Details of a Researcher - Tanaka, Nobuyuki

Papers - Tanaka, Nobuyuki

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BCG-induced cytokine release in bladder cancer cells is regulated by Ca 2+ signaling

Ibarra C., Karlsson M., Codeluppi S., Varas-Godoy M., Zhang S., Louhivuori L., Mangsbo S., Hosseini A., Soltani N., Kaba R., Kalle Lundgren T., Hosseini A., Tanaka N., Oya M., Wiklund P., Miyakawa A., Uhlén P.

Molecular Oncology (Molecular Oncology) 13 ( 2 ) 202 - 211 2019.02

ISSN 15747891

© 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. Bacillus Calmette–Guérin (BCG) is widely used in the clinic to effectively treat superficial urinary bladder cancer. However, a significant proportion of patients who fail to respond to BCG risk cystectomy or death. Though more than 3 million cancer treatments with BCG occur annually, surprisingly little is known about the initial signaling cascades activated by BCG. Here, we report that BCG induces a rapid intracellular Ca 2+ (calcium ion) signal in bladder cancer cells that is essential for activating the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and for synthesizing and secreting proinflammatory cytokines, including interleukin 8 (IL-8). A similar Ca 2+ response was observed when cells were exposed to the supernatant of BCG. Studying cellular molecular mechanisms involved in the BCG signaling event, we found pivotal roles for phospholipase C and the Toll-like receptor 4. Further assessment revealed that this signaling pathway induces synthesis of IL-8, whereas exocytosis appeared to be controlled by global Ca 2+ signaling. These results shed new light on the molecular mechanisms underlying BCG treatment of bladder cancer, which can help in improving therapeutic efficacy and reducing adverse side effects.

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Impact of inflammatory marker levels one month after the first-line targeted therapy initiation on progression-free survival prediction in patients with metastatic clear cell renal cell carcinoma

Ito K., Masunaga A., Tanaka N., Mizuno R., Shirotake S., Yasumizu Y., Ito Y., Miyazaki Y., Hagiwara M., Kanao K., Mikami S., Momma T., Masuda T., Nakagawa K., Oyama M., Asano T., Oya M.

Japanese Journal of Clinical Oncology (Japanese Journal of Clinical Oncology) 49 ( 1 ) 69 - 76 2019

ISSN 03682811

© The Author(s) 2018. Published by Oxford University Press. All rights reserved. Objectives: Progression-free survival of first-line targeted therapy greatly influences the survival of patients with metastatic renal cell carcinoma. We evaluated whether post-treatment inflammatory markers and lactate dehydrogenase levels had impacts on progression-free survival prediction in addition to those of conventional predictors. Methods: Two hundred and fifteen patients whose tumors were clear cell type and in whom first-line targeted therapies could be continued for >1 month were evaluated. Pretreatment clinical factors, pathological factors and laboratory data 1 month after targeted therapy initiation—including inflammatory markers (neutrophil count, neutrophil-to-lymphocyte ratio and C-reactive protein) and lactate dehydrogenase—were reviewed. To identify progression-free survival predictors, multivariate analyses were done. Results: The 1-year progression-free survival rate was 47%. Female gender, Karnofsky performance status <80%, time from diagnosis to systemic treatment <12 months, pretreatment C-reactive protein >3.0 mg/dl and post-treatment neutrophil-to-lymphocyte ratio >3.0 were independent predictors for progression-free survival. In contrast, neither C-reactive protein increase nor neutrophil-to-lymphocyte ratio increase after targeted therapy initiation were independent predictors. Pretreatment lactate dehydrogenase, post-treatment lactate dehydrogenase and lactate dehydrogenase decline were not independent predictors. When all patients were stratified by these independent factors into three groups (0 risk vs. 1 or 2 risks vs. 3 or more risks), there were significant differences in progression-free survival rates between the groups (P < 0.0001). Furthermore, there were also significant differences in overall survival rates between the groups (P < 0.0001). Conclusions: Integration of post-treatment neutrophil-to-lymphocyte ratio value with pretreatment factors may lead to the establishment of effective predictive model for disease progression in patients with metastatic clear cell renal cell carcinoma who received first-line targeted therapies.

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The prognostic value of zonal origin and extraprostatic extension of prostate cancer for biochemical recurrence after radical prostatectomy

Takamatsu K., Matsumoto K., Shojo K., Tanaka N., Takeda T., Morita S., Kosaka T., Mizuno R., Shinojima T., Kikuchi E., Asanuma H., Oya M.

Urologic Oncology: Seminars and Original Investigations (Urologic Oncology: Seminars and Original Investigations) 37 ( 9 ) 575.e19 - 575.e25 2019

ISSN 10781439

© 2019 Elsevier Inc. Objective: To investigate the influence of the zonal origin of prostate cancer and extraprostatic extension on biochemical recurrence (BCR). Patients and methods: We included 638 consecutive patients undergoing radical prostatectomy between 2005 and 2015 who did not receive neoadjuvant/adjuvant therapy. The largest lesion was defined as the index tumor. We categorized each patient into the transition zone (TZ) or peripheral zone (PZ) group based on the lesion where the index tumor existed. Differences in the BCR defined as increasing prostate-specific antigen rate between groups were examined by Kaplan-Meier analysis and the Cox proportional hazards model. Results: There were 293 (46%) patients with TZ cancer and 345 (54%) with PZ cancer. TZ cancer was significantly associated with a higher prostate-specific antigen (P = 0.012), lower biopsy positive core rate (P = 0.020), lower pathological Gleason score (P = 0.017), lower pathological stage (P = 0.002), and lower rate of seminal vesicle invasion (P = 0.002). During a median follow-up period of 59 months, 79 patients (12%) developed BCR. In the entire cohort, the PZ origin (hazard ratio: 1.68, P = 0.033) and extraprostatic extension were independent risk factors for BCR. The 3-, 5-, and 7-year BCR-free survival rates of patients with pT3a TZ cancer were 89%, 88%, and 86%, respectively, which were significantly better than those of patients with pT3a PZ cancer (80%, 74%, and 62%, P = 0.012), but were similar to those of the pT2 cancer cohort (92%, 91%, and 90%, P = 0.376). Conclusion: TZ cancer had more favorable pathological characteristics and oncological outcome than PZ cancer especially in pT3a cases.

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Volumetric imaging: a potential tool to stage upper tract urothelial carcinoma

Grahn A., Tanaka N., Uhlén P., Brehmer M.

World Journal of Urology (World Journal of Urology) 37 ( 11 ) 2297 - 2302 2019

ISSN 07244983

© 2019, The Author(s). Purpose: To investigate whether volumetric imaging of tumor vasculature can be used to phenotypically characterize advanced upper tract urothelial carcinoma, and if this technique can distinguish aggressive invasive tumors from non-aggressive superficial ones. Methods: In a pilot study, two TaG1 and two T3G3 formalin-fixed paraffin-embedded (FFPE) tumor samples were examined using the DIPCO pipeline (Tanaka et al. in Nature Biomed Eng 1(10):796–806. https://doi.org/10.1038/s41551-017-0139-0, 2017). Briefly, punch biopsies of FFPE tumors were deparaffinized, cleared, immunolabeled with the vessel marker CD34 and imaged with a light-sheet microscope. Thereafter, the three-dimensional (3D) vasculature of the tumors was analyzed and characterized using a specialized image processing software. Results: We found that T3G3 tumors had increased CD34 density kurtosis and skewness compared to TaG1 tumors. This suggests that analysis of the 3D vasculature can distinguish between high-grade invasive and low-grade superficial tumors. Conclusions: Volumetric imaging of tumor samples may represent novel methodology that can complement conventional histopathology. Volumetric imaging enabled us to differentiate between invasive and non-invasive upper tract urothelial carcinoma. The method is of particular interest in diagnostic work-up of patients with upper tract urothelial carcinoma as previous findings indicate that volumetric imaging of vascular patterns could be used to differentiate superficial and invasive urothelial carcinoma, irrespective of if the tumor sample was deep or superficial. However, further and more extensive studies are required before this method can be applied clinically.

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Prognostic value of serum C-reactive protein level prior to second-line treatment in intermediate risk metastatic renal cell carcinoma patients

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

International Journal of Clinical Oncology (International Journal of Clinical Oncology) 24 ( 9 ) 1069 - 1074 2019

ISSN 13419625

© 2019, Japan Society of Clinical Oncology. Background: The later-line treatment of metastatic renal cell carcinoma (mRCC) has been drastically changing by the development of immune-oncology drugs and molecular targeted treatment in recent years. Although the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model is useful for second-line setting, this model has the problem that over 50% patients are classified as intermediate risk group. The aim of this study is to evaluate whether the serum C-reactive protein (CRP) levels prior to second-line treatment could divide intermediate risk group patients. Methods: We retrospectively reviewed 82 consequent intermediate-risk mRCC patients who received second-line molecular targeted therapy. We classified patients who had serum CRP higher than 0.5 mg/dl in elevated CRP group because the median baseline serum CRP level before second-line treatment was 0.51 mg/dl. We assessed the prognostic impact of serum CRP levels prior to second-line treatment initiation to predict overall survival (OS). Results: Thirty-three out of 82 (40%) patients demonstrated elevated baseline CRP levels. The median OS of elevated and non-elevated CRP group was 11.5 (95% CI 5.4–17.5) and 29.4 (95% CI 25.5–33.5) months, respectively (p = 0.001). The serum CRP elevation could predict prognosis in intermediate risk patients treated with second-line treatment (HR 2.5, 95% CI 1.4–4.2, p = 0.001). Conclusions: The serum CRP levels after first-line treatment termination could divide intermediate risk group mRCC patients into two prognostic subgroups in second-line targeted treatment setting.

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Type of patients in whom biochemical recurrence after radical prostatectomy can be observed without salvage therapy

Matsumoto K., Niwa N., Hagiwara M., Kosaka T., Tanaka N., Takeda T., Morita S., Mizuno R., Shinojima T., Hara S., Asanuma H., Oya M.

World Journal of Urology (World Journal of Urology) 38 ( 7 ) 1749 - 1756 2019

ISSN 07244983

© 2019, Springer-Verlag GmbH Germany, part of Springer Nature. Purpose: To examine the prognosis after BCR with and without salvage therapy, including radiation and/or androgen deprivation. Methods: The study population consisted of 431 patients, all of whom underwent radical prostatectomy and developed BCR (PSA > 0.2 ng/mL). According to the two risk factors [Gleason score ≥ 8 and PSA-doubling time (DT) < 6 months], we divided the patients into two groups. The high/intermediate-risk group consisted of patients with both or one risk factor. On the other hand, patients with neither factor were in the low-risk group. We set the starting point at the timing of BCR, and the endpoints were development to castration-resistant prostate cancer (CRPC) and cancer-specific death. Results: During the mean follow-up period of 8.3 years after BCR, CRPC was observed in 49 patients (11.4%), and 21 patients (4.9%) died due to prostate cancer. We first divided the 191 high/intermediate-risk patients according to the PSA level (PSA < 1.0 ng/mL, PSA 1.0–4.0, and PSA > 4.0 or no therapy) at the initiation of salvage therapy, including radiation and/or androgen deprivation. We found that delayed (PSA > 4.0 ng/mL) or no salvage therapy was significantly associated with CRPC and cancer-specific death. In the 240 low-risk patients, Kaplan–Meier curves demonstrated no significant difference in CRPC-free survival or cancer-specific survival within 10 years from the timing of BCR. Conclusions: Observation after BCR without salvage therapy or delayed administration may be an option for low-risk patients with a Gleason score ≤ 7 and PSA-DT ≥ 6 months when their life expectancy is within 10 years.

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Mapping of the three-dimensional lymphatic microvasculature in bladder tumours using light-sheet microscopy

Tanaka, Nobuyuki, Kaczynska, Dagmara, Kanatani, Shigeaki, Sahlgren, Cecilia, Mitura, Przemyslaw, Stepulak, Andrzej, Miyakawa, Ayako, Wiklund, Peter, Uhlen, Per

BRITISH JOURNAL OF CANCER (British Journal of Cancer) 118 ( 7 ) 995 - 999 2018.04

Research paper (scientific journal), ISSN 0007-0920

© 2018 The Author(s). Background: Cancers are heterogeneous and contain various types of irregular structures that can go undetected when examining them with standard two-dimensional microscopes. Studies of intricate networks of vasculature systems, e.g., the tumour lymphatic microvessels, benefit largely from three-dimensional imaging data analysis. Methods: The new DIPCO (Diagnosing Immunolabeled Paraffin-Embedded Cleared Organs) imaging platform uses three-dimensional light-sheet microscopy and whole-mount immunolabelling of cleared samples to study proteins and micro-anatomies deep inside of tumours. Results: Here, we uncovered the whole three-dimensional lymphatic microvasculature of formalin-fixed paraffin-embedded (FFPE) tumours from a cohort of 30 patients with bladder cancer. Our results revealed more heterogeneous spatial deviations in more advanced bladder tumours. We also showed that three-dimensional imaging could determine tumour stage and identify vascular or lymphatic system invasion with higher accuracy than standard two-dimensional histological diagnostic methods. There was no association between sample storage times and outcomes, demonstrating that the DIPCO pipeline could be successfully applied on old FFPE samples. Conclusions: Studying tumour samples with three-dimensional imaging could help us understand the pathological nature of cancers and provide essential information that might improve the accuracy of cancer staging.

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Single-cell RNA-seq analysis reveals the platinum resistance gene COX7B and the surrogate marker CD63

Tanaka Nobuyuki, Katayama Shintaro, Reddy Aparna, Nishimura Kaneyasu, Niwa Naoya, Hongo Hiroshi, Ogihara Koichiro, Kosaka Takeo, Mizuno Ryuichi, Kikuchi Eiji, Mikami Shuji, Miyakawa Ayako, Arenas Ernest, Kere Juha, Oya Mototsugu, Uhlén Per

Cancer Medicine (Cancer Medicine) 7 ( 12 ) 6193 - 6204 2018.01

Cancers acquire resistance to systemic treatment with platinum-based chemotherapy (eg, cisplatin [CDDP]) as a result of a dynamic intratumoral heterogeneity (ITH) and clonal repopulation. However, little is known about the influence of chemotherapy on ITH at the single-cell level. Here, mapping the transcriptome of cancers treated with CDDP by scRNA-seq, we uncovered a novel gene, COX7B, associated with platinum-resistance, and surrogate marker, CD63. Knockdown of COX7B in cancer cells decreased the sensitivity of CDDP whereas overexpression recovered the sensitivity of CDDP. Low COX7B levels correlated with higher mortality rates in patients with various types of cancer and were significantly associated with poor response to chemotherapy in urinary bladder cancer. Tumor samples from patients, who underwent CDDP therapy, showed decreased COX7B protein levels after the treatment. Analyzing scRNA-seq data from platinum-naïve cancer cells demonstrated a low-COX7B subclone that could be sorted out from bulk cancer cells by assaying CD63. This low-COX7B subclone behaved as cells with acquired platinum-resistance when challenged to CDDP. Our results offer a new transcriptome landscape of platinum-resistance that provides valuable insights into chemosensitivity and drug resistance in cancers, and we identify a novel platinum resistance gene, COX7B, and a surrogate marker, CD63.

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History of Non–Muscle-Invasive Bladder Cancer May Have a Worse Prognostic Impact in cT2-4aN0M0 Bladder Cancer Patients Treated With Radical Cystectomy

Kayama Emina, Kikuchi Eiji, Fukumoto Keishiro, Shirotake Suguru, Miyazaki Yasumasa, Hakozaki Kyohei, Kaneko Gou, Yoshimine Shunsuke, Tanaka Nobuyuki, Takahiro Maeda, Kanai Kunimitsu, Oyama Masafumi, Nakajima Yosuke, Hara Satoshi, Monma Tetsuo, Oya Mototsugu

Clinical Genitourinary Cancer (Clinical Genitourinary Cancer) 16 ( 5 ) e969 - e976 2018.01

Research paper (scientific journal), ISSN 1558-7673

We performed a retrospective study comparing clinical outcomes between patients with initially diagnosed muscle-invasive bladder cancer (MIBC) without a history of non-MIBC (NMIBC) and those with MIBC that progressed from NMIBC. A history of NMIBC was independently associated with cancer death in cT2-T4a MIBC patients treated with radical cystectomy and without lymph node involvement. MIBC that progresses from NMIBC may not respond to neoadjuvant chemotherapy. Purpose: To investigate whether a history of non–muscle-invasive bladder cancer (NMIBC) plays a prognostic role in patients with muscle-invasive bladder cancer (MIBC) treated with radical cystectomy in the era when neoadjuvant chemotherapy was established as standard therapy for MIBC. Patients and Methods: A total of 282 patients who were diagnosed with cT2-T4aN0M0 bladder cancer treated with open radical cystectomy at our institutions were included. Initially diagnosed MIBC without a history of NMIBC was defined as primary MIBC group (n = 231), and MIBC that progressed from NMIBC was defined as progressive MIBC (n = 51). Results: The rate of cT3/4a tumors was significantly higher in the primary MIBC group than in the progressive MIBC group (P = .004). Five-year recurrence-free survival and cancer-specific survival (CSS) rates for the primary MIBC group versus progressive MIBC group were 68.2% versus 55.9% (P = .039) and 76.1% versus 61.6% (P = .005), respectively. Progressive MIBC (hazard ratio, 2.170; P = .008) was independently associated with cancer death. In the primary MIBC group, the 5-year CSS rate in patients treated with neoadjuvant chemotherapy was 85.4%, which was significantly higher than that in patients without (71.5%, P = .023). In the progressive MIBC group, no significant differences were observed in CSS between patients treated with and without neoadjuvant chemotherapy. Conclusion: MIBC that progressed from NMIBC had a significantly worse clinical outcome than MIBC without a history of NMIBC and may not respond as well to neoadjuvant chemotherapy. These results are informative, even for NMIBC patients treated with conservative intravesical therapy.

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BCG-induced cytokine release in bladder cancer cells is regulated by Ca²⁺ signaling

Ibarra Cristián, Karlsson Marie, Codeluppi Simone, Varas-Godoy Manuel, Zhang Songbai, Louhivuori Lauri, Mangsbo Sara, Hosseini Arad, Soltani Navid, Kaba Rahim, Kalle Lundgren T., Hosseini Abolfazl, Tanaka Nobuyuki, Oya Mototsugu, Wiklund Peter, Miyakawa Ayako, Uhlén Per

Molecular Oncology 2018.01

ISSN 1574-7891

Bacillus Calmette–Guérin (BCG) is widely used in the clinic to effectively treat superficial urinary bladder cancer. However, a significant proportion of patients who fail to respond to BCG risk cystectomy or death. Though more than 3 million cancer treatments with BCG occur annually, surprisingly little is known about the initial signaling cascades activated by BCG. Here, we report that BCG induces a rapid intracellular Ca²⁺ (calcium ion) signal in bladder cancer cells that is essential for activating the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and for synthesizing and secreting proinflammatory cytokines, including interleukin 8 (IL-8). A similar Ca²⁺ response was observed when cells were exposed to the supernatant of BCG. Studying cellular molecular mechanisms involved in the BCG signaling event, we found pivotal roles for phospholipase C and the Toll-like receptor 4. Further assessment revealed that this signaling pathway induces synthesis of IL-8, whereas exocytosis appeared to be controlled by global Ca²⁺ signaling. These results shed new light on the molecular mechanisms underlying BCG treatment of bladder cancer, which can help in improving therapeutic efficacy and reducing adverse side effects.

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Whole-tissue biopsy phenotyping of three-dimensional tumours reveals patterns of cancer heterogeneity (vol 1, pg 796, 2017)

Tanaka, Nobuyuki, Kanatani, Shigeaki, Tomer, Raju, Sahlgren, Cecilia, Kronqvist, Pauliina, Kaczynska, Dagmara, Louhivuori, Lauri, Kis, Lorand, Lindh, Claes, Mitura, Przemyslaw, Stepulak, Andrzej, Corvigno, Sara, Hartman, Johan, Micke, Patrick, Mezheyeuski, Artur, Strell, Carina, Carlson, Joseph W., Moro, Carlos Fernandez, Dahlstrand, Hanna, Ostman, Arne, Matsumoto, Kazuhiro, Wiklund, Peter, Oya, Mototsugu, Miyakawa, Ayako, Deisseroth, Karl, Uhlen, Per

NATURE BIOMEDICAL ENGINEERING 2 ( 1 ) 48 - 48 2018.01

Research paper (scientific journal), ISSN 2157-846X

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Variant isoforms of CD44 involves acquisition of chemoresistance to cisplatin and has potential as a novel indicator for identifying a cisplatin-resistant population in urothelial cancer

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

BMC CANCER (BMC Cancer) 18 ( 1 ) 995 - 999 2018.01

Research paper (scientific journal), ISSN 1471-2407

© 2018 The Author(s). Background: Cisplatin is the most commonly used chemotherapeutic agent in the treatment of patients with metastatic and/or recurrent urothelial cancer. However, the effectiveness of these treatments is severely limited due to the development of cisplatin resistance. Cancer stem cells have been documented as one of the key hypotheses involved in chemoresistance. CD44v8-10 has been identified as one of the new cancer stem cells markers and was recently shown to enhance the antioxidant system by interaction with xCT, a subunit of the cystine transporter modulating intracellular glutathione synthesis. The aim of the present study was to investigate the clinical role of CD44v8-10 and the molecular mechanism underlying the acquisition of cisplatin resistance through CD44v8-10 in urothelial cancer. Methods: We analyzed the clinical significance of the immunohistochemical CD44v9 expression, which detects the immunogen of human CD44v8-10, in 77 urothelial cancer patients treated with cisplatin-based systemic chemotherapy for recurrence and/or metastasis. We then evaluated the biological role of CD44v8-10 in the acquisition of cisplatin resistance using the urothelial cancer cell lines, T24 and T24PR, which were generated to acquire resistance to cisplatin. Results: The 5-year cancer-specific survival rate was significantly lower in the CD44v9-positive group than in the CD44v9-negative group (P = 0.008). Multivariate analyses revealed that CD44v9 positivity was an independent risk factor of cancer-specific survival (P = 0.024, hazard ratio = 5.16) in urothelial cancer patients who had recurrence and/or metastasis and received cisplatin-based chemotherapy. The expression of CD44v8-10 and xCT was stronger in T24PR cells than in T24 cells. The amount of intracellular glutathione was significantly higher in T24PR cells than in T24 cells (p < 0.001), and intracellular reactive oxygen species production by cisplatin was lower in T24PR cells than in T24 cells. Furthermore, the knockdown of CD44v8-10 by siRNA led to the recovery of cisplatin sensitivity in T24PR cells. Conclusions: CD44v9 in tumor specimens has potential as a novel indicator for identifying a cisplatin-chemoresistant population among urothelial cancer patients. CD44v8-10 contributes to reactive oxygen species defenses, which are involved in chemoresistance, by promoting the function of xCT, which adjusts the synthesis of glutathione.

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Significance of a frozen section analysis of the ureteral margin in bladder cancer patients treated with radical cystectomy and neoadjuvant chemotherapy

Hakozaki Kyohei, Kikuchi Eiji, Fukumoto Keishiro, Shirotake Suguru, Miyazaki Yasumasa, Maeda Takahiro, Kaneko Gou, Yoshimine Shunsuke, Tanaka Nobuyuki, Kanai Kunimitsu, Oyama Masafumi, Nakajima Yosuke, Momma Tetsuo, Oya Mototsugu

Medical Oncology 34 ( 12 ) 2017.12

Research paper (scientific journal), ISSN 1357-0560

Although the clinical utility of a frozen section analysis (FSA) at the time of radical cystectomy (RC) has already been established, its significance and utility in bladder cancer patients receiving neoadjuvant chemotherapy (NAC) have not yet been fully evaluated. We identified 458 patients (937 ureters) who underwent open RC for bladder cancer at our 7 Japanese institutions between 2004 and 2015. Among these patients, 139 (284 ureters) received NAC before RC (NAC group), while 319 (653 ureters) underwent RC alone (non-NAC group). FSA was performed on 356 out of 937 (38.0%) ureters and 179 out of 458 (39.1%) patients. FSA was positive in 30 out of 356 (8.4%) ureters and its sensitivity, specificity, and accuracy were 89.3, 98.5, and 97.8%, respectively. In the NAC group, FSA was performed on 138 out of 284 (48.6%) ureters and 68 out of 139 (48.9%) patients. FSA was positive in 8 out of 138 ureters (5.8%), and its sensitivity, specificity, and accuracy were 77.8, 99.2, and 97.8%, respectively. In the non-NAC group, FSA was performed on 218 out of 653 (33.4%) ureters and 111 out of 319 (34.8%) patients. FSA was positive in 22 out of 218 (10.1%) ureters, and its sensitivity, specificity, and accuracy were 94.7, 98.0, and 97.7%, respectively. No correlation was observed between preoperative clinical factors and FSA positivity in the NAC group; however, in the non-NAC group, the incidence of FSA positivity in the ureters of patients with concomitant CIS in TUR-BT specimens was 8/41 (19.5%), which was significantly higher than that in their counterpart (14/177, 7.9%, p = 0.033). Even in the era of NAC in the management of bladder cancer patients, the performance of FSA does not change and FSA at the time of RC may provide useful diagnostic information.

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Whole-tissue biopsy phenotyping of three-dimensional tumours reveals patterns of cancer heterogeneity

NATURE BIOMEDICAL ENGINEERING 1 ( 10 ) 796 - 806 2017.10

Research paper (scientific journal), ISSN 2157-846X

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Prognostic value of neutrophil-to-lymphocyte ratio in patients with metastatic renal cell carcinoma treated with first-line and subsequent second-line targeted therapy: A proposal of the modified-IMDC risk model

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

UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS 35 ( 2 ) E425 - E426 2017.02

Research paper (scientific journal), ISSN 1078-1439

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Acquired platinum-resistance involves epithelial-to-mesenchymal transition through ubiquitin ligase FBXO32 dysregulation.

Tanaka, Nobuyuki, Kosaka, Takeo, Miyazaki, Yasumasa, Mikami, Shuji, Niwa, Naoya, Otsuka, Yutaro, Minamishima, Yoji Andrew, Mizuno, Ryuichi, Kikuchi, Eiji, Miyajima, Akira, Sabe, Hisataka, Okada, Yasunori, Uhlén, Per, Suematsu, makoto, Oya, Mototsugu.

Journal of Clinical Investigation Insight 1 ( 18 ) e83654 2016.11

Research paper (scientific journal)

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Plasma fibrinogen level: an independent prognostic factor for disease-free survival and cancer-specific survival in patients with localised renal cell carcinoma

Obata, Jun, Tanaka, Nobuyuki, Mizuno, Ryuichi, Kanao, Kent, Mikami, Shuji, Matsumoto, Kazuhiro, Kosaka, Takeo, Kikuchi, Eiji, Jinzaki, Masahiro, Oya, Mototsugu

BJU INTERNATIONAL 118 ( 4 ) 598 - 603 2016.10

Research paper (scientific journal), ISSN 1464-4096

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External Validation of the MSKCC and IMDC Risk Models in Patients Treated with Targeted Therapy as a First-line and Subsequent Second-line Treatment

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

European Urology Focus 2 ( 3 ) 303 - 309 2016.08

Research paper (scientific journal), ISSN 2405-4569

Background Two risk models, the Memorial Sloan Kettering Cancer Center (MSKCC) model and the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model, have been studied in metastatic renal cell carcinoma (mRCC) treated with targeted therapy. Objective To validate externally the predictive accuracies of the MSKCC and IMDC models for prognosis in mRCC patients treated with first-line and subsequent second-line targeted therapy. Design, setting, and participants A total of 311 patients were assessed retrospectively. Intervention All patients underwent targeted therapy. Outcome measurements and statistical analysis Survival outcomes were assessed using Kaplan-Meier analysis. The predictive ability was evaluated using the c-index. Results and limitations Regarding to the first-line targeted therapy, the 3-yr overall survival (OS) rates of the MSKCC (p < 0.001) and IMDC models (p < 0.001) were 76.2% and 77.3%, respectively, in the favorable-risk group; 46.7% and 47.9%, respectively, in the intermediate-risk group; and 13.4% and 15.6%, respectively, in the poor-risk group. The c-indexes were 0.68 for the MSKCC model and 0.69 for the IMDC model in a first-line setting. Regarding the second-line targeted therapy, the 1-yr OS rates of the MSKCC (p < 0.001) and IMDC models (p < 0.001) were 80.9% and 90.5%, respectively, in the favorable-risk group; 71.4% and 70.6%, respectively, in the intermediate-risk group; and 31.7% and 24.6%, respectively, in the poor-risk group. The c-indexes were 0.66 for the MSKCC model and 0.65 for the IMDC model in the second-line setting. The study is limited by its retrospective nature. Conclusions The results may assist physicians in providing more appropriate patient counseling and imply the need for a future prognostic tool in mRCC treated with targeted therapy. Patient summary Both risk models were useful for the risk stratification in metastatic renal cell carcinoma (mRCC) patients treated with first-line and second-line targeted therapy; however, it might be necessary to further update or optimize the models for our Japanese cohort of mRCC patients.

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Effect of reclassification of the IMDC model in patients with metastatic renal cell carcinoma treated with targeted therapy in the first-line and second-line settings

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

UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS 34 ( 7 ) 554 - 559 2016.07

Research paper (scientific journal), ISSN 1078-1439

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Patient age was an independent predictor of cancer-specific survival in male patients with upper tract urothelial carcinoma treated by radical nephroureterectomy

Kobayashi, Hiroaki, Kikuchi, Eiji, Tanaka, Nobuyuki, Shirotake, Suguru, Miyazaki, Yasumasa, Ide, Hiroki, Obata, Jun, Hoshino, Katsura, Matsumoto, Kazuhiro, Kaneko, Gou, Hagiwara, Masayuki, Kosaka, Takeo, Oyama, Masafumi, Nakajima, Yosuke, Oya, Mototsugu

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 46 ( 6 ) 554 - 559 2016.06

Research paper (scientific journal), ISSN 0368-2811

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