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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.15449

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

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Language：English   Publisher：International Journal of Urology  

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

DOI： 10.1111/iju.15379

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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：Clinical Genitourinary Cancer  

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

DOI： 10.1016/j.clgc.2023.09.003

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

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

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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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。

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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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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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Language：English   Publisher：Urology Practice  

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

DOI： 10.1097/UPJ.0000000000000404

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

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

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

DOI： 10.1111/iju.15188

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DOI： 10.1111/iju.15119. Epub 2022 Dec 7.

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

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

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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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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.

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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。

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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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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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DOI： 10.1016/j.ajur.2022.02.008. Epub 2022 Apr 22.

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DOI： 10.1007/s00345-022-04245-3. Epub 2022 Dec 17.

Language：English   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

Publishing type：Research paper (scientific journal)  

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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DOI： 10.31662/jmaj.2022-0096. Epub 2022 Sep 20.

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DOI： 10.1111/iju.14953. Epub 2022 Jun 18.

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。

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Language：English   Publisher：Endocrine-Related Cancer  

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

DOI： 10.1530/ERC-22-0140

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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)

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

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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Language：Japanese   Publisher：(一社)西日本泌尿器科学会  

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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： 10.1038/s41598-022-12528-3.

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DOI： 10.1111/cas.15280. Epub 2022 Apr 1.

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DOI： 10.1111/iju.14802. Epub 2022 Jan 31.

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DOI： 10.1016/j.prnil.2021.10.001. Epub 2021 Oct 30.

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

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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DOI： 10.1016/j.prnil.2022.01.001. Epub 2022 Jan 11.

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DOI： 10.1111/and.14307. Epub 2021 Nov 8.

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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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DOI： 10.1097/CAD.0000000000001170.

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DOI： 10.31662/jmaj.2021-0163. Epub 2021 Dec 28.

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DOI： 10.1111/iju.14702. Epub 2021 Sep 22.

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

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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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。

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Informa UK Limited  

DOI： 10.2147/CMAR.S326114

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DOI： 10.21873/anticanres.15373.

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DOI： 10.1016/j.urolonc.2021.05.034. Epub 2021 Jun 29.

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DOI： 10.21873/anticanres.15183.

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DOI： 10.1093/jjco/hyab019.

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DOI： 10.1016/j.prnil.2020.12.001. Epub 2020 Dec 30.

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DOI： 10.1016/j.urolonc.2020.09.036. Epub 2020 Oct 17.

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DOI： 10.3389/fonc.2021.697955. eCollection 2021.

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DOI： 10.1111/cas.14695. Epub 2020 Nov 24.

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DOI： https://doi.org/10.1111/iju.14396

Other Link： https://onlinelibrary.wiley.com/doi/abs/10.1111/iju.14396

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DOI： 10.1038/s41389-017-0009-3

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DOI： 10.18632/oncotarget.12117

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