Prostatic Neoplasms: Hara I

Tanaka M, Ono Y, Matsuda T, Terachi T, Suzuki K, Baba S, Hara I, Hirao Y, Anonymous00107. · Department of Urology, Fukuoka University Faculty of Medicine, Fukuoka, Japan. ~u.ac.jp · Int J Urol. · Pubmed #19228223 No free full text.

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Kamidono S, Ohshima S, Hirao Y, Suzuki K, Arai Y, Fujimoto H, Egawa S, Akaza H, Hara I, Hinotsu S, Kakehi Y, Hasegawa T, Anonymous00384. · No affiliation provided · Int J Urol. · Pubmed #18184166 No free full text.

This publication has no abstract.

Miyake H, Hara I, Fujisawa M, Gleave ME. · Hyogo Medical Center for Adults, Department of Urology, 13-70 Kitaohji-cho, Akashi 673-8558, Japan. · Expert Opin Investig Drugs. · Pubmed #16634689 No free full text.

Abstract: This review summarise the authors' recent experience in the development of antisense (AS) oligodeoxynucleotide (ODN) therapy that targets a cytoprotective gene, clusterin, for the treatment of prostate cancer. The acquisition of resistance to a wide variety of proapototic stimuli was initially demonstrated by introducing the clusterin gene into prostate cancer cells. Furthermore, silencing clusterin expression using AS ODN synergistically enhanced the effects of several conventional therapeutic modalities through the effective induction of apoptosis in prostate cancer xenograft models. Based on these outcomes, Phase I clinical trials were conducted using AS clusterin ODN incorporating 2'-O-(2-methoxy)ethyl-gapmer backbone (OGX-011), and the optimal dose of OGX-011 capable of inducing </= 90% suppression of clusterin in human prostate cancer tissue was determined. Collectively, these findings suggest the utility of inactivating clusterin function using AS ODN technology as a novel therapeutic strategy for prostate cancer treatment. There have been four kinds of Phase II studies that have begun to further evaluate the efficacy of OGX-011 in patients with prostate, breast and lung cancers.

Hara I. · Division of Urology, Kobe University Graduate School of Medicine. · Gan To Kagaku Ryoho. · Pubmed #16484852 No free full text.

Abstract: The number of prostate cancer patients is rapidly increasing in Japan, as aging people are more common and the lifestyle is more westernized. Another reason is that prostate specific antigen (PSA) is prevalent and PSA test can detect organ-confined prostate cancer in the early stage. In the past, endocrine therapy was the main treatment modality since many prostate cancer patients were diagnosed in the advanced stage. However, endocrine therapy is not suitable for young patients with organ-confined prostate cancer. Surgery and radiation therapy are becoming standard therapy for these patients. Although retropubic radical prostatectomy is widely performed,urinary incontinence and sexual dysfunction are still problems. Other approaches such as laparoscopic prostatectomy, portless endoscopic prostatectomy and perineal prostatectomy are also performed. Radiation therapy is commonly used for organ-confined prostate cancer in Europe and the U.S.A. The advancement in computer technology has made it possible to accumulate enough radiation dose to target without damaging the surrounding organs (3 D conformal, intensity-modulated radiotherapy). Heavy ion particle radiotherapy is also attempted in some institutes. Moreover, brachytherapy can be another choice in radiation therapy. In Japan, only high-dose brachytherapy with (192)Ir has been performed. In July 2003, permanent seed brachytherapy with (121)I was legally approved in Japan, and more organ-confined prostate cancer patients are expected to undergo this treatment. There are several treatment modalities for organ-confined prostate cancer patients these days. Therefore, not only tumor grade and stage, but also patients'lifestyle and thought should be considered in determining treatment.

Miyake H, Hara I, Gleave ME. · The Prostate Center, Vancouver General Hospital, Vancouver, Canada. · Int J Urol. · Pubmed #16201973 No free full text.

Abstract: BACKGROUND: The objective of this study was to review our experience in the development of antisense (AS) oligodeoxynucleotide (ODN) therapy for prostate cancer targeting antiapoptotic gene, clusterin. METHODS: We initially summarized our data demonstrating that clusterin could be an optimal therapeutic target for prostate cancer, then presented the process of developing AS ODN therapy using several preclinical animal models. Finally, the preliminary data of the recently completed phase I clinical trial using AS clusterin ODN as well as the future prospects of this therapy are discussed. RESULTS: Expression of clusterin was highly up-regulated after androgen withdrawal and during progression to androgen-independence, but low or absent in untreated tissues in both prostate cancer animal model systems and human clinical specimens. Introduction of the clusterin gene into human prostate cancer cells confers resistance to several therapeutic stimuli, including androgen ablation, chemotherapy and radiation. AS ODN targeting the translation initiation site of the clusterin gene markedly inhibited clusterin expression in prostate cancer cells in a dose-dependent and sequence-specific manner. Systemic treatment with AS clusterin ODN enhanced the effects of several conventional therapies through the effective induction of apoptosis in prostate cancer xenograft models. Based on these findings, a phase I clinical trial was completed using AS clusterin ODN incorporating 2'-O-(2-methoxy)ethyl-gapmer backbone (OGX-011), showing up to 90% suppression of clusterin in prostate cancer. CONCLUSIONS: The data described above identified clusterin as an antiapoptotic gene up-regulated in an adaptive cell survival manner following various cell death triggers that helps confer a phenotype resistant to therapeutic stimuli. Inhibition of clusterin expression using AS ODN technology enhances apoptosis induced by several conventional treatments, resulting in the delay of AI progression and improved survival. Clinical trials using AS ODN confirm potent suppression of clusterin expression and phase II studies will begin in early 2005.

Gotoh A, Shirakawa T, Wada Y, Hinata N, Terao S, Hara I, Arakawa S, Kamidono S, Okada H, Takenaka A, Fujisawa M. · The International Center for Medical Research, Kobe University School of Medicine. · Hinyokika Kiyo. · Pubmed #15773357 No free full text.

Abstract: We selected bone-metastatic prostate cancer as the target form of recurrent prostate cancer and developed a suicide-gene therapy based on an adenovirus vector with an organ-specific osteocalcin promoter. Related clinical studies have already been conducted in the United States at the University of Virginia, where results so far have established the safety of this therapy. In the present paper, in addition to presenting the results of these gene-therapy studies from the basic research to the clinical stage, we discuss the clinical studies begun by our group in August 2003. In the 21st century, therapeutic systems in use are undergoing major changes. Gene therapy is likely to become an important therapeutic option in recurrent prostate cancer. In terms of theory and technology however, this form of treatment is still at a very immature stage of development. We look forward to evolution in this field to provide an established treatment for recurrent prostate cancer and are committed to actively continuing with the development of gene therapy through translational research.

Miyake H, Hara I, Kamidono S, Gleave ME. · The Prostate Center, Vancouver General Hospital, Vancouver, Canada. · Int J Urol. · Pubmed #11442654 No free full text.

Abstract: Progression to androgen-independence remains the main obstacle to improving survival for patients with advanced prostate cancer. In this review, findings are summarized that have recently been demonstrated to establish novel therapeutic strategy targeting several genes playing functionally important roles after androgen withdrawal and during androgen-independent progression. The authors initially characterized changes in gene expression after androgen withdrawal in the androgen-dependent Shionogi and LNCaP tumor models using cDNA arrays. Based on these results, they focused on genes highly upregulated after androgen ablation (i.e. bcl-2, bcl-xL, TR.PM-2, IGFBP-5), which have anti-apoptotic or mitogenic activities, and thereby confer a resistance to androgen withdrawal as well as cytotoxic chemotherapy. The authors further demonstrated the efficacy of an antisense oligodeoxynucleotide (ODN) strategy for patients with advanced prostate cancer through the inhibition of target gene expression, resulting in a delay in the progression to androgen-independence by enhancing apoptotic cell death induced by androgen ablation and chemotherapy. The authors also showed the effectiveness of combined antisense ODN therapy and cytotoxic chemotherapy by achieving additive or synergistic effects. These findings provide a basic significance for the design of clinical studies using antisense ODN either alone or in combination with chemotherapeutic agents in patients with advanced prostate cancer.

Sato M, Mori T, Shirai S, Kishi K, Inagaki T, Hara I. · Department of Radiology, Wakayama Medical University, Wakayama, Japan. · Int J Radiat Oncol Biol Phys. · Pubmed #18448272 No free full text.

Abstract: PURPOSE: To evaluate the preliminary outcomes of high-dose-rate (HDR) brachytherapy of a single implant with two fractions and external beam radiotherapy (EBRT) for hormone-naive prostate cancer. METHODS AND MATERIALS: Between March 2000 and Sept 2003, a total of 53 patients with tumor Stage T1c-T3b N0 M0 prostate cancer were treated with HDR brachytherapy boost doses (7.5 Gy/fraction) and 50-Gy EBRT during a 5.5-week period. Median follow-up was 61 months. Patients were divided into groups with localized (T1c-T2b) and advanced disease (T3a-T3b). We used the American Society for Therapeutic Radiology and Oncology (ASTRO) definition for biochemical failure. According to recommendations of the Radiation Therapy Oncology Group-ASTRO Phoenix Consensus Conference, biochemical failure-free control rates (BF-FCRs) at 3 years were investigated as 2 years short of the median follow-up. RESULTS: Between April 2000 and Sept 2007, Common Terminology Criteria for Adverse Events Version 2.0 late Grade 2 genitourinary and gastrointestinal toxicity rates were 0% and 3.8%, respectively. Erectile preservation was 25% at 5 years. Overall survival was 88.1% and cause-specific survival was 100%. At 3 years, ASTRO BF-FCRs of the localized and advanced groups were 100% and 42%, respectively (p = 0.001). CONCLUSIONS: The HDR brachytherapy of a single implant with two fractions plus EBRT is effective in treating patients with localized hormone-naive prostate cancer, with the least genitourinary and gastrointestinal toxicities; however, longer median BF-FCR follow-up is required to assess these findings.

Shirakawa T, Terao S, Hinata N, Tanaka K, Takenaka A, Hara I, Sugimura K, Matsuo M, Hamada K, Fuji K, Okegawa T, Higashihara E, Gardner TA, Kao C, Chung LW, Kamidono S, Fujisawa M, Gotoh A. · International Center for Medical Research and Treatment, Kobe University School of Medicine, Kobe 650-0017, Japan. · Hum Gene Ther. · Pubmed #18021019 No free full text.

Abstract: We evaluated the long-term safety and efficacy of Ad-OC-TK (recombinant adenoviral vector carrying an osteocalcin promoter-driven herpes simplex virus thymidine kinase gene) plus VAL (valacyclovir) gene therapy for hormone-refractory prostate cancer. Ad-OC-TK/VAL therapy is the first in vivo adenovirus-mediated gene therapy to be used to treat metastatic prostate cancer, including bone metastasis. Six patients were enrolled in this trial, and two doses of Ad-OC-TK (2.5 x 10(9) or 2.5 x 10(10) plaque-forming units) were injected into locally recurrent tumor or bone metastasis on day 1 and day 8. Patients were also given VAL (3 g/day) for 21 days. Safety and efficacy were evaluated for at least 8 months in each patient. All patients tolerated this therapy with no serious adverse events. One prostate-specific antigen (PSA) response (from 318.3 to 4.9 ng/ml) was observed with a time to PSA progression (TTP) of 12 months. Docetaxel (30 mg/m2 per week) and estramustine (560 mg/day) combination chemotherapy (DE) was given to three docetaxel-naive patients on PSA failure after gene therapy. All three patients had a PSA response to DE therapy with 21, 7, and 4 months of TTP. These results suggest that additional trials are warranted.

Hara I, Kawabata G, Tanaka K, Kanomata N, Miyake H, Takenaka A, Fujisawa M. · Division of Urology, Kobe University School of Medicine, Kobe, Japan. · Int J Urol. · Pubmed #17593096 No free full text.

Abstract: AIM: Oncological outcomes including surgical margin status and biological progression-free survival (bPFS) were analyzed in patients who underwent laparoscopic prostatectomy (LRP) only. METHODS: A total of 136 patients who underwent LRP only without lymph node metastasis or perioperative supportive therapy between April 2000 and October 2005 were analyzed. All patients received > or =6 months postoperative follow-up. Biological progression was defined as elevation of prostate-specific antigen by >0.2 ng/mL. RESULTS: The positive margin (ew+) rate was 36.8% and the 3-year bPFS was 72.6% for all patients. Positive margin rates in pT2a-b, pT2c, pT3a and pT3b were 10.0%, 27.5%, 77.3% and 53.8%, respectively. Three-year bPFS rates in pT2, pT3a and pT3b were 91.8%, 66.8% and 44.9%, respectively. Although the positive margin rate at posterior and anterior sites decreased as more patients were recruited, no significant improvements were observed at apex and base sites. Three-year bPFS rates in pT2 ew-, pT2 ew+, pT3 ew- and pT3 ew+ were 95.8%, 85.7%, 81% and 48.5%, respectively, indicating that positive margins exert a greater impact in pT3 disease than in pT2 disease. CONCLUSIONS: Although 3-year bPFS results were almost identical to previous reports of LRP and retropubic radical prostatectomy, the positive margin rate in pT3a disease was particularly high, probably due to immature surgical skill. Although positive margins at posterior and anterior sites decreased with the leaning curve, improvements are needed to reduce positive margin rates at the apex. Positive margins exert greater impact in pT3 disease than in pT2 disease.

Hinata N, Shirakawa T, Terao S, Goda K, Tanaka K, Yamada Y, Hara I, Kamidono S, Fujisawa M, Gotoh A. · Division of Urology, Department of Organ Therapeutics, Faculty of Medicine, Kobe University Graduate School of Medicine, Kobe, Japan. · Int J Urol. · Pubmed #16834676 No free full text.

Abstract: There is no effective therapy for hormone-refractory prostate cancer and a novel therapeutic modality, such as a gene therapy, should be actively pursued. Previously, Gardner and Chung conducted a phase I clinical trial of Ad-OC-TK (recombinant adenoviral vector containing osteocalcin promoter-driven herpes simplex virus thymidine kinase gene) plus VAL (valacyclovir) for the treatment of hormone-refractory prostate cancer at the University of Virginia. We report on our ongoing phase I/II clinical trial of Ad-OC-TK plus VAL for the treatment of advanced prostate cancer at the Kobe University Hospital, Japan.

Miyake H, Muramaki M, Kurahashi T, Yamanaka K, Hara I, Fujisawa M. · Department of Urology, Hyogo Medical Center for Adults, 13-70 Kitaohji-cho, Akashi, Japan. · Anticancer Res. · Pubmed #16619575 No free full text.

Abstract: BACKGROUND: The objectives of this study were to characterize changes in the expression of heat shock protein 27 (HSP27) in prostate cancer before and after androgen withdrawal therapy and to assess the prognostic significance of HSP27 expression in patients undergoing radical prostatectomy (RP) following neoadjuvant hormonal therapy (NHT). MATERIALS AND METHODS: This study included 97 patients with clinically localized prostate cancer who received NHT followed by RP. Paired needle biopsy and corresponding RP specimens obtained from these patients were analyzed for expression of the HSP27 protein by immunohistochemical staining. These findings were evaluated with respect to several clinicopathological factors. RESULTS: HSP27 expression in the RP specimens following NHT was significantly up-regulated compared with that in the corresponding needle biopsy specimens. The expression level of HSP27 in the biopsy specimens was significantly associated with the biopsy Gleason score, but not with other factors available before RP. HSP27 expression in the RP specimens was significantly correlated with the pre-operative value of serum prostate-specific antigen and pathological stage, but not with other pathological factors. Biochemical recurrence-free survival in patients with strong HSP27 expression in the RP specimens was significantly lower than that in those with weak HSP27 expression; however, the expression level of HSP27 was not an independent predictor of biochemical recurrence. CONCLUSION: Despite the lack of independent significance, the expression level of HSP27 in prostate cancer tissue after NHT, which may inversely reflect the therapeutic effect of NHT, could be a useful parameter predicting biochemical recurrence in patients undergoing RP.

Miyake H, Hara I, Yamazaki H, Eto H. · Department of Urology, Hyogo Medical Center for Adults, 13-70 Kitaohji-cho, Akashi 673-8558, Japan. · Oncol Rep. · Pubmed #16077973 No free full text.

Abstract: There is no standard therapeutic strategy for advanced hormone refractory prostate cancer after the initial hormonal therapy fails. The objective of this study was to retrospectively evaluate the clinical outcome of the oral anticancer agent, uracil/tegafur (UFT) for patients with hormone refractory prostate cancer. This study included 68 patients with hormone refractory prostate cancer treated by oral administration of UFT (300-600 mg/day). All patients had previously received maximum androgen blockade (MAB) which failed. In this series, response was defined as more than 50% decrease from the baseline prostate specific antigen (PSA) value at the start of second line therapy. Upon initiating administration of UFT, a reduction in PSA value was observed in 41 of the 68 patients (60.3%), among whom 13 (19.1%) were regarded as responders; however, PSA value continued to increase in the remaining 27 (39.7%). Median duration of PSA response was 7 months (range 1-22 months). During the observation period, there were no severe side effects due to UFT administration, but 7 patients transiently presented appetite loss. Patients without bone metastasis at the initial diagnosis or whose serum PSA value at the start of UFT therapy was less than 2.0 ng/ml showed a significantly higher incidence of PSA response to UFT; however, other factors examined had no significant impact on PSA response to UFT. Furthermore, cause-specific survival in responders to UFT therapy was significantly better than that in non-responders. These findings suggest that administration of UFT after the failure of initial MAB therapy can achieve a comparatively favorable PSA response without severe side effects; therefore, it may be worthy to consider administering UFT to patients with hormone refractory prostate cancer.

Hara I, Kawabata G, Miyake H, Hara S, Fujisawa M, Okada H, Arakawa S, Kamidono S. · Department of Urology, Kobe University School of Medicine, Kobe, Japan. · Int J Urol. · Pubmed #12534908 No free full text.

Abstract: OBJECTIVES: The objective of this study was to present the clinical outcomes of 26 patients who underwent laparoscopic radical prostatectomy at our institution. METHODS: We performed laparoscopic prostatectomy on patients who were clinical stage T1 or T2. The mean age was 70 years old (range: 52-76). The mean level of pre-treatment prostate-specific antigen (PSA) was 8.7 ng/mL (range: 3.3-45). The Gleason score of the needle biopsy was < 7 in 21 patients and > or = 7 in five patients. Clinical stage was T1c in 17 patients, T2a in 6 patients and T2b in 3 patients. Operative techniques followed those of the French groups. Five trocars were introduced into the peritoneal cavity. The vas deferens and seminal vesicles were dissected to reach the posterior wall of the prostate and the retroperitoneal space was dissected around the urinary bladder. Incision of endopelvic fascia and dorsal vein complex (DVC) ligation were performed. The bladder neck and prostate were divided, then the distal urethra was cut. The lateral pedicles of the prostate were cut and the entire prostate was removed. Vesico-urethral anastomosis was performed at eight points. RESULTS: Mean operation time was 7 h 30 min. Mean bleeding volume (including urine volume) was 850 mL (range: 32-3135). All patients underwent autologous blood transfusion. Only one patient required further blood transfusion. Gleason scores of resected specimens were < 7 in 10 patients, and > or = 7 in 16 patients. Pathological stage was T0 in 1 patient, T2a in 6 patients, T2b in 13 patients, T3a in 5 patients and T3b in 1 patient. The PSA value was undetectable in all patients one month after surgery. Ten patients who survived for 6 months after surgery had complete urinary continence without a pad. In 7 of the 12 patients who were potent before surgery, neurovascular bundles were preserved, and 5 of them (71%) achieved complete or incomplete erection 3 months after surgery. However, only one patient (14%) could have sexual intercourse. CONCLUSION: Although longer follow-up is necessary to evaluate this surgical technique, laparoscopic prostatectomy seems to be a reasonable option in the treatment of organ-confined prostate cancer.

Hara I, Miyake H, Yamada Y, Takechi Y, Hara S, Gotoh A, Fujisawa M, Okada H, Arakawa S, Soejima T, Sugimura K, Kamidono S. · Department of Urology, Kobe University School of Medicine, Japan. · Int J Urol. · Pubmed #12269247 No free full text.

Abstract: BACKGROUND: It is unclear whether positive interactions between radiation and androgen withdrawal for patients with locally advanced prostate cancer is synergistic or additive. The present study aimed to clarify the significance of neoadjuvant androgen ablation prior to external radiotherapy in a human prostate LNCaP tumor model and in patients with locally advanced prostate cancer. METHODS: Comparisons were made between the effect of castration prior to radiation on the growth of subcutaneous LNCaP tumors implanted into male nude mice and their serum prostate-specific antigen (PSA) levels, and the results of castration or radiation alone. Twenty-nine patients with histologically proven and locally advanced adenocarcinoma of the prostate were treated with luteinizing hormone-releasing hormone analog at least 3 months before, during, and after external radiation therapy with a total dose of 70 Gy. The toxicity and response to this therapy were evaluated. RESULTS: Treatment combining castration and radiation resulted in synergistic inhibition of LNCaP tumor growth and a significant delay in the emergence of androgen-independent recurrence as opposed to either treatment alone. The external radiotherapy was completed in 28 patients (96.6%), resulting in a reduction of serum PSA levels in all 28 patients to below 1.0 ng/mL. All patients were alive after a mean follow-up period of 34 months (range 11-53) with a 3-year PSA relapse-free survival rate of 83.7%. Among several factors examined, only the Gleason score was significantly associated with PSA relapse-free survival in univariate analysis, but not in multivariate analysis. Thirteen of 28 patients (46%) and 7 of 28 (25%) also showed at least one form of gastrointestinal or genitourinary toxicity, respectively. Of these patients, 8 with gastrointestinal toxicities, and 1 with genitourinary toxicity, experienced acute complications higher than grade 3. CONCLUSION: The experimental findings objectively suggested the use of neoadjuvant androgen withdrawal prior to radiation therapy. Although our clinical experience is preliminary, combined androgen ablation and radiation therapy may also be effective in controlling locally advanced prostate cancer, with tolerable side-effects.

Fujisawa M, Higuchi A, Gotoh A, Matsui T, Hara I, Gohji K, Okada H, Arakawa S, Kamidono S. · Department of Urology, Kobe University School of Medicine, Japan. · Int J Urol. · Pubmed #10226811 No free full text.

Abstract: PURPOSE: In order to evaluate precise anastomosis using a Foley catheter, complications following radical retropubic prostatectomy were examined. METHODS: Twenty-one patients underwent radical retropubic prostatectomy. Precise vesicourethral anastomosis was performed, visualizing the urethral stump by raising up the urogenital diaphragm using a Foley catheter. Complications, such as prolonged urinary extravasation and temporary urinary retention, were checked when the catheter was removed. Incontinence was evaluated both within 6 weeks and more than 6 weeks after operation. Anastomotic and urethral strictures were also checked during follow up. RESULTS: The follow-up period ranged from 4 to 47 months (mean (+/- SD) 22.0 +/- 12.1 months). Eighteen of 21 patients (85.7%) achieved continence after the operation. However, two patients still had stress incontinence and one patient had mild incontinence. Neither prolonged urinary extravasation nor temporally urinary retention were observed. Anastomotic and urethral stricture were not experienced during follow up. CONCLUSIONS: Precise anastomosis using a Foley catheter is technically easy and useful, even for relatively inexperienced urologists, to perform. Patients can often achieve continence following this procedure.

Takenaka A, Yamada Y, Miyake H, Hara I, Fujisawa M. · Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan. · Int J Urol. · Pubmed #18380817 No free full text.

Abstract: OBJECTIVES: We analyzed the clinical outcomes of instillation therapy with Bacillus Calmette-Guerin (BCG) to treat carcinoma in situ (CIS) and searched for prognostic factors that could predict disease progression. METHODS: Between January 1995 and January 2001, 185 patients (male, 155; female, 30) diagnosed with bladder CIS underwent weekly BCG instillations (80 mg of Tokyo 172 strain) for eight weeks. Primary, concomitant, and secondary CIS was found in 62 (33.5%), 60 (32.4%) and 63 (34.1%), patients, respectively. Seventy-five (40.5%) and 64 (34.6%) patients had limited and extensive CIS, respectively. The median follow up period was 37.5 months (range 4-95 months). RESULTS: The overall complete response rate was 86.5%. The five-year progression-free survival rate was 78.5%. Several factors, such as age (<60 or >or=60 years), gender, previous transurethral resection, type of CIS, and CIS extension (three or more positive sites out of four to six biopsy sites was defined as extensive), were examined by multivariate analysis to predict progression. The extension of CIS was the only independent prognostic factor. The five-year recurrence-free rate of complete responders (n = 160) was 66.0%. Radical cystectomy was performed in 10 patients (6.3%) during follow up incomplete responders, of whom seven had invasive bladder cancer. Extravesical involvement was identified in 30 patients (16.2%) among whom, 21 (11.3%) had upper urinary tract recurrence and nine (4.9%) had prostatic involvement. CONCLUSION: Therapy with BCG is effective against CIS, the extent of which might be a prognostic factor. Disease progression including extravesical involvement should be carefully monitored over the long-term after BCG therapy.

Miyake H, Kurahashi T, Takenaka A, Hara I, Fujisawa M. · Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan. · Urol Int. · Pubmed #18025846 No free full text.

Abstract: INTRODUCTION: The objective of this study was to determine whether an increased number of transrectal biopsy cores improves the accuracy of the biopsy Gleason score. MATERIALS AND METHODS: This study included a total of 225 patients who were diagnosed as having prostate cancer by transrectal needle biopsy and subsequently underwent radical prostatectomy (RP) without neoadjuvant therapy. The rate of grading concordance between biopsy and RP specimens was analyzed by dividing these patients into 2 groups as follows: group A, 107 patients who underwent transrectal biopsy sampling of 9 cores or less (median 8 cores), and group B, 118 patients who underwent biopsy sampling of 10 cores or more (median 12 cores). RESULTS: Concordance between the biopsy and RP Gleason scores in group A (53.3%) was significantly lower than that in group B (69.5%). Upgrading of the biopsy Gleason score in group A (38.3%) was significantly more frequent than that in group B (21.2%). Furthermore, these findings tended to be more prominent as the biopsy Gleason score was lower. Multivariate analysis identified the number of biopsy cores and percent of positive biopsy cores as independent predictors of accurate Gleason grading regardless of other parameters examined in this study. CONCLUSION: These findings suggest that obtaining a greater number of biopsy cores contributes to improving the accuracy of the biopsy Gleason score for predicting the RP Gleason score; therefore, extended sampling of biopsy cores could provide optimal guidance to determine the therapeutic options in patients with prostate cancer.

Terakawa T, Miyake H, Nakano Y, Tanaka K, Takenaka A, Hara I, Fujisawa M. · Division of Urology, Kobe University Graduate School of Medicine. · Hinyokika Kiyo. · Pubmed #18018591 No free full text.

Abstract: We report a case of prostatic abscess in a 22-year-old man with metastatic testicular cancer being treated by BEP (bleomycin, etoposide and cisplatin) chemotherapy. This abscess was successfully treated by surgical drainage with transurethral resection of the prostate (TURP) under the guidance of transrectal ultrasound, allowing the patient to continue be receiving BEP without significant interruption. Drainage TURP is suggested to be a useful strategy for prostate abscess, when prompt control of symptoms caused by prostatic abscess is required.

Kurahashi T, Miyake H, Shinozaki M, Oka N, Takenaka A, Hara I, Matsumura Y, Fujisawa M. · Division of Urology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. · Int Urol Nephrol. · Pubmed #17619159 No free full text.

Abstract: OBJECTIVES: The objectives of this study were to evaluate the usefulness of serum prostate-specific antigen (PSA) screening in detecting prostate cancer in Japanese men on hemodialysis, and to analyze features of prostate cancer detected in these patients. MATERIALS AND METHODS: This study included 115 male hemodialysis patients aged > 55 years who agreed to the measurement of serum PSA value (group A) and 7529 men aged > 55 years participating in a PSA mass screening test in Kobe City (group B) between April 2005 and March 2006. Prostate biopsy was recommended in men with serum PSA > 4.0 ng/ml in both groups. Seventy-eight patients with normal renal function aged > 55 years diagnosed as having prostate cancer during the same time period as groups A and B were also included as a comparison group (group C). RESULTS: There was no significant difference in the distribution of serum PSA values between groups A and B. Prostate biopsy was performed in 8 and 205 men in groups A and B, respectively, and prostate cancer was detected in 5 and 68 in groups A and B, respectively; that is, there was no significant difference in the rate of positive prostate biopsy between these two groups (group A, 62.5%; group B, 33.2%), while the cancer detection rate in group A (4.3%) was significantly greater than that in group B (0.90%). In addition, there was no evident metastasis in five patients on hemodialysis who were diagnosed as having prostate cancer, and their serum PSA, clinical T stage and biopsy Gleason score were similar to those in group C. However, the percent of positive biopsy cores in these five was significantly greater than that in group C. All five were treated by maximal androgen blockade therapy, and all are currently alive without emergence of hormone-refractory diseases. CONCLUSIONS: These findings indicate that hemodialysis patients may have an increased risk of prostate cancer, and that prostate cancer detected in such patients tends to be relatively advanced. Therefore, it would be recommended for hemodialysis patients to undergo PSA testing to screen for prostate cancer.

Furukawa J, Miyake H, Takenaka A, Hara I, Fujisawa M. · Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan. · BJU Int. · Pubmed #17511772 No free full text.

Abstract: OBJECTIVES: To characterize the changes in the expression of Aurora-A protein in prostate cancer before and after androgen-withdrawal therapy, and to assess the prognostic significance of the Aurora-A expression in patients undergoing radical prostatectomy (RP) after neoadjuvant hormonal therapy (NHT). PATIENTS AND METHODS: The study included 97 patients with clinically localized prostate cancer who received NHT followed by RP. Paired needle biopsy and corresponding RP specimens obtained from these patients were analysed for the expression of Aurora-A protein by immunohistochemical staining. These findings were then evaluated in relation to several clinicopathological factors. RESULTS: There were various levels of Aurora-A protein expression in most prostate cancer tissues before NHT; however, the Aurora-A expression in RP specimens after NHT was significantly down-regulated compared with that in corresponding needle-biopsy specimens. The expression level of Aurora-A in biopsy specimens was significantly associated with the biopsy Gleason score, but not with other factors available before RP. The Aurora-A expression in the RP specimens correlated significantly with the preoperative value of the serum prostate specific antigen and pathological stage, but not with any other clinicopathological factors examined. Furthermore, cell proliferative activity in the RP specimens, measured by Ki-67 immunostaining, was proportional to the expression of Aurora-A. The biochemical recurrence-free survival in patients with a persistent Aurora-A expression in RP specimens was significantly lower than that in those with a weak Aurora-A expression, but the expression level of Aurora-A was not an independent predictor of biochemical recurrence. CONCLUSIONS: Despite the lack of any independent significance, the expression level of Aurora-A in prostate cancer tissue after NHT, which might inversely reflect the therapeutic effect of NHT, could therefore be a useful variable for predicting biochemical recurrence in patients undergoing RP.

Hara I, Tanaka K, Yamada Y, Miyake H, Takenaka A, Fujisawa M. · Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan. · Int J Urol. · Pubmed #17511739 No free full text.

Abstract: Laparo- or retroperitoneoscopic biopsy was performed for five male patients with retroperitoneal lymph node swelling of unknown origin. Previous core needle biopsies were useless or inapplicable in all patients. A laparoscopic approach was used for two patients, with a retroperitoneoscopic approach for the remaining three patients. Sufficient specimens for not only pathological diagnosis but also further examinations such as immunophenotyping or DNA analysis were safely obtained. Convalescence was satisfactory and all patients were treated appropriately according to the resulting diagnosis. This technique should be performed by urologists, who are more familiar with laparo- or retroperitoneoscopic approach targeting retroperitoneal organs.

Miyake H, Harada K, Inoue TA, Takenaka A, Hara I, Fujisawa M. · Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan. · Urology. · Pubmed #17445661 No free full text.

Abstract: OBJECTIVES: To evaluate the significance of additional routine biopsies targeting the dorsal apex (DA) in men undergoing transrectal ultrasound (TRUS)-guided biopsies. METHODS: This study included 429 patients undergoing TRUS-guided biopsy of the prostate. As a rule, 12 cores were taken from each patient, with 8 cores taken from the peripheral zones, 2 cores from the transition zones, and 2 additional cores from the DA. RESULTS: Cancer was detected in 150 patients, of whom 97 had positive cores in the DA. Furthermore, cancer was detected only in the DA in 14 patients; that is, the increase in the cancer detection rate by additional sampling from the DA was 9.3%. Significant differences were found in the prostate-specific antigen level, prostate-specific antigen density, digital rectal examination findings, TRUS findings, clinical T stage, and percentage of positive biopsy cores among the 14 men with positive cores in the DA alone (group 1), 83 in the DA and other regions (group 2), and 53 in regions except for the DA (group 3). Of these, radical prostatectomy was performed in 6, 41, and 26 in groups 1, 2, and 3, respectively. No significant differences were found in the several pathologic factors among these groups, and 5 of the 6 patients in group 1 had a tumor volume greater than 0.5 cm3. CONCLUSIONS: Additional sampling of biopsy cores from the DA significantly improved the cancer detection rate, particularly for early disease; however, this method does not appear to increase the detection of insignificant cancer. Accordingly, we recommend performing systematic biopsy routinely targeting the DA.

Miyake H, Hara I, Kurahashi T, Inoue TA, Eto H, Fujisawa M. · Department of Urology, Kobe University School of Medicine, Kobe, Japan. · Clin Cancer Res. · Pubmed #17317829 links to  free full text

Abstract: PURPOSE: Routine pathologic examination can miss micrometastatic tumor foci in the lymph nodes of patients with prostate cancer, resulting in confusion during tumor staging and clinical decision-making. The objective of this study was to clarify the significance of micrometastases in pelvic lymph nodes in patients who underwent radical prostatectomy for prostate cancer. EXPERIMENTAL DESIGN: The expression of prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) in 2,215 lymph nodes isolated from 120 patients with clinically localized prostate cancer was assessed by a fully quantitative real-time reverse transcriptase-PCR. We regarded specimens in which either PSA or PSMA mRNAs were positive as proof of the "presence of micrometastasis." Immunohistochemical staining of lymph node specimens with an antibody against PSA was also done. RESULTS: Pathologic examinations detected tumor cells in 29 lymph nodes from 11 patients, and real-time reverse transcriptase-PCR further identified micrometastasis in 143 lymph nodes from 32 patients with no pathologic evidence of lymph node involvement. The presence of micrometastatic cancer cells was confirmed by immunohistochemical staining in 61 lymph nodes from 17 patients with pathologically negative lymph nodes. The presence of micrometastases was significantly associated with other conventional prognostic variables, including serum PSA value, pathologic stage, Gleason score, and tumor volume. Biochemical recurrence was detected in 32 patients, 17 of whom were negative for lymph node metastasis by pathologic examination (including 4 patients with pathologically organ-confined disease), but were diagnosed as having micrometastasis. Biochemical recurrence-free survival rate in patients without micrometastasis was significantly higher than in those with micrometastasis irrespective of the presence of pathologically positive nodes. Furthermore, only the presence of micrometastasis was independently associated with biochemical recurrence regardless of other factors examined. CONCLUSIONS: These findings suggest that approximately 30% of clinically localized prostate cancers shed cancer cells to the pelvic lymph nodes, and that biochemical recurrence after radical prostatectomy could be explained, at least in part, by micrometastases in pelvic lymph nodes.

Kurahashi T, Miyake H, Hara I, Fujisawa M. · Department of Urology, Kobe University School of Medicine, Hara Genitourinary Hospital, Kobe, Japan. · J Urol. · Pubmed #17222676 No free full text.

Abstract: PURPOSE: We evaluated expression levels of major heat shock proteins in radical prostatectomy specimens to clarify the significance of heat shock protein expression in prostate cancer. MATERIALS AND METHODS: Expression levels of heat shock proteins 27, 70 and 90 in radical prostatectomy specimens from 172 patients with clinically organ confined prostate cancer who had not received neoadjuvant hormonal therapy were measured by immunohistochemical staining. Cell proliferative activities and apoptotic features in these specimens were investigated using Ki-67 immunostaining and TUNEL assay, respectively. These findings were analyzed with respect to several clinicopathological factors. RESULTS: Various levels of heat shock protein 27 expression were noted in all prostate cancer specimens. Expression levels of heat shock protein 27 in prostate cancer tissues was significantly associated with pathological stage, Gleason score, surgical margin status, lymph node metastasis and tumor volume but not with other parameters, including patient age, serum prostate specific antigen and perineural invasion. Similarly most prostate cancer tissues showed heat shock protein 70 and 90 expression. However, there was no significant correlation between expression levels of these 2 heat shock proteins and several clinicopathological factors examined. Cell proliferative activity in prostate cancer specimens was significantly associated with heat shock protein 27 expression but not with that of heat shock proteins 70 and 90, while there was no significant correlation between the apoptotic index and the expression of these 3 heat shock proteins. Furthermore, despite the lack of prognostic significance in heat shock proteins 70 and 90 expression, biochemical recurrence-free survival in patients with strong heat shock protein 27 expression in radical prostatectomy specimens was significantly lower than that in those with weak heat shock protein 27 expression. However, multivariate analysis showed that strong heat shock protein 27 expression could not be an independent predictor of biochemical recurrence after radical prostatectomy. CONCLUSIONS: These findings suggest that, despite the limited significance of heat shock proteins 70 and 90 expression, heat shock protein 27 may be involved in the progression of prostate cancer. The expression level of heat shock protein 27 in prostate cancer tissue could be used as a useful predictor of biochemical recurrence in patients undergoing radical prostatectomy.