研究者詳細 - 田中　伸之

論文 - 田中　伸之

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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年03月

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年03月

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年02月

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年

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年10月

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年10月

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年09月

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年08月

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年07月

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年06月

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年04月

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年01月

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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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年

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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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年

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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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年

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年12月

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年10月

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年09月

© 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年06月

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年

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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