研究者詳細 - 田中　伸之

論文 - 田中　伸之

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Genomic alteration and clinical significance of circulating tumor DNA in patients with advanced urothelial cancer: SCRUM-Japan monstar screen project.

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

NPJ precision oncology 9 （ 1 ） 362 2025年11月

ISSN 2397-768X

This prospective study evaluated the clinical significance of circulating tumor DNA (ctDNA) profiling in patients with advanced urothelial carcinoma (aUC) using FoundationOne®Liquid CDx. A total of 133 Japanese patients (SCRUM-Japan cohort) were analyzed, including serial ctDNA sampling before and after platinum-based chemotherapy or pembrolizumab. Cross-sectional comparison was made with 1059 patients from the U.S.-based Foundation Medicine cohort (FMI cohort). The most frequent genomic alterations in the SCRUM-Japan cohort were TP53 (43%), MLL2 (26%), and TERT (19%). Compared to the FMI cohort, the prevalence of TP53 and TERT alterations was lower, while KRAS alterations were more frequent in upper tract urothelial carcinoma (UTUC) than in bladder cancer (BC) across both cohorts. High ctDNA tumor fraction (≥10%) was associated with significantly worse overall survival, and alterations in TERT, and TP53 were also linked to significantly worse prognosis. The concordance rate of gene alterations before and after chemotherapy was 61%, and 66% for pembrolizumab. In contrast, concordance between tissue and ctDNA profiling was only 46%, with ctDNA identifying additional actionable mutations not detected in tissue. These findings underscore the potential of ctDNA as a non-invasive tool for dynamic molecular monitoring and prognostication in aUC, supporting its integration into clinical practice.

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ASO Author Reflections: Advancing AI-Based Surgical Phase Recognition in Robot-Assisted Radical Prostatectomy.

Konnai Y, Fukumoto K, Takeuchi M, Takeuchi R, Fujiwara S, Yasumizu Y, Tanaka N, Takeda T, Matsumoto K, Kosaka T, Kawakubo H, Kitagawa Y, Oya M

Annals of surgical oncology 2025年11月

ISSN 1068-9265

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Clonal diversity shapes the tumour microenvironment leading to distinct immunotherapy responses in metastatic urothelial carcinoma.

Kamatani T, Umeda K, Iwasawa T, Miya F, Matsumoto K, Mikami S, Hara K, Shimoda M, Suzuki Y, Nishino J, Kato M, Kakimi K, Tanaka N, Oya M, Tsunoda T

Nature communications 16 （ 1 ） 7995 2025年08月

Repeated oncogenic mutations and polyclonal proliferation are evident in cancers. However, little is known about the polyclonal principles governing the systemic cancerous lineage during immunotherapy. Here, we examine a unique autopsy case of metastatic urothelial carcinoma that exhibits different treatment responses to anti-PD-1 therapy at each tumor site. By performing in-depth analyses of different multiregional bulk tumor masses, we reveal that subsets of subclones acquire potential driver mutations under treatment selection pressure. Spatial transcriptomics analysis reveals that subclones resistant to immunotherapy form distinct immunosuppressive environments consistent with their habitats. Furthermore, different cancer hallmarks are identified in each of the subclones that expand under immunotherapy at single-cell level; for example, one subclone is more proliferative, and another is more stem-cell-like. In summary, this study provides an overall picture of the polyclonal competition and changes in the immune microenvironment that are related to resistance to immunotherapy in patients with malignancies.

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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年04月

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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【泌尿器科手術ヒヤリ・ハット-トラブル対処法109の知恵】開放手術　尿失禁・骨盤臓器脱の手術　手術時にストレステストがうまくいかない

田中伸之, 安水洋太, 大家基嗣

臨床泌尿器科（(株)医学書院） 79 （ 4 ） 252 - 254 2025年04月

ISSN 0385-2393

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年03月

Purpose: Genomic characterization of the predisposition of tumors to metastasize to specific sites has been performed in a few studies using mainly tissue-derived genomes. This nationwide prospective observational study investigated the association between genomic characteristics using circulating tumor DNA (ctDNA), and the synchronous and metachronous metastasis of tumors to specific target organs in advanced prostate cancer. Methods: Patients with advanced prostate cancer undergoing systemic treatment were included. ctDNA was analyzed using the FoundationOne®Liquid CDx assay at enrollment. Associations between genomic characteristics and metastatic status were examined. Results: Alterations in the genes MYC, APC, and BRCA2 and the DNA repair, MYC, and WNT pathways were associated with lung and liver metastasis. PTEN gene alterations and PI3K pathway alteration were associated with synchronous lung metastasis. RB1 gene alteration and RAS/RAF/MAPK pathway alteration were associated with synchronous liver metastasis. RB1 and BRCA2 gene alterations predicted metachronous lung metastasis, while TP53 and MYC gene alterations predicted metachronous liver metastasis. Conclusions: This study identifies genomic alterations in ctDNA associated with synchronous and metachronous metastases. These findings may be clinically helpful for treating, managing, and monitoring cancer.

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Predictors of Pentafecta Failure Despite Trifecta Achievement in Robot-Assisted Partial Nephrectomy

Kamisawa K., Takeda T., Nishimoto Y., Tanigawa M., Fukumoto K., Yasumizu Y., Tanaka N., Matsumoto K., Morita S., Kosaka T., Asanuma H., Oya M.

Asian Journal of Endoscopic Surgery 18 （ 1 ） e70167 2025年01月

ISSN 17585902

Introduction: The present study examined factors preventing the achievement of pentafecta in patients who have already met trifecta criteria following robot-assisted partial nephrectomy (RAPN). Methods: A retrospective observational study was conducted on 103 patients who underwent RAPN for localized renal tumors at Keio University Hospital between 2019 and 2023. Clinical characteristics, surgical parameters, and postoperative renal function were analyzed. Multivariate logistic regression analyses were performed to identify independent predictors of trifecta and pentafecta achievement. Results: The achievement rates for trifecta and pentafecta were 88% and 27%, respectively. Independent predictors of trifecta achievement were tumor size ≤ 20 mm (OR = 5.496, p = 0.039) and estimated blood loss ≤ 50 cc (OR = 7.983, p = 0.011). Significant predictors of pentafecta achievement were age ≤ 63 years (OR = 3.753, p = 0.026) and tumor exophyticity ≥ 50% (OR = 4.054, p = 0.018). Independent predictors of pentafecta failure despite trifecta achievement were age > 63 years (OR = 0.223, 95% CI: 1.347–14.904, p = 0.014) and tumor exophyticity < 50% (OR = 0.205, 95% CI: 1.474–16.159, p = 0.009). The pentafecta failure rate was 95% in patients who achieved trifecta but had both risk factors, namely, older age and embedded tumors. Conclusion: Older age and tumor exophyticity < 50% are significant predictors of pentafecta failure despite achieving trifecta. The consideration of these factors may help refine surgical planning and postoperative management.

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Pure Retroperitoneal Robot-Assisted Radical Nephroureterectomy (RANU): Initial Experience Using the Hinotori Surgical Robot System

Konnai Y., Matsumoto K., Fukumoto K., Takeda T., Yasumizu Y., Tanaka N., Oya M.

Asian Journal of Endoscopic Surgery 18 （ 1 ） e70174 2025年01月

ISSN 17585902

Background: Upper tract urothelial carcinoma (UTUC) often requires nephroureterectomy. The retroperitoneal robotic approach, particularly using the hinotori system, may offer advantages, especially for smaller-framed patients. Methods: Five UTUC patients (≤ 162 cm) underwent pure retroperitoneal robot-assisted nephroureterectomy (RANU) using the hinotori system (July–December 2024). Standardized trocar placement was used without port relocation. Outcomes included operative time, re-docking, and complications. Results: Median patient age was 82 years. All surgeries were completed without peritoneum opening, conversion to open surgery, or major complications. Mean operative time was 257 min, with re-docking averaging 18 min. All cases achieved negative margins, and no readmissions occurred within 30 days. Conclusions: Pure retroperitoneal RANU using the hinotori system is safe and feasible, particularly for smaller patients. This approach minimizes procedural interference and may serve as an alternative to transperitoneal nephroureterectomy. Further studies are needed to evaluate oncological outcomes and refine surgical techniques.

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Artificial-Intelligence-based Surgical Phase Recognition in Robot-Assisted Radical Prostatectomy and Cross-Surgeon Validation

Konnai Y., Fukumoto K., Takeuchi M., Takeuchi R., Fujiwara S., Yasumizu Y., Tanaka N., Takeda T., Matsumoto K., Kosaka T., Kawakubo H., Kitagawa Y., Oya M.

Annals of Surgical Oncology 2025年

ISSN 10689265

Background: Artificial intelligence (AI) has shown potential in various fields; however, its practical application in surgery remains limited. We developed an AI system capable of automatically recognizing surgical phases in robot-assisted radical prostatectomy (RARP) and confirmed its accuracy through cross-surgeon validation. Materials and Methods: We analyzed clinical data from 102 patients who underwent RARP, including 81 consecutive patients operated on by one surgeon (surgeon A) and 21 operated on by five other surgeons (surgeons B–F). In total, 65 of the 81 patients were used for AI development, while the remaining 16, in addition to the 21 patients operated on by surgeons B–F, were used for AI validation. We classified surgical operations into nine phases. Well-trained surgeons annotated the time corresponding to each surgical phase for each video. We used Temporal Convolutional Networks for the Operating Room (TeCNO) to develop the AI model and evaluated its precision. Results: In AI development, 919,231 frames were utilized. Testing involved 216,357 frames from surgeon A and 249,553 frames from surgeons B–F. When the developed AI was used to analyze surgical videos from surgeon A, precision reached 0.94. In contrast, when the AI was applied to videos from surgeons B–F, precision was 0.83. Conclusions: The AI we developed not only showed high accuracy, but also demonstrated generalizability across different surgeons. By comprehensively evaluating surgical videos, our AI may be used to assess the quality of surgeries, thereby providing valuable feedback to surgeons and enhancing the effectiveness of surgical education.

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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 75 （ 8 ） 403 - 413 2025年

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 133 （ 1 ） 111 - 120 2025年

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年12月

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年12月

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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【臨床腎・泌尿器癌(中)-基礎・臨床研究の進歩-】膀胱癌の特徴　膀胱癌の発症・進展メカニズム

田中伸之

日本臨床（(株)日本臨床社） 82 （増刊9 臨床腎・泌尿器癌(中) ） 23 - 27 2024年11月

ISSN 0047-1852

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年10月

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年10月

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年08月

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年07月

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年07月

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年06月

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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