今村 有佑

BACKGROUND: We retrospectively assessed the clinical significance of the Prostate Imaging Reporting and Data System (PI-RADS), version 2, criteria based on biparametric magnetic resonance imaging (bp-MRI), together with the International Society of Urological Pathology (ISUP) grade, for predicting biochemical recurrence (BCR) after radical prostatectomy. MATERIALS AND METHODS: The data from 126 patients who had undergone radical prostatectomy were retrospectively analyzed. The prognostic significance of the PI-RADS v2 score based on bp-MRI was assessed with other clinical factors, including the ISUP grade. We defined a positive PI-RADS and ISUP score as ≥ 4 and ≥ 3, respectively. Statistical analysis was performed using Cox proportional hazard models, logistic regression analysis, and the Kaplan-Meier method. RESULTS: The median age and median prostate-specific antigen level were 66 years and 7.96 ng/mL, respectively. The number of positive PI-RADS scores was 106 (84.1%) and the number of positive ISUP grade scores was 71 (56.3%). PI-RADS ≥ 4 (P = .0031) and ISUP ≥ 3 (P = .070) were the 2 independent prognostic factors predictive of BCR. A positive PI-RADS score was related to tumor volume (P = .014), and a positive ISUP score was related to prostate-specific antigen level (P = .043), extraprostatic extension (P = .029), and Gleason upgrading (P < .0001). After stratifying patients into risk groups according to PI-RADS and ISUP positivity, the poor-risk group (PI-RADS and ISUP grade positive) showed significantly worse BCR-free survival compared with that of the favorable- and intermediate-risk groups (P < .0001), with a median survival difference of 21 months. CONCLUSION: Biparametric PI-RADS v2 and ISUP grade criteria predicted for BCR after radical prostatectomy. PI-RADS v2 combined with the ISUP grade might be helpful in choosing the treatment modality of patients with localized prostate cancer.

OBJECTIVES: To identify pre-treatment factors affecting the duration of post-surgical steroid replacement in patients undergoing adrenalectomy for subclinical Cushing syndrome. METHODS: The present retrospective analysis included 64 patients who underwent unilateral laparoscopic adrenalectomy for subclinical Cushing syndrome. Adrenal tumor and contralateral adrenal sizes together with various clinical factors were studied in association with the duration of post-surgical steroid replacement. Adrenal tumor and contralateral adrenal size were measured at the level of the maximum transverse plane of the adrenal glands using computed tomography scan or magnetic resonance imaging. Cox's proportional hazards model was used for the statistical analysis. RESULTS: All 64 patients were treated with post-surgical steroid replacement after adrenalectomy. The median duration of the steroid treatment was 6 months. When assessing the duration of post-surgical steroid replacement, contralateral adrenal volume <0.745 cm3 , contralateral adrenal width <6.15 mm and serum cortisol after a 1-mg dexamethasone suppression test >2.65 μg/dL were significant predictors of prolonged post-surgical steroid treatment on univariate analysis. On multivariate analysis, contralateral adrenal width <6.15 mm was the only independent predictive factor for the prolonged post-surgical steroid replacement. CONCLUSIONS: Contralateral adrenal width seems to represent a significant predictive factor for the duration of post-surgical steroid replacement in subclinical Cushing syndrome patients. Pre-surgical assessment of image findings might help clinicians determine the total duration of steroid therapy after adrenalectomy.

OBJECTIVES: To determine the predictors of testosterone recovery after termination of androgen deprivation therapy in high/intermediate-risk prostate cancer patients receiving external beam radiation therapy with neoadjuvant and adjuvant androgen deprivation therapy. METHODS: A total of 82 patients who underwent external beam radiation therapy with androgen deprivation therapy for prostate cancer were retrospectively analyzed. Serum testosterone levels after androgen deprivation therapy terminations were studied. Cox proportional hazard models and the Kaplan-Meier method were used for statistical analysis. RESULTS: Median age, baseline testosterone, nadir testosterone and duration of androgen deprivation therapy were 73 years, 456 ng/dL, 16 ng/dL and 26 months, respectively. Androgen deprivation therapy duration of 33 months (hazard ratio 0.13; P = 0.0018), nadir testosterone of 20 ng/dL (hazard ratio 0.35; P = 0.0112) and testosterone >50 ng/dL at 6 months after androgen deprivation therapy termination (hazard ratio 0.21; P = 0.0075) were significantly associated with testosterone recovery to normal levels (200 ng/dL) on multivariate analysis. Androgen deprivation therapy duration of 33 months (hazard ratio 0.31; P = 0.0023) and nadir testosterone of 20 ng/dL (hazard ratio 0.38; P = 0.0012) were significantly associated with testosterone recovery to the supracastrate level (50 ng/dL) on multivariate analysis. After dividing patients into three risk groups, the rate of testosterone recovery to the normal level after 2 years of androgen deprivation therapy termination was 100% in the low-risk group versus 20.8% in the high-risk group (P < 0.0001); the rate of testosterone recovery to the supracastrate level was 100% in the low-risk group versus 51.5% in the high-risk group (P < 0.0001). CONCLUSIONS: Duration of androgen deprivation therapy and achievement of nadir testosterone 20 ng/dL both predict testosterone recovery to the supracastrate level in prostate cancer patients undergoing external beam radiation therapy with androgen deprivation therapy.

(Purpose) Targeted therapy has been standard therapeutic approach for advanced renal cell carcinoma (RCC). General fatigue is frequently observed in patients who receive targeted therapies for advanced RCC. General fatigue makes it difficult to continue a standard schedule of treatment in many cases. In this preliminary report, we explored the effect of Koujin powder (red ginseng powder) with Ninjin-youeito for general fatigue induced by targeted therapies for advanced RCC. (Material and method) The patients who complained of general fatigue during the treatment of Tyrosine Kinase Inhibitors (TKIs) as targeted therapies for advanced RCC were included in this retrospective analysis. Thirty patients with advanced RCC were enrolled from January 2016 to December 2016 at Chiba University Hospital. Twelve patients were given 3 g of Koujin powder with 9 g of Ninjin-youeito orally for two to four weeks (ginseng combination group). Eighteen patients who were not orally administered were compared as a control group (ginseng non-combination group). General fatigue was assessed with the Cancer Fatigue Scale (CFS), which divides quality of fatigue into three subgroups by using a "physical subscale", an "affective subscale", and a "cognitive subscale". We compared CFS scores at baseline and 2-8 weeks after administration. (Results) There was no statistical difference in the clinical variables between the two groups. The total CFS score was significantly decreased after treatment in the ginseng combination group (average score, 21.8 points at baseline vs 18.5 points after treatment; p=0.041). On subgroup analyses, the physical subscale score was significantly reduced after treatment in the ginseng combination group (average score, 9.7 points at baseline vs 7 points after treatment; p=0.0042). In the ginseng non-combination group, the total CFS score was significantly increased during the course (average score, 16.2 points at baseline vs 20.6 points during the course; p=0.047). On subgroup analyses, the physical subscale score was significantly increased during the course (average score, 4.4 points at baseline vs 7.3 points during the course; p=0.0042). (Conclusions) Koujin powder with Ninjin-youeito can be a therapeutic approach for general fatigue induced by targeted therapies. The precise management for general fatigue can keep patients on therapy, consequently provides a survival benefit.

Androgen receptor (AR) is a validated drug target for all stages of prostate cancer including metastatic castration-resistant prostate cancer (CRPC). All current hormone therapies for CRPC target the C-terminal ligand-binding domain of AR and ultimately all fail with resumed AR transcriptional activity. Within the AR N-terminal domain (NTD) is activation function-1 (AF-1) that is essential for AR transcriptional activity. Inhibitors of AR AF-1 would potentially block most AR mechanisms of resistance including constitutively active AR splice variants that lack the ligand-binding domain. Here we provide evidence that sintokamide A (SINT1) binds AR AF-1 region to specifically inhibit transactivation of AR NTD. Consistent with SINT1 targeting AR AF-1, it attenuated transcriptional activities of both full-length AR and constitutively active AR splice variants, which correlated with inhibition of growth of enzalutamide-resistant prostate cancer cells expressing AR splice variants. In vivo, SINT1 caused regression of CRPC xenografts and reduced expression of prostate-specific antigen, a gene transcriptionally regulated by AR. Inhibition of AR activity by SINT1 was additive to EPI-002, a known AR AF-1 inhibitor that is in clinical trials (NCT02606123). This implies that SINT1 binds to a site on AF-1 that is unique from EPI. Consistent with this suggestion, these two compounds showed differences in blocking AR interaction with STAT3. This work provides evidence that the intrinsically disordered NTD of AR is druggable and that SINT1 analogs may provide a novel scaffold for drug development for the treatment of prostate cancer or other diseases of the AR axis.

The androgen receptor is a transcription factor and validated therapeutic target for prostate cancer. Androgen deprivation therapy remains the gold standard treatment, but it is not curative, and eventually the disease will return as lethal castration-resistant prostate cancer. There have been improvements in the therapeutic landscape with new agents approved, such as abiraterone acetate, enzalutamide, sipuleucel-T, cabazitaxel and Ra-223, in the past 5 years. New insight into the mechanisms of resistance to treatments in advanced disease is being and has been elucidated. All current androgen receptor-targeting therapies inhibit the growth of prostate cancer by blocking the ligand-binding domain, where androgen binds to activate the receptor. Persuasive evidence supports the concept that constitutively active androgen receptor splice variants lacking the ligand-binding domain are one of the resistant mechanisms underlying advanced disease. Transcriptional activity of the androgen receptor requires a functional AF-1 region in its N-terminal domain. Preclinical evidence proved that this domain is a druggable target to forecast a potential paradigm shift in the management of advanced prostate cancer. This review presents an overview of androgen receptor-related mechanisms of resistance as well as novel therapeutic agents to overcome resistance that is linked to the expression of androgen receptor splice variants in castration-resistant prostate cancer.

Constitutively active splice variants of androgen receptor (AR-Vs) lacking ligand-binding domain (LBD) are a mechanism of resistance to androgen receptor LBD-targeted (AR LBD-targeted) therapies for metastatic castration-resistant prostate cancer (CRPC). There is a strong unmet clinical need to identify prostate cancer patients with AR-V-positive lesions to determine whether they will benefit from further AR LBD-targeting therapies or should receive taxanes or investigational drugs like EPI-506 or galeterone. Both EPI-506 (NCT02606123) and galeterone (NCT02438007) are in clinical trials and are proposed to have efficacy against lesions that are positive for AR-Vs. AR activation function-1 (AF-1) is common to the N-terminal domains of full-length AR and AR-Vs. Here, we provide proof of concept for developing imaging compounds that directly bind AR AF-1 to detect both AR-Vs and full-length AR. 123I-EPI-002 had specific binding to AR AF-1, which enabled direct visualization of CRPC xenografts that express full-length AR and AR-Vs. Our findings highlight the potential of 123I-EPI-002 as an imaging agent for the detection of full-length AR and AR-Vs in CRPC.

PURPOSE: The PI3K/Akt/mTOR pathway is activated in most castration-resistant prostate cancers (CRPC). Transcriptionally active androgen receptor (AR) plays a role in the majority of CRPCs. Therefore, cotargeting full-length (FL) AR and PI3K/Akt/mTOR signaling has been proposed as a possible, more effective therapeutic approach for CRPC. However, truncated AR-splice variants (AR-V) that are constitutively active and dominant over FL-AR are associated with tumor progression and resistance mechanisms in CRPC. It is currently unknown how blocking the PI3K/Akt/mTOR pathway impacts prostate cancer driven by AR-Vs. Here, we evaluated the efficacy and mechanism of combination therapy to block mTOR activity together with EPI-002, an AR N-terminal domain (NTD) antagonist that blocks the transcriptional activities of FL-AR and AR-Vs in models of CRPC. EXPERIMENTAL DESIGN: To determine the functional roles of FL-AR, AR-Vs, and PI3K/Akt/mTOR pathways, we employed EPI-002 or enzalutamide and BEZ235 (low dose) or everolimus in human prostate cancer cells that express FL-AR or FL-AR and AR-Vs (LNCaP95). Gene expression and efficacy were examined in vitro and in vivo RESULTS: EPI-002 had antitumor activity in enzalutamide-resistant LNCaP95 cells that was associated with decreased expression of AR-V target genes (e.g., UBE2C). Inhibition of mTOR provided additional blockade of UBE2C expression. A combination of EPI-002 and BEZ235 decreased the growth of LNCaP95 cells in vitro and in vivo CONCLUSIONS: Cotargeting mTOR and AR-NTD to block transcriptional activities of FL-AR and AR-Vs provided maximum antitumor efficacy in PTEN-null, enzalutamide-resistant CRPC. Clin Cancer Res; 22(11); 2744-54. ©2015 AACR.

BACKGROUND: Although transperineal (TP) prostate biopsy is growing in popularity, its safety has not been evaluated based on extensive studies. We prospectively assessed the adverse events associated with transrectal ultrasound (TRUS)-guided TP 16-core prostate biopsy at a single institution. PATIENTS AND METHODS: We enrolled 2,086 males who underwent first-time TRUS-guided TP prostate biopsy under lumbar spinal anesthesia at Chiba Cancer Center between 2009 and 2013. Eight adverse events were assessed prospectively using a purpose-designed questionnaire. The prevalence and duration of all adverse events were evaluated. We performed subgroup analyses for hematuria and urinary retention in relation to clinical factors. RESULTS: Questionnaires were collected from 1,663 cases (79.7 %). The cancer detection rate was 53.5 % in all patients. The prevalence and duration of complications were as follows: hematuria, 73.4 % and 4.51 ± 2.88 days; perineal bleeding, 7.1 % and 2.20 ± 2.24 days; hematospermia 14.4 %; dysuria, 15.7 % and 3.12 ± 2.71 days; urinary tract pain, 49.5 % and 2.43 ± 2.08 days; perineal pain, 35.5 % and 3.53 ± 2.59 days; fever ≥37 °C, 1.7 % and 1.79 ± 1.72 days; and headache, 22.1 % and 3.40 ± 2.10 days. Seventeen patients (1.1 %) required indwelling urethral catheterization for grade 2 urinary retention. Pre-biopsy International Prostate Symptom Score (p = 0.014) was an independent related factor for hematuria. Prostate volume (p = 0.001) was an independent related factor for grade 2 urinary retention. CONCLUSIONS: TRUS-guided TP prostate biopsy under lumbar spinal anesthesia can be performed safely with only minor adverse events.

PURPOSE: Renal cell carcinoma expresses CXCR3 but the function of CXCR3 in renal cell carcinoma has not been clarified. We explored the function of CXCR3 in renal cell carcinoma and investigated CXCR3 regulating factors. MATERIALS AND METHODS: We obtained 56 clinical samples of clear cell renal cell carcinoma and corresponding normal renal tissue samples from the surgical specimens of Japanese patients who underwent radical nephrectomy at Chiba University Hospital between 2000 and 2011. As renal cell carcinoma cell lines, we used 786-O, ACHN and Caki-1. The expression profiles of CXCR3 and its splice variants were examined. For functional analyses 786-O and interferon-γ inducible 10 kDa protein or IP-10 (CXCL10) were selected as representatives. RESULTS: CXCR3 and its ligands were abundant in renal cell carcinoma samples compared to corresponding normal kidney samples. The CXCR3-A-to-CXCR3-B ratio was 1.5 times higher in renal cell carcinoma samples than in normal kidney samples. CXCL10 treatment induced 786-O cell migration and invasion, and these effects were inhibited by neutralizing antibody. Phosphorylated RhoA and pro/active matrix metalloproteinase-9 expression was up-regulated by CXCL10 treatment. In clinical samples CXCR3 and CXCR3-A expression was significantly higher in metastatic than in nonmetastatic carcinoma samples. Finally, the expression of CXCR3-A and HIF-1α correlated significantly in clinical samples. In 786-O treatment with CoCl2 up-regulated CXCR3 and HIF-1α expression 4.5 and 2.2-fold, respectively. CONCLUSIONS: We determined the association of CXCR3 and renal cell carcinoma metastasis. CXCR3 expression may be regulated by hypoxia.

OBJECTIVES: To develop and to internally validate a novel nomogram for predicting the stone-free rate after transurethral ureterolithotripsy. METHODS: A total of 412 patients with 534 ureteral stones were treated with transurethral ureterolithotripsy using semi-rigid ureteroscopes. Treatment efficacy was evaluated 3 months after the procedure. Multivariate stepwise logistic regression analysis was used to identify independent predictors of being stone-free in the model-building set. A total of 427 stones (80% of 534) were randomly allocated for identification and statistical analysis to build the model, and the remaining 107 (20%) were used for cross-validation. A nomogram for the stone-free rate was developed based on the final logistic regression model. RESULTS: Stone length, number of stones, stone location and the presence of pyuria were independent factors related to the stone-free rate after transurethral ureterolithotripsy treatment, and these were used to develop a nomogram. In this nomogram, the area under the receiver operating characteristic curve was 0.7432 for the nomogram, 0.5641 for stone size, 0.5908 for the number of stones, 0.6594 for stone location and 0.6076 for pyuria. Validation using 20% of the data also achieved a reasonable predictive accuracy (area under the receiver operating characteristic curve = 0.682). CONCLUSIONS: The first nomogram for predicting the stone-free rate after transurethral ureterolithotripsy was developed. It has a reasonable predictive accuracy, and in combination with extracorporeal shock wave lithotripsy nomograms, it might be useful for deciding treatment methods.

【目的】ロボット支援腹腔鏡下前立腺全摘除術（RALP）の初期治療成績につき検討を行った．<br>  【対象】2011年9月より2012年12月までにRALPを行った120例を対象として検討した．<br>  【結果】平均出血量は85ml，輸血は自己血のみが2例，術中に開腹手術への移行は認めなかった．平均手術時間は273分，平均コンソール時間は204分，術者のラーニングカーブは良好であり20例ほどの経験で安定した手術を行えるようになった．pT2の断端陽性率はdorsal vein complexの無結紮法導入前は40.9％に認めたが，導入後は8.7％と改善を認めた．全体の95.2％がクリティカルパス通りに退院可能であった．尿の禁制率もsafety pad（0-1枚/日）の確率が術後3月，6月で82.1％，100％と良好であった．<br>  【結論】腹腔鏡下前立腺全摘除術の経験はなくともスムーズにRALPの導入，移行ができると考えられた．合併症も少なく，患者にとっても利益の大きい治療であると考えられた．

Fork-head box protein A1 (FOXA1) is a "pioneer factor" that is known to bind to the androgen receptor (AR) and regulate the transcription of AR-specific genes. However, the precise role of FOXA1 in prostate cancer (PC) remains unknown. In this study, we report that FOXA1 plays a critical role in PC cell proliferation. The expression of FOXA1 was higher in PC than in normal prostate tissues (P = 0.0002), and, using immunohistochemical analysis, we found that FOXA1 was localized in the nucleus. FOXA1 expression levels were significantly correlated with both PSA and Gleason scores (P = 0.016 and P = 0.031, respectively). Moreover, FOXA1 up-regulation was a significant factor in PSA failure (P = 0.011). Depletion of FOXA1 in a prostate cancer cell line (LNCaP) using small interfering RNA (siRNA) significantly inhibited AR activity, led to cell-growth suppression, and induced G0/G1 arrest. The anti-proliferative effect of FOXA1 siRNA was mediated through insulin-like growth factor binding protein 3 (IGFBP-3). An increase in IGFBP-3, mediated by depletion of FOXA1, inhibited phosphorylation of MAPK and Akt, and increased expression of the cell cycle regulators p21 and p27. We also found that the anti-proliferative effect of FOXA1 depletion was significantly reversed by simultaneous siRNA depletion of IGFBP-3. These findings provide direct physiological and molecular evidence for a role of FOXA1 in controlling cell proliferation through the regulation of IGFBP-3 expression in PC.

The objective of the present study was to document the treatment efficacy and safety of sorafenib in Japanese patients with advanced renal cell carcinoma (RCC). A retrospective analysis of 50 consecutive patients with metastatic RCC between January 2005 and December 2009 was carried out. Patients received sorafenib after failed cytokine therapy or first-line sorafenib treatment. All received 400 mg of sorafenib orally twice daily. Five of 14 patients with bone metastases were also given bisphosphonates. Tumor response was evaluated every 1-2 months according to the Response Evaluation Criteria in Solid Tumors. Adverse events (AE) were evaluated at each visit during and after treatment, and were recorded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events version 3.0. Dose modification of sorafenib was permitted if grade 3 or 4 AE occurred. Treatment continued until disease progression or treatment intolerance occurred. Partial response, and stable disease as best objective responses were observed in 11 (22%) and 23 (46%) patients, respectively. Median progression-free survival was 7.3 months and median overall survival was 11.9 months. All patients experienced AE and one or more grade 3/4 AE occurred in 43 of 50 (86%) patients. Although it requires close monitoring, sorafenib treatment seemed to be effective in the present study population.