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DOI： 10.1007/s00345-024-05316-3

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Language：English   Publisher：International Journal of Urology  

DOI： 10.1111/iju.15607

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DOI： 10.1245/s10434-024-16344-z

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Language：English   Publisher：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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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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Language：English   Publisher：シュプリンガー・ジャパン(株)  

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1245/s10434-024-16294-6

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Language：English   Publisher：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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Language：English   Publisher：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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Language：English   Publisher：Oxford University Press  

Language：English   Publisher：Prostate  

DOI： 10.1002/pros.24784

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Publisher：株式会社医学書院  

DOI： 10.11477/mf.1413208189

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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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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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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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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

Publisher：株式会社医学書院  

DOI： 10.11477/mf.1413208183

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Language：English   Publishing type：Research paper (scientific journal)  

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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Language：English   Publisher：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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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

Language：English   Publishing type：Research paper (scientific journal)  

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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DOI： 10.1245/s10434-024-15088-0

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DOI： 10.1245/s10434-024-14999-2

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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。

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DOI： 10.4049/jimmunol.2300308

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DOI： 10.1038/s44276-024-00049-7

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DOI： 10.1111/iju.15370

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DOI： 10.1111/iju.15484

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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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DOI： 10.1111/iju.15371

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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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DOI： 10.1111/iju.15379

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Language：English   Publisher：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。

Language：English   Publisher：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。

Language：English   Publisher：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。

Language：English   Publisher：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。

Language：English   Publisher：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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DOI： 10.1111/iju.15449

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DOI： 10.1016/j.clgc.2023.09.003

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DOI： 10.1002/ctd2.264

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DOI： 10.1111/iju.15434

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DOI： 10.1038/s41391-024-00808-0

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Language：English   Publisher：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)。

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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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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

Language：Japanese   Publisher：Japanese Society of Endourology and Robotics  

<p>  During laparoscopic or robot-assisted laparoscopic surgery, carbon dioxide gas is generally used for insufflation. Pulmonary carbon dioxide gas embolization, which is one of the complications during laparoscopic or robot-assisted laparoscopic surgery, is rarely symptomatic, while some reports indicate a high mortality rate in symptomatic cases. Pulmonary carbon dioxide gas embolization should be suspected if there is a sudden decrease in end-tidal CO₂ (EtCO₂) and/or saturation of percutaneous oxygen (SpO₂) intraoperatively. In such cases, we should interrupt insufflation or decrease the insufflation pressure, provide pure oxygen, and close the injured vessels. Here, we encountered a case of cerebral gas embolization following pulmonary gas embolization. To our knowledge, only six cases of cerebral gas embolization during laparoscopic or robot-assisted laparoscopic renal surgery have been reported, and two of seven patients, including our case, resulted in death. Although hyperbaric oxygen therapy has been reported to be effective for cerebral gas embolization, it is important to prevent gas embolization itself due to its severity. Therefore, it is important not to excessively raise the pneumoperitoneal pressure, apply renal vein clamping in some cases, clip the vascular vessels as much as possible, and suture them as soon as possible when they are injured.</p>

DOI： 10.11302/jserjje.37.2_290

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DOI： 10.1111/iju.15273

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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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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。

Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

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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Language：English   Publisher：(一社)日本癌治療学会  

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DOI： 10.1111/iju.15265

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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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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。

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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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DOI： 10.1097/UPJ.0000000000000404

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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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DOI： 10.1111/iju.15188

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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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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。

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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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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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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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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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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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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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Language：English   Publisher：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。

Language：English   Publisher：(一社)日本泌尿器科学会総会事務局  

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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。

Language：English   Publisher：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。

Language：English   Publishing type：Research paper (scientific journal)  

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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Language：Japanese   Publisher：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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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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Language：English   Publisher：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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Language：English   Publisher：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。

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DOI： 10.1002/cam4.4955

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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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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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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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Language：English   Publisher：Current Cancer Drug Targets  

DOI： 10.2174/1568009623666230220121610

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Publisher：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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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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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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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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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s00345-022-04245-3

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Other Link： https://link.springer.com/article/10.1007/s00345-022-04245-3/fulltext.html

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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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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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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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Language：English   Publisher：The Lancet Oncology  

DOI： 10.1016/S1470-2045(22)00614-3

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Bioscientifica  

DOI： 10.1530/ERC-22-0140

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

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 &lt; 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&lt;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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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/iju.15078

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japan Medical Association / The Japanese Associaiton of Medical Sciences  

<p><b>Introduction</b>: 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.</p><p><b>Methods</b>: 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.</p><p><b>Results</b>: 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; <i>P</i> = 0.047), but inversely related to anorexia (grade ≥ 2; odds ratio, 0.093; 95% confidence interval, 0.011-0.784; <i>P</i> = 0.029).</p><p><b>Conclusions</b>: Psoas muscle ratio is a predictive marker of fatigue and anorexia in patients treated with enzalutamide.</p>

DOI： 10.31662/jmaj.2022-0096

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DOI： 10.1111/iju.14953

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：English   Publisher：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。

Language：English   Publisher：(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。

Language：English   Publisher：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。

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DOI： 10.1111/cas.15438

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Language：English   Publisher：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。

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.3390/cancers14174161

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DOI： 10.1080/03007995.2022.2096353

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DOI： 10.2147/CMAR.S326114

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Language：English   Publisher：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。

Language：Japanese   Publisher：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)

Language：Japanese   Publisher：(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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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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Language：English   Publisher：Oxford University Press  

Language：English   Publishing type：Research paper (scientific journal)  

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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DOI： 10.3390/cancers14112696

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DOI： 10.3390/cancers14112696

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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% confidence interval 0.84-1.37; P = 0.580), whereas that of the ≥80 group was significantly worse (hazard ratio 1.41; 95% 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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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。

Language：English   Publisher：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。

Language：English   Publisher：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。

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<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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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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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/iju.14900

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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% 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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Language：Japanese   Publisher：(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)

Language：English   Publisher：(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。

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DOI： 10.1111/iju.14864

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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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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% confidence interval [CI]; 1.87, 1.14-3.05, P = 0.012) and multivariate analysis (HR, 95% 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% CI; 0.43, 0.24-0.78, P = 0.0056) and multivariate analysis (HR, 95% 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.

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DOI： 10.1016/j.prnil.2021.10.001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier {BV}  

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%) and 93 men (43.3%) 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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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

DOI： 10.1200/JCO.2022.40.6_suppl.099

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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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japan Medical Association / The Japanese Associaiton of Medical Sciences  

<p><b>Introduction:</b> 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.</p><p><b>Methods:</b> 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.</p><p><b>Results:</b> In total, 88 patients were enrolled. Forty-one (46.6%), 37 (42.0%), and 10 (11.4%) 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% 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% (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.</p><p><b>Conclusions:</b> 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.</p>

DOI： 10.31662/jmaj.2021-0163

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

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%) and 1346 (65.7%) patients were classified as the low- and high-burden groups, respectively. In each group, >80% 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% confidence interval 0.34-0.71; instrumental variables method, hazard ratio 0.80, 95% 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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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%) 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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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%) and 135 (53.2%) 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% confidence interval 0.42-0.92, P = 0.016) and overall survival (hazard ratio 0.61, 95% 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% confidence interval 0.2-2.8 months) compared with those who received docetaxel (median 5.0 months, 95% 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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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%) 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% 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%. 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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Language：Japanese   Publisher：(有)科学評論社  

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Language：English   Publisher：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。

Language：English   Publisher：(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。

Language：Japanese   Publisher：Japanese Society of Endourology and Robotics  

<p>  Intraoperative laparoscopic ultrasound in robot-assisted partial nephrectomy is essential to reliably remove a renal tumor. The L43K probe used for intraoperative laparoscopic ultrasound is one of the ultrasound probes used in this surgery, and the fins of the probe are grasped with fenestrated forceps during surgery. Surgeons must manipulate the robot in a narrow retroperitoneal cavity and often grip the fins from the probe’s tip. The conventional probe fin toward the probe tip has a structure in which the inclination becomes low grasp is not spread radially, and is designed not to be gripped from the probe tip. Therefore, the unstable while gripping the probe’s tip, and surgeons have frequently dropped the probe. In this study, we propose a solution to resolve this gripping difficulty by developing a probe attachment.</p>

DOI： 10.11302/jserjje.35.1_109

CiNii Research

Language：Japanese   Publisher：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

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ctarc.2022.100606

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/iju.14709

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1158/1078-0432.CCR-21-2328

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/iju5.12349

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.21873/anticanres.15373

Language：English   Publishing type：Research paper (scientific journal)  

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

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.21873/anticanres.15282

Language：English   Publishing type：Research paper (scientific journal)  

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

Language：English   Publishing type：Research paper (scientific journal)  

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

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1245/s10434-021-10282-w

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.21873/anticanres.15183

Language：English   Publishing type：Research paper (scientific journal)  

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

Language：English   Publishing type：Research paper (scientific journal)  

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

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41397-021-00220-0

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/iju5.12291

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3390/biomedicines9080893

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.21037/atm-21-2956

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/jjco/hyab019

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/iju.14525

Language：English   Publishing type：Research paper (scientific journal)  

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

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.urolonc.2020.09.036

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.urolonc.2021.03.001

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/iju.14518

Language：English   Publishing type：Research paper (scientific journal)  

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

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.31662/jmaj.2021-0004

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s13691-020-00464-w

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1080/07357907.2020.1871486

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/and.13856

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41397-020-00188-3

Language：English   Publishing type：Research paper (scientific journal)  

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

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/iju.14396

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DOI： 10.1111/iju.14366

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DOI： 10.1016/j.urolonc.2020.08.018

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1080/07357907.2020.1833212

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DOI： 10.1016/j.urolonc.2020.06.033

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DOI： 10.1002/bco2.35

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DOI： 10.1016/j.urolonc.2020.04.032

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DOI： 10.21037/tau-20-866

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/iju5.12181

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/pros.24022

Language：English   Publishing type：Research paper (scientific journal)  

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

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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

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DOI： 10.1111/iju.14184

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DOI： 10.1111/iju.14184

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DOI： 10.1097/CAD.0000000000000884

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DOI： 10.1016/j.prnil.2019.11.002

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DOI： 10.1016/j.prnil.2019.11.002

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DOI： 10.1097/CAD.0000000000000884

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DOI： 10.1111/iju.14156

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DOI： 10.1111/iju.14156

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DOI： 10.1111/iju.14143

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DOI： 10.1111/iju.14143

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DOI： 10.21873/anticanres.13957

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DOI： 10.21873/anticanres.13957

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DOI： 10.1016/j.prnil.2019.10.003

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DOI： 10.1016/j.prnil.2019.10.003

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DOI： 10.1016/j.urolonc.2019.04.020

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DOI： 10.1016/j.urolonc.2019.04.020

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DOI： 10.1111/and.13354

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DOI： 10.1007/s00280-019-03874-7

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DOI： 10.1007/s00280-019-03874-7

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DOI： 10.21873/anticanres.13598

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DOI： 10.21873/anticanres.13612

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DOI： 10.3390/ijms20163936

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DOI： 10.1159/000497280

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DOI： 10.1002/pros.23828

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DOI： 10.1016/j.clgc.2019.03.021

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DOI： 10.21873/anticanres.13457

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DOI： 10.6004/jnccn.2019.7302

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DOI： 10.1111/luts.12247

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DOI： 10.1007/s12032-019-1257-1

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DOI： 10.1007/s12032-019-1257-1

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DOI： 10.1111/iju.13870

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DOI： 10.1016/j.urolonc.2018.10.020

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DOI： 10.1001/jamanetworkopen.2019.0115

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DOI： 10.3390/jcm8020225

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DOI： 10.1007/s00280-019-03811-8

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DOI： 10.21873/anticanres.13598

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DOI： 10.1111/and.13119

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DOI： 10.3892/mco.2018.1718

Language：Japanese  

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)

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/pros.23661

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DOI： 10.1111/cas.13751

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DOI： 10.1016/j.prnil.2017.10.002

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DOI： 10.21873/anticanres.12702

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DOI： 10.3892/mco.2018.1602

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DOI： 10.1007/978-981-10-7013-6_21

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DOI： 10.1007/s13691-017-0316-8

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DOI： 10.1016/j.juro.2017.09.076

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DOI： 10.15252/emmm.201707689

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DOI： 10.1507/endocrj.EJ18-0025

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DOI： 10.3389/fonc.2018.00635

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DOI： 10.1038/s41389-017-0009-3

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DOI： 10.21873/anticanres.11998

Language：Japanese  

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DOI： 10.1016/j.clgc.2017.01.006

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DOI： 10.1093/jjco/hyx013

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1245/s10434-016-5705-2

Language：English   Publishing type：Research paper (scientific journal)  

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

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/annonc/mdw646

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DOI： 10.1002/pros.23254

Language：English   Publishing type：Research paper (scientific journal)  

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

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/pros.23269

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DOI： 10.1111/bju.13483

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DOI： 10.1016/j.bioelechem.2016.01.010

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DOI： 10.1007/s13691-016-0252-z

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/jjco/hyw098

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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DOI： 10.1159/000445752

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DOI： 10.1111/cas.12948

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DOI： 10.1093/jnci/djw005

Language：English   Publishing type：Research paper (scientific journal)  

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

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DOI： 10.1038/pcan.2016.2

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DOI： 10.1111/iju.13091

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DOI： 10.1016/j.eururo.2015.07.025

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DOI： 10.1007/s00428-015-1885-6

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Language：English   Publishing type：Research paper (scientific journal)  

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Language：English   Publishing type：Research paper (scientific journal)