[show abstract][hide abstract] ABSTRACT: To determine the influence of maximal androgen blockade (MAB) and non-MAB hormonal therapy with an luteinizing hormone releasing hormone (LHRH) analog on overall survival of prostate cancer patients in the Japan Study Group of Prostate Cancer (J-CaP) registry according to risk, as assessed using the novel J-CAPRA risk instrument. To undertake a multivariate analysis combining J-CAPRA risk score, type of hormonal therapy and comorbidities, in order to assess their impact on overall survival.
The J-CaP database includes men in Japan diagnosed with any stage of prostate cancer between 2001 and 2003 and treated with primary androgen deprivation therapy (PADT), as monotherapy or in combination. A total of 26,272 men were enrolled and of these 19,265 were treated with PADT. This analysis was undertaken using the latest data set (30 April, 2010) including a total of 15,727 patients who received PADT and had follow-up data for periods ranging from 0 to 9.2 years.
MAB for prostate cancer patients with intermediate- or high-risk disease has a significant benefit in terms of overall survival compared with LHRH analog monotherapy or surgical castration alone. Better results may be achieved in older (≥75 years) patients. Patient comorbidities are an important factor in determining overall survival, notably in older patients, and should be considered when selecting therapy.
Based on large-scale registry data, this report is the first to analyze the outcomes of MAB therapy in patients with prostate cancer at a wide range of disease stages. MAB therapy may provide significant survival benefits in intermediate- and high-risk patients.
[show abstract][hide abstract] ABSTRACT: Recently, genome-wide association studies have independently identified multiple prostate cancer risk variants on 8q24 and 17q in European and American populations. In this study, we examined the association between three key single-nucleotide polymorphisms (SNPs) in these two regions and the risk of prostate cancer in a Japanese population.
The associations between the rs6983561, rs4430796, and rs1859962 SNPs and prostate cancer susceptibility and tumor aggressiveness were examined in a total of 950 Japanese subjects (518 with sporadic prostate cancer (SPCa), 109 with latent prostate cancer (LPCa), and 323 controls).
After adjustments for age, the C allele of rs6983561 and the A allele of rs4430796 were significantly more frequent among the SPCa patients than among the controls. Men who carry these risk alleles have an estimated odds ratio (OR) of 1.55 and 1.35, respectively. Furthermore, the SNPs rs6983561 and rs4430796 were associated with a susceptibility to aggressive prostate cancer, whereas rs1859962 was associated with non-aggressive prostate cancer. However, no significant difference was observed between these three polymorphisms and the risk of LPCa. We also examined the cumulative association of these three SNPs and prostate cancer susceptibility. Compared with men who do not have any risk alleles, the ORs increased according to the number of risk alleles that were present (P-value for trend: 8.1 × 10(-4) ).
Our results further confirmed that variants at 8q24 and 17q are associated with the risk of prostate cancer and play an important role in tumor aggressiveness.
The Prostate 07/2011; 71(10):1023-32. · 3.84 Impact Factor
[show abstract][hide abstract] ABSTRACT: We conducted present study to address whether the rs6983561 polymorphism, an established genetic marker for prostate cancer susceptibility, was a prognostic indicator. We genotyped 518 Japanese patients with prostate cancer and analysed their survival retrospectively. As a result, patients with the CA/CC genotype of rs6983561 survived significantly longer than those with the AA genotype (P = .033).
Genome-wide association studies have revealed several genetic variants at 8q24 that are associated with prostate cancer susceptibility. Rs6983561 (A/C) is a single-nucleotide polymorphism located at 8q24 that has been established as a genetic risk marker for prostate cancer susceptibility. The present study investigated the association between the rs6983561 polymorphism and prostate cancer mortality in a Japanese population.
The study examined 518 native Japanese male patients with sporadic prostate cancer. Germline DNA samples were obtained from all participants and genotyping of rs6983561 was performed using a TaqMan assay. Observation periods were from the date of diagnosis of prostate cancer to May 21, 2010. The Cox proportional hazards model was used to estimate the cause-specific survival (CSS) and the overall survival (OS).
Patients with the CA/CC genotype of rs6983561 survived significantly longer than those with the AA genotype. In a multivariate model, the hazard ratios (HRs) and 95% confidence intervals (CIs) of the CSS and the OS for the rs6983561 polymorphism were 2.438 (1.262 - 5.046, P = .007) and 1.957 (1.142 - 3.485, P = .014), respectively. When the analysis was restricted to subjects with metastatic disease, the HRs of the CSS and the OS were 3.353 (95% CI, 1.689 - 7.446; P = 3.76 x 10(-4)) and 3.361 (95% CI, 1.741 - 7.136; P = 1.70 x 10(-4)), respectively.
In the Japanese population examined in this study, the rs6983561 polymorphism at 8q24 was significantly associated with prostate cancer mortality, especially among patients with metastatic disease.
Clinical Genitourinary Cancer 06/2011; 9(1):46-52. · 1.43 Impact Factor
[show abstract][hide abstract] ABSTRACT: To clarify the survival benefit of immunotherapy for renal cell carcinoma patients with lung metastasis using low-dose interleukin-2 plus interferon-α, we examined survival outcomes and factors associated with prognosis.
This was a multicenter prospective study. Nephrectomized renal cell carcinoma patients with lung metastasis were treated with interleukin-2 (0.7 × 10(6) unit, 5 days a week) and interferon-α (6 × 10(6) IU, 3 days a week) for the first 8 weeks, and then with both interleukin-2 and interferon-α, 2 or 3 days a week for 16 additional weeks.
Median follow-up period for 42 patients was 28.3 months (range: 4.2-43.8). Two-year overall survival rate was 82% and the probability of 3 year survival rate was 71%. Median progression-free survival was 10.4 months. While no difference was found in survival among patients assessed as complete response, partial response and no change, survival of patients assessed as NC or better was significantly better than those assessed as progressive disease (P < 0.0001). Furthermore, multivariate analyses identified pre-treatment serum sodium (P = 0.004) as an independent prognostic factor. The sodium level was also statistically associated with tumor response (p = 0.035). Patients with normal sodium level survived significantly longer (P = 0.0005) than those with low sodium level showing median survival of 12.2 months.
Combination immunotherapy with low-dose interleukin-2 plus interferon-α showed survival benefit for patients with lung metastasis whose tumor responded as no change or better. This combination immunotherapy could be beneficial for patients selected by metastatic organ and their pre-treatment serum sodium level.
Japanese Journal of Clinical Oncology 06/2011; 41(8):1023-30. · 1.90 Impact Factor
[show abstract][hide abstract] ABSTRACT: Prostate cancer development is associated with hyperactive androgen signaling. However, the molecular link between androgen receptor (AR) function and humoral factors remains elusive. A prostate cancer mouse model was generated by selectively mutating the AR threonine 877 into alanine in prostatic epithelial cells through Cre-ERT2-mediated targeted somatic mutagenesis. Such AR point mutant mice (ARpe-T877A/Y) developed hypertrophic prostates with responses to both an androgen antagonist and estrogen, although no prostatic tumor was seen. In prostate cancer model transgenic mice, the onset of prostatic tumorigenesis as well as tumor growth was significantly potentiated by introduction of the AR T877A mutation into the prostate. Genetic screening of mice identified Wnt-5a as an activator. Enhanced Wnt-5a expression was detected in the malignant prostate tumors of patients, whereas in benign prostatic hyperplasia such aberrant up-regulation was not obvious. These findings suggest that a noncanonical Wnt signal stimulates development of prostatic tumors with AR hyperfunction.
Proceedings of the National Academy of Sciences 03/2011; 108(12):4938-43. · 9.74 Impact Factor
[show abstract][hide abstract] ABSTRACT: In our previous study, a combination therapy of interleukin-2 and interferon-alpha was found to be more effective than monotherapy, especially for lung metastasis. In order to determine the genetic markers of those who positively responded, a multi-institutional open study was conducted on the patients with lung metastasis. In this paper, the clinical response to our combination therapy is reported.
Untreated patients with lung metastasis were enrolled in this study. Patients received interleukin-2 (0.7 x 10(6) U/day) and interferon-alpha (6 x 10(6) IU/day): interleukin-2, 5 days a week and interferon-alpha, 3 days a week for the first 8 weeks, and then both interleukin-2 and interferon-alpha, 2 or 3 days a week for 16 additional weeks.
Forty-two patients were able to be evaluated for response. The overall positive response rate was 35.7% (15 of 42) including 2 patients with complete response. Progression-free patients were observed more frequently in patients with lung metastasis only (80.6%) than those with lung plus other organ metastasis (54.5%). Tumor shrinkage was observed in 81.0% (34 of 42) of patients. Progression-free survival rate at 200 days was 63.6%. Toxicities observed were primarily flu-like symptoms due to the cytokines and were typical of those observed with each single agent.
Combination therapy of interleukin-2 and interferon-alpha was confirmed to be effective for renal cell carcinoma patients with lung metastasis. Identification of genetic markers is now ongoing with the tissue samples from this trial.
Japanese Journal of Clinical Oncology 04/2010; 40(7):684-9. · 1.90 Impact Factor
[show abstract][hide abstract] ABSTRACT: Interleukin (IL)-2 and interferon (IFN)-α combination therapy for metastatic renal cell carcinoma (RCC) improves the prognosis for a subset of patients, while some patients suffer from severe adverse drug reactions with little benefit. To establish a method to predict responses to this combination therapy (approximately 30% response rate), the gene expression profiles of primary RCCs were analyzed using an oligoDNA microarray consisting of 38,500 genes or ESTs, after enrichment of the cancer cell population by laser micro-beam microdissection. The analysis of 10 responders and 18 non-responders identified 24 genes that exhibited significant differential expression between the two groups. In addition, the patients whose tumors did not express HLA-DQA1 or HLA-DQB1 molecules demonstrated poor clinical response. Exclusion of patients with tumors lacking either of these two genes is likely to improve the response rate to IL-2 and IFN-α combination therapy from 30 to 67%, indicating that a simple pretreatment test provides useful information with which to subselect patients with renal cancer in order to improve the efficacy of this treatment and reduce unnecessary medical costs.
Experimental and therapeutic medicine 01/2010; 1(6):955-961. · 0.34 Impact Factor
[show abstract][hide abstract] ABSTRACT: In order to assess the efficacy and toxicity of oral estramustine phosphate (EMP) administration, low-dose EMP monotherapy (study 1) and very low-dose EMP therapy with luteinizing hormone-releasing hormone (LH-RH) agonist (study 2) were conducted in previously untreated prostate cancer and long-term outcomes were compared between the 2 study groups.
Studies 1 and 2 were independently performed beginning in June 1999 and November 2001, respectively. Study 1 was composed of 87 patients including 85 assessable patients. All 108 patients recruited for study 2 were assessable. Low-dose EMP monotherapy (2 capsules/day or 280 mg/day) was used in study 1 and very low-dose EMP (1 capsule/day or 140 mg/day) combined with LH-RH agonist was adopted in study 2.
Overall prostate specific antigen (PSA) -response rates in studies 1 and 2 were 92.3% and 94.2%, respectively, and overall toxicity rates were 54.1% and 38.9%, respectively. EMP discontinuation due to side effects was encountered more often in study 1 (45.9%) than in study 2 (27.8%). Among the adverse side effects gastrointestinal toxicity was most prevalent in both studies. One patient died of acute pulmonary embolism in study 1, but no one died in study 2. There were 6 cancer deaths in the gastrointestinal tract in study 1 but only 2 cancer deaths in study 2.
Our data indicate that the overall PSA response rate was comparable between both studies. However, rates in overall toxicity and drug discontinuation were higher in study 1 than in study 2. We consider that study 2 is more promising for the treatment of previously untreated advanced prostate cancer, although the rate of adverse side effects is still high as compared with other hormonal therapies. In order to overcome the high toxicity rate, especially the gastrointestinal toxicity, we recently elaborated a method employing tailor-made medicine using SNPs of 1A1 gene in cytochrome P-450 for decreasing the rate of gastrointestinal toxicity. Using this method of patient selection, study 3 has been successfully launched on September 2005 with high drug compliance. Better clinical results are being accumulated.
[show abstract][hide abstract] ABSTRACT: Side population (SP) cells are an enriched population of stem, and the existence of SP cells has been reported in human cancer cell lines. In this study, we performed an SP analysis using 11 human cancer cell lines and confirmed the presence of SP cells in an embryonic carcinoma cell line, NEC8. NEC8 SP cells showed characteristics of cancer stem cells, such as high growth rate, chemoresistance and high invasiveness. To further characterize the NEC8 SP cells, we used DNA microarrays. Among 38,500 genes, we identified 12 genes that were over-expressed in SP cells and 1 gene that was over-expressed in non-SP cells. Among these 13 genes, we focused on GADD45b. GADD45b was over-expressed in non-SP cells, but the inhibition of GADD45b had no effect on non-SP cells. Paradoxically, the inhibition of GADD45b significantly reduced the viability of NEC8 SP cells. The inhibition of ABCG2, which determines the SP phenotype, had no effect on the invasiveness of NEC8 SP cells, but the inhibition of GADD45b significantly reduced invasiveness. These results suggest that GADD45b, but not ABCG2, might determine the cancer stem cell-like phenotype, such as chemoresistance and the high invasiveness of NEC8 SP cells, and might be a good therapeutic target.
[show abstract][hide abstract] ABSTRACT: This article has been withdrawn at the request of the editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.
Biochemical and Biophysical Research Communications 12/2009; · 2.41 Impact Factor
[show abstract][hide abstract] ABSTRACT: To investigate the influence of single nucleotide polymorphisms (SNP) on transcription of the 17beta-hydroxysteroid dehydrogenase (HSD17B7) gene.
Luciferase reporter genes containing a 5'-flanking of the HSD17B7 gene, as well as the sequence around the SNP, were transfected into LNCaP and DU145 cells. Then, luciferase assays were carried out.
The presence of the G allele resulted in an increase of transcriptional activity derived from the 5'-flanking region of the HSD17B7 gene by 270% and 370% in LNCaP and DU145 cells, respectively. Transcriptional activity of the HSD17B7 gene containing the G allele was higher than that of the C allele.
The transcriptional activity of the HSD17B7 gene containing the G allele is higher than that of the C allele. This difference in HSD17B7 expression may regulate the risk of peripheral edema as an adverse reaction induced by estramustine phosphate sodium.
International Journal of Urology 10/2009; 16(10):836-41. · 1.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: To evaluate CYP3A4 expression in human prostrate cancer (PCa) tissues. Enzymes of the cytochrome P450 (CYP) family are key inactivators of testosterone in the liver and prostate. We previously reported that CYP2B6 is a growth-inhibitory and prognostic factor in human PCa; however, the status of CYP3A4 in PCa remains unclear.
We used immunohistochemistry to analyze CYP3A4 expression in 107 human PCa specimens obtained by radical prostatectomy. Stained slides were evaluated for the proportion and staining intensity of positively stained cells. Total immunoreactivity scores (0-8) were obtained as the sum of the proportion and intensity scores. In addition, we estimated the relationship between CYP3A4 status and clinicopathologic features.
CYP3A4 immunoreactivity was identified in the cytoplasm of prostate cells. The CYP3A4 immunoreactive PCa score (3.6+/-2.6) was significantly lower than that of benign epithelium (4.5+/-2.1; P < .0001). In addition, CYP3A4 immunoreactivity correlated inversely with the Gleason score (P < .0001). Decreased CYP3A4 immunoreactivity was significantly related to a poor prognosis in human PCa (P = .0175).
We demonstrated differential CYP3A4 expression in prostatic tissues, indicating that decreased CYP3A4 expression may contribute to the development of PCa.
[show abstract][hide abstract] ABSTRACT: BKV is widespread among humans, infecting children asymptomatically and then persisting in renal tissue. Based on the serological or phylogenetic method, BKV isolates worldwide are classified into four subtypes (I-IV), with subtypes I and IV further divided into several genetically-distinct subgroups. Since, similarly to JCV, a close relationship exists between BKV lineages and human populations, BKV should be useful as a marker to trace human migrations. To elucidate ancient human migrations in northeast Asia, urine samples were collected from immunocompetent elderly patients in Shanghai, China; Anyang, South Korea; and various locations in Japan. Partial and complete BKV genomes from these samples were amplified and sequenced using PCR, and the determined sequences were classified into subtypes and subgroups by phylogenetic and SNP analyses. In addition, based on an SNP analysis, the major subtype I subgroup (I/c) was classified into two subdivisions, I/c/Ch and I/c/KJ. The distribution patterns of BKV subgroups and subdivisions among the three regions were compared. Some aspects of the subgroup and subdivision distribution were more similar between Korea and Japan, but others were more similar between China and Korea or between China and Japan. Based on these findings, we inferred various northeast Asian migrations. Most of the JCV-based inferences of northeastern Asian migrations were consistent with those based on BKV, but the previously suggested migration route from the Asian continent to the Japanese archipelago seemed to need revision.
Microbiology and Immunology 06/2009; 53(5):266-76. · 1.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: The objective of this study was to assess disease-associated pain and quality of life (QOL) in patients with prostate cancer (PC). A total of 102 PC patients (clinical stage B, C: 20, D2: 82) patients were enrolled. QOL was assessed using the Functional Assessment of Cancer Therapy, General and Prostate (FACT-G/P). Disease-specific pain response was assessed using the visual analog scale and the face rating scale. In patients with stage D2 PC, mean age, serum prostate-specific antigen level, and performance status were 72.5 +/- 7.1 years (range, 55-88), 217 +/- 467 ng/mL (range, 0.1-2600), and 1.4 (0-4), respectively. The score of physical well-being and FACT-P was significantly lower in stage D2 patients, compared with those of stage B/C (P = 0.02, 0.0088, respectively). Performance status, extent of disease, and the visual analog scale were related with a poor QOL score (P = 0.0054, 0.01, <0.0001, respectively). Thirty-two patients (39%) had disease-specific pain, and 25 patients received a related treatment. Ten patients under morphine analgesics maintained better QOL in almost all domains, compared with the seven patients without any painkillers. Combined use of FACT and pain scales enhances the objective assessment of QOL and pain status in PC patients. Control of disease-associated pain is crucial to improving QOL in stage D2 PC patients.
International Journal of Urology 05/2009; 16(5):522-5. · 1.73 Impact Factor