記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：World Journal of Urology  

Purpose: No study has compared cancer regression (d) and growth (g) rates in patients with advanced castration-sensitive prostate cancer (CSPC) treated with androgen deprivation therapy. The comparison of d and g rates provides insight into the differential impact of ADT regimens on tumor dynamics, potentially guiding more personalized treatment strategies. Therefore, we aimed to estimate these rates and evaluate their impact on survival outcomes. Methods: Sequential prostate-specific antigen (PSA) data was obtained from the KYUCOG-1401 trial including patients with advanced CSPC randomized to gonadotropin-releasing hormone (GnRH) antagonist (group A) and GnRH agonist plus bicalutamide (group B). d and g rates were estimated by applying mathematical models and were compared in subgroups. PSA-progression-free survival (PSA-PFS), radiographic progression-free survival (rPFS), and overall survival (OS) were compared by lower and higher than the median of these rates. Results: Patients with higher PSA and higher extent of disease score at enrollment presented higher d rates (0.03965 vs. 0.03546, p = 0.0006) and (0.03947 vs. 0.03587, p = 0.0113) for groups A and B, respectively. The median d rate was lower for group A than group B (0.03306 vs. 0.039965, respectively [p = 0.0002]). The median g rate was higher for group A than group B (0.00016 vs. 0.00002, respectively [p = 0.0014]). The g rate, but not the d rate discriminated PSA-PFS, rPFS, and OS. Conclusion: Our results suggest that GnRH agonist plus bicalutamide reduced PSA level faster and suppressed PSA rising longer than GnRH antagonist. Moreover, measuring the g rate can predict PSA-PFS, rPFS, and OS in patients with advanced CPSC treated with androgen deprivation therapy. These findings suggest that incorporating g rate measurements into clinical practice could improve prognostic accuracy and guide treatment decisions in advanced CSPC.

DOI： 10.1007/s00345-024-05316-3

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記述言語：英語   出版者・発行元：International Journal of Urology  

DOI： 10.1111/iju.15607

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Annals of Surgical Oncology  

DOI： 10.1245/s10434-024-16344-z

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記述言語：英語   出版者・発行元：Archives of Biochemistry and Biophysics  

Autophagy induction in cancer is involved in cancer progression and the acquisition of resistance to anticancer agents. Therefore, autophagy is considered a potential therapeutic target in cancer therapy. In this study, we found that long-chain fatty acids (LCFAs) have inhibitory effects on Atg4B, which is essential for autophagosome formation, through screening based on the pharmacophore of 21f, a recently developed Atg4B inhibitor. Among these fatty acids, docosahexaenoic acid (DHA), a polyunsaturated fatty acid, exhibited the most potent Atg4B inhibitory activity. DHA inhibited autophagy induced by androgen receptor signaling inhibitors (ARSI) in LNCaP and 22Rv1 prostate cancer cells and significantly increased apoptotic cell death. Furthermore, we investigated the effect of DHA on resistance to ARSI by establishing darolutamide-resistant prostate cancer 22Rv1 (22Rv1/Dar) cells, which had developed resistance to darolutamide, a novel ARSI. At baseline, 22Rv1/Dar cells showed a higher autophagy level than parental 22Rv1 cells. DHA significantly suppressed Dar-induced autophagy and sensitized 22Rv1/Dar cells by inducing apoptotic cell death through mitochondrial dysfunction. These results suggest that DHA supplementation may improve prostate cancer therapy with ARSI.

DOI： 10.1016/j.abb.2024.110135

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：The Prostate  

BACKGROUND: Proton pump inhibitors (PPIs) are widely used due to their affordability and minimal severe side effects. However, their influence on the efficacy of cancer treatments, particularly androgen receptor signaling inhibitors (ARSIs), remains unclear. This study investigates the impact of PPI usage on the treatment outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: A total of 117 mCRPC patients were retrospectively analyzed and divided into two groups based on the concomitant use of PPI at the initiation of ARSI treatment: PPI+ (n = 38) and PPI- (n = 79). Patient characteristics, including age at ARSI treatment administered, prostate-specific antigen (PSA) value at ARSI treatment administered, International Society of Urological Pathology grade group at prostate biopsy, metastatic site at ARSI treatment administered, prior docetaxel (DTX) treatment, and type of ARSI (abiraterone acetate or enzalutamide) were recorded. Progression-free survival (PFS), overall survival (OS), and PSA response rates were compared between the two groups. Patients were further stratified by clinical background to compare PFS and OS between the two groups. RESULTS: The PPI- group exhibited significantly extended PFS and a trend toward improved OS. For PSA response (reduction of 50% or more from baseline), the rates were 62.3% and 45.9% in the PPI- group and the PPI+ group, respectively. For deep PSA response (reductions of 90% or more from baseline), the rates were 36.4% and 24.3% in the PPI- group and the PPI+ group, respectively. The effects were consistent across subgroups divided by prior DTX treatment and type of ARSI administered. CONCLUSIONS: The administration of PPIs appears to diminish the therapeutic efficacy of ARSIs in mCRPC patients. Further prospective studies are needed to confirm these findings and explore the biological mechanisms involved.

DOI： 10.1002/pros.24769

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記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Annals of surgical oncology  

BACKGROUND: This study aimed to show the association between tumor location and laterality of positive lymph nodes by evaluating biopsy and magnetic resonance imaging (MRI) findings, and to optimize the extended pelvic lymph node dissection (ePLND) side for prostate cancer. METHODS: The study enrolled patients who underwent robot-assisted radical prostatectomy with ePLND. Tumor locations were determined according to International Society of Urological Pathology grade group 4/5 in biopsies and Prostate Imaging-Reporting and Data System category 4/5 in MRI results. The concordance of tumor location lobe and positive lymph node side with the performance of tumor location-guided ePLND for positive lymph node detection was evaluated. RESULTS: For 301 patients who underwent ePLND at Kyushu University Hospital, tumor locations determined by biopsy and MRI findings showed no lesion in 8 (2.7%) patients, unilateral lobe in 223 (74.1%) patients, and bilateral lobe in 70 (23.3%) patients. The accuracies for detection of any and all positive lymph nodes by tumor location-guided unilateral ePLND were 99.6% and 97.3%, respectively. Among the patients at St. Luke's International Hospital, the accuracies for detection of any and all positive lymph nodes by tumor location-guided unilateral ePLND were estimated to be 99.0% and 97.3%, respectively. CONCLUSIONS: This study proposed tumor location-guided ePLND according to biopsy and MRI findings. This novel strategy is expected to reduce the burden of bilateral ePLND at the cost of acceptable risk of failing to detect positive lymph nodes.

DOI： 10.1245/s10434-024-16294-6

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記述言語：英語   出版者・発行元：World Journal of Urology  

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

DOI： 10.1007/s00345-024-05240-6

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DOI： 10.1038/s44276-024-00093-3

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記述言語：英語   出版者・発行元：In Vivo  

Background/Aim: In patients with metastatic castration-sensitive prostate cancer (mCSPC), upfront treatment intensification with the addition of new hormonal agents and/or docetaxel to androgen deprivation therapy (ADT) is recommended. However, this modality is potentially excessive in a subset of these patients. This study aimed to identify patients who may be eligible to omit upfront treatment intensification. Patients and Methods: Patients with mCSPC who underwent ADT were enrolled. The association between undetectable prostate-specific antigen (PSA) (<0.2 ng/ml) after ADT initiation and overall or castration-resistance-free survival was evaluated. Results: Ninety-seven out of the 242 enrolled patients had low-risk and/or low-volume cancer and were further analyzed. Of these, 45 (46.4%) patients achieved undetectable PSA. The median follow-up period after ADT initiation was 70 months. The median overall survival among patients with undetectable PSA was quite long, reaching 226 months and significantly longer than that among patients with detectable PSA [71 months, hazard ratio (HR)=0.27, 95% confidence interval (CI)=0.15-0.49, p<0.001]. Time to development of

DOI： 10.21873/invivo.13698

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記述言語：英語   出版者・発行元：Oxford University Press  

記述言語：英語   出版者・発行元：Prostate  

DOI： 10.1002/pros.24784

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Free Radical Biology and Medicine  

Androgen receptor (AR)-targeting therapy induces oxidative stress in prostate cancer. However, the mechanism of oxidative stress induction by AR-targeting therapy remains unclear. This study investigated the mechanism of oxidative stress induction by AR-targeting therapy, with the aim to develop novel therapeutics targeting oxidative stress induced by AR-targeting therapy. Intracellular reactive oxygen species (ROS) was examined by fluorescence microscopy and flow cytometry analysis. The effects of silencing gene expression and small molecule inhibitors on gene expression and cytotoxic effects were examined by quantitative real-time PCR and cell proliferation assay. ROS induced by androgen depletion co-localized with peroxisomes in prostate cancer cells. Among peroxisome-related genes, PPARA was commonly induced by AR inhibition and involved in ROS production via PKC signaling. Inhibition of PPARα by specific siRNA and a small molecule inhibitor suppressed cell proliferation and increased cellular sensitivity to the antiandrogen enzalutamide in prostate cancer cells. This study revealed a novel pathway by which AR inhibition induced intracellular ROS mainly in peroxisomes through PPARα activation in prostate cancer. This pathway is a promising target for the development of novel therapeutics for prostate cancer in combination with AR-targeting therapy such as antiandrogen enzalutamide.

DOI： 10.1016/j.freeradbiomed.2024.05.030

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出版者・発行元：株式会社医学書院  

DOI： 10.11477/mf.1413208189

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Robotic Surgery  

Our objective was to investigate the long-term functional outcomes of robot-assisted partial nephrectomy (RAPN) combined with three-dimensional (3D) imaging. The 3D images, reconstructed using computed tomography, were introduced in RAPN procedures. The demographic, oncological, functional, and volumetric outcomes of 296 patients who underwent RAPN with and without 3D imaging between 2013 and 2021 were analyzed retrospectively. Propensity score matching (1:1) was performed to adjust for potential baseline confounders. After matching, 71 patients were allocated to each group. In the 3D RAPN (3DRPN) group, functional outcomes significantly improved: the number of patients with over 90% estimated glomerular filtration rate (eGFR) preservation rate (40 vs. 43, P = 0.044), eGFR preservation rate (88.0% vs. 91.6%, P = 0.006), the number of patients with chronic kidney disease (CKD) upstaging (26 vs. 13, P = 0.023), and split renal function preservation rate (operated kidney: 84.9% vs. 88.5%, P = 0.015). The 3DRPN group showed superiority in terms of >90% eGFR preservation (P = 0.010), CKD upstaging-free survival rates (P < 0.001), and volumetric outcomes (excess parenchymal volume: 27.9 vs. 17.7 mL, P = 0.030; parenchyma volume preservation rate: 81.6% vs. 88.8%, P = 0.006). Three-dimensional imaging was positively associated with eGFR preservation (P = 0.023, odds ratio: 2.34) and prevention of CKD upstaging (P = 0.013, odds ratio: 2.90). In this study, RAPN combined with 3D imaging underscored the preservation of eGFR > 90% and the prevention of CKD upstaging by improving the preservation rate of renal parenchyma and split renal function.

DOI： 10.1007/s11701-024-02070-x

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記述言語：英語   出版者・発行元：International Journal of Clinical Oncology  

In the last decade, the standard treatment for advanced renal cell carcinoma (RCC) has evolved, mainly driven by the development and approval of immune checkpoint inhibitors (ICIs). Currently, ICI monotherapy and ICI-based combinations with tyrosine kinase inhibitors and targeted therapies against mammalian target of rapamycin or vascular endothelial growth factor have become new standard treatments for first-line and subsequent-line therapies. ICIs play an important role as an adjuvant postoperative therapy, and this field is the subject of active research. Furthermore, ongoing randomized controlled trials are investigating the clinical value of more intense treatments by combining multiple effective treatments for RCC. Additionally, novel biomarkers for prognosis have been investigated. This study reviews the current evidence on immunotherapy as a treatment for RCC patients, randomized controlled trials, and ongoing studies including RCC patients and recent findings, and discusses future perspectives.

DOI： 10.1007/s10147-023-02446-3

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記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

出版者・発行元：株式会社医学書院  

DOI： 10.11477/mf.1413208183

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Clinical Oncology  

Background: The therapeutic role of pelvic lymph node dissection (PLND) during radical prostatectomy (RP) for prostate cancer is not established. In clinical practice, PLND is primarily performed in cases of high-risk prostate cancer. The detection of lymph node metastasis plays a crucial role in determining the need for subsequent treatments. This study aims to evaluate the prognosis of prostate cancer patients with lymph node involvement (LNI) by stratifying them based on postoperative prostate-specific antigen (PSA) levels to identify biomarkers that can guide postoperative treatment strategies. Methods: Analysis was conducted on 383 patients, selected from 572 initially eligible, who underwent RP with LNI across 33 Japanese Urological Oncology Group institutions from 2006 to 2019. Patients were grouped according to postoperative PSA levels and salvage treatments received. Follow-up focused on castration resistance-free survival (CRFS), metastasis-free survival (MFS), and overall survival (OS). Results: In the persistent PSA group (PSA ≥ 0.1 ng/mL), CRFS and MFS were significantly shorter compared to the non-persistent PSA group (PSA < 0.1 ng/mL), and there was a tendency for shorter OS. In the persistent PSA group, patients with postoperative PSA values above the median (PSA ≥ 0.52 ng/mL) showed shorter CRFS and MFS. Furthermore, in the PSA ≥ 0.52 group, androgen deprivation therapy (ADT) plus radiotherapy (RT) combination had prolonged CRFS and MFS compared with ADT alone. Conclusions: This study provides valuable insights into stratifying patients based on postoperative PSA levels to tailor postoperative treatment strategies, potentially improving the prognosis of prostate cancer patients with LNI.

DOI： 10.1007/s10147-024-02580-6

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記述言語：英語   出版者・発行元：Scientific Reports  

A multicenter study of nonmetastatic castration-resistant prostate cancer (nmCRPC) was conducted to identify the optimal cut-off value of prostate-specific antigen (PSA) doubling time (PSADT) that correlated with the prognosis in Japanese nmCRPC. Of the 515 patients diagnosed and treated for nmCRPC at 25 participating Japanese Urological Oncology Group centers, 450 patients with complete clinical information were included. The prognostic values of clinical factors were evaluated with respect to prostate specific antigen progression-free (PFS), cancer-specific survival (CSS), and overall survival (OS). The optimal cutoff value of PSADT was identified using survival tree analysis by Python. The Median PSA and PSADT at diagnosis of nmCRPC were 3.3 ng/ml, and 5.2 months, respectively. Patients treated with novel hormonal therapy (NHT) showed significantly longer PFS (HR: hazard ratio 0.38, p < 0.0001) and PFS2 (HR 0.45, p < 0.0001) than those treated with vintage nonsteroidal antiandrogen agent (Vintage). The survival tree identified 4.65 months as the most prognostic PSADT cutoff point. Among the clinical and pathological factors PSADT of < 4.65 months remained an independent prognostic factor for OS (HR 2.96, p = 0.0003) and CSS (HR 3.66, p < 0.0001). Current data represented optimal cut-off of PSADT 4.65 months for a Japanese nmCRPC.

DOI： 10.1038/s41598-024-65969-3

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記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japanese Journal of Clinical Oncology  

Background: In previous large-scale studies conducted through 2010, androgen deprivation therapy (ADT) was the most common initial treatment for prostate cancer patients in Japan. However, recent advancements in treatment technologies have significantly affected the management of prostate cancer in Japan. This study analyzed the trends in initial treatments for prostate cancer based on two nationwide surveys. Methods: Two Japan-wide multi-institutional surveys, J-CaP2010 and J-CaP2016, were conducted to enroll patients newly histologically diagnosed with prostate cancer in 2010 and 2016-18, respectively. Both surveys included age at diagnosis, initial PSA level, ISUP Grade Group, TNM classification, and initial treatment for prostate cancer. Results: J-CaP2010 included data from 8192 patients across 140 institutions, whereas J-CaP2016 included data from 21 841 patients across 186 institutions. In J-CaP2016, the proportion of radical prostatectomy (RP) and radiation therapy (RT) in the initial treatment increased (from 32% to 36% and 21% to 26%, respectively), whereas the proportion of ADT decreased (from 40% to 29%) compared with those in J-CaP2010. The increase in RP or RT was noticeable in patients aged 75 years and older (from 20% to 38%) and those with high-risk localized cancer (from 58% to 74%) or locally advanced cancer (from 38% to 56%). The proportion of active surveillance or watchful waiting increased in patients with low-risk localized cancer (from 21% to 41%). The proportion of robot-assisted RP within all RPs and the proportion of intensity-modulated RT within all RTs increased remarkably (from 2.3% to 78% and 20% to 50%, respectively). Conclusions: In Japan, RP and RT have increased as initial treatments for prostate cancer, whereas ADT has decreased. Consequently, RP has emerged as the most commonly selected initial treatment, replacing ADT.

DOI： 10.1093/jjco/hyae079

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記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：Annals of Surgical Oncology  

DOI： 10.1245/s10434-024-15088-0

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記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：Annals of Surgical Oncology  

Background: This study aimed to create a prognostic model to predict disease recurrence among patients with lymph node involvement but no prostate-specific antigen (PSA) persistence and to explore its clinical utility. Methods: The study analyzed patients with lymph node involvement after pelvic lymph node dissection with radical prostatectomy in whom no PSA persistence was observed between 2006 and 2019 at 33 institutions. Prognostic factors for recurrence-free survival (RFS) were analyzed by the Cox proportional hazards model. Results: Among 231 patients, 127 experienced disease recurrence. The factors prognostic for RFS were PSA level at diagnosis (≥ 20 vs. < 20 ng/mL: hazard ratio [HR], 1.66; 95% confidence interval [CI], 1.09–2.52; P = 0.017), International Society of Urological Pathology grade group at radical prostatectomy (RP) specimen (group ≥ 4 vs. ≤ 3: HR, 1.63; 95% CI 1.12–2.37; P = 0.010), pathologic T-stage (pT3b/4 vs. pT2/3a: HR, 1.70; 95% CI 1.20–2.42; P = 0.0031), and surgical margin status (positive vs. negative: HR, 1.60; 95% CI 1.13–2.28; P = 0.0086). The prognostic model using four parameters were associated with RFS and metastasis-free survival. Conclusion: The prognostic model in combination with postoperative PSA value and number of lymph nodes is clinically useful for discussing treatment choice with patients.

DOI： 10.1245/s10434-024-14999-2

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記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

AJCC/UICC TNM第8版で提案された前立腺癌における直径2mm以下のリンパ節微小転移(LN+)の有用性を、リンパ節最大腫瘍径(MTD)カットオフ値を用いて多施設共同後ろ向き研究で検討した。根治的前立腺摘除術(RP)および骨盤リンパ節郭清(PLND)後にLN+であった前立腺癌患者282例を、MTDカットオフ値2mm以下群(MTD以下群)76例(診断時年齢中央値68.0歳)と2mm超群(MTD超群)206例(同中央値68.0歳)に分け、無去勢抵抗性生存期間(CRFS)、無転移生存期間(MFS)、癌特異的生存期間(CSS)、全生存期間(OS)を比較した。MTD超群ではCRFSとMFSが有意に低下し、CSSとOSは不良であった。PLND数が14以上の場合、MTD以下群は去勢抵抗性前立腺癌を発症した患者はいなかった。多変量解析では、郭清リンパ節数、RP Gleasonパターン5、LN+におけるMTDがCRFSを有意に予測可能であった。RP後の直径2mm以下のリンパ節微小転移患者の予後は良好であった。

記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Immunology  

Immune checkpoint blockade therapies are widely used for cancer treatment, including advanced renal cell carcinoma (RCC). This study aimed to investigate the impact of zygosity in HLA genes and individual HLA genotypes on the efficacy of an anti-PD-1 Ab, nivolumab, in treating advanced RCC. Patient enrollment was conducted across 23 institutions in Japan from August 19, 2019, to September 30, 2020, with follow-up concluding on March 31, 2021. HLA genotype imputation of HLA-A, B, and C, DQB1, and DRB1 loci was performed. Among 222 patients, the presence of at least one homozygosity of the HLA-II allele significantly improved the best objective response (hazard ratio, 0.34; 95% confidence interval, 0.21-0.96; p 5 0.042). The HLA evolutionary divergence (HED) of the HLA-A and HLA-B loci was higher than the HLA-C (p < 0.0001 and p < 0.0001, respectively), with high HED of the HLA-B locus correlating to clinical benefits in nivolumab treatment (hazard ratio, 0.44; 95% confidence interval, 0.21-0.90; p 5 0.024) and improving cancer-specific survival compared with the low group (p 5 0.0202). Additionally, high HED of the HLA-B locus was correlated with the number of infiltrated CD8+ cells in the tumor microenvironment (correlation coefficient, 0.4042). These findings indicate that the diversity of the HLA-B locus plays a significant role in the anti-tumor effect of nivolumab treatment in advanced RCC, potentially offering insights for improved risk stratification in nivolumab treatment and leading to better medical management of advanced RCC. The Journal of Immunology, 2024, 213: 23-28.

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記述言語：英語  

DOI： 10.1038/s44276-024-00049-7

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記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Urology  

Objectives: Excellent anticancer effect for solid tumors with microsatellite instability (MSI)-high by anti-PD-1 antibody has been reported. In this study, we investigated the clinical impact of MSI status in bladder cancer. Methods: This study included 205 Japanese patients who underwent transurethral resection for bladder cancer between 2005 and 2021. The prevalence rates of microsatellite stable (MSS), MSI-low (MSI-L), and MSI-high (MSI-H) were determined using molecular testing. We examined the association of MSI status (MSS versus MSI-L/H) with clinicopathological characteristics and oncological outcomes. Results: MSI-L/H tumors were associated with higher T-category in non-muscle invasive bladder cancer (NMIBC). Additionally, MSI-L/H tumors were associated with a higher risk of intravesical recurrence in NMIBC patients treated with intravesical bacillus Calmette-Guérin (BCG) but not with non-BCG therapy. Conclusions: This study suggested that the MSI status might serve as a predictive marker for intravesical recurrence after BCG intravesical therapy in NMIBC and highlighted an unmet need for an alternative treatment in patients with MSI-L/H tumors.

DOI： 10.1111/iju.15370

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記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Urology  

Objectives: To compare the effectiveness and safety of gonadotropin-releasing hormone (GnRH) antagonist monotherapy to combined androgen blockade (CAB) with a GnRH agonist and bicalutamide in patients with advanced hormone-sensitive prostate cancer (HSPC). Methods: The study was conducted as KYUCOG-1401 trial (UMIN000014243) and enrolled 200 patients who were randomly assigned to either group A (GnRH antagonist monotherapy followed by the addition of bicalutamide) or group B (CAB by a GnRH agonist and bicalutamide). The primary endpoint was PSA progression-free survival. The secondary endpoints were the time to CAB treatment failure, radiographic progression-free survival, overall survival, changes in serum parameters, including PSA, hormones, and bone and lipid metabolic markers, and adverse events. Results: PSA progression-free survival was significantly longer in group B (hazard ratio [HR], 95% confidence interval [CI]; 1.40, 1.01–1.95, p = 0.041). The time to CAB treatment failure was slightly longer in group A (HR, 95% CI; 0.80, 0.59–1.08, p = 0.146). No significant differences were observed in radiographic progression-free survival or overall survival. The percentage of patients with serum testosterone that did not reach the castration level was higher at 60 weeks (p = 0.046) in group A. No significant differences were noted in the serum levels of bone metabolic or lipid markers between the two groups. An injection site reaction was more frequent in group A. Conclusions: The present results support the potential of CAB using a GnRH agonist and bicalutamide as a more effective treatment for advanced HSPC than GnRH antagonist monotherapy.

DOI： 10.1111/iju.15371

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記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Urology  

DOI： 10.1111/iju.15484

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Endocrine-Related Cancer  

Androgen receptor signaling is crucial for the development of treatment resistance in prostate cancer. Among steroidogenic enzymes, 3β-hydroxysteroid dehydrogenases (3βHSDs) play critical roles in extragonadal androgen synthesis, especially 3βHSD1. Increased expression of 3βHSDs is observed in castration-resistant prostate cancer tumors compared with primary prostate tumors, indicating their involvement in castration resistance. Recent studies link 3βHSD1 to resistance to androgen receptor signaling inhibitors. The regulation of 3βHSD1 expression involves various factors, including transcription factors, microenvironmental influences, and post-transcriptional modifications. Additionally, the clinical significance of HSD3B1 genotypes, particularly the rs1047303 variant has been extensively studied. The impact of HSD3B1 genotypes on treatment outcomes varies according to the therapy administered, suggesting the potential of HSD3B1 genotyping for personalized medicine. Targeting 3βHSDs may be a promising strategy for prostate cancer management. Overall, understanding the roles of 3βHSDs and their genetic variations may enable the development and optimization of novel treatments for prostate cancer.

DOI： 10.1530/ERC-24-0023

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記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：Anticancer Research  

Background/Aim: Obesity is correlated with an increased risk of developing malignancies, including prostate cancer. Adipocytokines, such as leptin and adiponectin, are a family of hormones derived from adipose tissue that are involved not only in metabolism, but also in the development and progression of various malignancies. However, little is known about their role in prostate cancer. This study aimed to determine how leptin, adiponectin, and their receptors impact the spread of prostate cancer. Materials and Methods: We first performed immunohistochemical analysis of prostate cancer tissue microarrays to detect leptin, leptin receptor (Ob-R), adiponectin, and adiponectin receptors 1 and 2 (AdipoR1 and AdipoR2). Wound healing assays and western blot analysis were then performed in human prostate cancer cell lines. Results: Immunohistochemistry showed that prostate tissue was not significantly positive for adiponectin. However, its expression tended to decrease according to the International Society of Urological Pathology (ISUP) grade of prostate cancer (p=0.056). In prostate cancer cell lines, administration of the synthetic adiponectin AdipoRon suppressed cell migration as well as the expression of phospho-NF-κB and cyclooxygenase-2, whereas leptin stimulated these effects. Conclusion: Adiponectin expression tended to be suppressed according to ISUP grade in prostate cancer tissues. In vitro, tumor cell migration was induced by leptin but suppressed by adiponectin. Targeting adipocytokines could be a novel treatment strategy for prostate cancer.

DOI： 10.21873/anticanres.16933

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記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Urology  

Background: Early detection of biochemical recurrence (BCR) after radical prostatectomy (RP) is crucial for early treatment and improving survival outcomes. The optimal prostate-specific antigen (PSA) monitoring remains unclear, and several models have been proposed. We aimed to externally validate four models for optimal PSA monitoring after RP and propose modifications to improve them. Methods: We reviewed the clinicopathological data of 896 patients who underwent robot-assisted RP between 2009 and 2022. We examined all PSA values and estimated the PSA value for four monitoring schedules at each time point in the virtual follow-up. We defined the ideal PSA for BCR detection between 0.2 and 0.4 ng/mL. Results: During the median follow-up of 21.4 months, 128 (14.3%) patients presented BCR. The original and modified Keio models, National Cancer Center Hospital model, and American Urological Association/American Society for Radiation Oncology model detected BCR in 14 (10.9%), three (2.3%), 12 (9.4%), and 11 (8.6%) patients with PSA >0.4 ng/mL. Most patients experienced BCR detected with PSA >0.4 ng/mL during the first year postoperative. The modification of interval within 6 months postoperative avoided BCR detection with PSA >0.4 ng/mL within the first year postoperative in 8/9 (88.9%), 1/2 (50.0%), 5/6 (83.3%), and 4/4 (100%) for the original and modified Keio models, National Cancer Center Hospital model, and American Urological Association/American Society for Radiation Oncology model, respectively. Conclusion: We validated four models for PSA monitoring after RP to detect BCR and suggested modifications to avoid detections out of the desired range of PSA. These modifications could help to establish an optimal PSA monitoring schedule after RP.

DOI： 10.1111/iju.15379

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記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

進行性ホルモン感受性前立腺癌(HSPC)に対するゴナドトロピン放出ホルモン(GnRH)アンタゴニスト単独療法と、GnRHアゴニストとビカルタミド併用による複合アンドロゲン遮断療法(CAB)の有効性と安全性を、無作為化非盲検多施設共同試験(KYUCOG-1401試験)で比較した。患者200例を登録し、A群(GnRHアンタゴニスト単独療法後にビカルタミドを追加)またはB群(GnRHアゴニストとビカルタミド併用によるCAB)に無作為化した。A群100例、B群98例を解析した。主要評価項目の前立腺特異抗原(PSA)無増悪生存期間(PFS)はB群で有意に長かった(ハザード比:1.40、95%CI:1.01～1.95、p=0.041)。副次評価項目のCAB治療不成功までの期間はA群の方がわずかに長かった(ハザード比:0.80、95%CI:0.59～1.08、p=0.146)。X線画像上のPFSおよび全生存期間に有意な群間差は認められなかった。60週時に血清テストステロン値が去勢レベルに達しなかった患者の割合はA群の方が高かった(p=0.046)。血清骨代謝マーカー値や脂質マーカー値に有意な群間差はなかった。注射部位反応の発生率はA群の方が高かった。以上より、進行性HSPCに対するGnRHアゴニストとビカルタミドを併用したCABは、GnRHアンタゴニスト単独療法よりも有効な治療法である可能性が示唆された。

記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

手術室と遠隔地にそれぞれ触覚フィードバック付きの術者用コンソールを設置し、遠隔手術における触覚フィードバックの有用性を検証し、さらに遠隔ロボット手術の安全性向上を目的として、動物実験を行った。術者用コンソールは福岡市と別府市の手術室に設置し、3段階の触覚フィードバックレベルをランダム順に設定した。術者(現地5名、遠隔地5名)を盲検化し、各触覚レベルでロボット鉗子によりブタの腸を把持する、持ち上げる、下げる、離すという一連の動作を10回繰り返してもらった。その結果、課題の精度や平均把持力には、術者の場所による顕著な差は見られなかった。しかし、遠隔地の場合は現地よりも平均課題完了時間が有意に長く、system usability scaleが有意に低かった。触覚フィードバックレベル間で、課題の精度や課題完了時間に顕著な差はなかったが、触覚フィードバックがある場合はない場合よりも有意に弱い力で臓器を把持することができた。さらに、触覚フィードバックがある場合、ロボット手術の経験が豊富な外科医は、経験の浅い外科医よりも弱い把持力で同等のタスクを行う傾向があった。

記述言語：英語   出版者・発行元：Surgery Today  

Purpose: To verify the usefulness of haptic feedback in telesurgery and improve the safety of telerobotic surgery. Methods: The surgeon's console was installed at two sites (Fukuoka and Beppu; 140 km apart), and the patient cart was installed in Fukuoka. During the experiment, the surgeon was blinded to the haptic feedback levels and asked to grasp the intestinal tract in an animal model. The surgeon then performed the tasks at each location. Results: No marked differences in task accuracy or average grasping force were observed between the surgeon locations. However, the average task completion time was significantly longer, and the system usability scale (SUS) was significantly lower rating for remote operations than for local ones. No marked differences in task accuracy or task completion time were observed between the haptic feedback levels. However, with haptic feedback, the organ was grasped with a significantly weaker force than that without it. Furthermore, with haptic feedback, experienced surgeons in robotic surgery tended to perform an equivalent task with weaker grasping forces than inexperienced surgeons. Conclusion: The haptic feedback function is a tool that allows the surgeon to perform surgery with an appropriate grasping force, both on site and remotely. Improved safety is necessary in telesurgery; haptic feedback will thus be an essential technology in robotic telesurgery going forward.

DOI： 10.1007/s00595-023-02732-7

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記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

マイクロサテライト不安定性(MSI)の状態が膀胱癌に及ぼす臨床的影響を検討した。2005～2021年に膀胱癌に対し経尿道的切除術を受けた日本人患者を対象とした。分子検査でマイクロサテライト安定型(MSS)、低頻度MSI(MSI-L)、および高頻度MSI(MSI-H)を判定し、MSIの状態(MSS対MSI-LおよびMSI-H)と臨床病理学的特徴および腫瘍学的転帰との関連を調べた。患者205例[筋層非浸潤性膀胱癌(NMIBC)145例、筋層浸潤性膀胱癌(MIBC)60例]を解析した。18例でMSI-L/Hを認め、127例はMSSであった。NMIBCにおいて、MSI-L/H腫瘍はT分類の進行度と関連した。また、カルメット・ゲラン桿菌(BCG)膀胱内投与による治療を受けたNMIBC患者において、MSI-L/H腫瘍は膀胱内再発リスクの高さと関連したが、BCG治療を受けなかったNMIBC患者でその関連は認められなかった。以上より、NMIBCではMSIの状態がBCG膀胱内療法後の膀胱内再発の予測マーカーとなる可能性が示唆された。

記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

根治的前立腺摘除術(RP)後に行う前立腺特異抗原(PSA)モニタリングの4つのモデルの妥当性を検証し、生化学的再発(BCR)検出を改善する修正モデルを検討した。2009～2022年にロボット支援RPを受けた患者の臨床病理学的データを調べ、4つのモデルで仮想上経過観察時のPSA値を推定した。BCR検出に最適なPSA値は0.2～0.4ng/mLと定義した。患者896例(年齢中央値66歳)を解析した。追跡期間中央値21.4ヵ月の間に128例(14.3%)がBCRを認めた。BCRが検出されたPSA値0.4ng/mL超の患者は、慶應モデル、修正慶應モデル、国立がん研究センター中央病院(NCCH)モデル、および米国泌尿器科学会(AUA)/米国放射線腫瘍学会(ASTRO)モデルでそれぞれ14例(10.9%)、3例(2.3%)、12例(9.4%)、および11例(8.6%)であった。殆どの患者は、術後1年目にPSA値0.4ng/mL超でBCRが検出された。術後6ヵ月以内の間隔に変更すると、術後1年以内のPSA>0.4ng/mLのBCR検出は上記のモデルそれぞれで8/9例(88.9%)、1/2例(50.0%)、5/6(83.3%)、4/4例(100%)で回避された。以上より、RP後のBCR検出のためのPSAモニタリングを最適にするための修正案が示唆された。

記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Urology  

DOI： 10.1111/iju.15449

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記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：Clinical Genitourinary Cancer  

Introduction: Recently, many agents and combinations for metastatic and advanced renal cell carcinoma have been approved. This study aims to highlight the comprehensive differences in adverse events (AEs) between cabozantinib (CAB) plus nivolumab (NIVO) and ipilimumab (IPI) plus NIVO based on a real-world big dataset. Material and Methods: We downloaded AE datasets of IPI + NIVO and CAB + NIVO from the Food and Drug Administration Adverse Event Reporting System database. We used the Medical Dictionary for Regulatory Activities to treat each AE as a preferred term and grouped it into the System Organ Class (SOC). We performed logistic regression analyses to compare IPI + NIVO and CAB + NIVO. Results: The incidence rates of 7 types of toxicities were higher for CAB + NIVO than for IPI + NIVO. On the other hand, the incidence rates of 3 types of toxicities were higher for IPI + NIVO than for CAB + NIVO. Serious AEs were higher in patients receiving IPI + NIVO. Conclusion: Our findings suggest that both combination therapies presented a disproportionate distribution of toxicities in several SOC. These findings may help clinicians select suitable therapy for the individual and improve the safety profile in patients with advanced renal cell carcinoma receiving NIVO + IPI and NIVO + CAB in a real-world setting.

DOI： 10.1016/j.clgc.2023.09.003

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記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：Clinical and Translational Discovery  

DOI： 10.1002/ctd2.264

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記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：Prostate Cancer and Prostatic Diseases  

Background: Immune editing, in which human leukocyte antigens (HLA) have critical roles, has been suggested to shape the landscape of human cancer. This study prospectively investigated whether HLA gene zygosity is associated with the prognosis of primary androgen deprivation therapy in advanced prostate cancer. Methods: KYUCOG-1401-A was conducted in conjunction with a prospective clinical trial (KYUCOG-1401). Among the patients enrolled in KYUCOG-1401 and treated with primary androgen deprivation therapy, only Japanese patients were included. HLA genotypes of HLA-A, B, C, DRB1, DQB1, and DPB1 were determined. The effect of divergence of HLA genotypes on time to progression, prostate cancer-specific survival, and overall survival was evaluated. Results: Among 127 patients, homozygosity for HLA-DRB1 (HR, 95% CI; 4.05, 1.54–10.7, P = 0.0047) and HLA-DQB1 (HR, 95% CI; 3.75, 1.47–9.58, P = 0.0058) was associated with an increased risk of prostate cancer-specific mortality. Patients with higher HLA evolutionary divergence scores at HLA-DQB1 (HR, 95% CI; 0.90, 0.82–0.97, P = 0.0093) had lower risks of prostate cancer-specific mortality. Androgen-responsive gene sets were upregulated in CD4low and CD8low tumors in the prostate cancer cohort, but not in the bladder and kidney cancer cohorts. Conclusions: This study suggested that the diversity of HLA-II loci including HLA-DRB1 and HLA-DQB1 plays an important role in advanced prostate cancer survival, contributing to improved risk stratification in advanced prostate cancer. Moreover, it was shown that CD4+ T cells play an important role in androgen deprivation therapy, suggesting that immunotherapy targeting CD4+ T cells is promising for prostate cancer.

DOI： 10.1038/s41391-024-00808-0

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記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Urology  

Objectives: The American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) 8th edition has proposed micrometastasis as a lymph node metastasis (LN+) of diameter ≤2 mm in prostate cancer. However, supporting evidence has not described. We evaluated LN+ patients' survival after radical prostatectomy (RP) based on the LN maximum tumor diameter (MTD). Methods: Data from 561 LN+ patients after RP and pelvic LN dissection (PLND) treated between 2006 and 2019 at 33 institutions were retrospectively investigated. Patients were stratified by a LN+ MTD cutoff of 2 mm. Outcomes included castration resistance-free survival (CRFS), metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS). Results: In total, 282 patients were divided into two groups (LN+ MTD >2 mm [n = 206] and ≤2 mm [n = 76]). Patients of LN+ status >2 mm exhibited significantly decreased CRFS and MFS, and poorer CSS and OS. No patients developed CRPC in the LN+ status ≤2 mm group when the PLND number was ≥14. Multivariate analysis showed the number of LN removed, RP Gleason pattern 5, and MTD in LN+ significantly predicted CRFS. Conclusions: Patients of LN+ status ≤2 mm showed better prognoses after RP. In all the patients in the ≤2-mm group, the progression to CRPC could be prevented with appropriate interventions, particularly when PLND is performed accurately. Our findings support the utility of the pN substaging proposed by the AJCC/UICC 8th edition; this will facilitate precision medicine for patients with advanced prostate cancer.

DOI： 10.1111/iju.15434

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記述言語：英語   出版者・発行元：Oxford University Press  

去勢抵抗性前立腺癌(CRPC)の日本人患者に対し、実臨床で行われた網羅的ゲノムプロファイル検査の結果を後ろ向きに解析した。2021～2022年に単一施設においてCRPCの日本人成人患者57名で行われた上記検査例60件(年齢中央値74歳)を解析対象とした。検査システムには、FoundationOne CDx、FoundationOne Liquid CDx、Guardant360 CDx、OncoGuide NCCオンコパネルシステム、の4種が使用されていた。全検査例のうち、CRPCが転移性のものであった例は57件(95%)に上った。検出された遺伝子変化のうち、アンドロゲン受容体の遺伝子変化は最も多く17件(28.3%)に上り、以下順に、TP53変異が15件(25.0%)、CDK12変異が14件(23.3%)、phosphatase and tensin homolog(PTEN)変異が10件(16.7%)、ATM変異が9件(15.0%)、となった。治療標的となる遺伝子変異は15件で見つかり、うち13件(全検査例の21.7%)の患者は本検査結果に従って全身化学療法を受けていた。この全身化学療法群の全生存率は、同療法が新たに行われなかった残り47件の患者よりも有意に高かった(P=0.041)。

記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：Asian Journal of Endoscopic Surgery  

Purpose: This study presents the surgical and oncological outcomes of salvage robot-assisted radical prostatectomy (RARP) after carbon ion radiotherapy at a single institution. Methods: Patients who underwent salvage RARP for local recurrence after carbon ion radiotherapy at Kyushu University Hospital between 2020 and 2023 were included. A single surgeon performed salvage RARP with extended pelvic lymph node dissection. Clinicopathological characteristics and perioperative and postoperative outcomes were prospectively collected and electronically recorded. Results: Ten cases were included. The preoperative clinical T-stage was T2, except for one case with T3a. The median console time was 171 min (range, 135–226 min). No severe perioperative or postoperative complications were noted. The pathological T-stage was T2, T3a, and T3b in four, four, and two cases, respectively. Biochemical recurrence was observed in one patient at 31.2 months after surgery. For patients with more than 1 year of follow-up, urinary continence recovery with ≤1 pad was achieved in two cases within 1 year, whereas four cases did not recover urinary continence within 1 year. Conclusions: This case series demonstrated the feasibility of salvage RARP after carbon ion radiotherapy. Although the urinary continence recovery was modest, short-term disease control was favorable.

DOI： 10.1111/ases.13279

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記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

記述言語：日本語   出版者・発行元：一般社団法人 日本泌尿器内視鏡・ロボティクス学会  

<p>　腹腔鏡手術あるいはロボット支援手術では, 一般的に炭酸ガスを用いた気腹を行い手術が行われるが, 合併症として炭酸ガス塞栓に注意が必要である. 肺炭酸ガス塞栓をきたしても症候性となるものは稀である一方, 症候性となったものは高い致死率を示すとする報告もある. 術中に呼気終末二酸化炭素分圧 (EtCO₂) の急激な低下, 経皮的動脈血酸素飽和度 (SpO₂) の低下がみられた場合は肺炭酸ガス塞栓を疑う. その場合, 速やかに気腹の中断あるいは減圧を行い, 純酸素を投与し, 同時にガス流入部である血管損傷部を閉鎖することが重要である. 今回, 我々は肺ガス塞栓に続き脳内にガス塞栓をきたした脳ガス塞栓の症例を経験した. 腎の腹腔鏡あるいはロボット支援手術において脳ガス塞栓をきたした症例の報告は我々の知る限りこれまで6例のみであり, うち2例は死亡に至っている. 脳ガス塞栓に対して高圧酸素療法が有効との報告もあるが, 発症すると重篤であるため, まずガス塞栓を発生させないことが重要である. そのため, 気腹圧を上げすぎないこと, 症例によっては腎静脈クランプを併用すること, 脈管はできるだけクリップ等により処理し開放した場合は速やかに縫合を行うことなどが重要と考えられた.</p>

DOI： 10.11302/jserjje.37.2_290

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記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Urology  

DOI： 10.1111/iju.15273

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記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

転移性去勢感受性前立腺癌(mCSPC)の根治的放射線療法(RT)が癌特異的生存率(CSS)を向上させるかを転移およびリスク群別に検討した。日本泌尿器腫瘍グループ(JUOG)のde novo mCSPCデータベースから患者を抽出した。患者を疾患負荷(低負荷:領域外リンパ節転移または骨転移4ヶ所未満、内臓転移なし、高負荷:骨転移4ヶ所以上または内臓転移あり)とリスク(危険因子0、1、2～3個はそれぞれ低、中、高リスク)により分類した。カプランマイヤー法を用いて、3年全死亡率および3年CSSを算出した。患者1981例[低負荷746例(低、中、高リスク群それぞれ231例、330例、185例)、高負荷1235例(同リスク群それぞれ369例、705例、401例)]を解析した。全患者のうち240例が根治的RTを受けた。3年後の推定全死亡率が40%未満の場合、RT群の3年CSSはより良好であった。低負荷の患者では、どのリスク群でも3年CSSは非RT群よりRT群の方が良好であった。高負荷の患者では、低リスク群と中リスク群において3年CSSはRT群の方が良好で、高リスク群の場合はRT群の方が不良であった。以上より、疾患負荷とリスクが高い患者または3年全死亡率が40%超の患者を除いて、前立腺への根治的RTはCSSを高める可能性があることが示唆された。

DOI： 10.1016/j.annonc.2023.10.386

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記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

二塩化ラジウム223(Ra-223)で治療した骨転移した去勢抵抗性前立腺癌(CRPC)患者の症候性骨関連事象(SSE)に対する骨修飾薬(BMA)の効果について検討した。2016年6月～2018年12月に日本の10施設でRa-223治療を受けた20歳以上の患者を後ろ向きに調べた。SSEは骨痛緩和目的の外部照射、新たな症候性病的骨折、脊髄圧迫、または腫瘍関連の整形外科的介入と定義した。最初のSSEまでの時間をカプランマイヤー法で推定し、ログランク検定で群間比較した。単変量解析で変数とSSEとの関連を確認した。患者73例を解析した。追跡期間(中央値12.7ヵ月)中12例(16.4%)でSSEが発現した。SSEが発現した群は発現しなかった群より年齢が若く(68歳対74歳、p=0.01)、BMAの使用率が高かった(65%対25%、p=0.009)。Ra-223治療開始からの1年無SSE生存率は82.4%(95%CI 69.4%～90.2%)であった。BMAの使用は無SSE生存率の高さと関連した(ハザードリスク0.23、95%CI 0.061～0.85、p=0.027)。BMA使用群の2例(4.7%)、非使用群7例(23.3%)で症候性病的骨折が発現した(p=0.017)。以上より、Ra-223で治療した骨転移したCRPC患者におけるBMAの有用性が示唆された。

記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japanese Journal of Clinical Oncology  

Abstract

Objective

Comprehensive genomic profiling testing using a hybrid-capture next-generation sequencing is commonly used in clinical practice to employ precision medicine in cancer treatment worldwide. In this study, we aimed to analyze the profiles obtained using comprehensive genomic profiling testing that was performed in Japanese castration-resistant prostate cancer patients and to discuss the genetic findings in a real-world setting.

Methods

A total of 60 cases and 57 castration-resistant prostate cancer patients underwent comprehensive genomic profiling testing between 1 January 2021 and 31 December 2022. Four types of comprehensive genomic profiling testing were selected, and clinically significant cancer-specific gene alterations were identified.

Results

The median age of patients was 74 years, and the median prostate-specific antigen value at the time of submission was 18.6 ng/ml. Fifty-seven (95%) of 60 cases were metastatic castration-resistant prostate cancers, and 3 cases (5%) were non-metastatic. Among all genetic alterations, androgen-receptor alteration was the most frequently detected in 17 cases (28.3%), followed by 15 cases of TP53 (25.0%), 14 cases of CDK12 (23.3%), 10 cases of phosphatase and tensin homolog (16.7%) and 9 cases of ATM (15.0%) mutations. A total of 13 patients (21.7%) received systemic therapy according to the comprehensive genomic profiling testing results. Overall, the survival rate was significantly greater in the group treated through systemic therapy based on comprehensive genomic profiling testing compared with the group without new therapeutic treatment (P = 0.041).

Conclusions

Comprehensive genomic profiling testing is recommended in castration-resistant prostate cancer patients identified as resistant to standard therapy as this can provide a new therapeutic option.

DOI： 10.1093/jjco/hyad148

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記述言語：英語   出版者・発行元：(一社)日本癌治療学会  

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記述言語：英語   出版者・発行元：(一社)日本癌治療学会  

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記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Urology  

Background: This study is part of the SNPs in Nivolumab PD-1 inhibitor for RCC (SNiP-RCC). Here we aimed to reveal clinical factors for tumor response, progression, and survival in nivolumab for advanced clear cell renal cell carcinoma (RCC) in Japanese patients. Methods: We included patients from 23 institutions in Japan. We evaluated the objective response, radiographic progression-free survival (PFS), overall survival (OS), and treatment-related grade ≥ 3 (serious adverse events [SAEs]). Results: We included 222 patients. The median age was 69 years (interquartile range 62–74 years), and 71% of the patients were male. Pancreas metastasis, lung metastases, prior cytokine therapy, and SAEs, were associated with objective response. The median PFS was 18 months. Liver metastases (hazard ratio [HR], 1.61), age ≥ 75 (HR, 0.48), previous resection of primary sites (HR, 0.47), and SAEs (HR, 0.47) were independent prognostic factors for PFS. Karnofsky Performance Status <70 (HR, 2.90), high platelets (HR, 4.48), previous resection of primary sites (HR, 0.23), and pathological grade (HR, 0.19 for grade 2 and HR, 0.12 for grade 3) were independent prognostic factors for OS. SAEs were reported in 45 (20.3%) cases. In the group of patients with prior nephrectomy, SAEs were associated with objective response, PFS, and OS. Conclusion: The SNiP-RCC study identified clinical parameters correlated with treatment outcomes in Japanese patients with priorly treated advanced clear cell RCC undergoing nivolumab monotherapy.

DOI： 10.1111/iju.15265

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記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：Anticancer Research  

Background/Aim: Testosterone is essential for prostate cancer development and growth. This study aimed to investigate the relationship between testosterone in seminal vesicles and prostate cancer incidence and its malignant phenotype. Patients and Methods: After obtaining institutional review board approval, seminal vesicle fluid samples were collected from patients who underwent prostatectomy or cystectomy. Pathological review demonstrated that 26 patients had benign prostate tissue and 149 had prostate cancer. First, testosterone levels in seminal vesicle fluid from benign prostate and prostate cancer samples were compared. Next, the relationship between pathological stage, International Society of Urological Pathology (ISUP) score, and testosterone concentrations in seminal vesicle fluid in the prostate cancer group were examined. Results: Testosterone in seminal vesicles was significantly higher in the prostate cancer group [median (range), 1.94 (0.17-4.32) ng/ml] than in the benign prostate group (mainly bladder cancer) [1.45 (0.60-2.78) ng/ml] (p=0.001). Testosterone in seminal vesicles showed no difference in relation to pathological stage (pT2 vs. pT3) or ISUP score (12 vs. 345) (p=0.480 and p=0.964, respectively). Neoadjuvant chemotherapy for other cancers (e.g., bladder or rectal cancer) significantly reduced testosterone in seminal vesicles (p=0.013). Multivariate regression analysis revealed that testosterone in seminal vesicles was significantly correlated with prostate cancer, and not with neoadjuvant chemotherapy (p=0.023, p=0.457, respectively). Conclusion: Testosterone in seminal vesicles may contribute to prostate cancer incidence, but has no relationship with pathological grading.

DOI： 10.21873/anticanres.16618

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記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

SNPs in Nivolumab PD-1 inhibitor for RCC(SNiP-RCC)研究の一環として、進行淡明細胞型腎細胞癌の日本人患者へニボルマブ治療を行った時の腫瘍反応、進行、生存性に関わる臨床因子を明らかにした。国内23施設で患者222名(男性71%、年齢中央値69歳)を組み入れた。客観的反応と関連していた因子としては、膵転移、肺転移、サイトカイン療法の既治療歴、重篤な有害事象(SAE)が同定された。放射線学的無増悪生存期間(PFS)の中央値は18ヵ月であり、PFSの独立予後因子は肝転移、75歳以上、原発巣切除の既往、SAEであった。全生存期間(OS)の独立予後因子は、Karnofskyパフォーマンスステータスが70未満、血小板数の高値、原発巣切除の既往、病理学的グレード2とグレード3、であった。SAEは45名(20.3%)で報告された。腎切除術の既往がある患者の群では、SAEは客観的反応、PFS、OSと関連していた。

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Robotic Surgery  

The novel technique of lateral pelvic fascia preservation (LPFP) in robot-assisted radical prostatectomy (RARP) has been reported to improve urinary continence recovery. We aimed to investigate surgical and oncological outcomes after RARP using the LPFP technique and compare them with conventional RARP. This study included patients who underwent RARP with and without the LPFP technique. Time to urinary continence recovery was compared between the LPFP and non-LPFP groups using univariate, multivariate, and propensity-score matched analysis. Perioperative and postoperative outcomes were compared between the two groups using univariate analysis. We included 139 patients who underwent RARP, 68 in the LPFP group and 71 in the non-LPFP group. The LPFP technique was associated with a shorter time to urinary continence recovery, a shorter operative time and lower estimated blood loss. Surgical and oncological outcomes, including complications, pathological T-stage, surgical margin status, and biochemical recurrence-free survival, were comparable between the two groups. This study demonstrated that the LPFP technique improves urinary continence recovery and operative times without compromising surgical and oncological outcomes. The use of this technique in patients with clinically localized prostate cancer is recommended.

DOI： 10.1007/s11701-023-01702-y

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記述言語：日本語  

記述言語：日本語   出版者・発行元：医学図書出版(株)  

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記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：Urology Practice  

Introduction:This study aimed to highlight the comprehensive differences in adverse events between abiraterone and enzalutamide based on a big data data set.Methods:We downloaded adverse event data sets of abiraterone and enzalutamide from the Food and Drug Administration Adverse Event Reporting System database. We used the Medical Dictionary for Regulatory Activities to treat each adverse event as a preferred term and grouped it into the System Organ Class. Logistic regression analyses were performed to compare abiraterone and enzalutamide.Results:In total, we extracted 59,680 data sets. After exclusion by criteria, we included 26,015 reports on enzalutamide and 7,507 on abiraterone. Enzalutamide and abiraterone presented different toxicity profiles in most System Organ Classes. Overall, the reporting odds ratio indicated a higher incidence rate of serious adverse events for abiraterone than enzalutamide.Conclusions:In conclusion, our findings suggest that both drugs present a discrete and nonoverlapping toxicity profile that varies by System Organ Class and patient age. This data set confirms, for the most part, what has been reported in clinical trials as well as true real-world reports.

DOI： 10.1097/UPJ.0000000000000404

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記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Urology  

Introduction

Radium‐223 (Ra‐223) dichloride therapy increases overall survival and delays time to the first symptomatic skeletal event (SSE) in patients with castration‐resistant prostate cancer (CRPC) and bone metastases. Bone‐modifying agents (BMA) reduce SSE in patients with bone metastasis, but there is little information on their use with Ra‐223. This study aimed to investigate the effect of BMA on SSE in patients with bone metastatic CRPC treated with Ra‐223 in real‐world practice.

Methods

We included 73 patients treated with Ra‐223 from 10 institutions in Japan. Time to the first SSE was estimated using the Kaplan–Meier method and compared between groups using the log‐rank test. We used univariate analysis to ascertain the association between variables and SSE.

Results

During a median follow‐up of 12.7 months (interquartile range, 7–21.7), 12 (16.4%) patients presented SSE. Age and BMA use were different between men with and without SSE. The 1‐year SSE‐free survival rate from Ra‐223 treatment initiation was 82.4% (95% CI, 69.4%–90.2%). BMA use was associated with favorable SSE‐free survival (hazard risk, 0.23; 95% confidence interval, 0.061–0.85; p = 0.027). Two (4.7%) and seven (23.3%) patients presented symptomatic pathological bone fracture in groups with and without BMA use, respectively (p = 0.017).

Conclusion

This study stresses the importance of BMA use in patients with CRPC and bone metastases in Ra‐223 treatment.

DOI： 10.1111/iju.15259

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記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Urology  

Objective: The precise diagnosis of prostate cancer (PC) is crucial to avoid underdiagnosis, overdiagnosis, and overtreatment. We aimed to compare clinically significant PC (csPC) detection between MRI/ultrasound fusion-targeted prostate (TBx) compared to systematic biopsy (SBx) in biopsy-naïve Japanese men. Methods: We included patients with suspect PC due to elevated PSA level or abnormal digital rectal examination, or both. csPC was defined as International Society Urological Pathology (ISUP) grade group ≥2 (csPC-A) and ISUP grade group ≥3 (csPC-B). Results: This study included 143 patients. Overall PC detection was 66.4% for SBx and 67.8% for MRI-TBx. MRI-TBx presented a significantly higher rate of csPC detection (csPC-A 67.1% vs. 58.7%, p = 0.04, and csPC-B 49.6% vs. 39.9%, p < 0.001) and significantly lower detection of non-csPC-A (0.6% vs. 6.7%). Importantly, MRI-TBx missed 4.9% (7/143) of csPC-A and only 0.7% (1/143) of csPC-B. On the other hand, SBx alone missed 13.3% (19/143) of csPC-A and 4.2% (6/143) of csPC-B. Conclusion: MRI-TBx significantly outperformed 12-cores SBx for csPC detection and decreased non-csPC detection in biopsy-naive men. Performing MRI-TBx without SBx would have missed some csPC, supporting that MRI-TBx synergizes with SBx to increase csPC detection.

DOI： 10.1111/iju.15188

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Drug Resistance Updates  

This study investigated cellular mechanisms in steroidogenesis responsible for treatment resistance to the novel antiandrogen agent darolutamide in prostate cancer. HSD3B1 was overexpressed in darolutamide-resistant cells and induced by darolutamide treatment and AR knockdown. Inversely, HSD3B1 knockdown increased cellular sensitivity to darolutamide. Similarly, its upstream regulator NR5A2 was up-regulated in darolutamide-resistant cells and induced by darolutamide treatment and AR knockdown. Inversely, NR5A2 knockdown and NR5A2 inhibitor ML180 decreased expression of various steroidogenic enzymes including HSD3B1, leading to increased cellular sensitivity to darolutamide. The NR5A2/HSD3B1 pathway promoted cellular resistance to darolutamide and targeting NR5A2/HSD3B1 pathway is a promising therapeutic strategy to overcome darolutamide resistance.

DOI： 10.1016/j.drup.2023.100990

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記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

前立腺癌(PC)が疑われる生検歴のない日本人男性において、MRI-超音波融合標的前立腺生検(TBx)と系統生検(SBx)を用いて、臨床的に重大なPC(csPC)の検出率を比較した。2020～2022年に日本の単一施設でPC疑いのためにMRI-TBx+SBxを行った143例(中央値70歳)を対象とするコホート研究を行った。csPCの定義は、国際泌尿器病理学会(ISUP)グレード群2以上(csPC-A)およびISUPグレード群3以上(csPC-B)とした。全PC検出率は、SBxで66.4%、MRI-TBxで67.8%であった。MRI-TBxはSBxに比べてcsPC検出率が有意に高く(csPC-Aは67.1 vs 58.7%、csPC-Bは49.6 vs 39.9%)、非csPC-A検出率が有意に低かった(0.6 vs 6.7%)。MRI-TBxの見逃し率はcsPC-Aは4.9%(7/143例)、csPC-Bは0.7%(1/143例)であったが、SBxではそれぞれ13.3%(19/143例)、4.2%(6/143例)であった。

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cancer Immunology, Immunotherapy  

Background: Anti-PD-1 antibodies are widely used for cancer treatment including advanced renal cell carcinoma (RCC). However, their therapeutic and adverse effects vary among patients. This study aimed to identify genetic markers that predict outcome after nivolumab anti-PD-1 antibody treatment for advanced RCC. Methods: This study was registered on the website of the University Hospital Medical Information Network (protocol ID, UMIN000037739). Patient enrollment was conducted at 23 institutions in Japan between August 19, 2019, and September 30, 2020. Patient follow-up ended on March 31, 2021. Patients were treated with nivolumab for advanced clear cell RCC. A genome-wide association study was performed in the development set, while genotyping of target regions in the validation set was undertaken. Single nucleotide polymorphisms (SNPs) in genes of interest CD274, PDCD1LG2 and PDCD1 were genotyped in the combined set. The primary endpoint was the association of SNPs with objective response following nivolumab treatment. As secondary endpoints, the associations of SNPs with radiographic progression-free survival (rPFS) and treatment-related grade ≥ 3 adverse events (AEs) were evaluated. Results: A genome-wide association study followed by a validation study identified that SNPs in FARP1 (rs643896 and rs685736) were associated with objective response and rPFS but not AEs following nivolumab treatment. Furthermore, SNPs in PDCD1LG2 (rs822339 and rs1411262) were associated with objective response, rPFS, and AEs following nivolumab treatment. Genetic risk category determined according to the number of risk alleles in SNPs (rs643896 in FARP1 and rs4527932 in PDCD1LG2) excellently predicted objective response and rPFS in nivolumab treatment. Conclusion: This study revealed that SNPs in FARP1 and PDCD1LG2 were correlated with outcome in nivolumab treatment. The use of these SNPs may be beneficial in selecting appropriate treatment for individual patients and may contribute to personalized medicine.

DOI： 10.1007/s00262-023-03367-w

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記述言語：英語   出版者・発行元：Surgical Endoscopy  

Background: Although several studies on telesurgery have been reported globally, a clinically applicable technique has not yet been developed. As part of a telesurgical study series conducted by the Japan Surgical Society, this study describes the first application of a double-surgeon cockpit system to telesurgery. Methods: Surgeon cockpits were installed at a local site and a remote site 140 km away. Three healthy pigs weighing between 26 and 29 kg were selected for surgery. Non-specialized surgeons performed emergency hemostasis, cholecystectomy, and renal vein ligation with remote assistance using the double-surgeon cockpits and specialized surgeons performed actual telesurgery. Additionally, the impact of adding internet protocol security (IPsec) encryption to the internet protocol-virtual private network (IP-VPN) line on communication was evaluated to address clinical security concerns. Results: The average time required for remote emergency hemostasis with the double-surgeon cockpit system was 10.64 s. A non-specialized surgeon could safely perform cholecystectomy or renal vein ligation with remote assistance. Global Evaluative Assessment of Robotic Skills and System Usability Scale scores were higher for telesurgical support-assisted surgery by a non-specialized surgeon using the double-surgeon cockpits than for telesurgery performed by a specialized surgeon without the double-cockpit system. Adding IPsec encryption to the IP-VPN did not have a significant impact on communication. Conclusion: Telesurgical support through our double-surgeon cockpit system is feasible as first step toward clinical telesurgery.

DOI： 10.1007/s00464-023-10061-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Clinical Pharmacology  

The development of a novel therapy to overcome primary and acquired resistance to abiraterone is an unmet need. This study aimed to evaluate the efficacy and safety of adding 5α-reductase inhibitor dutasteride to abiraterone, explore proof of concept, and identify candidates suitable for combination therapy. This phase II, single-arm, and open-label study enrolled second-generation antiandrogen- and chemotherapy-naïve patients with castration-resistant prostate cancer. Patients received abiraterone and prednisolone for 4 weeks, followed by adding dutasteride. The primary end point was a 50% prostate-specific antigen response rate. Serum concentrations of abiraterone and its metabolites as well as HSD3B1 and SRD5A2 genotypes were measured. The association between drug metabolism and genotypes and their impact on the efficacy of combination therapy were assessed. Among 21 patients, 18 (85.7%) achieved ≥50% PSA reduction. Median time to treatment failure was not reached during the median follow-up of 15.4 months. No patients experienced grade ≥3 adverse events. Although dutasteride reduced serum 3-keto-5α-abiraterone concentrations, higher serum 3-keto-5α-abiraterone concentrations on combination therapy were associated with a shorter time to treatment failure. HSD3B1 and SRD5A2 genotypes were associated with serum Δ4-abiraterone and 3-keto-5α-abiraterone concentrations before adding dutasteride, respectively. Time to treatment failure was longer in patients with homozygous wild-type HSD3B1, but comparable between those with the SRD5A2 genotype. The promising outcomes of this study warrant further investigation of combination therapy in a randomized trial. Stratification by HSD3B1 and SRD5A2 genetic profiles might identify patients suitable for combination therapy.

DOI： 10.1002/jcph.2191

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cancer Science  

Genetic variations represented by single-nucleotide polymorphisms (SNPs) could be helpful for choosing an effective treatment for patients with prostate cancer. This study investigated the prognostic and predictive values of SNPs associated with the prognoses of pharmacotherapy for prostate cancer through their pharmacological mechanisms. Patients treated with docetaxel or androgen receptor pathway inhibitors (ARPIs), such as abiraterone and enzalutamide, for castration-resistant prostate cancer were included. The SNPs of interest were genotyped for target regions. The prognostic and predictive values of the SNPs for time to progression (TTP) were examined using the Cox hazard proportional model and interaction test, respectively. Rs1045642 in ABCB1, rs1047303 in HSD3B1, rs1856888 in HSD3B1, rs523349 in SRD5A2, and rs34550074 in SLCO2A1 were differentially associated with TTP between docetaxel chemotherapy and ARPI treatment. In addition to rs4775936 in CYP19A1, rs1128503 in ABCB1 and rs1077858 in SLCO2B1 might be differentially associated with TTP between abiraterone and enzalutamide treatments. Genetic predictive models using these SNPs showed a differential prognosis for treatments. This study identified SNPs that could predict progression as well as genetic models that could predict progression when patients were treated with docetaxel versus ARPI and abiraterone versus enzalutamide. The use of genetic predictive models is expected to be beneficial in selecting the appropriate treatment for the individual patient.

DOI： 10.1111/cas.15718

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記述言語：英語  

A 67-year-old man with metastatic prostate cancer was treated with leuprorelin and enzalutamide, but presented radiographic progression after 1 year. Although docetaxel chemotherapy was initiated, liver metastasis appeared with elevation of nerve-specific enolase in serum. Pathological findings of needle biopsy of lymph node metastasis in the right inguinal region showed neuroendocrine carcinoma. FoundationOne CDx® using a biopsy sample of the prostate at initial diagnosis detected the BRCA1 mutation (deletion of intron 3-7), but BRACAnalysis® test revealed no BRCA mutation in germline. Then, olaparib treatment was initiated, resulting in remarkable remission of tumors, but comorbidity with interstitial pneumonia. This case suggested that olaparib could be effective for neuroendocrine prostate cancer with BRCA1 gene mutation, but may cause interstitial pneumonia.

DOI： 10.1007/s13691-022-00592-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Endocrine-Related Cancer  

Androgen deprivation therapy (ADT) has been widely used for the treatment of advanced prostate cancer. However, prognosis and adverse events vary among patients. This study aimed to identify genetic markers able to predict the outcome of ADT. Japanese patients treated with primary ADT for advanced prostate cancer in the KYUCOG-1401 trial were enrolled as a development set. A distinct population of advanced prostate cancer cases treated with ADT was included as a validation set. Single-nucleotide polymorphisms (SNPs) associated with radiographic progression-free survival (PFS) at 1 year and adverse events including de novo diabetes mellitus, arthralgia, and de novo dyslipidemia were identified in the development set by a genome-wide association study (GWAS). The SNPs associated with radiographic PFS in the development study were then genotyped in the validation set. GWAS followed by validation identified SNPs (rs76237622 in PRR27 and rs117573572 in MTAP) that were associated with overall survival in ADT. A genetic prognostic model using these SNPs showed excellent predictive efficacy for PFS and overall survival in ADT. In addition, GWAS showed that several SNPs were associated with de novo diabetes mellitus, arthralgia, and de novo dyslipidemia in ADT. This study identified novel multiple SNPs that correlated with outcomes in ADT. Future studies on correlations affecting the therapeutic efficacy of ADT-based combination therapies would make a valuable contribution to the development of personalized medicine.

DOI： 10.1530/ERC-23-0044

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記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

症例は67歳男性で、グリソンスコア5+5の前立腺腺癌と多発性の骨転移とリンパ節転移がみつかり、リュープロレリンとエンザルタミドの併用療法を受けた。1年後、鼠径部を含む多発リンパ節の腫大と骨転移が認められ、当科に紹介された。ドセタキセル+プレドニゾロンによる治療を開始した。さらに、脊髄転移が脊髄を圧迫し、両下肢麻痺を引き起こしたため、Th3、Th12、骨盤への放射線治療(29Gy/13分割)を行った。ドセタキセルを4サイクル行った後、多発肝転移とリンパ節転移のさらなる拡大を認めた。鼠径部のリンパ節転移の針生検の病理所見は神経内分泌癌であった。初診時の前立腺生検サンプルを用いたFoundationOne CDxではBRCA1変異(イントロン3-7欠失)が検出されたが、BRACAnalysis検査では生殖細胞系列にBRCA変異は認めなかった。その後、オラパリブ治療を開始した。1ヵ月後、リンパ節と肝臓の多発転移巣が縮小し、部分奏効を認めた。しかし、2ヵ月後、高熱と呼吸困難を呈した。CTスキャンで両側肺野にすりガラス影を認めた。間質性肺炎の併発と診断し、ステロイドパルス療法で治療した。肺炎は改善したが、全身状態は悪化し、緩和ケアと支持療法を行った。オラパリブ治療開始5ヵ月後に前立腺癌で死亡した。

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Urology  

Objectives: To investigate the impact of extended pelvic lymph node dissection (ePLND) on urinary incontinence (UI) at early post-surgery robot-assisted radical prostatectomy (RARP). Methods: Patients who underwent RARP without cavernous nerve sparing were included between 2014 and 2019. Patient data were obtained prospectively. The associations between ePLND and postoperative urinary continence were defined as a maximum of one daily pad use. International prostate symptom score (IPSS) was examined. Expression of synaptophysin and tyrosine hydroxylase (TH) in perilymph node adipose tissue (PLA) was evaluated by immunohistochemistry. Results: In total, 186 and 163 patients underwent RARP with and without ePLND. Urinary continence rate at 1 month postoperatively among patients with ePLND was lower than those without ePLND (24.1% vs. 35.1%, p < 0.05), however, not significantly different at 3, 6, and 12 months after RARP (57.4 vs. 62.6%, 73.1 vs. 74.2%, and 83.0 vs. 81.2%, respectively). Total and voiding plus postvoiding IPSS scores at 1 month were higher in patients with ePLND than in those without ePLND (14.5 ± 0.5 vs. 13.6 ± 0.6, 7.0 ± 0.3 vs. 6.2 ± 0.4, respectively, p < 0.05). In univariate and multivariate analyses, larger prostate volume and ePLND were factors associated with an increased UI rate. Among patients who underwent ePLND, synaptophysin and TH-positive nerve fibers were detected in PLA. Conclusions: Detection of synaptophysin and TH-immunopositive nerves suggested denervation of sympathetic and peripheral nerves caused by ePLND might be associated with a higher UI rate and poor urinary symptoms at an early stage after RARP.

DOI： 10.1111/iju.15119

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記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

去勢抵抗性前立腺癌に対してドセタキセルまたはアビラテロンやエンザルタミドなどのアンドロゲン受容体経路阻害薬(ARPI)による治療を受けた患者を対象に、一塩基多型(SNP)の予後予測能について検討した。対象となるSNPは標的領域について遺伝子型を決定した。進行までの時間(TTP)に対するSNPの予後および予測値を、それぞれCoxハザード比例モデルおよび相互作用試験を用いて解析した。その結果、ABCB1のrs1045642、HSD3B1のrs1047303、HSD3B1のrs1856888、SRD5A2のrs523349、およびSLCO2A1のrs34550074は、ドセタキセル化学療法とARPI治療との間でTTPと異なる関連を示した。CYP19A1のrs4775936に加えて、ABCB1のrs1128503とSLCO2B1のrs1077858は、アビラテロン治療とエンザルタミド治療の間でTTPと異なる関連を示す可能性があった。以上より、本研究の遺伝子予測モデルはドセタキセル化学療法とARPI治療およびアビラテロンとエンザルタミド治療における進行を予測することができた。

記述言語：英語   出版者・発行元：(一社)日本泌尿器科学会総会事務局  

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記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

ロボット支援根治的前立腺摘出術(RARP)後早期において拡大骨盤リンパ節郭清(ePLND)が尿失禁(UI)に及ぼす影響について検討した。海綿体神経温存を行わずにRARPを行った349例をePLND施行群186例(中央値66.5歳)とePLND非施行群163例(中央値68歳)に分類した。術後早期における排尿調節率のほか、国際前立腺症状スコア(IPSS)、リンパ節周囲脂肪組織(PLA)中のシナプトフィジンとチロシンヒドロラーゼ(TH)発現を評価した。ePLND施行群、非施行群とも術前にUIの発症はなく、術後1ヵ月における排尿調節率はePLND群が24.1%、非ePLND群が35.1%であり、ePLND群の方が有意に低かった。3、6、12ヵ月後の排尿調節率に有意な群間差はみられなかった。IPSS総スコアは1ヵ月後においてePLND群の方が有意に高く、3、6、12ヵ月後に有意差はなく、IPSS蓄尿スコアはいずれの時点でも有意な群間差はなく、IPSS排尿・排尿後症状スコアは1ヵ月後においてePLND群の方が有意に高値を示していた。多変量ロジスティック回帰分析では、前立腺容積とePLNDの施行がUI発症の独立予測因子として抽出された。ePLND群ではPLAにおいてシナプトフィジンとTH陽性神経線維が検出され、ePLNDの施行による脱神経がUI発症と関連することが示唆された。

記述言語：日本語   出版者・発行元：日本腎泌尿器疾患予防医学研究会  

過去9ヵ月間に前立腺癌に対してSpaceOARを用いてハイドロゲルスペーサーを留置した19例(56～85歳、中央値73歳)を対象に、ハイドロゲルスペーサー留置後30日以内の合併症について検討した。その結果、合併症は2例で、1例はハイドロゲルが直腸内へ迷入、1例は前立腺被膜へ迷入した。いずれも導入初期に起きており、生理食塩水で前立腺直腸間のスペースが十分に拡がることを確認した。針先を動かさずハイドロゲルを注入することが重要である。

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Archives of Biochemistry and Biophysics  

Prostate cancer has a relatively good prognosis, but most cases develop resistance to hormone therapy, leading to castration-resistant prostate cancer (CRPC). Androgen receptor (AR) antagonists and a cytochrome P450 17A1 inhibitor have been used to treat CRPC, but cancer cells readily develop resistance to these drugs. In this study, to improve the therapy of CRPC, we searched for natural compounds which block androgen signaling. Among cinnamic acid derivatives contained in Brazilian green propolis, artepillin C (ArtC) suppressed expressions of androgen-induced prostate-specific antigen and transmembrane protease serine 2 in a dose-dependent manner. Reporter assays revealed that ArtC displayed AR antagonist activity, albeit weaker than an AR antagonist flutamide. In general, aberrant activation of the androgen signaling is involved in the resistance of prostate cancer cells to hormone therapy. Recently, apalutamide, a novel AR antagonist, has been in clinical use, but its drug-resistant cases have been already reported. To search for compounds which overcome the resistance to apalutamide, we established apalutamide-resistant prostate cancer 22Rv1 cells (22Rv1/APA). The 22Rv1/APA cells showed higher AR expression and androgen sensitivity than parental 22Rv1 cells. ArtC inhibited androgen-induced proliferation of 22Rv1/APA cells by suppressing the enhanced androgen signaling through blocking the nuclear translocation of AR. In addition, ArtC potently sensitized the resistant cells to apalutamide by inducing apoptotic cell death due to mitochondrial dysfunction. These results suggest that the intake of Brazilian green propolis containing ArtC improves prostate cancer therapy.

DOI： 10.1016/j.abb.2023.109519

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記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

前立腺癌に対する根治的前立腺全摘除術(RP)においてリンパ節浸潤と病理診断された患者について、ロボット支援前立腺全摘除術(RARP)が腹腔鏡下RP(LRP)や開腹RP(ORP)と比べて優れた腫瘍学的転帰をもたらすかどうかについて検討した。2006年から2019年までに33施設において骨盤内リンパ節郭清(PLND)を伴うRPの際にリンパ節陽性前立腺癌と診断された561例(年齢中央値68歳)を対象とした。その結果、RARP、LRP、ORPの三つの手術群間で、無転移生存率、全生存率、癌特異的生存率、生化学的無再発生存率のいずれについても有意差はなかった。しかし、RARPではORPやLRPと比較して、より多いリンパ節収量が達成された。PLNDの範囲を閉鎖リンパ節に限定した場合、切除したリンパ節の数は三つの手術群間で同等であった。しかし、PLNDを外腸骨リンパ節や内腸骨リンパ節に拡張した場合、RARPではORPと比較してより多くの切除したリンパ節数が達成された(P<0.001)。以上より、RARP、LRP、ORPは、pN1前立腺癌に対する手術成績が同等であり、予後はすべての手術群で比較的良好であった。

記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

骨転移のある去勢抵抗性前立腺癌患者に対する塩化ラジウム223(Ra-223)の臨床診療における有効性と安全性ならびに全生存期間(OS)と関連する臨床パラメータを検討した。2016年6月～2018年12月に10施設でRa-223治療を受けた骨転移のある去勢抵抗性前立腺癌患者73例(中央値73歳)を対象とした。OS中央値は20.9ヵ月であった。アルカリホスファターゼ値は治療後に有意に低下した(p=0.03)。3例(4.1%)にグレード3以上の貧血、4例(5.5%)にグレード3以上の非病的骨折が発生した。病的骨折は9例(12.3%)に発生し、骨修飾薬非併用下では30例中7例(23.3%)に発生したのに対し、骨修飾薬併用下では43例中2例(4.7%)のみであった(p=0.03)。OS中央値は3サイクル以上の治療を受けた患者(27.2ヵ月、p<0.001[vs 2サイクル以下])、ヘモグロビン値12g/dL以上の患者(27.2ヵ月、p=0.001[vs 12g/dL未満])、骨痛のない患者(36.3ヵ月、p=0.004[vs 骨痛あり])で有意に長かった。

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記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cancer Medicine  

Objective: The study objectives were to understand how patients view the quality of life in non-metastatic castration-resistant prostate cancer (nmCRPC), including unmet needs and what patients consider most important in treatment outcomes. A gap analysis was conducted on existing patient-reported outcomes (PROs) measures versus what is missing from the patient perspective, to guide future development of PRO-based real-world evidence for nmCRPC in Japan. A conceptual model for nmCRPC Japanese patients’ HRQOL was also created. Methods: This non-interventional, qualitative study consisted of a targeted literature review, PRO instrument review, and interviews with 20 nmCRPC patients and five treating physicians. Triangulation of the gap analysis, evidence from the targeted review of the literature, and qualitative interview findings were employed to assess the comprehensiveness of current nmCRPC and HRQOL measures. Results: Symptoms most reported by patients were frequent urination (70%), nocturia (65%), and general pain (65%). Others reported included lack of strength (30%). HRQOL impacts most reported were anxiety (45%) and worry (50%) about their diagnosis. Additional impacts mentioned were weight changes, loss of sleep, difficulty walking, loss of appetite, and difficulty traveling and seeking toilets in public. The gap analysis revealed 31 symptoms and 33 impacts not covered in existing prostate cancer-specific PRO instruments. Patients mentioned musculoskeletal symptoms such as fractures, leg pain, cramps, numbness, and loss of leg bone strength. Impacts not previously discussed in the literature or in outcome measures were feelings of self-consciousness around diagnosis, stigma around illness, and the impact on mobility including traveling. Conclusion: Key results reveal pain and urinary symptoms are the most experienced by Japanese nmCRPC patients. The diagnosis and treatment of disease leads to significant impacts in patient lives. Analysis revealed that symptoms and life impacts are missing in the current literature and outcome measures. Testing and debriefing of specific items could further substantiate these dimensions.

DOI： 10.1002/cam4.4955

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Asian Journal of Urology  

OBJECTIVE: There are many models to predict extracapsular extension (ECE) in patients with prostate cancer. We aimed to externally validate several models in a Japanese cohort. METHODS: We included patients treated with robotic-assisted radical prostatectomy for prostate cancer. The risk of ECE was calculated for each patient in several models (prostate side-specific and non-side-specific). Model performance was assessed by calculating the receiver operating curve and the area under the curve (AUC), calibration plots, and decision curve analyses. RESULTS: We identified ECE in 117 (32.9%) of the 356 prostate lobes included. Patients with ECE had a statistically significant higher prostate-specific antigen level, percentage of positive digital rectal examination, percentage of hypoechoic nodes, percentage of magnetic resonance imaging nodes or ECE suggestion, percentage of biopsy positive cores, International Society of Urological Pathology grade group, and percentage of core involvement. Among the side-specific models, the Soeterik, Patel, Sayyid, Martini, and Steuber models presented AUC of 0.81, 0.78, 0.77, 0.75, and 0.73, respectively. Among the non-side-specific models, the memorial Sloan Kettering Cancer Center web calculator, the Roach formula, the Partin tables of 2016, 2013, and 2007 presented AUC of 0.74, 0.72, 0.64, 0.61, and 0.60, respectively. However, the 95% confidence interval for most of these models overlapped. The side-specific models presented adequate calibration. In the decision curve analyses, most models showed net benefit, but it overlapped among them. CONCLUSION: Models predicting ECE were externally validated in Japanese men. The side-specific models predicted better than the non-side-specific models. The Soeterik and Patel models were the most accurate performing models.

DOI： 10.1016/j.ajur.2022.02.008

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：European Journal of Clinical Pharmacology  

Purpose: We assessed the impact of plasma trough concentrations of abiraterone (ABI) and its metabolite Δ4-abiraterone (D4A) and related polymorphisms on adverse events (AEs) in patients with metastatic prostate cancer who received abiraterone acetate (AA). Methods: This prospective study enrolled patients with advanced prostate cancer treated with AA between 2016 and 2021. Plasma trough concentrations of ABI and D4A were measured using high-performance liquid chromatography. The impact of HSD3B1 rs1047303, SRD5A2 rs523349, and cytochrome P450 family 3A member 4 rs2242480 polymorphisms on plasma concentrations of ABI and D4A and the incidence of AEs were also assessed. Results: In 68 patients treated with AA, the median ABI and D4A concentrations were 18.1 and 0.94 ng/mL, respectively. The high plasma trough concentration of ABI (≥ 20.6 ng/mL) was significantly associated with the presence of any AE and its independent risk factor based on multivariable analysis (odds ratio, 7.20; 95% confidence interval (CI): 2.20–23.49). Additionally, a high plasma trough concentration of ABI was an independent risk factor of time to withdraw AA (hazard ratio, 4.89; 95% CI: 1.66–14.38). The risk alleles of three polymorphisms were not statistically associated with the ABI and D4A concentrations and the incidence of AEs. Conclusions: The plasma trough concentration of ABI is associated with the presence of AEs and treatment failure after AA administration. ABI concentration monitoring may be useful in patients with prostate cancer who received AA.

DOI： 10.1007/s00228-022-03420-0

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記述言語：英語   出版者・発行元：Current Cancer Drug Targets  

DOI： 10.2174/1568009623666230220121610

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出版者・発行元：Nishinihon Journal of Urology  

A study of the clinical statistics at our department for the period 2018-2020 revealed the following results. 1) The number of outpatients was 41,442, including 2,823 new patients. The most common diseases among the new patients were urogenital malignant tumors 1,293 (45.8%), benign prostatic hyperplasia 303 (10.7%), neurogenic bladder 128 (4.5%), inflammatory diseases 122 (4.3%), and urolithiasis 104 (3.7%). 2) The total number of inpatients was 2,775 (2,175 males and 600 females), and the majority of them comprised males aged 60-79 years. The main disease among the inpatients was urogenital neoplasms 1,957 (70.5%). 3) A total of 1,662 cases underwent surgery, with 87 cases undergoing open surgery, 678 cases undergoing laparoscopic surgery, and 789 cases undergoing endourological surgery.

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掲載種別：研究論文（学術雑誌）  

A study of the clinical statistics at our department for the period 2018-2020 revealed the following results. 1) The number of outpatients was 41,442, including 2,823 new patients. The most common diseases among the new patients were urogenital malignant tumors 1,293 (45.8%), benign prostatic hyperplasia 303 (10.7%), neurogenic bladder 128 (4.5%), inflammatory diseases 122 (4.3%), and urolithiasis 104 (3.7%). 2) The total number of inpatients was 2,775 (2,175 males and 600 females), and the majority of them comprised males aged 60-79 years. The main disease among the inpatients was urogenital neoplasms 1,957 (70.5%). 3) A total of 1,662 cases underwent surgery, with 87 cases undergoing open surgery, 678 cases undergoing laparoscopic surgery, and 789 cases undergoing endourological surgery.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Clinical Oncology  

OBJECTIVES: To compare the therapeutic features and oncological outcomes of robot-assisted radical prostatectomy (RARP) with those of open radical prostatectomy (ORP) or laparoscopic radical prostatectomy (LRP) in lymph node (LN) positive prostate cancer patients in a retrospective observational multi-institutional study. PATIENTS AND METHODS: We evaluated the clinical results of 561 patients across 33 institutions who underwent RARP, LRP, or ORP and who were diagnosed with LN-positive prostate cancer during RP with pelvic LN dissection (PLND). We determined the following survival outcomes: metastasis-free survival, overall survival, cancer-specific survival, and biochemical recurrence-free survival. The Kaplan-Meier method, log-rank test, and Cox proportional hazards regression model were used to evaluate the effect of treatment on oncological outcomes. Statistical significance was set at P < 0.05. RESULTS: There was no significant difference for any of the survival outcomes between the three surgical groups. However, RARP achieved a greater LN yield compared to that of ORP or LRP. When the extent of PLND was limited to the obturator LNs, the number of removed LNs (RLNs) was comparable between the three surgical groups. However, higher numbers of RLNs were achieved with RARP compared to the number of RLNs with ORP (P < 0.001) when PLND was extended to the external and/or internal iliac LNs. CONCLUSION: RARP, LRP, and ORP provided equal surgical outcomes for pN1 prostate cancer, and the prognosis was relatively good for all procedures. Increased numbers of RLNs may not necessarily affect the oncological outcome.

DOI： 10.1007/s10147-022-02278-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BMC Cancer  

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

DOI： 10.1186/s12885-022-10398-6

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記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：Continence  

Introduction: The objective of this study was to investigate the efficacy of the β3-adrenoreceptor agonist vibegron for the treatment of neurogenic lower urinary tract storage dysfunction in patients with spinal cord injury (SCI). Materials and Methods: Twenty-three SCI patients treated with vibegron (50 mg/day) for at least 28 days were included in the study. All patients had urinary management with clean intermittent catheterization, and suffered from urinary incontinence (UI) associated with neurogenic detrusor overactivity (NDO) diagnosed with cystometrogram (CMG). Subjective symptoms and objective parameters were retrospectively evaluated before and after treatment with vibegron, using the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) and CMG parameters, respectively. Results: ICIQ-SF scores for the frequency, amount, and overall impact of UI, as well as the total score, were statistically significantly improved after treatment with vibegron. In terms of objective parameters, maximum detrusor pressure during storage phase statistically significantly decreased with vibegron treatment (53.0 vs 23.0 cmH2O, P<0.001). In addition, maximum cystometric capacity (291 vs 401 ml, P<0.001), bladder volume at first NDO (160 vs 270 ml, P=0.002), and bladder compliance (7.2 vs 25.4 ml/cmH2O, P<0.001) all statistically significantly improved after treatment with vibegron. Conclusion: Vibegron improved UI symptoms and CMG parameters in SCI patients. These results suggest that vibegron would be an efficacious treatment option for neurogenic lower urinary tract storage dysfunction in patients with SCI.

DOI： 10.1016/j.cont.2022.100516

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記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：World Journal of Urology  

Purpose: Conditional survival represents the probability of subsequent survival given that patients have already survived a certain length of time. Several models predict biochemical recurrence (BCR) after radical prostatectomy. However, none of them include postoperative prostate-specific antigen (PSA). We aimed to analyze BCR-free survival evolution over time and develop a nomogram incorporating the postoperative PSA value to predict BCR-free survival. Material and Methods: We included patients treated with robot-assisted radical prostatectomy (RARP) for prostate cancer between 2009 and 2021 and calculated conditional survival. Cox proportional hazard regression analysis was used to assess the predictive variables of BCR. We developed a nomogram predicting BCR-free survival three and five years after RARP. We used c-index and decision curve analyses to compare the nomogram with the Cancer of the Prostate Risk Assessment post-Surgical (CAPRA-S) score. Results: We included 718 patients. The overall 3- and 5-year BCR-free survival rates were 85.1% and 75.7%, respectively. The 5-year BCR-free survival rates increased to 78.9%, 82.9%, 85.2%, and 84.7% for patients surviving 1, 2, 3, and 4 years without BCR, respectively. We developed a nomogram including the pathological Gleason score and T stage, positive surgical margin, PSA ≥ 0.05 ng/mL at one year, and lymph node involvement to predict BCR at 3 and 5 years postoperatively. Our nomogram presented a higher c-index (0.89) than the CAPRA-S score (0.78; p = 0.001) and a positive net benefit at 3 and 5 years postoperatively in the decision curve analyses. Conclusion: The 5-year conditional BCR-free survival increased with survival without BCR. The developed nomogram significantly improved the accuracy in predicting BCR-free survival after RARP.

DOI： 10.1007/s00345-022-04245-3

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その他リンク： https://link.springer.com/article/10.1007/s00345-022-04245-3/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Molecular Sciences  

Prostate cancer (PC) represents the most common cancer disease in men. Since high levels of androgens increase the risk of PC, androgen deprivation therapy is the primary treatment; however this leads to castration-resistant PC (CRPC) with a poor prognosis. The progression to CRPC involves ectopic androgen production in the adrenal glands and abnormal activation of androgen signaling due to mutations and/or amplification of the androgen receptor (AR) as well as activation of androgen-independent proliferative pathways. Recent studies have shown that adrenal-derived 11-oxygenated androgens (11-ketotestosterone and 11-ketodihydrotestosterone) with potencies equivalent to those of traditional androgens (testosterone and dihydrotestosterone) are biomarkers of CRPC. Additionally, dehydrogenase/reductase SDR family member 11 (DHRS11) has been reported to be a 17β-hydroxysteroid dehydrogenase that catalyzes the production of the 11-oxygenated and traditional androgens. This study was conducted to evaluate the pathophysiological roles of DHRS11 in PC using three LNCaP, C4-2 and 22Rv1 cell lines. DHRS11 silencing and inhibition resulted in suppression of the androgen-induced expression of AR downstream genes and decreases in the expression of nuclear AR and the proliferation marker Ki67, suggesting that DHRS11 is involved in androgen-dependent PC cell proliferation. We found that 5,7-dihydroxy-8-methyl-2-[2-(4-hydroxyphenyl)ethenyl]-4H-1-benzopyran-4-one (Kobochromone A, KC-A), an ingredient in the flowers of Carex kobomugi, is a novel potent DHRS11 inhibitor (IC50 = 0.35 μM). Additionally, KC-A itself decreased the AR expression in PC cells. Therefore, KC-A suppresses the androgen signaling in PC cells through both DHRS11 inhibition and AR downregulation. Furthermore, KC-A enhanced the anticancer activity of abiraterone, a CRPC drug, suggesting that it may be a potential candidate for the development of drugs for the prevention and treatment of CRPC.

DOI： 10.3390/ijms232214356

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：British Journal of Cancer  

BACKGROUND: The prognostic significance of germline variants in homologous recombination repair genes in advanced prostate cancer (PCa), especially with regard to hormonal therapy, remains controversial. METHODS: Germline DNA from 549 Japanese men with metastatic and/or castration-resistant PCa was sequenced for 27 cancer-predisposing genes. The associations between pathogenic variants and clinical outcomes were examined. Further, for comparison, DNA from prostate biopsy tissue samples from 80 independent patients with metastatic PCa were analysed. RESULTS: Forty-four (8%) patients carried germline pathogenic variants in one of the analysed genes. BRCA2 was most frequently altered (n = 19), followed by HOXB13 (n = 9), PALB2 (n = 5) and ATM (n = 5). Further, the BRCA1, BRCA2, PALB2 and ATM variants showed significant association with a short time to castration resistance and overall survival (hazard ratio = 1.99 and 2.36; 95% CI, 1.15-3.44 and 1.23-4.51, respectively), independent of other clinical variables. Based on log-rank tests, the time to castration resistance was also significantly short in patients with BRCA1, BRCA2, PALB2 or ATM somatic mutations and TP53 mutations. CONCLUSIONS: Germline variants in BRCA1, BRCA2, PALB2 or ATM are independent prognostic factors of the short duration of response to hormonal therapy in advanced PCa.

DOI： 10.1038/s41416-022-01915-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Urologic Oncology: Seminars and Original Investigations  

Castration resistance is in part attributable to aberrant activation of androgen receptor (AR) signaling by the intracrine activation of androgen precursors derived from adrenal glands. To overcome this, novel AR pathway inhibitors (ARPIs) that suppress androgen synthesis by CYP17 inhibition or AR activation by antiandrogen effects have been developed. However, primary or acquired resistance to these ARPIs occurs; in turn attributable, at least in part, to the maintained androgen milieu despite intensive suppression of AR signaling similar to castration resistance. In addition to the classical pathway to produce potent androgens such as testosterone and dihydrotestosterone, the alternative pathway and the backdoor pathway which bypasses testosterone to produce dihydrotestosterone have been shown to play a role in intratumor steroidogenesis. Furthermore, the 11β-hydroxyandrostenedione pathway to produce the potent oxygenated androgens 11-ketotestosterone and 11-ketodihydrotestosterone has been suggested to be functional in prostate cancer. These steroidogenesis pathways produce potent androgens that promote tumor resistance to endocrine therapy including novel ARPIs. Here, we overview the current evidence on the pathological androgen milieu by altered metabolism and transport in prostate cancer, leading to resistance to endocrine therapy.

DOI： 10.1016/j.urolonc.2022.10.018

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記述言語：英語   出版者・発行元：The Lancet Oncology  

DOI： 10.1016/S1470-2045(22)00614-3

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記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：Endocrine-Related Cancer  

Hormonal therapies including androgen deprivation therapy and androgen receptor (AR) pathway inhibitors such as abiraterone and enzalutamide have been widely used to treat advanced prostate cancer. However, treatment resistance emerges after hormonal manipulation in most prostate cancers, and it is attributable to a number of mechanisms, including AR amplification and overexpression, AR mutations, the expression of constitutively active AR variants, intra-tumor androgen synthesis, and promiscuous AR activation by other factors. Although various AR mutations have been reported in prostate cancer, specific AR mutations (L702H, W742L/C, H875Y, F877L, and T878A/S) were frequently identified after treatment resistance emerged. Intriguingly, these hot spot mutations were also revealed to change the binding affinity of ligands including steroids and antiandrogens and potentially result in altered responses to AR pathway inhibitors. Currently, precision medicine utilizing genetic and genomic data to choose suitable treatment for the patient is becoming to play an increasingly important role in clinical practice for prostate cancer management. Since clinical data between AR mutations and the efficacy of AR pathway inhibitors are accumulating, monitoring the AR mutation status is a promising approach for providing precision medicine in prostate cancer, which would be implemented through the development of clinically available testing modalities for AR mutations using liquid biopsy. However, there are few reviews on clinical significance of AR hot spot mutations in prostate cancer. Then, this review summarized the clinical landscape of AR mutations and discussed their potential implication for clinical utilization.

DOI： 10.1530/ERC-22-0140

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記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Urology  

Objective

Radium‐223 (Ra‐223) dichloride is the bone‐targeted radioligand therapy that prolongs overall survival (OS) in patients with bone‐metastatic castration‐resistant prostate cancer (CRPC). We aimed to evaluate the safety and effectiveness of this treatment in real‐world practice.

Methods

We included Japanese men treated with Ra‐223 for bone‐metastatic CRPC from 10 institutions, retrospectively. Primary endpoint was OS. Secondary endpoint was maximum decline of alkaline phosphatase (ALP), lactate dehydrogenase, and prostate‐specific antigen values, the rate of adverse events, and time to pathological fracture after Ra‐223 treatment. Exploratory endpoint was the associations between clinical parameters and OS.

Results

In total, 73 men with bone metastatic CRPC treated with Ra‐223 were enrolled. The median OS was 20.9 months. ALP levels decreased significantly from pre‐treatment (p = 0.03). Anemia occurred in three (4.1%) patients. Grade ≥ 3 non‐pathological fractures occurred in four (5.5%) men. Nine (12.3%) patients presented pathological fracture; 7/30 (23.3%) were in men without concomitant use of a bone‐modifying agent (BMA) while 2/43 (4.7%) were in patients with concomitant BMA (p = 0.03). The median OS in patients with ≥3 cycles treatment (27.2 months, p < 0.001) or hemoglobin ≥12 g/dl (27.2 months, p = 0.001) or absence of bone pain (36.3 months, p = 0.004) was significantly longer compared to those who with ≤2 cycles or hemoglobin<12 g/dl or presence of bone paint, respectively.

Conclusions

This study has shown the outcomes of Ra‐223 treatment in real‐world practice, where the number of treatment cycles, baseline anemia and bone pain may be useful to predict OS in Ra‐223 treatment.

DOI： 10.1111/iju.15078

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/iju.15078

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：公益社団法人 日本医師会 / 日本医学会  

INTRODUCTION: Enzalutamide is approved for the treatment of patients with metastatic castration-resistant prostate cancer. Adverse effects (e.g., fatigue and anorexia) are often observed and cause difficulty with continuous therapy; however, no clinical data describing which patients are more likely to suffer adverse effects were observed. Therefore, this study hypothesized that body composition, comprising body fat distribution and psoas muscle volume, may affect the occurrence of subjective symptoms (e.g., fatigue and anorexia) in prostate cancer patients treated with enzalutamide. METHODS: Adverse effects, especially fatigue, anorexia, insomnia, and pain, were retrospectively evaluated by CTCAE v4.0 criteria. Sixty-seven prostate cancer patients treated with enzalutamide were enrolled, and body fat, visceral fat percentage, and psoas muscle ratio (psoas muscle, in cubic centimeter/height, in meters) were calculated using computed tomography images evaluated before enzalutamide, with SYNAPSE VINCENT software. Univariate analysis was performed to identify the factors associated with adverse effects. RESULTS: Univariate analysis showed that high psoas muscle ratio was significantly associated with fatigue (grade ≥ 2; odds ratio, 3.875; 95% confidence interval, 1.016-17.134; P = 0.047), but inversely related to anorexia (grade ≥ 2; odds ratio, 0.093; 95% confidence interval, 0.011-0.784; P = 0.029). CONCLUSIONS: Psoas muscle ratio is a predictive marker of fatigue and anorexia in patients treated with enzalutamide.

DOI： 10.31662/jmaj.2022-0096

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記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Urology  

Objectives: Semen comprises prostatic fluid and seminal vesicle fluid, and seminal vesicle fluid contains various factors such as prostaglandin E2 (PGE2), zinc, and testosterone, which play important roles in sperm motility. It is not known whether these factors affect erectile function. In this study, we investigated factors in seminal vesicle fluid that may affect erectile function. Methods: After receiving institutional review board approval, we collected seminal vesicle fluid samples from 134 Japanese patients with localized prostate cancer who underwent robot-assisted radical prostatectomy. We examined the relationship between the results of the Sexual Health Inventory for Men (SHIM), erection hardness score, an original questionnaire on the presence or absence of sexual desire, and concentrations of several factors in seminal vesicle fluid (testosterone, PGE2, transforming growth factor β1, and 8-hydroxy-2-deoxyguanosine), as well as the serum testosterone level. Results: Median participant age was 67 (range 51–77) years. Median concentrations were as follows: seminal vesicle testosterone 1.85 (range 0.17–4.32) ng/ml and serum testosterone 4.60 (range 1.75–10.82) ng/ml. When the SHIM score was divided into two groups, seminal vesicle testosterone concentration was significantly increased (p = 0.002) in participants with a SHIM score ≥17, and no significant difference was observed in serum testosterone levels (p = 0.661). Multivariate analysis revealed that seminal vesicle testosterone was significantly correlated with the SHIM score (≥17 vs. <17; odds ratio 2.137, 95% confidence interval 1.148–3.978, p = 0.016). Conclusions: Testosterone levels in seminal vesicle fluid can reflect erectile function in patients with prostate cancer, suggesting that seminal vesicle testosterone is very important for male erectile function.

DOI： 10.1111/iju.14953

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記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

de novo転移性前立腺癌(mPCa)高齢患者の生存転帰を評価する多施設共同後ろ向き研究を行った。2008年3月～2017年5月にmPCaと診断された患者を対象とした。全患者はアンドロゲン遮断療法による初回治療を受けた。患者を75歳未満、75～79歳、80歳以上の3群に分け、傾向スコアマッチング後の各群の癌特異的生存率を評価した。Pohar-Perme法と2019年生命表を用いて、各群の5年純全生存率を算出し一般集団と比較した相対生存率を求めた。患者2784例(中央値72.3歳)を解析した。追跡期間(中央値34ヵ月)に1014例が死亡し、mPCa進行による死亡は807例であった。75歳未満群と比較した癌特異的生存率は75～79歳群では差がなく(ハザード比1.07、95%CI:0.84～1.37、P=0.580)、80歳以上群では有意に低かった(同1.41、1.10～1.80、P=0.006)。5年純全生存率は75歳未満群0.678、75～79歳群0.761、80歳以上群0.718であった。腫瘍量が少ない患者と多い患者の5年純全生存率は80歳以上群(それぞれ0.893、0.586)と75歳未満群(0.872、0.586)で同等であった。以上から、80歳以上のmPCa患者の癌特異的生存率は75歳未満の患者より低かったが、5年純全生存率は同等であった。

記述言語：英語   出版者・発行元：(一社)日本癌治療学会  

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記述言語：英語   出版者・発行元：(一社)日本癌治療学会  

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記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

精嚢液中の因子が勃起機能に及ぼす影響を明らかにするため、精嚢液中の因子と勃起機能との関連を評価した。2017年5月～2020年8月に当院でロボット支援根治的前立腺摘除術を受けた限局性前立腺癌日本人患者を登録し、精嚢液サンプルを収集した。Sexual Health Inventory for Men(SHIM)、Erection Hardness Score(EHS)、および性的欲求の有無に関する独自の調査票の結果と、精嚢液中因子(テストステロン、PGE2、TGFβ1、8-OHdGの濃度)および血清テストステロン濃度との関連を調べた。患者134例(中央値67歳)を解析した。精嚢液テストステロン濃度はSHIMスコア17以上(勃起機能あり)の患者で17未満の患者より有意に高かったが(p=0.002)、血清テストステロン濃度に有意差はなかった(p=0.661)。多変量解析で、精嚢液テストステロン濃度とSHIMスコアとに有意な関連が認められた(オッズ比:2.137、95%CI:1.148～3.978、p=0.016)。以上から、精嚢液のテストステロン濃度は、前立腺癌患者の勃起機能を反映する可能性が示唆された。

記述言語：英語   出版者・発行元：(公社)日本医師会  

2011年8月～2018年9月に日本の単一施設でエンザルタミド治療を行った去勢抵抗性前立腺癌(CRPC)患者67例(中央値73歳)を対象に、身体組成と主観的症状(疲労、食欲不振、疼痛、不眠症)の関連を後向きに検討した。エンザルタミド治療の開始前に行ったCT画像を用いて、体脂肪率、内臓脂肪率、腰筋量を算出した。腰筋量の中央値(160.1cm3/m)で高値群と低値群に分類した場合、腰筋量高値群ではグレード2以上の疲労が有意に増加し(オッズ比3.875、95%CI 1.016～17.134)、グレード2以上の食欲不振が有意に減少した(オッズ比0.093、95%CI 0.011～0.784)。エンザルタミド治療を行ったCRPC患者において、腰筋量は疲労および食欲不振の予測マーカーであることが示された。

記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cancer Science  

Early detection and long-term monitoring are important for urothelial carcinoma of the bladder (UCB). Urine cytology and existing markers have insufficient diagnostic performance. Here, we examined medium-sized extracellular vesicles (EVs) in urine to identify specific markers for UCB and evaluated their usefulness as diagnostic material. To identify specific markers in urinary EVs derived from UCB, we undertook shotgun proteomics using urine from four UCB patients and four healthy subjects. Next, 29 healthy specimens, 18 noncancer specimens, and 33 UCB specimens, all from men, were analyzed for urinary EVs by flow cytometry to evaluate the diagnostic performance of UCB-specific EVs. Nanoparticle-tracking analysis indicated that the size of EVs extracted from urine was mostly <400 nm. By shotgun proteomics, we detected several proteins characteristic of UCB and found that carcinoembryonic antigen-related adhesion molecule (CEACAM) proteins were increased in patients. Flow cytometric analysis revealed that the degree of expression of CEACAM1, CEACAM5, and CEACAM6 proteins on the surface of EVs varied among patients. Extracellular vesicles expressing CEACAM proteins also expressed mucin 1, suggesting that they were derived from tumorigenic uroepithelial cells. The number of EVs expressing CEACAM1, 5, and 6 proteins was significantly increased in UCB (mean ± SD, 8.6 ± 13%) compared to non-UCB (0.69 ± 0.46) and healthy (0.46 ± 0.34) by flow cytometry. The results of receiver operating characteristic (ROC) analysis showed a good score of area under the ROC curve of 0.907. We identified EVs that specifically express CEACAM proteins in urine and have potential for diagnostic applications. These EVs are potential targets in a new liquid biopsy test for UCB patients.

DOI： 10.1111/cas.15438

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記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

膀胱尿路上皮癌(UCB)患者の尿から抽出した細胞外小胞(EV)画分のプロテオミクス解析を行い、特異的な表面抗原となりうるタンパク質の探索を行った。UCB患者4例と健常者4例の尿についてショットガンプロテオミクスを実施し、次に健常者29検体、非癌18検体、UCB 33検体(全て男性)の尿中EVをフローサイトメトリー(FCM)で分析した。ナノ粒子トラッキング解析により、尿から抽出されたEVのサイズは大部分が400nm未満であった。ショットガンプロテオミクスにより、UCB患者でcarcinoembryonic antigen-related adhesion molecule(CEACAM)タンパク質が増加していることを見出した。FCM解析により、EV表面のCEACAM1、CEACAM5、CEACAM6タンパク質の発現の程度は患者によって異なっていた。CEACAMを発現しているEVはムチン1も発現しており、腫瘍形成尿路上皮細胞に由来することが示唆された。FCMによりCEACAM1、5、6タンパク質を発現するEV数は、非UCB(0.69±0.46%)および健常者(0.46±0.34%)に比べてUCB(8.6±13%)で有意に増加していた。ROC曲線下面積は0.907と良好であった。以上より、CEACAMタンパク質を特異的に発現し、診断への応用が期待される尿中EVを同定した。

記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cancers  

Active surveillance (AS) is a monitoring strategy to avoid or defer curative treatment, minimizing the side effects of radiotherapy and prostatectomy without compromising survival. AS in intermediate-risk prostate cancer (PC) has increasingly become used. There is heterogeneity in intermediate-risk PC patients. Some of them have an aggressive clinical course and require active treatment, while others have indolent disease and may benefit from AS. However, intermediate-risk patients have an increased risk of metastasis, and the proper way to select the best candidates for AS is unknown. In addition, there are several differences between AS protocols in inclusion criteria, monitoring follow-up, and triggers for active treatment. A few large series and randomized trials are under investigation. Therefore, more research is needed to establish an optimal therapeutic strategy for patients with intermediate-risk disease. This study summarizes the current data on patients with intermediate-risk PC under AS, recent findings, and discusses future directions.

DOI： 10.3390/cancers14174161

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記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：Current Medical Research and Opinion  

Objective: To assess the correlation between PFS2 and OS among patients with advanced prostate cancer (PC) in a real-world setting for Japan. Methods: This was a retrospective analysis using the Japanese MDV database. Patients with nmCRPC (non-metastatic Castration-Resistant PC), mCRPC (metastatic Castration-Resistant PC), and mCNPC (metastatic Castration-Naïve PC) were identified and their medical records were investigated for PFS2 and death. Association between PFS2 and OS was determined using the Pearson’s, Spearman’s, Kendall's Tau, and Fleischers’ correlation coefficients. Results: A total of 386,484 patients with PC were identified from the database, of which, 1,783 patients with nmCRPC, 630 with mCRPC, and 454 with mCNPC met the predefined eligibility criteria. Significant correlation between PFS2 and OS was observed in patients with nmCRPC (Pearson’s r = 0.873; 95% CI: 0.849−0.897, Spearman’s r = 0.909; 95% CI: 0.893−0.925; Kendall’s Tau r = 0.831; 95% CI: 0.812−0.850, Fleischers’ r = 0.682; 95% CI: 0.601−0.764), mCRPC (Pearson’s r = 0.812; 95% CI: 0.758−0.865, Spearman’s r = 0.895; 95% CI: 0.868−0.923, Kendall’s Tau r = 0.789; 95% CI: 0.755−0.823, Fleischers’ r= 0.439; 95% CI: 0.334−0.544), and mCNPC (Pearson’s r = 0.931; 95% CI: 0.899−0.964, Spearman’s r = 0.943; 95% CI: 0.922−0.964, Kendall’s Tau r = 0.866; 95% CI: 0.836−0.896, Fleischers’ r = 0.756; 95% CI: 0.624−0.888). Conclusions: The results of this study indicate a significant correlation between PFS2 and OS, which adds additional evidence to the existing literature of using PFS2 as a surrogate endpoint for OS in patients with PC.

DOI： 10.1080/03007995.2022.2096353

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記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cancer Management and Research  

Several studies have identified various targetable genomic alterations in prostate cancer, which accumulate during carcinogenesis and cancer progression. Genomic alterations in genes involved in DNA damage repair by homologous recombination repair may predict increased sensitivity to poly-ADP ribose polymerase (PARP) inhibitors. The Phase 3 PROfound trial has shown that treatment with the PARP inhibitor olaparib was associated with an improved radiographic progression-free survival and overall survival among patients with homologous recombination repair-deficient metastatic castration-resistant prostate cancer (mCRPC) after the treatment with androgen receptor targeting therapy, especially in men with BRCA1 or BRCA2 mutation. In Japan, olaparib was approved in December 2020 for the treatment of mCRPC with BRCA1 or BRCA2 mutation. In addition, genetic tests to detect BRCA1 or BRCA2 mutation to select patients who are likely to benefit from olaparib were also approved. This review summarizes the status of olaparib treatment for mCRPC, focusing on the situation in Japan.

DOI： 10.2147/CMAR.S326114

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記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

ロボット支援根治的前立腺全摘除術(RARP)での神経温存により切除断端陽性率や生化学的再発リスクが高まるかを検討した。2009～2021年に限局性前立腺癌の一次治療としてRARPを受けた患者を対象とした。ロジスティック回帰分析とCox比例ハザードモデルを用いた。患者814例(年齢中央値66歳)を解析した。片側神経温存は152例(18.6%)、両側神経温存は118例(14.5%)で行われた。術前因子を調整した多変量解析では、非神経温存と比較して、神経温存および両側神経温存が切除断端陽性のリスク増加と関連していた。切除断端陽性(部位を問わない)は生化学的再発リスク増加の独立危険因子であった。片側神経温存では、神経温存側の手術断端陽性が生化学的再発のリスク増加と関連したが、非神経温存側では関連がなかった。以上から、RARPでの神経温存では手術断端陽性に関連する生化学的再発リスクがあり、外科医は神経温存に適した患者を選択する必要があると考えられた。

記述言語：日本語   出版者・発行元：医学図書出版(株)  

アビラテロン酢酸エステルおよび代謝産物であるΔ4a-abiraterone(D4A)の血中濃度と治療効果の関連が報告されるが本邦の検討は少ない。今回われわれはアビラテロン酢酸エステルを投与したmetastatic castration-sensitive prostate cancer(mCSPC)およびmetastatic castration-resistant prostate cancer(mCRPC)症例における血中濃度とアウトカムの関連を検討した。2016年3月から2021年5月までに国内2施設でアビラテロン酢酸エステルを投与したmCSPC、mCRPC症例のうち、血中濃度測定が可能な68例を対象とした。患者血漿を用い高速液体クロマトグラフィー法で血中濃度を測定し、ABI濃度中央値18.1ng/mL、D4A濃度中央値0.97ng/mL、D4A/ABI中央値0.047であった。治療効果と血中濃度に有意な関連を認めなかった。Grade 1以上の有害事象発症率は51.5%であり、有害事象ありは有意にABI濃度が高値であった。有害事象発症を予測するABI濃度最適カットオフ値は20.6ng/mLであり、ABI高値(≧20.6ng/mL)はABI低値(<20.6ng/mL)に比較しアビラテロン酢酸エステル継続期間が有意に短かった。ABI濃度はmCSPC、mCRPC症例の患者モニタリングに有用な可能性がある。(著者抄録)

記述言語：日本語   出版者・発行元：(一社)西日本泌尿器科学会  

本邦でも2019年にがんゲノムプロファイル検査が保険承認され,がんゲノム医療が臨床実装されるに至った。九州大学病院もがんゲノム医療中核拠点病院としてがんゲノム医療において中心的な役割を担っている。そこで,がんゲノムプロファイル検査およびその結果に基づく受療機会の提供についての我々の経験について報告する。対象は2019年6月から2021年10月までに九州大学病院泌尿器・前立腺・腎臓・副腎外科においてがんゲノムプロファイル検査を施行した症例を対象とし,患者背景,臨床情報,がんゲノムプロファイル検査結果を電子カルテから収集した。その結果,腎癌4症例,尿路上皮癌9症例,前立腺癌9症例でがんゲノムプロファイル検査が施行されていた。がんゲノムプロファイル検査の結果,5症例で遺伝子異常に基づく治療が推奨されたが,受療機会の創出に結びついたのは2症例のみであった。本邦におけるがんゲノム医療は徐々に普及しているが,受療機会の提供につながる症例は少なく,がんゲノム医療の課題と考えられる。保険診療での治療に加え,治験や臨床試験での受療機会の拡大を通じて,治療につながるような継続的な取り組みが求められている。(著者抄録)

DOI： 10.1016/j.annonc.2022.05.033

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記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

リンパ節転移(LNI)を有する前立腺癌患者に対する根治的前立腺全摘除術(RP)後の治療戦略について、日本泌尿器腫瘍学会参加33施設による後方視的研究を実施した。2006年から2019年までに治療を受けたRPと骨盤リンパ節郭清後のLNI患者561例(診断時年齢中央値68歳)を対象とした。無転移生存率(MFS)を主要評価項目とし、RP後の前立腺特異抗原(PSA)持続によって患者を層別化した。PSAが持続している患者は、持続していない患者に比べて、MFSや全生存期間の予後が著しく劣っていた。多変量解析では、アンドロゲン遮断療法(ADT)+放射線療法(RT)は、PSAが持続する患者においてADT単独よりも良好なMFSと関連していた(ハザード比0.37、95%CI 0.15-0.93、p=0.034)。同様に、傾向スコアマッチング後、PSAが持続する患者において、ADT+RTはADT単独よりもMFSおよび全生存率が有意に良好であった。以上より、LNIを有する前立腺癌におけるPSA持続は予後不良のリスクを増加させ、ADTにRTを追加することを特徴とする集中治療が生存率を改善する可能性が示された。

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記述言語：英語   出版者・発行元：Oxford University Press  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Scientific Reports  

Chemotherapy is a standard therapy for muscle-invasive bladder cancer (MIBC). However, genomic alterations associated with chemotherapy sensitivity in MIBC have not been fully explored. This study aimed to investigate the genomic landscape of MIBC in association with the response to chemotherapy and to explore the biological role of genomic alterations. Genomic alterations in MIBC were sequenced by targeted exome sequencing of 409 genes. Gene expression in MIBC tissues was analyzed by western blotting, immunohistochemistry, and RNA microarray. Cellular sensitivity to gemcitabine and gemcitabine metabolite was examined in bladder cancer cells after modulation of candidate gene. Targeted exome sequencing in 20 cases with MIBC revealed various genomic alterations including pathogenic missense mutation of DPYD gene encoding dihydropyrimidine dehydrogenase (DPD). Conversely, high DPYD and DPD expression were associated with poor response to gemcitabine-containing chemotherapy among patients with MIBC, as well as gemcitabine resistance in bladder cancer cells. DPD suppression rendered cells sensitive to gemcitabine, while DPD overexpression made cells gemcitabine-resistant through reduced activity of the cytotoxic gemcitabine metabolite difluorodeoxycytidine diphosphate. This study revealed the novel role of DPD in gemcitabine metabolism. It has been suggested that DPYD genomic alterations and DPD expression are potential predictive biomarkers in gemcitabine treatment.

DOI： 10.1038/s41598-022-12528-3

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記述言語：その他   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/cancers14112696

記述言語：その他   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/cancers14112696

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Urology  

OBJECTIVE: This study aimed to assess survival outcomes in older patients with de novo metastatic prostate cancer who initially received androgen deprivation therapy. METHODS: The retrospective multicenter study included 2784 men with metastatic prostate cancer who were treated with androgen deprivation therapy between 2008 and 2017. Patients were classified into <75, 75-79, and ≥80 age groups. Propensity score matching was conducted to assess the cancer-specific survival of the groups. The 5-year net overall survival of each group was derived to evaluate relative survival compared with the general population using the Pohar-Perme estimator and the 2019 Japan Life Table. RESULTS: During the follow-up (median, 34 months), 1014 patients died, of which 807 died from metastatic prostate cancer progression. Compared with the <75 group, the cancer-specific survival of the 75-79 group was similar (hazard ratio 1.07; 95&#37; confidence interval 0.84-1.37; P = 0.580), whereas that of the ≥80 group was significantly worse (hazard ratio 1.41; 95&#37; confidence interval 1.10-1.80; P = 0.006). The 5-year net overall survival of the <75, 75-79, and ≥80 age groups were 0.678, 0761, and 0.718, respectively. The 5-year net overall survival of patients aged ≥80 years with low- and high-volume disease were 0.893 and 0.586, respectively, which was comparable with those in patients aged <75 years (0.872 and 0.586, respectively). CONCLUSIONS: Older metastatic prostate cancer patients aged ≥80 years had poorer cancer-specific survival compared with younger patients. Conversely, 5-year net overall survival in older patients aged ≥80 years was comparable with that in younger patients aged <75 years.

DOI： 10.1111/iju.14938

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記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

転移性ホルモン感受性前立腺癌患者の予後に対する複合アンドロゲン遮断(CAB)療法の有効性を腫瘍量別に検討した。2008～2017年に日本の30施設においてアンドロゲン遮断療法を施行した2048例のうち、702例(34.3%)が低腫瘍量群、1346例(65.7%)が高腫瘍量群(骨転移巣4個以上または臓器転移)であった。いずれの群でも80%を超える患者がCAB療法を施行されていた。全生存については、高腫瘍量群、低腫瘍量群のいずれにおいてもアンドロゲン遮断療法の相違による有意差は認めなかった。無増悪生存については、高腫瘍量群のCAB療法施行患者で去勢単独療法施行患者に比べて有意に良好であり、inverse probability of treatment weighting method(IPTW)法によるハザード比は0.49(95%CI 0.34～0.71)、操作変数法によるハザード比は0.80(95%CI 0.60～0.98)であった。

記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

リボソームS6キナーゼを標的とするファーストインクラス低分子阻害剤であるPMD-026のYボックス結合タンパク質1(YB-1)/アンドロゲン受容体(AR)シグナルに対する作用と前立腺癌に対する抗腫瘍効果について検討した。in vitro試験において、PMD-026は、高レベルのAR変異体を発現する去勢抵抗性前立腺癌由来の22Rv1細胞におけるYB-1リン酸化、AR V7 mRNAおよびAR変異体の発現を低下させた。前立腺癌由来のAR陰性PC-3細胞やDU145細胞および完全長ARのみを発現するLNCaP細胞に対するPMD-026の細胞毒性は、22Rv1細胞に対する細胞毒性と比較して顕著ではなかった。PMD-026は、単独および第2世代抗アンドロゲン薬であるエンザルタミドやダロルタミドとの併用により、細胞のアポトーシスとG2/M停止を誘導することで細胞増殖を抑制した。22Rv1細胞を免疫不全マウスへ移植したマウス異種移植モデルにおいて、PMD-026とエンザルタミドの併用は、PMD-026単独投与よりも顕著に腫瘍増殖を抑制した。以上より、去勢抵抗性前立腺癌に対する新規リボソームS6キナーゼ阻害剤PMD-026の優れた抗腫瘍効果および抗アンドロゲン薬エンザルタミドとの併用効果が示された。

記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

日本人の前立腺癌患者コホートにおいて、13種のリンパ節転移確率予測モデルの検証を行った。ロボット支援前立腺全摘除術および拡大骨盤リンパ節郭清術を施行した331例中61例(18.4%)にリンパ節転移を認めた。Receiver operating characteristic(ROC)曲線下面積が最も大きかったのはMemorial Sloan Kettering Cancer Center(MSKCC) web calculator(0.78)、次いでYale formula(0.77)、Brigantiノモグラム2017(0.76)、TosoianらのPartin table(0.75)であったが、これらのモデルの95%信頼区間は重複していた。較正プロットではMSKCC web calculatorとBrigantiノモグラム2017が良好であった。Decision curve analysisではすべての予測モデルがnet benefitを示したが、リンパ節転移リスク<35%においてはMSKCC web calculatorとBrigantiノモグラム2017が最も大きなnet benefitを示した。

記述言語：英語   出版者・発行元：公益社団法人 日本医師会 / 日本医学会  

<p><b>Introduction</b>: The Halabi model predicts the overall survival (OS) of patients with metastatic castration-resistant prostate cancer (mCRPC) treated with second-line therapy after docetaxel. We aimed to validate this model externally with an independent cohort, outside the setting of a clinical trial.</p><p><b>Methods</b>: In a multi-institutional study, we included 66 patients treated with cabazitaxel after docetaxel for mCRPC. Patients were stratified according to the two- and three-risk groups of the Halabi nomogram. Kaplan-Meier and Cox proportional hazard analyses were performed to estimate survival and hazard ratios (HRs). The model performance was assessed using receiver operating characteristic curves, and the associated c-index (area under the curve [AUC]).</p><p><b>Results</b>: The median OS in the two-risk groups was 5.06 months in the high-risk group (n=22) and 12.9 months in the low-risk group (n=44, p<0.001). High-risk patients had an HR of 9.50 (95% confidence interval (CI) 4.12-21.6, p<0.001) compared to low-risk patients. For the three-risk groups, the median OS was 6.44 months in the high-risk group (n=15), 5.75 months in the intermediate-risk group (n=11), and 13.7 months in the low-risk group (n=40, p=0.84). Compared to low-risk patients, intermediate-risk patients had an HR of 7.49 (95% CI 3.08-20.4, p<0.001), and high-risk patients had an HR of 8.48 (95% CI, 3.39-21.7, p<0.001). The AUC was 0.72 (95% CI 0.64-0.76) for the two-risk stratification. When comparing different risks, the AUCs were 0.48 (high vs intermediate), 0.66 (high vs low), and 0.65 (intermediate vs low).</p><p><b>Conclusions</b>: The two-risk stratification version but not the three-risk group analysis confirmed the ability of the model to predict survival. These results support the value of the Halabi nomogram in men receiving post-docetaxel second-line chemotherapy for mCRPC.</p>

DOI： 10.31662/jmaj.2021-0198

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記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Urology  

Objectives

Nerve sparing may increase positive surgical margin rate during radical prostatectomy. Our objective was to analyze the positive surgical margin rate and location as well as its impact on biochemical recurrence according to nerve sparing procedure in robot‐assisted radical prostatectomy.

Methods

We included 814 patients treated with robot‐assisted radical prostatectomy between 2009 and 2021, and evaluated the impact of nerve sparing on positive surgical margin and biochemical recurrence using logistic regression and Cox models.

Results

Unilateral nerve sparing and bilateral nerve sparing were performed in 152 (18.6%) cases and 118 (14.5%) cases, respectively. On multivariable analysis, in addition to nerve sparing, bilateral nerve sparing, but not unilateral nerve sparing was associated with an increased risk of positive surgical margin compared with non‐nerve sparing. Positive surgical margin at any location increased the risk of biochemical recurrence. During unilateral nerve sparing, positive surgical margin in nerve sparing side, but not in non‐nerve sparing side was associated with increased risk of biochemical recurrence on multivariate analysis.

Conclusions

Taken together, surgeons need to notice an increased risk of biochemical recurrence associated with positive surgical margin when performing nerve sparing in robot‐assisted radical prostatectomy, and then need to choose the patients suitable for nerve sparing.

DOI： 10.1111/iju.14900

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/iju.14900

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cancer Science  

The treatment for lymph node involvement (LNI) after radical prostatectomy (RP) has not been established. This study aimed to reveal the outcomes of various management strategies among patients with LNI after RP. Retrospectively, 561 patients with LNI after pelvic lymph node dissection (PLND) with RP treated between 2006 and 2019 at 33 institutions participating in the Japanese Urological Oncology Group were investigated. Metastasis-free survival (MFS) was the primary outcome. Patients were stratified by prostate-specific antigen (PSA) persistence after RP. Cox regression models were used to analyze the relationships between clinicopathological characteristics and survival. Survival analyses were conducted using the Kaplan-Meier method and log-rank test with or without propensity score matching. Prognoses, including MFS and overall survival, were prominently inferior among patients with persistent PSA compared with those without persistent PSA. In multivariate analysis, androgen deprivation therapy (ADT) plus radiotherapy (RT) was associated with better MFS than ADT alone among patients with persistent PSA (hazard ratio = 0.37; 95&#37; confidence interval = 0.15-0.93; p = 0.034). Similarly, MFS and overall survival were significantly better for ADT plus RT than for ADT alone among patients with persistent PSA after propensity score matching. This study indicated that PSA persistence in LNI prostate cancer increased the risk of poor prognoses, and intensive treatment featuring the addition of RT to ADT might improve survival.

DOI： 10.1111/cas.15383

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記述言語：英語   出版者・発行元：(公社)日本医師会  

ドセタキセル後に二次化学療法を受ける転移性去勢抵抗性前立腺癌(mCRPC)患者の全生存期間(OS)を予測するHalabiモデルの外的妥当性を、臨床試験とは独立の患者集団で検証した。2014年～2017年に多施設でドセタキセル後にカバジタキセルで治療したmCRPC患者を対象とした。Halabiノモグラムに基づき患者を2群または3群に層別化した。カプランマイヤー法およびCox比例ハザード分析で生存期間とハザード比(HR)を推定した。モデルの性能はROC曲線によるC統計量(AUC)で評価した。患者66例を解析した。患者をリスクにより2群に分けた場合、OS中央値は高群(22例)5.06ヵ月、低群(44例)12.9ヵ月で(p<0.001)、低群に対する高群のHRは9.50(95%CI:4.12～21.6)であった。3群に分けた場合、OS中央値は高群(15例)6.44ヵ月、中群(11例)5.75ヵ月、低群(40例)13.7ヵ月で(p=0.84)、低群に対する中群のHRは7.49(3.08～20.4)、高群のHRは8.48(3.39～21.7)であった。2群に層別化した場合のAUCは0.72、3群に層別化した場合のAUCは高群対中群0.48、高群対低群0.66、中群対低群0.65であった。以上から、2群のリスク層別化モデルで生存期間の予測能が確認された。

記述言語：日本語   出版者・発行元：(一社)日本泌尿器内視鏡・ロボティクス学会  

ロボット支援腎部分切除術の術中超音波検査は,腎腫瘍を確実に切除するために必須である.術中超音波検査に用いられるL43Kプローブは,この術式に使用される超音波プローブの1つであり,術中はフェネストレイテッド鉗子でプローブのフィンを把持して使用する.RAPNは狭い後腹膜腔で鉗子を使ってプローブを操作しなければならず,プローブ先端からフィンを把持することが頻回にあった.このフィンはプローブ先端に向かって傾斜が低くなりかつ放射状に広がっている構造のため,プローブ先端から把持できない設計になっている.これが原因でプローブ先端からの把持は安定せず,プローブを頻回に落としていた.今回我々はプローブの先端から把持しづらい課題に対して,医工連携を通してプローブアタッチメントを開発して解決したので報告する.(著者抄録)

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Urology  

DOI： 10.1111/iju.14864

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cancer Immunology, Immunotherapy  

The intravesical administration of bacillus Calmette-Guérin (BCG) is widely used to control the intravesical recurrence of non-muscle-invasive bladder cancer (NMIBC). This study aimed to reveal the effects of zygosity on human leukocyte antigen (HLA) genes and individual HLA genotypes on intravesical recurrence after intravesical BCG therapy for NMIBC. This study included Japanese patients who had received intravesical BCG for NMIBC. HLA genotyping of HLA-A, B, C, and DRB1 was performed. The effect of HLA zygosity and HLA genotype on intravesical recurrence was evaluated. Among 195 patients, those homozygous for the HLA-B supertype were more likely than those heterozygous for the HLA-B supertype to experience intravesical recurrence by univariate analysis (hazard ratio [HR], 95&#37; confidence interval [CI]; 1.87, 1.14-3.05, P = 0.012) and multivariate analysis (HR, 95&#37; CI; 2.26, 1.02-5.01, P = 0.045). Patients with B07 or B44 had a decreased risk of intravesical recurrence by univariate analysis (HR, 95&#37; CI; 0.43, 0.24-0.78, P = 0.0056) and multivariate analysis (HR, 95&#37; CI; 0.36, 0.16-0.82, P = 0.016). This study suggests the importance of the diversity and specificity of HLA-B loci in the antitumor effect of BCG immunotherapy for NMIBC. These findings may contribute to the delineation of risk strata for BCG therapy and improve the medical management of NMIBC.

DOI： 10.1007/s00262-021-03032-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japanese Journal of Clinical Oncology  

The role of local treatment in patients with de novo metastatic prostate cancer is controversial. In population-based retrospective studies, metastatic prostate cancer patients who received local treatment with prostate radiotherapy showed a better prognosis than those who did not. In addition, several prospective randomized studies demonstrated that prostate radiotherapy achieves a survival benefit for patients with oligo-metastasis. Moreover, the efficacy of metastasis-directed radiotherapy was evaluated, revealing a potential benefit for patients with oligo-metastasis. Importantly, these radiotherapies may reduce the occurrence of symptomatic local events. In this review, the rationale, efficacy and future perspectives for local prostate and metastasis-directed radiotherapy in the treatment of metastatic prostate cancer were described and summarized.

DOI： 10.1093/jjco/hyac035

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Prostate International  

Background: The CHAARTED and LATITUDE trials demonstrated a survival benefit of docetaxel and abiraterone for hormone-sensitive prostate cancer. In this study, we examined the impact of the risk stratification criteria used in the CHAARTED and LATITUDE trials on the prognosis of castration-resistant prostate cancer (CRPC). We also tested whether these risk stratification criteria could help in selecting effective initial treatment for CRPC. Method: Japanese patients with CRPC who were treated with docetaxel or androgen receptor pathway inhibitors such as abiraterone acetate or enzalutamide between 2014 and 2018 were included in this study. Clinicopathological factors, progression-free survival, and overall survival were investigated. Results: Of 215 patients, 110 men (51.2&#37;) and 93 men (43.3&#37;) were grouped as high volume by CHAARTED criteria and high risk by LATITUDE criteria, respectively. Median progression-free survival was 10.3/4.5 months (P < 0.0001) for low/high volume (CHAARTED criteria) and 9.9/4.8 months (P = 0.0032) for low/high risk (LATITUDE criteria). The median overall survival was 44.8/17.4 months (P < 0.0001) for low/high volume (CHAARTED criteria) and 37.4/17.4 months (P = 0.0011) for low/high risk (LATITUDE criteria). The prognostic impact of CHAARTED and LATITUDE criteria was comparable between androgen receptor pathway inhibitors and docetaxel as first-line treatment for CRPC. Conclusion: The CHAARTED and LATITUDE criteria were prognostic, but not useful to discriminate the therapeutic outcome between androgen receptor pathway inhibitors and docetaxel for CRPC.

DOI： 10.1016/j.prnil.2022.01.001

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記述言語：その他   掲載種別：研究論文（学術雑誌）   出版者・発行元：Prostate International  

Background: Androgen receptor pathway inhibitors (ARPIs) such as abiraterone and enzalutamide have been shown to prolong survival in patients with advanced prostate cancer. However, there is limited evidence on the anticancer effect of a reduced dose of ARPIs. This study compared the prognosis in patients with chemotherapy-naïve castration-resistant prostate cancer (CRPC) between ARPI treatment with standard dose and treatment with reduced dose. Methods: Japanese patients who were treated with ARPI as first-line treatment for CRPC between 2014 and 2018 were included. The associations between dose reduction and clinicopathological factors, progression-free survival, and overall survival were investigated. Results: Of the 162 patients included, 33 (20.4%) patients had their dose reduced during ARPI treatment. In the multivariate analysis, higher PSA, abiraterone treatment, and dose reduction were significant prognostic factors for progression-free survival (PFS); however, dose reduction was not associated with overall survival. In the enzalutamide-treated group, the median PFS was 12.1 months (95% CI, 8.5–21.4 months) in the standard-dose group and 7.2 months (95% CI, 5.0–11.5 months) in the reduced-dose group (P = 0.038). Conclusion: This study suggests inferior oncological outcome when treated with reduced-dose ARPI for CRPC. Full-dose administration of ARPI for CRPC may be appropriate if feasible.

DOI： 10.1016/j.prnil.2021.10.001

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記述言語：英語   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

DOI： 10.1200/JCO.2022.40.6_suppl.099

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cancer Science  

Ribosomal S6 kinase has been shown to play a key role in cellular resistance to endocrine therapy in prostate cancer through its regulation of YB-1/androgen receptor (AR) signaling. PMD-026, an oral first-in-class small molecule kinase inhibitor, is the first identified ribosomal S6 kinase inhibitor. This study investigated the effect of PMD-026 on YB-1/AR signaling and its antitumor effect in prostate cancer in vitro and in vivo. Castration-resistant prostate cancer 22Rv1 cells that express high-level AR variants were used in this study. The effect of PMD-026 on YB-1/AR signaling was investigated by quantitative real-time PCR and western blot analysis. The effects of PMD-026 on prostate cancer cells were investigated by cytotoxicity analysis, apoptosis assay, and cell cycle assay in vitro and a mouse castration model in vivo. PMD-026 decreased YB-1 phosphorylation as well as AR V7 mRNA and AR variant expressions in 22Rv1 cells. PMD-026 suppressed cell proliferation alone and in combination with the second-generation antiandrogens enzalutamide and darolutamide by inducing cellular apoptosis and G2/M arrest. In a mouse xenograft model, PMD-026 suppressed tumor growth, and the combination of PMD-026 and enzalutamide inhibited tumor growth more prominently than single treatments. Our results demonstrate an excellent antitumor effect of the novel ribosomal S6 kinase inhibitor PMD-026 and the combination effect with the antiandrogen enzalutamide in castration-resistant prostate cancer. These findings warrant a clinical trial of PMD-026 in prostate cancer patients.

DOI： 10.1111/cas.15280

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Andrologia  

This study aimed to investigate the significance of HSD3B1 gene status including germline polymorphism and somatic alterations in prostate cancer. Patients with prostate cancer treated with androgen-deprivation therapy, as well as tissues from metastatic prostate cancer, were included. Genomic DNA was extracted from cancer tissues and whole blood samples, and HSD3B1 (rs1047303, 1245C) was genotyped by Sanger sequencing. The association of HSD3B1 genotype with progression-free survival according to metastatic volume was examined. Copy number alteration and gene expression of HSD3B1 were examined in prostate cancer cells and public datasets. Among 194 patients, 121 and 73 patients were categorized into low- and high-volume diseases respectively. In multivariate analysis, the adrenal-permissive genotype (AC/CC) was significantly associated with increased risk of progression compared with the adrenal-restrictive genotype (AA) in low volume, but not high-volume diseases. Somatic mutation in HSD3B1 was detected at least in two cases of castration-resistant prostate cancer tissues. HSD3B1 amplification and overexpression were detected in castration-resistant prostate cancer cells and tissues. The current findings suggest that both germline and somatic alterations of HSD3B1 may cooperatively promote castration resistance in prostate cancer and HSD3B1 as a promising biomarker for precision medicine, warranting further investigations.

DOI： 10.1111/and.14307

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：公益社団法人 日本医師会 / 日本医学会  

Introduction: Studies on the effect of androgen receptor pathway inhibitors (ARPI), docetaxel (DTX), and radium-223 (Ra-223) after first-line treatment with ARPI in patients with castration-resistant prostate cancer (CRPC) are scarce. This study compared the efficacy of treatment after ARPI for CRPC. Methods: Patients with CRPC who received ARPI as first-line treatment and different second-line treatments were retrospectively reviewed. Clinicopathological backgrounds and treatment outcomes, including maximum prostate-specific antigen (PSA) decrease, progression-free survival (PFS), and overall survival (OS), were compared between second-line treatments. Results: In total, 88 patients were enrolled. Forty-one (46.6&#37;), 37 (42.0&#37;), and 10 (11.4&#37;) patients were treated with ARPI, DTX, and Ra-223, respectively. Patients whose PSA levels were not adequately reduced by first-line treatment with ARPI were eventually enrolled in the DTX treatment (P = 0.030). PSA decrease was not significantly different when comparing treatments. PFS in the DTX group was significantly better than in the other two groups (P = 0.023). In multivariate analysis, DTX was an independent prognostic factor for better PFS compared to ARPI (hazard ratio, 95&#37; confidence interval; 0.44, 0.25-0.79, P = 0.006). Subgroup analysis showed a favorable impact of DTX on PFS in patients with Gleason score >8 (interaction P = 0.027) and a PSA decline >50&#37; (interaction P = 0.019) during first-line treatment with ARPI. However, no significant difference in OS was observed between groups of different second-line treatments. Conclusions: This study suggests that in patients with CRPC, second-line treatment with DTX following progression in patients who received ARPI as first-line treatment is more beneficial compared with second-line treatment with ARPI or Ra-233.

DOI： 10.31662/jmaj.2021-0163

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Anti-Cancer Drugs  

There are multiple reports on the value of complete blood count (CBC)-related parameters on prognosis in docetaxel-treated castration-resistant prostate cancer (CRPC) patients before the emergence of androgen receptor pathway inhibitors (ARPIs). We investigated the prognostic significance of CBC-related parameters in docetaxel-treated CRPC patients. Patients treated with docetaxel chemotherapy for CRPC between 2008 and 2018 were included. We analyzed the relevance of CBC-related parameters to oncological prognosis in docetaxel chemotherapy, associated with prior use of novel ARPIs. Among 144 Japanese men treated with docetaxel, 49 men (34.0&#37;) had already received ARPI therapy. A high neutrophil-lymphocyte ratio (NLR) was a prognostic factor for poor progression-free survival and overall survival (OS) in both univariate and multivariate analyses. In addition, a low hemoglobin (Hb) level and a high systemic immune-inflammation index (SII) were prognostic factors of poor OS in univariate analysis. Hb level was a prognostic factor of OS in both ARPI-naive and ARPI-treated patients. However, a high NLR and SII were only associated with a poor prognosis in ARPI-naive but not in ARPI-treated patients. Hb, NLR, and SII have been suggested to be prognosticators in docetaxel-treated CRPC patients. The differential prognostic value of NLR and SII between ARPI-naive and ARPI-treated patients may require caution when using these markers in docetaxel-treated CRPC patients.

DOI： 10.1097/CAD.0000000000001170

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Urology  

OBJECTIVE: To determine the effect of combined androgen blockade with a first-generation anti-androgen on the prognoses of metastatic hormone-sensitive prostate cancer patients stratified by tumor burden. METHODS: We retrospectively analyzed the cases of metastatic hormone-sensitive prostate cancer patients who were treated with androgen deprivation therapy in 2008-2017 at 30 institutions in Japan. To compare the overall survival and progression-free survival rates of the patients treated with castration monotherapy and combined androgen blockade, we carried out a Cox proportional hazards regression analysis using both inverse probability of treatment weighting and instrumental variables methods. High-burden disease was defined as the presence of four or more bone metastases and/or visceral metastasis. RESULTS: Of 2048 patients, 702 (34.3&#37;) and 1346 (65.7&#37;) patients were classified as the low- and high-burden groups, respectively. In each group, >80&#37; of the patients were treated with combined androgen blockade. Although there was no significant between-group difference in the overall survival according to the androgen deprivation therapy method, in the high-burden group the progression-free survival of the combined androgen blockade-treated patients was significantly better than that of patients treated with castration monotherapy: inverse probability of treatment weighting method, hazard ratio 0.49, 95&#37; confidence interval 0.34-0.71; instrumental variables method, hazard ratio 0.80, 95&#37; confidence interval 0.60-0.98. CONCLUSION: In the high-burden group, combined androgen blockade with a first-generation anti-androgen resulted in superior progression-free survival compared with castration monotherapy. For well-selected metastatic hormone-sensitive prostate cancer patients, the use of combined androgen blockade might still have some suitable scenarios.

DOI： 10.1111/iju.14793

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記述言語：日本語  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Urology  

OBJECTIVES: To investigate predictive factors of survival of metastatic castration-resistant prostate cancer patients undergoing first-line treatment with androgen receptor pathway inhibitors or docetaxel. METHODS: Japanese patients with metastatic castration-resistant prostate cancer treated with androgen receptor pathway inhibitor or docetaxel between 2008 and 2018 were included. The differential impact of various clinicopathological factors on the outcome, including progression-free survival and overall survival, was compared between treatment with androgen receptor pathway inhibitor and docetaxel. RESULTS: Of 254 patients with metastatic castration-resistant prostate cancer, 119 (46.9&#37;) and 135 (53.2&#37;) were treated with androgen receptor pathway inhibitor and docetaxel, respectively. The multivariate analysis showed that androgen receptor pathway inhibitor was an independent prognostic factor for better progression-free survival (hazard ratio 0.62, 95&#37; confidence interval 0.42-0.92, P = 0.016) and overall survival (hazard ratio 0.61, 95&#37; confidence interval 0.41-0.93, P = 0.021), compared with docetaxel. Pretreatment prostate-specific antigen levels and time to castration-resistant prostate cancer were differentially associated with progression-free survival and overall survival between androgen receptor pathway inhibitor or docetaxel. In patients who presented <6 months to castration-resistant prostate cancer, progression-free survival was shorter in those treated with androgen receptor pathway inhibitor (median 1.1 months, 95&#37; confidence interval 0.2-2.8 months) compared with those who received docetaxel (median 5.0 months, 95&#37; confidence interval 1.8-6.7 months; P = 0.014). CONCLUSIONS: First-line therapy with androgen receptor pathway inhibitor is associated with a better prognosis when compared with docetaxel, even after adjustment for prognostic factors. However, a shorter time to castration-resistant prostate cancer is associated with better progression-free survival for patients receiving docetaxel, suggesting that docetaxel is the preferred option for patients with a shorter time to castration-resistant prostate cancer.

DOI： 10.1111/iju.14702

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Urology  

OBJECTIVES: There are many models to predict lymph node involvement in patients with prostate cancer. We aimed to externally validate several models in a Japanese cohort. METHODS: We considered patients who were treated with robotic-assisted radical prostatectomy with extended pelvic lymph node dissection for prostate cancer. The risk of lymph node involvement was calculated for each patient in several models. Model performance was assessed by calculating the receiver operating characteristic curve and the area under the curve, calibration plots, and decision curve analyses. RESULTS: We identified lymph node involvement in 61 (18.4&#37;) of the 331 considered patients. Patients with lymph node involvement had a higher prostate-specific antigen level, percentage of positive biopsy cores, primary Gleason grade, Gleason group grade, and clinical T-stage category. The Memorial Sloan Kettering Cancer Center web calculator presented the highest area under the curve (0.78) followed by the Yale formula area under the curve (0.77), the updated version of Briganti nomogram of 2017 area under the curve (0.76), and the updated version of the Partin table by Tosoian et al. had an area under the curve of 0.75. However, the 95&#37; confidence interval for these models overlapped. The calibration plot showed that the Memorial Sloan Kettering Cancer Center web calculator and the updated version of the Briganti nomogram calibrated better. In the decision curve analyses, all models showed net benefit; however, it overlapped among them. However, the Memorial Sloan Kettering Cancer Center web calculator and the updated Briganti nomogram presented the highest net benefit for lymph node involvement risks <35&#37;. CONCLUSION: Models predicting lymph node involvement were externally validated in Japanese men. The Memorial Sloan Kettering Cancer Center web calculator and the updated Briganti nomogram of 2017 were the most accurate performing models.

DOI： 10.1111/iju.14802

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記述言語：日本語   出版者・発行元：(有)科学評論社  

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記述言語：英語   出版者・発行元：(公社)日本医師会  

去勢抵抗性前立腺癌患者88例を対象とした後ろ向き研究を実施し、androgen receptor pathway inhibitors(ARPI)による初回治療後の2次治療効果を比較した。2次治療によりARPI群41例(年齢中央値76歳)、ドセタキセル(DTX)群37例(年齢中央値74歳)、Ra-223群10例(年齢中央値73歳)に分けて検討した。評価項目は臨床病理学的特徴、前立腺特異抗原(PSA)の最大低下率、無増悪生存期間(PFS)、全生存期間(OS)などとした。その結果、治療群間でPSA減少に有意差は認められなかった。また、DTX群では他2群と比較してPFSが良好であることが示された。また、多変量解析の結果、ARPIと比較してDTXはPFS改善の独立した予後因子であった(ハザード比0.44、P=0.006)。サブグループ解析の結果、ARPIによる初回治療時、グリソンスコア>8であった患者、PSA低下率>50%の患者において、DTXがPFSへ好影響をもたらすことが示された(交互作用P=0.027、P=0.019)。しかし、二次治療間でOSに有意差は認められなかった。以上のように、ARPIによる初回治療後の二次治療として、DTXはARPIまたはRa-233と比較してより有益であることが示唆された。

記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

転移性去勢抵抗性前立腺癌(CRPC)の第一選択治療としてアンドロゲン受容体経路阻害剤(ARPI)やドセタキセルの臨床転帰に関する予測マーカーを検討した。2008年から2018年までにARPIまたはドセタキセルによる治療を受けた転移性CRPCの日本人患者254例(年齢中央値73歳)を対象とした。転移性CRPC患者254例のうち、119例と135例がそれぞれARPIとドセタキセルを受けた。多変量解析の結果、ARPIは、ドセタキセルと比較して、無増悪生存期間(PFS)(ハザード比0.62、95%CI 0.42～0.92、p=0.016)および全生存期間(OS)(ハザード比0.61、95%CI 0.41～0.93、p=0.021のより良い独立した予後因子であった。治療前の前立腺特異抗原レベルとCRPCになるまでの期間は、ARPIとドセタキセルでは、PFSやOSと異なる相関が認められた。CRPCを6ヵ月未満で発症した患者のうち、ARPIを受けた患者のPFS(中央値1.1ヵ月、95%CI 0.2～2.8ヵ月)は、ドセタキセルを受けた患者のPFS(中央値5.0ヵ月、95%CI 1.8～6.7ヵ月、p=0.014)よりも短かった。以上より、ARPIによる一次治療は、予後因子を調整した後でも、ドセタキセルと比較してより良い予後と関連していた。

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cancer Treatment and Research Communications  

Since 1941, the standard treatment for metastatic castration-sensitive prostate cancer (mCSPC) was androgen deprivation therapy (ADT) by surgical or medical castration with or without first-generation antiandrogen. However, the efficacy of ADT does not last in most cases. In the 2010s, de-intensification by intermittent ADT was evaluated by RCTs for mCSPC to mitigate the treatment-emerged burdens. However, intermittent ADT failed to show non-inferiority in OS for mCSPC and is an optional treatment for selected patients with mCSPC. The treatment for patients with mCSPC has improved in the last years. Currently, based on the evidence from RCTs, intensification treatment by adding docetaxel, novel androgen receptor pathway inhibitors and multimodal treatment using radiotherapy to the primary have become new standard treatments for mCSPC. Furthermore, ongoing RCTs have been investigating the clinical values of more intensified treatments by combining multiple effective treatment for mCSPC. In addition, novel treatment using immunotherapeutics such as anti-PD-1 antibody and precision medicine approach using novel imaging and genomic marker has been investigated vigorously. Thus, we review current treatment evidence obtained by RCTs that included patients with mCSPC. The future key to mCSPC treatment could be personalized medicine including translational and clinical medicine aspects, with molecular testing to assess the biological tumor behavior to optimize clinical decision-making.

DOI： 10.1016/j.ctarc.2022.100606

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記述言語：日本語   出版者・発行元：一般社団法人 日本泌尿器内視鏡・ロボティクス学会  

<p>　腎腫瘍は局在と形態は多岐にわたり, 腎血管の数と形態にも個体差がある. 従って, ロボット支援腎部分切除術 (robot-assisted partial nephrectomy ; RAPN) では多様な解剖学的特徴を踏まえ手術のアプローチ方法を術前に計画しておく必要がある. この術前計画において, 医療画像から作成された腎癌3D画像は, 腎腫瘍や腎血管の情報を視覚的に理解するのに役立ち, この画像を使った3次元的な解剖理解によって腎動脈の遮断予定部位, 温存可能な血管の確認と腫瘍切除に伴う尿路の損傷範囲を予測することが可能となり, 詳細な術前計画を立てることができる. しかし, 3D画像を生成するためには, 医用画像解析ワークステーションとソフトウエアが必要となり, これらを扱うための専門知識がユーザーには求められる. また, 多様なソフトウエアをクラウドベースまたはサブスクライブされたアプリケーションの中から, ユーザーの用途に合わせて選択しなければならない. そして, ユーザーはソフトウエアを使って腎臓, 腫瘍, 腎血管や尿路をセグメンテーションしてラベルデータを作成し, このデータをレンダリングして3D画像を作成することになる. 従って, ソフトウエアを使った腎癌3D画像の作成は, RAPNのナビゲーションを実施する上で重要でかつ最初のタスクである. しかし, このタスクを遂行する上で, 多くの医療者は医療解析ソフトの特性からその操作方法に至るまでの知識と経験を持ち合わせていない場合があり, 3D画像を使ったRAPNのナビゲーションの導入についてハードルが高く感じていることがある.</p><p>　本稿では, ナビゲーションを実践するために重要な腎癌3D画像の作成について, 最新の知見を含め報告する.</p>

DOI： 10.11302/jserjje.35.2_198

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記述言語：日本語   出版者・発行元：一般社団法人 日本泌尿器内視鏡・ロボティクス学会  

<p>　ロボット支援腎部分切除術の術中超音波検査は, 腎腫瘍を確実に切除するために必須である. 術中超音波検査に用いられるL43Kプローブは, この術式に使用される超音波プローブの1つであり, 術中はフェネストレイテッド鉗子でプローブのフィンを把持して使用する. RAPNは狭い後腹膜腔で鉗子を使ってプローブを操作しなければならず, プローブ先端からフィンを把持することが頻回にあった. このフィンはプローブ先端に向かって傾斜が低くなりかつ放射状に広がっている構造のため, プローブ先端から把持できない設計になっている. これが原因でプローブ先端からの把持は安定せず, プローブを頻回に落としていた. 今回我々はプローブの先端から把持しづらい課題に対して, 医工連携を通してプローブアタッチメントを開発して解決したので報告する.</p>

DOI： 10.11302/jserjje.35.1_109

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/iju.14709

記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Although cell-free DNA (cfDNA) testing is expected to drive cancer precision medicine, little is known about the significance of detecting low-frequency variants in circulating cell-free tumor DNA (ctDNA) in castration-resistant prostate cancer (CRPC). We aimed to identify genomic profile including low-frequency variants in ctDNA from patients with CRPC and investigate the clinical utility of detecting variants with variant allele frequency (VAF) below 1&#37;. EXPERIMENTAL DESIGN: This prospective, multicenter cohort study enrolled patients with CRPC eligible for treatment with abiraterone or enzalutamide. We performed targeted sequencing of pretreatment cfDNA and paired leukocyte DNA with molecular barcodes, and ctDNA variants with a VAF ≥0.1&#37; were detected using an in-house pipeline. We investigated progression-free survival (PFS) and overall survival (OS) after different ctDNA fraction cutoffs were applied. RESULTS: One hundred patients were analyzed (median follow-up 10.7 months). We detected deleterious ATM, BRCA2, and TP53 variants even in samples with ctDNA fraction below 2&#37;. When the ctDNA fraction cutoff value of 0.4&#37; was applied, significant differences in PFS and OS were found between patients with and without defects in ATM or BRCA2 [HR, 2.52; 95&#37; confidence interval (CI), 1.24-5.11; P = 0.0091] and TP53 (HR, 3.74; 95&#37; CI, 1.60-8.71; P = 0.0014). However, these differences were no longer observed when the ctDNA fraction cutoff value of 2&#37; was applied, and approximately 50&#37; of the samples were classified as ctDNA unquantifiable. CONCLUSIONS: Detecting low-frequency ctDNA variants with a VAF <1&#37; is important to identify clinically informative genomic alterations in CRPC.

DOI： 10.1158/1078-0432.CCR-21-2328

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/iju5.12349

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: To explore the prognostic value of lower urinary tract symptoms (LUTS) in patients with newly diagnosed regional lymph node-positive prostate cancer. PATIENTS AND METHODS: The prognostic value of LUTS for progression-free (PFS) and overall (OS) survival, as well as the differential prognostic impact of radiotherapy by LUTS was investigated. RESULTS: Univariate Cox-model analysis showed a statistically significantly increased hazard risk for PFS and OS for men with International Prostate Symptom Score (IPSS)≥19 and Overactive Bladder Symptom Score (OABSS) ≥8 at diagnosis. Patients with lower IPSS had a better PFS at 5 years (70.0&#37; vs. 51.9&#37;, p=0.027) and OS at 5 year (89.3&#37; vs. 73.6&#37;, p=0.016). Similarly, a lower OABSS was associated with greater PFS at 5 years (67.4&#37; vs. 23.4&#37;, p<0.001) and OS at 5 years (85.3&#37; vs. 57.1&#37;, p=0.012). CONCLUSION: IPSS and OABSS were prognostic for PFS and OS in patients with regional lymph node-metastatic prostate cancer.

DOI： 10.21873/anticanres.15373

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Bacillus Calmette-Guérin (BCG) instillation therapy is widely used to reduce intravesical recurrence in non-muscle invasive bladder cancer (NMIBC). In this study, we aimed to reveal the genetic variations associated with intravesical recurrence after BCG therapy for NMIBC in a genome-wide association study (GWAS). MATERIALS AND METHODS: This study included Japanese patients with NMIBC, in whom genomic DNA was obtained from whole blood samples. The association between genetic variation and treatment failure was analyzed by GWAS in 44 patients treated with BCG instillation as a discovery cohort. Candidate single-nucleotide polymorphisms (SNPs) were examined separately in 47 patients treated with BCG instillation and in 62 patients treated with chemotherapeutic agent instillation as validation studies. RESULTS: Among the 44 patients in the discovery cohort, 14 cases experienced intravesical recurrent diseases. GWAS identified 12 candidate SNPs (rs9374832, rs35176001, rs363765, rs2127120, rs4277759, rs73664140, rs1607282, rs12141654, rs4541358, rs6986852, rs12373386, and rs17637903). In the validation study, a genetic risk stratification model using the number of risk alleles in rs363765 and rs6986852 discriminated the risk of intravesical recurrence after BCG therapy, but not after non-BCG therapy. CONCLUSION: This study suggested that several SNPs were associated with intravesical recurrence after BCG therapy for NMIBC. A genetic risk model may be useful to predict intravesical recurrence after BCG therapy, warranting further research and development for clinical application.

DOI： 10.1016/j.urolonc.2021.05.034

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Remarkable developments in the treatment of metastatic castration-resistant prostate cancer (mCRPC) have been achieved over the past decade. Although targeting the novel androgen receptor axis and using chemotherapeutic agents have improved survival, mCRPC is still a lethal disease. A better molecular characterization of cancer resulted in the determination of the important role of homologous recombination repair (HRR) genes in cancer development, and poly (ADP-ribose) polymerase (PARP) is one of the most attractive therapeutic targets. Recent clinical studies have demonstrated that PARP inhibitors significantly improve oncological outcomes in patients with mCRPC harboring BRCA mutations, and PARP inhibitors are becoming a standard of care for these patients. However, not only PARP inhibitors, but also chemotherapeutic agents such as platinum agents, taxanes, and radium-223 are active in HRR gene mutation carriers, and platinum sensitivity may predict the efficacy of PARP inhibitors for mCRPC. The combination of PARP inhibitors with other anti-cancer agents may overcome resistance mechanisms against PARP inhibitors and lead to survival benefits. Appropriate treatment sequences and combinations may change the therapeutic landscape of DNA repair deficient mCRPC.

DOI： 10.21873/anticanres.15282

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: The objectives of this study were to analyze the conditional survival and prognostic factors in androgen deprivation therapy for prostate cancer using the Japan Study Group of Prostate Cancer database. METHODS: Data on patients treated with primary androgen deprivation therapy between 2001 and 2003 from a nationwide database of the Japan Study Group of Prostate Cancer were used. The conditional 5-year progression-free rate, cancer-specific survival and overall survival, as well as the conditional mortality owing to prostate cancer and other causes were calculated as per subgroups. Prognostic factors for progression-free rate, cancer-specific survival and overall survival at each time after androgen deprivation therapy initiation were calculated using the Cox proportional hazards model. RESULTS: The conditional 5-year progression-free rate and cancer-specific survival, but not overall survival, gradually increased with time. The prognostic impact of stage IV characteristics (T4, N1 and M1) changed over time; however, the prognostic impact of the Gleason score remained unchanged. In the subgroup analysis, prostate-specific mortality risk reduced over time in patients with stage IV prostate cancer, whereas non-prostate cancer mortality increased over time in elderly patients. CONCLUSIONS: Information regarding conditional survival and mortality obtained in this study would provide a benchmark for physicians and cancer survivors.

DOI： 10.1111/iju.14605

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The metastatic burden is a critical factor for decision-making in the treatment of metastatic hormone-sensitive prostate cancer (HSPC). This study aimed to develop and validate a novel risk model for survival in patients with de novo low- and high-burden metastatic HSPC. The retrospective observational study included men with de novo metastatic prostate cancer who were treated with primary androgen-deprivation therapy at 30 institutions across Japan between 2008 and 2017. We created a risk model for overall survival (OS) in the discovery cohort (n = 1449) stratified by the metastatic burden (low vs high) and validated its predictive ability in a separate cohort (n = 951). Based on multivariate analyses, lower hemoglobin levels, higher Gleason grades, and higher clinical T-stage were associated with poor OS in low-burden disease. Meanwhile, lower hemoglobin levels, higher Gleason grade group, liver metastasis, and higher extent of disease scores in bone were associated with poor OS in patients with high-burden disease. In the discovery and validation cohorts, the risk model using the aforementioned parameters exhibited excellent discriminatory ability for progression-free survival and OS. The predictive ability of this risk model was superior to that of previous risk models. Our novel metastatic burden-stratified risk model exhibited excellent predictive ability for OS, and it is expected to have several clinical uses, such as precise prognostic estimation.

DOI： 10.1111/cas.15038

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1245/s10434-021-10282-w

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Currently, there is no established prognostic serum parameter except PSA in clinically regional lymph node-positive prostate cancer. The aim of this study was to identify serum prognostic factors in clinically regional lymph node-positive prostate cancer. PATIENTS AND METHODS: Patients diagnosed with regional lymph node-positive prostate cancer between 2008 and 2017 were included. The prognostic value of serum parameters for progression-free survival (PFS) and overall survival (OS) was investigated. RESULTS: Univariate and multivariate analyses showed a statistically significant increased hazard risk for PFS and OS for men with lactate dehydrogenase (LDH) ≥230 IU/l at diagnosis. PFS at 5 years for patients with high and low LDH levels were 69.9&#37; (95&#37; CI=56.8-79.8&#37;) and 18.9&#37; (95&#37; CI=1.23-53.2&#37;), respectively (p=0.003). OS at 5 years for low and high LDH levels were 89.2&#37; (95&#37; CI=78.6-94.7&#37;) and 46.3 (95&#37; CI=11.2-76.2&#37;), respectively (p=0.006). CONCLUSION: This study shows that LDH is an independent predictor of PFS and OS in patients with regional lymph node metastatic prostate cancer.

DOI： 10.21873/anticanres.15183

記述言語：英語   掲載種別：研究論文（学術雑誌）  

This study aimed to analyze the survival rate and to examine the risk of death from prostate cancer when accounting for competing risk of death, in men aged ≥80 y treated with primary androgen deprivation therapy (ADT). Data of patients with prostate cancer who had received ADT were extracted from a nationwide community-based database established by the Japan Study Group for Prostate Cancer. Prognostic variables, including progression-free survival, cancer-specific survival, overall survival, and death rates were compared between men stratified by prostate cancer risk. Overall, 4760 patients older than 80 y were included. The proportion of low-, intermediate-, high-, or very high-risk, regional, and metastatic prostate cancer among super-elderly men was 9.5&#37;, 14.6&#37;, 48.8&#37;, 9.0&#37;, 3.2&#37;, and 24.9&#37;, respectively. Survival rates decreased with increasing risk stratification. The cumulative 5-y death rate by prostate cancer for low-, intermediate-, high-, or very high-risk, regional, and metastatic prostate cancer, was 0.92&#37; (95&#37; confidence interval [CI]: 0.2&#37;-3.6&#37;), 1.6&#37; (95&#37; CI: 0.8&#37;-3.4&#37;), 5.75&#37; (95&#37; CI: 4.25&#37;-7.75&#37;), 15.6&#37; (95&#37; CI: 11.6&#37;-23.3&#37;), 20.7&#37; (95&#37; CI: 13.1&#37;-31.7&#37;), and 36.9&#37; (95&#37; CI: 32.8&#37;-41.4&#37;), respectively. Our findings support that there is no need for immediate ADT for low- and intermediate-risk groups. Conversely, in high- or very high-risk, regional, and metastatic prostate cancer, more efforts for curative therapy and intensive therapy are needed in selected patients.

DOI： 10.1111/cas.14974

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although docetaxel (DTX) confers significant survival benefits in patients with castration-resistant prostate cancer (CRPC), resistance to DTX inevitably occurs. Therefore, clarifying the mechanisms of DTX resistance may improve survival in patients with CRPC. Claspin plays a pivotal role in DNA replication stress and damage responses and is an essential regulator for the S-phase checkpoint. CLSPN is an oncogenic gene that contributes to tumor proliferation in several human solid tumors. However, the clinical significance of claspin in prostate cancer (PCa) has not been examined. The present study aimed to elucidate the role of claspin and its relationship with DTX resistance in PCa. We immunohistochemically analyzed the expression of claspin in 89 PCa cases, of which 31 (35&#37;) were positive for claspin. Claspin-positive cases were associated with higher Gleason score, venous invasion, and perineural invasion. Kaplan-Meier analysis showed that high claspin expression was related to poor prostate-specific antigen (PSA) relapse-free prognosis. In a public database, high CLSPN expression was associated with poor PSA relapse-free prognosis, Gleason score, T stage, lymph node metastasis, CRPC, and metastatic PCa. Claspin knockdown by siRNA decreased cell proliferation, upregulated DTX sensitivity, and suppressed the expression of Akt, Erk1/2, and CHK1 phosphorylation in DU145 and PC3 cell lines. Furthermore, claspin expression was much more upregulated in DTX-resistant DU145 (DU145-DR) than in parental DU145 cells. Claspin knockdown significantly upregulated the sensitivity to DTX in DU145-DR cells. These results suggest that claspin plays an important role in PCa tumor progression and DTX resistance.

DOI： 10.1002/cam4.4113

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Missense polymorphism in HSD3B1, encoding 3β-hydroxysteroid dehydrogenase-1, was associated with outcome after abiraterone treatment. Other androgen-metabolizing enzymes may be involved in therapeutic effect in abiraterone. In this study, we investigated the significance of polymorphisms in genes involved in androgen and abiraterone metabolisms in prostate cancer patients treated with abiraterone. A total of 99 Japanese male castration-resistant prostate cancer patients treated with abiraterone between 2014 and 2018 were included. Genomic DNA was obtained from whole blood samples, and genotyping on SRD5A2 (rs523349), CYP17A1 (rs743572), CYP17A1 (rs2486758), and AKR1C3 (rs12529) was performed by PCR-based technique. Among the 99 patients, 32 (32.3&#37;), 49 (49.5&#37;), and 18 patients (18.2&#37;) carried GG, GC, and CC alleles in SRD5A2, respectively. CC allele was associated with lower risk of treatment failure (hazard ratio, 0.43; 95&#37; confidence interval, 0.20-0.87; P = 0.017) on multivariate analyses, compared with GG/GC alleles. In the combination model using HSD3B1 and SRD5A2 polymorphisms, compared with the combination of AA in HSD3B1 and GG/GC in SRD5A2, other combinations were associated with lower risk of treatment failure (hazard ratio, 0.34; 95&#37; confidence interval, 0.17-0.62; P = 0.0003) on multivariate analyses. This study showed that SRD5A2 genetic variation was associated with the risk of treatment failure in abiraterone. Combinational use of genetic variation in HSD3B1 with SRD5A2 genetic variation augmented the ability of prognostic stratification.

DOI： 10.1038/s41397-021-00220-0

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/iju5.12291

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: The International Reporting Items for Practice Guidelines in Healthcare (RIGHT) statement is a set of recommendations for reporting in clinical practice guidelines (CPGs). We aimed to use RIGHT to evaluate the reporting quality of CPGs on prostate cancer. Methods: We systematically searched literature databases and websites from January 1, 2018 to December 1, 2020 to identify CPGs on prostate cancer. Two investigators reviewed the identified articles and assessed the reporting quality independently by using the RIGHT checklist. We reported the proportions of guidelines that complied with each of the 35 RIGHT checklist item and the mean reporting compliance percentages for each of the seven domains of RIGHT. Results: A total of 38 CPGs were included. The mean overall reporting rate over the included CPGs was 51.6&#37;. Eighteen items were reported by more than half of the guidelines four items (1a 3, 7a and 13a) were reported by all guidelines. Items 7b (10.5&#37;), 13b (10.5&#37;), 14c (13.2&#37;), and 18b (7.9&#37;) had the lowest reporting proportions. The mean reporting rates in each RIGHT domain were 74.6&#37; for "Basic Information", 26.3&#37; for "Review and quality assurance", 59.9&#37; for "Background", 43.7&#37; for "Evidence", 43.2&#37; for "Recommendations", 43.4&#37; for "Funding and declaration and management of interests", and 43.0&#37; for "Other information". Conclusions: The overall adherence of CPGs on prostate cancer to RIGHT checklist is poor. Following the RIGHT checklist during the development of the guideline could improve the quality of reporting in the future.

DOI： 10.21037/atm-21-2956

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Homeobox genes function as master regulatory transcription factors during embryogenesis. HOXB5 is known to play an important role in several cancers. However, the biological role of HOXB5 in prostate cancer (PCa) is not fully elucidated. This study aimed to analyze the expression and function of HOXB5 and involvement of HOXB5 in neuroendocrine differentiation in PCa. Immunohistochemistry showed that 56 (43.8&#37;) of 128 cases of localized PCa were positive for HOXB5. HOXB5-positive cases were associated with poor prostate-specific antigen recurrence-free survival after prostatectomy. Among 74 cases of metastatic PCa, 43 (58.1&#37;) were positive for HOXB5. HOXB5 expression was higher in metastatic PCa than that in localized PCa. HOXB5 knockdown suppressed cell growth and invasion, but HOXB5 overexpression increased cell growth and invasion in PCa cell lines. Furthermore, HOXB5 regulated RET expression. Gene set enrichment analysis revealed that Nelson androgen response gene set was enriched in low HOXB5 expression group. RB1 knockout increased HOXB5 expression. Of note, additional p53 knockdown further increased HOXB5 expression in RB1 knockout cells. In silico analysis showed that HOXB5 expression was increased in neuroendocrine PCa (NEPC). These results suggest that HOXB5 may be a promising prognostic marker after prostatectomy and is involved in progression to NEPC.

DOI： 10.3390/biomedicines9080893

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: This study aimed to reveal the prognostic values of prior local therapy in first-line therapy using androgen receptor-axis targeting agents (abiraterone or enzalutamide) or docetaxel for castration-resistant prostate cancer (CRPC). METHODS: The study included 303 patients treated with first-line therapy for non-metastatic and metastatic CRPC. The association between prior local therapy and therapeutic outcome including progression-free survival and overall survival was investigated by univariate and multivariate analyses as well as propensity score-matched analysis. RESULTS: In univariate analysis, local prior therapy was associated with a lower risk of all-cause mortality (hazard ratio, 0.56, 95&#37; confidence interval, 0.40-0.79; P = 0.0009). Overall survival, but not progression-free survival, was better among patients with prior local therapy compared with patients without prior local therapy even after multivariate analysis and propensity score-matched analysis. CONCLUSIONS: This study robustly indicated that prior local treatment was prognostic for overall survival among patients with CRPC. This finding is useful to predict patient prognosis in CRPC.

DOI： 10.1093/jjco/hyab019

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: To identify predictors of renal function preservation, and to compare the global and split renal function outcomes of robot-assisted partial nephrectomy and laparoscopic partial nephrectomy. METHODS: Demographic, operative and pathological data, as well as renal function outcomes, of 251 patients who underwent laparoscopic (n = 104) and robot-assisted (n = 147) partial nephrectomy between 2008 and 2018 were retrospectively analyzed. Propensity score matching (1:1) was carried out to adjust for potential baseline confounders. Functional outcomes were assessed based on the estimated glomerular filtration rate and dynamic renal scintigraphy (using 99m Tc-mercaptoacetyltriglycine), including renal volumetric analysis. RESULTS: A total of 98 patients were allocated to each partial nephrectomy group. Ischemic (laparoscopic vs robot-assisted partial nephrectomy: 29 vs 15 min, P < 0.001) and operative times (181 vs 100 min, P < 0.001) were shorter in robot-assisted partial nephrectomy. The preservation ratio of global renal function at 3 months (88.3&#37; vs 91.4&#37;, P = 0.040) and 12 months (87.8&#37; vs 91.5&#37;, P = 0.010) postoperatively, and the renal function of the operated kidney (80.3&#37; vs 88.2&#37;, P < 0.001) were greater after robot-assisted partial nephrectomy. In robot-assisted partial nephrectomy, the volume of resected parenchyma was significantly smaller (27.2 vs 15.5 mL, P < 0.001), resulting in greater postoperative normal parenchymal volumes (120 vs 132 mL, P < 0.001) and a greater parenchymal preservation ratio (81.1&#37; vs 90.1&#37;, P < 0.001). The parenchymal preservation ratio was the strongest predictor of renal function preservation after surgery (P < 0.001, odds ratio 6.02). CONCLUSIONS: Robot-assisted partial nephrectomy allows better preservation of split renal function than laparoscopic partial nephrectomy by increasing the parenchymal preservation ratio. This translates into better postoperative global renal function.

DOI： 10.1111/iju.14525

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: There is little data on the outcome of cabazitaxel (CBZ) treatment of elderly patients with castration-resistant prostate cancer (CRPC). This study assessed the efficacy and safety of CBZ chemotherapy in patients with CRPC aged 75 years or older in a multiinstitutional study. Methods: We retrospectively reviewed the 74 patients with CRPC treated with CBZ enrolled in 10 institutions. Clinicopathological backgrounds, prognosis including prostate-specific antigen decline, time to treatment failure, progression-free survival, overall survival, and safety profiles were compared between younger (<75 years) and elder (≥75 years) patients. Results: In total, 74 patients were enrolled; 50 patients were younger than 75 years and 24 were ≥75 years. Clinicopathological characteristics were comparable between younger and elder patients, with the exception of serum albumin values at the time of CBZ treatment. The median prostate-specific antigen decline in younger and elder men was -8.8&#37; and -32.3&#37; from baseline, respectively. The median time to treatment failure, progression-free survival, and overall survival for younger and elder men were 0.24 and 0.33 years, 0.23 and 0.43 years, and 0.69 and 1.17 years, respectively. In addition, safety profiles were comparable between younger and elder patients. Conclusions: This multiinstitutional study suggests that patients with CRPC aged 75 years or older eligible for CBZ treatment can be treated safely and with noninferior efficacy compared with those younger than 75 years.

DOI： 10.1016/j.prnil.2020.12.001

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: This study investigated the prognostic significance of complete blood count data in castration-resistant prostate cancer patients treated using androgen receptor pathway inhibitors (ARPIs). PATIENTS AND METHODS: Patients treated with an ARPI, abiraterone or enzalutamide, as first-line therapy for castration-resistant prostate cancer from 2014 to 2018 were included. The association between complete blood count data and prognoses including progression-free survival and overall survival (OS) was investigated. RESULTS: High white blood cell counts (<median vs. ≥median; hazard ratio [HR], 1.82, 95&#37; confidence interval [CI], 1.14-2.89; P = 0.012) and high neutrophil-to-lymphocyte ratios (<median vs. ≥median; HR, 1.90, 95&#37; CI, 1.11-3.27; P = 0.020) were associated with a high risk of progression in univariate analysis. In univariate analysis, high hemoglobin (Hb) levels (<median vs. ≥median; HR, 0.41, 95&#37; CI, 0.24-0.73; P = 0.0023) and high red cell distribution widths (<median vs. ≥median; HR, 2.41, 95&#37; CI, 1.37-4.25; P = 0.0023) were associated with a low and a high risk of all-cause mortality, respectively. In multivariate analysis, high Hb levels (<median vs. ≥median; HR, 0.42, 95&#37; CI, 0.22-0.79; P = 0.0076) were repeatedly associated with a low risk of all-cause mortality. CONCLUSION: We found that white blood cell counts and neutrophil-to-lymphocyte ratios may be prognostic for progression-free survival while red cell distribution widths may be prognostic for OS. In particular, a low Hb level was a robust prognostic factor for poor OS. These findings could be useful in predicting prognosis in CRPC patients treated with ARPIs.

DOI： 10.1016/j.urolonc.2020.09.036

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Tubulin-β3 encoded by the Tubulin-β3 (TUBB3) gene is a microtubule protein. Previous studies have shown that TUBB3 expression is upregulated in castration-resistant prostate cancer (CaP) and is involved in taxane resistance. However, the biological mechanism of TUBB3 involvement in the progression to castration-resistant CaP is not fully elucidated. This study aimed to analyze the expression and function of TUBB3 in localized and metastatic CaP. METHODS: TUBB3 expression was determined using immunohistochemistry in localized and metastatic CaP. We also investigated the association between TUBB3, phosphatase and tensin homolog (PTEN), and neuroendocrine differentiation and examined the involvement of TUBB3 in new antiandrogen drugs (enzalutamide and apalutamide) resistance in metastatic CaP. RESULTS: In 155 cases of localized CaP, immunohistochemistry showed that 5 (3.2&#37;) of the CaP cases were positive for tubulin-β3. Kaplan-Meier analysis showed that high expression of tubulin-β3 was associated with poor prostate-specific antigen recurrence-free survival after radical prostatectomy. In 57 cases of metastatic CaP, immunohistochemistry showed that 14 (25&#37;) cases were positive for tubulin-β3. Tubulin-β3 expression was higher in metastatic CaP than in localized CaP. High tubulin-β3 expression was correlated with negative PTEN expression. TUBB3 expression was increased in neuroendocrine CaP based on several public databases. PTEN knockout decreased the sensitivity to enzalutamide and apalutamide in 22Rv-1 cells. TUBB3 knockdown reversed the sensitivity to enzalutamide and apalutamide in PTEN-CRISPR 22Rv-1 cells. High expression of tubulin-β3 and negative expression of PTEN were significantly associated with poor overall survival in metastatic CaP treated with androgen deprivation therapy. CONCLUSIONS: These results suggest that TUBB3 may be a useful predictive biomarker for survival and play an essential role in antiandrogen resistance in CaP.

DOI： 10.1016/j.urolonc.2021.03.001

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: To examine the differences in prognosis of prostate cancer patients receiving primary androgen deprivation therapy by region and facility type using a Japan-wide database. METHODS: Data on patients treated with primary androgen deprivation therapy between 2001 and 2003 from a nationwide community-based database established by the Japan Study Group of Prostate Cancer were obtained. Clinicopathological characteristics and prognostic variables, including progression, cancer-specific survival and overall survival, were compared according to region and facility type where the patients were treated. RESULTS: Among 19 162 patients, 7102 (37.1&#37;) and 12 060 (62.9&#37;) men were in urban and rural areas, respectively, and 3556 (18.6&#37;), 13 623 (71.1&#37;) and 1983 (10.3&#37;) patients were enrolled from academic centers, non-academic hospitals and urological clinics, respectively. The risks of progression, cancer-specific mortality and all-cause mortality were comparable between urban and rural areas in propensity-score matched analysis. Risks of progression, cancer-specific mortality and all-cause mortality in urological clinics were higher than those in academic centers in propensity-score matched analysis. CONCLUSIONS: Our findings suggest that Japan facility type, but not geographical regions, might affect the prognosis of prostate cancer patients receiving primary androgen deprivation therapy.

DOI： 10.1111/iju.14518

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Metastatic burden is a critical factor for therapy decision-making in metastatic hormone-sensitive prostate cancer. The present study aimed to identify prognostic factors in men with high- or low-metastatic burden treated with primary androgen-deprivation therapy. The study included 2450 men with de novo metastatic prostate cancer who were treated with primary androgen-deprivation therapy at 30 institutions across Japan between 2008 and 2017. We investigated the prognostic value of various clinicopathological parameters for progression-free survival (PFS) and overall survival (OS) in patients stratified by low- or high-metastatic burden. Among the 2450 men, 841 (34.3&#37;) and 1609 (65.7&#37;) were classified as having low- and high-metastatic burden, respectively. Median PFS of the low- and high-burden groups were 44.5 and 16.1 months, respectively, and the median OS was 103.2 and 62.7 months, respectively. Percentage of biopsy-positive core, biopsy Gleason grade group, T-stage, and N-stage were identified to be differentially prognostic. M1a was associated with worse PFS than was M1b in the low-burden group, whereas lung metastasis was associated with better PFS and OS than was M1b in the high-burden group. Differential prognostic factors were identified for patients with low- and high-burden metastatic prostate cancer. These results may assist in decision-making to select the optimal therapeutic strategies for patients with different metastatic burdens.

DOI： 10.1111/cas.14722

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The therapeutic landscape of pharmacotherapy for prostate cancer has dramatically evolved, and multiple therapeutic options have become available for prostate cancer patients. Therefore, useful biomarkers to identify suitable candidates for treatment are required to maximize the efficacy of pharmacotherapy. Genetic polymorphisms such as single-nucleotide polymorphisms (SNPs) and tandem repeats have been shown to influence the therapeutic effects of pharmacotherapy for prostate cancer patients. For example, genetic polymorphisms in the genes involved in androgen receptor signaling are reported to be associated with the therapeutic outcome of androgen-deprivation therapy as well as androgen receptor-pathway inhibitors. In addition, SNPs in genes involved in drug metabolism and efflux pumps are associated with therapeutic effects of taxane chemotherapy. Thus, genetic polymorphisms such as SNPs are promising biomarkers to realize personalized medicine. Here, we overview the current findings on the influence of genetic polymorphisms on the outcome of pharmacotherapy for prostate cancer and discuss current issues as well as future visions in this field.

DOI： 10.31662/jmaj.2021-0004

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Salvage radical prostatectomy is a therapeutic option for the biochemical recurrence of prostate cancer after radiotherapy. However, only one case report of salvage radical prostatectomy after carbon ion radiotherapy has been reported. We report a case of salvage robot-assisted radical prostatectomy for local recurrence of prostate cancer after carbon ion radiotherapy with surgical video. Owing to adhesion and degeneration after radiotherapy, difficulties in surgery and post-operative complications have been anticipated. However, surgery was feasible without severe peri- and post-operative complications. Salvage robot-assisted radical prostatectomy after carbon ion radiotherapy may be a reasonable therapeutic option. Supplementary Information: The online version contains supplementary material available at 10.1007/s13691-020-00464-w.

DOI： 10.1007/s13691-020-00464-w

記述言語：英語   掲載種別：研究論文（学術雑誌）  

We investigated the efficacy and safety profiles of 4-weekly docetaxel for castration-resistant prostate cancer. Patients treated with ≥2 courses of docetaxel chemotherapy (median, 70 mg/m2) between 2008 and 2018 were included. Among 125 Japanese men, 40 (32.0&#37;) and 85 (68.0&#37;) were treated with 3-weekly and 4-weekly regimens, respectively. In the 4-weekly regimen, the risks of progression, treatment failure, and any-cause mortality were comparable to those in the 3-weekly regimen. The incidences of severe adverse events were also similar between the 3-weekly and 4-weekly regimens. These data suggest that the 4-weekly regimen may be an acceptable option for selected patients.

DOI： 10.1080/07357907.2020.1871486

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/and.13856

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Genetic polymorphism in YB-1 was previously shown to be associated with the prognosis of advanced prostate cancer patients treated with primary androgen-deprivation therapy. However, the significance of this polymorphism remains invalidated. In this study, we aimed to validate the prognostic significance of the YB-1 genetic polymorphism in metastatic prostate cancer. This study included 79 Japanese patients who were diagnosed as metastatic prostate cancer between 2000 and 2016. Genomic DNA was obtained from patient whole blood samples, and genotyping on YB-1 (rs12030724) was performed by PCR-based technique. The association of genotype in YB-1 with clinicopathological parameters and oncological outcome, including progression-free survival and overall survival, was examined. Homozygous wild-type (AA), heterozygous variant (AT), and homozygous variant (TT) were identified in 47 (59.5&#37;), 26 (32.9&#37;) and 6 patients (7.6&#37;), respectively. Heterozygous/homozygous variant (AT/TT) in YB-1 was significantly associated with lower progression risk compared with homozygous wild-type (AA) (hazard ratio = 0.52; 95&#37; confidence interval = 0.30-0.88, P = 0.015). Consistent with this finding, heterozygous/homozygous variant (AT/TT) in YB-1 was significantly associated with lower risk of any-cause mortality compared with homozygous wild-type (AA) (hazard ratio = 0.46; 95&#37; confidence interval = 0.21-0.93, P = 0.031). Gene polymorphism in YB-1 rs12030724 was validated to be a promising predictive biomarker of androgen-deprivation therapy in metastatic prostate cancer to identify patients requiring more intensive therapeutics.

DOI： 10.1038/s41397-020-00188-3

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although Y-box binding protein-1 (YB-1) is known to be overexpressed in prostate cancer, especially castration-resistant prostate cancer (CRPC), the mechanism of its overexpression remains unclear. We aimed to elucidate the mechanism of YB-1 overexpression in CRPC. Gene amplification in CRPC cells and tissues was examined by public database analysis, and digital PCR. The significance of YB-1 amplification for the YB-1/androgen receptor (AR) axis and prognosis was examined by public database analysis and immunohistochemistry. YB-1 amplification was mainly observed in CRPC tissues by public database analysis and confirmed in CRPC cells and tissues by digital PCR. Expression of YB-1 was increased in CRPC tissues compared with treatment-naïve tissues. Furthermore, YB-1 and phosphorylated YB-1 levels were associated with AR and AR V7 expression levels. Finally, YB-1 amplification was associated with poor outcomes in CRPC. Taken together, the present findings suggest that YB-1 amplification contributes to progression to CRPC through regulation of AR and AR V7 expressions, and that YB-1 is a promising therapeutic target in CRPC.

DOI： 10.1111/cas.14695

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: To investigate the somatic mutation profiles of testicular germ cell tumors in Japanese men. METHODS: We analyzed the somatic missense mutation profile of testicular germ cell tumors among 21 Japanese men with seminoma (n = 14), pure embryonic carcinoma (n = 3) and mixed testicular germ cell tumor (n = 4) by targeted next-generation sequencing of 409 cancer-related genes covering 1.23 Mb of the genome. RESULTS: We identified a total of 22 missense mutations in 21 primary testicular germ cell tumor samples (0.89 mutations/Mb), of which seven mutations were confirmed to be absent from the germline. KIT:p.Asn822Tyr, KIT:p.Leu576Pro, PIK3CA:p.Glu542Lys and FBXW7:p.Arg505His were statistically and functionally potential. A total of 18 missense mutations were previously unknown in testicular germ cell tumors. PDGFRA amplification from one patient with seminoma was detected. KIT, BCR,PIK3CG, PIK3CA and PDGFRA mutations involved in aberrant signaling of the KIT-PI3K-AKT pathway was detected in 27.3&#37; of detected mutations. CONCLUSIONS: The present investigation identified a low mutation rate in testicular germ cell tumors among Asian patients, 18 novel mutations and PDGFRA amplification. Limitations of the present study are the small sample and missing normal DNA for some testicular germ cell tumors.

DOI： 10.1111/iju.14396

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: To assess the impact of antiandrogen withdrawal syndrome after bicalutamide withdrawal in castration-resistant prostate cancer patients treated with androgen receptor-axis targeted agents. METHODS: The study cohort comprised 94 patients treated with abiraterone (n = 34) or enzalutamide (n = 60) as a first-line androgen receptor-axis targeted agent for castration-resistant prostate cancer despite combined androgen blockade by castration with bicalutamide as the first-line therapy. The association between clinicopathological factors (including antiandrogen withdrawal syndrome) and therapeutic outcome after using abiraterone and enzalutamide was investigated. RESULTS: The decline in the prostate-specific antigen level after use of abiraterone or enzalutamide was comparable between patients with and without antiandrogen withdrawal syndrome. Antiandrogen withdrawal syndrome (hazard ratio 3.84, 95&#37; confidence interval 1.29-11.45; P = 0.016) was associated with a higher risk of progression on multivariate analysis, but not all-cause death after abiraterone use. Progression-free survival and overall survival after enzalutamide use did not differ between patients with and without antiandrogen withdrawal syndrome. CONCLUSIONS: The present data suggest a modest therapeutic efficacy of abiraterone in castration-resistant prostate cancer patients with anti-androgen withdrawal syndrome after bicalutamide withdrawal.

DOI： 10.1111/iju.14366

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: This study aimed to identify the prognostic and predictive factors of local radiotherapy in clinically regional lymph node-positive prostate cancer. PATIENTS AND METHODS: This study includes patients who were newly diagnosed with regional lymph node-positive prostate cancer between 2008 and 2017. We investigated the prognostic value of clinicopathological parameters for progression-free survival (PFS) and overall survival (OS) as well as the differential prognostic impact of radiotherapy by subgroup analysis. RESULTS: Among the 93 men enrolled as patients, 48 (51.6 &#37;) were treated with radiotherapy. The biopsy positive core rate and biopsy Gleason score were associated with PFS, and the number of lymph node metastases was associated with both PFS and OS. Patients who underwent radiotherapy showed better PFS and OS. High-risk features (at least 2 criteria among ≥75&#37; biopsy positive core rate, Gleason score ≥9, and ≥2 positive lymph nodes) were especially associated with improved outcomes after undergoing radiotherapy. CONCLUSION: We identified prognostic factors for clinically regional lymph node-positive prostate cancer and showed the benefits of local radiation therapy. Patients with high-risk features may be especially suitable candidates for radiotherapy.

DOI： 10.1016/j.urolonc.2020.08.018

記述言語：英語   掲載種別：研究論文（学術雑誌）  

We analyzed the association between smoking and oncological outcome after radical prostatectomy with neoadjuvant hormonal therapy. This study included men who had undergone radical prostatectomy with neoadjuvant hormonal therapy between 2003 and 2016. We evaluated the association between clinicopathological factors and smoking status as well as the prognostic significance of smoking status in biochemical recurrence. The patients' backgrounds were comparable between smokers and nonsmokers. Smoking status were identified as significant risk factors of biochemical recurrence. Smoking was a risk factor of biochemical recurrence, suggesting that smoking may promote cancer recurrence after surgical treatment combined with hormonal therapy.

DOI： 10.1080/07357907.2020.1833212

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Androgen metabolism is a key component in therapeutic resistance to androgen deprivation therapy (ADT). This study aimed to reveal the significance of genetic polymorphisms in genes involved in androgen metabolism, including CYP17A1, AKR1C3, and HSD17B, on serum testosterone levels during ADT, as well as the prognosis of men undergoing ADT for metastatic prostate cancer (CaP). MATERIALS AND METHODS: This study included 104 Japanese patients with metastatic CaP, for whom serum testosterone data during ADT were available for 80 patients. The association of CYP17A1 (rs743572), AKR1C3 (rs12529), HSD17B1 (rs605059), HSD17B3 (rs2066479), and HSD17B4 (rs7737181) with serum testosterone levels during ADT and prognosis (progression-free survival and overall survival) was examined. Enzymatic activity in AKR1C3 H5Q was examined using recombinant protein. RESULTS: Homozygous wild-type (GG allele; median [interquartile range], 12.0 ng/ml [8.0-19.0 ng/ml]) AKR1C3 rs12529 was associated with higher serum testosterone levels during ADT compared with variant-type (GC/CC alleles; median [interquartile range], 9.0 ng/ml [6.4-10.8 ng/ml]). Consistently, variant-type (GC/CC alleles) AKR1C3 rs12529 showed significantly lower risk of progression (hazard ratio [95&#37; confidence interval], 0.47 [0.24-0.96], P = 0.039) compared with homozygous wild-type (GG allele) on multivariate analysis. Meanwhile, other genetic variations were associated with neither serum testosterone during ADT nor prognosis. Enzyme activity of wild-type AKR1C3 was comparable to the H5Q mutant. CONCLUSIONS: Taken together, this study demonstrated that AKR1C3 polymorphism, which was associated with serum testosterone levels during ADT, may be a prognostic factor of the progression to castration-resistant prostate cancer in Japanese men with metastatic CaP.

DOI： 10.1016/j.urolonc.2020.06.033

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objectives: To evaluate the association between the use of local radiotherapy (RT) with the survival of patients with de novo metastatic prostate cancer and symptomatic local events (SLEs). Patients and methods: Patients were initially diagnosed with metastatic prostate cancer between 2008 and 2017 at 30 institutes in Japan. Prostate-specific antigen (PSA) progression-free survival (PSA-PFS) under initial androgen deprivation therapy and overall survival (OS) was compared between patients receiving local RT (RT group) and no RT (no-RT group) by multivariate Cox proportional hazard analyses. The occurrence rate of grade ≥2 SLEs was compared by multivariate logistic regression analyses. Propensity score matching (PSM) analyses were performed to compare PSA-PFS and OS of the groups in the high and low metastatic burden cohort. Results: Two hundred and five (7&#37;) of 2829 patients received RT before PSA progression. Median PSA-PFS and OS were significantly longer in the RT group than in the no-RT group and the difference was significant in multivariate analyses (HR = 0.44, 95&#37; CI = 0.33-0.57 and HR = 0.40, 95&#37; CI = 0.27-0.60, respectively). The occurrence rate of grade ≥2 SLEs was significantly lower in the RT group (2&#37;) than the no-RT group (9&#37;) and the difference was significant in multivariate analyses (HR = 0.28, 95&#37; CI = 0.10-0.76). Using PSM analyses, PSA-PFS and OS remained significantly different (HR = 0.64, 95&#37; CI = 0.46-0.89 and HR = 0.47, 95&#37; CI = 0.30-0.72, respectively), between the RT (n = 182) and the no-RT (n = 182) groups. The difference in OS was significant in the high metastatic burden cohort (HR = 0.55, 95&#37; CI = 0.37-0.81). Conclusions: Addition of local RT to standard treatment for de novo metastatic prostate cancer patients tends to have the potential to extend survival, even in patients with high metastatic burden, and to reduce SLEs.

DOI： 10.1002/bco2.35

記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Microtubule-associated protein tau (MAPT), facilitates tubulin assembly and microtubule stabilization. Several studies have shown that overexpression of MAPT is linked to poor prognosis and is involved in taxane resistance in cancer. This study aimed to assess the expression and function of MAPT in prostate cancer (CaP). METHODS: The expression of MAPT was determined using immunohistochemistry in CaP. We analyzed the interaction between MAPT, Phosphatase and Tensin Homolog (PTEN), and androgen receptor and investigated the role of MAPT in bicalutamide resistance. RESULTS: Immunohistochemistry in 155 CaP cases showed that 15&#37; of them were positive for MAPT. High MAPT expression was significantly orrelated with high Gleason score and high T stage. Kaplan-Meier analysis showed that the high MAPT expression was significantly associated with poor prostate-specific antigen recurrence survival after radical prostatectomy. There was an inverse correlation between MAPT and PTEN. In the CaP cell lines, knockout of PTEN increased the expression of MAPT, whereas knockdown of MAPT suppressed the expression of androgen receptor and increased the sensitivity to bicalutamide. Furthermore, immunohistochemical staining of MAPT showed that high MAPT expression was significantly associated with poor overall survival in 74 CaP patients who were treated with androgen deprivation therapy. CONCLUSION: These results suggest that MAPT may be a promising predictive biomarker for survival and play an essential role in bicalutamide resistance in CaP.

DOI： 10.1016/j.urolonc.2020.04.032

記述言語：英語  

DOI： 10.21037/tau-20-866

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/iju5.12181

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Eradication of persistent androgen receptor (AR) activity in castration-resistant prostate cancer may be a promising strategy to overcome castration resistance. We aimed to identify novel compounds that inhibit AR activity and could be potential therapeutic agents for prostate cancer. Methods: A high-throughput screening system involving cell lines stably expressing AR protein and AR-responsive luciferase was employed for the 1260 compound library. Molecular and antitumor effects on candidate pathways that interacted with AR signaling were examined in prostate cancer cells expressing AR. Results: The high-throughput screening identified various potential compounds that interfered with AR signaling through known and novel pathways. Among them, a 5-hydroxytryptamine 5A (5-HT5A) receptor antagonist suppressed AR activity through protein kinase A signaling, which was confirmed by 5-HT5A receptor knockdown. Consistently, 5-HT5A receptor inhibitors showed cytotoxic effects toward prostate cancer cells. Conclusions: Taken together, this study identifies 5-HT5A receptor as a promising therapeutic target for prostate cancer via its interaction with AR signaling.

DOI： 10.1002/pros.24022

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Eradication of persistent androgen receptor (AR) activity in castration-resistant prostate cancer may be a promising strategy to overcome castration resistance. We aimed to identify novel compounds that inhibit AR activity and could be potential therapeutic agents for prostate cancer. METHODS: A high-throughput screening system involving cell lines stably expressing AR protein and AR-responsive luciferase was employed for the 1260 compound library. Molecular and antitumor effects on candidate pathways that interacted with AR signaling were examined in prostate cancer cells expressing AR. RESULTS: The high-throughput screening identified various potential compounds that interfered with AR signaling through known and novel pathways. Among them, a 5-hydroxytryptamine 5A (5-HT5A) receptor antagonist suppressed AR activity through protein kinase A signaling, which was confirmed by 5-HT5A receptor knockdown. Consistently, 5-HT5A receptor inhibitors showed cytotoxic effects toward prostate cancer cells. CONCLUSIONS: Taken together, this study identifies 5-HT5A receptor as a promising therapeutic target for prostate cancer via its interaction with AR signaling.

DOI： 10.1002/pros.24022

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Bacillus Calmette-Guérin (BCG) instillation is a key therapy to manage non-muscle invasive bladder cancer (NMIBC). However, intravesical BCG therapy fails in approximately half of the patients, leading to recurrence and progression. We aimed to reveal the genetic variations associated with treatment failure after intravesical BCG therapy for NMIBC. This study included 91 Japanese patients treated with BCG instillation for NMIBC. Genomic DNA was obtained from patient whole-blood samples, and a genome-wide association study and genotyping for target regions were performed. The association between genetic variation and treatment failure was analyzed by genome-wide association in 44 patients as the discovery cohort. As a validation study, candidate single nucleotide polymorphisms (SNPs) were examined among 47 patients in another cohort. The genome-wide association study indicated 19 candidate SNPs (rs1607282, rs7825442, rs1319325, rs3738088, rs4250, rs11894207, rs161448, rs2764326, rs2814707, rs3787194, rs58081719, rs3095966, rs73520681, rs16877113, rs16887173, rs10269584, rs11772249, rs118137814, and rs61094339) associated with BCG failure. Following the cumulative analysis of candidate SNPs, 2-gene (rs73520681 and rs61094339) and 4-gene (rs4250, rs11894207, rs73520681, and rs61094339) models successfully predicted treatment failure after intravesical BCG therapy. This study showed that several SNPs were possibly associated with outcome after intravesical BCG therapy in a Japanese population with NMIBC. The cumulative models of these SNPs may have value in clinical applications, although this should be confirmed in future studies.

DOI： 10.1007/s00262-020-02533-8

記述言語：その他   掲載種別：研究論文（学術雑誌）  

A study of the clinical statistics at our department for the period 2015-2017 revealed the following results: 1) The number of outpatients was 42,745, including 3,203 new patients. The most common diseases among the new patients were urogenital malignant tumors (37.0%), benign prostatic hyperplasia (11.2%), neurogenic bladder (5.7%), urolithiasis (2.8%) and inflammatory diseases (2.7%). 2) The total number of inpatients was 2,731 (2,259 males and 472 females), and the majority of them comprised males aged 60-79 years. The main disease among the inpatients was urogenital neoplasms (69.7%). 3) A total of 1,576 cases underwent surgery, with 107 cases undergoing open surgery, 751 cases undergoing laparoscopic surgery, 704 cases undergoing endourological surgery and 11 cases undergoing ES.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objectives: To determine the association between hormone therapy and outcomes in a cohort of prostate cancer patients with a family history of prostate cancer. Methods: Data of patients with prostate cancer who had received hormone therapy were extracted from a nationwide community-based database established by the Japan Study Group for Prostate Cancer. Family history of prostate cancer was available for 13 346 of these patients, who thus comprised the study cohort. Prognostic variables, including progression-free survival, cancer-specific survival and overall survival, were compared between men with familial and men with sporadic prostate cancer. Results: A positive family history was identified in 220 patients (1.6%). Patients with a positive family history were younger than those without; however, other clinicopathological characteristics and prognoses were comparable. In subgroup analysis, family history was identified as a possible favorable prognostic factor for overall survival among patients with a prostate-specific antigen level at diagnosis <100 ng/mL and those with low or intermediate Japan Cancer of the Prostate Risk Assessment. Conclusions: Our findings show that familial prostate cancer has an early-onset feature or is diagnosed earlier than sporadic prostate cancer. However, the prognosis of individuals with familial prostate cancer undergoing hormone therapy is comparable to those with sporadic prostate cancer.

DOI： 10.1111/iju.14184

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: To determine the association between hormone therapy and outcomes in a cohort of prostate cancer patients with a family history of prostate cancer. METHODS: Data of patients with prostate cancer who had received hormone therapy were extracted from a nationwide community-based database established by the Japan Study Group for Prostate Cancer. Family history of prostate cancer was available for 13 346 of these patients, who thus comprised the study cohort. Prognostic variables, including progression-free survival, cancer-specific survival and overall survival, were compared between men with familial and men with sporadic prostate cancer. RESULTS: A positive family history was identified in 220 patients (1.6&#37;). Patients with a positive family history were younger than those without; however, other clinicopathological characteristics and prognoses were comparable. In subgroup analysis, family history was identified as a possible favorable prognostic factor for overall survival among patients with a prostate-specific antigen level at diagnosis <100 ng/mL and those with low or intermediate Japan Cancer of the Prostate Risk Assessment. CONCLUSIONS: Our findings show that familial prostate cancer has an early-onset feature or is diagnosed earlier than sporadic prostate cancer. However, the prognosis of individuals with familial prostate cancer undergoing hormone therapy is comparable to those with sporadic prostate cancer.

DOI： 10.1111/iju.14184

記述言語：英語   掲載種別：研究論文（学術雑誌）  

This multi-institutional study aimed to identify prognostic factors for cabazitaxel treatment of castration-resistant prostate cancer (CRPC). This study included 74 Japanese patients with CRPC who were treated with cabazitaxel between 2014 and 2017. Associations between clinicopathological factors including serum markers and progression-free survival (PFS) and overall survival (OS) were investigated. On multivariate analysis, high Gleason score [≥9 vs. ≤7; hazard ratio (HR), 95% confidence interval (CI): 2.00 (1.01-4.34); P = 0.047], presence of pain [HR, 95% CI: 2.02 (1.14-3.58); P = 0.016], and lactate dehydrogenase (LDH) level [HR, 95% CI: 47.31 (3.79-577.49); P = 0.0019] were significantly associated with PFS. Similarly, number of docetaxel cycles [HR, 95% CI: 0.050 (0.0037-0.45); P = 0.0057], performance status [≥2 vs. 0; HR, 95% CI: 5.07 (1.57-16.24); P < 0.0001], and LDH level [HR, 95% CI: 2946 (50-420994); P = 0.0001] were significantly associated with OS. This study showed that LDH level is robustly prognostic for both PFS and OS in cabazitaxel chemotherapy for CRPC.

DOI： 10.1097/CAD.0000000000000884

記述言語：英語   掲載種別：研究論文（学術雑誌）  

This multi-institutional study aimed to identify prognostic factors for cabazitaxel treatment of castration-resistant prostate cancer (CRPC). This study included 74 Japanese patients with CRPC who were treated with cabazitaxel between 2014 and 2017. Associations between clinicopathological factors including serum markers and progression-free survival (PFS) and overall survival (OS) were investigated. On multivariate analysis, high Gleason score [≥9 vs. ≤7; hazard ratio (HR), 95&#37; confidence interval (CI): 2.00 (1.01-4.34); P = 0.047], presence of pain [HR, 95&#37; CI: 2.02 (1.14-3.58); P = 0.016], and lactate dehydrogenase (LDH) level [HR, 95&#37; CI: 47.31 (3.79-577.49); P = 0.0019] were significantly associated with PFS. Similarly, number of docetaxel cycles [HR, 95&#37; CI: 0.050 (0.0037-0.45); P = 0.0057], performance status [≥2 vs. 0; HR, 95&#37; CI: 5.07 (1.57-16.24); P < 0.0001], and LDH level [HR, 95&#37; CI: 2946 (50-420994); P = 0.0001] were significantly associated with OS. This study showed that LDH level is robustly prognostic for both PFS and OS in cabazitaxel chemotherapy for CRPC.

DOI： 10.1097/CAD.0000000000000884

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: To evaluate the relationship between body composition and the oncological outcome of androgen deprivation therapy (ADT), we investigated whether body composition features including the psoas muscle may be predictive factors of ADT. Methods: This study enrolled patients with hormone-naïve metastatic prostate cancer who were treated with primary ADT from April 1996 to November 2013 at Kyushu University Hospital and who underwent a computed tomography scan before primary ADT for calculating body fat percentage, psoas muscle ratio (psoas muscle, cm³/height, cm), and body mass index. Results: Of the 178 patients enrolled, 60 patients died during follow-up. Median follow-up was 32 months, and progression-free survival and overall survival (OS) were 28 and 80 months, respectively. Multivariate analysis revealed that the psoas muscle ratio was correlated with OS (hazard ratio: 0.448; 95% confidence interval = 0.206–0.922; p = 0.028). Conclusions: This study demonstrated that higher psoas muscle ratio predicts longer OS among patients with nonlocalized prostate cancer treated with primary ADT.

DOI： 10.1016/j.prnil.2019.11.002

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: To evaluate the relationship between body composition and the oncological outcome of androgen deprivation therapy (ADT), we investigated whether body composition features including the psoas muscle may be predictive factors of ADT. Methods: This study enrolled patients with hormone-naïve metastatic prostate cancer who were treated with primary ADT from April 1996 to November 2013 at Kyushu University Hospital and who underwent a computed tomography scan before primary ADT for calculating body fat percentage, psoas muscle ratio (psoas muscle, cm3/height, cm), and body mass index. Results: Of the 178 patients enrolled, 60 patients died during follow-up. Median follow-up was 32 months, and progression-free survival and overall survival (OS) were 28 and 80 months, respectively. Multivariate analysis revealed that the psoas muscle ratio was correlated with OS (hazard ratio: 0.448; 95&#37; confidence interval = 0.206-0.922; p = 0.028). Conclusions: This study demonstrated that higher psoas muscle ratio predicts longer OS among patients with nonlocalized prostate cancer treated with primary ADT.

DOI： 10.1016/j.prnil.2019.11.002

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/iju.14156

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/iju.14156

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/iju.14143

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/iju.14143

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: The novel taxane cabazitaxel has been shown to exert excellent anticancer effects after androgen receptor axis-targeting (ARAT) agents in clinical data, but not in in vitro data. We investigated the clinical outcome of cabazitaxel chemotherapy after docetaxel according to use of ARAT agents. PATIENTS AND METHODS: Prostate specific antigen (PSA) response, progression-free survival, and overall survival were compared between cases with and without prior use of ARAT agents in 74 Japanese patients with metastatic castration-resistant prostate cancer treated with cabazitaxel chemotherapy. RESULTS: Background characteristics were comparable between patients with and without prior use of ARAT agents. PSA response, progression-free survival, and overall survival in cabazitaxel chemotherapy were comparable between patients with and without prior use of ARAT agents. CONCLUSION: No detrimental effects of prior ARAT agents on clinical outcome were observed for cabazitaxel chemotherapy in the post-docetaxel setting, suggesting that cabazitaxel can be expected to remain active even after ARAT agent therapy.

DOI： 10.21873/anticanres.13957

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background/Aim: The novel taxane cabazitaxel has been shown to exert excellent anticancer effects after androgen receptor axis-targeting (ARAT) agents in clinical data, but not in in vitro data. We investigated the clinical outcome of cabazitaxel chemotherapy after docetaxel according to use of ARAT agents. Patients and Methods: Prostate specific antigen (PSA) response, progression-free survival, and overall survival were compared between cases with and without prior use of ARAT agents in 74 Japanese patients with metastatic castration-resistant prostate cancer treated with cabazitaxel chemotherapy. Results: Background characteristics were comparable between patients with and without prior use of ARAT agents. PSA response, progression-free survival, and overall survival in cabazitaxel chemotherapy were comparable between patients with and without prior use of ARAT agents. Conclusion: No detrimental effects of prior ARAT agents on clinical outcome were observed for cabazitaxel chemotherapy in the postdocetaxel setting, suggesting that cabazitaxel can be expected to remain active even after ARAT agent therapy.

DOI： 10.21873/anticanres.13957

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objective: The outcome of the androgen-deprivation therapy (ADT) may be affected by metabolic diseases such as diabetes mellitus (DM) and dyslipidemia and/or by their treatments. We aimed to evaluate the prognostic impact of these disorders and corresponding medications in Japanese men treated with ADT for prostate cancer. Methods: This study retrospectively included 121 patients with metastatic prostate cancer who were treated with primary ADT at our hospital between 2001 and 2013. All patients received primary ADT with castration and/or an antiandrogen agent (bicalutamide or flutamide). Associations between clinicopathological factors, metabolic disease profiles, medication use, and prognosis (progression-free survival [PFS] and overall survival [OS]) were evaluated by univariate and multivariate analysis. Results: The median follow-up time was 54.9 months, and the median PFS and OS were 23.9 months and 73.0 months, respectively. High serum glucose levels at baseline (hazard ratio [HR], 95% confidence interval [CI]: 2.12, 1.16–3.76; P = 0.015), and concurrent DM (HR, 95% CI: 2.07, 1.06–3.94; P = 0.034) were significantly associated with poorer OS after adjustment for age, prostate-specific antigen levels at diagnosis, Gleason score, and clinical stage. Treatment with sulfonylurea drugs was significantly associated with a reduced risk of disease progression in men with DM (HR, 95% CI: 0.36, 0.12–0.90; P = 0.028). Conclusions: Impaired glucose tolerance and treatment with sulfonylureas have prognostic significance in prostate cancer. These findings demonstrate the importance of managing DM during ADT and point to a possible favorable effect of sulfonylureas on prostate cancer.

DOI： 10.1016/j.prnil.2019.10.003

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objective: The outcome of the androgen-deprivation therapy (ADT) may be affected by metabolic diseases such as diabetes mellitus (DM) and dyslipidemia and/or by their treatments. We aimed to evaluate the prognostic impact of these disorders and corresponding medications in Japanese men treated with ADT for prostate cancer. Methods: This study retrospectively included 121 patients with metastatic prostate cancer who were treated with primary ADT at our hospital between 2001 and 2013. All patients received primary ADT with castration and/or an antiandrogen agent (bicalutamide or flutamide). Associations between clinicopathological factors, metabolic disease profiles, medication use, and prognosis (progression-free survival [PFS] and overall survival [OS]) were evaluated by univariate and multivariate analysis. Results: The median follow-up time was 54.9 months, and the median PFS and OS were 23.9 months and 73.0 months, respectively. High serum glucose levels at baseline (hazard ratio [HR], 95&#37; confidence interval [CI]: 2.12, 1.16-3.76; P = 0.015), and concurrent DM (HR, 95&#37; CI: 2.07, 1.06-3.94; P = 0.034) were significantly associated with poorer OS after adjustment for age, prostate-specific antigen levels at diagnosis, Gleason score, and clinical stage. Treatment with sulfonylurea drugs was significantly associated with a reduced risk of disease progression in men with DM (HR, 95&#37; CI: 0.36, 0.12-0.90; P = 0.028). Conclusions: Impaired glucose tolerance and treatment with sulfonylureas have prognostic significance in prostate cancer. These findings demonstrate the importance of managing DM during ADT and point to a possible favorable effect of sulfonylureas on prostate cancer.

DOI： 10.1016/j.prnil.2019.10.003

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Purpose: Comorbidity with hypertension (HTN) may affect the outcome of castration-resistant prostate cancer (CRPC). In this study, we evaluated the prognostic impact of antihypertensive agents in patients with CRPC treated with androgen receptor axis-targeting (ARAT) agents or docetaxel chemotherapy. Patients and methods: This study included 156 Japanese men with CRPC who were treated with ARAT agents (n = 85) or docetaxel (n = 71) at our hospital between 2008 and 2017. Associations between clinicopathological factors, HTN status, progression-free survival (PFS) and overall survival (OS) were evaluated by univariate and multivariate analysis. Results: When adjusted for age, prostate-specific antigen levels at pretreatment, Gleason score, and clinical M-stage, comorbid HTN was significantly associated with better OS (hazards ratio, 95% confidence interval: 0.41, 0.21–0.77; P = 0.0051), but not with PFS (hazards ratio, 95% confidence interval: 0.64, 0.38–1.11; P = 0.11) in patients treated with ARAT agent. However, HTN was not associated with PFS or OS for patients treated with docetaxel. Conclusions: Use of antihypertensive agents has prognostic significance for patients with CRPC treated with ARAT agent, but not docetaxel.

DOI： 10.1016/j.urolonc.2019.04.020

記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Comorbidity with hypertension (HTN) may affect the outcome of castration-resistant prostate cancer (CRPC). In this study, we evaluated the prognostic impact of antihypertensive agents in patients with CRPC treated with androgen receptor axis-targeting (ARAT) agents or docetaxel chemotherapy. PATIENTS AND METHODS: This study included 156 Japanese men with CRPC who were treated with ARAT agents (n = 85) or docetaxel (n = 71) at our hospital between 2008 and 2017. Associations between clinicopathological factors, HTN status, progression-free survival (PFS) and overall survival (OS) were evaluated by univariate and multivariate analysis. RESULTS: When adjusted for age, prostate-specific antigen levels at pretreatment, Gleason score, and clinical M-stage, comorbid HTN was significantly associated with better OS (hazards ratio, 95&#37; confidence interval: 0.41, 0.21-0.77; P = 0.0051), but not with PFS (hazards ratio, 95&#37; confidence interval: 0.64, 0.38-1.11; P = 0.11) in patients treated with ARAT agent. However, HTN was not associated with PFS or OS for patients treated with docetaxel. CONCLUSIONS: Use of antihypertensive agents has prognostic significance for patients with CRPC treated with ARAT agent, but not docetaxel.

DOI： 10.1016/j.urolonc.2019.04.020

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Several endocrinological and physical activities orchestrate men's sexual activities. To determine whether body composition calculated by computed tomography measurements is useful for estimating sexual function, we evaluated sexual function of localised prostate cancer patients using the Sexual Health Inventory for Men score, an original questionnaire, and computed tomography and magnetic resonance imaging. The imaging was performed to determine body composition, particularly the psoas muscle. Univariate and multivariate analyses were performed to identify factors affecting sexual activity. The multivariate analysis showed that the volume of the psoas muscle was significantly correlated with sexual activity (odds ratio [95&#37; confidence interval]) (2.507 [1.029-6.109], p = 0.043) and erectile dysfunction (0.261 [0.098-0.692], p = 0.006). We concluded that the psoas muscle is an important predictor of sexual activity and erectile function.

DOI： 10.1111/and.13354

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objective: This study aimed to reveal the efficacy and safety profiles of 4-weekly cabazitaxel in patients with castration-resistant prostate cancer (CRPC). Methods: The study included 62 Japanese patients who were treated for CRPC with ≥ 2 courses of cabazitaxel between 2014 and 2017. The oncological outcomes and adverse events were compared between 16 (25.8%) and 46 (74.2%) men who were treated with standard 3-weekly and alternative 4-weekly regimens, respectively. Results: The prostate-specific antigen (PSA) response was comparable between the 3-weekly and 4-weekly regimens (median [interquartile range]: − 9.9% [− 64.5 to 13.0%] and − 30.7% [− 52.8 to 10.9%], P = 0.89), respectively. For patients on the 4-weekly regimen, the risks of progression (hazard ratio [HR], 95% confidence interval [CI] 1.27, 0.71–2.43, P = 0.44), treatment failure (HR, 95% CI 0.84, 0.48–1.55, P = 0.57) and any-cause mortality (HR, 95% CI 1.09, 0.58–2.17, P = 0.79) were comparable to those for patients on the 3-weekly regimen. The incidences of severe adverse events were also similar between the 3-weekly and 4-weekly regimens. Conclusions: 3-weekly and 4-weekly regimens of cabazitaxel showed similar efficacy and safety profiles in a real-world clinical setting. These data suggest that a 4-weekly regimen may be acceptable for selected patients.

DOI： 10.1007/s00280-019-03874-7

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: This study aimed to reveal the efficacy and safety profiles of 4-weekly cabazitaxel in patients with castration-resistant prostate cancer (CRPC). METHODS: The study included 62 Japanese patients who were treated for CRPC with ≥ 2 courses of cabazitaxel between 2014 and 2017. The oncological outcomes and adverse events were compared between 16 (25.8&#37;) and 46 (74.2&#37;) men who were treated with standard 3-weekly and alternative 4-weekly regimens, respectively. RESULTS: The prostate-specific antigen (PSA) response was comparable between the 3-weekly and 4-weekly regimens (median [interquartile range]: - 9.9&#37; [- 64.5 to 13.0&#37;] and - 30.7&#37; [- 52.8 to 10.9&#37;], P = 0.89), respectively. For patients on the 4-weekly regimen, the risks of progression (hazard ratio [HR], 95&#37; confidence interval [CI] 1.27, 0.71-2.43, P = 0.44), treatment failure (HR, 95&#37; CI 0.84, 0.48-1.55, P = 0.57) and any-cause mortality (HR, 95&#37; CI 1.09, 0.58-2.17, P = 0.79) were comparable to those for patients on the 3-weekly regimen. The incidences of severe adverse events were also similar between the 3-weekly and 4-weekly regimens. CONCLUSIONS: 3-weekly and 4-weekly regimens of cabazitaxel showed similar efficacy and safety profiles in a real-world clinical setting. These data suggest that a 4-weekly regimen may be acceptable for selected patients.

DOI： 10.1007/s00280-019-03874-7

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: The significance of second transurethral resection (TUR), and identification of predictive factors for residual cancer remain unrevealed. This study aimed to find residual cancer and up-staging rates, as well as predictive factors for residual cancer, in patients who undergo second TUR for non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: Patients who underwent second TURs for NMIBC between 2015 and 2017, were included in the study and their clinicopathological characteristics were analyzed for predictors of residual cancer. RESULTS: Among 143 Japanese patients whose tumors were initially diagnosed as high-risk NMIBC, residual cancers detected at second TURs were, Tis: n=22 (15.4&#37;), Ta: n=15 (10.5&#37;) and T1: n=29 (20.3&#37;). No patients showed up-staging from NMIBC to MIBC. The presence of carcinoma-in situ at initial TUR was an independent risk factor for any residual cancer (Tis, Ta and T1), non-flat residual cancer (Ta and T1), and flat residual cancer (Tis). CONCLUSION: The presence of carcinoma-in situ is suggested to be an independent predictor of residual cancer. This may help guide decisions to perform second TUR.

DOI： 10.21873/anticanres.13598

記述言語：英語   掲載種別：研究論文（学術雑誌）  

We conducted a review of the literature to identify the clinical benefits of pelvic lymph node dissection (PLND) during radical prostatectomy for clinically localized prostate cancer. The most recent guidelines recommend PLND, particularly extended PLND, during radical prostatectomy for localized prostate cancer. PLND is undoubtedly the most accurate method for nodal staging, and most patients, particularly those with high-risk cancer, are likely to undergo PLND during radical prostatectomy. Although many retrospective studies have assessed oncologic outcomes after PLND, its therapeutic benefit remains controversial. Patients with positive node(s) often have other more common unfavorable prognostic factors, such as seminal vesicle invasion, extra-prostatic extension, and positive surgical margins. Oncologic outcomes in patients who have not undergone PLND and those who have undergone PLND are almost identical. If an effective standard adjuvant therapy after prostatectomy is defined, the nodal status may be important and valuable. However, adjuvant treatment strategies for patients with a positive node have not been identified thus far. Therefore, determining the nodal status at surgery may not provide therapeutic benefit. PLND requires additional surgical time and is associated with several complications. Therefore, the indication for PLND should be considered carefully until well-designed prospective randomized trials establish high-quality clinical evidence.

DOI： 10.1159/000497280

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Cabazitaxel use has usually been limited to up to 10 cycles in most countries according to the protocol in the TROPIC trial. Therefore, clinical data on cabazitaxel use beyond 10 cycles is limited. The aim of this study was to report the therapeutic outcome of cabazitaxel chemotherapy administered for >10 cycles. PATIENTS AND METHODS: This study included 74 Japanese patients with prostate cancer between 2014 and 2017. Patients background, and treatment outcomes including PSA decline, progression-free survival, treatment-failure-free survival, overall survival, and adverse events were investigated, comparing patients treated with ≤10 and >10 cycles. RESULTS: Patients characteristics were favorable as indicated by the higher number of cycles of prior docetaxel chemotherapy, absence of pain, and absence of bony and visceral metastases among men who received >10 cycles of cabazitaxel. PSA response, progression-free survival, treatment-failure-free survival and overall survival were better among patients treated with >10 cycles of cabazitaxel compared to those treated with ≤10 cycles. The incidence of severe adverse events was similar between the two groups. CONCLUSION: Taken together, this study suggested that continuous chemotherapy with cabazitaxel beyond 10 cycles may be beneficial.

DOI： 10.21873/anticanres.13612

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Recent studies have reported that TUBB3 overexpression is involved in docetaxel (DTX) resistance in prostate cancer (PCa). The aim of this study was to clarify the role of TUBB3 in DTX and cabazitaxel (CBZ) resistance, and cross-resistance between DTX and CBZ in PCa. We analyzed the effect of TUBB3 knockdown on DTX and CBZ resistance and examined the interaction between TUBB3 and PTEN. We also investigated the role of phosphoinositide 3-kinases (PI3K) inhibitor (LY294002) in DTX and CBZ resistance. TUBB3 expression was upregulated in DTX-resistant and CBZ-resistant cells. TUBB3 knockdown re-sensitized DTX-resistant cells to DTX and CBZ-resistant cells to CBZ. Additionally, TUBB3 knockdown re-sensitized DTX-resistant cell lines to CBZ, indicating that TUBB3 mediates cross-resistance between DTX and CBZ. Knockdown of TUBB3 enhanced PTEN expression, and PTEN knockout enhanced TUBB3 expression. LY294002 suppressed TUBB3 expression in DTX-resistant and CBZ-resistant cell lines. LY294002 re-sensitized DTX-resistant cell lines to DTX and CBZ-resistant cell lines to CBZ. These results suggest that TUBB3 is involved in DTX resistance and CBZ resistance. A combination of LY294002/DTX and that of LY294002/CBZ could be potential strategies for PCa treatment.

DOI： 10.3390/ijms20163936

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Cigarette smoking is associated with worse outcomes in prostate cancer, whose growth is dependent on androgen receptor (AR) signaling. We aimed to elucidate the biological effect of cigarette smoking on AR signaling and its clinical influence on oncological outcome. METHODS: Gene expression levels after exposure to tobacco smoke condensate (TSC) were evaluated by quantitative real-time polymerase chain reaction and Western blot analysis in prostate cancer cells. Cellular sensitivities to enzalutamide and docetaxel after TSC exposure were evaluated using a prostate cancer cell proliferation assay. Prognosis was compared between current smokers and nonsmokers when treated with AR-axis-targeting (ARAT) agent enzalutamide and docetaxel. RESULTS: Expression of AR variants as well as prostate-specific antigen was augmented after TSC exposure, which occurred after Akt phosphorylation. These inductions were suppressed by Akt inhibitor LY294002 as well as antioxidant N-acetylcysteine. Consistently, TSC exposure augmented cellular resistance to enzalutamide. In clinical data, cigarette smoking was associated with worse progression-free survival and cancer-specific survival when patients with prostate cancer were treated with ARAT agents but not docetaxel. CONCLUSIONS: It was suggested that cigarette smoking leads to detrimental oncological outcome when prostate cancer patients are treated with ARAT agents through induction of aberrant AR signaling. Accordingly, we recommend that patients with advanced prostate cancer should refrain from cigarette smoking.

DOI： 10.1002/pros.23828

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Introduction: Testosterone suppression in serum during androgen deprivation therapy (ADT) can affect the oncologic outcome of ADT. Although genetic variants in sex hormone-binding globulin (SHBG) were reported to be correlated with serum testosterone level, the association with serum testosterone during ADT remains unclear. Therefore, this study investigated the impact of a missense polymorphism in the SHBG gene among men treated with primary ADT for metastatic prostate cancer. Patients and Methods: This study included 104 Japanese men with metastatic prostate cancer. The association of SHBG gene polymorphism (rs6259, D356N) with clinicopathologic parameters including serum testosterone levels during ADT, as well as prognosis, including progression-free survival and overall survival, was examined. Results: The serum testosterone levels during ADT were comparable between men carrying the homozygous wild-type (GG) and heterozygous/homozygous variant (GA/AA) in the SHBG gene. When adjusted for age, Gleason score, initial prostate-specific antigen, and clinical T-stage, the heterozygous/homozygous variant (GA/AA) in the SHBG gene was associated with a higher risk of progression (hazard ratio, 2.20; 95% confidence interval, 1.10-4.18; P =.027) and any-cause death (hazard ratio, 3.21; 95% confidence interval, 1.31-7.35; P =.012). Conclusions: This study suggested genetic variation in SHBG (rs6259) might be an independent prognostic biomarker among men treated with primary ADT for metastatic prostate cancer.

DOI： 10.1016/j.clgc.2019.03.021

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: To date, several serum prognostic factors have been reported in metastatic prostate cancer. In this study, we examined the prognostic value of these serum markers in Japanese men. PATIENTS AND METHODS: This study included 104 patients with metastatic prostate cancer who were treated with primary androgen-deprivation therapy from 2001 to 2013. Clinicopathological factors including several serum markers were investigated for association with progression-free (PFS) and overall (OS) survival. RESULTS: During a median follow-up of 48.1 months, median PFS and OS were 24.0 months and 67.4 months, respectively. When adjusted by age, prostate-specific antigen at diagnosis, Gleason score, and clinical stage, serum lactate dehydrogenase value was significantly associated with PFS [hazard ratio (HR)=1.42, 95&#37; confidence interval (CI)=1.15-1.74; p=0.0004] and OS (HR=1.46, 95&#37; CI=1.13-1.82; p=0.0014), in addition to alkaline phosphatase value for OS (HR=1.04; 95&#37; CI=1.00-1.07; p=0.015). CONCLUSION: This study demonstrates the prognostic significance of alkaline phosphatase and lactate dehydrogenase values in Japanese men with de novo metastatic hormone-sensitive prostate cancer.

DOI： 10.21873/anticanres.13457

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.6004/jnccn.2019.7302

記述言語：英語   掲載種別：研究論文（学術雑誌）  

This multi-institutional study aimed to investigate the efficacy and safety profiles of cabazitaxel after prior docetaxel chemotherapy in patients with castration-resistant prostate cancer (CRPC). This study included 63 Japanese patients with CRPC who were treated with cabazitaxel from 2014 to 2017. The oncological outcomes and adverse events (AEs) were documented, and prognostic factors for oncological outcomes and predictive factors for AEs were analysed. PSA decline was observed in 68.3% of patients, including 25.4% who achieved a ≥ 50% decline. The median progression-free survival, treatment failure-free survival, and overall survival were 4.3, 4.1, and 9.0 months, respectively. More cycles of prior docetaxel therapy was identified as common favourable prognostic factors for progression-free survival, treatment failure-free survival, and overall survival. Severe neutropenia, febrile neutropenia, and severe non-haematological AEs were observed in 73.0%, 33.3%, and 23.8% of patients, respectively. However, > 10 cycles of docetaxel was not associated with increased incidence of AEs. In conclusion, cabazitaxel chemotherapy was still active in Japanese CRPC patients treated with > 10 cycles of docetaxel chemotherapy, with an acceptable risk of AE burden. Treatment with cabazitaxel after > 10 cycles of docetaxel may be an appropriate option when it can be administered.

DOI： 10.1007/s12032-019-1257-1

記述言語：英語   掲載種別：研究論文（学術雑誌）  

This multi-institutional study aimed to investigate the efficacy and safety profiles of cabazitaxel after prior docetaxel chemotherapy in patients with castration-resistant prostate cancer (CRPC). This study included 63 Japanese patients with CRPC who were treated with cabazitaxel from 2014 to 2017. The oncological outcomes and adverse events (AEs) were documented, and prognostic factors for oncological outcomes and predictive factors for AEs were analysed. PSA decline was observed in 68.3&#37; of patients, including 25.4&#37; who achieved a ≥ 50&#37; decline. The median progression-free survival, treatment failure-free survival, and overall survival were 4.3, 4.1, and 9.0 months, respectively. More cycles of prior docetaxel therapy was identified as common favourable prognostic factors for progression-free survival, treatment failure-free survival, and overall survival. Severe neutropenia, febrile neutropenia, and severe non-haematological AEs were observed in 73.0&#37;, 33.3&#37;, and 23.8&#37; of patients, respectively. However, > 10 cycles of docetaxel was not associated with increased incidence of AEs. In conclusion, cabazitaxel chemotherapy was still active in Japanese CRPC patients treated with > 10 cycles of docetaxel chemotherapy, with an acceptable risk of AE burden. Treatment with cabazitaxel after > 10 cycles of docetaxel may be an appropriate option when it can be administered.

DOI： 10.1007/s12032-019-1257-1

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Recently, several novel agents including abiraterone, enzalutamide, docetaxel, cabazitaxel and radium-223 have become available for the treatment of castration-resistant prostate cancer (CRPC) and as a result, prognosis has improved. However, the criteria for selection of a suitable therapy have not been established. Much research on the genome has been carried out to enable precision medicine to be applied in cases of CRPC. Among them, germline polymorphisms in genes involved in androgen metabolism, such as HSD3B1, have been supposed to be the critical determinants of therapeutic outcomes in hormone therapy. Moreover, somatic aberrations such as androgen receptor, DNA-repair genes and tumorsuppressor genes (PTEN, TP53 and RBI) are also expected to act as biomarkers for therapeutic selection in CRPC. We herein report the significance of genetic polymorphism and somatic gene aberration in pharmacotherapy for prostate cancer, and we also present the current status and future perspectives with regard to the development of novel therapeutics based on genome information.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objective: We previously found that mirabegron exerts a relaxant effect in the presence of the β ₃ -adrenoceptor antagonist SR58894A during carbachol-induced contraction in human and pig detrusor. The aim of this study was to explore the possible mechanism underlying the relaxant effects of mirabegron using detrusor smooth muscle. Methods: Human tissue was obtained from urinary bladders of patients undergoing radical cystectomy at Kyushu University and Harasanshin Hospital. Pig tissue was obtained from an abattoir. Tension force (organ bath experiments) was measured in intact or permeabilised (α-toxin or β-escin) detrusor smooth muscle strips. The contribution of cAMP-dependent signaling and the inhibition of Ca ²⁺ sensitization to the relaxant effects of mirabegron were characterized using 1 μM SR58894A, 100 μM SQ22536 (an adenylyl cyclase inhibitor), 10 μM H-89 (a protein kinase [PK] A inhibitor), 10 μM Y-27632 (a selective Rho kinase inhibitor), and 10 μM GF-109203X (a selective PKC inhibitor). Results: 30 μM Mirabegron impaired carbachol (0.03-1 μM)-induced contraction in human detrusor smooth muscle. SR58894A only partially attenuated the relaxant effects of mirabegron in human and pig detrusor strips precontracted with 1 μM carbachol. In α-toxin-permeabilized detrusor strips, tension force at 1 μM [Ca ²⁺ ] _i was decreased by mirabegron in a concentration-dependent manner. The relaxant effect of mirabegron was only slightly attenuated by H-89 and not significantly affected by SQ22536. Y-27632 potentiated the relaxation response to mirabegron, but attenuated responses to cAMP; GF-109203X had little effect. Mirabegron but not cAMP had a notable relaxant effect in the pig detrusor smooth muscle permeabilized with β-escin. Conclusions: Mirabegron-induced relaxation of pig and human detrusor smooth muscle occurs via both a β ₃ -adrenoceptor/cAMP-dependent and -independent pathway.

DOI： 10.1111/luts.12247

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/iju.13870

記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Currently, several therapeutic options for castration-resistant prostate cancer (CRPC) are available, for which predictive biomarkers have not been established. Therefore, we aimed to reveal the association between pretreatment serum testosterone level and antitumor outcomes when treated with androgen receptor axis-targeting agents and taxane chemotherapies for CRPC. PATIENTS AND METHODS: The present study included Japanese patients with metastatic prostate cancer whose serum testosterone levels during androgen-deprivation therapy were available. The antitumor outcomes when treated with enzalutamide, abiraterone, docetaxel, and cabazitaxel with clinicopathological parameters including serum testosterone levels during androgen-deprivation therapy, as well as prognoses including progression-free survival and overall survival, were examined. RESULTS: Progression-free survival among men with higher serum testosterone level was superior to that among men with lower serum testosterone level when treated with enzalutamide. On the contrary, progression-free survival and overall survival among men with higher serum testosterone level were significantly inferior to those among men with lower serum testosterone level when treated with docetaxel and cabazitaxel, respectively. CONCLUSIONS: The present study indicated distinct prognostic values of serum testosterone level when treated with androgen receptor axis-targeting agent and taxane chemotherapy for CRPC, suggesting that serum testosterone level may be useful predictive biomarker to navigate the appropriate therapy in patients with CRPC.

DOI： 10.1016/j.urolonc.2018.10.020

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Importance: Recently, genetic polymorphism in HSD3B1 encoding 3β-hydroxysteroid dehydrogenase-1 has been shown to be associated with oncological outcome when treated with androgen-deprivation therapy (ADT) for prostate cancer. Upfront abiraterone combined with ADT has proved survival benefit. However, its effect on oncological outcome among different ethnicities and in abiraterone treatment remain unclear. Objective: To investigate the significance of missense polymorphism in HSD3B1 gene among men treated with primary ADT or abiraterone. Design, Setting, and Participants: This prognostic study included Japanese patients with metastatic hormone-sensitive prostate cancer between June 1993 and July 2005 and with castration-resistant prostate cancer between September 2014 and February 2018. Genome DNA was obtained from patient whole blood samples, and genotyping on HSD3B1 (rs1047303, 1245C) was performed by Sanger sequencing. Exposures: Primary ADT for metastatic hormone-sensitive prostate cancer and abiraterone for castration-resistant prostate cancer. Main Outcomes and Measures: The association of genotype in HSD3B1 with clinicopathological parameters and oncological outcome, including prostate-specific antigen response, progression-free survival, treatment failure-free survival, and overall survival was examined. Results: Of 203 men, 104 were in the primary ADT cohort (median [interquartile range] age, 72 [67-76] years) and 99 men were in the abiraterone group (median [interquartile range] age, 74 [67-80] years). Most patients carried metastatic lesions in each cohort. Among the cohort of primary ADT, men carrying heterozygous and homozygous variant types in HSD3B1 gene showed higher progression risk (hazard ratio [HR], 2.34; 95&#37; CI, 1.08-4.49; P = .03) but not any-caused death risk (HR, 1.36; 95&#37; CI, 0.52-2.92; P = .50), compared with men carrying homozygous wild type. In contrast, among the abiraterone cohort, men carrying variant type in HSD3B1 gene showed lower progression risk (HR, 0.32; 95&#37; CI, 0.12-0.69; P = .006) and lower all-cause mortality risk (HR, 0.40; 95&#37; CI, 0.13-0.94; P = .04) compared with men carrying homozygous wild type. Conclusions and Relevance: This study showed that HSD3B1 genetic variant is distinctly associated with oncological outcome between primary ADT and abiraterone in Japanese men, suggesting universal significance among different ethnicities in primary ADT, as well as promise as a predictive biomarker of ADT and abiraterone.

DOI： 10.1001/jamanetworkopen.2019.0115

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Kinesin family member C1 (KIFC1) is a minus end-directed motor protein that plays an essential role in centrosome clustering. Previously, we reported that KIFC1 is involved in cancer progression in prostate cancer (PCa). We designed this study to assess the involvement of KIFC1 in docetaxel (DTX) resistance in PCa and examined the effect of KIFC1 on DTX resistance. We also analyzed the possible role of a KIFC1 inhibitor (CW069) in PCa. We used DTX-resistant PCa cell lines in DU145 and C4-2 cells to analyze the effect of KIFC1 on DTX resistance in PCa. Western blotting showed that KIFC1 expression was higher in the DTX-resistant cell lines than in the parental cell lines. Downregulation of KIFC1 re-sensitized the DTX-resistant cell lines to DTX treatment. CW069 treatment suppressed cell viability in both parental and DTX-resistant cell lines. DTX alone had little effect on cell viability in the DTX-resistant cells. However, the combination of DTX and CW069 significantly reduced cell viability in the DTX-resistant cells, indicating that CW069 re-sensitized the DTX-resistant cell lines to DTX treatment. These results suggest that a combination of CW069 and DTX could be a potential strategy to overcome DTX resistance.

DOI： 10.3390/jcm8020225

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Purpose: Inadequate suppression of testosterone during androgen-deprivation therapy impairs its efficacy. This study investigated the significance of genetic polymorphism in CYP19A1, which encodes aromatase that catalyzes androgens into estrogens, among men treated with primary ADT for metastatic prostate cancer. Methods: This study included 80 Japanese patients with metastatic prostate cancer whose serum testosterone levels during ADT were available. The association of CYP19A1 gene polymorphism (rs1870050) with clinicopathological parameters including serum testosterone levels during ADT as well as progression-free survival and overall survival was examined. Results: Serum testosterone levels during ADT of men carrying homozygous wild-type (AA) in the CYP19A1 gene [median (interquartile range); 11.6 (8.3–20.3) ng/dl] were higher than those in men carrying the heterozygous/homozygous variant (AC/CC) [median (interquartile range); 10.0 (6.4–12.8) ng/dl]. When adjusted by Gleason score, initial PSA, M-stage and serum testosterone level during ADT, heterozygous/homozygous variant (AC/CC) in the CYP19A1 gene was associated with a lower risk of progression to castration resistance [hazard ratio (95% confidence interval), 0.53 [0.29–0.92], p = 0.025], but not to any-cause death [hazard ratio (95% confidence interval), 0.74 [0.36–1.49], p = 0.40]. Conclusions: These findings suggest that genetic variation in CYP19A1 (rs1870050) might affect the prognosis of patients with metastatic prostate cancer when treated with ADT by regulating serum testosterone levels.

DOI： 10.1007/s00280-019-03811-8

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background/Aim: The significance of second transurethral resection (TUR), and identification of predictive factors for residual cancer remain unrevealed. This study aimed to find residual cancer and up-staging rates, as well as predictive factors for residual cancer, in patients who undergo second TUR for non-muscle-invasive bladder cancer (NMIBC). Patients and Methods: Patients who underwent second TURs for NMIBC between 2015 and 2017, were included in the study and their clinicopathological characteristics were analyzed for predictors of residual cancer. Results: Among 143 Japanese patients whose tumors were initially diagnosed as high-risk NMIBC, residual cancers detected at second TURs were, Tis: n=22 (15.4%), Ta: n=15 (10.5%) and T1: n=29 (20.3%). No patients showed upstaging from NMIBC to MIBC. The presence of carcinoma-in situ at initial TUR was an independent risk factor for any residual cancer (Tis, Ta and T1), non-flat residual cancer (Ta and T1), and flat residual cancer (Tis). Conclusion: The presence of carcinoma-in situ is suggested to be an independent predictor of residual cancer. This may help guide decisions to perform second TUR.

DOI： 10.21873/anticanres.13598

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cigarette smoking is suggested to influence androgen milieu, which is closely associated with pathogenesis and prognosis of prostate cancer. In this study, we investigated the association between serum testosterone level before or during androgen-deprivation therapy (ADT) as well as prognoses and cigarette smoking status among men with metastatic prostate cancer. Serum testosterone level before ADT in current smokers (n = 6, median [interquartile range, IQR]; 454 ng/ml [426-478 ng/ml]) was significantly higher than that in nonsmokers (n = 26, median [IQR]; 397 ng/ml [312-435 ng/ml]). Serum testosterone level during ADT in current smokers (n = 7, median [IQR]; 7 ng/ml [3-11 ng/ml]) was comparable with that in nonsmokers (n = 55, median [IQR]; 9 ng/ml [3-20 ng/ml]). Progression-free survival and overall survival were comparable between current smokers and nonsmokers when adjusted with serum testosterone level before ADT or during ADT. These results suggest adequate pharmacological effect of ADT, even in current smokers. However, serum testosterone level before ADT was higher in current smokers. Thus, we need to interpret serum testosterone level in current smokers with caution.

DOI： 10.1111/and.13119

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The present study investigated clinical factors affecting perioperative outcomes in robot-assisted radical prostatectomy (RARP). The study included 625 Japanese cases treated with RARP between 2009 and 2017. The association between clinical factors (age, overweight status, prostate volume, clinical T-stage, nerve sparing, lympho-node dissection, and the number of experienced cases) and perioperative outcomes (operation time, estimated blood loss, catheterization duration, and perioperative complication) were analyzed. Results revealed that overweight status, prostate volume, lymph-node dissection, and the number of experienced cases were associated with operation time. For estimated blood loss, the identified risk factors were overweight status, prostate volume, nerve sparing, lymph-node dissection, and the number of experienced cases. Lymph-node dissection and the number of experienced cases were also associated with catheterization duration. Additionally, only lymph-node dissection was associated with increased perioperative complication. Taken together, the present study identified several clinical factors affecting perioperative outcomes in RARP. This information may help surgeons to estimate perioperative outcomes as well as to inform patients.

DOI： 10.3892/mco.2018.1718

記述言語：日本語  

症例は60歳代、男性。骨髄異形成症候群に対して同種骨髄移植後、左陰嚢腫大を主訴に当科紹介受診された。初診時の所見として、左精巣の無痛性腫大と硬結を触知したほか、造影CTで左精巣から精索に高吸収病変を認め、左精巣腫瘍の診断で左高位精巣摘除術を行った。病理組織診断の結果は、精巣、精索のいずれもMyeloid sarcomaであった。Myeloid sarcomaは骨髄外で骨髄芽球が腫瘍性に増殖し腫瘤を形成する稀な疾患であるが、急性骨髄性白血病などの骨髄系腫瘍と関連するとされ、同疾患の既往がある患者では鑑別診断の1つとして念頭におく必要がある。(著者抄録)

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Currently, the optimal sequential use of androgen receptor (AR) axis-targeted agents and taxane chemotherapies remains undetermined. We aimed to elucidate the resistance status between taxanes and enzalutamide, and the functional role of the AR axis. Enzalutamide-resistant 22Rv1 cells showed collateral resistance to taxanes, including docetaxel and cabazitaxel. However, taxane-resistant cells showed no collateral resistance to enzalutamide; taxane-resistant cells expressed comparable protein levels of full-length AR and AR variants. Knockdown of both full-length AR and AR variants rendered cells sensitive to taxanes, whereas knockdown of AR variants sensitized cells to enzalutamide, but not to taxanes. In contrast, overexpression of full-length AR rendered cells resistant to taxanes. Consistently, the prostate-specific antigen response and progression-free survival in docetaxel chemotherapy were worse in cases with prior use of ARAT agents compared with cases without. Collateral resistance to taxanes was evident after obtaining enzalutamide resistance, and aberrant AR signaling might be involved in taxane resistance.

DOI： 10.1111/cas.13751

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Corticosteroids play important roles in prostate cancer therapeutics. However, their role when combined with enzalutamide remains obscure. Then, we aimed to elucidate the functional and clinical impact of corticosteroids on steroid receptors in androgen receptor (AR)-targeting therapy utilizing enzalutamide. METHODS: The therapeutic effect was studied according to concomitant use of corticosteroids in 86 men treated with enzalutamide. The sensitivity to various agents was evaluated using cytotoxicity assays in prostate cancer cells. Gene expression levels were evaluated by quantitative real-time polymerase chain reaction in prostate cancer cells and tissues. RESULTS: The therapeutic effect of enzalutamide was particularly lessened with concomitant treatment with dexamethasone. Consistently, dexamethasone increased cellular resistance to enzalutamide while prednisolone and aldosterone decreased cellular resistance to enzalutamide in prostate cancer cells. Inversely, mineralocorticoid receptor (MR) knockdown augmented the activity of AR signaling and the cellular resistance to enzalutamide. CONCLUSIONS: MR plays a critical role in resistance to AR-targeting therapies, which may be overcome by activation of MR signaling.

DOI： 10.1002/pros.23661

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: We aimed to identify the candidate prostate cancer patients suitable for neoadjuvant androgen-deprivation therapy (ADT) with radical prostatectomy (RP). MATERIALS AND METHODS: This study included 711 Japanese patients with clinically localized prostate cancer who were treated with RP between 2000 and 2013. Patients were treated with or without neoadjuvant ADT before RP. The prognostic significance of neoadjuvant ADT on biochemical recurrence (BCR) was analyzed according to various clinicopathological characteristics. RESULTS: BCR occurred in 186 (26.2&#37;) of 711 patients. The group treated with neoadjuvant ADT showed higher levels of prostate-specific antigen at diagnosis and advanced clinical T-stage, but suppressed pathological T-stage. Neoadjuvant ADT was not associated with the risk of BCR. In subgroup analysis, neoadjuvant ADT was significantly associated with increased BCR in patients aged >65 years [hazard ratio (95&#37; confidence interval), 2.04 (1.13-3.43), P = 0.020]. Among the 53 patients with available serum testosterone levels, neoadjuvant ADT was associated with the risk of BCR according to serum testosterone levels. CONCLUSION: This study demonstrated that neoadjuvant ADT showed potential deleterious effects in older patients and patients with lower serum testosterone levels, while a possible improved prognosis in patients with high serum testosterone levels treated with neoadjuvant ADT was suggested, warranting further exploration.

DOI： 10.1016/j.prnil.2017.10.002

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: We aimed to identify prognostic and predictive factors for anti-androgen withdrawal syndrome (AWS) to help guide decisions on anti-androgen withdrawal in castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: This study included 95 patients with prostate cancer which progressed to CRPC despite primary androgen-deprivation therapy (ADT). AWS was defined as >50&#37; prostate-specific antigen decline after anti-androgen withdrawal. Associations between AWS, and clinicopathological factors and prognosis were investigated. RESULTS: Among the 95 patients, 84 (88.4&#37;) underwent anti-androgen withdrawal, among whom AWS was recognized in nine (10.8&#37;). Gleason score and response duration to primary ADT were predictors of AWS. Long duration of response to primary ADT was also associated with better progression-free survival [hazard ratio (HR)=0.021, 95&#37; confidence interval (CI)=0.0025-0.14, p<0.0001] and overall survival (HR=0.0042, 95&#37; CI=0.0001-0.089, p<0.0001). Age (HR=7.19, 95&#37; CI=1.08-54.27, p=0.041) and radiological/clinical progression (HR=3.14, 95&#37; CI=1.35-6.43, p=0.010) were associated with worse overall survival. Intriguingly, radiological/clinical progression was associated with the differential effect of anti-androgen withdrawal on overall survival (interaction p=0.031). CONCLUSION: Patients who suffer radiological/clinical progression are unsuitable candidates for anti-androgen withdrawal.

DOI： 10.21873/anticanres.12702

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The aim of the present study was to evaluate the prognostic impact of size and number of tumors in primary low-grade (LG) Ta bladder urothelial carcinoma (UC), and thus allow accurate risk stratification of low-risk non-muscle invasive bladder cancer (NMIBC). This study was a retrospective analysis of 245 patients with primary LG Ta UC of the urinary bladder who were treated with transurethral resection. Differences in intravesical recurrence-free survival (RFS) according to various cutoff values of tumor size and tumor number were calculated using Cox proportional hazards model. Median maximum size of tumor was 1.4 cm, and 153 patients (62.4&#37;) had solitary tumors. Forty-nine patients experienced intravesical recurrence during a median 34 months of follow-up. Patients with solitary tumors had significantly longer RFS times compared with those with ≥8 tumors (P=0.003). Patients with larger tumors had significantly shorter RFS times for each cutoff value (P=0.01 for 1.0 cm, P<0.0001 for 1.5 and 2.0 cm, P=0.006 for 3.0 cm). On multivariate analysis, each cutoff value of tumor size was found to be a predictor of RFS; among them, the cutoff of 1.5 cm showed the strongest association (hazard ratio, 4.12; 95&#37; confidence interval, 2.11-8.81; P<0.001). If we consider only lower risk NMIBC patients, such as primary LG Ta, the appropriate cutoff value of tumor size to predict intravesical recurrence might be 1.5 cm, but not 3.0 cm generally adopted in various guidelines. These findings suggest the need for rational risk assessment with consideration of the diversity of patients with NMIBC.

DOI： 10.3892/mco.2018.1602

記述言語：英語  

Androgen deprivation therapy can induce oxidative stress by increasing reactive oxygen species levels and/or decreasing cellular antioxidant capacity, which in turn cause genetic and epigenetic effects in prostate cancer. Oxidative stress increases androgen receptor (AR) activation through several possible mechanisms, including AR overexpression, AR activation by co-regulators and intracellular signal transduction pathways, mutation of AR and AR-related proteins, expression of AR splice variants, de novo androgen synthesis, and changes in non-AR signaling. Alterations in AR and non-AR signaling appear to have pro-survival and anti-apoptotic effects on prostate cancer cells, resulting in the development of castration-resistant prostate cancer. Thus, antioxidant therapy could be a promising strategy for the treatment of prostate cancer. Oxidative stress also influences the activity of several prostate cancer therapies, such as taxanes, radiotherapy, and AR-targeting agents. Taken together, these observations suggest that oxidative stress-induced AR signaling is a critical resistance factor and a crucial target for prostate cancer treatment.

DOI： 10.1007/978-981-10-7013-6_21

記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 67-year-old man with metastatic prostate cancer presented with progression to castration-resistant prostate cancer. After sequential therapies with flutamide, estramustine phosphate, docetaxel, enzalutamide, and cabazitaxel for castration-resistant prostate cancer, radium-223 was initiated and continued up to 4 cycles. However, concurrently with radiological and clinical progressions, pancytopenia was observed due to bone-marrow carcinomatosis by prostatic adenocarcinoma. This case suggested that radium-223 should be employed at appropriated timing before appearances of extraosseous and bone-marrow lesions in addition to visceral metastasis.

DOI： 10.1007/s13691-017-0316-8

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Purpose: Serum testosterone suppression during androgen deprivation therapy has been reported to affect the efficacy of androgen deprivation therapy. However, the factors impacting hormonal variations during androgen deprivation therapy remain unclear. Therefore, in this study we investigated the significance of missense polymorphisms in the gene encoding GNRH in men treated with primary androgen deprivation therapy for metastatic prostate cancer. Materials and Methods: This study included 80 Japanese patients with metastatic prostate cancer with available serum testosterone levels during androgen deprivation therapy. We examined the association of GNRH1 (rs6185, S20W) and GNRH2 (rs6051545, A16V) gene polymorphisms with clinicopathological parameters, including serum testosterone levels during androgen deprivation therapy, as well as prognosis, including progression-free and overall survival. Results: The CT and CT/TT alleles in the GNRH2 gene (rs6051545) were associated with higher serum testosterone during androgen deprivation therapy compared with those of the CC allele. Consequently the CT alleles were associated with a higher risk of progression after adjustment for age and serum testosterone during androgen deprivation therapy (HR 1.73, 95% CI 1.00–3.00, p = 0.049). Conclusions: Taken together these findings suggest that rs6051545 (GNRH2) genetic variation may result in inadequate suppression of serum testosterone during androgen deprivation therapy. This may lead to detrimental effects of androgen deprivation therapy on prognosis in men with metastatic prostate cancer.

DOI： 10.1016/j.juro.2017.09.076

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Growth factor receptor tyrosine kinase (RTK) pathway activation is a key mechanism for mediating cancer growth, survival, and treatment resistance. Cognate ligands play crucial roles in autocrine or paracrine stimulation of these RTK pathways. Here, we show SEMA3C drives activation of multiple RTKs including EGFR, ErbB2, and MET in a cognate ligand-independent manner via Plexin B1. SEMA3C expression levels increase in castration-resistant prostate cancer (CRPC), where it functions to promote cancer cell growth and resistance to androgen receptor pathway inhibition. SEMA3C inhibition delays CRPC and enzalutamide-resistant progression. Plexin B1 sema domain-containing:Fc fusion proteins suppress RTK signaling and cell growth and inhibit CRPC progression of LNCaP xenografts post-castration in vivo. SEMA3C inhibition represents a novel therapeutic strategy for treatment of advanced prostate cancer.

DOI： 10.15252/emmm.201707689

記述言語：英語   掲載種別：研究論文（学術雑誌）  

In ectopic ACTH-secreting pheochromocytoma, combined ACTH-driven hypercortisolemia and hypercatecholaminemia are serious conditions, which can be fatal if not diagnosed and managed appropriately, especially when glucocorticoid-driven positive feedback is suggested with a high ACTH/cortisol ratio. A 46-year-old man presented with headache, rapid weight loss, hyperhidrosis, severe hypertension and hyperglycemia without typical Cushingoid appearance. Endocrinological examinations demonstrated elevated plasma and urine catecholamines, serum cortisol and plasma ACTH. Moreover, his ACTH/cortisol ratio and catecholamine levels were extremely high, suggesting catecholamine-dominant ACTH-secreting pheochromocytoma. Computed tomography revealed a large right adrenal tumor.¹⁸F-FDG positron emission tomography showed uptake in the area of the adrenal tumor, while¹²³I-metaiodobenzylguanidine scintigraphy showed no accumulation. His plasma ACTH level paradoxically became elevated after a dexamethasone suppression test. After metyrapone administration, not only serum cortisol but also plasma ACTH levels were exponentially decreased almost in parallel, suggesting a glucocorticoid-driven positive-feedback regulation in this rapidly exacerbated ectopic ACTH-producing pheochromocytoma. Interestingly enough, plasma catecholamine levels were also decreased by metyrapone, although they remained extremely high. He became severely dehydrated due to hypoadrenalism requiring hydrocortisone supplementation. His clinical signs and symptoms were improved, and right adrenalectomy was performed uneventfully, resulting in complete remission of pheochromocytoma and Cushing’s syndrome. A glucocorticoid-driven positive-feedback regulation in this ectopic ACTH-secreting pheochromocytoma created a vicious cycle with rapid exacerbation of both hypercortisolemia and hypercatecholaminemia with extremely elevated plasma ACTH level. Metyrapone was clinically effective to stop this vicious cycle; nonetheless, great care must be taken to avoid hypoadrenalism especially when hypercatecholaminemia remained.

DOI： 10.1507/endocrj.EJ18-0025

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Mineralocorticoid receptor (MR) signaling which is closely associated with hypertension plays important roles in resistance to antiandrogen therapy in prostate cancer. However, its impact on the prognosis in androgen-deprivation therapy (ADT) has not been elucidated. Then, we investigated the impact of genetic variation in MR and comorbidity with hypertension on the prognosis in ADT. This study included 182 Japanese patients with prostate cancer treated with ADT, whose comorbidity status with hypertension were available. The associations of MR polymorphism (rs5522) and comorbidity with hypertension with clinicopathological parameters as well as progression-free survival and overall survival were examined. Clinicopathological characteristics were comparable between genetic variation in MR. However, homozygous variant in MR was associated with shorter time to castration resistance (P = 0.014) and any-cause death (P = 0.024). In patients' background, presence of comorbidity with hypertension showed the trend with lower PSA level at diagnosis and lower biopsy Gleason score, as well as significant association with less incidence of N1. Comorbidity with hypertension was associated with longer time to castration resistance (P = 0.043) and any-cause death (P = 0.046), which was diminished on multivariate analysis including age, PSA level at diagnosis, biopsy Gleason score, clinical stage, and the modality of hormonal therapy. Genetic variation in MR (rs5522) and comorbidity with hypertension were significantly and potentially associated with prognosis when treated with ADT, respectively. This suggests that the individual intensity of MR signaling may be associated with resistance to ADT and a promising biomarker in ADT.

DOI： 10.3389/fonc.2018.00635

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Tumor heterogeneity can be traced back to a small subset of cancer stem cells (CSCs), which can be derived from a single stem cell and show chemoresistance. Recent studies showed that CSCs are sensitive to mitochondrial targeting antibiotics such as doxycycline. However, little is known about how cancer cells undergo sphere formation and how antibiotics inhibit CSC proliferation. Here we show that under sphere-forming assay conditions, prostate cancer cells acquired CSC-like properties: promoted mitochondrial respiratory chain activity, expression of characteristic CSC markers and resistance to anticancer agents. Furthermore, those CSC-like properties could reversibly change depending on the culture conditions, suggesting some kinds of CSCs have plasticity in tumor microenvironments. The sphere-forming cells (i.e. cancer stem-like cells) showed increased contact between mitochondria and mitochondrial associated-endoplasmic reticulum (ER) membranes (MAM). Mitochondrial targeting doxycycline induced activating transcription factor 4 (ATF4) mediated expression of ER stress response and led to p53-upregulated modulator of apoptosis (PUMA)-dependent apoptosis only in the cancer stem-like cells. We also found that doxycycline effectively suppressed the sphere formation in vitro and blocked CD44v9-expressing tumor growth in vivo. In summary, these data provide new molecular findings that monolayer cancer cells acquire CSC-like properties in a reversible manner. These findings provide important insights into CSC biology and a potential new treatment of targeting mitochondria dependency.

DOI： 10.1038/s41389-017-0009-3

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background/Aim: Salvage androgen-deprivation therapy (ADT) is standard treatment for recurrent prostate cancer after curative therapy. However, the prognostic impact of different treatment modalities on the time to castration resistance remains unclear. In this study, we investigated the prognosis of men treated with salvage ADT after initial radical prostatectomy or radiotherapy for prostate cancer. Patients and Methods: Between 2000 and 2013, 149 Japanese men with recurrent prostate cancer who were initially treated with radical prostatectomy (n=95) or radiotherapy (n=54) and were subsequently treated with salvage ADT after disease recurrence were enrolled in this study. The prognostic significance of the curative treatment modality and clinicopathological findings were analyzed. Results: During a median follow-up period of 4.7 years after recurrence, castration-resistant progression was observed in 22 men. The 5-year progression-free survival, metastasis-free survival, cause-specific survival, and overall survival rates for all patients were 86.3%, 81.4%, 95.7%, and 94.5%, respectively. Multivariate analysis identified the biopsy Gleason score at initial diagnosis and the initial curative treatment modality as significant predictors of castration resistance. Conclusion: This study showed that low biopsy Gleason score (≤7) at diagnosis and radical prostatectomy as the curative treatment may be favorable prognostic factors for treatment with salvage ADT.

DOI： 10.21873/anticanres.11998

記述言語：日本語  

新膀胱輸入脚狭窄により腎後性腎不全を発症した1例

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Among patients with prostate cancer, the prognosis after androgen deprivation therapy differs significantly among individuals and among races; however, the reasons underlying these differences are poorly understood. Several single nucleotide polymorphisms in genes associated with prostate cancer progression or castration resistance might serve as the host factor that influences prognosis and, thus, accounts for these individual and racial gaps in treatment outcomes. Accordingly, single nucleotide polymorphisms associated with treatment outcomes could be used as predictive and/or prognostic biomarkers for patient stratification and to identify personalized treatment and follow-up protocols. The present review has summarized the genetic polymorphisms that have been reported to associate with androgen deprivation therapy outcomes among patients with prostate cancer and compared the allele frequencies among different ethnic groups.

DOI： 10.1016/j.clgc.2017.01.006

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objective: To analyze the association between smoking and oncological outcome after radical prostatectomy in patients with prostate cancer.Methods: This study included men who underwent radical prostatectomy between 2003 and 2013. The association of clinicopathological factors with smoking status and the prognostic significance of clinicopathological factors and smoking status on biochemical recurrence (BCR) were evaluated.Results: Of the 1165 included patients, 226 (19.4%) were current smokers and 939 (80.6%) were nonsmokers. The median observation period was 39 months (interquartile range, 15-75 months). Current smokers were younger than nonsmokers and had higher PSA levels, higher biopsy and pathological Gleason scores, and more frequent lymph-node involvement than nonsmokers. Pathological Gleason score, extracapsular extension, seminal vesicle invasion, positive surgical margin, lymph-node involvement, and current smoking (hazard ratio [95% confidence interval]; 1.31 [1.00-1.72], P = 0.046) were identified as significant risk factors of BCR on univariate analysis. However, smoking status was not an independent predictive marker on multivariate analysis.Conclusions: Current smokers had adverse clinicopathological characteristics including high PSA level, high Gleason score, and lymph node involvement, suggesting that smoking promoted the progression of prostate cancer.

DOI： 10.1093/jjco/hyx013

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Purpose: This study aimed to examine the differential impact of body mass index and the feature of metabolic syndrome (MetS; obesity, hypertension, diabetes mellitus, and dyslipidemia) on biochemical recurrence (BCR) following radical prostatectomy (RP) treatment for prostate cancer using different surgical procedures. Methods: This study included 283 Japanese patients with clinically localized prostate cancer who were treated with RP between 2008 and 2012. The prognostic significance of overweight and the feature of MetS were analyzed according to surgical procedures. Results: BCR occurred in 68/283 (24.0%) men. Overweight and the feature of MetS were predictors of BCR in patients who had undergone open RP (ORP), but not in those treated with laparoscopic surgery. Multivariate analyses incorporating preoperative and postoperative risk factors revealed that overweight and the feature of MetS were independent BCR risk factors when treated with ORP. Conclusions: In Japanese men, overweight and the feature of MetS were associated with worse outcomes following RP, particularly ORP, compared with those following laparoscopic surgery. These results suggest that laparoscopic surgery can overcome the surgical challenges associated with abdominal obesity.

DOI： 10.1245/s10434-016-5705-2

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The progression of prostate cancer to metastatic and castration-resistant disease represents a critical step. We previously showed that protein kinase C (PKC) activation followed by Twist1 and androgen receptor (AR) induction played a critical role in castration resistance, but the precise molecular mechanism remains unknown. This study aimed to elucidate the relevant molecular mechanism, focusing on NF-κB transcription factor. We examined the activity of NF-κB after PKC inhibition, and the expression of Twist1 and AR after inhibition of NF-κB in human prostate cancer cells. We also investigated the status of PKC/NF-κB after inhibition of AR signaling in cells resistant to hormonal therapy. As a result, inhibition of PKC signaling using knockdown and smallmolecule inhibition of PKC suppressed RelA activity, while blocking NF-κB suppressed Twist1 and AR expression. Conversely, inhibition of AR signaling by androgen depletion and the novel antiandrogen enzalutamide induced PKC and RelA activation, resulting in Twist1/AR induction at the transcript level. Moreover, inhibition of NF-κB signaling prevented enzalutamide-induced Twist1 and AR induction. Finally, NF-κB was activated in both castration-resistant and enzalutamide-resistant cells. In conclusion, NF-κB signaling was responsible for Twist1 upregulation by PKC in response to AR inhibition, resulting in aberrant activation of AR. NF-κB signaling thus appears to play a critical role in promoting both castration resistance and enzalutamide resistance in PKC/Twist1 signaling in prostate cancer.

DOI： 10.1530/ERC-16-0384

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/annonc/mdw646

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: FOXO3a is a member of the forkhead O transcription factors. FOXO3a induces the factors that contribute to cell cycle arrest and is considered a tumor suppressor in several malignant tumors. Y-box binding protein-1 (YB-1) is a multifunctional protein whose high expression is correlated with poor prognoses in various malignant tumors. In the current study, we investigated the relationship between FOXO3a and YB-1 to validate their functional roles in prostate cancer. METHODS: Western blotting and cytotoxicity assays were conducted in prostate cancer cells, LNCaP, and 22Rv1 cells. We also evaluated the protein expressions of FOXO3a and YB-1 in human prostate cancer tissues, using radical prostatectomy specimens. Then, we investigated the correlations between protein expressions and clinicopathologic parameters. RESULTS: We found that both FOXO3a and YB-1 proteins were phosphorylated by ERK signaling, resulting in FOXO3a inactivation and YB-1 activation in LNCaP and 22Rv1 cells. Inversely, inhibition of MEK or treatment with metformin activated FOXO3a through inactivation of ERK signaling and suppressed the viability of LNCaP and 22Rv1 cells in a dose-dependent manner. In immunohistochemical analysis, FOXO3a nuclear expression was inversely correlated with YB-1 nuclear expression (P < 0.0001). Furthermore, high FOXO3a nuclear expression was inversely correlated with a higher Gleason grade (P < 0.0001) and higher preoperative PSA (P = 0.0437). CONCLUSIONS: These results showed that in prostate cancer, FOXO3a, and YB-1 play inverse reciprocal roles as a tumor-suppressor gene and oncogene, respectively, through their master regulator ERK. Prostate 77:145–153, 2017.

DOI： 10.1002/pros.23254

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Purpose We determined whether intravesical recurrence is affected by inhibition of androgen signaling among men with nonmuscle invasive bladder cancer. Materials and Methods We examined the intravesical recurrence rate among men treated with or without androgen suppression therapy by androgen deprivation therapy for prostate cancer or 5α-reductase inhibitor dutasteride for benign prostatic hyperplasia. Results We studied 228 men, including 32 with and 196 without androgen suppression therapy. During a median followup of 3.6 and 3.0 years intravesical recurrence developed in 4 (12.5%) and 59 men (30.1%) with and without androgen suppression therapy, respectively. On multivariate analysis multiple tumors (HR 1.82, p = 0.027), a large tumor (HR 2.13, p = 0.043) and ever smoking (HR 2.45, p = 0.020) as well as the presence of androgen suppression therapy (HR 0.36, p = 0.024) were independent risk factors for intravesical recurrence. Notably, tumor progressed to muscle invasive bladder cancer in 6 men (3.1%) without androgen suppression therapy. No man with androgen suppression therapy progressed to muscle invasive bladder cancer. Conclusions Our study suggests the possibility of androgen suppression therapy as prophylaxis for intravesical recurrence of bladder cancer. Further explorations are warranted of the prophylactic effect of androgen suppression therapy on bladder cancer pathogenesis.

DOI： 10.1016/j.juro.2016.08.006

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: LIM and SH3 domain protein 1 (LASP1) has been implicated in several human malignancies and has been shown to predict PSA recurrence in prostate cancer. However, the anti-tumor effect of LASP1 knockdown and the association between LASP1 and the androgen receptor (AR) remains unclear. The aim of this study is to clarify the significance of LASP1 as a target for prostate cancer, and to test the effect of silencing LASP1 in vivo using antisense oligonucleotides (ASO). METHODS: A tissue microarray (TMA) was performed to characterize the differences in LASP1 expression in prostate cancer treated after hormone deprivation therapy. Flow cytometry was used to analyze cell cycle. We designed LASP1 ASO for knockdown of LASP1 in vivo studies. RESULTS: The expression of LASP1 in TMA was increased after androgen ablation and persisted in castration resistant prostate cancer (CRPC). Also in TMA, compared with LNCaP cell, LASP1 expression is elevated in CRPC cell lines (C4-2 and VehA cells). Interestingly, suppression of AR elevated LASP1 expression conversely, AR activation decreased LASP1 expression. Silencing of LASP1 reduced cell growth through G1 arrest which was accompanied by a decrease of cyclin D1. Forced overexpression of LASP1 promoted cell cycle and induced cell growth which was accompanied by an increase of cyclin D1. Systemic administration of LASP1 ASO with athymic mice significantly inhibited tumor growth in CRPC xenografts. CONCLUSIONS: These results indicate that LASP1 is negatively regulated by AR at the transcriptional level and promotes tumor growth through induction of cell cycle, ultimately suggesting that LASP1 may be a potential target in prostate cancer treatment. Prostate 77:309–320, 2017.

DOI： 10.1002/pros.23269

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Several bacterial flavin adenine dinucleotide (FAD)-harboring dehydrogenase complexes comprise three distinct subunits: a catalytic subunit with FAD, a cytochrome c subunit containing three hemes, and a small subunit. Owing to the cytochrome c subunit, these dehydrogenase complexes have the potential to transfer electrons directly to an electrode. Despite various electrochemical applications and engineering studies of FAD-dependent dehydrogenase complexes, the intra/inter-molecular electron transfer pathway has not yet been revealed. In this study, we focused on the conserved Cys-rich region in the catalytic subunits using the catalytic subunit of FAD dependent glucose dehydrogenase complex (FADGDH) as a model, and site-directed mutagenesis and electron paramagnetic resonance (EPR) were performed. By co-expressing a hitch-hiker protein (γ-subunit) and a catalytic subunit (α-subunit), FADGDH γα complexes were prepared, and the properties of the catalytic subunit of both wild type and mutant FADGDHs were investigated. Substitution of the conserved Cys residues with Ser resulted in the loss of dye-mediated glucose dehydrogenase activity. ICP-AEM and EPR analyses of the wild-type FADGDH catalytic subunit revealed the presence of a 3Fe-4S-type iron-sulfur cluster, whereas none of the Ser-substituted mutants showed the EPR spectrum characteristic for this cluster. The results suggested that three Cys residues in the Cys-rich region constitute an iron-sulfur cluster that may play an important role in the electron transfer from FAD (intra-molecular) to the multi-heme cytochrome c subunit (inter-molecular) electron transfer pathway. These features appear to be conserved in the other three-subunit dehydrogenases having an FAD cofactor.

DOI： 10.1016/j.bioelechem.2016.01.010

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objective: To investigate the potential relationship of steroid usage with prostate-specific antigen (PSA) flare as well as the prognostic impact of PSA flare, which is known to occur in 10–20% of patients with metastatic castration-resistant prostate cancer during docetaxel chemotherapy. Patients and Methods: This study included 71 patients with metastatic castration-resistant prostate cancer treated by docetaxel chemotherapy with co-introduction of a steroid. PSA flare was defined as a transient PSA increase followed by a PSA decrease. Results: PSA flare was recognized in 7.0–23.9% of patients according to the definition used. Intriguingly, men with steroid intake before the initiation of docetaxel chemotherapy experienced significantly fewer PSA flares. The progression-free survival rate in men with PSA flare was equivalent to that of PSA responders, but significantly better than men with PSA failure. Conclusions: Our results suggest that de novo steroid co-introduction with docetaxel chemotherapy induces the PSA flare phenomenon. This novel finding may account for the mechanism of PSA flare as well as being valuable for distinguishing PSA elevation attributable to PSA flare from that attributable to PSA failure.

DOI： 10.1111/bju.13483

記述言語：英語  

A 66-year-old man presented with macrohematuria. Cystoscope examination found a 5 mm nodular tumor at external urethral orifice and multiple papillary tumors at fossa navicularis of urethra; those are non-black colored. Transurethral resection of the urethra tumor was performed, and pathologically diagnosed as malignant melanoma. Image examinations showed no lymphadenopathy and metastasis. Accordingly, total penectomy was conducted to remove the remaining tumors, resulting in surgically curative resection. After the operation, monthly interferon-β injection into inguinal region has been administered as adjuvant therapy, resulting in no recurrence at 6 months after penectomy.

DOI： 10.1007/s13691-016-0252-z

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objective: Although it is well known that radiotherapy for prostate cancer increases comorbid rate of secondary bladder cancer, the effect of aging and smoking with radiotherapy on incidence rate of secondary bladder cancer remains unknown. Then, this study investigated the combinational effect of external beam radiotherapy for prostate cancer and aging or smoking on comorbid rate of secondary bladder cancer.Methods: This study included 754 Japanese patients with prostate cancer treated with radiotherapy (n = 319) and radical prostatectomy (n = 435) from 2000 through 2013. The relationship between therapeutic modality for prostate cancer as well as age or smoking status and comorbid rate of secondary bladder cancer was examined.Results: During the median follow-up period of 4.3 and 3.1 years, secondary bladder cancer occurred in 11 (3.4%) and 5 (1.1%) of patients with prostate cancer treated with external beam radiotherapy and radical prostatectomy, respectively. The 5-year bladder cancer-free survival rate was 97.3% in the external beam radiotherapy group and 99.4% in the radical prostatectomy group. Age (hazard ratio = 1.15, P = 0.027) and ever smoking (hazard ratio = 5.65, P = 0.011) were significant predictive factors of secondary bladder cancer incidence in the external beam radiotherapy cohort, but not in the radical prostatectomy cohort. Inversely, among men with ever smoking, but not among older men, external beam radiotherapy (hazard ratio = 9.64, P = 0.0052) was a significant risk factor of secondary bladder cancer.Conclusions: Taken together, these findings suggest that smoking history might be one of criteria to choose radical prostatectomy than external beam radiotherapy for prostate cancer, and that age would not be a criterion for therapeutic selection in terms of secondary bladder cancer.

DOI： 10.1093/jjco/hyw098

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objectives: To review the quality of our extended pelvic lymph node dissection (ePLND) and to evaluate the accuracy of preoperative nomograms predicting lymph node involvement (LNI) in patients who underwent ePLND during robot-assisted radical prostatectomy (RARP). Patients and methods: The study included 83 patients who underwent ePLND during RARP between November 2012 and May 2015. We performed ePLND in patients with T3 disease, DAmico high-risk disease, and in those where the risk of LNI was higher than 5% as estimated by the Japan PC Table. Preoperative and postoperative patient data were collected retrospectively. We carried out ROC analyses for external validation of preoperative LNI-predicting nomograms. Results: The median number of lymph nodes removed was 19. LNI was found in 15 of the 83 patients (18%). In the 15 patients with nodal metastasis, a total of 28 positive lymph nodes were detected, 30% of which were in the obturator area, 17% in the external iliac area and 48% in the internal iliac area. In the external validation of LNI prediction by preoperative nomograms using ROC analyses, AUC of the Briganti nomogram was 0.80 whereas that of the Japan PC Table was 0.68. Conclusions: The number of lymph nodes removed and lymph node positivity by ePLND during RARP in our institution were comparable to previous reports based on an open radical prostatectomy series. In this study, the Japan PC Table was inferior to the Briganti nomogram for prediction of LNI, and therefore the development of an updated nomogram for Japanese patients who undergo ePLND is required.

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Aims: The aims of this study were to investigate the association of renal cell carcinoma (RCC) displaying rhabdoid features and morphologically mesenchymal characteristics with epithelial to mesenchymal transition (EMT), and to clarify the expression of EMT markers. Methods: We investigated the expression of EMT markers (E-cadherin, vimentin, Snail, Slug, ZEB1, ZEB2 and Twist1) using immunohistochemistry, Western blotting and real-time polymerase chain reaction in 18 cases of clear cell RCC (ccRCC) with rhabdoid features and 74 ccRCC cases with Fuhrman grade 1-3 (G1 to G3). Results: In ccRCCs with rhabdoid features, low E-cadherin and high vimentin expression were found. In G1 to G3 ccRCCs, low E-cadherin expression and high expression of vimentin, ZEB1 and ZEB2 were found. There was no significant difference in the immunoexpression of E-cadherin and vimentin between the two ccRCC groups. Conclusions: The rhabdoid features may histologically and biologically be associated with EMT in ccRCC. There is a possibility that in G1 to G3 ccRCCs showing epithelial structures, other cell-cell adhesion mechanisms apart from E-cadherin adhesion may continue to work, and that ccRCC with rhabdoid features may be caused by an inactivation or loss of these mechanisms.

DOI： 10.1159/000445752

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Chemopreventive and potential therapeutic effects of soy isoflavones have been shown to be effective in numerous preclinical studies as well as clinical studies in prostate cancer. Although the inhibition of androgen receptor signaling has been supposed as one mechanism underlying their effects, the precise mechanism of androgen receptor inhibition remains unclear. Thus, this study aimed to clarify their mechanism. Among soy isoflavones, equol suppressed androgen receptor as well as prostate-specific antigen expression most potently in androgen-dependent LNCaP cells. However, the inhibitory effect on androgen receptor expression and activity was less prominent in castration-resistant CxR and 22Rv1 cells. Consistently, cell proliferation was suppressed and cellular apoptosis was induced by equol in LNCaP cells, but less so in CxR and 22Rv1 cells. We revealed that the proteasome pathway through S-phase kinase-associated protein 2 (Skp2) was responsible for androgen receptor suppression. Taken together, soy isoflavones, especially equol, appear to be promising as chemopreventive and therapeutic agents for prostate cancer based on the fact that equol augments Skp2-mediated androgen receptor degradation. Moreover, because Skp2 expression was indicated to be crucial for the effect of soy isoflavones, soy isoflavones may be applicable for precancerous and cancerous prostates.

DOI： 10.1111/cas.12948

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/jnci/djw005

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Mycobacterium bovis Bacillus Calmette-Guérin (BCG) is used for the treatment of bladder cancer. The recruitment of neutrophlis to the bladder after BCG instillation exerts anti-tumor activity against bladder tumor. We have recently demonstrated that interleukin (IL)-17A produced by γδ T cells played a role in the recruitment of neutrophlis to the bladder after BCG instillation. IL-15 is known to play an important role in neutrophil migration during inflammation. We previously constructed a recombinant BCG strain expressing the fusion protein of IL-15 and Ag85B (BCG-IL-15) for prevention of Mycobacterium tuberculosis infection. Here we compared the efficacy of the BCG-IL-15 in protection against bladder cancer with that of rBCG-Ag85B (BCG). Six-week-old female C57BL/6 mice were inoculated with MB49 bladder tumor cells in the bladder and subsequently intravesically inoculated with BCG or BCG-IL-15. BCG-IL-15 treatment significantly prolonged survival of mice inoculated with bladder cancer cells compared with BCG treatment. Infiltration of neutrophils was significantly elevated in BCGB-IL-15 treated mice accompanied by increased chemokines (MIP-2 and MIP-1α) in the bladder. Thus, BCG-IL-15 exerted additive effect on Infiltration of neutrophils in the bladder. BCG-IL-15 may be a promising drug for non-muscle invasive bladder cancer.

DOI： 10.1016/j.intimp.2016.03.007

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background:Although testosterone suppression during androgen-deprivation therapy (ADT) and obesity have been reported to affect ADT efficacy, there are few comprehensive analyses on the impact on ADT outcome. Recently, we demonstrated that the SRD5A2 polymorphism was associated with metastatic prostate cancer prognosis. Therefore, in this study, we investigated the relationship between ADT serum testosterone levels or body mass index (BMI) and the prognosis among men treated with primary ADT for metastatic prostate cancer. In addition, we examined the association of serum testosterone levels during ADT with the SRD5A2 polymorphism.Methods:This study included 96 Japanese patients with metastatic prostate cancer. The relationship between clinicopathological parameters, including serum testosterone levels during ADT and BMI, and progression-free survival, overall survival and survival from progression following primary ADT treatment for metastatic prostate cancer was examined. Additionally, the association between the SRD5A2 gene polymorphism (rs523349) and serum testosterone levels during ADT was examined in 86 cases.Results:Among clinicopathological parameters, the lowest quartile of serum testosterone levels during ADT was a significant predictor of better overall survival as well as survival from castration resistance. However, BMI was not associated with prognosis. The CC allele in the SRD5A2 gene (rs523349), encoding the less active 5α-reductase, was associated with lower serum testosterone levels during ADT.Conclusions:Taken together, these findings revealed a dramatic suppression of serum testosterone by ADT was associated with better survival among men with metastatic prostate cancer that have undergone primary ADT, which may be affected by the SRD5A2 gene polymorphism.

DOI： 10.1038/pcan.2016.2

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Since 1941, androgen deprivation therapy has been the primary treatment for metastatic hormone-sensitive prostate cancer. Androgen deprivation therapy consists of several regimens that vary according to therapeutic modality, as well as treatment schedule. Androgen deprivation therapy initially shows excellent antitumor effects, such as relief of cancer-related symptoms, tumor marker decline and tumor shrinking. However, most metastatic hormone-sensitive prostate cancer cases eventually develop castration resistance and become lethal. Taxanes, such as docetaxel and cabazitaxel, as well as novel androgen receptor-targeting agents, such as abiraterone acetate and enzalutamide, have emerged for metastatic castration-resistant prostate cancer. The concept and principle of primary therapy for metastatic hormone-sensitive prostate cancer has remained unchanged for decades. Recently, upfront docetaxel chemotherapy has been shown to prolong overall survival in men with metastatic hormone-sensitive prostate cancer, and would lead to a paradigm shift in primary pharmacotherapy for metastatic hormone-sensitive prostate cancer. This raises the possibility of upfront use of taxanes, as well as novel androgen receptor-targeting agents combined with androgen deprivation therapy. The present review summarizes the current status of primary pharmacotherapy for metastatic hormone-sensitive prostate cancer, and discusses future perspectives in this field.

DOI： 10.1111/iju.13091

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Docetaxel is the only chemotherapy agent for castration-resistant prostate cancer (CRPC) that has been proven to prolong overall survival. In 2014, novel agents for CRPC including the CYP17 inhibitor, abiraterone, the antiandrogen agent, enzalutamide, and the taxane anticancer agent, cabazitaxel were also approved for use in Japan. These novel agents brought great advantages to both patients and physicians, but led to serious concerns as to how exactly these drugs should be used. There is no definitive answer as to how to use these agents with regard to proper sequence, proper patient selection, proper drug combination and proper administration timing. Accordingly, we utilize these agents sequentially based on a consensus set forward in guidelines, whilst considering some clinicopatholo- gical factors as well as the patient's condition and preferences. Several clinical trials have been on-going in an effort to obtain some answers to these problems, and these trials may reveal how to properly select a CRPC agent in the future. In addition, research into biomarkers for proper patient selection is being actively conducted, which may make it possible to select the mostbeneficial therapeutics based on information obtained from such biomarkers. In this review, we present the current status and future perspective on the proper use of therapeutic agents for CRPC.