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

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

Objective: To evaluated the trends of local intervention and their impact on oncological outcomes in metastatic hormone‐naïve prostate cancer (mHNPC) in real‐world practice. Methods: This retrospective multicenter study included 760 patients treated with either androgen deprivation therapy (ADT) without local treatment (no castration‐resistant prostate cancer [CRPC] progression within 12 months, control group) or ADT plus local intervention (intervention group) between January 2005 and March 2022. We evaluated the trends in the use of local intervention in patients with mHNPC and factors associated with CRPC‐free survival in the intervention group. Results: The use of local intervention gradually increased in combination with upfront combination treatment (docetaxel or androgen receptor axis‐targeted agents) for the duration of our study. The number of patients with local intervention combined with upfront treatment was significantly higher in patients with high tumor burden disease than in those with low tumor burden disease. Of the 108 patients who received local intervention, a duration of ≤7 months of initial therapy before local intervention and a level of prostate‐specific antigen ≥0.20 ng/mL at the time of local intervention were significantly associated with poor CRPC‐free survival. Conclusions: The use of local intervention in combination with upfront therapy to treat mHNPC increased for the duration of our study regardless of the tumor burden. Local intervention in addition to the standard of care for mHNPC may be a feasible treatment option for selected patients, taking into consideration the duration of and response to initial treatment. [ABSTRACT FROM AUTHOR]

A recent approach to radiotherapy for prostate cancer is the administration of high doses of radiation to the prostate while minimizing the risk of side effects. Thus, image-guided radiotherapy utilizes advanced imaging techniques and is a feasible strategy for increasing the radiation dose. New radioactive particles are another approach to achieving high doses and safe procedures. Prostate brachytherapy is currently considered as a combination therapy. Spacers are useful to protect adjacent organs, specifically the rectum, from excessive radiation exposure. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to investigate the oncologic efficacy of combining docetaxel with androgen deprivation therapy (ADT) versus nonsteroidal antiandrogen (NSAA) with ADT in patients with high-volume metastatic hormone-sensitive prostate cancer (mHSPC) with focus on the effect of sequential therapy in a real-world clinical practice setting. Methods: The records of 382 patients who harbored high-volume mHSPC, based on the CHAARTED criteria, and had received ADT with either docetaxel (n = 92) or NSAA (bicalutamide) (n = 290) were retrospectively analyzed. The cohorts were matched by one-to-one propensity scores based on patient demographics. Overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS), including time to castration-resistant prostate cancer (CRPC), and time to second-line progression (PFS2) were compared. 2nd-line PFS defined as the time from CRPC diagnosis to progression after second-line therapy was also compared. Results: After matching, a total of 170 patients were retained: 85 patients treated with docetaxel + ADT and 85 patients treated with NSAA + ADT. The median OS and CSS for docetaxel + ADT versus NSAA + ADT were not reached (NR) vs. 49 months (p = 0.02) and NR vs. 55 months (p = 0.02), respectively. Median time to CRPC and PFS2 in patients treated with docetaxel + ADT was significantly longer compared to those treated with NSAA (22 vs. 12 months; p = 0.003 and, NR vs. 28 months; p < 0.001, respectively). There was no significant difference in 2nd-line PFS between the two groups. Conclusions: Our analysis suggested that ADT with docetaxel significantly prolonged OS and CSS owing to a better time to CRPC and PFS2 in comparison to NSAA + ADT in high-volume mHSPC. [ABSTRACT FROM AUTHOR]

Objective: This study investigated the efficacy of docetaxel (DOC) and cabazitaxel (CBZ) and examined the factors associated with the prognosis of patients with castration‐resistant prostate cancer (CRPC) receiving DOC‐CBZ sequential treatment in Japanese real‐world data. Methods: We retrospectively evaluated data for 146 patients who received DOC followed by CBZ. The correlations of prostate specific antigen (PSA) decrease rate and time to progression between DOC and CBZ treatment were examined. Combined progression‐free survival (PFS) of DOC‐CBZ and overall survival (OS) from the initiation of DOC and the diagnosis of CRPC were evaluated and compared between patients with high and low PSA levels at the start of DOC and CBZ treatment. Results: No correlations of PSA decrease rate and time to progression were observed between DOC and CBZ. The patients for whom DOC was started in higher PSA levels had significantly shorter combined PFS (p = 0.003) and OS from the initiation of DOC (p = 0.002). In patients who started DOC at high PSA levels, those who switched to CBZ at low PSA levels had longer OS than those who switched at high PSA levels (p = 0.048). The OS from CRPC of patients who started DOC at low PSA levels was significantly longer than those that started at high PSA levels (p = 0.030). Conclusions: For patients for whom DOC was not effective, sequential CBZ might have change to be effective. The PSA levels at the start of DOC and CBZ might be a potential prognostic biomarker. [ABSTRACT FROM AUTHOR]

A 66-year-old male was diagnosed with cT4N0M1b small-cell neuroendocrine carcinoma of the prostate. Four months after the administration of combined androgen blockade, multiple novel metastatic regions in the lung and liver and progression of bone metastasis were observed. The patient was referred to our hospital because of biochemical and radiographic progression after four cycles of docetaxel as a first-line therapy for castration-resistant prostate cancer. Transurethral resection of the prostate and hepatic biopsy revealed small-cell carcinoma with positive expression of neuroendocrine markers. The FoundationOne CDx next-generation sequencing test revealed several pathogenic variants, including BRCA2 (W1692fs*3), KEAP1 (R320W), and TP53 (C2385) mutation. After four cycles of chemotherapy with carboplatin plus etoposide (CE), the metastatic regions regressed markedly. The prostate-specific antigen (PSA) and neuron-specific enolase (NSE) level decreased by 96.9% and 91.6%, respectively. However, 2 months after the completion of four cycles of CE, elevation of tumor marker levels, and re-growth of the metastatic regions were observed. Although olaparib, a poly (ADP-ribose) polymerase inhibitor (PARPi), achieved a 45.2% decrease in NSE, the patient rejected to continue therapy because of G2 adverse events. After receiving an additional two cycles of CE and one cycle of cabazitaxel, the patient died because of cancer progression 24 months after the initial treatment for prostate cancer. Here, we present a case of BRCA2-altered small-cell neuroendocrine prostate cancer treated with both platinum-containing chemotherapy and PARPi. Both therapies achieved an initial response; however, durable responses were not obtained. Additional discussion regarding the optimal treatment strategy for BRCA-altered small-cell/neuroendocrine prostate cancer is required. [ABSTRACT FROM AUTHOR]

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

Objective: We evaluated the impact of Gleason pattern 5 presence on prognosis among de novo metastatic hormone‐sensitive prostate cancer patients with a Gleason score ≥8. Methods: The data of 559 patients diagnosed as metastatic hormone‐sensitive prostate cancer with a Gleason score ≥8, who were initially treated with androgen deprivation therapy from 2008 to 2016, were retrospectively collected. Patients were divided into two groups as high and low volume based on the CHAARTED trial criteria. Results: The median overall survival of the 559 metastatic hormone‐sensitive prostate cancer patients with Gleason score ≥8 was 70 months, with a median follow‐up period of 36 months. Gleason pattern 5 was confirmed in 341 patients (61.0%), in which primary Gleason pattern 5 was confirmed in 164 patients (29.3%). The number of patients with high metastatic volume group was 363 (64.9%). In total and high metastatic volume groups, hemoglobin and lactate dehydrogenase were significant factors for predicting overall survival, but both Gleason pattern 5 and primary Gleason pattern 5 did not show a statistically significant difference. In the low‐volume metastatic group, the median overall survival in patients with or without primary Gleason pattern 5 was 40 and 78 months, respectively. In multivariate analysis, only primary Gleason pattern 5 was an independent predictive factor for overall survival in the low‐volume metastatic group (hazard ratio 2.76, 95% confidence interval 1.88–8.67; P = 0.0026). Conclusion: The presence of Gleason pattern 5 was not associated with overall survival in metastatic hormone‐sensitive prostate cancer with a Gleason score ≥8. In low‐metastatic volume metastatic hormone‐sensitive prostate cancer, primary Gleason pattern 5 was a poor prognostic factor, which might show a separate treatment option for this group. [ABSTRACT FROM AUTHOR]

Abstract Background To assess the outcome of neoadjuvant chemohormonal therapy comprising complete androgen blockade followed by treatment with docetaxel and estramustine phosphate before radical prostatectomy in Japanese patients with a high risk of localized prostate cancer (PCa). Methods Complete androgen blockade followed by 6 cycles of docetaxel (30 mg/m2) with estramustine phosphate (560 mg) were given to 18 PCa patients before radical prostatectomy. Subsequently, the clinical and pathological outcomes were analyzed. Results No patients had severe adverse events during chemohormonal therapy, and hence they were treated with radical prostatectomy. Two patients (11.1%) achieved pathological complete response. Surgical margins were negative in all patients. At a median follow-up of 18 months, 14 patients (77.8%) were disease-free without PSA recurrence. All 4 patients with PSA recurrence had pathologic T3b or T4 disease and 3 of these 4 patients had pathologic N1 disease. Conclusion We found that neoadjuvant chemohormonal therapy with complete androgen blockade followed by treatment with docetaxel and estramustine phosphate before radical prostatectomy was safe, feasible, and associated with favorable pathological outcomes in patients with a high risk of localized PCa.

Objectives: To evaluate the association of tumor burden with the prognosis in real‐world patients with metastatic castration‐sensitive prostate cancer and to investigate the eligibility for upfront intensification therapy. Methods: We retrospectively evaluated 679 patients with metastatic castration‐sensitive prostate cancer who were initially treated with conventional androgen deprivation therapy between August 2001 and November 2018. The primary purpose was to investigate the eligibility for upfront intensification therapy based on the progression of metastatic castration‐resistant prostate cancer. The secondary purpose included the comparison of the metastatic castration‐resistant prostate cancer progression rate, metastatic castration‐resistant prostate cancer‐free survival and overall survival after castration‐resistance in CHAARTED low‐ or high‐volume disease patients. Results: The number of patients with metastatic castration‐resistant prostate cancer progression was 119 (52%) and 319 (71%) in the low‐ and high‐volume disease groups, respectively. The metastatic castration‐resistant prostate cancer progression rate (P < 0.001) and castration‐resistant prostate cancer‐free survival (P < 0.001) were significantly different between the low‐ and high‐volume disease groups, but no difference was found for overall survival after castration resistance (P = 0.363). Multivariate Cox regression analysis showed no significant association between tumor burden and overall survival after castration resistance (P = 0.522; hazard ratio 1.14). Conclusions: The progression rate in metastatic castration‐resistant prostate cancer patients with the low‐volume disease under conventional androgen deprivation therapy is approximately 50%. Upfront intensification therapy might be beneficial for approximately half of patients with low‐volume disease. A novel maker to predict the castration‐resistant status is required to select optimal patients for upfront intensification therapy. [ABSTRACT FROM AUTHOR]

Purpose: Clinical outcomes of patients with newly diagnosed metastatic hormone-naïve prostate cancer (mHNPC) and initially treated with androgen deprivation therapy (ADT) were evaluated. Methods: The medical records of 605 consecutive mHNPC patients with initial ADT or combined androgen blockade (CAB) at nine study centers between 2008 and 2016 were retrospectively reviewed. Castration-resistant prostate cancer (CRPC)-free and overall survival (OS) were estimated by the Kaplan–Meier method. The association of pretreatment risk factors with CRPC-free survival and OS was evaluated by Cox proportional hazard models and differences in survival were classified by the number of risk factors. Results: Median follow-up was 2.95 years, median CRPC-free survival was 21.9 months and median OS was 5.37 years. Multivariable analysis found that four risk factors, a Gleason score ≥ 9, lymph node metastasis, an extent of disease score ≥ 2, and serum LDH of > 220 IU were independently associated with both CRPC-free survival and OS. Median CRPC-free survival of low-risk patients with no or one factor was 86.5 months, 17.9 months in intermediate-risk patients with two or three factors, and 11.0 months in high-risk patients with four factors. Median OS was 4.72 years in intermediate- and 2.44 years in high-risk patients. It was not reached in low-risk patients. Conclusion: In this series, CRPC-free and OS of a subset of mHNPC patients in Japan who were treated with ADT or CAB had better CRPC-free and overall survivals in Japan. Risk-adapted treatment based on the presence of novel prognostic factors may be beneficial for selected mHNPC patients. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to identify predictive factors associated with conditional net survival in patients with metastatic hormone‐naive prostate cancer (mHNPC) initially treated with androgen deprivation therapy (ADT). Methods: At nine hospitals in Tohoku, Japan, the medical records of 605 consecutive patients with mHNPC who initially received ADT were retrospectively reviewed. The Pohar Perme estimator was used to calculate conditional net cancer‐specific survival (CSS) and overall survival (OS) for up to 5 years subsequent to the diagnosis. Using multiple imputation, proportional hazard ratios for conditional CSS and OS were calculated with adjusted Cox regression models. Results: During a median follow up of 2.95 years, 208 patients died, of which 169 died due to progressive prostate cancer. At baseline, the 5‐year CSS and OS rates were 65.5% and 58.2%, respectively. Conditional 5‐year net CSS and OS survival gradually increased for all the patients. In patients given a 5‐year survivorship, the conditional 5‐year net CSS and OS rates improved to 0.906 and 0.811, respectively. Only the extent of disease score (EOD) ≥2 remained a prognostic factor for CSS and OS up to 5 years; as survival time increased, other variables were no longer independent prognostic factors. Conclusions: The conditional 5‐year net CSS and OS in patients with mHNPC gradually increased; thus, the risk of mortality decreased with increasing survival. The patient's risk profile changed over time. EOD remained an independent prognostic factor for CSS and OS after 5‐year follow‐up. Conditional net survival can play a role in clinical decision‐making, providing intriguing information for cancer survivors. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the association between the Geriatric Nutritional Risk Index (GNRI) and prognosis of patients with metastatic hormone-naïve prostate cancer (mHNPC) and to design the optimal risk score predicting for prognosis. Methods: We retrospectively reviewed data from the Michinoku Japan Urological Cancer Study Group database, containing information about 656 patients with mHNPC who initially received androgen-deprivation therapy between 2005 and 2017. The baseline GNRI was calculated using serum albumin level and body mass index. Poor nutrition was defined as GNRI < 92.0. The impact of GNRI, CHAARTED criteria, and laboratory parameters on oncological outcomes was investigated using the multivariable Cox regression models. We developed the risk comprising GNRI and laboratory parameters and compared its prognostic performance with the CHAARTED criteria using the receiver operating characteristic curve with the DeLong method. Results: Of 339 patients with sufficient data, 66 (19%) were diagnosed with poor nutrition. Multivariate analyses showed that GNRI < 92.0 was an independent prognostic factor of cancer-specific survival [hazard ratio (HR) 1.76; 95% confidence interval (CI) 1.04–2.98, P = 0.035] and overall survival (HR 1.80; 95% CI 1.13–2.89, P = 0.013), in addition to hemoglobin (Hb) and lactic dehydrogenase (LDH) levels. We designed the risk score comprising GNRI < 92.0, Hb < 13.0 g/dL, and LDH > 222 IU/L. The predictive value of the risk score was significantly superior to that of the CHAARTED criteria. Conclusions: Poor nutrition may predict mortality in patients with mHNPC. Risk factors, such as nutritional status and laboratory parameters, may be useful in decision-making regarding aggressive treatments for patients with mHNPC. [ABSTRACT FROM AUTHOR]

Objectives To assess the risk factors for biochemical recurrence in D'Amico intermediate-risk prostate cancer patients treated using radical prostatectomy. Methods We retrospectively reviewed the medical records of 1268 men with prostate cancer treated using radical prostatectomy without neoadjuvant therapy. The association between various risk factors and biochemical recurrence was then statistically evaluated. The Kaplan-Meier method, log-rank tests and Cox proportional hazards models were used for statistical analysis. Results In the intermediate-risk group, 96 patients (14.5%) experienced biochemical recurrence during a median follow up of 41 months. In the intermediate-risk group, preoperative prostate-specific antigen level, prostate volume and prostate-specific antigen density were significant preoperative risk factors for biochemical recurrence, whereas other factors including age, primary Gleason 4, clinical stage >T2 and percentage of positive biopsies were not. In multivariate analysis, higher preoperative prostate-specific antigen level and density, and a smaller prostate volume were independent risk factors for biochemical recurrence in the intermediate-risk group. Biochemical recurrence-free survival of patients in the intermediate-risk group with a higher prostate-specific antigen level and density (≥15 ng/mL, ≥0.6 ng/mL/cm3, respectively), and lower prostate volume (≤10 mL) was comparable with that of high-risk group individuals ( P = 0.632, 0.494 and 0.961, respectively). Conclusions Preoperative prostate-specific antigen, prostate volume and prostate-specific antigen density are significant risk factors for biochemical recurrence in D'Amico intermediate-risk prostate cancer patients treated using radical prostatectomy. Using these variables, a subset of the intermediate-risk patients can be identified as having equivalent outcomes to high-risk patients. [ABSTRACT FROM AUTHOR]

Objective. Prostate cancer (PCa) may be a multifocal and bilateral disease. Patients with low-risk PCa and a low number of positive biopsy cores may choose to undergo active surveillance or focal therapy. The aim of this study was to determine the correlation between a solitary positive prostate biopsy core and the pathological outcome after radical prostatectomy (RP). Material and methods. The Michinoku Japan Urological Cancer Study Group database contains data, including preoperative and postoperative information, on 1268 consecutive patients with PCa treated with RP alone at four institutions. This study focused on 151 patients with a single positive biopsy core, preoperative prostate-specific antigen (PSA) level less than 10 ng/ml, biopsy Gleason score less than 8, and clinical stage T1c/T2a/T2b disease. Potential preoperative predictors of unilateral PCa were age, preoperative PSA level, biopsy Gleason score and clinical T stage. Results. The median age and preoperative PSA level were 65 years (range 47-76 years) and 6.00 ng/ml (range 0.50-9.80 ng/ml), respectively. Unilateral PCa was identified in 41% of the patients. Extraprostatic extension or seminal vesicle invasion was observed in 26% of all patients. Conclusion. Serum PSA levels were significantly higher in the bilateral PCa group than in the unilateral PCa group in the current study. For patients with PCa having a solitary positive prostate biopsy core, definitive therapy such as RP should be considered. [ABSTRACT FROM AUTHOR]

Objective To determine whether the currently available pretreatment risk classification systems are applicable in Japanese prostate cancer patients. Methods Using data obtained from 1264 consecutive patients with prostate cancer treated with radical prostatectomy at four hospitals in Japan, biochemical recurrence-free survival rates were estimated and compared between the D' Amico, the National Institute for Health and Clinical Excellence, the Cancer of the Prostate Strategic Urological Research Endeavor, the National Comprehensive Cancer Network, and the European Society of Medical Oncology risk groups by using the Kaplan- Meier method and log-rank test. Results The 5-year biochemical recurrence-free survival rates in the D' Amico low-, intermediate-, and high-risk groups were 88.3%, 84.7% and 66.9%, respectively (low and intermediate risk vs high risk, P < 0.001). The 5-year biochemical recurrence-free survival rates in the National Institute for Health and Clinical Excellence, National Comprehensive Cancer Network, and European Society of Medical Oncology low-, intermediate- and high-risk groups were 88.3%, 84.3%, and 60.3%, respectively (low and intermediate risk vs high risk, P < 0.001). The 5-year biochemical recurrence-free survival rates in the Cancer of the Prostate Strategic Urological Research Endeavor low-, intermediate-, and high-risk groups were 90%, 83.5% and 60.3%, respectively (low and intermediate risk vs high risk, P < 0.001). Low- and intermediate-risk groups according to any of the risk stratification systems did not show significant differences in biochemical recurrence-free survival. Conclusion Current risk stratification systems do not discriminate between low- and intermediate-risk groups in the Japanese population. A novel, pretreatment risk stratification system including other prognostic factors is necessary for an adequate prostate cancer risk assessment in the Japanese population. [ABSTRACT FROM AUTHOR]

CYP19 catalyzes the conversion of androgens to estrogens and is a critical enzyme affecting the sex hormone milieu. In this study, we investigated the functions of CYP19A1 polymorphisms and their associations with prostate cancer risk and clinical outcome. This case-control study evaluated the effects of three single nucleotide polymorphisms (SNPs) in CYP19A1 on the risk of prostate cancer in 330 prostate cancer patients and 354 normal controls. The associations between each SNP and sex hormone levels were evaluated in 164 healthy male patients. The functions of the SNPs were determined by reporter gene assays in PC3 and DU145 cell lines. Prostate-specific antigen nadir was evaluated in 142 patients with metastatic prostate cancer treated with androgen deprivation therapy. Cancer-specific survival (CSS) was determined in 166 patients with metastatic prostate cancer, to evaluate the influence of the three SNPs. Each variant allele of the three SNPs significantly decreased the risk of prostate cancer. Haplotype analysis showed that the T-A-G haplotype (corresponding to rs2470152-rs10459592-rs4775936) increased the risk of prostate cancer, while the C-C-A haplotype decreased the risk. The estrone/androstenedione ratio was significantly higher in men with the C allele of rs2470152, the C allele of rs10459592, and the A allele of rs4775936 in a gene-dosage-dependent manner. Patients with the variant allele at rs4775936 had significantly shorter CSS. These results indicate that CYP19A1 polymorphisms may influence prostate cancer risk and survival by modifying promoter activity, with subsequent effects on the sex hormone milieu. [ABSTRACT FROM AUTHOR]

Background: The insulin-like growth factor-1 (IGF-1) plays an important role in growth of prostate cancer (PCa) cells and facilitating the development and progression of PCa. This study aimed to evaluate the association of polymorphisms in three linkage disequilibrium (LD) blocks of the IGF-1 on the survival of metastatic PCa patients. Methods: A total of 215 patients with bone metastases at initial presentation were included in this study. The cytosine-adenine (CA) repeat polymorphism and rs12423791 were selected as representative polymorphisms in the LD blocks 1 and 2, respectively. Haplotype in the LD block 3 was analyzed using two tag single nucleotide polymorphisms (SNPs), rs6220 and rs7136446. Cancer-specific survival rate was estimated from the Kaplan-Meier curve, and the survival data were compared using the log-rank test. Results: Cancer-specific survival was significantly associated with the CA repeat polymorphism, rs12423791, and rs6220 (P = 0.013, 0.014, and 0.014, respectively). Although rs7136446 had no significant association with survival, the haplotype in the LD block 3 was significantly associated with cancer-specific survival (P = 0.0003). When the sum of the risk genetic factors in each LD block (19-repeat allele, C allele of rs12423791, or C-T haplotype) was considered, patients with all the risk factors had significantly shorter cancer specific-survival than those with 0-2 risk factors (P = 0.0003). Conclusions: Polymorphisms in the IGF-1, especially a haplotype in the LD block 3, are assumed to be genetic markers predicting the outcome of metastatic PCa [ABSTRACT FROM AUTHOR]

Fibroblast growth factor-inducible 14 (Fn14), a transmembrane receptor binding to the multifunctional cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK), is known to modulate many cellular activities including cancer progression. Here, we demonstrated the significant role of Fn14 in invasion, migration and proliferation of androgen-independent prostate cancer (AIPC) cells. Fn14 and its ligand TWEAK were highly expressed in two AIPC cell lines, DU 145 and PC-3, whereas expression was weak in androgen-sensitive LNCaP cells. Fn14 knockdown using small-interfering RNAs attenuated migration, invasion and proliferation and enhanced apoptosis in the AIPC cell lines. Both forced overexpression of Fn14 by stable Fn14 complementary DNA transfection to PC-3 cells (PC-3/Fn14) and ligand activation by recombinant TWEAK in PC-3 cells enhanced invasion. Fn14 was shown to modulate expression of matrix metalloproteinase (MMP)-9, and MMP-9 mediated the invasive potential influenced by Fn14 in PC-3 cells. In vivo, subcutaneous xenografts of PC-3/Fn14 grew significantly faster than xenograft of PC-3/Mock, and the invasive capacity in PC-3/Fn14 was found to be higher than that of PC-3/Mock as evaluated in an invasion model of the diaphragm. Furthermore, the messenger RNA expressions of MMP-9 in PC-3/Fn14 xenografts were significantly higher than those in PC-3/Mock xenografts. Clinically, high expression of Fn14 was significantly associated with higher prostate-specific antigen recurrence rate in patients who underwent radical prostatectomy. In conclusion, the overexpression of Fn14 may contribute to multiple malignant cellular phenotypes associated with prostate cancer (PCa) progression, in part via MMP-9. TWEAK-Fn14 signaling may be a novel therapeutic target of PCa. [ABSTRACT FROM AUTHOR]

Objective: We evaluated the clinicopathological findings and short- and long-term outcomes of prostate cancer (PCa) patients with bladder neck invasion who underwent cystoprostatectomy. Patients and Methods: Between 1989 and 2005, we performed 17 cystoprostatectomies for PCa patients having bladder neck invasion without distant visceral or distant lymph node metastasis. Of the 17 patients, 11 were treated with neoadjuvant hormone therapy and all patients were treated with adjuvant hormone therapy immediately after surgery. Results: All 7 patients in whom pelvic lymph node swelling was identified by preoperative imaging studies had pathological lymph node metastasis. Of the 10 patients judged as cN0 preoperatively, 7 (70.0%) had lymph node metastasis. Although local recurrence was found in 2 (11.8%) patients, no additional urinary diversion or inconvenient urinary symptoms due to PCa progression were observed in any patients. The 5-year prostate-specific antigen recurrence-free survival rate was 62.2%. Cause-specific survival at 5 years after surgery was 87.1%. The 5-year cause-specific survival rate of node-positive patients was 92.3%. Conclusion: Cystoprostatectomy followed by immediate hormone therapy may be a feasible treatment option to achieve excellent local control for patients with previously untreated PCa, even in the presence of pelvic lymph node metastasis. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Lard diet (LD) is a risk factor for prostate cancer (PCa) development and progression. Two immunocompetent mouse models fed with isocaloric specific fat diets (LD) enriched in saturated and monounsaturated fatty acid (SMFA), showed significanftly enhanced PCa progression with weight gain compared with a fish oil diet (FOD). High gut microbial divergency resulted from difference in diets, and the abundance of several bacterial species, such as in the orders Clostridiales and Lactobacillales, was markedly altered in the feces of LD- or FOD-fed mice. The proportion of the order Lactobacillales in the gut was negatively involved in SMFA-induced body weight gain and PCa progression. We found the modulation of lipid metabolism and cholesterol biosynthesis pathways with three and seven commonly up- and downregulated genes in PCa tissues, and some of them correlated with the abundance of the order Lactobacillales in mouse gut. The expression of sphingosine 1-phosphate receptor 2, which is associated with the order Lactobacillales and cancer progression in mouse models, was inversely associated with aggressive phenotype and weight gain in patients with PCa using the NCBI Gene Expression Omnibus database. Therefore, SMFA may promote PCa progression with the abundance of specific gut microbial species and overexpression of lipogenic genes in PCa. Therapeutics with alteration of gut microbiota and candidate genes involved in diet-induced PCa progression may be attractive in PCa. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to evaluate the role of osteoprotegerin gene (OPG) polymorphisms as genetic modifiers in the etiology of prostate cancer (PCa) and disease progression. Methods: Three hundred and sixty one patients with PCa and 195 normal controls were enrolled in the study, and two genetic polymorphisms, 149 T/C and 950 T/C in the putative promoter region of OPG, were genotyped. Results: There was no significant difference in the genotype frequencies between PCa patients and controls (P = 0.939 and 0.294 for 149 T/C and 950 T/C polymorphisms, respectively). However, those patients with TC and TT genotypes in the 950 T/C polymorphism had a significantly increased risk of extraprostatic (age-adjusted odds ratio; aOR = 1.74 and 2.03 for TC and TT genotypes compared with the CC genotype, P = 0.028) and metastatic disease (aOR = 1.72 and 2.76 for TC and TT genotypes compared with the CC genotype, P = 0.009) compared with those with the CC genotype. In addition, analysis of the metastatic PCa patients (Stage D) showed that the presence of the T allele of the OPG 950 T/C polymorphism was an independent risk factor predicting survival by Cox proportional hazard regression analyses (P = 0.031). Conclusion: Progression of PCa may be influenced by an intrinsic genetic factor of the host's bone metabolism. The variant C allele of 950 T/C in the OPG promoter may play a major role as a genetic safe guard against progression in patients with PCa. [ABSTRACT FROM AUTHOR]

CHAARTED-HVD was defined as the presence of visceral metastases and/or four more bone metastases with at least one outside of the vertebral column and pelvis.[2] CRPC-FS and OS were compared using Kaplan-Meier with the log-rank test and uni-/multivariate Cox regression analyses. Similar to the present study, a retrospective study reported the utility of the CHAARTED criteria in Japanese mHNPC patients.[4] However, the presence of visceral metastasis was not significantly associated with prognosis in the present study. Impact of the site of metastases on survival in patients with metastatic prostate cancer. [Extracted from the article]

Phosphoinositides (PIPs) participate in many cellular processes, including cancer progression; however, the metabolic features of PIPs associated with prostate cancer (PCa) are unknown. We investigated PIPs profiles in PTEN-deficient prostate cancer cell lines, human prostate tissues obtained from patients with PCa and benign prostate hyperplasia (BPH) specimens using mass spectrometry. In immortalized normal human prostate PNT1B cells, PTEN deficiency increased phosphatidylinositol tris-phosphate (PIP3) and decreased phosphatidylinositol mono- and bis-phosphate (PIP1 and PIP2), consistent with PTEN's functional role as a PI(3,4,5)P3 3-phosphatase. In human prostate tissues, levels of total (sum of all acyl variants) phosphatidylinositol (PI) and PIP1 in PCa were significantly higher than in BPH, whereas PIP2 and PIP3 contents were significantly lower than in BPH. PCa patients had significantly higher proportion of PI, PIP1, and PIP2 with 0–2 double bonds in acyl chains than BPH patients. In subgroup analyses based on PCa aggressiveness, mean total levels of PI with 0–2 double bonds in acyl chains were significantly higher in patients with pathological stage T3 than in those with pathological stage T2. These data indicate that alteration of PIPs level and the saturation of acyl chains may be associated with the development and aggressiveness of prostate cancer, although it is unknown whether this alteration is causative. [ABSTRACT FROM AUTHOR]

Although recent evidence has suggested that a high-fat diet (HFD) plays an important role in prostate carcinogenesis, the underlying mechanisms have largely remained unknown. This review thus summarizes previous preclinical studies that have used prostate cancer cells and animal models to assess the impact of dietary fat on prostate cancer development and progression. Large variations in the previous studies were found during the selection of preclinical models and types of dietary intervention. Subcutaneous human prostate cancer cell xenografts, such as LNCaP, LAPC-4, and PC-3 and genetic engineered mouse models, such as TRAMP and Pten knockout, were frequently used. The dietary interventions had not been standardized, and distinct variations in the phenotype were observed in different studies using distinct HFD components. The use of different dietary components in the research models is reported to influence the effect of diet-induced metabolic disorders. The proposed underlying mechanisms for HFD-induced prostate cancer were divided into (1) growth factor signaling, (2) lipid metabolism, (3) inflammation, (4) hormonal modulation, and others. A number of preclinical studies proposed that dietary fat and/or obesity enhanced prostate cancer development and progression. However, the relationship still remains controversial, and care should be taken when interpreting the results in a human context. Future studies using more sophisticated preclinical models are imperative in order to explore deeper understanding regarding the impact of dietary fat on the development and progression of prostate cancer. [ABSTRACT FROM AUTHOR]

Background: Less evidence is known about the role of early changes in serum biomarker after androgen deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer (mHSPC). Here we evaluated the impact of pre-treatment prognostic factors and early changes in serum biomarkers on prostate specific antigen (PSA) progression-free and overall survival rates in mHSPC.Methods: We retrospectively reviewed the medical records of 60 mHSPC patients (median age 72 years) treated with ADT whose laboratory data at baseline and following 12 weeks were available.Results: Forty-four patients (73%) had PSA progression and 27 patients (45.0%) died during a median follow-up of 34 months. The multivariable Cox hazard model demonstrated that a log-transformed baseline PSA level (p = 0.003) and an extent of bone disease (EOD) score of ≥3 (p = 0.004) were statistically associated with an increased risk for PSA progression whereas one unit increase in a log-transformed PSA change (baseline-12 weeks) was associated with a decreased risk for PSA progression (p = 0.004). For overall survival, a high level of alkaline phosphatase (ALP) at 12 weeks was associated with increased risk (p = 0.030) whereas a one-unit increase in the log-transformed PSA change was associated with decreased risk (p = 0.001).Conclusions: An increased level of PSA at baseline, or an EOD score of ≥3 may be a good predictor of PSA progression, and a high level of ALP at 12 weeks may be a risk predictor of death. A larger decline in PSA at 12 weeks from the baseline was associated with both PSA progression-free and overall survival time. Early changes in serum biomarkers may be useful in predicting poor outcomes in patients with mHSPC who are initially treated with ADT. [ABSTRACT FROM AUTHOR]

Androgen deprivation therapy (ADT) for patients with metastatic or locally advanced prostate cancer reduces bone mineral density by stimulating receptor activator of nuclear factor kappa-B (RANK) signaling in osteoclasts. The involvement of the RANK/RANKL signaling in ADT-induced acceleration of bone metastasis in castration-insensitive prostate cancer was examined in a murine model using osteoprotegerin (OPG). Male Balb/c nude mice were divided into three groups: the non-castration, castration, and castration + OPG groups. PC-3M-luc-C6 was injected into the left ventricle of the mice. Recombinant OPG was injected intravenously twice weekly in the castration + OPG group. In-vivo imaging system (IVIS®) determined that the prevalence and photon counts of bone metastasis in the castration group were significantly higher than that in the non-castration and castration + OPG groups. The mean number of RANKL-positive osteoblasts and the mean serum RANKL level in the castration group were significantly higher than those in the non-castration group. RANKL-enhanced activation of osteoclasts was attenuated in the castration + OPG group. These results suggest that the mechanisms of RANK/RANKL signaling are involved in the ADT-induced acceleration of bone metastasis in castration-insensitive prostate cancer. [ABSTRACT FROM AUTHOR]

Abstract: The CYP3A5 gene (CYP3A5) encodes the cytochrome P450 3A5, which catalyzes the 6β-hydroxylation of testosterone. We explored association between the CYP3A5 A6986G polymorphism and a risk of prostate cancer in 260 prostate cancer patients, 199 BPH patients and 212 male controls. The CYP3A5 gene polymorphism did not influence significantly a risk of developing of prostate cancer in general. However, compared with males with the GG genotype, those with the AA genotype had a 0.23-fold decreased risk of developing low-grade prostate cancer (P=0.023), and a 0.31-fold decreased risk of developing localized (stages A–C) prostate cancer (P=0.044). The CYP3A5 A6986G polymorphism may be specifically associated with a decreased risk of low-grade or early stage prostate cancer. [Copyright &y& Elsevier]

Highlights: [•] We developed novel immunoassay to measure aberrant glycosylated PSA (S2,3PSA). [•] Serum S2,3PSA in PCa group was significantly higher than that in non-PCa group. [•] The area under the curve of S2,3PSA assay was significantly higher than conventional PSA. [•] We examined that LNCaP cells produce PCa-associated S2,3PSA. [•] S2,3PSA may improve the accuracy of PCa detection and reduce unnecessary biopsy. [Copyright &y& Elsevier]

Abstract: The expression of core 2 β1,6-N-acetylglucosaminyltransferase-1 (C2GnT) is associated with development and progression of malignancy. Sequence analysis showed that the codon 152 of C2GnT has a polymorphism having GTT encoding valine or ATT encoding isoleucine. By examining the polymorphism in prostate cancer and benign prostatic hyperplasia patients, we found that the C2GnT G allele was more frequently observed in the prostate cancer group (p=0.015) than the control group. Men with the GG genotype had a 3.60-fold increased risk of prostate cancer, and men with the AG genotype had a 1.58-fold increased risk of prostate cancer compared with those with the AA genotype. The G allele was found to have a gene dosage effect for prostate cancer risk. No such risk was associated for benign prostatic hyperplasia. These results demonstrate that C2GnT A/G polymorphism is associated with the susceptibility to prostate cancer in a Japanese population. [Copyright &y& Elsevier]