Details of a Researcher - Tanaka, Nobuyuki

Papers - Tanaka, Nobuyuki

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Prognostic impact and landscape of cellular CXCR5 chemokine receptor expression in clear-cell renal cell carcinoma.

Arai M, Tanaka N, Takamatsu K, Murakami T, Mikami S, Imamura T, Nakamura K, Nishihara H, Oya M

Cancer immunology, immunotherapy : CII 74 ( 5 ) 166 2025.04

ISSN 0340-7004

CXCR5 is a chemokine receptor that promotes B cell follicular formation and antibody production. Indeed, CXCR5 has been found to be expressed in a variety of cancers; however, the role of CXCR5 expression in clear-cell renal cell carcinoma (ccRCC) remains unclear. We aimed to determine the impact of cellular CXCR5 expression on cancer outcomes, the PD-1/PD-L1 axis, and genetic states in patients with ccRCC. First, multiplex immunofluorescence staining for CXCR5, CD4, CD8, and AE1/AE3, along with automated single-cell counting, was performed to assess cellular CXCR5 expression in ccRCC and its association with prognosis. Second, the tumour microenvironment (TME) was analysed, with a focus on the relationship between the PD-1/PD-L1 axis and CXCR5 expression. Finally, an integrated analysis of CXCR5 expression and genomic mutation information was conducted to reveal the genetic background underlying CXCR5 expression. A total of 105 ccRCC patients were included. Among the 696,964 cells analysed, the distribution of CXCR5-expressing cells was as follows: 30% CXCR5+CD4+ cells, 9% CXCR5+CD8+ cells, and 26% CXCR5+AE1/AE3+ cells. Survival analysis revealed that tumours with low-CXCR5+CD8+ cells had a poor prognosis; TME analysis revealed a relationship between low-CXCR5+CD8+ status and a highly suppressive PD-L1-positive immune environment. Genomic analysis revealed a correlation between low-CXCR5+CD8+ status and high rates of alterations in chromatin remodelling genes, including PBRM1. This study highlights the significance of CXCR5+CD8+ cells in ccRCC, demonstrating their clinical implications and revealing the immunogenomic landscape underlying CXCR5 expression.

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Genomic characterization of metastatic patterns in prostate cancer using circulating tumor DNA data from the SCRUM-Japan MONSTAR SCREEN project.

Shiota M, Matsubara N, Kato T, Eto M, Osawa T, Abe T, Shinohara N, Nishimoto K, Yasumizu Y, Tanaka N, Oya M, Fujisawa T, Horasawa S, Nakamura Y, Yoshino T, Nonomura N

The journal of liquid biopsy 7 100282 2025.03

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Increased Expression of AXL and c-MET in High-Grade Clear Cell Renal Cell Carcinoma and Its Association With VEGFR-TKI Treatment and PD-L1 Expression

Mikami S., Mizuno R., Tanaka N., Hakozaki K., Takamatsu K., Oya M.

Pathology International 2025

ISSN 13205463

Cabozantinib, a newly developed vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI), is an effective treatment for advanced renal cell carcinoma (RCC). However, the molecular mechanisms responsible for the superior effectiveness of cabozantinib to other drugs remain unclear. Since cabozantinib inhibits AXL and c-MET in addition to VEGFR, the expression of these molecules was immunohistologically examined in 110 cases of primary clear cell RCC (ccRCC) and eight of sunitinib (VEGFR-TKI)-treated primary ccRCC. AXL expression correlated with the primary tumor stage, while c-MET expression correlated with distant metastasis, the histological grade, and overall survival. Furthermore, the number of programmed death-ligand 1 (PD-L1)-positive tumor-infiltrating immune cells was higher in ccRCC tissues with high c-MET expression than in those with low c-MET expression. The expression of AXL and c-MET was higher in sunitinib-treated ccRCC tissues than in untreated tissues. These results suggest that AXL and c-MET play important roles in the progression of ccRCC and resistance to sunitinib. Furthermore, c-MET may modify the immune microenvironment by inducing PD-L1 expression in immune cells within RCC tissues. These molecular pathways may be related to responses to cabozantinib.

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Prognostic significance of circulating tumor DNA alterations in advanced renal cell carcinoma from SCRUM-Japan MONSTAR-SCREEN: a nationwide genomic profiling project: Genetics and Genomics

Kato T., Shiota M., Nishimoto K., Matsubara N., Osawa T., Abe T., Yasumizu Y., Tanaka N., Yamamoto Y., Ishizuya Y., Abutani H., Bando H., Fujisawa T., Nakamura Y., Oya M., Shinohara N., Eto M., Yoshino T., Nonomura N.

British Journal of Cancer 2025

ISSN 00070920

Background: Circulating tumor DNA (ctDNA) is a promising tool for diagnosing and predicting cancer prognosis. However, its clinical utility in metastatic renal cell carcinoma (mRCC) remains unclear, particularly in terms of clinical prognosis. Methods: We enrolled 124 patients with mRCC in the MONSTAR-SCREEN study (UMIN 000036749) between August 2019 and February 2022, a national observational ctDNA-based screening study, and performed ctDNA sequencing before and at the time of resistance to systemic therapy. Results: ctDNA were assessed in 178 samples containing 432 mutations. The most frequently altered genes at baseline were VHL (25.0%), PBRM1 (10.9%), TERT2 (8.7%), BAP1 (8.7%), and MTOR (7.6%). Patients receiving first-line therapy with tumor fraction (TF) < 1.2% showed significantly better progression-free survival than those with TF ≥ 1.2% (Hazard ratio (HR) = 0.467; 95% CI 0.229–0.979; p = 0.0425). BAP1 mutational status of ctDNA at baseline led to poor OS (HR = 0.4867; 95% CI 0.322–0.736; p = 0.0003). Serial ctDNA analysis showed that 46.8% of patients developed new ctDNA mutations at disease progression, which was linked to shorter time to progression (p = 0.046). Conclusions: Our findings demonstrated that ctDNA profiling is feasible in mRCC and can predict disease progression after treatment.

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Prediction of pathological up-staging after radical nephroureterectomy in patients with upper tract urothelial carcinoma

Shojo K., Takeda T., Akita H., Suzuki T., Mikami S., Shigeta K., Yasumizu Y., Tanaka N., Matsumoto K., Morita S., Kosaka T., Mizuno R., Asanuma H., Jinzaki M., Oya M.

World Journal of Urology (World Journal of Urology) 42 ( 1 ) 192 2024.12

ISSN 07244983

Purpose: The diagnostic accuracy of computed tomography urography for upper tract urothelial carcinoma is high; however, difficulties are associated with precisely assessing the T stage. Preoperative tumor staging has an impact on treatment options for upper tract urothelial carcinoma. We herein attempted to identify preoperative factors that predict pathological tumor up-staging, which will facilitate the selection of treatment strategies. Materials and methods: We retrospectively identified 148 patients with upper tract urothelial carcinoma who underwent computed tomography urography preoperatively followed by radical nephroureterectomy without preoperative chemotherapy at our institution between 2000 and 2021. Preoperative factors associated with cT2 or lower to pT3 up-staging were examined using a multivariate logistic regression analysis. Results: Ninety out of 148 patients were diagnosed with cT2 or lower, and 22 (24%) were up-staged to pT3. A multivariate analysis identified a positive voided urine cytology (HR 4.69, p = 0.023) and tumor length ≥ 3 cm (HR 6.33, p = 0.003) as independent predictors of pathological tumor up-staging. Conclusions: Patients diagnosed with cT2 or lower, but with preoperative positive voided urine cytology and/or tumor diameter ≥ 3 cm need to be considered for treatment as cT3.

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Prediction of undetectable circulating tumor DNA by comprehensive genomic profiling assay in metastatic prostate cancer: the SCRUM-Japan MONSTAR SCREEN project

Shiota M., Matsubara N., Kato T., Eto M., Osawa T., Abe T., Shinohara N., Nishimoto K., Yasumizu Y., Tanaka N., Oya M., Fujisawa T., Horasawa S., Nakamura Y., Yoshino T., Nonomura N.

World Journal of Urology 42 ( 1 ) 526 2024.12

ISSN 07244983

Background: Undetectable circulating tumor DNA (ctDNA) is an obstacle to performing comprehensive genomic profiling in daily practice to identify genomic alterations. We investigated the associations between clinicopathological factors and undetectable ctDNA using a commercially available comprehensive genomic profiling assay in metastatic prostate cancer. Patients and methods: Patients treated with systemic treatment for metastatic prostate cancer were included. ctDNA was analyzed by FoundationOne®Liquid CDx at enrollment. The associations between clinicopathological characteristics and ctDNA detection were analyzed. Results: The number of bone metastasis was associated with ctDNA detection (odds ratio [95% confidence interval], 13.6 [1.71–108], P = 0.014). An algorithm predicting ctDNA detection using clinicopathological parameters was created. If ≥ 4 bone metastases were observed, ctDNA detection was estimated to be 98.9%. Among the patients with < 4 bone metastases, if two or three features among ISUP grade group 5, PSA level ≥ 10 ng/ml, and castration resistance were present, the ctDNA detection rate was 96.7% while the ctDNA detection rate was 86.3% if no or only one feature was present. Conclusions: An algorithm created in this study is helpful in determining when to undertake comprehensive genomic profiling assay using blood.

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Tumor immune microenvironment dynamics and outcomes of prognosis in non-muscle-invasive bladder cancer.

Kamitani R, Tanaka N, Anno T, Murakami T, Masuda T, Yasumizu Y, Takeda T, Morita S, Kosaka T, Mikami S, Matsumoto K, Oya M

Cancer science 115 ( 12 ) 3963 - 3972 2024.10

ISSN 1347-9032

Agents that target PD-1 and PD-L1 have been developed in the treatment of bladder cancer (BC). However, the diversity of immune cell infiltration in non-muscle-invasive BC (NMIBC) and the dynamics of the microenvironment as it progresses to muscle-invasive/metastatic disease remains unknown. To assess tumor immune activity, hierarchical clustering was applied to 159 BC samples based on cellular positivity for the defined immune cellular markers (CD3/CD4/CD8/FOXP3/CD20/PD-1/PD-L1/LAG3/TIGIT), divided into two clusters. There was a “hot cluster” (25%) consisting of patients with a high expression of these markers and a “cold cluster” (75%) comprising those without. The expression of CD39, CD44, CD68, CD163, IDO1, and Ki67 was significantly higher in tumors in the hot cluster. Immunologically, high-grade T1 tumors were significantly hotter, whereas tumors that had progressed to muscle invasion turned cold. However, a certain number of high-grade NMIBC patients were in the cold cluster, and these patients had a significantly higher risk of disease progression. Using an externally available TCGA dataset, RB1 and TP53 alterations were more frequently observed in TCGA hot cluster; rather FGFR3, KDM6A, and KMT2A alterations were common in TCGA cold/intermediate cluster. Analyses of recurrent tumors after BCG therapy revealed that tumor immune activity was widely maintained before and after treatment, and high FGFR3 expression was detected after recurrence in tumors initially classified into the cold cluster. Collectively, we revealed the dynamics of the tumor microenvironment in BC as a whole and identified candidate molecules as therapeutic targets for recurrent NMIBC, e.g., after BCG therapy.

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Multiplexed Spatial Imaging at the Single-Cell Level Reveals Mutually Exclusive Expression of B7 Family Proteins

Shojo K., Tanaka N., Murakami T., Anno T., Teranishi Y., Takamatsu K., Mikami S., Imamura T., Matsumoto K., Oya M.

Laboratory Investigation 104 ( 10 ) 102131 2024.10

ISSN 00236837

Targeting novel inhibitory ligands beyond anti-PD-1 and PD-L1 and CTLA-4 therapies is essential for the next decade of the immunotherapy era. Agents for the B7 family molecules B7-H3, B7-H4, and B7-H5 are emerging in clinical trial phases; therefore, further accumulation of evidence from both clinical and basic aspects is vital. Here, we applied a 7-color multiplexed imaging technique to analyze the profile of B7 family B7-H3/B7-H4/B7-H5 expression, in addition to PD-L1, and the spatial characteristics of immune cell infiltrates in urothelial carcinoma (UC). The results revealed that B7-H3 and B7-H4 were mainly expressed on tumor cells and B7-H5 on immune cells in UC, and most of the B7-H3/B7-H4/B7-H5-positive cells were mutually exclusive with PD-L1-positive cells. Also, the expression of B7-H4 was elevated in patients with advanced pathologic stages, and high B7-H4 expression was a significant factor affecting overall mortality following surgery in UC. Furthermore, spatial analysis revealed that the distance from the B7-H4+ cells to the nearest CD8+ cells was markedly far compared with other B7 family-positive tumor cells. Interestingly, the distance from B7-H4+ cells to the nearest CD8+ cells was significantly farther in patients dying from cancer after surgery or immune checkpoint inhibitors compared with cancer survivors; thus, high B7-H4 expression in tumor cells may inhibit CD8 infiltration into the tumor space and that B7-H4-positive cells form a specific spatial niche. In summary, we performed a comprehensive evaluation of B7 family member expression and found that the spatial distribution of B7-H4 suggests the potentially useful role of combination blockade with both B7-H4 and the current anti-PD-1/PD-L1 axis in the treatment of UC.

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多発病変の中の小さな最高grade病変は,MRIで検出できるのか

松本一宏, 秋田大宇, 橋口明典, 武田利和, 小坂威雄, 福本桂資郎, 安水洋太, 田中伸之, 森田伸也, 水野隆一, 浅沼宏, 大家基嗣, 陣崎雅弘

泌尿器外科 (医学図書出版(株)) 37 ( 8 ) 942 - 944 2024.08

ISSN 0914-6180

Three-dimensional imaging of upper tract urothelial carcinoma improves diagnostic yield and accuracy

Fukumoto K., Kanatani S., Jaremko G., West Z., Li Y., Takamatsu K., Al Rayyes I., Mikami S., Niwa N., Axelsson T.A., Tanaka N., Oya M., Miyakawa A., Brehmer M., Uhlén P.

JCI Insight 9 ( 14 ) 2024.07

Upper tract urothelial carcinoma (UTUC) is a rare form of urothelial cancer with a high incidence of recurrence and a low survival rate. Almost two-thirds of UTUCs are invasive at the time of diagnosis; therefore, improving diagnostic methods is key to increasing survival rates. Histopathological analysis of UTUC is essential for diagnosis and typically requires endoscopy biopsy, tissue sectioning, and labeling. However, endoscopy biopsies are minute, and it is challenging to cut into thin sections for conventional histopathology; this complicates diagnosis. Here, we used volumetric 3-dimensional (3D) imaging to explore the inner landscape of clinical UTUC biopsies, without sectioning, revealing that 3D analysis of phosphorylated ribosomal protein S6 (pS6) could predict tumor grade and prognosis with improved accuracy. By visualizing the tumor vasculature, we discovered that pS6+ cells were localized near blood vessels at significantly higher levels in high-grade tumors than in low-grade tumors. Furthermore, the clustering of pS6+ cells was associated with shorter relapse-free survival. Our results demonstrate that 3D volume imaging of the structural niches of pS6 cells deep inside the UTUC samples improved diagnostic yield, grading, and prognosis prediction.

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Volumetric imaging of the tumor microvasculature reflects outcomes and genomic states of clear cell renal cell carcinoma.

Kaneko Y, Masuda T, Takamatsu K, Mikami S, Nakamura K, Nishihara H, Mizuno R, Tanaka N, Oya M

The journal of pathology. Clinical research (Journal of Pathology: Clinical Research) 10 ( 4 ) e12388 2024.07

Tumor structure is heterogeneous and complex, and it is difficult to obtain complete characteristics by two-dimensional analysis. The aim of this study was to visualize and characterize volumetric vascular information of clear cell renal cell carcinoma (ccRCC) tumors using whole tissue phenotyping and three-dimensional light-sheet microscopy. Here, we used the diagnosing immunolabeled paraffin-embedded cleared organs pipeline for tissue clearing, immunolabeling, and three-dimensional imaging. The spatial distributions of CD34, which targets blood vessels, and LYVE-1, which targets lymphatic vessels, were examined by calculating three-dimensional density, vessel length, vessel radius, and density curves, such as skewness, kurtosis, and variance of the expression. We then examined those associations with ccRCC outcomes and genetic alteration state. Formalin-fixed paraffin-embedded tumor samples from 46 ccRCC patients were included in the study. Receiver operating characteristic curve analyses revealed the associations between blood vessel and lymphatic vessel distributions and pathological factors such as a high nuclear grade, large tumor size, and the presence of venous invasion. Furthermore, three-dimensional imaging parameters stratified ccRCC patients regarding survival outcomes. An analysis of genomic alterations based on volumetric vascular information parameters revealed that PI3K-mTOR pathway mutations related to the blood vessel radius were significantly different. Collectively, we have shown that the spatial elucidation of volumetric vasculature information could be prognostic and may serve as a new biomarker for genomic alterations. High-end tissue clearing techniques and volumetric immunohistochemistry enable three-dimensional analysis of tumors, leading to a better understanding of the microvascular structure in the tumor space.

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Detection of the Highest-Grade Lesion in Multifocal Discordant Prostate Cancer by Multiparametric Magnetic Resonance Imaging

Matsumoto K., Akita H., Hashiguchi A., Takeda T., Kosaka T., Fukumoto K., Yasumizu Y., Tanaka N., Morita S., Mizuno R., Asanuma H., Oya M., Jinzaki M.

Clinical Genitourinary Cancer (Clinical Genitourinary Cancer) 22 ( 3 ) 102084 2024.06

ISSN 15587673

Purpose: Prostate cancer generally occurs multifocally. The lesions of the largest size and highest-grade are often concordant, and defined as an index tumor. However, these factors sometimes do not coincide within one lesion. In such discordant cases, not the largest size lesion but the highest-grade lesion is known to determine the prognosis. We focused on the multiparametric magnetic resonance imaging (mpMRI) detectability of the highest-grade tumors in discordant cases. Materials and Methods: We investigated the detectability of the highest-grade tumor using preoperative mpMRI in 50 discordant patients who underwent radical prostatectomy. The radiologist was informed of the tumor location on the pathological tumor map, and mpMRI interpretation for each tumor was performed. Results: Prostate Imaging-Reporting and Data System (PI-RADS) scores of 1, 2, 3, 4, and 5 on preoperative mpMRI were assigned to 13, 1, 9, 16, and 11 of the largest tumors, respectively. On the other hand, scores of 1, 2, 3, 4, and 5 were assigned to 23, 0, 7, 19, and 1 of the highest-grade tumors, respectively. The difference between them was statistically significant (p=0.007). We also found that the largest anterior tumor frequently hid the ipsilateral posterior highest-grade tumor; the detection rate of the highest-grade tumor in this pattern was 42.1% (8 of 19 cases) Conclusion: We found that mpMRI detectability of the highest-grade tumor in discordant cases was inferior to that of the largest tumor with low malignant potential. Our results suggest that the risk of high-grade tumors which determine patient prognosis being overlooked.

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Risk factors for postoperative fever after laparoscopic adrenalectomy focusing on hormones produced: a case control study.

Izawa M, Takeda T, Anno T, Iwasawa T, Yasumizu Y, Tanaka N, Matsumoto K, Morita S, Kosaka T, Mizuno R, Asanuma H, Oya M

BMC urology 24 ( 1 ) 90 2024.04

Background: Laparoscopic adrenalectomy is widely performed for a number of hormone-producing tumors and postoperative management depends on the hormones produced. In the present study, we conducted a retrospective analysis to clarify the risk factors for postoperative complications, particularly postoperative fever after laparoscopic adrenalectomy. Methods: We analyzed 406 patients who underwent laparoscopic adrenalectomy at our hospital between 2003 and 2019. Postoperative fever was defined as a fever of 38 °C or higher within 72 h after surgery. We investigated the risk factors for postoperative fever after laparoscopic adrenalectomy. Results: There were 188 males (46%) and 218 females (54%) with a median age of 52 years. Among these patients, tumor pathologies included 188 primary aldosteronism (46%), 75 Cushing syndrome (18%), and 80 pheochromocytoma (20%). Postoperative fever developed in 124 of all patients (31%), 30% of those with primary aldosteronism, 53% of those with pheochromocytoma, and 8% of those with Cushing syndrome. A multivariate logistic regression analysis identified pheochromocytoma and non-Cushing syndrome as independent predictors of postoperative fever. Postoperative fever was observed in 42 out of 80 cases of pheochromocytoma (53%), which was significantly higher than in cases of non-pheochromocytoma (82/326, 25%, p < 0.01). In contrast, postoperative fever developed in 6 out of 75 cases of Cushing syndrome (8%), which was significantly lower than in cases of non-Cushing syndrome (118/331, 35.6%, p < 0.01). Conclusion: Since postoperative fever after laparoscopic adrenalectomy is markedly affected by the hormone produced by pheochromocytoma and Cushing syndrome, it is important to carefully consider the need for treatment.

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Genomic profiling and clinical utility of circulating tumor DNA in metastatic prostate cancer: SCRUM-Japan MONSTAR SCREEN project.

Shiota M, Matsubara N, Kato T, Eto M, Osawa T, Abe T, Shinohara N, Nishimoto K, Yasumizu Y, Tanaka N, Oya M, Fujisawa T, Horasawa S, Nakamura Y, Yoshino T, Nonomura N

BJC reports 2 ( 1 ) 28 2024.04

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Impact of prostatic shape on the difficulty of robot-assisted laparoscopic radical prostatectomy.

Kamisawa K, Matsumoto K, Takeda T, Takamatsu K, Niwa N, Yasumizu Y, Tanaka N, Morita S, Kosaka T, Mizuno R, Asanuma H, Oya M

Asian journal of endoscopic surgery (Asian Journal of Endoscopic Surgery) 17 ( 2 ) e13291 2024.04

ISSN 1758-5902

Introduction: To investigate the impact of prostatic shape observed on preoperative magnetic resonance imaging (MRI) on the difficulty of robot-assisted laparoscopic radical prostatectomy (RALP). Methods: We retrospectively reviewed the operative records of 211 patients who underwent RALP. We excluded patients who received neoadjuvant therapy. All surgeries in this study were performed by two surgeons. Each patient clinicopathological and surgical data were reviewed. Prostate sphericity was evaluated by measuring the roundness of the prostate at the largest axial slice by MRI. The console time was adopted as an objective indicator for assessing surgical difficulty. Results: The mean prostate volume was 34 cc (range 14–88) and the mean prostate roundness was 0.55 (range 0.24–0.90). The mean console time was 194 min (range 95–296). To assess the relationship between prostate volume and console time, scatter plot analysis was performed. The prostate volume had a weak positive correlation with the console time (r =.165, p =.016). Similarly, scatter plot analysis between the prostate roundness and console time demonstrated a weak positive correlation (r =.167, p =.015). Next, we performed subgroup analysis of 56 patients with a large prostate volume (≥40 cc), and the positive correlation between the prostate volume and the console time disappeared (r =.142, p =.296). On the other hand, the prostate roundness was more strongly correlated with the console time (r =.439, p =.001). Conclusions: The spherical shape of the prostate is associated with the surgical difficulty of RALP, especially in patients with a large prostate volume.

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Profiling Fibroblast Growth Factor Receptor 3 Expression Based on the Immune Microenvironment in Upper Tract Urothelial Carcinoma.

Shigeta K, Matsumoto K, Kitaoka S, Omura M, Umeda K, Arita Y, Mikami S, Fukumoto K, Yasumizu Y, Tanaka N, Takeda T, Morita S, Kosaka T, Mizuno R, Hara S, Oya M

European urology oncology 7 ( 6 ) 1338 - 1349 2024.02

BACKGROUND: Although several studies have shown favorable outcomes in upper tract urothelial carcinoma (UTUC) with fibroblast growth factor receptor 3 (FGFR3) mutations and/or expression, the relationship between immune cell markers and FGFR3 expression remains unknown. OBJECTIVE: To clarify the FGFR3-based immune microenvironment and investigate biomarkers to predict the treatment response to pembrolizumab (Pem) in patients with UTUC. DESIGN, SETTING, AND PARTICIPANTS: We conducted immunohistochemical staining in 214 patients with UTUC. The expression levels of FGFR3, CD4, CD8, CD68, CD163, CD204, and programmed cell death ligand 1 (PD-L1) were examined. INTERVENTION: All UTUC patients underwent radical nephroureterectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We assessed the relationship between these immune markers and patient prognosis. RESULTS AND LIMITATIONS: A total of 109 (50.9%) patients showed high FGFR3 expressions and a favorable prognosis compared with the remaining patients. Among the six immune markers, CD8 high expression was an independent favorable factor, whereas CD204 expression was an independent prognostic factor for cancer death. From the FGFR3-based immune clustering, three immune clusters were identified. Cluster A showed low FGFR3 with tumor-associated macrophage-rich components (CD204+) followed by a poor prognosis due to a poor response to Pem. Cluster B showed low FGFR3 with an immune hot component (CD8+), followed by the most favorable prognosis owing to a good response to Pem. Cluster C showed high FGFR3 expression but an immune cold component, followed by a favorable prognosis due to the high FGFR3 expression, but a poor response was confirmed with Pem. CONCLUSIONS: Although most patients exhibit a poor response to Pem, individuals with low FGFR3 expression and immune hot status may benefit clinically from Pem treatment. PATIENT SUMMARY: We conducted immunohistochemical staining to evaluate fibroblast growth factor receptor 3 (FGFR3)-related immune microenvironment by evaluating the expressions of CD4, CD8, CD68, CD163, CD204, and PD-L1 in 214 upper tract urothelial carcinoma patients. We identified three distinct immune clusters based on FGFR3 expressions and found that patients with a low FGFR3 expression but immune hot status received the maximum benefit from an immune checkpoint inhibitor.

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Anemia in patients ≥ 75 years with metastatic clear cell renal cell carcinoma: an important poor prognostic factor in the international metastatic renal cell carcinoma database consortium model.

Mizuno R, Yasumizu Y, Tanaka N, Takeda T, Morita S, Matsumoto K, Kosaka T, Asanuma H, Oya M

BMC urology (BMC Urology) 24 ( 1 ) 13 2024.01

Background: Due to an increase in life expectancy, the incidence of metastatic renal cell carcinoma (mRCC) in patients aged ≥75 years has been increasing. In this study we investigated the characteristics before treatment and the outcomes of systemic therapies for patients aged ≥75 years with mRCC and compared the results with those for patients aged < 75 years in order to determine whether differences in age influenced survival. Methods: A total of 206 consecutive Japanese patients with mRCC, including 47 patients aged ≥75 years, who received systemic therapy were included. Clinical data from medical records were retrieved and analyzed retrospectively. Survival analyses were determined using a Kaplan–Meier method, and analyzed with a log-rank test. Results: Elderly patients categorized as favorable risk group based on the International Metastatic RCC Database Consortium (IMDC) stratification system were significantly lower. Among IMDC risk factors, the rate of anemia was significantly higher in elderly patients. No statistically significant benefit in progression free survival for first and second line treatment was observed, whereas improvements in overall survival as well as cancer specific survival were seen in patients aged < 75 years. Conclusions: For mRCC patients aged ≥75 years, a higher proportion of base line anemia, which resulted in higher rates of IMDC intermediate/poor risk, would be responsible for shorter OS/CSS. Furthermore, mRCC patients aged ≥75 years tend to receive BSC instead of second line active treatment. Overcoming under-treatment in elderly patients might help to prolong survival in mRCC.

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尿管狭窄に対して口腔粘膜を用いた拡大onlay法尿管形成術を施行した1例

岩佐俊, 浅沼宏, 高橋遼平, 福本桂資郎, 安水洋太, 田中伸之, 武田利和, 松本一宏, 森田伸也, 小坂威雄, 水野隆一, 大家基嗣

日本泌尿器科学会雑誌 ((一社)日本泌尿器科学会) 115 ( 1 ) 37 - 41 2024.01

ISSN 0021-5287

症例は14歳男子.12歳時に水腎症と腎機能の増悪を認め,近医で膀胱腫瘍,左尿管腫瘍の診断となった.前医で経尿道的膀胱腫瘍切除術,尿管腫瘍生検が施行され,線維上皮性ポリープの診断となった.尿管ポリープに対して経尿道的切除を試みられたが尿道狭窄を併発したため到達困難となり,左腎瘻造設,経皮的レーザー焼灼術が施行された.術後4ヵ月,尿管狭窄もきたし,尿路再建の目的に当院へ紹介となった.尿道狭窄に対して13歳時に包皮利用Palminteri法尿道形成術を施行した.逆行性腎盂造影,腎瘻造影検査で脊椎L4レベルに2cmの尿管狭窄,尿管鏡検査で脊椎L5レベルに残存ポリープを認めた.14歳時に尿管再建術を行った.端々吻合では吻合部の緊張が強いと考えられ,口腔粘膜利用拡大onlay法尿管形成術を行う方針とした.完全閉塞部と残存ポリープ部のみを最小限切除し,緊張のかからない尿管壁同士を一部端々吻合した.吻合部の対側の尿管壁は健常部まで十分にspatulateし,尿管ステントを留置後に15×40mm大の頬粘膜を縫着,頬粘膜のグラフト床として腹腔内から遊離した大網を吻合部に全周性に縫着した.術後13日で腎瘻を抜去,術後4ヵ月で尿管ステントを抜去した.術後1年および2年の逆行性腎盂造影,尿管鏡検査で再狭窄やポリープの再発は認めず,術後3年現在,左側腹部痛,腎盂腎炎,腎盂拡張などを認めず経過良好である.(著者抄録)

下大静脈後尿管を合併した膀胱尿管逆流に対して逆流防止術を施行した2例の比較

岩佐俊, 浅沼宏, 高橋遼平, 安水洋太, 田中伸之, 武田利和, 松本一宏, 森田伸也, 小坂威雄, 水野隆一, 大家基嗣

日本逆流性腎症フォーラム記録集 (日本逆流性腎症フォーラム) 30回 19 - 21 2024.01

ISSN 2435-323X

症例1(26歳女性)。11歳時に右膀胱尿管逆流(VUR)に対しCohen法による逆流防止術が施行された。今回、右水腎症を契機に下大静脈後尿管(RCU)の合併が明らかになり、右尿管尿管吻合術を行った結果、術後4年半経過現在、水腎症は改善している。尚、本症例は逆流防止術前にRCUの診断がされておらず、尿管の対側への牽引がRCUによる腎盂尿管移行部通過障害を悪化させた可能性が考えられた。症例2(19歳女性)。反復する発熱、右水腎症を主訴とした。超音波検査、CT検査、排尿時膀胱尿道造影の所見を踏まえて、RCU合併の右VURと診断された。尿管の牽引を伴わないLich-Gregoir法による逆流防止術を施行した結果、術後は水腎症の増悪なく、良好である。

Concomitant Prostate Needle Biopsy and Laser Vaporization of the Prostate Could Be a Risk of Postoperative Hemoglobin Decline, a Retrospective Study.

Ezaki T, Hongo H, Takamatsu K, Tanaka N, Oya M

Research and reports in urology (Research and Reports in Urology) 16 123 - 129 2024

ISSN 2253-2447

Purpose: Contact laser vaporization of the prostate (CVP) for benign prostatic hyperplasia is a widely accepted and safe procedure for elderly patients because of its lower bleeding risks. However, CVP lacks a postoperative pathological examination for prostate cancer. Concomitant prostate biopsy and CVP may complement this disadvantage; however, the risk of bleeding associated with this procedure remains unclear. This study aimed to evaluate the safety of a concomitant prostate biopsy and CVP. Patients and Methods: This retrospective study included 106 men who had undergone CVP in Nerima General Hospital. Prostate biopsies and CVP were performed simultaneously on 16 patients. We defined the “hemorrhage group” by a >5% decrease in hemoglobin the day after surgery. Preoperative and operative indices were evaluated based on the association with the hemorrhage group. Results: Participants in the concomitant biopsy group were older (p = 0.001), had larger prostates (p = 0.014), a lower rate of prostate biopsy history (p = 0.046), longer postoperative urinary catheter duration (p = 0.024), and a higher rate of decline in hemoglobin levels the day after surgery (p = 0.023). Patients in the hemorrhage group (n = 20, 18.9%) showed a significantly higher rate of concomitant biopsy and CVP (p = 0.006). Multivariate analysis showed that concomitant prostate biopsy (p = 0.009, odds ratio = 4.61) was the sole statistically significant predictive factor for hemorrhage. Conclusion: Concomitant prostate biopsy and CVP of the prostate may increase the risk of bleeding.

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Appropriate definition of non-metastatic castration-resistant prostate cancer (nmCRPC) and optimal timing of androgen receptor signaling inhibitor (ARSI)

Matsumoto K., Kosaka T., Takeda T., Fukumoto K., Yasumizu Y., Tanaka N., Morita S., Mizuno R., Asanuma H., Oya M.

International Journal of Clinical Oncology (International Journal of Clinical Oncology) 29 ( 8 ) 1198 - 1203 2024

ISSN 13419625

Background: Defined by rising PSA levels under androgen deprivation therapy (ADT) despite no visible metastases on conventional imaging, non-metastatic castration-resistant prostate cancer (nmCRPC) represents a complex clinical challenge. A significant subset of these patients rapidly develops metastatic disease, negatively impacting survival. We examined the difference in prognosis of nmCRPC patients according to the timing of therapeutic interventions with androgen receptor signaling inhibitor (ARSI). Methods: We examined 102 nmCRPC patients treated with ARSI. We divided patients according to their PSA levels when ARSI was administered: Cohort A (PSA 0.5–2.0 ng/mL), Cohort B (PSA 2.0–4.0 ng/mL), and Cohort C (PSA > 4.0 ng/mL). Utilizing the Kaplan–Meier method for survival analysis, our analytical starting point was the moment when PSA levels exceeded 0.5 ng/mL post-ADT nadir, ensuring a fair comparison and minimizing lead-time bias. Results: After excluding 5 patients whose PSA nadir after ADT > 0.5 ng/mL, patient distribution across Cohort A, Cohort B, and Cohort C was 32, 24, and 41 patients, respectively. Kaplan–Meier survival analysis highlighted a 2-year metastasis-free survival rate of 97% for Cohort A, 87% for Cohort B, and 73% for Cohort C. A marked statistical difference emerged when comparing Cohort A with Cohorts B and C, with a p-value of 0.043. Conclusion: The timely initiation of ARSI is paramount in nmCRPC management. Our findings strongly advocate for consideration of ARSI administration in nmCRPC patients before their PSA levels exceed 2.0 ng/mL. Our results indicated a PSA threshold of 1.0 ng/mL for nmCRPC definition which is more reasonable to administer ARSI without delay.

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AUGMENTED ONLAY BUCCAL MUCOSAL GRAFT URETEROPLASTY FOR URETERAL STRICTURE: A CASE REPORT

Iwasa S., Asanuma H., Takahashi R., Fukumoto K., Yasumizu Y., Tanaka N., Takeda T., Matsumoto K., Morita S., Kosaka T., Mizuno R., Oya M.

Japanese Journal of Urology 115 ( 1 ) 37 - 41 2024

ISSN 00215287

A 14-year-old boy developed hydronephrosis and worsening renal function due to fibroepithelial polyps of the bladder and left ureter at the age of 12 years. The endoscopic treatment of ureteral polyps was attempted by his previous doctor; however urethral stricture and ureteral stricture developed and was untreatable. Therefore, he was referred to our hospital for further reconstructive treatment. He underwent Palminteri urethroplasty with penile skin graft for urethral stricture at the age of 13 years, followed by ureteroplasty at the age of 14 years. The stenotic ureter was minimally resected, with only complete obstruction and residual polyps, and augmented onlay ureteroplasty with a buccal mucosa graft was performed. Nephrostomy was removed 13 days after surgery, followed by the ureteral stent 4 months after surgery. Retrograde pyelography and ureteroscopy were performed 1 year and 2 years postoperatively, and neither recurrent strictures nor polyps were observed. The patient is doing well 3 years postoperatively.

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進行性尿路上皮癌に対するペムブロリズマブ投与中に副腎皮質刺激ホルモン単独欠損症をきたした血液透析患者の1例

北岡壮太郎, 水野隆一, 吉田理, 高橋遼平, 安水洋太, 田中伸之, 森田伸也, 大家基嗣

泌尿器外科 (医学図書出版(株)) 36 ( 11 ) 1258 - 1261 2023.11

ISSN 0914-6180

症例は79歳女性。右腎盂癌(pT1N0M0)にて右腎尿管全摘除術を施行後の約1年後に血液透析導入となった。術後2年で多発肺転移にて再発し,救援化学療法を2コース施行するもPDであったため,2次化学療法としてペムブロリズマブを開始した。6コース投与後に持続する発熱,倦怠感,脱力,意識障害にて当院に入院し,ACTH単独欠損症の診断となりirAEと考えられた。維持透析下でヒドロコルチゾンを補充し症状は改善,そのままペムブロリズマブを投与再開し,9ヵ月間PRを維持できた。(著者抄録)

Prognostic impact of tumor ureteral invasion on recurrence after radical cystectomy.

Saito T, Matsumoto K, Tanaka N, Fukumoto K, Yasumizu Y, Takeda T, Morita S, Kosaka T, Mizuno R, Asanuma H, Hara S, Oya M

International urology and nephrology (International Urology and Nephrology) 56 ( 1 ) 129 - 135 2023.09

ISSN 0301-1623

Purpose: Several preoperative factors have been suggested to be risk factors of disease recurrence after radical cystectomy. There is no study focusing on the impact on prognosis of bladder tumor ureteral invasion in preoperative imaging. Methods: The study population consisted of 136 patients, all of whom underwent radical cystectomy during the period between 2007–2019. We excluded patients with concurrent or a history of upper tract urothelial carcinoma and who underwent radical cystectomy for other cancers or nononcologic reasons. The starting point of this study was the timing of neoadjuvant chemotherapy or radical cystectomy and the endpoint was the timing of disease recurrence. To identify the factors influencing recurrence, univariate and multivariate analyses were performed using the Cox proportional hazard model. Recurrence-free survival curves were constructed using the Kaplan–Meier method. Results: Ureteral invasion was observed in 20 (14.7%) patients. Disease recurrence was observed in 11 (55.0%) of 20 ureteral invasion positive patients and 35 (30.2%) of 116 ureteral invasion negative patients, respectively. In the ureteral invasion positive group, clinical T and N stage were higher and hydronephrosis were more common than in the ureteral invasion negative group. According to the multivariate analysis, ureteral invasion (hazard ratio: 2.307, p = 0.016) and clinical N stage ≥ 1 (hazard ratio: 2.140, p = 0.028) were independent risk factors for postoperative recurrence. In the ureteral invasion positive group, more local recurrences were observed. Conclusion: This study suggested that ureteral invasion in preoperative imaging is a significant risk factor for postoperative recurrence.

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ASO Visual Abstract: Long-Term Prognosis and Treatment Strategy of Persistent PSA After Radical Prostatectomy.

Komori T, Matsumoto K, Kosaka T, Takeda T, Kamitani R, Yasumizu Y, Tanaka N, Morita S, Mizuno R, Asanuma H, Oya M

Annals of surgical oncology (Annals of surgical oncology) 30 ( 11 ) 6945 2023.07

ISSN 1068-9265

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Factors affecting the selection of eligible candidates for focal therapy for prostate cancer

Takeda T., Narita K., Yasumizu Y., Tanaka N., Matsumoto K., Morita S., Kosaka T., Mizuno R., Asanuma H., Jinzaki M., Oya M.

World Journal of Urology (World Journal of Urology) 41 ( 7 ) 1821 - 1827 2023.07

ISSN 07244983

Purpose: Focal therapy (FT) is a treatment modality for prostate cancer that aims to reduce side effects. However, it remains difficult to select eligible candidates. We herein examined eligibility factors for hemi-ablative FT for prostate cancer. Methods: We identified 412 patients who were diagnosed with unilateral prostate cancer by biopsy and had undergone radical prostatectomy between 2009 and 2018. Among these patients, 111 underwent MRI before biopsy, had 10–20 core biopsies performed, and did not receive other treatments before surgery. Fifty-seven patients with prostate-specific antigen ≥ 15 ng/mL and biopsy Gleason score (GS) ≥ 4 + 3 were excluded. The remaining 54 patients were evaluated. Both lobes of the prostate were scored using Prostate Imaging Reporting and Data System version 2 on MRI. Ineligible patients for FT were defined as those with ≥ 0.5 mL GS6 or GS ≥ 3 + 4 in the biopsy-negative lobe, ≥ pT3, or lymph node involvement. Selected predictors of eligibility for hemi-ablative FT were analyzed. Results: Among our cohort of 54 patients, 29 (53.7%) were eligible for hemi-ablative FT. A multivariate analysis identified a PI-RADS score < 3 in the biopsy-negative lobe (p = 0.016) as an independent predictor of eligibility for FT. Thirteen out of 25 ineligible patients had GS ≥ 3 + 4 tumors in the biopsy-negative lobe, half of whom (6/13) also had a PI-RADS score < 3 in the biopsy-negative lobe. Conclusion: The PI-RADS score in the biopsy-negative lobe may be important in the selection of eligible candidates for FT. The findings of this study will help reduce missed significant prostate cancers and improve FT outcomes.

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Strategy for PSA progression in patients undergoing salvage radiation for biochemical recurrence after radical prostatectomy

Saito T., Matsumoto K., Kosaka T., Yasumizu Y., Tanaka N., Takeda T., Morita S., Mizuno R., Asanuma H., Oya M.

International Journal of Clinical Oncology (International Journal of Clinical Oncology) 28 ( 5 ) 707 - 715 2023.05

ISSN 13419625

Background: The treatment strategy for prostate-specific antigen (PSA) progression in patients who receive salvage radiation therapy (RT) for biochemical recurrence (BCR) after radical prostatectomy (RP) is salvage androgen deprivation therapy (ADT). However, its optimal timing is highly controversial. Methods: The study sample consisted of 77 men who underwent RP, received salvage RT against BCR, and underwent salvage ADT for PSA progression. The endpoint of this study was development to castration-resistant prostate cancer (CRPC), from the start of salvage RT. Results: The median follow-up time was 9.5 years, and 20 patients experienced CRPC. The multivariable analysis identified PSA-doubling time (PSA-DT) ≤ 12 months (hazard ratio, 3.5) and seminal vesicle invasion (SVI) (hazard ratio, 4.4) as independent risk factors. We defined the high-risk and low-risk groups as those with one or two risk factors and no risk factors, respectively. In the high-risk group, a significant difference in time to CRPC was observed between patients who received salvage ADT at PSA ≤ 1.0 ng/mL (n = 8) and at > 1.0 ng/mL (n = 27) (10-year non-CRPC rate: 100.0% vs. 46.3%, respectively). In contrast, in the low-risk group, no significant difference in CRPC-free survival was observed between patients who received salvage ADT at PSA ≤ 1.0 ng/mL (n = 14) and at > 1.0 ng/mL (n = 28) (10-year non-CRPC rate: 86.4% vs. 80.8%, respectively). Conclusion: In high-risk patients (PSA-DT ≤ 12 months and/or SVI), salvage ADT for PSA progression after salvage RT should be started before the PSA levels exceed 1.0 ng/mL.

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Single-Cell Phenotyping of CD73 Expression Reveals the Diversity of the Tumor Immune Microenvironment and Reflects the Prognosis of Bladder Cancer.

Izawa M, Tanaka N, Murakami T, Anno T, Teranishi Y, Takamatsu K, Mikami S, Kakimi K, Imamura T, Matsumoto K, Oya M

Laboratory investigation; a journal of technical methods and pathology (Laboratory investigation; a journal of technical methods and pathology) 103 ( 4 ) 100040 2023.01

ISSN 0023-6837

The cutting edge of cancer immunotherapy extends to ecto-5'-nucleotidase (CD73), a cell membrane enzyme that targets the metabolism of extracellular adenosine. We herein focused on the expression of CD73 to clarify the state of CD73 positivity in cancer immunity and tumor microenvironment, thereby revealing a new survival predictor for patients with bladder cancer (BCa). We used clinical tissue microarrays of human BCa and simultaneously performed the fluorescent staining of cell type-specific markers (CD3, CD8, Foxp3, programmed cell death protein 1, and programmed death-ligand 1 [PD-L1]) and CD73 together with DAPI for nuclear staining. In total, 156 participants were included. Multiplexed cellular imaging revealed a unique interaction between CD73 expression and CD8+ cytotoxic T cells (CTLs) and Foxp3+ regulatory T (Treg) cells in human BCa, showing the high infiltration of CD8+CD73+ CTLs and Foxp3+CD73+ Treg cells in tumors to be associated with tumorigenesis and poor prognosis in BCa. Interestingly, from a biomarker perspective, the high infiltration of CD73+ Treg cells in tumors was identified as an independent risk factor for overall survival in addition to clinicopathologic features. Regarding the relationship between immune checkpoint molecules and CD73 expression, both CD73+ CTLs and CD73+ Treg cells tended to coexpress programmed cell death protein 1 as tumor invasiveness and nuclear grade increased. Additionally, they may occupy a spatial niche located distantly from PD-L1+ cells in tumors to interfere less with the cancerous effects of PD-L1+ cells. In conclusion, the present results on the status of CD73 in cancer immunity suggest that CD73 expression on specific T-cell types has a negative immunoregulatory function. These findings may provide further insights into the immunobiological landscape of BCa, which may be translationally linked to improvements in future immunotherapy practice.

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Predictors of urinary function recovery after laparoscopic and robot-assisted radical prostatectomy.

Hakozaki K, Takeda T, Yasumizu Y, Tanaka N, Matsumoto K, Morita S, Kosaka T, Mizuno R, Asanuma H, Oya M

International braz j urol : official journal of the Brazilian Society of Urology (International braz j urol : official journal of the Brazilian Society of Urology) 49 ( 1 ) 50 - 60 2023.01

ISSN 1677-5538

INTRODUCTION: Even in the era of laparoscopic radical prostatectomy (LRP) and robot-assisted laparoscopic radical prostatectomy (RALP), we sometimes encounter patients with severe urinary incontinence after surgery. The aim of the present study was to identify predictors of urinary continence recovery among patients with urinary incontinence immediately after surgery (UIIAS). MATERIALS AND METHODS: We identified 274 patients with clinically localized prostate cancer who underwent LRP and RALP between 2011 and 2018. UIIAS was defined as a urine loss ratio > 0.15 on the first day of urethral catheter removal. Urinary continence recovery was defined as using ≤ 1 pad/day one year after surgery. In the present study, we evaluated factors affecting urinary function recovery one year after surgery among patients with urinary incontinence immediately after LRP and RALP. RESULTS: UIIAS was observed in 191 out of 274 patients (69.7%). A multivariate analysis identified age (<65 years, p = 0.015) as an independent predictor affecting immediate urinary continence. Among 191 incontinent patients, urinary continence one year after surgery improved in 153 (80.1%). A multivariate analysis identified age (<65 years, p = 0.003) and estimated blood loss (≥ 100 mL, p = 0.044) as independent predictors affecting urinary continence recovery one year after surgery. CONCLUSION: The present results suggest that younger patients and patients with higher intraoperative blood loss recover urinary continence one year after surgery even if they are incontinent immediately after surgery.

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Long-Term Prognosis and Treatment Strategy of Persistent PSA After Radical Prostatectomy

Komori T., Matsumoto K., Kosaka T., Takeda T., Kamitani R., Yasumizu Y., Tanaka N., Morita S., Mizuno R., Asanuma H., Oya M.

Annals of Surgical Oncology (Annals of Surgical Oncology) 30 ( 11 ) 6936 - 6942 2023

ISSN 10689265

Purpose: Prostate-specific antigen (PSA) is thought to be undetectable (< 0.1 ng/mL) after radical prostatectomy (RP), and persistent PSA (≥ 0.1 ng/mL) is considered a failure of curative treatment. Materials and Methods: The study population consisted of 135 patients, all of whom underwent RP for localized prostate cancer, and developed persistent PSA. We set the starting point at the timing of RP, and the endpoints were the development of castration-resistant prostate cancer (CRPC) and cancer-specific survival. Results: Salvage radiation therapy (RT) and androgen deprivation therapy (ADT) were performed in 53 (39.3%) and 64 (47.4%) patients, respectively. Eighteen (13.3%) patients didn't receive any salvage treatment. During the median follow-up of 10.1 years, CRPC was observed in 23 patients, and 6 patients died due to prostate cancer. Kaplan-Meier curves demonstrated the 15-year CRPC-free and cancer-specific survivals were 79.5% and 92.7%, respectively. Cox multivariate analysis demonstrated that seminal vesicle invasion (SVI) (p = 0.007) and nadir PSA ≥1.0 ng/mL (p = 0.002) were independent risk factors for CRPC. Salvage RT demonstrated better cancer control (the 10-and 15-year CRPC-free survival was 94.1% and 94.1%) compared to ADT (75.9% and 58.5%, p = 0.017) after 1:1 propensity score matching. Conclusions: SVI and nadir PSA ≥1.0 ng/mL are independent risk factors for CRPC in patients with persistent PSA after RP. Salvage RT is considered to be the optimal treatment for this condition.

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Prognostic role of the innate immune signature CD163 and “eat me” signal calreticulin in clear cell renal cell carcinoma

Anno T., Tanaka N., Takamatsu K., Hakozaki K., Kufukihara R., Baba Y., Takeda T., Matsumoto K., Morita S., Kosaka T., Mikami S., Nishihara H., Mizuno R., Oya M.

Cancer Immunology, Immunotherapy (Cancer Immunology, Immunotherapy) 72 ( 6 ) 1779 - 1788 2023

ISSN 03407004

The effects of the innate immune status on patients with clear cell renal cell carcinoma (ccRCC) currently remain unknown. We herein provided more extensive information about the inner landscape of immunobiology of ccRCC. In total, 260 ccRCC samples from three different cohorts consisting of 213 primary tumors and 47 metastases were obtained. We focused on five representative innate immune signatures, CD68, CD163, the “eat me” signal calreticulin, the “don't eat me” signal CD47, and signal regulatory protein α, and examined the role of each signature by quantitative immunohistochemistry. We then conducted an integrated genome mutation analysis by next-generation sequencing. Among the five markers, high CD163 and low calreticulin expression levels were prognostic in ccRCC. The application of a new risk model based on CD163 and calreticulin levels, named the innate immune risk group (high risk: high-CD163/low calreticulin, intermediate risk: high-CD163/high calreticulin or low CD163/low calreticulin, low risk: low-CD163/high calreticulin), enabled the sequential stratification of patient prognosis and malignancy. Although organ-specific differences were observed, metastases appeared to have a higher innate immune risk, particularly in the lungs, with 50% of ccRCC metastases being classified into the high-risk group according to our risk score. An analysis of genomic alterations based on the innate immune risk group revealed that alterations in the TP53/Cell cycle pathway were highly prevalent in high-risk ccRCC patients according to two innate immune signatures CD163 and calreticulin. The present results provide insights into the immune-genomic biology of ccRCC tumors for innate immunity and will contribute to future therapies focused on the innate immune system in solid cancers.

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Surgical Treatment for Metastatic Brain Tumor in the Cerebellar Hemisphere from Small-cell Neuroendocrine Carcinoma of the Urinary Bladder: A Case Report and Review of the Literature.

Sogano J, Takahashi S, Tanaka N, Kubo H, Okita H, Oya M, Toda M

NMC case report journal 10 235 - 239 2023

ISSN 2188-4226

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IMAGENE trial: multicenter, proof-of-concept, phase II study evaluating the efficacy and safety of combination therapy of niraparib with PD-1 inhibitor in solid cancer patients with homologous recombination repair genes mutation

Kato T., Matsubara N., Shiota M., Eto M., Osawa T., Abe T., Shinohara N., Yasumizu Y., Tanaka N., Oya M., Nishimoto K., Hayashi T., Nakayama M., Kojima T., Namikawa K., Fujisawa T., Okano S., Hida E., Nakamura Y., Bando H., Yoshino T., Nonomura N.

BMC Cancer (BMC Cancer) 22 ( 1 ) 1292 2022.12

Background: Previous clinical trials have demonstrated the potential efficacy of poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) in patients with cancer involving homologous recombination repair (HRR) gene-mutation. Moreover, HRR gene-mutated cancers are effectively treated with immune checkpoint inhibitors (ICIs) with the increase in tumor mutation burden. We have proposed to conduct a multicenter, single-arm phase II trial (IMAGENE trial) for evaluating the efficacy and safety of niraparib (PARPi) plus programmed cell death-1 inhibitor combination therapy in patients with HRR gene-mutated cancers who are refractory to ICIs therapy using a next generation sequencing-based circulating tumor DNA (ctDNA) and tumor tissue analysis. Methods: Key eligibility criteria for this trial includes HRR gene-mutated tumor determined by any cancer gene tests; progression after previous ICI treatment; and Eastern Cooperative Oncology Group Performance Status ≤ 1. The primary endpoint is the confirmed objective response rate (ORR) in all patients. The secondary endpoints include the confirmed ORR in patients with HRR gene-mutation of ctDNA using the Caris Assure (CARIS, USA). The target sample size of the IMAGENE trial is 57 patients. Biomarker analyses will be performed in parallel using the Caris Assure, proteome analysis, and T cell repertoire analysis to reveal tumor immunosurveillance in peripheral blood. Expected outcome: Our trial aims to confirm the clinical benefit of PARPi plus ICI combination therapy in ICI-resistant patients. Furthermore, through translational research, our trial will shed light on which patients would benefit from the targeted combination therapy for patients with HRR gene-mutated tumor even after the failure of ICIs. Trial registration: The IMAGENE trial: jRCT, Clinical trial no.: jRCT2051210120, Registered date: November 9, 2021.

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Predictors of renal function after adrenalectomy in patients with Cushing or subclinical Cushing syndrome.

Kufukihara R, Takeda T, Hakozaki K, Yasumizu Y, Tanaka N, Matsumoto K, Morita S, Kosaka T, Mizuno R, Asanuma H, Miyashita K, Kurihara I, Oya M

International journal of urology : official journal of the Japanese Urological Association (International Journal of Urology) 29 ( 12 ) 1447 - 1454 2022.08

ISSN 0919-8172

Purpose: The postoperative course of renal function remains unclear in Cushing syndrome. We examined changes in renal function after adrenalectomy in patients with Cushing syndrome and attempted to identify predictors of renal impairment. Methods: The study population comprised 76 patients who underwent adrenalectomy for Cushing and subclinical Cushing syndrome between 2001 and 2018. Renal function and other factors were evaluated pre-operation, at 1 postoperative month, and 1 postoperative year. We defined a ≥10% decrease in the estimated glomerular filtration rate at 1 postoperative year as renal impairment, and predictors associated with this reduction were investigated. The relationship between renal function and steroid replacement after surgery was also examined. Results: Mean pre-operative estimated glomerular filtration rate was 82.2 ml/min/1.73 m2. While mean estimated glomerular filtration rate was significantly lower at 1 postoperative month than the pre-operative value (71.7 ml/min/1.73 m2 [89.1%], p < 0.001), no significant differences were observed between 1 postoperative year and pre-operation (79.5 ml/min/1.73 m2 [97.6%], p = 0.108). Twenty-six patients (34.2%) developed renal impairment. A multivariate analysis identified a low pre-operative adrenocorticotropic hormone level as an independent predictor of renal impairment (odds ratio 6.30, p = 0.031). Among 43 patients with available records of steroid replacement history, 18 (41.9%) developed renal impairment. The ratio of patients with a reduced steroid replacement dose at 1 postoperative month was significantly lower among patients with renal impairment than those without (22.2% vs. 56.0%, p = 0.027). Conclusions: The pre-operative adrenocorticotropic hormone level was a predictor of renal function after adrenalectomy in patients with Cushing or subclinical Cushing syndrome.

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Site-Specific Differences in PD-1 Blockade Success and Biomarkers in Urothelial Carcinoma Treated with Pembrolizumab.

Umeda K, Tanaka N, Yasumizu Y, Takeda T, Matsumoto K, Morita S, Kosaka T, Mizuno R, Oya M

Clinical genitourinary cancer (Clinical Genitourinary Cancer) 21 ( 1 ) 128 - 135 2022.08

ISSN 1558-7673

Introduction: Since tumors in different human organs may have different tumor microenvironments, we evaluate time-course changes in all tumor locations after pembrolizumab treatment in urothelial carcinoma (UC) to examine the differences in efficacy of pembrolizumab per organ. Further, we uncover the usefulness of inflammatory markers such as neutrophil-to-lymphocyte ratio (NLR), CRP, and kinetics of these markers to predict pembrolizumab success and relation to overall survival (OS) in UC. Patients and Methods: A total of 115 cancerous lesions from 44 UC patients were measurable based on RECIST 1.1 criteria. The serum CRP and NLR levels were measured at baseline prior to pembrolizumab treatment and at least every 3 weeks just prior to pembrolizumab administration. Results: Site-specific success (ie, patients with CR/PR/SD by RESIST 1.1) rates for pembrolizumab treatments were as follows: primary tumors: 67%, lymph node: 70%, lung: 44%, liver: 40%, and peritoneal metastasis: 56%. Focusing on the major metastasis sites, lymph nodes and lungs, we examined the relationships between NLR, CRP, or that kinetics and pembrolizumab success. In lymph nodes, both early NLR kinetics (P = .005) and CRP kinetics (P = .035) was a predictor for pembrolizumab success. On the other hand, none of 4 was not in lung metastases. Regarding to the mortality, the multivariate analysis revealed that early NLR kinetics was a prognostic biomarker for OS among the 4, independent of performance status and liver metastasis. Conclusion: We revealed that site-specific pembrolizumab success in UC. Early NLR kinetics was a predictor for lymph node pembrolizumab success and OS in our cohorts.

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Principal component analysis of early immune cell dynamics during pembrolizumab treatment of advanced urothelial carcinoma

Teshima T., Kobayashi Y., Kawai T., Kushihara Y., Nagaoka K., Miyakawa J., Akiyama Y., Yamada Y., Sato Y., Yamada D., Tanaka N., Tsunoda T., Kume H., Kakimi K.

Oncology Letters (Oncology Letters) 24 ( 2 ) 265 2022.08

ISSN 17921074

Immune checkpoint inhibitors have been approved as second-line therapy for patients with advanced urothelial carcinoma (UC). However, which patients will obtain clinical benefit remains to be determined. To identify predictive biomarkers for the pembrolizumab (PEM) response early during treatment, the present study investigated 31 patients with chemotherapy-resistant recurrent or metastatic UC who received 200 mg PEM intravenously every 3 weeks. Blood was taken just before the first dose and again before the second dose, and the peripheral blood mononuclear cells of all 31 pairs of blood samples were immune phenotyped by flow cytometry. Data were assessed by principal component analysis (PCA), correlation analysis and Cox proportional hazards modeling in order to comprehensively determine the effects of PEM on peripheral mononuclear immune cells. Absolute counts of CD45RA+CD27-CCR7- terminally differentiated CD8+ T cells and KLRG1+CD57+ senescent CD8+ T cells were significantly increased after PEM administration (P=0.042 and P=0.043, respectively). Senescent and exhausted CD4+ and CD8+ T cell dynamics were strongly associated with each other. By contrast, counts of monocytic myeloid-derived suppressor cells (mMDSCs) were not associated with other immune cell phenotypes. The results of PCA and non-hierarchical clus-tering of patients suggested that excessive T cell senescence and differentiation early during treatment were not neces-sarily associated with a survival benefit. However, decreased mMDSC counts after PEM were associated with improved overall survival. In conclusion, early on-treatment peripheral T cell status was associated with response to PEM; however, it was not associated with clinical benefit. By contrast, decreased peripheral mMDSC counts did predict improved overall survival.

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射精機能温存の接触式レーザー前立腺蒸散術が施行された患者の治療成績

田中伸之, 三條丹星, 大家基嗣

日本排尿機能学会誌 ((一社)日本排尿機能学会) 32 ( 2 ) 429 - 433 2022.07

ISSN 1347-6513

目的:前立腺肥大症に対する接触式レーザー前立腺蒸散術(CVP)は,980nmダイオードレーザーで肥大した前立腺組織を気化・除去する.一方,通常の前立腺肥大症手術では,逆行性射精が合併する.この問題の解決に我々は,射精機能を温存するCVPに取り組んでいる.方法:当院で施行された射精機能温存CVPについて,周術期・術後アウトカムの臨床的検討を行った.前立腺レーザー蒸散は,中葉〜精丘付近〜側葉の順に蒸散を行った.射精機能を温存する場合は,精丘から7mm以上を肉眼的所見でのマージンとし,可能な限り低出力で周囲を蒸散した.結果:射精機能温存を行ったCVP患者12例においては,手術関連の重篤な合併症は認められず,術後排尿機能の改善も著明であった.射精機能は術後6ヵ月の時点で,12例中10例(83%)で保持されていた.結論:射精機能温存を試みたCVP施行12例の周術期・術後アウトカムを報告した.約8割の症例で順行性射精が可能であった.(著者抄録)

A low subcutaneous fat mass is a risk factor for the development of inguinal hernia after radical prostatectomy.

Umeda K, Takeda T, Hakozaki K, Yasumizu Y, Tanaka N, Matsumoto K, Morita S, Kosaka T, Mizuno R, Asanuma H, Oya M

Langenbeck's archives of surgery (Langenbeck's Archives of Surgery) 407 ( 7 ) 3107 - 3112 2022.06

ISSN 1435-2443

Purpose: Inguinal hernia (IH) after radical prostatectomy (RP) is a complication that impairs quality of life; however, the factors contributing to IH after RP remain unclear. Therefore, we herein attempted to identify the factors responsible for the development of IH after RP. Methods: We reviewed 622 patients who underwent laparoscopic or robot-assisted laparoscopic RP at our hospital between December 2011 and April 2020. The total fat area and visceral fat area were calculated at the level of the umbilicus using computed tomography, and the subcutaneous fat area (SFA) was calculated by subtracting the visceral fat area from the total fat area. The psoas muscle area was measured at the third lumbar vertebrae level using computed tomography to calculate the psoas muscle mass index, which is used in sarcopenia as an index of muscle mass. We investigated the risk factors for IH after laparoscopic or robot-assisted laparoscopic RP. Results: IH developed in 88 patients (16.7%). Fifty-seven of these patients underwent hernia repair at our hospital, and 56 (98.2%) had indirect hernias. A multivariate analysis identified SFA (odds ratios: 0.383, p < 0.001) as an independent predictor for the development of IH. Two-year IH-free survival rates were 77.3% in the small SFA group (SFA < 123 cm2) and 88.7% in the large SFA group (SFA ≥ 123 cm2) (p < 0.001). Conclusion: Subcutaneous fat was associated with the development of IH, particularly indirect IH, after laparoscopic or robot-assisted laparoscopic RP. An indirect IH prevention technique needs to be considered, particularly for patients with less subcutaneous fat.

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Profiling the Biological Characteristics and Transitions through Upper Tract Tumor Origin, Bladder Recurrence and Muscle-Invasive Bladder Progression in Upper Tract Urothelial Carcinoma

Shigeta K., Matsumoto K., Tanaka N., Mikami S., Kosaka T., Yasumizu Y., Takeda T., Mizuno R., Kikuchi E., Oya M.

International Journal of Molecular Sciences (International Journal of Molecular Sciences) 23 ( 9 ) 2022.05

ISSN 16616596

To evaluate biological characteristics and transitions of upper tract urothelial carcinoma (UTUC) through metachronous bladder tumors after radical nephroureterectomy (RNU), we con-ducted immunohistochemical (IHC) staining of tumor specimens of UTUC tumor origin, non-mus-cle-invasive bladder cancer (NMIBC) and MIBC progressed after intravesical recurrence (IVR), and bladder primary MIBC. Fibroblast growth factor receptor 3 (FGFR3), p53, cytokeratin 5/6 (CK5/6), and CK20 were stained to examine expression rates. After expression assessment with heatmap clustering, the overexpression of four biomarkers from UTUC origin to metachronous MIBC progression was analyzed with clinicopathological variables. We found that high CK20 and low CK5/6 expression were both observed in UTUC tumor origin and subsequent NMIBC after RNU. By in-vestigating molecular expression in the IVR specimen, we observed that low pT stage bladder recurrence occupied the majority of CK20 high CK5/6 low expression, but would change to CK20 low CK5/6 high expression as it progressed to MIBC. UTUC metachronous MIBC has different characteristics compared with bladder primary MIBC, which comprises favorable biological features such as high FGFR3 expression, and follows favorable prognosis compared to those without FGFR3 ex-pression. The present study demonstrated that the biological characteristics of UTUC tumor origin shifts from luminal to basal-like features with progression to MIBC, but FGFR3 expression taken over from UTUC origin may comprise a favorable entity compared to primary MIBC.

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【腹部の最新画像情報2022】症例　術後早期に遠隔転移を認めた表在性膀胱小細胞癌の2例

竹下諒, 有田祐起, 秋田大宇, 三上修治, 田中伸之, 奥田茂男, 大家基嗣, 陣崎雅弘

臨床放射線 (金原出版(株)) 67 ( 5 ) 505 - 510 2022.05

ISSN 0009-9252

症例1は60歳代女性。主訴は肉眼的血尿であった。MRI T2強調像で膀胱左側壁に21mm大の広基性腫瘤を認め、経尿道的膀胱腫瘍切除術を行った。病理学的に膀胱小細胞癌と診断した。2年後のFDG-PETで右腋窩・右側腹部の皮下腫瘤、左腸骨動脈リンパ節にFDGの強い集積亢進を認め、膀胱小細胞癌の転移と考えられた。症例2は60歳代男。主訴は肉眼的血尿であった。MRI T2強調像で膀胱前壁に12mm大の広基性腫瘤を認め、経尿道的膀胱腫瘍切除術、その後膀胱全摘術を行った。病理学的に膀胱小細胞癌と診断した。1年後のCTで両肺に多発する増大傾向の結節を認め、膀胱小細胞癌の転移と考えられた。

Endoscopic vaporization of benign prostatic hyperplasia using a contact 980 nm diode laser under antithrombotic therapy: A prospective survey.

Sanjo T, Tanaka N, Shinojima T, Yasumizu Y, Takeda T, Matsumoto K, Morita S, Kosaka T, Mizuno R, Asanuma H, Oya M

Asian journal of endoscopic surgery (Asian journal of endoscopic surgery) 15 ( 3 ) 585 - 590 2022.03

ISSN 1758-5902

INTRODUCTION: To prospectively clarify whether endoscopic contact laser vaporization of the prostate (CVP) can be safely performed even in patients undergoing antithrombotic therapy. METHODS: Fifty-five patients treated with CVP were enrolled. Patients were assigned to: (i) the antithrombotic therapy group (n = 21, 38%); or (ii) control group without antithrombotic therapy (n = 34, 62%). All patients in the antithrombotic therapy group continued all antithrombotic agents during the perioperative period and thereafter. RESULTS: No difference was noted in patient background between the two groups. In primary endpoints, decreases in the postoperative hemoglobin level were remarkable in the antithrombotic therapy group, while no serious effects were noted in either group. The control and antithrombotic therapy groups did not show a significant difference in the occurrence of catheter obstruction due to blood clots or serious hematuria following catheter removal. During follow-up, transurethral coagulation for hemostasis was needed only in the antithrombotic therapy group, with a frequency of transurethral coagulation of up to 14%. In secondary endpoints, no difference in the occurrence of perioperative or late-onset complications after surgery was noted between the two groups. Finally, no difference was noted in improvements in the International Prostate Symptom Score (IPSS), IPSS quality of life score, overactive bladder symptom score, maximum flow rate, or post-voiding residual urine volume between the two groups throughout the follow-up period. CONCLUSIONS: CVP can be performed safely and effectively in patients undergoing continuous antithrombotic therapy. However, the possibility of secondary bleeding after discharge in a subset of patients, such as those undergoing antithrombotic therapy, may be noted.

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Unique characteristics of tertiary lymphoid structures in kidney clear cell carcinoma: prognostic outcome and comparison with bladder cancer.

Masuda T, Tanaka N, Takamatsu K, Hakozaki K, Takahashi R, Anno T, Kufukihara R, Shojo K, Mikami S, Shinojima T, Kakimi K, Tsunoda T, Aimono E, Nishihara H, Mizuno R, Oya M

Journal for immunotherapy of cancer (Journal for ImmunoTherapy of Cancer) 10 ( 3 ) 2022.03

Background The aims of this study were (1) to clarify the impact of tertiary lymphoid structure (TLS) status on the outcome and immunogenomic profile of human clear cell renal cell carcinoma (ccRCC) and (2) to determine phenotypic differences in TLSs between different types of genitourinary cancer, that is, urinary ccRCC and bladder cancer. Methods We performed a quantitative immunohistological analysis of ccRCC tissue microarrays and conducted integrated genome mutation analysis by next-generation sequencing and methylation array analysis. Since the tumor immune microenvironment of ccRCC often differs from that of other cancer types, we analyzed the phenotypic differences in TLSs between ccRCC and in-house bladder cancer specimens. Results Varying distribution patterns of TLSs were observed throughout ccRCC tumors, revealing that the presence of TLSs was related to poor prognosis. An analysis of genomic alterations based on TLS status in ccRCC revealed that alterations in the PI3K-mTOR pathway were highly prevalent in TLS-positive tumors. DNA methylation profiling also revealed distinct differences in methylation signatures among ccRCC samples with different TLS statuses. However, the TLS characteristics of ccRCC and bladder cancer markedly differed: TLSs had the exact opposite prognostic impact on bladder cancer as on ccRCC. The maturity and spatial distribution of TLSs were significantly different between the two cancer types; TLSs were more mature with follicle-like germinal center organization and likely to be observed inside the tumor in bladder cancer. Labeling for CD8, FOXP3, PD-1, and PD-L1 showed marked differences in the diversity of the immune microenvironment surrounding TLSs. The proportions of CD8-, FOXP3-, and PD-L1-positive cells were significantly higher in TLSs in bladder cancer than in TLSs in ccRCC; rather the proportion of PD-1-positive cells was significantly higher in TLSs in ccRCC than in TLSs in bladder cancer. Conclusion The immunobiology of ccRCC is unique, and various cancerous phenomena conflict with that seen in other cancer types; therefore, comparing the TLS characteristics between ccRCC and bladder cancer may help reveal differences in the prognostic impact, maturity and spatial distribution of TLSs and in the immune environment surrounding TLSs between the two cancers.

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Predictors of Survival in Favorable Risk Patients with Metastatic Renal Cell Carcinoma Treated with a Single-Agent First-Line Therapy.

Mizuno R, Takamatsu K, Yasumizu Y, Tanaka N, Takeda T, Morita S, Matsumoto K, Kosaka T, Asanuma H, Mikami S, Oya M

Urologia internationalis (Urologia Internationalis) 106 ( 11 ) 1 - 5 2022.02

ISSN 0042-1138

Introduction: The aim of this retrospective study was to elucidate predictors of survival in metastatic renal cell carcinoma (mRCC) patients in an International Metastatic Renal Cell Carcinoma Database Consortium favorable risk group treated with frontline therapy without immune checkpoint inhibitors. Methods: A total of 238 patients with mRCC were reviewed. Among them, 55 patients in favorable risk group treated with single-agent systemic therapy were retrospectively analyzed. Clinical and pathological data were retrieved and analyzed retrospectively. The prognostic effect of each marker on overall survival (OS) was investigated with univariate and multivariate Cox's proportional hazards regression models. Results: After a median follow-up of 46.2 months after first-line treatment initiation, the median progression-free survival (PFS) was 29.3 months, and the median OS has not been reached. The estimated percentage of patients who were alive at 12 and 24 months were 96.1 and 94.1%, respectively. Multivariate analysis revealed that the long-term duration of first-line treatment (hazard ratio [HR]: 0.972, 95% confidence interval [CI]: 0.944-0.997, p = 0.0299) and the metastases limited to lung (HR: 3.852, 95% CI: 1.080-24.502, p = 0.0361) were independent predictors for longer OS in favorable risk mRCC patients. Conclusion: First-line systemic therapy for favorable risk mRCC patients with a single agent resulted in relatively longer PFS and OS. A longer duration of first-line treatment and lung only metastases are correlated with longer OS.

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Hybridisation chain reaction-based visualisation and screening for lncRNA profiles in clear-cell renal-cell carcinoma

Kufukihara R., Tanaka N., Takamatsu K., Niwa N., Fukumoto K., Yasumizu Y., Takeda T., Matsumoto K., Morita S., Kosaka T., Aimono E., Nishihara H., Mizuno R., Oya M.

British Journal of Cancer (British Journal of Cancer) 127 ( 6 ) 1133 - 1141 2022

ISSN 00070920

Background: Analysis of long noncoding RNA (lncRNA) localisation at both the tissue and subcellular levels can provide important insights into the cell types that are important for their function. Methods: By applying new fluorescent in situ hybridisation technique called hybridisation chain reaction (HCR), we achieved a high-throughput lncRNA visualisation and evaluation of clinical samples. Results: Assessing 1728 pairs of 16 lncRNAs and clear-cell renal-cell carcinoma (ccRCC) specimens, three lncRNAs (TUG1, HOTAIR and CDKN2B-AS1) were associated with ccRCC prognosis. Furthermore, we derived a new lncRNA risk group of ccRCC prognosis by combining the expression levels of these three lncRNAs. Examining genomic alterations underlying this classification revealed prominent features of tumours that could serve as potential biomarkers for targeting lncRNAs. We then derived combination of HCR with expansion microscopy and visualised nanoscale-resolution HCR signals in cell nuclei, uncovering intracellular colocalization of three lncRNA (TUG1, HOTAIR and CDKN2B-AS1) signals such as those located intra- or out of the nucleus or nucleolus in cancer cells. Conclusion: LncRNAs are expected to be desirable noncoding targets for cancer diagnosis or treatments. HCR involves plural probes consisting of small DNA oligonucleotides, clinically enabling us to detect cancerous lncRNA signals simply and rapidly at a lower cost.

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Landscape of prognostic signatures and immunogenomics of the AXL/GAS6 axis in renal cell carcinoma.

Hakozaki K, Tanaka N, Takamatsu K, Takahashi R, Yasumizu Y, Mikami S, Shinojima T, Kakimi K, Kamatani T, Miya F, Tsunoda T, Aimono E, Nishihara H, Mizuno R, Oya M

British journal of cancer (British Journal of Cancer) 125 ( 11 ) 1533 - 1543 2021.10

ISSN 0007-0920

Background: Cabozantinib is an oral tyrosine kinase inhibitor in renal cell carcinoma (RCC), whose targets include oncogenic AXL and unique ligand GAS6. Critical gaps in basic knowledge need to be addressed to devise an exclusive biomarker and candidate when targeting the AXL/GAS6 axis. Methods: To clarify the effects of the AXL/GAS6 axis on RCC, we herein performed a large-scale immunogenomic analysis and single-cell counts including various metastatic organs and histological subtypes of RCC. We further applied genome-wide mutation analyses and methylation arrays. Results: Varying patterns of AXL and GAS6 expression were observed throughout primary RCC tumours and metastases. Scoring individual AXL/GAS6 levels in the tumour centre and invasive margin, namely, the AXL/GAS6 score, showed a good ability to predict the prognosis of clear cell RCC. Metastasis- and histological subtype-specific differences in the AXL/GAS6 score existed since lung metastasis and the papillary subtype were weakly related to the AXL/GAS6 axis. Cell-by-cell immunohistological assessments clarified an immunosuppressive environment in tumours with high AXL/GAS6 scores. Genomic alterations in the PI3K-mTOR pathway and DNA methylation profiling revealed distinct differences with the AXL/GAS6 score in ccRCC. Conclusion: The AXL/GAS6 scoring system could predict the outcome of prognosis and work as a robust biomarker for the immunogenomic state in RCC.

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Multiplexed single-cell pathology reveals the association of CD8 T-cell heterogeneity with prognostic outcomes in renal cell carcinoma

Murakami T., Tanaka N., Takamatsu K., Hakozaki K., Fukumoto K., Masuda T., Mikami S., Shinojima T., Kakimi K., Tsunoda T., Sawada K., Imamura T., Mizuno R., Oya M.

Cancer Immunology, Immunotherapy (Cancer Immunology, Immunotherapy) 70 ( 10 ) 3001 - 3013 2021.10

ISSN 03407004

Despite the high sensitivity of renal cell carcinoma (RCC) to immunotherapy, RCC has been recognized as an unusual disease in which CD8+ T-cell infiltration into the tumor beds is related to a poor prognosis. To approach the inner landscape of immunobiology of RCC, we performed multiplexed seven-color immunohistochemistry (CD8, CD39, PD-1, Foxp3, PD-L1, and pan-cytokeratin AE1/AE3 with DAPI), which revealed the automated single-cell counts and calculations of individual cell-to-cell distances. In total, 186 subjects were included, in which CD39 was used as a marker for distinguishing tumor-specific (CD39+) and bystander (CD39−) T-cells. Our clear cell RCC cohort also revealed a poor prognosis if the tumor showed increased CD8+ T-cell infiltration. Intratumoral CD8+CD39+ T-cells as well as their exhausted CD8+CD39+PD-1+ T-cells in the central tumor areas enabled the subgrouping of patients according to malignancy. Analysis using specimens post-antiangiogenic treatment revealed a dramatic increase in proliferative Treg fraction Foxp3+PD-1+ cells, suggesting a potential mechanism of hyperprogressive disease after uses of anti-PD-1 antibody. Our cell-by-cell study platform provided spatial information on tumors, where bystander CD8+CD39− T-cells were dominant in the invasive margin areas. We uncovered a potential interaction between CD8+CD39+PD-1+ T-cells and Foxp3+PD-1+ Treg cells due to cell-to-cell proximity, forming a spatial niche more specialized in immunosuppression under PD-1 blockade. A paradigm shift to the immunosuppressive environment was more obvious in metastatic lesions; rather the infiltration of Foxp3+ and Foxp3+PD-1+ Treg cells was more pronounced. With this multiplexed single-cell pathology technique, we revealed further insight into the immunobiological standing of RCC.

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Profiling the inhibitory receptors LAG-3, TIM-3, and TIGIT in renal cell carcinoma reveals malignancy.

Takamatsu K, Tanaka N, Hakozaki K, Takahashi R, Teranishi Y, Murakami T, Kufukihara R, Niwa N, Mikami S, Shinojima T, Sasaki T, Sato Y, Kume H, Ogawa S, Kakimi K, Kamatani T, Miya F, Tsunoda T, Aimono E, Nishihara H, Sawada K, Imamura T, Mizuno R, Oya M

Nature communications (Nature Communications) 12 ( 1 ) 5547 2021.09

A cutting edge therapy for future immuno-oncology is targeting a new series of inhibitory receptors (IRs): LAG-3, TIM-3, and TIGIT. Both immunogenomic analyses and diagnostic platforms to distinguish candidates and predict good responders to these IR-related agents are vital in clinical pathology. By applying an automated single-cell count for immunolabelled LAG-3, TIM-3, and TIGIT, we reveal that individual IR levels with exclusive domination in each tumour can serve as valid biomarkers for profiling human renal cell carcinoma (RCC). We uncover the immunogenomic landscape associated with individual IR levels in human RCC tumours with metastases in various organs and histological subtypes. We then externally validate our results and devise a workflow with optimal biomarker cut-offs for discriminating the LAG-3, TIM-3, and TIGIT tumour profiles. The discrimination of LAG-3, TIM-3, and TIGIT profiles in tumours may have a broad impact on investigations of immunotherapy responses after targeting a new series of IRs.

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Germline whole-gene deletion of fh diagnosed from tumor profiling

Ueki A., Sugano K., Misu K., Aimono E., Nakamura K., Tanishima S., Tanaka N., Mikami S., Hirasawa A., Ando M., Yoshida T., Oya M., Nishihara H., Kosaki K.

International Journal of Molecular Sciences (International Journal of Molecular Sciences) 22 ( 15 ) 2021.08

ISSN 16616596

Hereditary leiomyomatosis and renal cell carcinoma (HL (RCC)) entails cutaneous and uterine leiomyomatosis with aggressive type 2 papillary RCC-like histology. HLRCC is caused by pathogenic variants in the FH gene, which encodes fumarate hydratase (FH). Here, we describe an episode of young-onset RCC caused by a genomic FH deletion that was diagnosed via clinical se-quencing. A 35-year-old woman was diagnosed with RCC and multiple metastases: histopathological analyses supported a diagnosis of FH-deficient RCC. Although the patient had neither skin tumors nor a family history of HLRCC, an aggressive clinical course at her age and pathological diagnosis of FH-deficient RCC suggested a germline FH variant. After counseling, the patient provided written informed consent for germline genetic testing. She was simultaneously subjected to paired tumor profiling tests targeting the exome to identify a therapeutic target. Although conventional germline sequencing did not detect FH variants, exome sequencing revealed a heterozygous germline FH deletion. As such, paired tumor profiling, not conventional sequencing, was required to identify this genetic deletion. RCC caused by a germline FH deletion has hitherto not been described in Japan, and the FH deletion detected in this patient was presumed to be of maternal European origin. Although the genotype-phenotype correlation in HLRCC-related tumors is unclear, the patient’s family was advised to undergo genetic counseling to consider additional RCC screening.

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Risk factors for haemodynamic instability and its prolongation during laparoscopic adrenalectomy for pheochromocytoma.

Takeda T, Hakozaki K, Yanai Y, Masuda T, Yasumizu Y, Tanaka N, Matsumoto K, Morita S, Kosaka T, Mizuno R, Kurihara I, Asanuma H, Itoh H, Oya M

Clinical endocrinology (Clinical Endocrinology) 95 ( 5 ) 716 - 726 2021.07

ISSN 0300-0664

Objective: Pheochromocytoma is a rare neuroendocrine tumour that secretes catecholamines and originates in the adrenal gland. Although surgical resection is the only curative therapy for pheochromocytoma, it is associated with a risk of haemodynamic instability (HDI), such as extremely high blood pressure and/or post tumour removal hypotension and shock. We investigated the risk factors for HDI during pheochromocytoma surgery. Design and Patients: Eighty-two patients who underwent laparoscopic adrenalectomy for pheochromocytoma between July 2002 and February 2020 were examined. We excluded 3 patients with bilateral disease and 11 without detailed 24 h urinary data. We defined HDI as systolic blood pressure ≥ 200 or <80 mmHg. We investigated the risk factors for HDI during laparoscopic adrenalectomy for pheochromocytoma. Results: There were 29 males and 39 females with a median age of 50.5 years. Tumours were localised on the right adrenal gland in 28 patients and on the left in 40. The median tumour diameter was 37.5 mm and the median pneumoperitoneum time was 93.5 min. Twenty-five out of sixty-eight patients (37%) developed HDI. A multivariate analysis identified diabetes mellitus (DM; odds ratio: 3.834; 95% confidence interval: 1.062–13.83; p =.04) as an independent predictor of HDI. In terms of hormonal data, median 24 h urinary epinephrine levels (p =.04) and metanephrine levels (p =.01) were significantly higher in the HDI group. DM was also considered as a risk factor for prolonged HDI (p =.02). Conclusion: Surgeons and anaesthesiologists need to be aware of the risk of HDI and its prolongation during laparoscopic adrenalectomy for pheochromocytoma for DM patients.

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Xp11.2転座型腎細胞癌においてInterleukin-6はprogrammed cell death-1 ligand(PDL1)発現を誘導する

高松公晴, 水野隆一, 田中伸之, 浅沼宏, 大家基嗣

日本小児泌尿器科学会雑誌 (日本小児泌尿器科学会) 30 ( 1 ) 17 - 20 2021.06

ISSN 1341-0784

【目的】Xp11.2転座/transcription factor enhancer3融合遺伝子関連腎細胞癌(Xp-RCC)は小児〜AYA世代の腎細胞癌(RCC:renal cell carcinoma)で最多の組織型だが、PDL1発現に関する報告は少ない。本研究ではXp-RCCにおけるPDL1発現と、炎症性サイトカインであるInterleukin-6(IL6)とPDL1発現の関連を評価した。【方法】RCC112検体(Xp-RCC7例、淡明細胞型RCC105例)を対象に免疫染色によりPDL1発現率を評価した。更に各種ヒトRCC細胞株(786-O、Caki2、ACHN)とXp-RCC細胞株(S-TFE)を用いてIL6刺激によるPDL1発現の変化を評価した。【結果】Xp-RCCではPDL1陽性率が57%で、淡明細胞型(25%)よりもPDL1陽性率が高い傾向がみられた(p=0.091)。IL6刺激によりS-TFE(p=0.014)、786O(p=0.011)、Caki2(p=0.016)、ACHN(p=0.002)でPDL1発現が上昇した。IL6+IL6中和抗体付加により、S-TFE(p=0.006)、786O(p=0.026)、Caki2(p=0.025)、ACHN(p=0.021)でIL6によるPDL1発現誘導効果は有意に抑制された。【結論】Xp-RCCでは淡明細胞型RCCと比較してPDL1発現が高い傾向を認めた。Xp-RCC細胞株(S-TFE)ではIL6刺激によりPDL1発現が誘導されることが示唆された。(著者抄録)

Grading of Multifocal Prostate Cancer Cases in which the Largest Volume and the Highest Grade do Not Coincide within One Lesion.

Matsumoto K, Omura M, Takeda T, Kosaka T, Hashiguchi A, Takamatsu K, Yasumizu Y, Tanaka N, Morita S, Mizuno R, Asanuma H, Oya M

The Journal of urology (The Journal of urology) 206 ( 2 ) 101097JU0000000000001765 - 345 2021.04

ISSN 0022-5347

PURPOSE: In general, the index lesion of prostate cancer has the largest tumor volume, the highest Grade Group (GG), and the highest stage (concordant cases). However, these factors sometimes do not coincide within one lesion (discordant cases). In such discordant cases, the largest tumor may not be of biological significance and the secondary tumor may more greatly impact the prognosis. MATERIALS AND METHODS: We retrospectively reviewed the medical records of patients who underwent radical prostatectomy, and we identified 580 (85.3%) concordant cases and 100 (14.7%) discordant cases. The end point of this study was biochemical recurrence, and median followup was 4.2 years. RESULTS: Among discordant cases in which GGs of the largest tumor and the highest GG tumor differed, the majority (67 patients) had the largest tumor of GG 2, and we set them as the study cohort. On the other hand, we regarded 212 concordant cases with an index tumor of GG 2 as the control cohort. The study cohort comprised 48 (71.6%) patients with a secondary tumor of GG 3 and 19 (28.4%) with a secondary tumor of GG 4/5. Kaplan-Meier curves revealed that the 5-year biochemical recurrence-free survival rates were 76%, and 67%, respectively. The 5-year biochemical recurrence-free survival rate of the control cohort was 91%, which was significantly better than that of the study cohort (p=0.013 and p=0.014, respectively). CONCLUSIONS: Our study suggests that the prognosis of discordant cases is better determined by the secondary cancer lesion with the highest GG instead of the largest lesion.

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Long-term follow-up comparing salvage radiation therapy and androgen-deprivation therapy for biochemical recurrence after radical prostatectomy.

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

International journal of clinical oncology (International Journal of Clinical Oncology) 26 ( 4 ) 744 - 752 2021.01

ISSN 1341-9625

© 2021, Japan Society of Clinical Oncology. Background: The salvage treatments for biochemical recurrence (BCR) include local external beam radiation therapy (RT) and systemic androgen-deprivation therapy (ADT). Methods: We reviewed patients who underwent radical prostatectomy (RP) and developed BCR at three institutions. After excluding patients whose nadir prostate-specific antigen (PSA) was higher than 0.2 ng/mL, those who received neoadjuvant/adjuvant therapy, and those whose BCR was not treated until their PSA exceeded 4.0 ng/mL, the remaining 335 patients comprised the cohort of this study. Salvage RT and ADT were performed for 154 and 181 patients, respectively. After the failure of salvage RT, all patients received subsequent ADT. The starting point of this study was the timing of BCR and the endpoint was the development of castration-resistant prostate cancer (CRPC). Results: During the mean follow-up period of 8.5 years after BCR, CRPC was observed in 13 patients administered RT and 24 patients administered ADT. Kaplan–Meier curves demonstrated no significant difference in CRPC-free survival between the RT and ADT groups (10-year CRPC-free survival 89.9 vs. 86.3%, p = 0.199). On the other hand, we found a significant difference in CRPC-free survival between the RT and ADT groups in 50 high-risk patients with two risk factors of Grade Group ≥ 4 and PSA-doubling time < 6 months (10-year CRPC-free survival 73.4 vs. 40.3%, p = 0.040). Conclusion: This study revealed that salvage RT increases the CRPC-free survival rate compared with salvage ADT in high-risk patients with Grade Group ≥ 4 and PSA-doubling time < 6 months.

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Negative impact of neoadjuvant hormonal therapy on detecting biochemical recurrence after radical prostatectomy

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

International Journal of Clinical Oncology (International Journal of Clinical Oncology) 26 ( 9 ) 1722 - 1728 2021

ISSN 13419625

Background: Routine use of neoadjuvant hormonal therapy (NHT) before radical prostatectomy (RP) is not recommended, but it is sometimes performed to reduce the prostate size and tumor volume or to prevent tumor progression during the wait times for surgery in clinical practice. On the other hand, the impact of NHT on the pattern of biochemical recurrence (BCR) is unknown. Methods: We retrospectively examined 1749 consecutive patients who underwent RP between 1996 and 2017. Among the patients who met the inclusion criteria, BCR developed in 240 of non-NHT patients and in 120 of NHT patients during the mean follow-up period of 6.9 years. We examined the impact of NHT on the PSA-doubling time (DT) following BCR at different times after RP. Results: The median PSA-DTs in non-NHT patients who experienced BCR in the first year after surgery, between 1 and 2 years, between 2 and 3 years, between 3 and 4 years, between 4 and 5 years, and at > 5 years were 5.5, 8.8, 11.3, 17.7, 18.2, and 18.4 months, respectively. On the other hand, those in NHT patients were 1.4, 4.1, 9.1, 13.4, 27.2, and 19.3 months, respectively. The differences of PSA-DTs in the first year after surgery (p < 0.001) and between 1 and 2 years (p = 0.005) were significant between non-NHT and NHT patients. Conclusion: Patients who received NHT had a higher risk of a rapid PSA increase when they experienced BCR, especially within 2 years after RP. In order to not miss the optimal timing of salvage treatment for BCR, intensive PSA follow-up is necessary.

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On-treatment C-reactive protein control could predict response to subsequent anti-PD-1 treatment in metastatic renal cell carcinoma

Takamatsu K., Mizuno R., Baba Y., Yasumizu Y., Tanaka N., Shirotake S., Takeda T., Morita S., Matsumoto K., Kosaka T., Asanuma H., Oyama M., Mikami S., Oya M.

International Journal of Clinical Oncology (International Journal of Clinical Oncology) 26 ( 8 ) 1500 - 1505 2021

ISSN 13419625

Objective: The aim of this study was to evaluate the clinical significance of the on-treatment C-reactive protein (CRP) status during systemic treatment as the predictive marker for the response of subsequent nivolumab monotherapy in patients with refractory metastatic renal cell carcinoma (mRCC). Patients and methods: A total of 73 mRCC patients treated with nivolumab were retrospectively reviewed. We evaluated the serum CRP levels before and after molecular-targeted treatments. Patients whose CRP did not exceed baseline value were defined as the CRP-control group and the others were defined as the CRP-progression group. The clinical impact of CRP-control on the efficacy of nivolumab was assessed. Results: Twenty-four patients (33%) were categorized into the CRP-control group. The CRP-control group patients (median PFS not reached) had significantly longer PFS than the CRP-progression group (median PFS 11.9 months, 95% confidence interval, CI 4.1–19.8, p = 0.038). The CRP-control group had a tendency of longer OS from nivolumab initiation than the CRP-progression group (p = 0.071). By multivariate analysis, the on-treatment CRP-control was the independent predictive factor for PFS (hazard ratio HR 0.37, 95% CI 0.14–0.99, p = 0.047). Conclusion: The on-treatment CRP-control could be the predictive factor for the efficacy of nivolumab in refractory mRCC patients.

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Does neoadjuvant chemotherapy have therapeutic benefit for node-positive upper tract urothelial carcinoma? Results of a multi-center cohort study

Shigeta K., Matsumoto K., Ogihara K., Murakami T., Anno T., Umeda K., Izawa M., Baba Y., Sanjo T., Shojo K., Tanaka N., Takeda T., Morita S., Kosaka T., Mizuno R., Arita Y., Akita H., Jinzaki M., Kikuchi E., Oya M.

Urologic Oncology: Seminars and Original Investigations (Urologic Oncology: Seminars and Original Investigations) 40 ( 3 ) 105.e19 - 105.e26 2021

ISSN 10781439

Objective: The indications of neoadjuvant chemotherapy (NAC) for lymph node-positive upper tract urothelial carcinoma (UTUC) have not been investigated regarding improved survival outcomes. Our specific aim was to compare the clinical outcomes of clinically node-positive UTUC patients who were treated by NAC followed by radical nephroureterectomy (RNU) or upfront RNU followed by adjuvant chemotherapy (AC). Materials and methods: Among 966 UTUC patients, we identified 89 with clinical nodal involvement who received either NAC before RNU nor AC after upfront RNU. Cox proportional hazard models were employed to evaluate the impact of chemotherapy modality on the oncological outcomes. Results: Of the patient cohort, 36 (40.4%) received NAC followed by RNU, whereas 53 (59.6%) underwent RNU followed by AC. Multivariate analysis revealed that tumor size ≥3 cm, clinical T4, and gemcitabine and cisplatin regimen were independent risk factors for disease recurrence, whereas NAC followed by RNU was an independent factor for favorable RFS. Furthermore, regarding cancer-specific survival (CSS), NAC followed by RNU remained an independent factor for favorable CSS. According to Kaplan-Meier analysis, the 1-year and 2-year RFS were 67.9% and 47.0%, respectively, in the NAC+RNU group, which were significantly higher than those in the RNU+AC group (43.9% and 24.6%, respectively, P = 0.006). Moreover, the 1-year and 2-year CSS were 80.5% and 64.2%, respectively, in the NAC+RNU group, which were higher than those in the RNU+AC group (68.6% and 48.2%, respectively, P = 0.016). Conclusion: For node-positive UTUC patients, NAC followed by RNU was more clinically beneficial than RNU followed by AC.

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The Clinicopathological Characteristics of Muscle-Invasive Bladder Recurrence in Upper Tract Urothelial Carcinoma.

Shigeta K, Matsumoto K, Ogihara K, Murakami T, Anno T, Umeda K, Izawa M, Baba Y, Sanjo T, Shojo K, Tanaka N, Takeda T, Kosaka T, Mizuno R, Mikami S, Kikuchi E, Oya M

Cancer science (Cancer Science) 112 ( 3 ) 1084 - 1094 2020.12

ISSN 1347-9032

© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. This study aimed to clarify the clinical characteristics and oncological outcomes of patients with upper tract urothelial carcinoma (UTUC) who developed muscle-invasive bladder cancer (MIBC) after radical nephroureterectomy (RNU). We identified 966 pTa-4N0-2M0 patients with UTUC who underwent RNU and clarified the risk factors for MIBC progression after initial intravesical recurrence (IVR). We also identified 318 patients with primary pT2-4N0-2M0 MIBC to compare the oncological outcomes with those of patients with UTUC who developed or progressed to MIBC. Furthermore, immunohistochemical examination of p53 and FGFR3 expression in tumor specimens was performed to compare UTUC of MIBC origin with primary MIBC. In total, 392 (40.6%) patients developed IVR after RNU and 46 (4.8%) developed MIBC at initial IVR or thereafter. As a result, pT1 stage on the initial IVR specimen, concomitant carcinoma in situ on the initial IVR specimen, and no intravesical adjuvant therapy after IVR were independent factors for MIBC progression. After propensity score matching adjustment, primary UTUC was a favorable indicator for cancer-specific death compared with primary MIBC. Subgroup molecular analysis revealed high FGFR3 expression in non-MIBC and MIBC specimens from primary UTUC, whereas low FGFR3 but high p53 expression was observed in specimens from primary MIBC tissue. In conclusion, our study demonstrated that patients with UTUC who develop MIBC recurrence after RNU exhibited the clinical characteristics of subsequent IVR more than those of primary UTUC. Of note, MIBC subsequent to UTUC may have favorable outcomes, probably due to the different molecular biological background compared with primary MIBC.

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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 2020.10

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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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 2020.09

© 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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Appropriate timing for a biochemical evaluation after adrenalectomy for unilateral aldosterone-producing adenoma

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

Clinical Endocrinology (Clinical Endocrinology) 92 ( 6 ) 503 - 508 2020.06

ISSN 03000664

© 2020 John Wiley & Sons Ltd Context: The oversecretion of plasma aldosterone by unilateral aldosterone-producing adenoma (APA) can be cured by adrenalectomy. However, the time needed for the endocrine environment to normalize remains unclear. Objective: To clarify adequate timing for a biochemical evaluation in unilateral APA patients after adrenalectomy. Design and patients: A total of 166 unilateral APA patients were retrospectively reviewed. We evaluated the plasma aldosterone concentration (PAC) (pg/mL), active renin concentration (ARC) (pg/mL), aldosterone-renin ratio (ARR; PAC/ARC), serum potassium concentration and estimated glomerular filtration rate (eGFR) at 1, 3 and 6 postoperation months (POM). Results: PAC was significantly lower at 1POM than at presurgery (presurgery; 407.2, 1 POM; 90.0 pg/mL, P <.001). ARC did not increase from baseline at 1POM, but significantly increased at 3POM (presurgery; 4.43, 1POM; 4.87, 3POM; 11.3 pg/mL, P <.001). ARR significantly decreased at 1POM (presurgery; 146.9, 1 POM; 26.3, P <.001) although ARC did not increase at 1POM. Among the 34 patients who had hypokalaemia presurgery, it was resolved in 28 (82%) at 1POM and in all (100%) at 3POM. The biochemical outcomes at 1POM were 131 (79%) complete, 20 (12%) partial and 15 (9%) absent successes, while at 3POM, 147 (89%) were complete, 9 (5%) partial and 10 (6%) absent. Twenty-three (14%) patients were reclassified into different biochemical outcomes between 1 and 3POM, whereas only 5 (3%) changed between 3 and 6POM. Conclusion: The appropriate timing for a biochemical evaluation of unilateral APA patients treated with laparoscopic adrenalectomy appears to be 3 months or more after surgery.

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External validation of the "optimal PSA follow-up schedule after radical prostatectomy” in a new cohort

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

International Journal of Clinical Oncology (International Journal of Clinical Oncology) 25 ( 7 ) 1393 - 1397 2020

ISSN 13419625

© 2020, Japan Society of Clinical Oncology. Background: Biochemical recurrence (BCR) after radical prostatectomy (RP) is most commonly diagnosed by detecting an increase in asymptomatic prostate-specific antigen (PSA). We previously reported the “optimal PSA follow-up schedule after RP”. The aim of this study was to confirm the usefulness and safety of that follow-up schedule in another cohort. Methods: We retrospectively reviewed the clinicopathological data of 798 consecutive patients who underwent radical prostatectomy between 2009 and 2017. We examined all PSA values measured during follow-up. Furthermore, we estimated the PSA value when we observed the “optimal PSA follow-up schedule” at each timing in the virtual follow-up. BCR was defined as an elevation of PSA to greater than 0.2 ng/ml, and the ideal PSA range for detection of BCR was regarded to be 0.2–0.4 ng/ml. Results: During the mean follow-up period of 5.8 years, BCR occurred in 115 (14.9%) patients and the frequency of virtual follow-up was significantly lower than the actual frequency. However, overlooking of BCR (detecting BCR when PSA exceeded 0.4 ng/ml) was observed in 17 patients, which is higher than the actual frequency of overlooking (12 patients). Therefore, we modified the follow-up schedule, which could achieve the lower follow-up frequency and a limited number of overlooking of BCR (7 patients). Conclusion: This external validation study revealed that the "modified optimal PSA follow-up schedule after RP" can reduce the frequency of PSA measurement with a limited risk of overlooking BCR.

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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

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

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

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

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 2019.11

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 2019.08

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 2019.08

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 2019.06

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 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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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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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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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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Refraining from Smoking for 15 Years or More Reduced the Risk of Tumor Recurrence in Non-muscle Invasive Bladder Cancer Patients

Ogihara, Koichiro, Kikuchi, Eiji, Yuge, Kazuyuki, Ito, Yujiro, Tanaka, Nobuyuki, Matsumoto, Kazuhiro, Miyajima, Akira, Asakura, Hirotaka, Oya, Mototsugu

ANNALS OF SURGICAL ONCOLOGY 23 ( 5 ) 1752 - 1759 2016.05

Research paper (scientific journal), ISSN 1068-9265

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

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

ANNALS OF SURGICAL ONCOLOGY 23 ( 2 ) 663 - 670 2016.02

Research paper (scientific journal), ISSN 1068-9265

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

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

Clinical Genitourinary Cancer 2016.01

Research paper (scientific journal), ISSN 1558-7673

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

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Are the Formulas Used to Estimate Renal Function Adequate for Patients Treated With Cisplatin-Based Chemotherapy After Nephroureterectomy for Upper Tract Urothelial Carcinoma?

Niwa Naoya, Kikuchi Eiji, Masashi Matsushima, Tanaka Nobuyuki, Nishiyama Toru, Miyajima Akira, Saito Shiro, Oya Mototsugu

Clinical Genitourinary Cancer 2015.12

Research paper (scientific journal), ISSN 1558-7673

Objective: The relationship between endogenous creatinine clearance (eCrCl) and renal function values obtained using mathematical formulas has not yet been fully elucidated, especially in patients with upper tract urothelial carcinoma that are treated with radical nephroureterectomy followed by cisplatin-based chemotherapy. Methods: Sixty patients who received cisplatin-based chemotherapy for locally advanced or metastatic upper tract urothelial carcinoma after radical nephroureterectomy between 2000 and 2012 were retrospectively identified. eCrCl was measured based on 24-hour urine specimens obtained immediately prior to each cycle of chemotherapy. Renal function was estimated with 4 different formulas: the Cockcroft-Gault, Modification of Diet in Renal Disease, Chronic Kidney Disease Epidemiology Collaboration, and Wright formulas. We evaluated the relationship between eCrCl and the renal function values obtained with each formula using the Pearson correlation coefficient and κ statistics. Results: The median eCrCl was 53.9 mL/min. The Pearson correlation coefficients and κ statistics for the relationships between eCrCl and the renal function values obtained with each of the mathematical formulas ranged from 0.600 to 0.763 and from 0.29 to 0.67, respectively. Among the patients with eCrCl of ≥ 60 mL/min, 70%, 60%, 50%, and 20% were estimated to have the renal function values of <60 mL/min by the Cockcroft-Gault, Modification of Diet in Renal Disease, Chronic Kidney Disease Epidemiology Collaboration, and Wright formulas, respectively. Conclusions: All 4 of the tested formulas underestimated eCrCl. The values obtained with the Wright formula were most closely associated with eCrCl.

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Nicotine induces tumor growth and chemoresistance through activation of the PI3K/Akt/mTOR pathway in bladder cancer

Yuge Kazuyuki, Kikuchi Eiji, Hagiwara Masayuki, Yasumizu Yota, Tanaka Nobuyuki, Kosaka Takeo, Miyajima Akira, Oya Mototsugu

Molecular Cancer Therapeutics 14 ( 9 ) 2112 - 2120 2015.09

Research paper (scientific journal), ISSN 1535-7163

Continued smoking is highly associated with not only a higher incidence but also greater risk of tumor recurrence, progression, and acquired chemoresistance of urothelial carcinoma. We investigated whether nicotine affects urothelial carcinoma, and the detailed mechanism by which nicotine could induce tumor growth and any associated chemoresistance. Cell viability was evaluated in the human bladder cancer cell line T24 exposed to nicotine with or without cisplatin (CDDP) and NVP-BEZ235 as a PI3K/mTOR dual inhibitor by the WST-1 assay. Protein expression of the PI3K/Akt/mTOR pathway was investigated by Western blotting or immunohistochemical analysis. The influence of nicotine on tumor growth was also evaluated with or without CDDP and/or NVP-BEZ235 in a subcutaneous bladder tumor model. The result demonstrated that cell proliferation was increased in T24 cells after exposure to nicotine. Phospho-specific Akt (pAkt) and phospho-specific p70 S6 kinase (pS6) were significantly upregulated by nicotine exposure. Tumor growth in vivo was significantly induced by nicotine exposure in accordance with increased pS6 expression. Nicotine attenuated inhibition of T24 cell growth by CDDP and further upregulated pS6 expression in vitro and in vivo. NVP-BZE235 inhibited T24 cell proliferation and pAkt and pS6 expression induced after exposure to nicotine and/or CDDP. In conclusion, nicotine increases tumor growth and induces acquired chemoresistance through activation of the PI3K/Akt/mTOR pathway in bladder cancer.

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Comparison of outcomes between ultrasonography and cystoscopy in the surveillance of patients with initially diagnosed TaG1-2 bladder cancers: A matched-pair analysis

Niwa, Naoya, Matsumoto, Kazuhiro, Hayakawa, Nozomi, Ito, Yujiro, Maeda, Takahiro, Akatsuka, Seiya, Masuda, Takeshi, Nakamura, So, Tanaka, Nobuyuki

UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS 33 ( 9 ) E13 - E13 2015.09

Research paper (scientific journal), ISSN 1078-1439

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Impact of Combined Use of Blood-based Inflammatory Markers on Patients with Upper Tract Urothelial Carcinoma Following Radical Nephroureterectomy

Tanaka Nobuyuki, Kikuchi Eiji, Kanao Kent, Matsumoto Kazuhiro, Shirotake Suguru, Miyazaki Yasumasa, Kobayashi Hiroaki, Kaneko Gou, Hagiwara Masayuki, Ide Hiroki, Obata Jun, Hoshino Katsura, Hayakawa Nozomi, Kosaka Takeo, Hara Satoshi, Nakagawa Ken, Jinzaki Masahiro, Oya Mototsugu

European Urology Focus 1 ( 1 ) 54 - 63 2015.08

Research paper (scientific journal)

Background: Previous studies showed the prognostic impact of preoperative levels of neutrophil-to-lymphocyte ratio (NLR), plasma fibrinogen, and serum C-reactive protein (CRP) in surgically treated upper tract urothelial carcinoma; however, few papers have discussed the proper use of these indices. Objective: To investigate whether combinations of these three markers, as a cumulative marker score (CMS), improve the accuracy of prognostic models following radical nephroureterectomy (RNU). Design, setting, and participants: A total of 394 patients from multiple institutions were included. Median follow-up was 30 mo. Intervention: All patients underwent RNU without neoadjuvant chemotherapy. Outcome measurements and statistical analysis: Associated outcomes were assessed using multivariate analysis. The CMS was defined as the number of elevated levels of preoperative NLR, plasma fibrinogen, and serum CRP. Results and limitations: Multivariate analyses revealed that an increasing CMS was independently associated with high rates of disease recurrence, cancer-specific mortality, and all-cause mortality following RNU. Addition of the CMS to a model that included standard clinicopathologic predictors significantly improved predictive accuracy by 2.7% for disease recurrence, 3.9% for cancer-specific mortality, and 4.0% for all-cause mortality, which were the highest among other prognostic models using each marker alone or combinations of two. The study is limited by its retrospective nature. Conclusions: Although the use of each inflammatory marker alone may be as predictive as clinicopathologic indices for prognosis, combinations like CMS can provide more accurate prognostic models following RNU. Patient summary: Elevation of blood-based inflammatory markers may be useful for predicting prognosis because of their low cost and accessibility. Among blood-based indices, we examined the efficacy of preoperative neutrophil-to-lymphocyte ratio, plasma fibrinogen, and serum C-reactive protein levels. Although use of each marker alone provides additional prognostic information, the combination of all three markers would be more predictive than any single marker or combinations of two.

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Down-regulation of NF kappa B activation is an effective therapeutic modality in acquired platinum-resistant bladder cancer

Ito, Yujiro, Kikuchi, Eiji, Tanaka, Nobuyuki, Kosaka, Takeo, Suzuki, Eriko, Mizuno, Ryuichi, Shinojima, Toshiaki, Miyajima, Akira, Umezawa, Kazuo, Oya, Mototsugu

BMC CANCER 15 2112 - 2120 2015.04

Research paper (scientific journal), ISSN 1471-2407

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Impact of an Adjuvant Chemotherapeutic Regimen on the Clinical Outcome in High Risk Patients with Upper Tract Urothelial Carcinoma: A Japanese Multi-Institution Experience

Shirotake, Suguru, Kikuchi, Eiji, Tanaka, Nobuyuki, Matsumoto, Kazuhiro, Miyazaki, Yasumasa, Kobayashi, Hiroaki, Ide, Hiroki, Obata, Jun, Hoshino, Katsura, Kaneko, Gou, Hagiwara, Masayuki, Kosaka, Takeo, Kanao, Kent, Kodaira, Kiichiro, Hara, Satoshi, Oyama, Masafumi, Momma, Tetsuo, Miyajima, Akira, Nakagawa, Ken, Hasegawa, Shintaro, Nakajima, Yosuke, Oya, Mototsugu

JOURNAL OF UROLOGY 193 ( 4 ) 1122 - 1128 2015.04

Research paper (scientific journal), ISSN 0022-5347

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Prognostic Impact of Renin–Angiotensin System Blockade on Renal Cell Carcinoma After Surgery

Miyajima Akira, Yazawa Satoshi, Kosaka Takeo, Tanaka Nobuyuki, Shirotake Suguru, Mizuno Ryuichi, Kikuchi Eiji, Oya Mototsugu

Annals of Surgical Oncology 22 ( 11 ) 3751 - 3759 2015.02

Research paper (scientific journal), ISSN 1068-9265

Background: Angiotensin 2 is a key biologic peptide in the renin–angiotensin system (RAS) that regulates blood pressure and renal hemodynamics. The potential role of the RAS in the promotion of tumor growth, angiogenesis, and metastasis also has been shown in the past few decades. This study investigated the prognostic impact of RAS blockade on patients with renal cell carcinoma (RCC) after surgery. Methods: The study identified 557 patients with pathologically diagnosed RCC (pT1-4 N0M0) and evaluated the prognostic factors after surgery for patients administered or not administered angiotensin-converting enzyme inhibitors (ACEs) or angiotensin 2 receptor blockers (ARBs). Results: The median follow-up period was 5.1 years. Radical nephrectomy was performed for 349 patients (62.7 %), whereas the remaining 208 patients (37.3 %) underwent partial nephrectomy. A total of 104 patients (18.7 %) were administered RAS inhibitors: ACEs (n = 22) or ARBs (n = 82). Multivariate analysis showed that administration of RAS inhibitors (P = 0.044; HR 2.69), longer tumor length (P < 0.001; HR 1.02), high-grade tumor (P < 0.001; HR 3.55), and positive microvascular invasion (P < 0.003; HR 3.13) were not independent risk factors for a decrease in subsequent disease-specific survival after surgery for RCC. The 5-year disease-specific survival rate was 96.8 % among the patients administered RAS inhibitors and 89.8 % among their counterparts (P = 0.019). Conclusions: The authors propose renin–angiotensin blockade as a possible potent choice for effective treatment after surgical treatment of RCC.

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A Multi-Institutional Validation of the Prognostic Value of the Neutrophil-to-Lymphocyte Ratio for Upper Tract Urothelial Carcinoma Treated with Radical Nephroureterectomy

Tanaka, Nobuyuki, Kikuchi, Eiji, Kanao, Kent, Matsumoto, Kazuhiro, Shirotake, Suguru, Miyazaki, Yasumasa, Kobayashi, Hiroaki, Kaneko, Gou, Hagiwara, Masayuki, Ide, Hiroki, Obata, Jun, Hoshino, Katsura, Hayakawa, Nozomi, Kosaka, Takeo, Hara, Satoshi, Oyama, Masafumi, Momma, Tetsuo, Nakajima, Yosuke, Jinzaki, Masahiro, Oya, Mototsugu

ANNALS OF SURGICAL ONCOLOGY 21 ( 12 ) 4041 - 4048 2014.11

Research paper (scientific journal), ISSN 1068-9265

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Ductal Adenocarcinoma of the Prostate Forming a Mass in the Retrovesical Space

Niwa, Naoya, Tanaka, Nobuyuki, Horinaga, Minoru, Hayashi, Yuichiro, Hisazumi, Hiromi, Masuda, Takeshi

UROLOGY 84 ( 4 ) E9 - E10 2014.10

Research paper (scientific journal), ISSN 0090-4295

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Independent Predictors for Bladder Outcomes after Treatment of Intravesical Recurrence following Radical Nephroureterectomy in Patients with Primary Upper Tract Urothelial Carcinoma

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

ANNALS OF SURGICAL ONCOLOGY 21 ( 9 ) 3151 - 3158 2014.09

Research paper (scientific journal), ISSN 1068-9265

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Optimal timing of hormonal therapy for prostate-specific antigen recurrence after radical prostatectomy

Matsumoto, Kazuhiro, Mizuno, Ryuichi, Tanaka, Nobuyuki, Ide, Hiroki, Hasegawa, Masanori, Ishida, Masaru, Hayakawa, Nozomi, Yasumizu, Yota, Hagiwara, Masayuki, Hara, Satoshi, Kikuchi, Eiji, Miyajima, Akira, Nakagawa, Ken, Nakajima, Yosuke, Nakamura, So, Nakashima, Jun, Oya, Mototsugu

MEDICAL ONCOLOGY 31 ( 7 ) 2019 - 2020 2014.07

Research paper (scientific journal), ISSN 1357-0560

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Survival following primary androgen deprivation therapy for localized intermediate- or high-risk prostate cancer: comparison with the life expectancy of the age-matched normal population

Matsumoto, Kazuhiro, Hagiwara, Masayuki, Tanaka, Nobuyuki, Hayakawa, Nozomi, Ishida, Masaru, Ninomiya, Akiharu, Nakajima, Yosuke, Nakamura, So

MEDICAL ONCOLOGY 31 ( 6 ) 3645 - 3649 2014.06

Research paper (scientific journal), ISSN 1357-0560

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Metastatic Behavior of Upper Tract Urothelial Carcinoma After Radical Nephroureterectomy: Association with Primary Tumor Location

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

ANNALS OF SURGICAL ONCOLOGY 21 ( 3 ) 1038 - 1045 2014.03

Research paper (scientific journal), ISSN 1068-9265

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Long term follow-up in patients with initially diagnosed low grade Ta non-muscle invasive bladder tumors

Kobayashi Hiroaki, Kikuchi Eiji, Mikami Shuji, Maeda Takahiro, Tanaka Nobuyuki, Miyajima Akira, Nakagawa Ken, Oya Mototsugu

BMC Urology 14 ( 1 ) 2014.01

Research paper (scientific journal)

Background: We evaluated the clinical outcome of low grade Ta bladder cancer followed-up for a long period using the 2004 WHO grading system. Methods. We retrospectively reviewed 190 patients with primary, low grade Ta bladder cancer. We defined worsening progression (WP) as confirmed high grade Ta, all T1 or Tis/concomitant CIS of bladder recurrence, upper urinary tract recurrence (UTR), or progression to equal to or more than T2. The associations between clinicopathological factors and tumor recurrence as well as WP pattern were analyzed. We also evaluated the late recurrence of 76 patients who were tumor-free for more than 5 years. Results: Tumor recurrence and WP occurred in 82 (43.2%) and 21 (11.1%) patients during follow-up (median follow-up: 101.5 months), respectively. WP to high grade Ta, all T1 or Tis/concomitant CIS was seen in 17 patients, and UTR and progression to equal to or more than T2 were seen in 2 and 2 patients, respectively. Multivariate analyses demonstrated that multiple tumor (p < 0.001, HR: 2.97) and absence of intravesical instillation (IVI) (p < 0.001, HR: 2.88) were significant risk factors for tumor recurrence while multiple tumor was the only risk factor for WP (p = 0.001, HR: 5.26). After a 5-year tumor-free period, 9 patients experienced late recurrence in years 5 and 10 and were diagnosed at a follow-up cystoscopy, however, only 2 patients recurred beyond 10 years and were found by gross hematuria. There were no significant risk factors of late recurrence. Conclusions: Multiple tumor was a risk factor for both tumor recurrence and WP while IVI did not affect the occurrence of WP. Our results suggest that routine follow-up of patients with low grade Ta bladder cancer is needed up to 10 years from the initial diagnosis.

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The Predictive Value of C-reactive Protein for Prognosis in Patients with Upper Tract Urothelial Carcinoma Treated with Radical Nephroureterectomy: A Multi-institutional Study

Tanaka, Nobuyuki, Kikuchi, Eiji, Shirotake, Suguru, Kanao, Kent, Matsumoto, Kazuhiro, Kobayashi, Hiroaki, Miyazaki, Yasumasa, Ide, Hiroki, Obata, Jun, Hoshino, Katsura, Hayakawa, Nozomi, Ito, Yujiro, Kosaka, Takeo, Kodaira, Kiichiro, Oyama, Masafumi, Miyajima, Akira, Momma, Tetsuo, Nakagawa, Ken, Ueno, Munehisa, Oya, Mototsugu

EUROPEAN UROLOGY 65 ( 1 ) 227 - 234 2014.01

Research paper (scientific journal), ISSN 0302-2838

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The predictive value of positive urine cytology for outcomes following radical nephroureterectomy in patients with primary upper tract urothelial carcinoma: A multi-institutional study

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

UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS 32 ( 1 ) E229 - E230 2014.01

Research paper (scientific journal), ISSN 1078-1439

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Survival following primary androgen deprivation therapy for localized intermediate- Or high-risk prostate cancer

Matsumoto Kazuhiro, Hagiwara Masayuki, Tanaka Nobuyuki, Hayakawa Nozomi, Ishida Masaru, Ninomiya Akiharu, Nakajima Yosuke, Nakamura So

Medical Oncology 31 ( 6 ) 2014

Research paper (scientific journal), ISSN 1357-0560

The representative guidelines do not recommend androgen deprivation therapy (ADT) as a primary treatment for localized prostate cancer. However, in clinical practice, the use of primary ADT for localized prostate cancer has been widespread, especially among older patients. We performed a retrospective review of the efficacy of primary ADT for localized prostate cancer and compared their outcomes with the life expectancy of the normal population. The study cohort consisted of 410 men diagnosed with localized intermediate- or high-risk prostate cancer over the period 1992-2012 at five institutions. All patients underwent ADT as a primary cancer therapy, and mean follow-up was 6.0 years. Their progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS) rates were calculated. Patients' expected survival rates were estimated by the Hakulinen method. Multivariate analysis demonstrated that Gleason score ≥8 and cT3a were independent risk factors for all of PFS, CSS, and OS. In patients who have none or one of these risk factors, minimum OS rates were not inferior to the expected survival curves of the normal population. Meanwhile, in patients with both risk factors, the OS curve fell below the expected survival rates, especially after 6 years of follow-up. We conclude that primary ADT might be one of the therapeutic options for localized intermediate- and high-risk prostate cancer. However, for high-risk cases with Gleason score ≥8 and cT3a, the choice of primary ADT should be deliberated carefully because the OS of these cases was inferior to the expected survival, especially at a late time point.

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Congenital Intrathoracic Kidney

Niwa, Naoya, Tanaka, Nobuyuki, Ueda, Soichiro, Masuda, Takeshi

INTERNAL MEDICINE 53 ( 17 ) 2019 - 2020 2014

Research paper (scientific journal), ISSN 0918-2918

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Third-line Hormonal Therapy to Treat Prostate Cancer Relapse after Initial and Second-line Hormonal Therapy: Report of 52 Cases and Literature Review

Matsumoto, Kazuhiro, Hagiwara, Masayuki, Hayakawa, Nozomi, Tanaka, Nobuyuki, Ito, Yujiro, Maeda, Takahiro, Ninomiya, Akiharu, Nagata, Hirohiko, Nakamura, So

ASIAN PACIFIC JOURNAL OF CANCER PREVENTION 15 ( 8 ) 3645 - 3649 2014

Research paper (scientific journal), ISSN 1513-7368

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

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

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

Research paper (scientific journal), ISSN 1068-9265

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

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Mucosa-associated lymphoid tissue lymphoma arising from the kidney

Niwa Naoya, Tanaka Nobuyuki, Horinaga Minoru, Hongo Hiroshi, Ito Yujiro, Watanabe Takuro, Masuda Takeshi

Journal of the Canadian Urological Association 8 ( 1-2 FEB ) 2014

Research paper (scientific journal), ISSN 1911-6470

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Efficacy of estramustine phosphate sodium hydrate (EMP) monotherapy in castration-resistant prostate cancer patients: report of 102 cases and review of literature

Matsumoto, Kazuhiro, Tanaka, Nobuyuki, Hayakawa, Nozomi, Ezaki, Taisuke, Suzuki, Kenjiro, Maeda, Takahiro, Ninomiya, Akiharu, Nakamura, So

MEDICAL ONCOLOGY 30 ( 4 ) 32 - 39 2013.12

Research paper (scientific journal), ISSN 1357-0560

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C-reactive protein: A biomarker of survival in patients with localized upper tract urothelial carcinoma treated with radical nephroureterectomy

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

UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS 31 ( 8 ) 1725 - 1730 2013.11

Research paper (scientific journal), ISSN 1078-1439

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The type of patients who would benefit from anti-androgen withdrawal therapy: could it be performed safely for aggressive prostate cancer?

Matsumoto, Kazuhiro, Tanaka, Nobuyuki, Hayakawa, Nozomi, Ezaki, Taisuke, Suzuki, Kenjiro, Maeda, Takahiro, Ninomiya, Akiharu, Nakamura, So

MEDICAL ONCOLOGY 30 ( 3 ) E161 - E161 2013.09

Research paper (scientific journal), ISSN 1357-0560

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Patient characteristics and outcomes in metastatic upper tract urothelial carcinoma after radical nephroureterectomy: the experience of Japanese multi-institutions

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

BJU INTERNATIONAL 112 ( 2 ) E28 - E34 2013.07

Research paper (scientific journal), ISSN 1464-4096

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Impact of Smoking Status on Bladder Tumor Recurrence After Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma

Hagiwara, Masayuki, Kikuchi, Eiji, Tanaka, Nobuyuki, Matsumoto, Kazuhiro, Ide, Hiroki, Miyajima, Akira, Masuda, Takeshi, Nakamura, So, Oya, Mototsugu

JOURNAL OF UROLOGY 189 ( 6 ) 2062 - 2068 2013.06

Research paper (scientific journal), ISSN 0022-5347

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The prognostic significance of vasohibin-1 expression in patients with prostate cancer

Kosaka T., Miyazaki Y., Miyajima A., Mikami S., Hayashi Y., Tanaka N., Nagata H., Kikuchi E., Nakagawa K., Okada Y., Sato Y., Oya M.

British Journal of Cancer 108 ( 10 ) 2123 - 2129 2013.05

Research paper (scientific journal), ISSN 0007-0920

Background:We recently isolated vasohibin-1 (VASH1), a novel angiogenic molecule that is specifically expressed in activated vascular endothelial cells (ECs), and the status of VASH1 expression has been documented in various cancer angiogenesis. The aim of this study was to assess the prognostic value of VASH1 expression in prostate cancer (PCa).Methods:In this study, we retrospectively analysed the clinical records and evaluated the VASH1 expression of tumour microvessels in 167 patients with PCa who underwent radical prostatectomy. We immunohistochemically examined the microvessels positive for anti-CD34 as microvessel density (MVD) and the microvessels with activated ECs positive for VASH1 density.Results:We found that the VASH1 expression was restricted to ECs in the tumour stroma. VASH1 density was significantly associated with pathological T stage, Gleason score and MVD. The 5-year PSA recurrence-free survival rate was 58.8% in patients with higher VASH1 density (≧12 per mm 2) and 89.1% in patients with lower VASH1 density (<12 per mm 2), respectively (P<0.001). Microvessel density was not an independent predictor of PSA recurrence. Multivariate analysis revealed that high VASH1 density was an independent prognostic indicator of PSA recurrence (P=0.007, HR=2.950).Conclusion:VASH1 density represents a clinically relevant predictor of patient prognosis and can be a new biomarker that would provide additional prognostic information in PCa.

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Prognostic value of plasma fibrinogen levels in patients with localized upper tract urothelial carcinoma

Tanaka, Nobuyuki, Kikuchi, Eiji, Matsumoto, Kazuhiro, Hayakawa, Nozomi, Ide, Hiroki, Miyajima, Akira, Nakamura, So, Oya, Mototsugu

BJU INTERNATIONAL 111 ( 6 ) 857 - 864 2013.05

Research paper (scientific journal), ISSN 1464-4096

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Bisebromoamide, an extract from Lyngbya species, induces apoptosis through ERK and mTOR inhibitions in renal cancer cells

Suzuki, Kenjiro, Mizuno, Ryuichi, Suenaga, Kiyotake, Teruya, Toshiaki, Tanaka, Nobuyuki, Kosaka, Takeo, Oya, Mototsugu

CANCER MEDICINE 2 ( 1 ) 32 - 39 2013.02

Research paper (scientific journal), ISSN 2045-7634

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Risk of subsequent tumour recurrence and stage progression in bacille Calmette-Guérin relapsing non-muscle-invasive bladder cancer

Matsumoto Kazuhiro, Kikuchi Eiji, Shirakawa Hiroshi, Hayakawa Nozomi, Tanaka Nobuyuki, Ninomiya Akiharu, Miyajima Akira, Nakamura So, Oya Mototsugu

BJU International 110 ( 11 B ) 2012.12

Research paper (scientific journal), ISSN 1464-4096

OBJECTIVE • To investigate the risk of subsequent tumour recurrence and stage progression in bacillus Calmette-Guérin (BCG)-relapsing non-muscle-invasive bladder cancer, defined as recurrence after achieving a disease-free status for 6 months. PATIENTS AND METHODS • A total of 183 patients with BCGrelapsing tumours were treated with conservative therapy between 1985 and 2008 at our three institutions. • We analysed the association between their clinicopathological parameters and subsequent tumour recurrence or stage progression. RESULTS • Additional induction courses of BCG or anticancer drug (mitomycin C or epirubicin) instillations were performed in 119 patients and 24 patients, respectively. The remaining 40 patients did not undergo any adjuvant therapy. • Multivariate analysis showed that a relapsing tumour with a pathologically high risk (defined as tumours with G3 and/or pT1 and/or concomitant carcinoma in situ ) was a significant risk factor for subsequent tumour recurrence ( P = 0.002; hazard ratio [ HR ] 2.15). Additional BCG instillation significantly decreased the subsequent tumour recurrence rate ( P < 0.001; HR 0.41). • Multivariate analysis also showed that a relapsing tumour with a pathologically high risk was also significantly associated with stage progression ( P < 0.001; HR 8.05). CONCLUSIONS • An additional course of BCG instillation might be effective in patients with BCG-relapsing tumours with pathologically intermediate risk. • Nevertheless, some patients with high-risk pathological features developed subsequent stage progression. Such patients should be followed up closely and counselled on the need for aggressive therapeutic options, such as radical cystectomy.

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Prognostic Value of Renin-Angiotensin System Blockade in Non-muscle-invasive Bladder Cancer

Yuge, Kazuyuki, Miyajima, Akira, Tanaka, Nobuyuki, Shirotake, Suguru, Kosaka, Takeo, Kikuchi, Eiji, Oya, Mototsugu

ANNALS OF SURGICAL ONCOLOGY 19 ( 12 ) 3987 - 3993 2012.11

Research paper (scientific journal), ISSN 1068-9265

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Prognostic significance of high nuclear grade in patients with pathologic t1a renal cell carcinoma

Suzuki Kenjiro, Mizuno Ryuichi, Mikami Shuji, Tanaka Nobuyuki, Kanao Kent, Kikuchi Eiji, Miyajima Akira, Nakagawa Ken, Oya Mototsugu

Japanese Journal of Clinical Oncology 42 ( 9 ) 831 - 835 2012.09

Research paper (scientific journal), ISSN 0368-2811

Objective: A reliable prognostic indicator in patients with pathologic T1a renal cell carcinoma has not yet been fully elucidated. The aim of this study was to investigate the prognosis of pathologic T1a renal cell carcinoma cases with a special focus on pathological factors. Methods: The study population consisted of 338 patients diagnosed with solitary renal cell carcinoma at our hospital between 1996 and 2009. The relationship between disease progression and clinicopathologic features was analyzed retrospectively to determine if it affected recurrence and distant metastasis. Results: The Fuhrman nuclear grade distribution between the tumors was 1, 2, 3 and 4 in 68 (20.1%), 242 (71.6%), 21 (6.2%) and 7 cases (2.1%), respectively. A total of 11 subjects were identified as having recurrent tumors (3.3%), 9 of whom had metastatic lesions. Multivariate analysis showed that the appearance of tumor Grade 3 and 4 (hazard ratio: 13.0, 95% confidence interval: 3.90-43.0, P < 0.001) was an independent risk factor for tumor recurrence, while no significant correlation was found between tumor recurrence and age, gender, tumor side, tumor size, surgical methods, histology, microvascular invasion or surgical margin status. The 5-year recurrence-free survival rate was 67.8% in patients with a high nuclear grade tumor, and 96.8% in their counterparts. Conclusions: High nuclear grade is possibly one of the most important prognostic factors for predicting tumor recurrence and metastasis after surgery in pathologic T1a renal cell carcinoma. Thus, careful follow-up may be required in patients with pathologic T1a renal cell carcinoma of a high nuclear grade.

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Prognostic significance of Bacillus Calmette-Guerin failure classification in non-muscle-invasive bladder cancer

Shirakawa, Hiroshi, Kikuchi, Eiji, Tanaka, Nobuyuki, Matsumoto, Kazuhiro, Miyajima, Akira, Nakamura, So, Oya, Mototsugu

BJU INTERNATIONAL 110 ( 6B ) E216 - E221 2012.09

Research paper (scientific journal), ISSN 1464-4096

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Prognostic Significance of High Nuclear Grade in Patients with Pathologic T1a Renal Cell Carcinoma

Suzuki, Kenjiro, Mizuno, Ryuichi, Mikami, Shuji, Tanaka, Nobuyuki, Kanao, Kent, Kikuchi, Eiji, Miyajima, Akira, Nakagawa, Ken, Oya, Mototsugu

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 42 ( 9 ) 831 - 835 2012.09

Research paper (scientific journal), ISSN 0368-2811

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Prognostic significance of Bacillus Calmette-Guérin failure classification in non-muscle-invasive bladder cancer

Shirakawa Hiroshi, Kikuchi Eiji, Tanaka Nobuyuki, Matsumoto Kazuhiro, Miyajima Akira, Nakamura So, Oya Mototsugu

BJU International 110 ( 6B ) 2012.09

Research paper (scientific journal), ISSN 1464-4096

Objective To investigate the differences in the clinical features and subsequent stage progression and disease-specific survival among patients with Bacillus Calmette-Guérin (BCG) failure, after dividing these patients into BCG-refractory, -resistant, -relapsing, and -intolerant groups. Patients and Methods We identified 173 patients with initial BCG failure from 521 patients who had undergone induction BCG therapy for non-muscle-invasive bladder cancer, excluding CIS, between 1987 and 2009. Patients were stratified into four BCG-failure groups, and each prognostic outcome was evaluated. Results Median follow-up period from initial BCG failure was 4.7 years. A total of 42 patients (24.3%) were stratified into the BCG-refractory, three (1.7%) into the BCG-resistant, 106 (61.3%) into the BCG-relapsing, and 22 (12.7%) into the BCG-intolerant group. Twenty-four patients (13.9%) experienced stage progression during follow-up. Multivariate analysis showed that pathological G3 at BCG failure (P= 0.014; risk ratio 2.84) and BCG-refractory (P < 0.001; risk ratio 4.68) were independent predictors for stage progression. The 10-year progression-free survival rates were 53.2%, 91.1% and 93.8% in the BCG-refractory, BCG-relapsing and BCG-intolerant groups, respectively. The stage progression rate was higher in the BCG-refractory than in the BCG-relapsing (P < 0.001) and BCG-intolerant (P= 0.007) groups. Similarly, the 10-year disease-specific survival rate in the BCG-refractory group was significantly worse than those in the other BCG failure groups (P < 0.001). Conclusions Stratification of BCG failure into the above-mentioned four groups can identify patients with BCG-failure in terms of their prognosis. The potential risk for critical adverse events was higher in the BCG-refractory group than in the other BCG-failure groups, despite the fact that patients in each group all underwent induction BCG therapy, therefore, treatment decisions, protocols and recommendations should be established based on each individual BCG-failure pattern.

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Transumbilical laparoendoscopic single-site varicocelectomy

Takeda Toshikazu, Miyajima Akira, Tanaka Nobuyuki, Kikuchi Eiji, Oya Mototsugu

Japanese Journal of Clinical Urology 66 ( 9 ) 675 - 678 2012.08

ISSN 0385-2393

We performed transumbilical laparoendoscopioc singlesite varicocelectomy (LESS-V) for three patients with left painful varicocele. Their average age was 34.7 years old (23-46 years old) and their varicocele grades were grade III in all cases. The operation was performed by the same laparoscopic surgeon. The average operative time was 65 minutes (49-96 minutes) and the estimated blood loss was little. Postoperative pain was tolerant and analgesics was not used in all cases. There were no remarkable complications and the patients were discharged 2 or 3 days after surgery. All cases had complete resolution of pain within 5 months (2-5 months) and hydrocele, testicular atrophy, or recurrence was not seen. LESS-V is safe and feasible for laparoscopic surgeons.

Renal cell carcinoma arising from a horseshoe kidney in a chronic hemodialysis patient

Miyazaki, Yasumasa, Miyajima, Akira, Maeda, Takahiro, Ito, Yujiro, Tanaka, Nobuyuki, Kosaka, Takeo, Masuda, Aya, Mizuno, Ryuichi, Kikuchi, Eiji, Nakagawa, Ken, Oya, Mototsugu

CLINICAL AND EXPERIMENTAL NEPHROLOGY 16 ( 4 ) 647 - 651 2012.08

Research paper (scientific journal), ISSN 1342-1751

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The Prognostic Significance of Vasohibin-1 Expression in Patients with Upper Urinary Tract Urothelial Carcinoma

Miyazaki, Yasumasa, Kosaka, Takeo, Mikami, Shuji, Kikuchi, Eiji, Tanaka, Nobuyuki, Maeda, Takahiro, Ishida, Masaru, Miyajima, Akira, Nakagawa, Ken, Okada, Yasunori, Sato, Yasufumi, Oya, Mototsugu

CLINICAL CANCER RESEARCH 18 ( 15 ) 4145 - 4153 2012.08

Research paper (scientific journal), ISSN 1078-0432

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Pelvic congenital arteriovenous malformation diagnosed by transrectal ultrasonography: A case report

Suzuki, Kenjiro, Tanaka, Nobuyuki, Ebine, Takashi, Momma, Tetsuo

CUAJ-CANADIAN UROLOGICAL ASSOCIATION JOURNAL 6 ( 2 ) E61 - E63 2012.04

Research paper (scientific journal), ISSN 1911-6470

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Three cases of granulocyte colony-stimulating factor-producing urinary upper tract carcinomas

Shirakawa, Hiroshi, Kikuchi, Eiji, Mikami, Shuji, Fukamachi, Shigeru, Miyazaki, Yasumasa, Tanaka, Nobuyuki, Miyajima, Akira, Oya, Mototsugu

SCANDINAVIAN JOURNAL OF UROLOGY AND NEPHROLOGY 46 ( 2 ) 136 - 141 2012.04

Research paper (scientific journal), ISSN 0036-5599

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Regulation of Monocyte Chemoattractant Protein-1 Through Angiotensin II Type 1 Receptor in Prostate Cancer

Shirotake, Suguru, Miyajima, Akira, Kosaka, Takeo, Tanaka, Nobuyuki, Kikuchi, Eiji, Mikami, Shuji, Okada, Yasunori, Oya, Mototsugu

AMERICAN JOURNAL OF PATHOLOGY 180 ( 3 ) 1008 - 1016 2012.03

Research paper (scientific journal), ISSN 0002-9440

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Preoperative Hydronephrosis: Independent Predictor for Changes in Renal Function Following Nephroureterectomy

Hoshino, Katsura, Kikuchi, Eiji, Tanaka, Nobuyuki, Akita, Hirotaka, Ito, Yujiro, Miyajima, Akira, Jinzaki, Masahiro, Oya, Mototsugu

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 42 ( 3 ) 202 - 207 2012.03

Research paper (scientific journal), ISSN 0368-2811

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Prognonstic impact of renin-angiotensin system blockade in localised upper-tract urothelial carcinoma

Tanaka N., Miyajima A., Kikuchi E., Matsumoto K., Hagiwara M., Ide H., Kosaka T., Masuda T., Nakamura S., Oya M.

British Journal of Cancer 106 ( 2 ) 290 - 296 2012.01

ISSN 0007-0920

Background: The potential role of the renin-angiotensin system (RAS) in the promotion of tumour growth has been investigated, and the administration of RAS inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), may improve disease control in malignancy. We investigated the prognostic impact of RAS inhibitors by analysing data from patients with upper-tract urothelial carcinoma (UTUC). Methods: A total of 279 patients who underwent nephroureterectomy for localised UTUC (pTa-3N0M0) were identified at our three institutions. We retrospectively investigated the prognostic outcomes following nephroureterectomy in patients administered or not administered ACEIs or ARBs. Results: The median follow-up period was 3.4 years. RAS inhibitors were administered to 48 patients (17.2%). Multivariate analysis showed that the appearance of pathological T3, positive lymphovascular invasion, and no RAS inhibitor administration (P=0.027 HR=3.14) were independent risk factors for a decrease in subsequent metastasis-free survival. The 5-year metastasis-free survival rate was 93.0% in patients who administered RAS inhibitors, and 72.8% in their counterparts who did not (P=0.008). Conclusion: The absence of RAS inhibitor administration was an independent risk factor for subsequent tumour metastasis in patients with localised UTUC. We propose RAS inhibitors may be a potent choice as an effective treatment following nephroureterectomy.

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Low-dose docetaxel enhances the sensitivity of S-1 in a xenograft model of human castration resistant prostate cancer

Hasegawa, Masanori, Miyajima, Akira, Kosaka, Takeo, Yasumizu, Yota, Tanaka, Nobuyuki, Maeda, Takahiro, Shirotake, Suguru, Ide, Hiroki, Kikuchi, Eiji, Oya, Mototsugu

INTERNATIONAL JOURNAL OF CANCER 130 ( 2 ) 431 - 442 2012.01

Research paper (scientific journal), ISSN 0020-7136

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Acquired platinum resistance enhances tumour angiogenesis through angiotensin II type 1 receptor in bladder cancer

Tanaka N., Miyajima A., Kosaka T., Miyazaki Y., Shirotake S., Shirakawa H., Kikuchi E., Oya M.

British Journal of Cancer 105 ( 9 ) 1331 - 1337 2011.10

Research paper (scientific journal), ISSN 0007-0920

Background: We investigated the changes in reactive oxygen species (ROS) and angiogenesis through angiotensin II (Ang II) type 1 receptor (AT1R) after the development of acquired platinum resistance in bladder cancer. Methods: Four invasive human bladder cancer cell lines, T24, 5637, T24PR, and 5637PR, were used in vitro, whereas in vivo, T24 and T24PR cells were used. T24PR and 5637PR cells were newly established at our institution as acquired platinum-resistant sublines by culturing in cisplatin (CDDP)-containing conditioned medium for 6 months. Results: Ang II induced significantly higher vascular endothelial growth factor (VEGF) production in T24PR and 5637PR cells than in their corresponding parent cells in vitro, whereas Ang II induced a further increase in VEGF production. These platinum-resistant cells also showed significantly higher AT1R expression than their corresponding parent cells. ROS was also significantly upregulated in T24PR and 5637PR cells, whereas increased AT1R expression was significantly downregulated by scavenging free radicals. We also demonstrated the efficacy of AT1R blockade at suppressing the growth of platinum-resistant xenograft model. Conclusion: Our findings indicate a new molecular mechanism for upregulated AT1R signalling through increased ROS when tumours progressed after the CDDP-based regimens, and shed light on the importance of AT1R blockade for platinum-resistant bladder cancers.

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Preoperative Hydronephrosis Grade Independently Predicts Worse Pathological Outcomes in Patients Undergoing Nephroureterectomy for Upper Tract Urothelial Carcinoma

Ito, Yujiro, Kikuchi, Eiji, Tanaka, Nobuyuki, Miyajima, Akira, Mikami, Shuji, Jinzaki, Masahiro, Oya, Mototsugu

JOURNAL OF UROLOGY 185 ( 5 ) 1621 - 1626 2011.05

Research paper (scientific journal), ISSN 0022-5347

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Angiotensin II Type 1 Receptor Expression and Microvessel Density in Human Bladder Cancer

Shirotake, Suguru, Miyajima, Akira, Kosaka, Takeo, Tanaka, Nobuyuki, Maeda, Takahiro, Kikuchi, Eiji, Oya, Mototsugu

UROLOGY 77 ( 4 ) 431 - 442 2011.04

Research paper (scientific journal), ISSN 0090-4295

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Frequency of Tumor Recurrence: A Strong Predictor of Stage Progression in Initially Diagnosed Nonmuscle Invasive Bladder Cancer

Tanaka, Nobuyuki, Kikuchi, Eiji, Matsumoto, Kazuhiro, Miyajima, Akira, Nakagawa, Ken, Oya, Mototsugu

JOURNAL OF UROLOGY 185 ( 2 ) 450 - 455 2011.02

Research paper (scientific journal), ISSN 0022-5347

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Cis-dichlorodiammineplatinum Upregulates Angiotensin II Type 1 Receptors through Reactive Oxygen Species Generation and Enhances VEGF Production in Bladder Cancer

Tanaka, Nobuyuki, Miyajima, Akira, Kosaka, Takeo, Shirotake, Suguru, Hasegawa, Masanori, Kikuchi, Eiji, Oya, Mototsugu

MOLECULAR CANCER THERAPEUTICS 9 ( 11 ) 2982 - 2992 2010.11

Research paper (scientific journal), ISSN 1535-7163

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Regulation of human dendritic cells by a novel specific nuclear factor-κB inhibitor, dehydroxymethylepoxyquinomicin

Shinoda Kazunobu, Nakagawa Ken, Kosaka Takeo, Tanaka Nobuyuki, Maeda Takahiro, Kono Hidaka, Mizuno Ryuichi, Kikuchi Eiji, Miyajima Akira, Umezawa Kazuo, Oya Mototsugu

Human Immunology 71 ( 8 ) 763 - 770 2010.08

Research paper (scientific journal), ISSN 0198-8859

Regulation of antigen-presenting cells (APC) is crucial in controlling allograft rejection. Dendritic cells (DC) are the most potent APC and must mature to present antigens to T-cell receptors. During DC maturation, nuclear factor-κB (NF-κB) is a key transcriptional factor. We synthesized dehydroxymethylepoxyquinomicin (DHMEQ), which specifically inhibits the final step of nuclear translocation of activated NF-κB proteins and examined its immunoregulatory effects on human monocyte-derived DC (Mo-DC). Regulatory Mo-DC were generated by pretreatment with DHMEQ before LPS stimulation, which were termed dl-DC. DHMEQ pretreatment (5 μg/ml) completely inhibited nuclear translocation of activated NF-κB. DHMEQ significantly inhibited DC production of κproinflammatory cytokines (IL-6, TNF-α, and IL-12 p70) in a dose-dependent manner. IL-12 was most potently inhibited. However, IL-10 production by dl-DC was only moderately affected by DHMEQ. Although CD40 and the expression of HLA-DR (HLA-DR) expression on dl-DC was downregulated, CD80 and CD86 expression was moderately upregulated. Induction of T helper 1 cell responses was efficiently impaired by dl-DC. This confirmed that DHMEQ-treated Mo-DC exhibited immunoregulatory effects. These findings suggest that DHMEQ has potential as an immunosuppressive drug for human immune cells.

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Late Recurrence and Progression in Non-muscle-invasive Bladder Cancers After 5-year Tumor-free Periods

Matsumoto, Kazuhiro, Kikuchi, Eiji, Horiguchi, Yutaka, Tanaka, Nobuyuki, Miyajima, Akira, Nakagawa, Ken, Nakashima, Jun, Oya, Mototsugu

UROLOGY 75 ( 6 ) 1385 - 1390 2010.06

Research paper (scientific journal), ISSN 0090-4295

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