Language：English   Publisher：International Journal of Urology  

DOI： 10.1111/iju.15484

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Language：English   Publisher：Endocrine-Related Cancer  

Androgen receptor signaling is crucial for the development of treatment resistance in prostate cancer. Among steroidogenic enzymes, 3β-hydroxysteroid dehydrogenases (3βHSDs) play critical roles in extragonadal androgen synthesis, especially 3βHSD1. Increased expression of 3βHSDs is observed in castration-resistant prostate cancer tumors compared with primary prostate tumors, indicating their involvement in castration resistance. Recent studies link 3βHSD1 to resistance to androgen receptor signaling inhibitors. The regulation of 3βHSD1 expression involves various factors, including transcription factors, microenvironmental influences, and posttranscriptional 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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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：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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Language：English   Publisher：International Journal of Urology  

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

DOI： 10.1111/iju.15370

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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   Publisher：Asian Journal of Endoscopic Surgery  

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

DOI： 10.1111/ases.13279

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

Language：English   Publisher：Journal of Robotic Surgery  

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

DOI： 10.1007/s11701-023-01702-y

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Language：English   Publisher：Anticancer Research  

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

DOI： 10.21873/anticanres.16618

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Language：English   Publisher：Drug Resistance Updates  

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

DOI： 10.1016/j.drup.2023.100990

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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。

Language：English   Publisher：International Journal of Urology  

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

DOI： 10.1111/iju.15188

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Language：English   Publisher：Asian Journal of Urology  

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

DOI： 10.1016/j.ajur.2022.02.008

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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：English   Publisher：Cancer Science  

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

DOI： 10.1111/cas.15438

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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：English   Publisher：Scientific Reports  

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

DOI： 10.1038/s41598-022-12528-3

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Fetal growth restriction (FGR) and pre-eclampsia with fetal growth restriction (PE/FGR) are high-risk perinatal diseases that may involve high levels of human chorionic gonadotropin (hCG) and mitochondrial dysfunction. However, little is known about how these factors affect placental function. We investigated how mitochondrial dysfunction and high hCG expression affected placental function in unexplained FGR and PE/FGR. We observed elevated expression of hCGβ and growth differentiation factor 15 mRNA and protein levels in the placenta with both diseases. Likewise, antiangiogenic factors, such as Ang2, IP10, sFlt1, IL8, IL1B, and TNFα, were also upregulated at the mRNA level. In addition, the expression of COXI and COXII which encoded by mitochondrial DNA were significantly decreased in both diseases, suggesting that mitochondrial translation was impaired. Treatment with hCG increased Ang2, IP10, IL8, and TNFα mRNA levels in a dose-dependent manner via the p38 and JNK pathways. Mitochondrial translation inhibitors increased hCGβ expression through stabilization of HIF1α, and increased IL8 and TNFα mRNA expression. These results revealed that high expression of hCG due to mitochondrial translational dysfunction plays an important role in the pathogenesis of FGR and PE/FGR.

DOI： 10.1038/s41598-022-07893-y

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Language：English   Publisher：International Journal of Urology  

Objectives: There are many models to predict lymph node involvement in patients with prostate cancer. We aimed to externally validate several models in a Japanese cohort. Methods: We considered patients who were treated with robotic-assisted radical prostatectomy with extended pelvic lymph node dissection for prostate cancer. The risk of lymph node involvement was calculated for each patient in several models. Model performance was assessed by calculating the receiver operating characteristic curve and the area under the curve, calibration plots, and decision curve analyses. Results: We identified lymph node involvement in 61 (18.4%) 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：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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Web of Science

Language：English   Publisher：Andrologia  

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

DOI： 10.1111/and.14307

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