Details of a Researcher - Oya, Mototsugu

Papers - Oya, Mototsugu

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CD8-positive T cells and CD204-positive M2-like macrophages predict postoperative prognosis of very high-risk prostate cancer.

Yanai Y, Kosaka T, Mikami S, Hongo H, Yasumizu Y, Takeda T, Matsumoto K, Miyauchi J, Kitano S, Oya M

Scientific reports (Scientific Reports) 11 ( 1 ) 22495 2021.11

ISSN 2045-2322

To stratify the heterogeneity of prostate cancer (PCa) with seminal vesicle invasion (SVI) immunologically after radical prostatectomy focusing on the tumor microenvironment. We retrospectively reviewed the clinicopathological data of 71 PCa patients with SVI, which is known as a factor of very high-risk PCa. Preoperative clinical variables and postoperative pathological variables were evaluated as predictors of biochemical recurrence (BCR) with a multivariate logistic regression. Immune cell infiltration including the CD8-positive cell (CD8+ cell) and CD204-positive M2-like macrophage (CD204+ cell) was investigated by immunohistochemistry. The cumulative incidence and risk of BCR were assessed with a Kaplan–Meier analysis and competing risks regression. A higher CD8+ cell count in the SVI area significantly indicated a favorable prognosis for cancers with SVI (p = 0.004). A lower CD204+ cell count in the SVI area also significantly indicated a favorable prognosis for cancers with SVI (p = 0.004). Furthermore, the combination of the CD8+ and CD204+ cell infiltration ratio of the SVI area to the main tumor area was a significant factor for BCR in the patients with the PCa with SVI (p = 0.001). In PCa patients with SVI, the combination of CD8+ and CD204+ cell infiltration is useful to predict the prognosis.

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Topoisomerase II alpha inhibition can overcome taxane-resistant prostate cancer through DNA repair pathways.

Hongo H, Kosaka T, Suzuki Y, Mikami S, Fukada J, Oya M

Scientific reports (Scientific Reports) 11 ( 1 ) 22284 2021.11

ISSN 2045-2322

Cabazitaxel (CBZ) is approved for the treatment of docetaxel-resistant castration-resistant prostate cancer (CRPC). However, its efficacy against CRPC is limited, and there are no effective treatments for CBZ-resistant CRPC. This study explored the optimal treatment for CRPC in the post-cabazitaxel setting. PC3 (CBZ-sensitive) and PC3CR cells (CBZ-resistant) were used in this study. We performed in silico drug screening for candidate drugs that could reprogram the gene expression signature of PC3CR cells. The in vivo effect of the drug combination was tested in xenograft mice models. We identified etoposide (VP16) as a promising treatment candidate for CBZ-resistant CRPC. The WST assay revealed that VP16 had a significant antitumor effect on PC3CR cells. PC3CR cells exhibited significantly higher topoisomerase II alpha (TOP2A) expression than PC3 cells. Higher TOP2A expression was a poor prognostic factor in The Cancer Genome Atlas prostate cancer cohort. In the Fred Hutchinson Cancer Research Center dataset, docetaxel-exposed tissues and metastatic tumors had higher TOP2A expression. In addition, VP16 significantly inhibited the growth of tumors generated from both cell lines. Based on these findings, VP16-based chemotherapy may be an optimal treatment for CPRC in the post-CBZ setting.

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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 2021.11

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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Does Neoadjuvant Chemotherapy have Therapeutic Benefit for Node-positive Upper Tract Urothelial Carcinoma? Results of a Multi-center Cohort Study.

Shigeta K, Matsumoto K, Oya M

European urology (European Urology) 81 ( 1 ) e20 - e21 2021.10

ISSN 0302-2838

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Urinary pH is an independent predictor of upper tract recurrence in non-muscle-invasive bladder cancer patients with a smoking history.

Ide H, Kikuchi E, Ogihara K, Niwa N, Shigeta K, Masuda T, Baba Y, Mizuno R, Oya M

Scientific reports (Scientific Reports) 11 ( 1 ) 20675 2021.10

ISSN 2045-2322

Limited information is currently available on predictors of upper tract urothelial carcinoma (UTUC) recurrence in non-muscle-invasive bladder cancer (NMIBC) patients according to smoking history, although smoking probably contributes to urothelial carcinogenesis. Therefore, the present study aimed to identify independent predictors of UTUC recurrence in all patients and those with a smoking history. Our study population comprised 1190 NMIBC patients who underwent transurethral resection of bladder tumor. UTUC developed in 43 patients during the follow-up. A history of bacillus Calmette-Guérin (BCG) therapy was independently associated with a lower incidence of UTUC (HR = 0.43; P = 0.011). In a subgroup of NMIBC patients with a smoking history, concomitant carcinoma in situ (CIS) and a lower urinary pH (< 6) were independently associated with a higher incidence of UTUC recurrence (HR = 3.34, P = 0.006 and HR = 3.73, P = 0.008, respectively). Among patients with a longer smoking duration (≥ 20 years) or larger smoking intensity (≥ 20 cigarettes per day), those with lower urinary pH (< 6) had a significantly higher UTUC recurrence rate than their counterparts. These results suggest that BCG instillation may prevent UTUC recurrence in NMIBC patients, while a lower urinary pH and concomitant CIS increase the risk of UTUC recurrence in those with a smoking history.

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A first case of ductal adenocarcinoma of the prostate having characteristics of neuroendocrine phenotype with PTEN, RB1 and TP53 alterations.

Hiroaki Kobayashi, Takeo Kosaka, Kohei Nakamura, Kazunori Shojo, Hiroshi Hongo, Shuji Mikami, Hiroshi Nishihara, Mototsugu Oya

BMC medical genomics (BMC Medical Genomics) 14 ( 1 ) 245 - 245 2021.10

Research paper (scientific journal), Joint Work

BACKGROUND: Ductal adenocarcinoma and neuroendocrine cancer are rare subtypes of prostate cancer with poor prognosis and limited therapeutic options. We present the first case of ductal adenocarcinoma having a neuroendocrine phenotype. CASE PRESENTATION: A 63-year-old man presented with gross hematuria and urinary retention, and his serum prostate-specific antigen level was 4.58 ng/mL. We performed transurethral resection of the prostate, and the diagnosis was ductal adenocarcinoma with a Gleason score of 5 + 4 for acinar adenocarcinoma. Magnetic resonance imaging showed local invasion of left lobe of the prostate and bone metastasis of the left trochanteric section of the femur. Multidisciplinary treatments such as androgen deprivation therapy, chemoradiation therapy, and surgery for metastatic lesions have led to long-term survival. Since next-generation sequencing revealed PTEN and RB1 co-loss and TP53 mutations, we re-evaluated the immunohistochemistry and he was found to be positive for synaptophysin. CONCLUSIONS: This is the first Japanese case of ductal adenocarcinoma with a neuroendocrine phenotype. Genetic analysis may help not only guide the therapeutic strategies, but also sometimes with the diagnosis.

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The Significance of PARP1 as a biomarker for Predicting the Response to PD-L1 Blockade in Patients with PBRM1-mutated Clear Cell Renal Cell Carcinoma.

Hagiwara M, Fushimi A, Matsumoto K, Oya M

European urology (European Urology) 81 ( 2 ) 145 - 148 2021.10

ISSN 0302-2838

Immune checkpoint inhibitors (ICIs) have become key agents in the management of clear cell renal cell carcinoma (ccRCC), but their benefits are limited and responders remain unidentified. We investigated the significance of PARP1 in ccRCC using RNA sequencing data for 311 tumors from patients enrolled in prospective clinical trials of PD-1 blockade. Among patients treated with nivolumab (n = 181), overall survival (OS) was significantly higher in the PARP1-low group than in the PARP1-high group (p = 0.006), and PARP1 status was significantly associated with OS (hazard ratio [HR] 1.7; p = 0.007). By contrast, for patients treated with everolimus (n = 130) there was no significant difference by PARP1 status for progression-free survival (PFS; p = 0.9) or OS (p = 0.38). In subgroup analysis for PBRM1-mutated ccRCC, PFS (p = 0.016) and OS (p = 0.004) were significantly longer in the group with PARP1-low status and PBRM1 mutation in comparison to the other groups. In addition, PARP1 status was significantly associated with PFS (HR 2.6; p = 0.007) and OS (HR 3.5; p = 0.016) among patients with PBRM1-mutated ccRCC treated with nivolumab. Our study suggests that PARP1 can be used as a biomarker for predicting response to ICI treatment for patients with PBRM1-mutated ccRCC. Patient summary: Immune checkpoint inhibitors (ICIs) are key agents in the treatment of multiple cancers. We found that expression of the PARP1 protein was associated with survival after ICI treatment and with the response to ICI treatment in patients with clear cell kidney cancer who have a mutation of the PBRM1 gene.

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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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Diagnostic value of texture analysis of apparent diffusion coefficient maps for differentiating fat-poor angiomyolipoma from non-clear-cell renal cell carcinoma

Yuki Arita, Soichiro Yoshida, Thomas C. Kwee, Hirotaka Akita, Shigeo Okuda, Yuki Iwaita, Kiyoko Mukai, Shunya Matsumoto, Ryo Ueda, Ryota Ishii, Ryuichi Mizuno, Yasuhisa Fujii, Mototsugu Oya, Masahiro Jinzaki

European Journal of Radiology (Elsevier BV) 143 109895 - 109895 2021.10

Research paper (scientific journal), Joint Work, ISSN 0720-048X

Purpose: To investigate the feasibility of texture analysis of apparent diffusion coefficient (ADC) maps for differentiating fat-poor angiomyolipomas (fpAMLs) from non-clear-cell renal cell carcinomas (non-ccRCCs). Methods: In this bi-institutional study, we included two consecutive cohorts from different institutions with pathologically confirmed solid renal masses: 67 patients (fpAML = 46; non-ccRCC = 21) for model development and 39 (fpAML = 24; non-ccRCC = 15) for validation. Patients underwent preoperative magnetic resonance imaging (MRI), including diffusion-weighted imaging. We extracted 45 texture features using a software with volumes of interest on ADC maps. Receiver operating characteristic curve analysis was performed to compare the diagnostic performance between the random forest (RF) model (derived from extracted texture features) and conventional subjective evaluation using computed tomography and MRI by radiologists. Results: RF analysis revealed that grey-level zone length matrix long-zone high grey-level emphasis was the dominant texture feature for diagnosing fpAML. The area under the curve (AUC) of the RF model to distinguish fpAMLs from non-ccRCCs was not significantly different between the validation and development cohorts (p = .19). In the validation cohort, the AUC of the RF model was similar to that of board-certified radiologists (p = .46) and significantly higher than that of radiology residents (p = .03). Conclusions: Texture analysis of ADC maps demonstrated similar diagnostic performance to that of board-certified radiologists for discriminating between fpAMLs and non-ccRCCs. Diagnostic performances in the development and validation cohorts were comparable despite using data from different imaging device manufacturers and institutions.

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

Tetsushi Murakami, Nobuyuki Tanaka, Kimiharu Takamatsu, Kyohei Hakozaki, Keishiro Fukumoto, Tsukasa Masuda, Shuji Mikami, Toshiaki Shinojima, Kazuhiro Kakimi, Tatsuhiko Tsunoda, Kazuaki Sawada, Takeshi Imamura, Ryuichi Mizuno, Mototsugu Oya

Cancer immunology, immunotherapy : CII (Cancer Immunology, Immunotherapy) 70 ( 10 ) 3001 - 3013 2021.10

Research paper (scientific journal), Joint Work, ISSN 0340-7004

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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Discovery of a new candidate drug to overcome cabazitaxel-resistant gene signature in castration-resistant prostate cancer by in silico screening.

Hongo H, Kosaka T, Suzuki Y, Oya M

Prostate cancer and prostatic diseases (Prostate Cancer and Prostatic Diseases) 2021.09

ISSN 1365-7852

Background: The taxane cabazitaxel (CBZ) is a promising treatment for docetaxel-resistant castration-resistant prostate cancer (CRPC). However, the survival benefit with CBZ for patients with CRPC is limited. This study used screening tests for candidate drugs targeting CBZ-resistant-related gene expression and identified pimozide as a potential candidate for overcoming CBZ resistance in CRPC. Methods: We established CBZ-resistant cell lines, DU145CR and PC3CR by incubating DU145 cells and PC3 cells with gradually increasing concentrations of CBZ. We performed in silico drug screening for candidate drugs that could reprogram the gene expression signature of a CBZ-resistant prostate cancer cells using a Connectivity Map. The in vivo effect of the drug combination was tested in xenograft mice models. Results: We identified pimozide as a promising candidate drug for CBZ-resistant CRPC. Pimozide had a significant antitumor effect on DU145CR cells. Moreover, combination treatment with pimozide and CBZ had a synergic effect for DU145CR cells in vitro and in vivo. Microarray analysis identified AURKB and KIF20A as potential targets of pimozide in CBZ-resistant CRPC. DU145CR had significantly higher AURKB and KIF20A expression compared with a non-CBZ-resistant cell line. Inhibition of AURKB and KIF20A had an antitumor effect in DU145CR xenograft tumors. Higher expression of AURKB and KIF20A was a poor prognostic factor of TGCA prostate cancer cohort. CBZ-resistant prostate cancer tissues in our institution had higher AURKB and KIF20A expression. Conclusions: Pimozide appears to be a promising drug to overcome CBZ resistance in CRPC by targeting AURKB and KIF20A.

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Erratum to: Subgroup analysis of the AFTER I-O study: a retrospective study on the efficacy and safety of subsequent molecular targeted therapy after immune-oncology therapy in Japanese patients with metastatic renal cell carcinoma.

Tomita Y, Kimura G, Fukasawa S, Numakura K, Sugiyama Y, Yamana K, Naito S, Kaneko H, Tajima Y, Oya M

Japanese journal of clinical oncology (Japanese Journal of Clinical Oncology) 51 ( 12 ) 1770 - 1770 2021.09

ISSN 0368-2811

In the originally published article there were errors in the legends to figures 3 and 4. Figure 3 should read: "Figure 3. PFS2 of nivolumab (NIVO) or nivolumab and ipilimumab combination therapy (NIVO+IPI). (a) PFS2 of NIVO, stratified by TT regimens after NIVO, sunitinib, or axitinib. (b) PFS2 of NIVO+IPI, stratified by TT regimens after NIVO+IPI, sunitinib, or axitinib, IMDC all risks." instead of: "Figure 3.OS from first-line therapy of patients treated with nivolumab (NIVO) or nivolumab and ipilimumab combination therapy (NIVO+IPI). (a) OS from first-linetherapy of patients treated with NIVO, stratified by TT regimens after NIVO, sunitinib or axitinib. (b) OS from first-line therapy of patients treated with NIVO+IPI,stratified by TT regimens after NIVO+IPI, sunitinib or axitinib, IMDC all risks.". Figure 4 should read: "Figure 4. OS from first-line therapy of patients treated with nivolumab (NIVO) or nivolumab and ipilimumab combination therapy (NIVO+IPI). (a) OS from first-linetherapy of patients treatedwithNIVO, stratified by TT regimens afterNIVO, sunitinib or axitinib. (b) OS from first-line therapy of patients treated with NIVO+IPI,stratified by TT regimens after NIVO+IPI, sunitinib or axitinib, IMDC all risks." instead of: "Figure 4. PFS2 of nivolumab (NIVO) or nivolumab and ipilimumab combination therapy (NIVO+IPI). (a) PFS2 of NIVO, stratified by TT regimens after NIVO, sunitinib, or axitinib. (b) PFS2 of NIVO+IPI, stratified by TT regimens after NIVO+IPI, sunitinib, or axitinib, IMDC all risks.". These errors have now been corrected online.

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

Kimiharu Takamatsu, Nobuyuki Tanaka, Kyohei Hakozaki, Ryohei Takahashi, Yu Teranishi, Tetsushi Murakami, Ryohei Kufukihara, Naoya Niwa, Shuji Mikami, Toshiaki Shinojima, Takashi Sasaki, Yusuke Sato, Haruki Kume, Seishi Ogawa, Kazuhiro Kakimi, Takashi Kamatani, Fuyuki Miya, Tatsuhiko Tsunoda, Eriko Aimono, Hiroshi Nishihara, Kazuaki Sawada, Takeshi Imamura, Ryuichi Mizuno, Mototsugu Oya

Nature Communications (Springer Science and Business Media LLC) 12 ( 1 ) 5547 2021.09

Research paper (scientific journal), Joint Work

<title>Abstract</title>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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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 2021.09

ISSN 1341-9625

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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Oncological outcomes of dose reductions in cisplatin due to renal dysfunction for patients with metastatic urothelial carcinoma

Tetsushi Murakami, Eiji Kikuchi, Hiroki Ide, Yuta Umezawa, Takayuki Takahashi, Mizuki Izawa, Kyohei Hakozaki, Keisuke Shigeta, Koichiro Ogihara, Hiroaki Kobayashi, Kunimitsu Kanai, Takahiro Maeda, Shunsuke Yoshimine, Ryuichi Mizuno, Koshiro Nishimoto, Mototsugu Oya

BJUI Compass (Wiley) 2 ( 5 ) 322 - 330 2021.09

Research paper (scientific journal), Joint Work, ISSN 2688-4526

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Analysis of the CLEAR study in patients (pts) with advanced renal cell carcinoma (RCC): depth of response and efficacy for selected subgroups in the lenvatinib (L) plus pembrolizumab (P) and sunitinib (S) treatment arms

Gruenwald V, Powles T., Kopyltsov E., Kozlov V, Alonso Gordoa T., Eto M., Hutson T., Motzer R., Winquist E., Maroto P., Keam B., Procopio G., Wong S., Melichar B., Rolland F., Oya M., Rodriguez-Lopez K., Saito K., Smith A., Porta C.

ONCOLOGY RESEARCH AND TREATMENT 44 25 - 25 2021.09

ISSN 2296-5270

Correction to: Prognostic value of programmed death-ligand 1 status in Japanese patients with renal cell carcinoma.

Motohide Uemura, Noboru Nakaigawa, Naoto Sassa, Katsunori Tatsugami, Kenichi Harada, Toshinari Yamasaki, Nobuaki Matsubara, Takuya Yoshimoto, Yuki Nakagawa, Tamaki Fukuyama, Mototsugu Oya, Nobuo Shinohara, Hirotsugu Uemura, Toyonori Tsuzuki

International journal of clinical oncology (International Journal of Clinical Oncology) 26 ( 11 ) 2085 - 2086 2021.08

Joint Work, ISSN 1341-9625

The article Prognostic value of programmed death‑ligand 1 status in Japanese patients with renal cell carcinoma, written by Motohide Uemura, Noboru Nakaigawa, Naoto Sassa, Katsunori Tatsugami, Kenichi Harada, Toshinari Yamasaki, Nobuaki Matsubara, Takuya Yoshimoto, Yuki Nakagawa, Tamaki Fukuyama, Mototsugu Oya, Nobuo Shinohara, Hirotsugu Uemura, and Toyonori Tsuzuki was originally published Online First without Open Access. With the author(s)’ decision to opt for Open Choice the copyright of the article changed on August 18, 2021 to © Author(s) 2021 and the article is forthwith distributed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4.0. The original article has been corrected. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

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

Keisuke Shigeta, Kazuhiro Matsumoto, Koichiro Ogihara, Tetsushi Murakami, Tadatsugu Anno, Kota Umeda, Mizuki Izawa, Yuto Baba, Tansei Sanjo, Kazunori Shojo, Nobuyuki Tanaka, Toshikazu Takeda, Shinya Morita, Takeo Kosaka, Ryuichi Mizuno, Yuki Arita, Hirotaka Akita, Masahiro Jinzaki, Eiji Kikuchi, Mototsugu Oya

Urologic Oncology: Seminars and Original Investigations (Elsevier BV) 40 ( 3 ) 105.e19 - 105.e26 2021.08

Research paper (scientific journal), Joint Work, ISSN 1078-1439

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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Effects of transurethral resection under general anesthesia on tumor recurrence in non-muscle invasive bladder cancer.

Yuto Baba, Eiji Kikuchi, Keisuke Shigeta, Koichiro Ogihara, Masashi Matsushima, Yui Nishimoto, Yasuaki Murata, Hirotaka Asakura, Masafumi Oyama, Ryuichi Mizuno, Mototsugu Oya

International journal of clinical oncology (International Journal of Clinical Oncology) 26 ( 11 ) 2094 - 2103 2021.08

Research paper (scientific journal), Joint Work, ISSN 1341-9625

BACKGROUND: The effects of the type of anesthesia (spinal (SA) vs. general (GA)) used for transurethral resection of bladder tumor (TURBT) on non-muscle invasive bladder cancer (NMIBC) recurrence and progression are controversial and our aim is to investigate their associations. METHODS: We identified 300 NMIBC patients who underwent initial TURBT with SA or GA. Cox's regression analysis was performed to examine the effects of anesthesia on tumor recurrence. RESULTS: Among 300 patients, 153 (51.0%) received GA and 147 (49.0%) SA. The 5-year recurrence-free survival (RFS) rate was 59.9% in the GA group, which was significantly lower than that in the SA group (74.4%, p = 0.029). GA (HR 1.57, p = 0.048), male sex (HR 2.72, p = 0.012), and tumor multiplicity (HR 1.96, p = 0.006) were independently associated with tumor recurrence. In a subgroup of 137 patients with high-risk NMIBC, the 5-year RFS rate was 50.3% in the GA group, which was significantly lower than that in the SA group (77.6%, p = 0.020), and GA remained an independent indicator of tumor recurrence (HR 2.35, p = 0.016). However, no significant differences were observed in the RFS rates of low- to intermediate-risk NMIBC patients between the GA and SA groups. CONCLUSIONS: The RFS rate was lower in NMIBC patients who received GA during TURBT than in those who received SA. Volatile anesthesia may increase tumor recurrence, particularly in high-risk NMIBC patients, which may be due to the inhibition of the immune response system during surgery.

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Subgroup analysis of the AFTER I-O study: a retrospective study on the efficacy and safety of subsequent molecular targeted therapy after immune-oncology therapy in Japanese patients with metastatic renal cell carcinoma

Yoshihiko Tomita, Go Kimura, Satoshi Fukasawa, Kazuyuki Numakura, Yutaka Sugiyama, Kazutoshi Yamana, Sei Naito, Hirokazu Kaneko, Yohei Tajima, Mototsugu Oya

Japanese Journal of Clinical Oncology (Oxford University Press (OUP)) 51 ( 11 ) 1656 - 1664 2021.08

Research paper (scientific journal), Joint Work, ISSN 0368-2811

<title>Abstract</title>
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<title>Background</title>
We performed subgroup analyses of the AFTER I-O study to clarify the association of time-to-treatment failure (TTF) and discontinuation reason of prior immune-oncology (I-O) therapy, and molecular targeted therapy (TT) regimen with the outcomes of TT after I-O.

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<title>Methods</title>
The data of Japanese metastatic renal cell carcinoma patients treated with TT after nivolumab (NIVO) (CheckMate 025) or NIVO + ipilimumab (IPI) (CheckMate 214) were retrospectively analyzed. The objective response rates (ORRs), progression-free survival (PFS) and overall survival (OS) of TT after I-O were analyzed by subgroups: TTF (&lt;6 or ≥6 months) and discontinuation reason of prior I-O (progression or adverse events), and TT regimen (sunitinib or axitinib). We also analyzed PFS2 of prior I-O and OS from first-line therapy.

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<title>Results</title>
The ORR and median PFS of TT after NIVO and NIVO+IPI among the subgroups was 17–36% and 20–44%, and 7.1–11.6 months and 16.3-not reached (NR), respectively. The median OS of TT after NIVO was longer in patients with longer TTF of NIVO and treated with axitinib. Conversely, median OS of TT after NIVO+IPI was similar among subgroups. The median PFS2 of NIVO and NIVO+IPI was 36.7 and 32.0 months, respectively. The median OS from first-line therapy was 70.5 months for patients treated with NIVO and NR with NIVO+IPI. The safety profile of each TT after each I-O was similar to previous reports.

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<title>Conclusions</title>
The efficacy of TT after NIVO or NIVO+IPI was favorable regardless of the TTF and discontinuation reason of prior I-O, and TT regimen.

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