研究者詳細 - 田中　伸之

論文 - 田中　伸之

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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

ISSN 15587673

© 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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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

ISSN 13205463

© 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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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

ISSN 10689265

© 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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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

ISSN 03011623

© 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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TNFAIP2 expression induces epithelial-to-mesenchymal transition and confers platinum resistance in urothelial cancer cells

Niwa N., Tanaka N., Hongo H., Miyazaki Y., Takamatsu K., Mizuno R., Kikuchi E., Mikami S., Kosaka T., Oya M.

Laboratory Investigation （Laboratory Investigation） 99 （ 11 ） 1702 - 1713 2019年11月

ISSN 00236837

© 2019, The Author(s), under exclusive licence to United States and Canadian Academy of Pathology. Cisplatin (CDDP)-based chemotherapy is the gold standard treatment for many types of cancer. However, the phenotypic hallmark of tumors often changes after CDDP treatment, with the acquisition of epithelial-to-mesenchymal transition (EMT) and platinum resistance. Furthermore, the mechanisms by which cancer cells acquire EMT under the control of CDDP remain unclear. Following an investigation of urothelial carcinoma (UC) before and after the acquisition of platinum resistance, we offer the new target TNFAIP2, which led to EMT and tumor invasion in platinum-treated UC cells. TNFAIP2 expression in cancer was examined at the protein and transcriptional levels. A potential target for TNFAIP2 during EMT was assessed by microarray. Clinically, upregulated TNFAIP2 expression was identified as a significant predictor of mortality following surgery in three different cohorts of patients with UC (n = 156, n = 119, and n = 54). Knockdown of TNFAIP2 resulted in upregulation of E-cadherin expression and downregulation of TWIST1 expression, which decreased motile function in platinum-resistant UC cells. TNFAIP2 overexpression led to downregulation of E-cadherin expression and upregulation of TWIST1 expression in platinum-naïve UC cells. Clinical investigation of matched pre- and post-CDDP-treated UC sections confirmed upregulation of TNFAIP2 expression in CDDP-treated tumors but downregulation of E-cadherin expression. Global gene expression analysis following TNFAIP2 knockdown identified MTDH as a positive regulator of TNFAIP2-derived EMT acquisition in cancer cells. The present results suggest a relationship between TNFAIP2 and EMT in cancers under the control of CDDP, in which MTDH expression levels in cancer cells are vital for promoting TNFAIP2-derived EMT acquisition.

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Sub-classification of patients with intermediate-risk metastatic renal cell carcinoma treated with targeted therapy

Kaneko G., Shirotake S., Nishimoto K., Miyazaki Y., Ito K., Ito Y., Hagiwara M., Kanao K., Nakagawa K., Momma T., Asano T., Tanaka N., Mizuno R., Oya M., Oyama M.

Japanese Journal of Clinical Oncology （Japanese Journal of Clinical Oncology） 49 （ 8 ） 780 - 785 2019年08月

ISSN 03682811

© The Author(s) 2019. Published by Oxford University Press. All rights reserved. Background: International Metastatic Renal Cell Carcinoma Database Consortium model predicts the outcomes of metastatic renal cell carcinoma stratified into favorable, intermediate, and poor risk groups (FG, IG, and PG, respectively), with approximately 50% of patients being classified as IG. We aimed to generate better risk model based on the sub-classification of IG. Methods: We analyzed records of 213 consecutive patients receiving molecular targeted therapy. Age, gender, histology, type of initial molecular targeted therapy, serum laboratory data, previous nephrectomy and immunotherapy, and metastatic sites were used for IG sub-stratification. Modified and original models were compared using a concordance correlation coefficient analysis. Results: Median follow-up was 17.8 months. Serum albumin, serum C-reactive protein, and bone metastases were independent predictors of overall survival (OS) in IG. IG was sub-classified into low-, middle-, and high-risk IG according to the number of predictors. The following modified model was developed: modified FG (FG & low-risk IG), modified IG (middle-risk IG), and modified PG (PG & high-risk IG). Concordance indices for original and modified models were 0.68 and 0.73, respectively (P < 0.001). OS was significantly longer in modified PG treated with mammalian target of rapamycin inhibitors as second-line therapy than with tyrosine kinase inhibitors, whereas this was not observed in the original model. Conclusions: We successfully developed modified IMDC model using a two-step process: the original IMDC plus an IG sub-stratification, and demonstrated that it predicts outcomes more accurately than original model.

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限局性前立腺がんに対する腫瘍発生領域の臨床的検討

高松公晴, 松本一宏, 服部盛也, 田中伸之, 武田利和, 森田伸也, 小坂威雄, 水野隆一, 篠島利明, 菊地栄次, 浅沼宏, 大家基嗣

泌尿器外科（医学図書出版(株)） 32 （ 8 ） 1011 - 1012 2019年08月

ISSN 0914-6180

TVT術後の難治性切迫性尿失禁に対して仙骨神経電気刺激療法が有効であった1例

篠島利明, 茂田啓介, 田中伸之, 大家基嗣

日本排尿機能学会誌（(一社)日本排尿機能学会） 29 （ 2 ） 460 - 463 2019年06月

ISSN 1347-6513

症例は53歳女性。尿パッドを1日10枚必要とする尿失禁にて当科紹介。ストレステスト、Qチップテストともに強陽性だが、OABSSは5点と過活動膀胱症状は軽度であった。腹圧性尿失禁を主とする混合性尿失禁に対して保存的治療を行うも有効でなくTVT手術を施行した。術後にストレステストは陰性化したが切迫性尿失禁が顕著となった。メッシュ露出、尿路感染や残尿を認めず、テープによる尿道の屈曲や圧排等の閉塞所見も明らかでなかった。ウロダイナミクス検査では排尿筋過活動、ならびに低尿流率かつ高排尿筋圧の所見を認めた。過活動膀胱治療薬による症状の改善は乏しい上、抗コリン剤は副作用で継続困難であった。OABSSは14点、切迫性尿失禁の回数は1位平均3回以上であった。また膀胱内圧検査では排尿筋過活動の所見を認めた。TVT術後9ヵ月目に仙骨神経電気刺激療法のリード留置術を施行したところ試験刺激により切迫性失禁が消失、刺激装置植え込み術後も有害事象を認めず、本症例では有効な治療法であった。(著者抄録)

BCG-induced cytokine release in bladder cancer cells is regulated by Ca <sup>2+</sup> 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年02月

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年

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年

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年

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年

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年

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 N., Kaczynska D., Kanatani S., Sahlgren C., Mitura P., Stepulak A., Miyakawa A., Wiklund P., Uhlén P.

British Journal of Cancer （British Journal of Cancer） 118 （ 7 ） 995 - 999 2018年04月

研究論文（学術雑誌）, 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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History of Non–Muscle-Invasive Bladder Cancer May Have a Worse Prognostic Impact in cT2-4aN0M0 Bladder Cancer Patients Treated With Radical Cystectomy

Kayama E., Kikuchi E., Fukumoto K., Shirotake S., Miyazaki Y., Hakozaki K., Kaneko G., Yoshimine S., Tanaka N., Takahiro M., Kanai K., Oyama M., Nakajima Y., Hara S., Monma T., Oya M.

Clinical Genitourinary Cancer （Clinical Genitourinary Cancer） 16 （ 5 ） e969 - e976 2018年01月

研究論文（学術雑誌）, ISSN 1558-7673

© 2018 Elsevier Inc. 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年01月

ISSN 1574-7891

<p>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.</p>

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

Tanaka N., Katayama S., Reddy A., Nishimura K., Niwa N., Hongo H., Ogihara K., Kosaka T., Mizuno R., Kikuchi E., Mikami S., Miyakawa A., Arenas E., Kere J., Oya M., Uhlén P.

Cancer Medicine （Cancer Medicine） 7 （ 12 ） 6193 - 6204 2018年01月

© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. 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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Publisher Correction: Whole-tissue biopsy phenotyping of three-dimensional tumours reveals patterns of cancer heterogeneity.

Tanaka N, Kanatani S, Tomer R, Sahlgren C, Kronqvist P, Kaczynska D, Louhivuori L, Kis L, Lindh C, Mitura P, Stepulak A, Corvigno S, Hartman J, Micke P, Mezheyeuski A, Strell C, Carlson JW, Fernández Moro C, Dahlstrand H, Östman A, Matsumoto K, Wiklund P, Oya M, Miyakawa A, Deisseroth K, Uhlén P

Nature biomedical engineering 2 （ 1 ） 48 - 48 2018年01月

研究論文（学術雑誌）, 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 M., Kikuchi E., Tanaka N., Kosaka T., Mikami S., Saya H., Oya M.

BMC Cancer （BMC Cancer） 18 （ 1 ） 995 - 999 2018年01月

研究論文（学術雑誌）, 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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