Association of SNP rs1447295 and microsatellite marker DG8S737 with familial prostate cancer and high grade disease.

PURPOSE: Several prior studies show a relationship between genetic markers at chromosome 8q24 and an increased prostate cancer risk. We confirmed the association of 8q24 markers with prostate cancer in the Japanese population and the association of these genetic variants with clinical characteristics. MATERIALS AND METHODS: Included in this study were 134 patients with familial prostate cancer, 158 with sporadic prostate cancer and 119 controls. All were Japanese. We genotyped the 2, 8q24 markers SNP rs1447295 and microsatellite marker DG8S737 using real-time polymerase chain reaction and polymerase chain reaction based assay with fluorescence labeled primers. RESULTS: There was a significant positive association between the DG8S737 -12 allele and familial prostate cancer risk (OR 1.86, 95% CI 1.11-3.00, p = 0.02) and a significant association of risk with the rs1447295 A allele (OR 2.36, 95% CI 1.41-3.94, p = 0.002). Significant associations were noted for each marker in men with a high Gleason score. CONCLUSIONS: Two alleles at 8q24 are genetic risk factors for familial prostate cancer and high grade disease.

[Prognostic factors for estrogen therapy of relapsed prostate cancer after maximal androgen blockade (MAB)].

PURPOSE: Advanced prostate cancer responds well to endocrine therapy initially, but soon becomes refractory and has a poor prognosis. We analyzed the prognostic factors of prostate cancer responding well initially to maximal androgen blockade (MAB) but later showing PSA relapse and treated with estrogen. MATERIALS AND METHODS: In prostate cancer patients newly diagnosed from January 1992 to December 2008 at our institution, there were 85 patients in that the PSA level dropped below 10 ng/ml by MAB, but showed PSA relapse thereafter and treated with estrogen. We investigated the relationship between age at diagnosis, clinical stage, pathological differentiation, initial PSA, the value of PSA nadir, duration between diagnosis and initiation of estrogen therapy, duration between PSA failure and initiation of estrogen therapy, the value of PSA at estrogen therapy, PSA doubling time (PSA-DT) at estrogen therapy, PSA response three months after initiation of estrogen therapy, use of diethylstilbestrol diphosphate (DES-P) at the initial stage of therapy, local radiotherapy to prostate, type of estrogen and prognosis after estrogen therapy. RESULTS: In Kaplan-Meier method, factors which showed poorer prognosis were stage B and D, poorly differentiated, PSA 11.9 ng/ml or higher at estrogen therapy, PSA-DT shorter than 2.3 months before estrogen therapy and PSA response without CR three months after initiation of estrogen therapy. In multivariate analysis, the factor that most significantly affected prognosis after estrogen therapy was PSA response three months after initiation of estrogen therapy (hazard ratio: 12.61), followed by PSA-DT at estrogen therapy (hazard ratio: 2.59). CONCLUSION: We investigated the prognostic factors refractory to MAB and treated with estrogen. These results are useful in planning the therapy, and in explaining the status or future prospective of the disease to families and patients.

Further evidence for null association of phenol sulfotransferase SULT1A1 polymorphism with prostate cancer risk: a case-control study of familial prostate cancer in a Japanese population.

Sulfation is a key pathway in xenobiotic metabolism and chemical defense, and phenol sulfotransferase SULT1A1 plays a central role in this reaction. Genetic polymorphism of the SULT1A1 gene, SULT1A1, was reported to be associated with risks of several cancers; however, one study showed no significant relation between SULT1A1 genotype with prostate cancer risk. The present study was conducted to confirm the association of a G638A polymorphism, Arg213His, in SULT1A1 with familial prostate cancer risk in a Japanese population. A case-control study consisting of 126 cases and 119 controls was performed. In controls, GG, GA, and AA genotypes were observed in 85 (71.4%), 32 (26.9%), and 2 (1.7%), respectively; whereas, GG, GA, and AA genotypes were observed in 94 (74.6%), 32 (25.4%), and 0 cases, respectively. No significant differences were found in genotypic frequencies among cases and controls. Furthermore, stratification of cases according to clinical stages (localized or metastatic), pathological grades (Gleason score <7, or >7), age at diagnosis (<70 years or >70) and the number of affected relatives (2 or >2) did not show any significant differences among categories. These findings suggested that genetic polymorphism of SULT1A1 might not be involved in genetic susceptibility to prostate cancer.

[Clinical study on poor PSA response to initial endocrine therapy with MAB or estrogenic drugs for treatment of prostate cancer].

PURPOSE: The prostate specific antigen (PSA) level usually is lowered in response to initial endocrine therapy even in advanced cases of prostate cancer, but in some cases, it is not. We examined the cases in which the PSA level was not sufficiently lowered by initial endocrine therapy with maximal androgen blockade (MAB) or estrogenic drugs. MATERIALS AND METHODS: The subjects were 20 patients with prostate cancer diagnosed between January 1992 and December 2005 whose PSA level was not lowered below 10 ng/ml after initial endocrine therapy with MAB or estrogenic drugs. We investigated the frequency of cases, pretreatment PSA levels, PSA nadir levels after initial endocrine therapy and throughout the therapy, PSA response to second line therapy, and the prognosis. RESULTS: The PSA level was not lowered below 10 ng/ml after initial endocrine therapy with MAB or estrogenic drugs in 4.9% of the cases. Cancer-specific survival rates in all cases were extremely poor, 75.0% at 1 year and 14.7% at 3 years. Prognosis tended to be worse in patients with a higher PSA nadir level throughout the therapy and on whom second therapy was not effective, although the difference was not statistically significant. CONCLUSION: The patients whose PSA levels were not lowered sufficiently by MAB or estrogenic drugs had an extremely poor prognosis. These results are useful in planning the therapy, and in explaining the status or future prospective of the disease to patients and their families.

[A case of combination with proliferative cystitis and pelvic lipomatosis causing bilateral hydronephrosis].

A 70-year-old man consulted our hospital complaining of gross hematuria and bilateral hydronephrosis. Cystoscopic findings suggested non-papillary sessile tumor at the bladder neck. CT findings revealed bilateral hydronephrosis caused by the stricture of lower ureters. Tumorous structure existed between bladder and prostate. Abundant fatty tissue was observed around bladder and rectum, the shape of the bladder was distorted to inverted tear-drop and the bladder was transferred anteriorly, showing findings of pelvic lipomatosis. Urethrocystography revealed elongation of prostatic urethra and anterior displacement of the bladder. Transurethral tumor resection was performed under spinal anesthesia. Pathological diagnosis was proliferative cystitis and no malignant cells were observed. Transperineal tumor biopsy also revealed no malignant cells. The patient was followed under administration of "Saireitou" (chinese medicine) and cetirizine hydrochloride, followed by antibiotics and anti-inflammatory enzyme preparations.

[Prognostic factors of superficial bladder cancer recurring after initial transurethral resection].

About 70% of bladder cancers are superficial at the initial state. If diagnosed at an early stage, the tumor may be resected completely and easily. However, recurrence is seen in many cases. Prognostic factors of recurrence were investigated in 55 cases of bladder cancer newly diagnosed (excluding carcinoma in situ) between 1995 and 2003, and in which complete resection by transurethral resection (TUR) was possible at first recurrence after initial TUR. One- and three-year postoperative non-recurrence rates were 51.9% and 36.3%, respectively. None of the factors studied, i.e., stage, grade, tumor multiplicity (at initial and at first recurrence), change of stage and grade at first recurrence compared with that of initial TUR, duration to recurrence and adjuvant therapy after TUR, were found to influence the prognosis after recurrence. Similar results were obtained for third TUR. Recurred pTa, grade 1 or solitary cancer at initial or at recurrence had the same prognosis as pT1, grade 2-3 or multiple cancers, and careful follow-up is needed.

[Prognostic factors for PSA relapse of prostate cancer after endocrine therapy].

PURPOSE: Advanced prostate cancer responds well to endocrine therapy initially, but soon becomes refractory and has a poor prognosis. We analyzed the prognostic factors of prostate cancer responding well initially to endocrine therapy with lowering of serum prostate specific antigen (PSA) level but later showing PSA relapse. MATERIALS AND METHODS: In prostate cancer patients newly diagnosed from January 1992 to December 2004 at our institution, there were 93 patients in that the PSA level of 10 ng/ml or more before therapy initially dropped below 10 ng/ml by endocrine therapy, but showed PSA relapse thereafter. We investigated the relationship between clinical stage, pathological differentiation, initial PSA, duration between initiation of therapy and PSA nadir, the value of PSA nadir, duration between initiation of therapy and PSA relapse, PSA doubling time (PSA-DT) at relapse, PSA response three months after initiation of second line therapy and prognosis after PSA relapse. RESULTS: In Kaplan-Meier method, between all or some categories investigated showed significant difference in prognosis after PSA relapse. In multivariate analysis, the factors that significantly affected prognosis after PSA relapse were clinical stage, pathological differentiation, PSA nadir value, duration between initiation of therapy and PSA relapse and PSA response three months after initiation of second line therapy. CONCLUSION: We investigated the prognostic factors refractory to endocrine therapy. These results are useful in planning the therapy, and in explaining the status or future prospective of the disease to patients and families.

[A case of prostate cancer diagnosed pathologically by bone metastatic site biopsy].

A 61-year-old man consulted our hospital complaining of high prostate specific antigen (PSA) value and difficulty to urinate. Prostate biopsy had been performed at another hospital, but did not reveal cancer. PSA was 18.5 ng/ml. Transrectal ultrasound-guided prostate biopsy was performed, but cancer was not detected. Later, PSA rose rapidly, and findings suggesting bone metastasis at right pubic bone and left sacro-ilial joint were found on computed tomography (CT), bone scintigraphy and magnetic resonance imaging (MRI). A repeat prostate biopsy was performed, but cancer was not detected from the prostate. On right pubic bone biopsy, poorly to moderately differentiated adenocarcinoma was detected. PSA immunohistochemical staining was positive, and the diagnosis was bone metastasis from prostate cancer. After endocrine therapy was started, PSA declined and bone metastasis disappeared on bone scintigraphy.

Association of the genetic polymorphism in cytochrome P450 (CYP) 1A1 with risk of familial prostate cancer in a Japanese population: a case-control study.

Association between genetic polymorphisms of CYP1A1 and familial prostate cancer risk was examined by a case-control study of 185 individuals. Although the individual analysis of m1 or m2 genotype of CYP1A1 showed no significant association with prostate cancer risk, the presence of any mutated alleles significantly increased prostate cancer risk in comparison with wild-type genotypes by combination analysis (odds ratio [OR]=2.38; 95% confidence interval [CI]=1.72-3.29; P=0.0069). Furthermore, metastatic cancer had a significant association with mutated alleles of m1 and m2. These finding suggested that CYP1A1 polymorphisms has an association with prostate cancer risk, especially with progression of prostate cancer.

Cyclin D1 gene polymorphism and familial prostate cancer: the AA genotype of A870G polymorphism is associated with prostate cancer risk in men aged 70 years or older and metastatic stage.

BACKGROUND: Cyclin D1 is a key protein involved in cell cycle regulation. A common A870G single nucleotide polymorphism in exon 4 of the cyclin D1 gene (CCND1) has an effect on the transcription of two different cyclin D1 mRNAs. Association of the genetic polymorphism of A870G of CCND1 with several cancer risks has been reported. MATERIALS AND METHODS: We performed a case-control study consisting of 99 familial prostate cancer cases and 115 noncancer controls to examine the genotypic frequency of the CCND1 polymorphism. RESULTS: We did not observe a significant association of the genotypic frequency of CCND1 with overall cases and controls. However, the AA genotype of CCND1 showed a tendency to increase prostate cancer risk in subjects aged 70 years or older (odds ratio [OR] = 2.14, 95% confidence interval [CI] = 0.86-5.27, p = 0.096). Stratification of cases according to clinical stages showed that the AA genotype was significantly frequently observed in metastatic cancer in comparison with GG + AG genotypes (OR = 3.03, 95% CI = 1.11-8.23, p = 0.026). CONCLUSION: The present study suggested that the genetic polymorphism might be associated with familial prostate cancer risk in a Japanese population.

Association of the genetic polymorphism of the CYP19 intron 4[TTTA]n repeat with familial prostate cancer risk in a Japanese population.

BACKGROUND: Estrogen is crucial for development of benign prostate hyperplasia and prostate cancer. Aromatase (CYP19) is a key enzyme for estrogen synthesis in males. The genetic polymorphism of the CYP19 intron 4 [TTTA]n tetranucleotide has been studied in relation to breast cancer susceptibility. MATERIALS AND METHODS: We examined the association of the tetranucleotide repeat polymorphism of the CYP19 gene with familial prostate cancer risk in a Japanese population by performing a case-control study consisting of 99 familial prostate cancer cases and 116 normal controls. RESULTS: [TTTA] repeats ranged from 7 to 13 and were designated as A1 to A7 according to the repeat number. We did not observe any A3 allele among cases and controls, nor A7 among cases. Short repeat alleles, A1 and A2, had a tendency to be frequently observed in cases (odds ratio [OR] = 1.43, 95% confidence interval [CI] = 0.96-2.14, p = 0.080). Analysis of polymorphic genotypes showed that short genotypes, i.e., A1A1, A1A2 and A2A2, significantly increased prostate cancer risk in comparison with other longer genotypes (OR = 1.80, 95% CI = 1.04-3.11, p = 0.035). Stratification of cases according to the pathological grade or the clinical stage showed no significant differences among categories. CONCLUSIONS: In the present study, we found that short polymorphic genotypes of [TTTA]n repeats of the CYP19 gene were associated with familial prostate cancer risk.

Association of genetic polymorphisms of glutathione-S-transferase genes (GSTM1, GSTT1 and GSTP1) with familial prostate cancer risk in a Japanese population.

BACKGROUND: Glutathione-S-transferases (GSTs) are active in the detoxification of a wide variety of toxins and carcinogens. The genetic polymorphisms of GSTM1, GSTT1 and GSTP1 genes have been studied to estimate the relative risk of various cancers. In the current study, we examined the association of the GST gene polymorphisms with familial prostate cancer in a Japanese population by performing a case-control study consisting of 81 familial prostate cancer cases and 105 normal controls. MATERIALS AND METHODS: No significant association of the GSTM1 and GSTT1 gene polymorphisms with familial prostate cancer risk was found; however, the Val/Val genotype of the GSTP1 gene significantly increased risk (OR = 9.31, 95% CI = 0.47-184, p = 0.030). The combination analysis of genotypes of the three genes showed that presence of two high-risk genotypes, i.e., null genotype of the GSTM1 or GSTT1 gene, or any Val genotypes of the GSP1 gene, significantly increased the risk of prostate cancer (OR = 2.67, 95% CI = 1.08-6.59, p = 0.03). Stratification of cases according to the pathological grade or the clinical stage showed no significant differences among categories. CONCLUSION: In the present study, we found that genotypes of GSTs, especially the Val-allele of the GSTP1 gene and the combination of three genotypes, were associated with familial prostate cancer risk.

Association of HPC2/ELAC2 polymorphism with prostate cancer risk in a Japanese population.

BACKGROUND: To investigate the relationship between two common variants (Ser217 and Ala541) of the HPC2/ELAC2 gene and prostate cancer risk in a Japanese population, we performed a case-control study. MATERIALS AND METHODS: Cases and controls consisted of 81 prostate cancer patients with a family history and 106 controls. Ser217 and Ala541 polymorphisms were analyzed by the restriction fragment length polymorphism method. RESULTS: In controls, 94.5% and 100.0% had wild-type Ser217Ser and Ala541Ala genotypes, respectively. 5.7% of the controls had the Leu217 genotype. No Thr541 genotype was observed in the controls. 92.6% and 97.5% of the cases had the Ser217Ser and Ala541Ala genotypes. No significant differences were observed in the genotypic frequencies between controls and cases. We stratified prostate cancer cases according to the pathological grade (low- or high-grade) or the clinical stage (localized or metastatic). There was no statistical difference between the genotypic frequencies between the groups. CONCLUSION: The present study suggested that the common variants in the HPC2/ELAC2 gene play a limited role in the risk of prostate cancer in the Japanese population.

[Chronological changes of incidence rates, clinical stages and pathological differentiation of prostate cancer in Gunma Prefecture, Japan].

Prostate cancer is the most common urogenital cancer, and is increasing rapidly. We performed an epidemiological study on prostate cancer in Gunma Prefecture, Japan. Registration of prostate cancer patients diagnosed at clinics and hospitals in and around Gunma Prefecture was started at Gunma University in 1985. The epidemiological characteristics of prostate cancer patients in Gunma Prefecture were analyzed by these data. The incidence and crude incidence rates have increased five-fold, from 114 and 12.0 in 1985 to 539 and 53.9 in 2000, respectively. The age-adjusted incidence rate (adjusted to the world population) was increased three-fold, from 8.3 in 1985 to 24.2 in 2000. The age-specific incidence rate showed an increase with age. The cancers in clinical stages A and D decreased, while those in stages B and C increased. No change in distribution was observed in pathological differentiation. Prostate cancer has increased rapidly during these 16 years in Gunma Prefecture. It is important to perform PSA testing aggressively in males age 50 or older, and detect prostate cancer in an early stage.

[Chronological and regional differences of testicular cancer--epidemiological analysis of incidence in gunma prefecture and estimated data of national survey, and of death in Japan].

PURPOSE: The incidence of testicular cancer is rare. However, it is a significant cancer in that it develops not only in old age but also in children and younger age. We investigated the epidemiological characteristics of testicular cancer in Japan, in order to elucidate its features and problems. PATIENTS AND METHODS: We surveyed hospitals and clinics in and around Gunma prefecture that treated patients with urologic diseases and reviewed the pathology records from 1985 to 1994, and calculated the annual age-adjusted incidence rates of testicular cancer. Incidence rates in Japan were taken from the estimates made by 'The Research Group for Population-based Cancer Registration in Japan'. The annual number of deaths, annual age-adjusted death rates from 1947 and 1998, the age-specific death rates and decrease rate of them, and the prefectural standardized mortality ratio (SMR) from 1973 and 1998 was calculated from the data reported by Ohno et al. and statistical tables kept in 'Statistics and Information Department, Minister's Secretariat, Ministry of Health and Welfare'. RESULTS: In Gunma Prefecture, the annual age-adjusted incidence rates tended to increase. In estimated data of national survey, it slightly increased from 1975-79 to 1980-84, and remained stable thereafter. The annual number of deaths and age-adjusted death rates tended to decrease from around 1980. The peak of age-specific death rates was seen in infants, age 20 to 40 and old age. The decrease in the age-specific death rate was prominent for age under 20 and old age, but not significant for age 25 to 34. Prefectures in which SMR was high (> or = 120) were distributed all over Japan, but prefectures in which SMR was low (< or = 80) were concentrated in western Japan. CONCLUSIONS: The annual number of deaths and age-adjusted death rates began to decrease from around 1980, which coincided with the time the clinical trial of cis-platinum began. More than 100 deaths of testicular cancer are reported even now, early diagnosis, early treatment, and improvement of treatment strategy to far-advanced cases are necessary.

[PSA-related parameters in prostate cancer relapsed after endocrine therapy].

PURPOSE: Prostate cancer is generally controlled by endocrine therapy even in an advanced state, but relapse may occur in many cases. Generally, the prognosis of a relapsed case is poor, but the prognosis differs case by case. We experienced 74 cases of prostate cancer relapsed after effective endocrine therapy, and investigated the relationship between the PSA-related parameters, clinical stage and prognosis. PATIENTS AND METHODS: We investigated 74 prostate cancer patients whose PSA declined 10 ng/ml or lower by the treatment consisting of endocrine therapy, but relapsed later. Pre-treatment PSA, the value of PSA nadir, the period from the start of treatment to PSA nadir, the period from the start of treatment to relapse, PSA doubling time (PSA-DT) at relapse and PSA response to the second line therapy at relapse were calculated, and compared with the clinical stage and prognosis. The relationship between each PSA parameter and clinical stage was tested using the Kruskal-Wallis test and chi 2 test. Cancer-specific survival after relapse in stage D patients was calculated by the Kaplan-Meier method and differences in prognosis were tested using the Logrank test. RESULTS: Pre-treatment PSA was significantly (p < 0.01) high, while the period from the start of treatment to relapse (p < 0.05) and PSA-DT at relapse (p < 0.01) was significantly short as the stage progressed. According to PSA response to the second line therapy at relapse, the rate of CR + PR was significantly (p < 0.05) high in clinical stage B + C group compared to clinical stage D group. The prognosis after relapse was significantly poorer in patients with relapse within 10 months after start of treatment than in those with relapse later, and in patients whose PSA-DT at relapse was shorter than 2 months than in those with a longer PSA-DT. CONCLUSIONS: The period from the start of treatment to relapse, and PSA-DT at relapse were useful PSA-related parameters for predicting prognosis after relapse, and for determining the strategy of cancer therapy after relapse. Using these data, the physician can inform the family and the patient of the prognosis more accurately, so that they can adjust future plans.