研究者詳細 - 大家　基嗣

論文 - 大家　基嗣

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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 10 （ 3 ） 2022年03月

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Incidence and location of perioperative deep vein thrombosis in patients with bladder cancer undergoing radical cystectomy.

Yamashita R, Nakamura M, Okayama Y, Kawase M, Muraoka N, Fujita A, Notsu A, Asakura K, Hashizume A, Shinsaka H, Matsuzaki M, Niwakawa M, Oya M

International journal of urology : official journal of the Japanese Urological Association （International Journal of Urology） 29 （ 3 ） 259 - 264 2022年03月

ISSN 0919-8172

Objectives: To determine the incidence and location of lower extremity deep vein thrombosis in patients undergoing radical cystectomy. Methods: We performed radical cystectomy in 137 patients with bladder cancer between August 2014 and February 2020. Since 2014, we have had a policy to screen for deep vein thrombosis using lower extremity ultrasonography both before and after radical cystectomy. We determined the incidence and location of deep vein thrombosis and classified it as either proximal or distal type. Furthermore, we explored the incidence of pulmonary embolism within 3 months after radical cystectomy. Results: After excluding six patients with a lack of ultrasonographic data, we evaluated 131 patients. Preoperative deep vein thrombosis (one proximal and 17 distal) was diagnosed in 18 patients (14%) with no symptoms. Postoperative deep vein thrombosis was diagnosed in 41 patients (31%; three proximal and 38 distal), of whom 26 (63%) had new-onset deep vein thrombosis after cystectomy. Three patients, two with proximal and one with distal type deep vein thrombosis, developed nonfatal pulmonary embolism postoperatively. Multivariate analysis showed that preoperative D-dimer levels (odds ratio 5.35, 95% confidence interval 1.74–16.50; P < 0.003), type of urinary diversion (ileal neobladder; odds ratio 11.15, 95% confidence interval 2.16–57.55; P = 0.004), and preoperative deep vein thrombosis (odds ratio 15.93, 95% confidence interval 3.82–66.30; P < 0.001) were significant risk factors for postoperative deep vein thrombosis. Conclusions: Pre- and post-radical cystectomy whole-leg ultrasonography can lead to an early perioperative diagnosis and immediate treatment of proximal deep vein thrombosis, thereby potentially preventing fatal pulmonary embolism.

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An organ-derived extracellular matrix triggers in situ kidney regeneration in a preclinical model.

Tajima K, Yagi H, Morisaku T, Nishi K, Kushige H, Kojima H, Higashi H, Kuroda K, Kitago M, Adachi S, Natsume T, Nishimura K, Oya M, Kitagawa Y

NPJ Regenerative medicine （npj Regenerative Medicine） 7 （ 1 ） 18 2022年02月

It has not been considered that nephrons regenerate in adult mammals. We present that an organ-derived extracellular matrix in situ induces nephron regeneration in a preclinical model. A porcine kidney-derived extracellular matrix was sutured onto the surface of partial nephrectomy (PN)-treated kidney. Twenty-eight days after implantation, glomeruli, vessels, and renal tubules, characteristic of nephrons, were histologically observed within the matrix. No fibrillogenesis was observed in the matrix nor the matrix-sutured kidney, although this occurred in a PN kidney without the matrix, indicating the structures were newly induced by the matrix. The expression of renal progenitor markers, including Sall1, Six2, and WT-1, within the matrix supported the induction of nephron regeneration by the matrix. Furthermore, active blood flow was observed inside the matrix using computed tomography. The matrix provides structural and functional foundations for the development of cell-free scaffolds with a remarkably low risk of immune rejection and cancerization.

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PROpel: Phase III trial of olaparib (ola) and abiraterone (abi) versus placebo (pbo) and abi as first-line (1L) therapy for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

Saad Fred, Armstrong Andrew J., Thiery-Vuillemin Antoine, Oya Mototsugu, Loredo Eugenia, Procopio Giuseppe, de Menezes Juliana Janoski, Girotto Gustavo Colagiovanni, Arslan Cagatay, Mehra Niven, Parnis Francis, Brown Emma, Schluermann Friederike, Joung Jae Young, Sugimoto Mikio, Poehlein Christian Heinrich, Harrington Elizabeth, Desai Chintu, Kang Jinyu, Clarke Noel

JOURNAL OF CLINICAL ONCOLOGY 40 （ 6 ） 2022年02月

ISSN 0732-183X

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Castration-resistant prostate cancer patient presenting with whole genome doubling with CDK-12 mutation.

Baba Y, Kosaka T, Kobayashi H, Nakamura K, Mikami S, Nishihara H, Nakanishi M, Oya M

BMC medical genomics （BMC Medical Genomics） 15 （ 1 ） 32 2022年02月

Background: The use of whole-genome sequencing in clinical practice has revealed variable genomic characteristics across cancer types, one of which is whole-genome doubling (WGD), which describes the duplication of a complete set of chromosomes. Yet it is relatively rare in prostate cancer and no such case has ever been reported in Japanese patients. Case presentation: A 54-year-old patient with prostatic adenocarcinoma with bone and lymph node metastases was started on androgen-deprivation therapy. As the prostate cancer turned castration-resistant, multimodal therapies including taxane- and platinum-based chemotherapy, androgen-receptor antagonist inhibitors, radiotherapy and radium-233 were introduced. Good controls of serum prostate-specific antigen (PSA) level and bone metastases were achieved for more than 13 years since after the initial treatment. During the treatment, a metastatic lymph node biopsy was performed to confirm the tumor histology, and spinal decompression surgery were performed for spinal compression due to lumber vertebral metastases. The immunohistochemical analysis identified PSA and androgen receptor positive tumor cells in both metastatic lesions, while no variable cancer cells were detected in the prostate on second biopsy. Whole-genome sequencing was performed on the biopsied metastatic lymph node in search for another possible treatment and it revealed that the tumor had WGD and CDK12 mutation. The WGD-positive tumor cells contained large and polymorphic nucleus, presumably reflecting on the ploidy abnormality of the chromosomes. Conclusions: This report is the first case of a Japanese patient presenting with WGD, who survived more than 13 years with multimodal chemotherapies and radiotherapies.

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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） 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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How to motivate young doctors to start translational research

Oya Mototsugu, Tanaka Nobuyuki, Kosaka Takeo

CANCER SCIENCE 113 1315 - 1315 2022年02月

ISSN 1347-9032

Structures and functions of O-glycans expressed in castration resistant prostate cancer cells

Yamamoto Daiki, Kosaka Takeo, Oya Mototsugu, Sato Toshinori

CANCER SCIENCE 113 1285 - 1285 2022年02月

ISSN 1347-9032

MUC1 induces neuroendocrine differentiation of prostate cancer

Yasumizu Yota, Kosaka Takeo, Hongo Hiroshi, Oya Mototsugu

CANCER SCIENCE 113 1595 - 1595 2022年02月

ISSN 1347-9032

特集尿道狭窄に対する尿道形成術の極意-〈特別付録Web動画〉前部尿道狭窄に対する代用組織を利用した二期的尿道形成術

浅沼宏, 岩佐俊, 高橋遼平, 大家基嗣

臨床泌尿器科（株式会社医学書院） 76 （ 1 ） 26 - 30 2022年01月

ISSN 0385-2393

Optimal surgical treatment for paratesticular leiomyosarcoma: retrospective analysis of 217 reported cases.

Kamitani R, Matsumoto K, Takeda T, Mizuno R, Oya M

BMC cancer （BMC Cancer） 22 （ 1 ） 15 2022年01月

Background: Paratesticular leiomyosarcoma (LMS) is a rare tumor. Conventionally, tumor resection by high inguinal orchiectomy is performed as the preferred treatment approach for paratesticular sarcoma. On the other hand, testis-sparing surgery has recently attracted attention as a less-invasive treatment option for paratesticular sarcoma. However, the prognostic predictors and optimal treatment strategy for paratesticular LMS remain unclear because of its rarity. In this study, we systematically reviewed previously reported cases of paratesticular LMS to evaluate the prognostic factors and establish the optimal treatment strategy. Methods: A systematic search of Medline, Web of Science, Embase, and Google was performed to find articles describing localized paratesticular LMS published between 1971 and 2020 in English. The final cohort included 217 patients in 167 articles. The starting point of this study was the time of definitive surgical treatment, and the end point was the time of local recurrence (LR), distant metastasis (DM), and disease-specific mortality. Results: Patients with cutaneous LMS had a slightly better LR-free survival, DM-free survival, and disease-specific survival than those with subcutaneous LMS (p = 0.745, p = 0.033, and p = 0.126, respectively). Patients with higher grade tumors had a significantly higher risk of DM and disease-specific mortality (Grade 3 vs Grade 1 p < 0.001, and Grade 3 vs Grade 1 p < 0.001, respectively). In addition, those with a microscopic positive margin had a significantly higher risk of LR and DM than those with a negative margin (p < 0.001, and p = 0.018, respectively). Patients who underwent simple tumorectomy had a slightly higher risk of LR than those who underwent high inguinal orchiectomy (p = 0.067). Subgroup analysis of cutaneous LMS demonstrated that the difference in LR between simple tumorectomy and high inguinal orchiectomy was limited (p = 0.212). On the other hand, subgroup analysis of subcutaneous LMS revealed a significant difference in LR (p = 0.039). Conclusions: Our study demonstrated that subcutaneous LMS and high-grade tumors are prognostic factors for paratesticular LMS. For subcutaneous LMS, tumorectomy with high inguinal orchiectomy should be the optimal treatment strategy to achieve a negative surgical margin.

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First successful case of platinum-based chemotherapy for neuroendocrine prostate cancer with <i>BRCA2</i> and <i>PTEN</i> alterations.

Omura M, Kosaka T, Aimono E, Nakamura K, Hongo H, Mikami S, Nishihara H, Oya M

IJU case reports （IJU Case Reports） 5 （ 1 ） 41 - 44 2022年01月

Introduction: Deoxyribonucleic acid repair gene mutations are now being studied in a variety of solid tumors, with the hope of predicting prognosis, pathogenesis, and treatment outcomes. Case presentation: We report the case of a Japanese patient with advanced castration-resistant prostate cancer who exhibited a prominent response to platinum therapy and had coexisting BRCA2 and PTEN mutations according to retrospective multigene panel analysis. Conclusion: Through a review of clinical outcomes and genetic/pathologic profiling, the presented case provides insights into future management strategies based on the tumor genetic status.

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Enzalutamide + androgen deprivation therapy (ADT) versus flutamide + ADT in Japanese men with castration-resistant prostate cancer: AFTERCAB study.

Uemura H, Kobayashi K, Yokomizo A, Hinotsu S, Horie S, Kakehi Y, Naito S, Nonomura N, Ogawa O, Oya M, Suzuki K, Saito A, Uno S, Akaza H

BJUI compass 3 （ 1 ） 26 - 36 2022年01月

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Synthetic magnetic resonance imaging for primary prostate cancer evaluation: Diagnostic potential of a non-contrast-enhanced bi-parametric approach enhanced with relaxometry measurements.

Arita Y, Akita H, Fujiwara H, Hashimoto M, Shigeta K, Kwee TC, Yoshida S, Kosaka T, Okuda S, Oya M, Jinzaki M

European journal of radiology open （European Journal of Radiology Open） 9 100403 2022年

Purpose: Bi-parametric magnetic resonance imaging (bpMRI) with diffusion-weighted images has wide utility in diagnosing clinically significant prostate cancer (csPCa). However, bpMRI yields more false-negatives for PI-RADS category 3 lesions than multiparametric (mp)MRI with dynamic-contrast-enhanced (DCE)-MRI. We investigated the utility of synthetic MRI with relaxometry maps for bpMRI-based diagnosis of csPCa. Methods: One hundred and five treatment-naïve patients who underwent mpMRI and synthetic MRI before prostate biopsy for suspected PCa between August 2019 and December 2020 were prospectively included. Three experts and three basic prostate radiologists evaluated the diagnostic performance of conventional bpMRI and synthetic bpMRI for csPCa. PI-RADS version 2.1 category 3 lesions were identified by consensus, and relaxometry measurements (T1-value, T2-value, and proton density [PD]) were performed. The diagnostic performance of relaxometry measurements for PI-RADS category 3 lesions in peripheral zone was compared with that of DCE-MRI. Histopathological evaluation results were used as the reference standard. Statistical analysis was performed using the areas under the receiver operating characteristic curve (AUC) and McNemar test. Results: In 102 patients without significant MRI artefacts, the diagnostic performance of conventional bpMRI was not significantly different from that of synthetic bpMRI for all readers (p = 0.11–0.79). The AUCs of the combination of T1-value, T2-value, and PD (T1 + T2 + PD) for csPCa in peripheral zone for PI-RADS category 3 lesions were 0.85 for expert and 0.86 for basic radiologists, with no significant difference between T1 + T2 + PD and DCE-MRI for both expert and basic radiologists (p = 0.29–0.45). Conclusion: Synthetic MRI with relaxometry maps shows promise for contrast media-free evaluation of csPCa.

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MUC1-C integrates type II interferon and chromatin remodeling pathways in immunosuppression of prostate cancer.

Hagiwara M, Fushimi A, Bhattacharya A, Yamashita N, Morimoto Y, Oya M, Withers HG, Hu Q, Liu T, Liu S, Wong KK, Long MD, Kufe D

Oncoimmunology （OncoImmunology） 11 （ 1 ） 2029298 2022年

ISSN 2162-4011

The oncogenic MUC1-C protein drives dedifferentiation of castrate resistant prostate cancer (CRPC) cells in association with chromatin remodeling. The present work demonstrates that MUC1-C is necessary for expression of IFNGR1 and activation of the type II interferon-gamma (IFN-γ) pathway. We show that MUC1-C→ARID1A/BAF signaling induces IFNGR1 transcription and that MUC1-C-induced activation of the NuRD complex suppresses FBXW7 in stabilizing the IFNGR1 protein. MUC1-C and NuRD were also necessary for expression of the downstream STAT1 and IRF1 transcription factors. We further demonstrate that MUC1-C and PBRM1/PBAF are necessary for IRF1-induced expression of (i) IDO1, WARS and PTGES, which metabolically suppress the immune tumor microenvironment (TME), and (ii) the ISG15 and SERPINB9 inhibitors of T cell function. Of translational relevance, we show that MUC1 associates with expression of IFNGR1, STAT1 and IRF1, as well as the downstream IDO1, WARS, PTGES, ISG15 and SERPINB9 immunosuppressive effectors in CRPC tumors. Analyses of scRNA-seq data further demonstrate that MUC1 correlates with cancer stem cell (CSC) and IFN gene signatures across CRPC cells. Consistent with these results, MUC1 associates with immune cell-depleted “cold” CRPC TMEs. These findings demonstrate that MUC1-C integrates chronic activation of the type II IFN-γ pathway and induction of chromatin remodeling complexes in linking the CSC state with immune evasion.

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Squamous cell carcinoma of the prostate with SMARCA4 alteration in a Japanese patient

Kaneko Y., Kosaka T., Nakamura K., Mikami S., Nishihara H., Oya M.

IJU Case Reports （IJU Case Reports） 2022年

Introduction: Squamous cell carcinoma of the prostate is very rare. Due to difficulty in diagnosis, it is often detected in advanced stages. Effective treatment of squamous cell carcinoma and the genetic profiling has not yet been established. Case presentation: We experienced the case of a 79-year-old man who was diagnosed with primary squamous cell carcinoma of the prostate. He had multiple lymph node metastases, liver metastases, and lung metastases, and he was treated with gemcitabine and carboplatin. However, he had poor patient status: it became difficult to continue after one course, and best supportive care was provided. We also performed targeted next-generation sequencing of 160 cancer-related genes and detected SMARCA4 mutation. Conclusion: This is the first study reporting the genomic profiling of squamous cell carcinoma of prostate in Japan.

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Bullous pemphigoid in patients receiving peritoneal dialysis: a case series and a literature survey.

Morimoto K, Yoshida T, Washida N, Uchiyama K, Nakayama T, Itoh H, Oya M

Renal failure （Renal Failure） 43 （ 1 ） 651 - 657 2021年12月

研究論文（学術雑誌）, 共著, ISSN 0886-022X

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease. Although several cases of BP in end-stage renal disease patients receiving peritoneal dialysis (PD) or hemodialysis have been reported, the incidence of BP in these patients remains unknown. We recently experienced three PD patients diagnosed with BP. The skin injury was likely to be a trigger of BP in all the three PD patients. Nifedipine and icodextrin exposures were possible factors directly or indirectly affecting the onset of BP, because they were common in the three cases. We also report that the incidence of BP in PD patients was 3/478.3 person-years in a single-center 10-year study. This case series with a literature survey describes that the skin and tissue injuries are potential triggers responsible for the onset of BP in dialysis patients and that the incidence of BP in these patients seems to be much higher than that in the general population.

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Perimortem changes in clinical parameters in patients undergoing maintenance hemodialysis

Yoshida T., Morimoto K., Nakayama T., Torimitsu T., Kosugi S., Oshida T., Yamaguchi N., Oya M.

Renal Replacement Therapy （Renal Replacement Therapy） 7 （ 1 ） 2021年12月

Background: End-of-life medical care for patients receiving maintenance hemodialysis (HD) therapy has become an increasingly important issue worldwide. Thus far, no clear indicators and/or biomarkers exist regarding the timing of HD therapy withdrawal. Methods: To clarify the perimortem circumstances, we examined temporal changes in multiple clinical parameters during the last 10 serial HD sessions of 65 terminal patients with end-stage renal disease who had undergone maintenance HD and died in our hospital. Results: The results showed that, while most of the laboratory data were unaltered, the physical parameters, such as systolic blood pressure and consciousness levels, gradually and significantly deteriorated toward the last HD session prior to death. The frequency of the use of vasopressors and O2 inhalation tended to increase. The accumulation of such severe conditions was observed at the last HD session. Of interest, the accumulation of severe conditions at the last HD session in patients with malignancies was significantly less than those with cardiovascular diseases or infectious diseases. The accumulation of severe conditions at the last HD session did not differ between patients who withdrew HD versus those who continued HD. Conclusion: The results of the present study suggest that predicting the timing of maintenance HD therapy withdrawal is likely to be difficult and that the timing of maintenance HD therapy termination may differ among patient groups with distinct comorbid conditions.

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集中治療にて救命しえた腎移植後COVID-19の1例

森田伸也, 高橋遼平, 浅岡雅人, 山元良, 長田大雅, 本間康一郎, 川田一郎, 吉田理, 石井誠, 浅沼宏, 中川健, 大家基嗣

日本臨床腎移植学会雑誌（(一社)日本臨床腎移植学会） 9 （ 2 ） 207 - 210 2021年12月

ISSN 2187-9907

56歳男性。紫斑病性腎炎による慢性腎不全にてX-19年血液透析導入、同年血液型適合生体腎移植施行。維持免疫抑制剤はシクロスポリン(CyA)、ミコフェノール酸モフェチル(MMF)、プレドニゾロン(PSL)であった。X年に頭重感と微熱を主訴に来院、CTにて肺一部にすりガラス影を認め、鼻咽頭PCRにてSARS-CoV-2陽性となり緊急入院。MMF減量しファビピラビル、セフトリアキソン投与開始した。さらに抗生剤をタゾバクタム/ピペラシリンに、PSLをデキサメタゾンとしMMFを中止した。肺炎増悪したためメチルプレドニゾロン(mPSL)90mg/day投与、抗凝固療法開始しCyA減量した。呼吸状態増悪のため人工呼吸器管理としCyA中止、レムデシビル投与開始、腹臥位療法を施行した。一時血液透析を3回施行。徐々に酸素化は改善しmPSLは漸減とした。細菌性肺炎合併を疑い抗生剤をバンコマイシンとメロペネムとし、肺炎は改善した。下気道PCRにてSARS-CoV-2陰性を2回確認後CyA、MMFを再開し退院となった。(著者抄録)

Vasohibin-1 expression as a biomarker of aggressive nature in ductal adenocarcinoma of the prostate: a retrospective cohort study at two centres in Japan.

Kobayashi H, Kosaka T, Mikami S, Kimura T, Hongo H, Kosugi M, Sato Y, Oya M

BMJ open （BMJ Open） 11 （ 11 ） e056439 2021年11月

ISSN 2044-6055

Objectives Vasohibin-1 (VASH1) is an endogenous angiogenesis regulator expressed in activated vascular endothelial cells. We previously reported that high VASH1 expression is a predictor of progression in acinar adenocarcinoma of the prostate. In this study, we evaluated the characteristics of ductal adenocarcinoma of the prostate by comparing the level of VASH1 expression between ductal and acinar adenocarcinoma specimens. Design and setting A retrospective cohort study at two centres in Japan. Participants Among the 1495 patients who underwent radical prostatectomy or transurethral resection for the past 15 years, a total of 14 patients diagnosed with ductal adenocarcinoma and 20 patients diagnosed with acinar adenocarcinoma with a Gleason score of 4+4 were included. Interventions We immunohistochemically examined the CD34 expression as the microvessel density (MVD) and activated endothelial cells as the VASH1 density (vessels per mm2). Primary and secondary outcome measures The primary outcome was the association of MVD and VASH1 density between ductal and acinar adenocarcinoma, and the secondary outcome was their oncological outcomes. Results Nine patients (64.3%) with ductal adenocarcinoma were diagnosed at an advanced clinical stage, and five patients (35.7%) died from cancer during a median follow-up of 56.0 months. The VASH1 densities (mean±SD) in ductal and acinar adenocarcinoma were 45.1±18.5 vs 16.1±21.0 (p<0.001), respectively, while the MVD (mean±SD) in ductal and acinar adenocarcinoma were 65.3±21.9 vs 80.8±60.7 (p=0.666), respectively. The 5-year cancer-specific survival rates for high and low VASH1 expression were 70.0% and 100.0% (p=0.006), respectively. High VASH1 expression and a diagnosis of ductal adenocarcinoma were significant predictors of cancer-specific survival. Conclusions Ductal adenocarcinoma was more aggressive and had higher VASH1 expression than acinar adenocarcinoma, although MVD was equivalent. These results indicate that VASH1 expression may serve as a novel biomarker for the aggressive nature of ductal adenocarcinoma.

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