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Androgen, acting via the androgen receptor (AR), is associated with the development and progression of prostate cancer. Anti-androgen therapy is widely used to manage prostate cancer. However, the conversion of the tumor from a hormone-sensitive to a hormone-insensitive status causes such therapy to fail. Several mechanisms have now been put forward for this conversion, including neuroendocrine (NE) differentiation of the tumor cells. In this study, we evaluated the prognostic significance of tumor-cell proliferation activity, NE differentiation and AR expression. Formalin-fixed, paraffin-embedded sections were prepared from 42 patients with adenocarcinoma of the prostate. Using antibodies to AR, the Ki-67 antigen (MIB-1), chromogranin A and synaptophysin, immunohistochemical expression of AR, tumor proliferation activity and NE differentiation were analyzed. Our study revealed that AR expression was significantly lower in adenocarcinoma (52.2 ± 27.1%) than in non-tumorous prostate tissue (68.3 ± 18.3%; P < 0.001). NE differentiation was found in 50% of the tumors, which was correlated with the Gleason score (P < 0.05). An univariate analysis revealed a significant correlation between progression-free survival with both AR expression (P < 0.01) and proliferation activity (P < 0.001). NE differentiation was not a prognostic factor in this study. [ABSTRACT FROM AUTHOR]

Prostatic basal cell carcinoma (BCC), a distinctive variant of adenocarcinoma, is rare. We report a patient with pure basaloid BCC showing an extraprostatic extension and lymph node metastases. A 67-year-old man with urinary outlet obstruction was referred to our hospital. Digital rectal examination disclosed a stony hard prostate. Serum prostate-specific antigen and prostatic acid phosphatase were within the normal range. Transrectal needle biopsy of the prostate was followed by transurethral resection as symptomatic treatment. The lesion was diagnosed histopathologically as BCC. Despite antiandrogen therapy distant metastases developed, and the patient died 5 months postoperatively. We discuss the histological and immunohistochemical findings in this case. [ABSTRACT FROM AUTHOR]

A 72-year-old Japanese man presented with a painless swollen left scrotal mass with elevated levels of serum α-fetoprotein and prostate specific antigen. The patient underwent high orchiectomy under diagnosis and a final pathological examination revealed embryonal carcinoma of the left testis. A systematic needle prostate biopsy under guidance of transrectal ultrasound revealed prostate cancer (Gleason score, 8) on the left lobe (T2aN0M0). Systemic chemotherapy was given for retroperitoneal lymph node metastasis of testicular cancer and hormonal therapy (LH-RH analog) was given for prostate cancer. The patient was well with no evidence of metastasis from the testicular cancer or prostate cancer and with no elevation of serum α-fetoprotein or prostate specific antigen 26 months after the orchiectomy. [ABSTRACT FROM AUTHOR]

Similar to fingerprints, humans have unique, genetically determined body odours. In case of urine, the odour can change due to variations in diet as well as upon infection or tumour formation. We investigated the use of mice in a manner similar to "sniffer dogs" to detect changes in urine odour in patients with bladder cancer. We measured the odour discrimination thresholds of mice in a Y-maze, using urine mixtures from patients with bladder cancer (Stage I) and healthy volunteers (dietary variations) as well as occult blood- or antibiotic drug metabolite-modulated samples. Threshold difference indicated that intensities of urinary olfactory cues increase in the following order: dietary variation < bladder cancer < occult blood < antibiotic drug metabolites. After training with patient urine mixtures, sniffer mice discriminated between urine odours of pre- and post-transurethral resection in individual patients with bladder cancer in an equal-occult blood diluted condition below the detection level of dietary variations, achieving a success rate of 100% (11/11). Furthermore, genetic ablation of all dorsal olfactory receptors elevated the discrimination thresholds of mice by ≥ 10 5 -fold. The marked reduction in discrimination sensitivity indicates an essential role of the dorsal olfactory receptors in the recognition of urinary body odours in mice.

Purpose: To evaluate the efficacy and safety of imidafenacin (IM), a novel short half-life anticholinergic, as add-on therapy for male LUTS with nocturia and nocturnal polyuria., Materials and Methods: This multicenter, prospective, randomized, open-labelled study was conducted and involved men who had frequency, urgency, and nocturia despite receiving a stable dose of α1-blocker for ≥1 month. Subjects were randomised to control (α1-blocker alone), IM twice/day (α1-blocker +0.1 mg imidafenacin twice daily), or IM nightly (α1-blocker plus 0.1 mg imidafenacin nightly) group; the treatment period was 8 weeks. Primary endpoints included improvements in night-time frequency and Nocturia Quality of Life Questionnaire (N-QOL) scores. Secondary endpoints included changes from the baseline in frequency volume chart variables, and post-void residual volume., Results and Limitations: Compared with the controls, IM twice/day and IM nightly patients had a significantly lower night-time frequency (changes from baseline: 0.1 ± 0.8 in control, -0.6 ± 0.9 in IM twice/day, and -0.4 ± 1.0 in IM nightly, p = 0.5227, 0.0006 and 0.0143, respectively). The hours of undisturbed sleep and N-QOL score were significantly improved in IM twice/day group, though not IM nightly group. Nocturnal urine volume was significantly reduced in IM nightly group, although total urine volume remained unchanged., Conclusions: A short half-life anticholinergic is suggested to be safe and effective as an add-on therapy for residual nocturia in patients with male LUTS receiving α1-blocker treatment. Anticholinergic administration nightly could reduce the nocturnal urine volume.

Aim: The aim was to compare patients' morbidity and response of bacillus Calmette-Guérin (BCG) prophylaxis after the intravesical instillation of low-dose Tokyo 172 strain and regular dose Connaught strain in patients with nonmuscle invasive bladder cancer (NMIBC)., Patients and Methods: This was a randomized, active-controlled, open-label, monocenter study. Thirty-eight, NMIBC patients were treated sequentially, in a random order, with low-dose Tokyo 172 strain and regular dose Connaught strain, receiving each therapy for 6 weeks. A total of 18 and 20 patients were randomly assigned to a Tokyo 172 strain arm and a Connaught strain arm, respectively. Complication, morbidity, and recurrence-free survival (RFS) after each treatment were compared., Results: There was no significant difference in the 1-year RFS rate in patients treated with Tokyo 172 strain and Connaught strain (72.2% vs. 83.5%, respectively; P = 0.698). There were no significant differences in adverse events between the arms. Severe adverse events (>Grade 3) were seen in 15% of the Connaught strain group while no severe adverse events were observed as a result of Tokyo 172 strain., Conclusion: Our results indicated that low-dose Tokyo 172 strain decreased adverse events although it was not significant, and the RFS difference was not statistically significant between the two arms. Further investigation is warranted.

Smac/DIABLO promotes apoptosis by antagonizing inhibitor of apoptosis proteins. The expression of Smac/DIABLO in tissues has been reported in various cancers; however, little is known about circulating levels of Smac/DIABLO. The present study was designed to first determine if Smac/DIABLO can be detected in the serum and then assess whether the circulating levels of Smac/DIABLO are of prognostic significance in patients with bladder cancer. The levels of Smac/DIABLO in the sera of 173 patients with bladder cancer and 36 normal donors were determined by using an enzyme-linked immunosorbent assay. The mean serum level of Smac/DIABLO in patients with bladder cancer was approximately 2-fold lower than that in normal donors. The mean level of serum Smac/DIABLO in patients with muscle-invasive bladder cancer was lower than that in patients with non-muscle invasive cancer. In addition, the mean serum Smac/DIABLO level in patients with T4 muscle-invasive bladder cancer was lower than that in patients with T2 and T3 cancers. The mean serum level of Smac/DIABLO in patients with Grade 3 bladder cancer was lower than that in patients with Grade 1 and Grade 2 cancers. Analysis by Kaplan-Meier revealed that patients with Ta and T1 non-muscle invasive bladder cancer with high level of serum Smac/DIABLO (more than mean value) had a longer post-operative tumor-free interval than those with low level (less than mean value) in the 3-year follow-up. Furthermore, patients with T2-T4 muscle-invasive bladder cancer with high serum Smac/DIABLO level (more than mean value) had a higher post-operative disease-free rate when compared with patients with low level (less than mean value) in the 5-year follow-up. The present study is the first to analyze circulating levels of Smac/DIABLO in the serum. The findings demonstrate that the mean serum level of Smac/DIABLO was downregulated in patients with bladder cancer compared to control healthy individuals, especially high grade muscle-invasive bladder cancer. Noteworthy, lower serum level of Smac/DIABLO predicted early recurrence in patients with bladder cancer. Overall, the findings suggest that measuring the levels of Smac/DIABLO in the serum may be considered a prognostic parameter in patients with bladder cancer. Furthermore, Smac/DIABLO may be a molecular therapeutic target in bladder cancer.

Urinary incontinence is a major complication following radical prostatectomy. The aim of the present study was to assess the association between urinary continence following laparoscopic radical prostatectomy (LRP) and various factors measured using real-time intraoperative transrectal ultrasonography (TRUS). Patients (n=53) with localized prostate cancer underwent LRP in combination with real-time intraoperative TRUS navigation and were evaluated for urinary continence for more than 6 months following LRP. Prostate size, membranous urethral length (MUL) and bladder-urethra angle were measured using real-time intraoperative TRUS immediately before and after surgery. Urinary continence was regained by 4, 15 and 27 patients 1, 3 and 6 months after LRP, respectively. Longer postoperative MUL was significantly correlated with recovery of urinary continence 1, 3 and 6 months after LRP. In addition, an increase in difference between preoperative and postoperative MUL was also associated with superior continence. No correlation was observed between postoperative MUL and the rate of tumor-positive surgical margins. Larger prostate volume was correlated to postoperative continence 6 months after surgery. Shorter operation time and less blood loss resulted in postoperative urinary continence 1 month after LRP. Preoperative MUL, bladder-urethra angle, age and body mass index had no correlation with urinary continence. Postoperative MUL was the most significant factor for early recovery of urinary continence following LRP. These results indicate that preservation of longer urethra during surgery may be recommended without tumor-positive surgical margins.

We report a case of Klinefelter syndrome with the chief complaint of male infertility. Normal pregnancy and delivery resulting from conventional testicular sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI) was possible by a previous doctor when he was 31 years old. He was referred to our hospital for treatment of infertility when he was 41 years old. Abdominal ultrasonography demonstrated a low echoic region with a relatively uniform content in the left testis and a central low echoic small mass surrounded by a high echoic region in the right testis. In excised tissue of the left testis, only a single seminiferous tubule containing spermatozoa was found and sperm was successfully retrieved by microdissection TESE.

A 46-year-old man who has a child from a previous marriage without artificial reproductive technologies was referred to our hospital with a chief complaint of infertility. He had suffered from bilateral orchitis after parotitis six years ago. On physical examination, both testes were soft and 4 ml in size. Semen analysis showed azoospermia and the serum follicle stimulating hormone value was high (36.9 mIU/ml). Microdissection testicular sperm extraction was performed, and motile sperm were successfully retrieved. The histological examination showed increased thickness of the basement membrane and, peritubular fibrosis in most seminiferous tubules, with few focal areas of normal spermatogenesis.

A 71-year-old man underwent left nephrectomy for metastasis from renal cell carcinoma (RCC) of the small intestine. In spite of post-operative therapy (interferon-alpha or interleukin-2), multiple lung metastases and intestinal hemorrhage by metastatic tumor of small intestine appeared 9 years after the operation. To control the bleeding from the small intestine, the small intestine was partially excised and the histopathological diagnosis was metastasis of RCC. He died 10 months later because of disease progression. Metastasis of RCC to the small intestine is rare. To our knowledge, this is the 40th case of small intestinal metastasis from RCC reported in the literature.

A total of 121 Japanese patients scheduled for prostate biopsy were randomly and double-blindly assigned to be given a single oral dose of 100 mg Tramadol mixed with 20 ml of sugar syrup or placebo, 30 minutes before the procedure. Pain severity was measured by verbal rating scale (VRS) and visual analog scales (VAS). We also analyzed cardio-respiratory parameters and complications. Of 121 patients, 117 replied validly to VRS and VAS ; and 91 of 117 patients replied to the cohort questionnaire for analysis of the late disorder, patient's impression, prolonged pain and past history of hemorrhoid treatment. Tramadol showed no significant effect on pain severity indicated by VRS and VAS, and no change in cardiorespiratory parameters. Furthermore, 70 patients without a history of hemorrhoid treatment, showed no significant analgesic benefits of Tramadol during the biopsy. In total, 3 patients had side effects of vomiting (CTCAE : grade 1)6), which subsided spontaneously. The oral administration of a single dose of 100 mg Tramadol 30 minutes before a transrectal needle biopsy of the prostate was safe, but was not effective to calm down the pain severity.

In the present study, we report the utility of transrectal ultrasonography guidance for laparoscopic radical prostatectomy (LRP), and the effect of a novel surgical approach of 'seven key elements of operative skill for the early recovery of urinary continence' ('7 key elements'). Among 170 patients who underwent laparoscopic prostatectomy between July 2007 and June 2010, 72 were treated on the basis of these 7 key elements (group 1), which included the preservation of 1) endopelvic fascia, 2) bladder neck, 3) pelvic nerve, 4) membranous urethra, 5) urethral sphincter and fixation of the organ positioning with 6) bladder neck sling suspension, and 7) restoration of the Denonvilliers' fascia, while the remaining 98 were not (group 2). We compared the data for the two groups with regards to the time taken for recovery of continence, and post-operative course. Application of the 7 key elements led to significantly earlier recovery of continence. In group 1, the number of urinary pads used after surgery was significantly reduced at all of the examined time-points after surgery (1, 3, 6 and 12 months) (p&lt;0.0001). In group 1, more than half of the patients (54%) achieved urinary continence within 3 months, 93% achieved it within 6 months, and all patients had achieved it within 12 months after surgery. However, in group 2, <10% of the patients (8.5%, p<0.0001) achieved continence within 3 months, and 23% (P<0.0001) achieved it within 6 months. Therefore, the results show that the 7 key elements of operative skill with transrectal ultrasonography guidance significantly improve the outcome of LRP, reducing the time required for the recovery of continence.

We investigated the prognostic value of BMI (body mass index) in Asian patients with RCC (renal cell carcinoma). We evaluated 170 Asian patients who underwent surgery for localized RCC (pathologic T1-4 tumors in the absence of nodal or distant metastases) between 1996 and 2004 at our institution. Patients were stratified by BMI: 22 or less vs. greater than 22. Overall, CSS (cancer-specific survival) and RFS (recurrence-free survival) was estimated using the Kaplan-Meier method. Multivariate analysis was performed with the Cox regression model. The mean age and BMI of all patients was 62.4 ± 11.4 yr and 23.1 ± 3.2 kg/m(2), respectively. Patients' population consisted of 114 (67.1%) men and 56 (32.9%) women. The median follow-up was 50 mo. The BMI was less than 22 in 83 (49%) patients and greater than 22 in 87 (51%). There was a trend toward worse Eastern Cooperative Oncology Group (ECOG) performance status, less likely to have an incidentaloma, higher pathological stage, and more frequent microvascular invasion with lower BMI. Only the correlations between BMI and ECOG performance status (P = 0.003) and pathological stage (P = 0.015) were statistically significant. Of other relevant factors including gender, mode of presentation, ECOG performance status, C-reactive protein, histological type, Fuhrman nuclear grade, microvascular invasion, pathological stage, and adjuvant cytokine therapy, smaller BMI remained an independent predictor for worse CSS (44.5 mo vs. 56.0 mo, P = 0.041, HR = 10.99) and RFS (43.0 mo vs. 55.0 mo, P = 0.03, HR = 2.653), but not for OS (overall survival) (46.0 mo vs. 55.5 mo, P = 0.13, HR = 2.217) on multivariate analysis. Our findings identify increasing BMI in the Asian population as an independent predictor for favorable CSS and RFS in patients with RCC treated by surgery. Further studies, including a multiinstitutional, prospective Asian cohort, are required to confirm these findings.

In this study, we investigated the novel bladder preservation therapy, the balloon-occluded arterial infusion (BOAI) of cisplatin/gemcitabine, concomitantly with hemodialysis, along with concurrent irradiation [the 'Osaka Medical College (OMC)-regimen'] in patients >70 years of age with muscle-invasive bladder cancer. Eighty-three such patients were assigned to receive either the OMC-regimen (n=56) or cystectomy (n=27). The OMC-regimen patients who failed to achieve complete response (CR) underwent cystectomy, or secondary BOAI with gemcitabine (1600 mg). The OMC-regimen, which delivers an extremely high concentration of anti-cancer agent to the tumor site without systemic adverse effects, yielded CR in >90% (39/43) of patients with locally invasive tumors [70% (39/56) of all patients including those with T4 and N+ disease]. None of the CR patients showed recurrence after a mean follow-up of 162 (range, 35-683) weeks, and 2 patients died of unrelated causes. The 5- and 12-year overall survival rates were 92.7 and 69.5% (vs. 59.6 and 20.9% for cystectomy; P<0.0092), respectively, although the median age in the OMC-regimen group was significantly greater than that in the cystectomy group (median, 77; range, 70-98; vs. 74; 70-79; p<0.0001). No patients suffered grade III or more severe toxicities. The oldest patient, aged 98 years, successfully completed this therapy. The OMC-regimen is a useful bladder preservation strategy for elderly patients with locally invasive bladder cancer, not only for those for whom cystectomy has been indicated, but also for patients whose condition is not amenable to curative treatment and for whom palliation would otherwise seem the only option.

Purpose: To assess the association between the development of a urethral stricture (US) and disease-free survival for patients with localized prostate cancer treated with high-intensity focused ultrasound (HIFU)., Patients and Methods: Patients with clinical stage T1-T2N0M0 prostate cancer were eligible for treatment with HIFU. Treatment failure was defined according to the Phoenix criteria, and the disease-free survival rate (DFSR) was evaluated using this definition. Patients were divided into two subgroups according to whether or not they developed a US or a subclinical urethral stricture (SCUS) during follow-up. SCUS was defined as clinically insignificant bladder outlet obstruction requiring transient catheterization., Results: A total of 144 patients were included in the present study. The median follow-up time was 47 months (range 2-70). Grade 1-4 US occurred during follow-up in 28 (19.5%) patients and SCUS was found in 30 (20.8%). The 5-year DFSR by Kaplan-Meier estimation was 61.2% for the entire cohort, 78.2% for patients who developed a US/SCUS and 47.8% for those without US or SCUS (p < 0.001). On Cox regression analysis, development of US/SCUS proved to be an independent predictor of DFSR., Conclusions: Development of US/SCUS was identified as a predictor of favorable HIFU treatment outcome., (Copyright © 2011 S. Karger AG, Basel.)

Background: We hypothesized that a superagonistic monoclonal antibody specific for CD28 (CD28SA), which expands regulatory T cells (Tregs) in vivo, would prevent acute rejection and prolong the survival of renal allograft., Methods: We examined whether CD28SA treatment induce donor-specific tolerance using our established rat renal allograft model (Wistar-Lewis)., Results: All control rats died within 13 days because of severe azotemia with marked destruction of graft tissue. In contrast, recipients treated with a triple injection of CD28SA (days -3, 0, and 3) showed good preservation of graft histology and function, with considerable infiltration of Tregs into the allografts; 92% of recipients survived for more than 100 days, and 77% survived by the day of harvest at 180 days. These long-surviving recipients received secondary heterotopic bicardiac allografts from both donor-matched Wistar and third-party Brown Norway rats simultaneously 120 days after kidney transplantation, and seven of eight (87.5%) rats exhibited donor-specific tolerance, accepting the Wistar heart, but acutely rejecting the Brown Norway heart. Interestingly, a single injection of CD28SA 3 days before (day -3), but not 3 days after (day 3), transplantation also induced donor-specific tolerance in some recipients. We then performed adoptive transfer of nonspecific CD4+CD25+ Tregs, purified from CD28SA-treated Lewis rats, with simultaneous injection of hepatocyte growth factor (500 μg/kg/day, intravenously). The treatment induced significant prolongation of graft survival (P<0.0001 vs. control group), and five of eight (62.5%) recipients survived until the day of harvest at 180 days with successful induction of donor-specific tolerance., Conclusions: We have established a novel therapeutic approach for inducing donor-specific tolerance in rats with renal allografts.

Basal cell carcinoma of the prostate, which has been generally considered to be indolent, is an unusual histological type of prostatic carcinoma and is extremely rare. This tumor has been classified according to the prevalent pattern of growth as adenoid cystic carcinoma or basaloid cell carcinoma (BCC), with the former growth pattern being considered to be the main feature of this entity. A 67-year-old Japanese man was admitted to a general hospital with obstructive urinary symptoms. His prostate was slightly enlarged, stony hard, and with a rough surface on digital rectal examination, while serum prostate-specific antigen and prostatic acid phosphatase concentrations were within the normal ranges (0.007 and 0.9 ng/mL, respectively). 2-Fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) exhibited multiple accumulations suspicious for cancer metastases. Specimens obtained by prostatic needle biopsy showed immunohistochemical reactivity for cytokeratin 34βE12 and P63, findings that were identical to those seen in basal cell carcinoma. Basal cell carcinoma of the prostate is a rare tumor, reported in 56 cases so far, and among all these, the pure form of BCC is extremely rare. Immunohistochemistry is indispensable to distinguish this neoplasm from other unusual histological types of prostatic carcinomas. Our findings reveal that tumors with a basaloid cell-predominant pattern have significant potential for a poor prognosis, in contrast with the conventional understanding regarding this neoplasm.

We investigated the effect of balloon-occluded arterial infusion (BOAI) of anticancer agent (cisplatin/gemcitabine), used concomitantly with hemodialysis, which delivers an extremely high concentration of anticancer agent to the site of a tumor without systemic adverse effects, along with concurrent radiation (referred to as the OMC-regimen) in patients with advanced bladder cancer. One hundred and ninety-two patients were assigned to receive either the OMC-regimen (n=96) or total cystectomy (n=96). Patients in the OMC-regimen group who failed to achieve CR underwent cystectomy, or secondary BOAI with an increased amount of CDDP or gemcitabine (1600 mg). The OMC-regimen allowed >89% (69/77) of patients with locally invasive tumors to achieve CR [>70% (70/96) of all patients including those with T4 and N(+) disease]. Most (68/69) of the CR patients were still alive with no evidence of recurrence after a mean follow-up of 161 (range 12-805) weeks. The 5- and 15-year overall survival rates were 91.5 and 81.3% (vs. 59.8% and 40.1% for cystectomy, P<0.0001), respectively. No patients suffered Grade III or more severe toxicities. In contrast, at 5 and 15 years after surgery in the total cystectomy group, about 50 and 60% of patients had suffered disease progression or had died, respectively. The OMC-regimen, a new bladder-preservation strategy for patients with locally invasive bladder cancer, can be curative not only in patients for whom cystectomy is indicated, but also in patients whose condition is not amenable to curative treatment and for whom merely palliative therapy would otherwise seem the only option.

Objective: To assess the feasibility of minimum-incision endoscopic radical prostatectomy (MIERP) in the management of localized prostate cancer., Methods: We conducted clinical evaluations of mean blood loss, operation time, and postoperative course in 50 cases of MIERP performed at Osaka Medical College Hospital from June 2006 to October 2009. The operations were performed according to the MIERP development protocol at our department, with incisions of 10 cm or less in the early cases and 6-7 cm in later cases., Results: In all 50 cases, average bleeding was significantly shortened compared with 19 cases by the conventional method at our institution. The postoperative start of oral intake, start of ambulation, use of analgesics, timing of catheter removal, and duration of hospitalization were all significantly improved with MIERP compared with the conventional method. MIERP patients were divided into 3 consecutive groups (initial 16 cases, midterm 17 cases, and latest 17 cases); mean operation time/mean blood loss were 253 min/1,485 mL, 253.4 min/2,340.9 mL, and 177 min/1,274 mL, respectively., Conclusion: Surgical experience involving approximately 30 cases was required to achieve stable clinical results. MIERP is less invasive than conventional retropubic radical prostatectomy and may be safely introduced to resident urologists., (Copyright © 2010 Asian Surgical Association. Published by Elsevier B.V. All rights reserved.)

Objectives: This study evaluated the safety profile and therapeutic value of a combination therapy of etoposide and ethinylestradiol, which is a novel treatment protocol for patients with hormone-refractory prostate cancer (HRPC)., Patients and Methods: Patients were given etoposide (25 mg/day, daily) and ethinylestradiol (3 mg/day, daily) orally until disease progression or unacceptable toxicity. The response rate, survival and safety profiles were evaluated., Results: Between 2003 and 2009, 61 patients were enrolled. In terms of PSA levels, >70% of patients showed a >50% reduction (complete response [CR] 51%, partial response 23%) and >90% showed a clinical response. Of 58 patients with measurable lesions, 24% (14/58) showed a CR, and most of these patients (13/14, 93%) survived without recurrence with median response duration of 28 months, Conclusion: The regimen was tolerable, with a significant improvement in quality of life, and produced an effective response in patients with HRPC.

Although the expression of Smac/DIABLO has been reported in various cancers, little is known about its clinical significance in bladder cancer. The present study was designed to evaluate the relationship between progression of disease and Smac/DIABLO expression by clinical pathological analysis of patients with bladder cancer. The level of Smac/DIABLO expression was quantified by Western blot analysis using non-fixed fresh frozen tissues derived from patients with bladder cancer. All normal bladders expressed Smac/DIABLO. However, 64/84 (76%) of bladder cancers expressed Smac/DIABLO and 24% were negative. In Ta and T1 superficial bladder cancers, 98% expressed Smac/DIABLO, whereas only 41% expressed Smac/DIABLO in muscle-invasive bladder cancers. Smac/DIABLO expression inversely correlated with the grade of bladder cancer. Patients with Ta and T1 superficial bladder cancer with higher Smac/DIABLO expression had a longer postoperative recurrence-free period than those with lower Smac/DIABLO expression after transurethral resection in the 5-year follow-up. Patients with invasive bladder cancer expressing Smac/DIABLO had a longer postoperative disease-specific survival than those without Smac/DIABLO expression after radical cystectomy in the 5-year follow-up. The cisplatin-resistant T24 bladder cancer line (T24/CDDP) and the adriamycin-resistant T24 line (T24/ADR) showed lower level of Smac/DIABLO expression, compared with the T24 parental line. In conclusion, the present study demonstrates for the first time that Smac/DIABLO expression was downregulated in bladder cancer, especially in high grade muscle-invasive bladder cancer, and that lower Smac/DIABLO expression in bladder cancer predicted a worse prognosis. In addition, the cisplatin-resistant T24/CDDP line and the adriamycin-resistant T24/ADR line expressed lower level of Smac/DIABLO expression. These results suggest that Smac/DIABLO expression in bladder cancer may be used as a prognostic parameter, and that low Smac/DIABLO expression in bladder cancer may be associated with resistance to chemotherapy.

A case of neuroendocrine (NE) differentiated prostate cancer is reported herein, which was progressed with NE differentiation during hormonal treatment in adenocarcinoma of the prostate. A 65-year-old man was admitted to our department with increased serum prostate specific antigen (PSA) (150 ng/ml). A prostate biopsy was performed and histological examinations indicated poorly differentiated adenocarcinoma with a Gleason score of 5 + 4 = 9. Further examinations showed metastases to systemic bones. The clinical stage was T3bN0M1b and hormonal therapy using leuprorelin was started. Eighteen months after hormonal therapy, the serum PSA level declined to 1.702 ng/ml. He subsequently experienced edema in his legs. Computed tomography (CT) demonstrated enlargement of the prostate and swelling of multiple pelvic lymph nodes. Immunohistochemical examination of a re-biopsy specimen revealed a neuroendocrine carcinoma. The neuron-specific enolase (NSE) level was 50.9 ng/ml. The treatment measure was changed from hormonal therapy to combination chemotherapy comprising cisplatin (CDDP) and irinotecan (CPT-11). Pelvic radiotherapy (50 Gy) was then performed. Two courses of the chemotherapy resulted in a great reduction of the tumor volume. However, he had liver metastases 3 months later. His condition worsened rapidly and he died at 8 months after definite diagnosis.

Postoperative urinary incontinence is a major impairment to patients' quality of life after prostatectomy, and is not limited to laparoscopic total prostatectomy. Improvements in devices and techniques of laparoscopic surgery have facilitated reliable cancer control, and in this situation there will now be increasing focus on postoperative quality of life (QOL), particularly urinary incontinence. Between July 2007 and March 2009, we have performed laparoscopic total prostatectomy for 53 patients, focusing on techniques to reduce urinary incontinence. Here we report the details of six key points of operative skill for achieving better urinary continence. These include (1) minimal distal incision of the endopelvic fascia; (2) preservation of the bladder neck; (3) bilateral nerve-sparing surgery; (4) preservation of the puboprostatic ligament and its refixation to the anterior aspect of the bladder neck (bladder neck sling suspension); (5) preservation of the posterior (membranous) urethra; (6) suturing of the posterior aspect of the rhabdosphincter, the remaining portion of the Denonvilliers fascia, and the bladder neck (restoration of the Denonvilliers fascia). Moreover, we separated the 53 patients into two groups: those who were not treated using the above six key points, and those who were. We then compared the data for the two groups with regard to the time taken for continence recovery, operative parameters (operation time and bleeding), and postoperative pathological findings.

A 69-year-old female presented with hypertension and a solid mass in the bladder on ultrasonography. Cystoscopy revealed a submucosal tumor in the right lateral wall of the bladder. A transurethral resection was performed. Histologically, pathologic examination revealed a malignant pheochromocytoma. She refused surgical therapy and radiation therapy. She had no treatment for two years. She suddenly complained of gross hematuria. T2-weighted magnetic resonance imaging showed a bladder tumor of high intensity and extra-bladder invasion. She was treated with chemotherapy (CVD) for 26 cycles. Since the tumor size was reduced, she was referred to our hospital for operative indication. Partial cystectomy was performed. Histologically, the tumor was a pheochromocytoma of the urinary bladder. Ten months after the operation, she has no clinical evidence of recurrence.

Objectives: We tested the usefulness of balloon-occluded arterial infusion (BOAI) of anticancer agent (cisplatin/gemcitabine), concomitant with hemodialysis, which delivers an extremely high concentration of anticancer agent to the site of a tumor without systemic adverse effects, along with concurrent radiation [Osaka-Medical College (OMC)-regimen] in patients with locally advanced bladder cancer. The results were compared with those of cystectomy., Methods: One hundred twenty-four patients were assigned to receive cystectomy (Gp1, n = 62) or OMC-regimen (Gp2, n = 62). In Gp2, patients besides undergoing complete response subsequently received secondary-BOAI with gemcitabine (1600 mg)., Results: In Gp1, 27 of 62 patients (43.5%) suffered disease recurrence, and more than half died within 1 year; the remainder died thereafter. The overall 5-, 10-, and 15-year survival rates were 53.8%, 46.0%, and 40.0%, respectively. In contrast, in Gp2, >70% of patients (44 of 62), especially >95% of patients with locally invasive tumors achieved complete response with no evidence of recurrent disease or metastasis after a mean follow-up of 163 (range, 32-736) weeks. At 14 years, overall survival was significantly improved at 79.7% (P = 0.015 vs. Gp1). Moreover, salvage therapy for secondary-BOAI with gemcitabine was effective in all 3 patients with T4 tumors or lymph node involvement, who showed stable disease (SD) after primary therapy with CDDP. No patients suffered Grade III or more severe toxicities., Conclusion: OMC-regimen, a new strategy for patients with locally-invasive bladder cancer, can be curative not only in patients for whom cystectomy is indicated, but also in patients whose condition is not amenable to curative treatment and for whom merely palliative treatment would otherwise seem the only option.

Stimulatory therapy with gonadotropins effectively induces spermatogenesis and increases the chances of successful reproduction. However, the optimal treatment modality and schedule, and required duration of treatment have not been determined. A 27-year-old man presented with erectile and ejaculatory disorder. Endocrinological examinations revealed isolated luteinizing hormone-releasing hormone (LHRH) deficiency of the hypothalamus, resulting in hypogonadotropic hypogonadism. No causative abnormality was detected in imaging studies. Having a diagnosis of adult-onset hypogonadotropic hypogonadism, the patient received pulsatile subcutaneous human chorionic gonadotropin (hCG) and human menopausal gonadotropin (hMG). Hypogonadism did not improve with hCG/hMG combination therapy. He was successfully treated with the replacement therapy from hMG into recombinant human follicular-stimulating hormone (rhFSH) for induction of spermatogenesis, along with pregnancy in the female partner.

A 59-year-old man visited another hospital with a chief complaint of malaise. Radiological examinations revealed a renal cell carcinoma associated with horseshoe kidney. He was referred to our hospital. The patient was successfully treated with open partial nephrectomy following isthmus division. Histological findings exhibited grade 2, pT1a, clear cell type, renal cell carcinoma. He is free of disease at twelve months after the operation.

Androgen-independent prostate cancer eventually develops metastasis, and radical treatment may not be possible for patients at this stage. In this study, we examined the gene-expression profiles of two prostate cancer cell lines, LNCaP (androgen-dependent) and C4-2 (androgen-independent), using cDNA-microarray hybridization. We focused on the expression of alpha-methylacyl-CoA racemase (AMACR), whose expression is much higher in C4-2 than in LNCaP, and investigated its biological role in acquisition of androgen-independent cancer growth. Immunohistochemistry and Western blot analysis of subcellular fractions revealed that AMACR expression was much stronger in C4-2 than in LNCaP. Inhibition of AMACR expression using AMACR-siRNA induced an increase in the expression of androgen receptor (AR) and B-cell translocation gene 1, along with a decrease in the expression of genes associated with cancer progression, including insulin-like growth factor I and platelet-derived growth factor alpha, in C4-2 with compared to non-treated C4-2. BrdU analysis and MTT assay demonstrated that AMACR inhibition induced a significant decrease of cell viability in C4-2 when cultured in androgen-depleted serum, becoming consistent with that of LNCaP, suggesting that AMACR inhibition may induce an increase in the expression of AR and characteristic conversion of prostate cancer cells from hormone independency to hormone dependency. We suggest that AMACR inhibition may be a new strategy for treatment of patients with hormone-refractory prostate cancer.

Between January 1997 and February 2005, a total of 106 patients with superficial bladder cancer were treated with transurethral resection of bladder tumor followed by intravesical instillation of Tokyo 172 strain bacillus Calmette-Guerin (BCG) once a week for six weeks. The endpoints were tumor recurrence, tumor progression, and disease-specific survival. At a median follow-up of 27 months (range 2 to 105 months), 67 patients (63.2%) were recurrence-free and superficial recurrence including disease progressed with local invasion was noted in 39 patients (36.8%). The non-recurrence rate at one and three years were 75.9 and 54.6%. Twenty-four patients received an additional course of BCG instillation, and 14 (58.3%) showed no further recurrence. Thus, the overall success rate of 2 courses of BCG instillation was 76.4% (81 of 106 patients). Nine patients (8.5%) had progression and died of cancer. There was no significant differernce in recurrence rate among tumor characteristics. However, there was a significant differernce in survival rate between non-invasive and invasive tumor shape (p = 0.0189). Univariate analysis (Cox's proportional hazard model) demonstrated that tumor shape was associated with survival (p = 0.0486). Multivariate analysis demonstrated that gender and tumor shape were associated with survival (p = 0.0183, 0.025). Adverse effects included bladder irritability in 16 patients (15.1%), gross hematuria in 15 (14.2%), fever in 24 (22.6%), contracted bladder in 1 (0.9%) and interstitial pneumonitis in 1 (0.9%). Interstitial pneumonitis improved after pulse steroid therapy. BCG was found to be very useful for the treatment of superficial bladder cancer. Intravesical BCG instillation was effective for first recurrent superficial bladder cancer because of the low recurrence rate after a second instillation of BCG.

Retroperitoneal liposarcoma is rare. Here we describe a case of retroperitoneal liposarcoma in a 61-year-old male. Preoperative computed tomography revealed an intraabdominal huge mass, and a clinical diagnosis of liposarcoma. Intraoperatively, the mass involved the right kidney and bladder, completely surrounding the right ureter. The tumor and the lower half ureter were removed. Successful reconstruction of a neoureter was performed with the Boari flap coupled with nephropexy and a psoas hitch. The detailed salient steps performed in this case are reported, together with a review of the literature.

Intravesical chemotherapy is performed after transurethral resection of bladder tumor (TURBT) for superficial bladder cancer. We conducted a prospective randomized controlled study on the prophylactic effects of intravesical instillation of epirubicin (EPI) against recurrence to determine the effective administration schedule. Between April 1999 and March 2003, 54 patients with superficial bladder tumor (pTa or pT1, and G1 or G2 cancer) were assigned to two groups (25 in Group A, 29 in Group B) after TURBT. The schedule of instillation (intravesically 40 mg of EPI dissolved in 40 ml saline) was subsequently once every two weeks for 3 months (7 times) starting one week after TURBT (Group A, short period), and subsequently added every two weeks for 3 months starting 6 months after TURBT (Group B, long period). The patients were followed up by cystoscopy and urinary cytology. There was no significant difference in non-recurrence rates after either one year (A; 62.5%, B; 82.8%) or three years (A; 53.6%, B; 67.3%). A univariate analysis demonstrated that tumor grade and staging were significant predictors of high risk for recurrence. A multivariate analysis performed by using the Cox's proportional hazard model showed that the schedule of instillation was an independent prognostic factor for reccurence. In the present study, only 2 patients showed progression and one patient died of UC. There was no adverse event that forced discontinuation of the therapy. In conclusion, epirubicin instillation influenced the prevention of recurrence, but the benefit of long-term period was not confirmed.

Nuclear factor-kappaB (NF kappaB) plays a pivotal role in cancer progression. In this study, we developed a decoy cis-element oligo-deoxyribonucleic acid against NF kappaB-binding site (NF kappaB-decoy), which effectively inhibits NF kappaB activity, and tested the effect of combined therapy comprising local transfection of NF kappaB-decoy into the liver and transportal injection of paclitaxel on cancer growth and metastasis using an orthotopic murine model of colon cancer liver metastasis. For NF kappaB-decoy transfection, we employed a novel approach using ultrasound exposure with an echocardiographic contrast agent, Optison. We examined the influence of NF kappaB-decoy transfer on susceptibility to paclitaxel in cancer cells and the mechanism involved using several in vitro analysis systems. We then studied the in vivo effect of combined NF kappaB-decoy transfer and paclitaxel in preventing cancer progression using a murine model of liver metastasis created by splenic injection of a human colon cancer cell line, HT29. In vitro experiments, including MTT-assay, fluorescence-activated cell sorter and cDNA array analysis, revealed that NF kappaB-decoy transfer significantly increased the susceptibility of cancer cells to paclitaxel, and that decreased expression of anti-apoptotic genes along with increased expression of genes relevant to the apoptosis-promotor may be involved. In vivo experiments showed that local transfection of NF kappaB-decoy into the liver followed by portal injection of paclitaxel effectively induced cancer cell apoptosis in the liver metastasis, and significantly prolonged animal survival compared to controls, without notable side effects. In conclusion, a combination of local NF kappaB-decoy transfer into the liver and transportal injection of paclitaxel may be a safe and effective new therapy for liver metastasis., ((c) 2007 Wiley-Liss, Inc.)

Objectives: We conducted the present study to evaluate the safety profile and therapeutic value of a combination of etoposide and fosfestrol for treatment of hormone-refractory prostate cancer (HRPC)., Methods: Forty patients with HRPC were included in the study. The median age was 71 years (range, 50-86 years), the Gleason's score ranged from 5 to 10, and the median prostate-specific antigen level was 62.6 ng/mL (range, 4.738-30789 ng/mL). The patients received oral etoposide 25 mg/d and fosfestrol 300 mg/d., Results: The response rate in terms of measurable disease, serum prostate-specific antigen level, and overall evaluation was 36.8% (CR: 18.4%; PR: 18.4%), 80% (CR: 55%; PR: 25%), and 40% (CR: 20%; PR: 20%) with a median duration of response of 13.6, 13.5, and 13.5 months, respectively. An objective clinical response for overall evaluation was shown by 90% (CR: 20%; PR: 20%; SD: 50%) of the patients, with a median response duration of 15.7 months; 16 patients (40%) are currently alive without recurrence after a median follow-up period of 21.2 months. The overall survival and progression-free survival was 30.5% and 28.8% at 40 months, respectively. No grade III toxicities occurred in any of the patients. Serial measurements in 34 patients using the Functional Assessment of Cancer Therapy-Prostate showed a significant improvement in quality of life as a result of the therapy., Conclusions: The combination of oral etoposide and fosfestrol is active in patients with HRPC. The regimen is tolerable and has a significant impact on quality of life as measured by the Functional Assessment of Cancer Therapy-Prostate in a limited sample of patients.

ComA of Streptococcus is a member of the bacteriocin-associated ABC transporters, which is responsible for both the processing of the propeptide ComC and secretion of the mature quorum-sensing signal. The quorum-sensing system is a bacterial intercellular communication system implicated in various functions including biofilm formation. In this study, the peptidase domains (PEPs) of the ComAs from six species of Streptococcus and ComCs from four species were expressed, purified, and characterized to address the mechanism of the substrate recognition of PEP. PEPs specifically cleaved ComCs after the Gly-Gly site in all the PEP-ComC combinations examined. The N-terminal leader region of ComC was found to form an amphiphilic alpha-helix structure upon binding to the PEP. Furthermore, mutagenesis studies revealed that four conserved hydrophobic residues in this leader region of ComC extending from -15 to -4 positions are critical in the interaction with PEP. Together with the double glycine motif, these structural features of ComC would explain the strict substrate specificity of the PEP.

Objective: We tested the usefulness of combined therapy using balloon-occluded arterial infusion (BOAI) of cisplatin and hemodialysis, which delivers an extremely high concentration of cisplatin to the site of a tumor without systemic adverse effects, with concurrent radiation in patients with locally advanced bladder cancer., Methods: Patients underwent transurethral resection of the bladder tumor followed by BOAI of cisplatin (100, 200, or 300 mg) concurrent with hemodialysis, via both common iliac veins, for 2 hours after initiation of BOAI. A total of 60.4 Gy of radiation was delivered, starting from the day of BOAI., Results: Forty-one patients (30 males and 11 females, aged 55-98 years) were enrolled and assessable for toxicity and response. None of the patients suffered grade II or more severe toxicities; some experienced grade I blood/bone marrow toxicity, gastrointestinal toxicity, or neuropathy. All patients with histologically confirmed transitional cell carcinoma stage T2 or T3 (29 patients) achieved a complete response and were able to retain their bladder with no evidence of recurrent disease or distant metastasis at a mean follow-up of 132 weeks (range 8-648 weeks) after therapy. Patients with stage T4 tumors, besides transitional cell carcinoma, or lymph node involvement had stable or progressive disease., Conclusion: This therapy is a new strategy for patients with locally advanced bladder cancer. It can be a curative treatment not only in patients for whom total cystectomy is indicated, but also in patients whose condition is not amenable to curative treatment and for whom merely palliative treatment would otherwise seem the only option.

Prostatic stromal sarcoma (PSS) is an unusual lesion that is reported only occasionally. Here we describe a case of prostatic stromal sarcoma in a 33-year-old man who had complained of perineal pain. The serum prostate-specific antigen (PSA) level was above the normal limit at 5.8 ng/ml, and abdominal computed tomography (CT) revealed a giant mass in the retrovesical region. Chest CT demonstrated lung metastases. Specimens obtained by transrectal needle biopsy of the prostate suggested a mesenchymal tumor, but a precise diagnosis required a larger specimen. Palliative transurethral resection (TUR-P) was performed because of obstruction of the urogenital tract, and the final diagnosis was made from this specimen. The tumor contained yellowish gelatinous materials, and the stromal element appeared histologically malignant, with increased cellularity, mitotic figures and pleomorphism. The histological diagnosis was PSS, and the patient received VIP (etoposide, ifosfamide, cisplatin) chemotherapy regimen. However, the pelvic mass continued to increase in size, and the patient's condition rapidly deteriorated and he died. Sarcoma of the prostate gland showing aggressive behavior is quite rare. The detailed histological and immunohistochemical findings in this case are reported, together with a review of the literature.

Background/aims: An oral adsorbent, AST-120, has been shown to retard the deterioration of renal function in patients with chronic kidney disease (CKD) by decreasing serum nephrotoxic substances such as indoxyl sulfate. Recent studies have suggested that a high level of serum indoxyl sulfate may be one of the mechanisms underlying the progression of atherosclerotic lesion, which is the leading cause of cardiovascular event or death in dialysis patients. In this study, we examined retrospectively whether AST-120 given to patients in the pre-dialysis period influences the prognosis after the initiation of dialysis., Methods: One hundred and ninety-two CKD patients on dialysis were studied. The survival and causes of death after the initiation of dialysis were compared between patients who were administrated AST-120 (AST-120 group, n = 101) and those not administrated AST-120 (non-AST-120 group, n = 91) prior to the initiation of dialysis., Results: The five-year survival rate was 72.6% in the AST-120 group and 52.6% in the non-AST-120 group, and was significantly higher in the AST-120 group (p = 0.018). The risk of death was increased 1.91-fold in the non-AST-120 group. However, no difference in the causes of death was observed between two groups., Conclusion: This study suggests that AST-120 given prior to the initiation of dialysis improves the prognosis of CKD patients under dialysis, although there is no association between AST-120 treatment and death caused by cardiovascular diseases such as heart failure, myocardial infarction, and cerebral hemorrhage. Further studies are needed to elucidate the effect of AST-120 on cardiovascular events and the prognosis in dialysis patients.

Molecular-targeted drugs are agents that act on molecules which are specifically expressed in cancer, or on molecules whose expression is increased in cancer compared to normal tissue, and suppress the growth, infiltration and metastasis of cancer while affecting normal tissue as little as possible by selectively impairing function in cancer tissue. The major molecular targets in cancer therapy include oncogene products, growth factors and their receptors, signal-transducing molecules, hormone receptors, cell cycle-related proteins, telomerase-related molecules, apoptosis-related molecules, angiogenesis-related molecules, anticancer drug resistance/sensitivity factors, transcription factors, and molecules related to infiltration and metastasis. This paper reports on the molecular-targeted drugs currently considered for bladder cancer.

We report a case of adrenal metastasis from renal cell carcinoma. A 52-year-old man was referred to our hospital for a left renal mass. A computed tomography revealed a left renal tumor. Liver cirrhosis and splenomegaly were observed. Blood tests revealed pancytopenia; platelet count was 2.5 x 10(4)/mm3. The patient was treated by partial splenic embolization (PSE) in an attempt to ensure a safe nephrectomy. After the embolization, his platelet count increased to 6.1 x 10(4)/mm3, and left nephrectomy was performed successfully. Histopathological finding was renal cell carcinoma (RCC). We concluded that PSE before surgery was useful for the patients with thrombocytopenia due to hypersplenism. Four years after surgery, computed tomography revealed the presence of a mass on the right adrenal gland. He was suspected of having a non-functioning adrenal tumor. Metastasis of the RCC was suspected and right adrenalectomy was performed by a laparoscopic procedure. Histologically, the mass was identified as a RCC metastasis. It is clinically rare for an RCC metastasis to the contralateral adrenal gland to occur.

Luteinizing hormone-releasing hormone agonist (LH-RH analogue) therapy, is one of the most widely used hormonal therapies. Recently, subcutaneous injection of a new long acting 3-month LHRH analogue depot has been developed. We investigated the adverse events induced by injection of an LH-RH analogue in 82 patients (median age was 75 year old, 59-87) using our questionnaire. Forty-eight and 34 cases had been administered leuprorelin acetate (LSR) and goserelin acetate (ZLA). The presentation rate of skin reaction was 8.8% (3/34) in the ZLA group and 14.6% (7/48) in the LSR group. There was no significant difference in rate of skin reaction between the LSR and ZLA group (p = 0.5113). Eight patients had induration (6 in LSR 2 in ZLA). We also present a case of subcutaneous granuloma formation at the injection site after using the three-month type preparation of leuprorelin acetate. We should be aware of the risk of skin reactions at the injection site and monitor carefully when using an LH-RH analogue.

A 60-year-old man was admitted to our department with a left renal artery aneurysm that was detected while performing an examination for dermatomyositis. A 3-dimensional image showed a saccular renal aneurysm whose diameter was 6 cm. He required operative intervention. Because of the location (near the renal hilum), selective transcatheter embolization using an interlocking detachable coil was performed for endovascular treatment. The postoperative course was uneventful. This method appears to be a good choice for the treatment of renal artery aneurysm, considering its safety and the likelihood of success.

Chymase is an important enzyme for the generation of angiotensin (Ang) II and in the activation of transforming growth factor (TGF)-beta1. Therefore, chymase may be involved in the hemodialysis access dysfunction, which is caused by intimal hyperplasia that occurs after polytetrafluoroethylene (PTFE) graft implantations. Bilateral U-shaped PTFE grafts were placed between the femoral vein and artery in dogs. Chymase inhibitor (NK3201, 1 mg/kg per day, p.o.) treatments were initiated 3 days before the operation. After the implantation, the stenosis by neointima proliferation was most frequently observed in the venous side of the PTFE grafts. In the hyperplastic neointima, myofibroblasts were the main cellular components. On the other hand, fibroblasts only occupied cellular components in a much smaller proportion in the neointima. However, these cells seem to be rich in the properties of proliferation and migration. After PTFE graft implantations, extensive accumulations of chymase-positive mast cells were found mainly in the tissue surrounding the grafts. The Ang II- and TGF-beta-positive cells were found in an adjacent section that was in close proximity to the chymase-positive cells. In contrast, the AT(1) receptors, as well as TGF-beta type II receptors, were expressed either in the neointima or in the outside adventitia of the PTFE grafts. Chymase inhibitor treatment resulted in a reduction of chymase, Ang II and TGF-beta1 expression, leading to a significant inhibition of neointimal formation. These findings indicating that an increase of chymase via promoting Ang II and TGF-beta1 generation plays a pivotal role in the neointimal formation after the implantation of PTFE grafts and also suggesting that chymase inhibition may be a new strategy that can be used to prevent PTFE graft dysfunctions in clinical settings.