Prostatic Neoplasms: Nakayama T

Hamashima C, Nakayama T, Sagawa M, Saito H, Sobue T. · Cancer Screening Assessment and Management Division, Research Center for Cancer Prevention and Screening, National Cancer Center, 5-1-1 Tsukiji Chuo-ku, Tokyo 104-0045, Japan. · Jpn J Clin Oncol. · Pubmed #19346535 No free full text.

Abstract: In 2005, there were 9264 deaths from prostate cancer, accounting for 4.7% of the total number of cancer deaths in Japan. As the population continues to age, interest in prostate cancer screening has increased, and opportunistic screening for prostate cancer has been conducted worldwide. The guideline for prostate cancer screening was developed based on the established method. The efficacies of prostate-specific antigen (PSA) and digital rectal examination (DRE) were evaluated. Based on the balance of the benefits and harms, recommendations for population-based and opportunistic screening were formulated. Two methods of prostate cancer screening were evaluated. Based on the analytic framework involving key questions, 1186 articles published from January 1985 to October 2006 were selected using MEDLINE and other methods. After the systematic literature review, 28 articles were identified as providing evidence of mortality reduction from prostate cancer, including 5 observational studies for DRE screening, 1 meta-analysis, 3 randomized controlled trials and 19 observational studies for PSA screening. Although several studies showed that PSA screening had a beneficial effect, the results of the selected studies were inconsistent. Overall, the evidence that screening reduced mortality from prostate cancer was insufficient. Furthermore, prostate cancer screening is associated with serious harms, including overdiagnosis, adverse effects of needle biopsy and adverse effects of local prostatectomy. At present, the evidence for the effect of prostate cancer screening is insufficient. Both PSA and DRE were not recommended for population-based screening programs, but they could be conducted as individual-based screening if basic requirements were met.

Okaneya T, Nishizawa S, Nakayama T, Kamigaito T, Hashida I, Hosaka N. · Department of Urology, Nagano Municipal Hospital, 1333-1 Tomitake, Nagano, Nagano 381-8551, Japan. · Int J Urol. · Pubmed #17645602 No free full text.

Abstract: OBJECTIVE: To evaluate the initial results of brachytherapy for prostate cancer with permanent iodine-125 implant in Japan. METHODS: The results obtained with brachytherapy in the initial 100 Japanese patients treated at Nagano Municipal Hospital were reviewed. Patients with a prostate-specific antigen (PSA) level of less than 10 ng/mL and a Gleason's scores of 5, 6, 3 + 4 were classified as having a low risk of recurrence. Patients with a PSA level of 10-20 ng/mL and/or a Gleason's score of 4 + 3 were classified as having an intermediate risk for recurrence. Seventy-eight of the low-risk patients and 19 of the intermediate-risk patients were treated by seed implants alone, or seed implants combined with preceding external radiation, respectively. A total of 53 patients received neoadjuvant hormone therapy. The efficacy and morbidity of brachytherapy were investigated using the serum PSA, International Prostate Symptom Score, quality of life score and uroflowmetry data. RESULTS: The average V100 and D90 obtained by post-implant dosimetry was 94.3 and 113.7%, respectively. Serum PSA decreased gradually after treatment, although it had still not reached a nadir after 1 year. There was little difference of the PSA level between the patients with and without neoadjuvant hormone therapy even at 1 year after seed implantation. There were no PSA biochemical failure or clinical recurrence during the follow-up period. Voiding symptoms worsened until 3 months after treatment, and then gradually improved. Acute urinary retention occurred transiently in one patient (1%). Rectal bleeding and severe diarrhea did not occur. CONCLUSION: Brachytherapy is a feasible and effective option for the treatment of prostate cancer in Japanese men. Brachytherapy may have a different effect in Japanese patients with respect to voiding symptoms. Urinary retention was rare, but voiding symptoms were persistent in Japanese patients. Neoadjuvant hormone therapy deserves investigation to determine whether it can achieve better results, especially in patients with an intermediate risk.

Kinebuchi Y, Noguchi W, Irie K, Nakayama T, Kato H, Nishizawa O. · Department of Urology, Shinshu University School of Medicine, Matsumoto, Japan. · Int J Urol. · Pubmed #17302572 No free full text.

Abstract: A 62-year-old man had been treated with combined androgen blockade due to cT2bN1M0 prostate cancer, and his serum prostate-specific antigen (PSA) levels decreased and remained under the level of 0.5 ng/mL during therapy. Approximately 40 months after the initial therapy, difficulty on urination and constipation developed gradually, and serum carcinoembryonic antigen (CEA) and pro-gastrin-releasing peptide (ProGRP) levels were high at this point. He underwent transrectal and transurethral biopsy of the prostate, which revealed adenocarcinoma positive for CEA and chromogranin A. He received palliative pelvic irradiation, and oral estramustine phosphate and etoposide combined therapy. Tumor markers decreased and clinical symptoms improved for several months. The patient died of encephalopathy of unknown etiology approximately 11 months after the relapse.

Ishizuka O, Tanabe T, Nakayama T, Kawakami M, Kinebuchi Y, Nishizawa O. · Department of Urology, Shinshu University School of Medicine, Matsumoto, Japan. · Int J Urol. · Pubmed #16174046 No free full text.

Abstract: AIM: In the present study, we evaluated the relationships between prostate-specific antigen (PSA) level and bone metastasis, between Gleason sum and bone metastasis, and between clinical T stage and bone metastasis in Japanese patients. METHODS: Between November 1998 and June 2004, we performed ultrasound-guided biopsies on 709 patients (mean age: 70.5 years, range: 39-90). Prostate cancer was detected in 339 patients (47.8%), 297 (87.6%) of whom underwent a radionuclide bone scan. In close collaboration with orthopedists, bone computed tomography scans, bone magnetic resonance imaging and/or plain rentogenograms were performed for cases that were difficult to diagnose as bone metastasis through radionuclide bone scans only. RESULTS: We detected 61 (20.6%) bone metastasis cases in 296 patients. A simple linear regression analysis between log[PSA] and bone metastasis (n = 296) produced a significant relationship (P < 0.05). When we set the cut-off PSA value for the indication for a bone scan at 15 ng/mL, the possibility of bone metastasis was 10%. However, from our experience, there was no bone metastasis in the patients whose Gleason sums were less than five, and in the patients whose Gleason sum were five or more, and the PSA levels were less than 15, there was no bone metastasis. The rate of bone metastasis increased with the increase of PSA level. In the clinical T1-T2 stage cases, there were significant higher PSA levels in the cases with bone metastasis. In the T1-T2 patients whose PSA levels were less than 16, there was no bone metastasis. CONCLUSIONS: From the analysis of PSA, Gleason sum and clinical T stage, we suggest that bone scan is unnecessary for patients whose PSA level is less than 15 ng/mL or Gleason sum is less than five.

Alipov G, Nakayama T, Ito M, Kawai K, Naito S, Nakashima M, Niino D, Sekine I. · Tissue and Histopathology Section, Division of Scientific Data Registry, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. · Histopathology. · Pubmed #15693893 No free full text.

Abstract: AIMS: The high incidence of clinically diagnosed prostatic cancer is exceeded by the frequency of tumours detected at autopsy. The Ets-1 proto-oncogene is expressed by a variety of malignant and normal tissues. Therefore, in this study, expression of Ets-1 protein was investigated in 'latent' prostatic cancer detected at autopsy, compared with benign prostatic hyperplasia, normal prostatic tissues and clinical prostatic cancer. METHODS AND RESULTS: Using immunohistochemistry, we analysed Ets-1 expression in 95 prostatic specimens including 19 cases of latent prostatic carcinoma (LPC) and 55 cases of clinical prostatic carcinoma (CPC), 11 cases of benign prostatic hyperplasia (BPH) and 10 cases of normal prostate (NP). Differences in the incidence of LPC and CPC suggest different courses for the biological progression of prostatic cancer. There was a significant difference in the degree of Ets-1 expression in CPC and LPC (P < 0.05). Ets-1 was not expressed in BPH and NP, but in malignant cases (57 of 74; 77.0%) commonly demonstrated immunoreactivity in the tumour cells. In our study the expression of Ets-1 between benign and malignant, and well, moderately and poorly differentiated adenocarcinomas of prostatic cancer showed significant differences. The presence of Ets-1 mRNA was confirmed by in-situ hybridization in human prostatic tissues. CONCLUSION: Our results suggest that Ets-1 might play an important role in carcinogenesis and/or the progression of human prostatic carcinomas.

Kito H, Suzuki H, Ichikawa T, Sekita N, Kamiya N, Akakura K, Igarashi T, Nakayama T, Watanabe M, Harigaya K, Ito H. · Department of Urology, Graduate School of Medicine, Chiba University, Chiba, Japan. · Prostate. · Pubmed #11582589 No free full text.

Abstract: BACKGROUND: CD44 is a metastasis suppressor gene for prostate cancer and the down-regulation of CD44 and its variants is associated with the progression of prostate cancer. Also, hypermethylation of the CpG islands of the CD44 gene is closely associated with transcriptional inactivation, resulting in the decreased expression of CD44. To clarify the exact role of methylation status of CpG islands of CD44 gene in the progression and metastasis of prostate cancer, we investigated the methylation status of this gene in primary and metastatic human prostate tumors obtained from surgery or autopsy. METHODS: We examined 97 samples from 40 Japanese patients with adenocarcinoma of the prostate. Tumor tissues were obtained from radical prostatectomy specimens from eight patients with stage B, 12 patients with stage C and three patients with stage D1 and at autopsy from 17 hormone-refractory metastatic cases, who had initially responded to the therapy and thereafter relapsed. Distant metastatic tissues were also obtained at autopsy (i.e., liver, lung, kidney, mammary gland, and pelvic lymph nodes) from 10 of 17 hormone-refractory cases. We analyzed the hypermethylation status of CD44 promotor region by PCR using genomic DNAs digested with the m(5)C-sensitive restriction enzyme HpaII. RESULTS: The correlation between the methylation status of CD44 gene and the stage progression of prostate cancer was statistically significant (P = 0.0438). In two of 10 hormone-refractory cases, a comparison of the methylation status of the CD44 gene in metastases to that in primary tumors revealed interfocal heterogeneity of CD44 methylation status. CONCLUSIONS: These results indicate an important role of CD44 methylation in the progression and metastasis of prostate cancer, although the amount of methylational heterogeneity is substantial among metastatic sites within the same patient.

Sekita N, Suzuki H, Ichikawa T, Kito H, Akakura K, Igarashi T, Nakayama T, Watanabe M, Shiraishi T, Toyota M, Yoshie O, Ito H. · Department of Urology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan. · Jpn J Cancer Res. · Pubmed #11572762 No free full text.

Abstract: Expression of the KAI1 gene, a metastasis-suppressor for prostate cancer, is reduced in all foci of prostatic metastasis. The altered regulatory mechanism is not strongly related to mutations or allelic losses of the KAI1 gene in prostate tumors. Since transcriptional silencing of genes has been found to be caused by epigenetic mechanisms, we have investigated the involvement of this epigenetic regulation of KAI1 expression in prostate cancers. The methylation status of the KAI1 promoter region was examined by restriction-enzyme digestion and sequencing, after amplifying a 331-bp fragment in the GC-rich promoter region from 4 human prostate cancer cell lines treated with bisulfite. The same 4 cell lines were also exposed to various concentrations of the demethylating agent, 5-aza-2'-deoxycytidine (5-AzaC) and / or the histone deacetylase inhibitor, trichostatin A (TSA). To clarify the influence of epigenetic modification on reduced KAI1 mRNA expression in the tumor cells, RT-PCR and northern-blot analyses were performed. Bisulfite-sequencing data showed a few methylated CpG islands in the promoter. RT-PCR analysis of 5-AzaC and / or TSA-treated cells indicated reversal of suppression of KAI1 transcription in two cell lines (PC-3 and DU-145), although the expression could not be detected by northern blots. From these results, it is suggested that epigenetic change is not the main mechanism of KAI1 down-regulation, though there remains a possibility that methylation in a more upstream region might be associated with this regulation.

Nakayama T, Watanabe M, Yamanaka M, Hirokawa Y, Suzuki H, Ito H, Yatani R, Shiraishi T. · Second Department of Pathology, Mie University School of Medicine, Mie, Japan. · Lab Invest. · Pubmed #11454993 No free full text.

Abstract: The retinoic acid receptor (RAR) beta gene is a putative tumor suppressor gene on chromosome 3p24, where a high incidence of loss of heterozygosity is detected in many types of tumors. Retinoic acid suppresses cancer cell growth through binding to RARs, especially RARbeta, indicating a critical role in mediating anticancer effects. Selective loss or down-regulation of RARbeta mRNA and protein has been reported in prostate cancers (PCas), although the mechanisms remain unclear. We investigated the role of epigenetic modification in RARbeta2 gene silencing. Aberrant methylation was detected in 11 of 14 (79%) primary PCas, 9 of 10 (90%) hormone-refractory PCas, and 2 of 4 (50%) PCa cell lines, but not in any normal prostate samples. Chromatin immunoprecipitation assay showed that all RARbeta2-negative cells (LNCaP, PC3, and DU145) were hypoacetylated at both histones H3 and H4. After exposure to 5-aza-2prime;-deoxycytidine treatment, Trichostatin A and all-trans retinoic acid induced partial demethylation, increased accumulation of acetylated histones, and markedly restored the expression of RARbeta2 in RARbeta2-negative cells. These data suggest that the RARbeta2 gene may be one of the frequently silenced genes by epigenetic modifications in PCa.

Nakayama T, Watanabe M, Suzuki H, Toyota M, Sekita N, Hirokawa Y, Mizokami A, Ito H, Yatani R, Shiraishi T. · Second Department of Pathology, Mie University School of Medicine, Japan. · Lab Invest. · Pubmed #11140692 No free full text.

Abstract: Epigenetic mechanisms including DNA methylation and histone deacetylation are thought to play important roles in gene transcriptional inactivation. Heterogenous expression of androgen receptor (AR), which appears to be related to variable responses to endocrine therapy in prostate cancer (PCa) may also be due to epigenetic factors. The methylation status of the 5' CpG island of the AR in 3 prostate cancer cell lines and 10 primary and 14 hormone-refractory PCa samples was determined using the bisulfite PCR methods. In DU145, CpG-rich regions of the AR were hypermethylated. By an immunohistochemical analysis, only one PCa sample had no AR expression, the others being heterogenous. Bisulfite sequencing and methylation-specific PCR analysis showed aberrant methylation of AR 5'-regulatory region in 20% of 10 primary and 28% of 14 hormone-refractory PCa samples. To clarify the effect of epigenetic regulation on AR expression, we treated three prostate cancer cell lines with a demethylating agent, 5-aza-2'-deoxycytidine (azaC), and a histone deacetylase inhibitor, Trichostatin A (TSA). In DU145, re-expression of AR mRNA was detected after treatment with azaC and/or TSA. Our results suggest that epigenetic regulations including CpG methylation and histone acetylation may play important roles in the regulation of the AR.