to eight per institute) performed the LESSDN. No significant differences were observed between the three groups regarding estimated blood loss and warm ischemic time. The operative time was significantly shorter in the LESSDN group than in the R-LDN group (p = 0.018). No significant differences were observed regarding the rates of blood transfusion, open conversion, visceral injuries, and postoperative complications. Furthermore, no significant differences were observed regarding the dose of analgesic and the rate of delayed graft function. One patient required open conversion due to injury to the renal artery. Selection of LESS procedure was not an independent risk factor for the median serum creatinine level of above 1.27 mg/dL in recipients at 1 year after kidney transplantation. Conclusion: The results showed the technical feasibility of LESSDN compared with the standard LDNs in a multi-institutional and multi-surgeon setting. A few observed non-negligible complications and the significantly higher levels of serum creatinine in patients who underwent LESSDN indicate that this procedure should be employed cautiously when performed by surgeons without ample experience in performing LESS procedures.

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