Prostate Cancer In Japanese Men Research Articles

Urine spermine and multiparametric magnetic resonance imaging for prediction of prostate cancer in Japanese men.

To investigate the role of urine spermine and spermine risk score in predicting prostate cancer (PCa) diagnoses in combination with multiparametric magnetic resonance imaging (mpMRI). Three hundred forty seven consecutive men with elevated prostate-specific antigen (PSA) with mpMRI examination were prospectively enrolled in this study. In 265 patients with PSA levels between 4 and20ng/ml, pre-biopsy urine samples were analyzed for spermine levels with ultra-high performance liquid chromatography (UPLC-MS/MS). Transperineal image-guided prostate biopsies with 16-18 cores were performed. Logistic regressions were used to form different models for the prediction of the PCa, and the performances were compared using the area under the curve (AUC). The median serum PSA level and prostate volume were 7.4ng/mL and 33.9mL, respectively. PCa and high-grade PCa (ISUP group ≥2, HGPCa) were diagnosed in 66.0% (175/265) and 132/265 (49.8%) cases, respectively. The urine spermine levels were significantly lower in men with PCa (0.87 vs. 2.20, P<0.001). Multivariate analyses showed that age, PSA, PV, urine spermine level, and Prostate Imaging Reporting and Data System (PI-RADS) findings were independent predictors for PCa. The Spermine Risk Score is a multivariable model including PSA, age, prostate volume, and urine spermine. Adding the Spermine Risk Score to PI-RADS improved the AUC from 0.73 to 0.86 in PCaand from 0.72 to 0.83 in high grade PCa (HGPCa) prediction (both P<0.001). At 90% sensitivity for HGPCa prediction using Spermine Risk Score, 31.1% of unnecessary biopsies could be avoided. In men with equivocal MRI PI-RADS score 3, the AUC for HGPCa prediction was 0.58, 0.79, and 0.87 for PSA, PSA density, and Spermine Risk Score, respectively. Urine Spermine Risk Score, including mpMRI could accurately identify men at high risk of HGPCa and reduce unnecessary prostate biopsies. Spermine Risk Score could more accurately predict HGPCa than PSA density in men with MRI showing equivocal PI-RADS 3 lesions.

Development of a Prognostic Model of Overall Survival for Metastatic Hormone-Naïve Prostate Cancer in Japanese Men.

Simple SummaryTreatment strategies have changed dramatically in recent years with the development of a variety of agents for metastatic hormone-naïve prostate cancer. There is a need to identify prognostic factors for the appropriate choice of treatment for patients with hormone-naïve prostate cancer in Japanese men. Among the prostate cancer patients receiving treatment at our institution from 2000 to 2019, 198 patients with bone or visceral metastases at the initial diagnosis were included in the study. We retrospectively examined these factors of the overall survival, and identified Gleason pattern 5 content, bone scan index ≥ 1.5, and lactate dehydrogenase evels ≥ 300 IU/L as prognostic factors. Using these three factors, we developed a new prognostic model for overall survival that can more objectively predict the prognosis of patients simply and objectively.Background: Treatment strategies have changed dramatically in recent years with the development of a variety of agents for metastatic hormone-naïve prostate cancer (mHNPC). There is a need to identify prognostic factors for the appropriate choice of treatment for patients with mHNPC, and we retrospectively examined these factors. Methods: Patients with mHNPC treated at our institution from 2000 to 2019 were included in this study. Overall survival (OS) was estimated retrospectively using the Kaplan–Meier method, and factors associated with OS were identified using univariate and multivariate analyses. A prognostic model was then developed based on the factors identified. Follow-up was terminated on 24 October 2021. Results: The median follow-up duration was 44.2 months, whereas the median OS was 85.2 months, with 88 patients succumbing to their disease. Multivariate analysis identified Gleason pattern (GP) 5 content, bone scan index (BSI) ≥ 1.5, and lactate dehydrogenase (LDH) levels ≥ 300 IU/L as prognostic factors associated with OS. We also developed a prognostic model that classified patients with mHNPC as low risk with no factor, intermediate risk with one factor, and high risk with two or three factors. Conclusions: Three prognostic factors for OS were identified in patients with mHNPC, namely GP5 inclusion, BSI ≥ 1.5, and LDH ≥ 300. Using these three factors, we developed a new prognostic model for OS that can more objectively predict patient prognosis.

Association between Coffee Consumption and Risk of Prostate Cancer in Japanese Men: A Population-Based Cohort Study in Japan.

Although numerous epidemiological studies have examined whether coffee consumption is associated with prostate cancer risk, the results remain controversial. Moreover, there are few studies in Asian populations. Therefore, we investigated the association between coffee consumption and the risk of prostate cancer in a large-scale prospective population-based cohort study in Japan. Study subjects were 48,222 men (40-69 years) who completed a questionnaire that included questions about their coffee consumption in 1990 for Cohort I and 1993 for Cohort II and were followed up until December 31, 2015. Newly diagnosed cases were classified into localized and advanced using information on local staging, the Gleason score, and degree of differentiation. Hazard ratios (HR) and 95% confidential intervals (95% CI) were estimated using Cox regression analysis. A total of 1,617 participants were newly diagnosed with prostate cancer during a mean follow-up period of 18.8 years. Of these, 1,099 and 461 patients had localized and advanced cancer, respectively. There was no association between coffee intake and prostate cancer risk. Comparison between the highest and lowest category of coffee consumption produced HRs of 1.08 (95% CI, 0.90-1.30), 1.08 (95% CI, 0.84-1.38), and 1.00 (95% CI, 0.67-1.47) for risk of total, localized, and advanced cancer, respectively. The same results were obtained even when we limited the analysis to patients with subjective symptoms. Our findings suggest that coffee consumption has no impact on prostate cancer risk in Japanese men. Coffee has no protective effects against prostate cancer among Japanese men.

Dairy products and the risk of developing prostate cancer: A large-scale cohort study (JACC Study) in Japan.

Dairy products have been indicated as a risk factor for prostate cancer. However, only a few epidemiological studies have reported dairy products as being a risk factor for prostate cancer in Japan, reporting contradictory results. We therefore investigated the association between the intake of dairy products and the occurrence of prostate cancer through a large‐scale cohort study. The Japan Collaborative Cohort study analyzed approximately 110,000 residents from various Japanese districts who participated in our questionnaire survey during 1988–1990. The subjects of the present study were 26,464 men (age range: 40–79 years) from 24 districts wherein cancer incidence was reported. Their clinical course was followed up until 2009. Hazard ratios (HRs) were calculated using Cox's proportional hazards model, adjusted for age, survey area, family history of prostate cancer, body mass index, and total energy intake. For diet, we calculated the HRs associated with intermediate and high consumption of dairy products and compared them with those associated with low consumption. There were 412 cases of prostate cancer in the survey population. As dairy products, milk, yogurt, cheese, and butter were evaluated. Among them, milk consumption was associated with a significant risk (HR = 1.37, p = 0.009) and a dose‐dependent response (p for trend = 0.009) adjusted for age and family history of prostate cancer, stratified by area. Milk and yogurt consumption showed a significantly positive risk and a dose–response relationship adjusted for age, family history of prostate cancer, body mass index, and total energy intake, stratified by area. In summary, a high intake of dairy products such as milk increased the risk of developing prostate cancer in Japanese men.

MP33-08 GUT MICROBIOTA PROFILE ASSOCIATED WITH HIGH-GRADE PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology I (MP33)1 Sep 2021MP33-08 GUT MICROBIOTA PROFILE ASSOCIATED WITH HIGH-GRADE PROSTATE CANCER Kazutoshi Fujita, Makoto Matsushita, Daisuke Motooka, Koji Hatano, Shota Fukae, Norihiko Kawamura, Eisuke Tomiyama, Yujiro Hayashi, Eri Banno, Tetsuya Takao, Shingo Takada, Shinichi Yachida, Takafumi Minami, Masahiro Nozawa, Kazuhiro Yoshimura, Hirotsugu Uemura, Shota Nakamura, and Norio Nonomura Kazutoshi FujitaKazutoshi Fujita More articles by this author , Makoto MatsushitaMakoto Matsushita More articles by this author , Daisuke MotookaDaisuke Motooka More articles by this author , Koji HatanoKoji Hatano More articles by this author , Shota FukaeShota Fukae More articles by this author , Norihiko KawamuraNorihiko Kawamura More articles by this author , Eisuke TomiyamaEisuke Tomiyama More articles by this author , Yujiro HayashiYujiro Hayashi More articles by this author , Eri BannoEri Banno More articles by this author , Tetsuya TakaoTetsuya Takao More articles by this author , Shingo TakadaShingo Takada More articles by this author , Shinichi YachidaShinichi Yachida More articles by this author , Takafumi MinamiTakafumi Minami More articles by this author , Masahiro NozawaMasahiro Nozawa More articles by this author , Kazuhiro YoshimuraKazuhiro Yoshimura More articles by this author , Hirotsugu UemuraHirotsugu Uemura More articles by this author , Shota NakamuraShota Nakamura More articles by this author , and Norio NonomuraNorio Nonomura More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002042.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The gut microbiota is involved in a variety of diseases that affect the entire body. Diet and body size influence the gut microbiota and are important risk factors for prostate cancer (PCa). However, the association between the gut microbiota and PCa is not well understood. To clarify this association, we analysed the gut microbiota profiles of men with high-grade PCa. METHODS: We collected rectal swab samples of 189 Japanese men who were suspected of PCa based on screening such as MRI or prostate specific antigen (PSA) tests and underwent prostate biopsies from December 2018 to March 2020 at the Osaka University Hospital, Osaka Police Hospital and Osaka General Medical Center. All hospitals are located in Osaka, Japan. RESULTS: One hundred fifty-two Japanese men undergoing prostate biopsies were included in the study and divided into two cohorts: discovery cohort (114 subjects, 72 with cancer and 42 without cancer) and external test cohort (38 subjects, 24 with cancer and 14 without cancer). The gut microbiota in the discovery cohort was compared between two groups, a high-grade PCa group (men with Gleason score 7 or higher PCa) and a negative+low-grade PCa group (men with negative biopsy or Gleason score 6 PCa) using 16S rRNA gene sequencing. Alpha diversity and beta diversity did not differ significantly between the two groups. Using the linear discriminant analysis (LDA) effect size (LEfSe) method, the relative abundance of Rikenellaceae, Alistipes, and Lachnospira were shown to be significantly increased in patients with high-grade PCa (LDA score>2.5). Phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) showed a significant increase in five metabolic pathways: multiple amino acid metabolisms, phenylalanine, tryptophan, tyrosine, and histidine (LDA score>2.0). In the receiver operating characteristic (ROC) curve analysis, the index calculated from the amount of 18 bacterial genera, including Lachnospira, which were selected by least absolute shrinkage and selection operator (LASSO) regression, detected high-grade PCa in the discovery cohort with higher accuracy than the prostate-specific antigen (PSA) test (area under the curve (AUC)=0.85 vs. 0.74). Validation of the index in the test cohort showed similar results (AUC = 0.81 vs. 0.67). CONCLUSIONS: The results demonstrate an association between a gut microbiota composed of 18 genera and the presence of high-grade PCa in Japanese men. This gut microbiota profile could be a novel useful marker for the detection of high-grade PCa with greater accuracy than the PSA test. Source of Funding: The Japanese Urological Association, Yakult Bio-Science Foundation © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e609-e609 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kazutoshi Fujita More articles by this author Makoto Matsushita More articles by this author Daisuke Motooka More articles by this author Koji Hatano More articles by this author Shota Fukae More articles by this author Norihiko Kawamura More articles by this author Eisuke Tomiyama More articles by this author Yujiro Hayashi More articles by this author Eri Banno More articles by this author Tetsuya Takao More articles by this author Shingo Takada More articles by this author Shinichi Yachida More articles by this author Takafumi Minami More articles by this author Masahiro Nozawa More articles by this author Kazuhiro Yoshimura More articles by this author Hirotsugu Uemura More articles by this author Shota Nakamura More articles by this author Norio Nonomura More articles by this author Expand All Advertisement Loading ...

Polymorphisms in androgen metabolism genes with serum testosterone levels and prognosis in androgen-deprivation therapy

ObjectiveAndrogen metabolism is a key component in therapeutic resistance to androgen deprivation therapy (ADT). This study aimed to reveal the significance of genetic polymorphisms in genes involved in androgen metabolism, including CYP17A1, AKR1C3, and HSD17B, on serum testosterone levels during ADT, as well as the prognosis of men undergoing ADT for metastatic prostate cancer (CaP). Materials and methodsThis study included 104 Japanese patients with metastatic CaP, for whom serum testosterone data during ADT were available for 80 patients. The association of CYP17A1 (rs743572), AKR1C3 (rs12529), HSD17B1 (rs605059), HSD17B3 (rs2066479), and HSD17B4 (rs7737181) with serum testosterone levels during ADT and prognosis (progression-free survival and overall survival) was examined. Enzymatic activity in AKR1C3 H5Q was examined using recombinant protein. ResultsHomozygous wild-type (GG allele; median [interquartile range], 12.0 ng/ml [8.0–19.0 ng/ml]) AKR1C3 rs12529 was associated with higher serum testosterone levels during ADT compared with variant-type (GC/CC alleles; median [interquartile range], 9.0 ng/ml [6.4–10.8 ng/ml]). Consistently, variant-type (GC/CC alleles) AKR1C3 rs12529 showed significantly lower risk of progression (hazard ratio [95% confidence interval], 0.47 [0.24–0.96], P = 0.039) compared with homozygous wild-type (GG allele) on multivariate analysis. Meanwhile, other genetic variations were associated with neither serum testosterone during ADT nor prognosis. Enzyme activity of wild-type AKR1C3 was comparable to the H5Q mutant. ConclusionsTaken together, this study demonstrated that AKR1C3 polymorphism, which was associated with serum testosterone levels during ADT, may be a prognostic factor of the progression to castration-resistant prostate cancer in Japanese men with metastatic CaP.

Testosterone Reduction of≥ 480 ng/dL Predicts Favorable Prognosis of Japanese Men With Advanced Prostate Cancer Treated With Androgen-Deprivation Therapy.

Reductions in testosterone concentration play a significant role in the treatment of prostate cancer. We studied the role of testosterone as a prognostic marker for advanced prostate cancer (stage C or higher) treated with primary androgen-deprivation therapy (ADT). A total of 348 patients were treated using ADT as first-line therapy for prostate cancer at Chiba University Hospital between 1999 and 2016. Of these, 222 patients with advanced prostate cancer (stage C or higher) were enrolled onto this study. The prognostic values of serum testosterone level and other clinical factors were evaluated in association with prostate-specific antigen (PSA), progression-free survival during first-line therapy, and overall survival. Median age was 73 years. PSA at baseline was 86 ng/mL. Gleason scores of≤ 6, 7, 8, and≥ 9 were seen in 2.3%, 19.4%, 21.2%, and 41.9%, respectively. Mean follow-up was 60.5 months. Median testosterone at baseline was 482 ng/dL and nadir testosterone was 13 ng/dL. No variable associated with testosterone predicted progression-free survival. With regard to overall survival, multivariate analysis identified nadir testosterone≤ 20 ng/dL (hazard ratio= 0.44, P= .026) and testosterone reduction≥ 480 ng/dL (hazard ratio= 0.35, P= .030) as independent prognostic factors. With regard to progression-free survival, multivariate analysis identified nadir PSA≤ 0.1 ng/mL (hazard ratio= 3.07, P< .001), presence of lymph node metastasis (hazard ratio= 1.67, P= .017), and time to nadir PSA (hazard ratio= 0.30, P< .001) as independent prognostic factors. Our data suggested both nadir testosterone (< 20 ng/dL; P= .026) and testosterone reduction (≥ 480 ng/dL; P= .030) to be key prognostic factors for primary ADT in advanced prostate cancer in Japanese men.

Clinicopathological importance of anterior prostate cancer in Japanese Men.

Prostate cancer of transition zone origin or anterior location has been recognized as infrequent, smaller in size and indolent, whereas, our previous report showed that transition zone/anterior cancer was frequently experienced in Japanese men. The current study was conducted to show clinicopathological characteristics of transition zone/anterior cancer. A total of 201 radical prostatectomy specimens were categorized as cancer of anterior or posterior prostate where more than two thirds of the tumor existed in the specific area. Clinicopathological characteristics including Gleason score, pathological stage, lymph node metastasis, extraprostatic extension, surgical incision into the prostate (shown as pT2+), and surgical margin status were compared between anterior and posterior cases. Cases were divided as 83, 73, and 45 of anterior, posterior cancer, and no dominance, respectively. Anterior cancers included significant numbers of high grade tumors (13/83 cases: 15.7%), which was less than posterior cancers (28.8%: 21/73). The cases in pT2+ were significantly more frequent in anterior cases than posterior ones (22.9% vs. 4.1%). No seminal vesicle invasion was shown in anterior cases. Thus, although anterior cancers are less aggressive than posterior cancers, a significant numbers of clinically important cancers were located in the anterior portion in Japanese men.

Secondary bladder cancer after anticancer therapy for prostate cancer: reduced comorbidity after androgen-deprivation therapy

Radiotherapy for prostate cancer is associated with an increased incidence of secondary bladder cancer (BC). We investigated the incidence, clinicopathological characteristics, and prognosis of BC after radiotherapy, surgical therapy, and primary androgen-deprivation therapy (ADT) for prostate cancer. This study included 1,334 Japanese patients with prostate cancer treated with radiotherapy (n=631), surgical therapy (n=437), and primary ADT (n=266). During the median follow-up period of 51.2, 44.8, and 45.5 months, secondary BC occurred in 14 (2.2%), 5 (1.1%), and 0 (0%) of patients with prostate cancer treated with radiotherapy, surgical therapy, and primary ADT, respectively. The 10-year BC-free survival rate was 91.3% in the radiotherapy group, 97.4% in the surgical therapy group, and 100% in the primary ADT group. The rates of intravesical recurrence, progression to muscle-invasive BC, and BC-specific death might be higher in secondary BC after radiotherapy compared with after surgical therapy. There was a significant difference in the incidence of secondary BC among different therapeutic modalities for prostate cancer in Japanese men, indicating significantly lower comorbidity rates of secondary BC after primary ADT for prostate cancer compared with radiotherapy.

Latent prostate cancer in Japanese men who die unnatural deaths: A forensic autopsy study.

An accurate natural history of prostate cancer (PC) can be obtained from forensic autopsies of individuals who had performed their normal daily activities immediately before death and had not undergone long-term medical interventions. A retrospective analysis of such individuals was performed to understand the features of latent PC in Japan. The findings of forensic autopsies performed at Dokkyo Medical University from August 2002 to July 2005 on men without severely destroyed or severely decomposed tissues were collected. Two cross sections, at the base and apex of the prostate, were examined histopathologically. Data collected included basic history, cause of death, location of PC, and Gleason score. Of 196 forensically autopsied males aged 0-90 years, 24 (12.7%) had latent PC. When analyzed by age group, PC was most prevalent among individuals in their eighties (33.3%). The prevalence of PC was similar in males who died of disease and of external causes. Most PCs were located at the base of the prostate, but were present on both the anterior and posterior sides. Nine of the 24 autopsied individuals also had other diseases, with three having cancers other than PC. This is the first report of the features of latent PC in Asian men who died of unnatural causes. Forensic autopsies can clarify the natural history of PC and may help fill knowledge gaps regarding latent PC.

Fiber intake and risk of subsequent prostate cancer in Japanese men

Dietary fiber may reduce the risk of prostate cancer, possibly by increasing circulating concentrations of sex hormone-binding globulin and improving insulin sensitivity. However, results from previous epidemiologic studies of fiber intake and prostate cancer are inconsistent, and to our knowledge, no study has comprehensively evaluated the effects of soluble and insoluble fiber on prostate cancer in Asia. The objective was to examine the association between fiber intake and prostate cancer in Japanese men. We conducted a population-based prospective study in 43,435 Japanese men aged 45-74 y. Participants responded to a validated questionnaire, which included 138 food items. Follow-up was from 1995 through 2009. HRs and 95% CIs of incidence were calculated according to quartiles of fiber intake. During the 11.6-y follow-up, of the 825 men newly diagnosed with prostate cancer, 213 had advanced-stage cancer, 582 had organ-localized disease, and 30 had an undetermined stage of disease. Among them, 217 cases were detected by subjective symptoms. Total fiber was not associated with total or advanced prostate cancer, with respective multivariable HRs for the highest and lowest quartiles of 1.00 (95% CI: 0.77, 1.29; P-trend = 0.97) and 0.67 (95% CI: 0.42, 1.07; P-trend = 0.30). Total fiber and insoluble fiber intake were associated with a decreased risk of advanced cancers detected by subjective symptoms, with multivariate HRs (95% CIs) across increasing quartiles of 1.00, 0.58, 0.62, and 0.44 (0.21, 0.92; P-trend = 0.05) for total fiber and 1.00, 0.60, 0.52, and 0.46 (0.22, 0.93; P-trend = 0.04) for insoluble fiber. Soluble fiber intake showed no association with prostate cancer. Dietary fiber is inversely associated with advanced prostate cancer detected by subjective symptoms even among populations with relatively low intake, such as Japanese. These results suggest that a very low intake of dietary fiber is associated with an increased risk of prostate cancer.

Controversies associated with the evaluation of elderly men with localized prostate cancer when considering radical prostatectomy.

The incidence of prostate cancer in Japan is increasing due to both the spread of screening and the rapid aging of the population. Most of this increase is expected to be attributable to the increase in the elderly male population. The management of various types of cancers in elderly patients is of growing interest, but several problems are encountered when evaluating elderly patients with localized prostate cancer, especially when radical prostatectomy (RP) is under consideration. First, life expectancy, health status, lifestyle, and available treatment modalities differ between regions, countries, and individuals, which potentially affects the choice of treatment options by both physicians and patients. Second, life expectancy is key when considering indications for RP. Many tools are available for predicting life expectancy, but their utilization varies greatly among physicians. Third, the malignant potential of latent or incidentally detected prostate cancer in Japanese men might be higher than those in other countries, and elderly men with prostate cancer are likely to have high-risk or locally advanced tumors, which may in turn support the more frequent use of radical treatments in elderly men. Fourth, patients treated with RP are likely to have fewer and less severe comorbidities than those treated with other treatments, which would complicate the comparison of outcomes. Fifth, the balance between survival benefits and adverse effects is an important influence on indications for RP. If robot-assisted laparoscopic RP can reduce the risk of adverse effects, indications for RP could be altered. Sixth, although several general health status screening tools such as the Geriatric 8 are available, no screening tools specialized for localized or Japanese prostate cancer patients exist. In conclusion, further study is needed to clarify the management of elderly Japanese patients with localized prostate cancer, because prostate cancer often requires different considerations to other types of cancer.

TMPRSS2 Met160Val polymorphism: significant association with sporadic prostate cancer, but not with latent prostate cancer in Japanese men.

To investigate the association between the TMPRSS2 Met160Val polymorphism and the risk of prostate cancer in Japanese men. Genomic DNA samples from 518 Japanese sporadic prostate cancer patients, 433 controls and 154 Japanese men who were diagnosed as having latent prostate cancer based on autopsy results were genotyped for the TMPRSS2 Met160Val polymorphism using a TaqMan assay. Logistic regression analyses were carried out to estimate the odds ratios and 95% confidence intervals. The relationship between the presence of the polymorphism, and clinicopathology and survival was also examined. The T allele frequency of the control group was 0.372, of the sporadic prostate cancer group was 0.435 and of the latent prostate cancer group was 0.370. The CT and TT genotypes were significantly associated with risk for sporadic prostate cancer; age-adjusted odds ratios (95% confidence intervals) were 1.418 (1.027-1.960) for CT, 1.907 (1.224-2.990) for TT and 1.524 (1.123-2.072) for CT/TT genotypes. There was no significant association observed between the TMPRSS2 Met160Val polymorphism and the risk for latent prostate cancer. The TMPRSS2 Met160Val polymorphism was not significantly associated with any clinicopathological features or prognosis. The TMPRSS2 Met160Val polymorphism is a genetic risk factor for sporadic prostate cancer in a Japanese population.

Alcohol and smoking and subsequent risk of prostate cancer in Japanese men: The Japan Public Health Center‐based prospective study

Although alcohol and smoking have not been established as risk factors for prostate cancer, they are important risk factors for other human cancers and potentially major avoidable factors. Alcohol drinkers and smokers might be less likely to get screening, which might lead to attenuation of the positive association. Here, we investigated the association of alcohol drinking and smoking and prostate cancer according to stage, as well as prostate cancer detected by subjective symptoms, in a large prospective study among Japanese men. The Japan Public Health Center-based prospective study (JPHC study) was established in 1990 for Cohort I and in 1993 for Cohort II. Subjects were 48,218 men aged 40-69 years who completed a questionnaire, which included their alcohol and smoking habits at baseline, and who were followed until the end of 2010. During 16 years of follow-up, 913 men were newly diagnosed with prostate cancer; of whom 248 had advanced cases, 635 were organ-localized and 30 were of an undetermined stage. Alcohol consumption was dose-dependently associated with advanced prostate cancer [nondrinkers: reference, 0-150 g/week: hazard ratio (HR) = 1.23, 95% confidence interval (CI) = 0.83-1.82; 150-300 g/week: HR = 1.51, 95% CI = 1.04-2.19; ≥ 300 g/week: HR = 1.41, 95% CI = 0.97-2.05, p for trend = 0.02]. The positive association was not substantially changed among cancers detected by subjective symptoms. Smoking was inversely associated with prostate cancer among total subjects, but tended to increase the risk of advanced prostate cancer detected by subjective symptoms. In conclusion, abstinence from alcohol and prohibition of smoking might be important factors in the prevention of advanced prostate cancer.

Impact of body mass index on clinicopathological outcome and biochemical recurrence after radical prostatectomy

Accumulating evidence suggests that obesity is associated with tumor progression in prostate cancer (PCa) patients after radical prostatectomy (RP). We conducted a retrospective multicenter study to determine the effect of body mass index (BMI) on the clinicopathological characteristics and biochemical recurrence of PCa in Japanese men who underwent RP. The medical records of 1257 men with PCa treated by RP without neoadjuvant therapy at four medical institutes between 2001 and 2009 were retrospectively reviewed. Patients were categorized into four groups using the World Health Organization (WHO) BMI classification and BMI quartiles. Associations of the various BMI categories with clinicopathological characteristics and biochemical recurrences were statistically evaluated. Biochemical recurrence was defined as a PSA level of >0.2 ng ml(-1). Of the 1257 patients, 230 (18.3%) experienced biochemical recurrence during the median follow-up period of 49 months. The median BMI was 23.8 kg m(-2), and 1.4% patients were underweight, 65.4% were of normal weight, 30.9% were overweight and 2.4% were obese (WHO classification). Preoperative PSA levels and PSA density (PSAD) tended to decrease as BMI increased. Pathological characteristics did not differ significantly among BMI categories. As per the WHO classification and quartile categories, biochemical recurrence rate was comparable among the BMI groups. After adjusting for other pre- and postoperative covariables, multivariate Cox proportional hazards analysis revealed that a high BMI did not have an independent impact on biochemical recurrence-free survival. Underweight Japanese PCa patients treated by RP had higher preoperative PSA levels and PSAD. High BMI was not associated with adverse pathological findings or increased biochemical recurrence rate in Japanese PCa patients treated with RP. Racial differences may exist in the relationship between obesity and outcomes of RP in PCa patients.

Clinical utility of the prostate cancer gene 3 (PCA3) urine assay in Japanese men undergoing prostate biopsy

WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: It is known that a prostate cancer gene 3 (PCA3) urine assay is superior to serum PSA level or PSA-related indices for predicting a positive biopsy result in European and US men. This is the first report on PCA3 in a large cohort of Japanese men. The diagnostic value of the PCA3 score in Japanese men was similar to those reported in European and US men. The study concludes that a combination of PSA density and PCA3 score may be useful for selecting patients who could avoid an unnecessary biopsy. To examine the diagnostic performance of the prostate cancer gene 3 (PCA3) score for prostate cancer in Japanese men undergoing prostate biopsy. This Japanese, multicentre study included 647 Asian men who underwent extended prostate biopsy with elevated prostate-specific antigen (PSA) and/or abnormal digital rectal examination (DRE). Urine samples were collected after DRE. The PCA3 score was determined using a PROGENSA PCA3 assay and correlated with biopsy outcome. Its diagnostic accuracy was compared with that of serum PSA level, prostate volume (PV), PSA density (PSAD), and free/total PSA ratio (f/t PSA). A total of 633 urine samples were successfully analysed (the informative rate was 98%). Median PSA was 7.6 ng/mL. Biopsy revealed cancer in 264 men (41.7%). The PCA3 score for men with prostate cancer was significantly higher than that for men with negative biopsies (median PCA3 score: 49 vs. 18; P < 0.001). The rate of positive biopsy was 16.0% in men with a PCA3 score of <20 and 60.6% in those with a PCA3 score of ≥50. Using a PCA3 score threshold of 35, sensitivity and specificity were 66.5 and 71.6%, respectively. The area under the curve of the PCA3 score was significantly higher than that of the f/t PSA in men with PSA 4-10 ng/mL (0.742 vs 0.647; P < 0.05). In men with PSAD < 0.15 and PCA3 < 20, only three (4.2%) out of 72 men had prostate cancer. The PCA3 score was significantly superior to f/t PSA in predicting a positive biopsy result for prostate cancer in Japanese men with PSA 4-10 ng/mL. The combination of PSAD and PCA3 score may be useful for selecting patients who could avoid an unnecessary biopsy.

Significance of docetaxel-based chemotherapy as treatment for metastatic castration-resistant prostate cancer in Japanese men over 75 years old

The objective of this study was to evaluate the significance of docetaxel-based chemotherapy in elderly Japanese men with metastatic castration-resistant prostate cancer (CRPC). This study included a total of 159 consecutive patients aged≥75 years with mCRPC who were treated with docetaxel-based chemotherapy. The efficacy and tolerability of this therapy were retrospectively analyzed. In these 159 patients, the median age and prostate-specific antigen (PSA) level before docetaxel-based chemotherapy were 78 years and 44.0 ng/ml, respectively. Of these patients, 42 (26.4%) and 117 (73.6%) received docetaxel as a weekly (30 mg/m2) and 3-weekly (70 mg/m2) regimen, respectively, and estramustine was administered combining with docetaxel in 77 (48.4%). Following docetaxel-based chemotherapy, PSA declined in 118 patients (74.3%), including 87 (54.6%) achieving a PSA decline≥50%, and the median progression-free survival and overall survival (OS) were 2.9 and 23.2 months, respectively. Of several factors examined, univariate analysis identified performance status (PS), significant clinical pain, bone metastasis, schedule of treatment, treatment cycle, and PSA response as significant predictors of OS, of which only PS, treatment cycle, and PSA response appeared to be independently associated with OS on multivariate analysis. The major grade 3-4 toxicities were myelosuppression, including neutropenia, anemia, and thrombocytopenia in 78 (49.1%), 22 (13.8%), and 14 (8.8%), respectively. These findings suggest that docetaxel-based chemotherapy is clinically feasible in Japanese men aged≥75 years with mCRPC considering the cancer control as well as safety associated with this therapy.

Genetic polymorphisms of CYP17A1 in steroidogenesis pathway are associated with risk of progression to castration-resistant prostate cancer in Japanese men receiving androgen deprivation therapy

Hormone ablation therapy is the standard therapy for prostate cancer; however, there are large individual differences in the duration of response to the therapy. We investigated, in this retrospective multicenter study, the association between genetic polymorphic variations in steroidogenesis-related genes and the risk of progression to castration-resistant prostate cancer (CRPC) in Japanese patients after androgen deprivation therapy. Two hundred and fourteen Japanese patients with prostate cancer who were receiving androgen deprivation therapy were enrolled in this study. We investigated 22 single-nucleotide polymorphisms (SNPs) from 8 genes related to steroidogenesis. The SNPs were assayed by polymerase chain reaction (PCR)-based methods. The different genotypes in this cohort were analyzed according to a case-control status of progression to CRPC at the median duration of hormonal therapy. A logistic regression method with adjustments for patients' characteristics was applied for the analysis.After applying the logistic regression method, we performed Cox regression analysis, following Kaplan-Meier and log-rank analyses. In the logistic regression analysis four genetic polymorphisms, rs743572, rs6162, rs6163, and rs1004467, in the CYP17A1 gene were significantly associated with a risk of progression to CRPC (p < 0.05). Cox regression analysis for these SNPs showed an association of risk of progression to CRPC with the rs743572 genotype (p = 0.02, odds ratio [OR] 0.43, 95 % confidence interval [CI] 0.22-0.85). The genetic backgrounds for CYP17A1 genes could influence the progression of prostate cancer to CRPC after androgen deprivation therapy.

Common variants at 11q12, 10q26 and 3p11.2 are associated with prostate cancer susceptibility in Japanese

We have previously reported multiple loci associated with prostate cancer susceptibility in a Japanese population using a genome-wide association study (GWAS). To identify additional prostate cancer susceptibility loci, we genotyped nine SNPs that were nominally associated with prostate cancer (P < 1 × 10(-4)) in our previous GWAS in three independent studies of prostate cancer in Japanese men (2,557 individuals with prostate cancer (cases) and 3,003 controls). In a meta-analysis of our previous GWAS and the replication studies, which included a total of 7,141 prostate cancer cases and 11,804 controls from a single ancestry group, three new loci reached genome-wide significance on chromosomes 11q12 (rs1938781; P = 1.10 × 10(-10); FAM111A-FAM111B), 10q26 (rs2252004; P = 1.98 × 10(-8)) and 3p11.2 (rs2055109; P = 3.94 × 10(-8)). We also found suggestive evidence of association at a previously reported prostate cancer susceptibility locus at 2p11 (rs2028898; P = 1.08 × 10(-7)). The identification of three new susceptibility loci should provide additional insight into the pathogenesis of prostate cancer and emphasizes the importance of conducting GWAS in diverse populations.

GPRC6A regulates prostate cancer progression

GPRC6A is a nutrient sensing GPCR that is activated in vitro by a variety of ligands, including amino acids, calcium, zinc, osteocalcin (OC), and testosterone. The association between nutritional factors and risk of prostate cancer, the finding of increased expression of OC in prostate cancer cells, and the association between GPRC6A and risk of prostate cancer in Japanese men implicates a role of GPRC6A in prostate cancer. We examined if GPRC6A is expressed in human prostate cancer cell lines and used siRNA-mediated knockdown GPRC6A expression in prostate cancer cells to explore the function of GPRC6A in vitro. To assess the role of GPRC6A in prostate cancer progression in vivo, we intercrossed Gprc6a(-/-) mice onto the TRAMP mouse prostate cancer model. GPRC6A transcripts were markedly increased in prostate cancer cell lines 22Rv1, PC-3, and LNCaP, compared to the normal prostate RWPE-1 cell line. In addition, a panel of GPRC6A ligands, including calcium, OC, and arginine, exhibited in prostate cancer cell lines a dose-dependent stimulation of ERK activity, cell proliferation, chemotaxis, and prostate specific antigen and Runx2 gene expression. These responses were inhibited by siRNA-mediated knockdown of GPRC6A. Finally, transfer of Gprc6a deficiency onto a TRAMP mouse model of prostate cancer significantly retarded prostate cancer progression and improved survival of compound Gprc6a(-/-) /TRAMP mice. GPRC6A is a novel molecular target for regulating prostate growth and cancer progression. Increments in GPRC6A may augment the ability of prostate cancer cells to proliferate in response to dietary and bone derived ligands.