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Introduction: Patients undergoing hemodialysis are at an increased risk of peripheral arterial disease, amputation of lower extremities, and decline of activities of daily living. Although a prosthesis is used to support activities of daily living, no previous study reported the association of prosthesis use with the change in activities of daily living following leg amputation in hemodialysis patients. The purpose of this study was to compare the changes in activities of daily living following amputation between those who created a prosthesis and those who did not., Methods: This study was a single-center, retrospective observational study. We screened medical records for hemodialysis patients who underwent below-knee amputation (BKA) and activities of daily living were examined two times with the functional independence measure (FIM) before BKA and at discharge. They were divided into two groups according to the creation of a prosthesis., Findings: We identified 28 eligible patients, among whom 12 patients used a prosthesis (prosthesis group), whereas 16 patients did not (non-prosthesis group). The FIM score was significantly decreased following BKA in the non-prosthesis group, whereas it was not significantly changed in the prosthesis group. The change in FIM score was significantly different between the two groups, and the difference remained significant after considering potential confounders., Discussion: The results of this study showed that use versus nonuse of a prosthesis was an independent factor associated with changes in activities of daily living in hemodialysis patients following BKA, supporting the important role of a prosthesis in maintaining activities of daily living in hemodialysis patients who need BKA., (© 2023 International Society for Hemodialysis.)

Coronavirus disease 2019 (COVID-19) vaccination reduces the risk of progression to severe COVID-19 in the general population. To examine that preventive effect in dialysis patients, the association of vaccination status with severe COVID-19 progression was investigated in this retrospective observational study conducted from December 2020 to May 2022 of 100 such patients hospitalized for non-severe COVID-19 at Inoue Hospital (Suita, Japan). Fifty-seven were fully vaccinated, defined as receiving a COVID-19 vaccine second dose at least 14 days prior to the onset of COVID-19, while 43 were not. Among all patients, 13 (13.0%) progressed to severe COVID-19 with a median (interquartile range) time of 6 (2.5-9.5) days, while 87 (87.0%) were discharged after 11 (8-16) days. Kaplan-Meier analysis showed that fully vaccinated patients had a significantly lower rate of progression to severe COVID-19 ( p = 0.001, log-rank test). Cox proportional hazard analysis also indicated that full COVID-19 vaccination was significantly associated with reduced instances of progression to severe COVID-19 (hazard ratio 0.104, 95% confidence interval 0.022 to 0.483; p = 0.004) after balancing patient background characteristics using an inverse probability of treatment weight method. These results suggest that full vaccination status contributes to reducing the risk of progression from non-severe to severe COVID-19 in dialysis patients.

OBJECTIVE: Our purposes of this study were to characterize a group of bulky cervical cancer patients who underwent a nerve sparing radical hysterectomy (NSRH) with or without neoadjuvant chemotherapy (NAC), to compare surgical outcomes and the preservation of bladder function, and to compare prognoses. RESULTS: Fifty-three patients had NSRH without NAC (Group A), and 33 patients had NSRH after NAC (Group B). With regard to prognostic factors, there was only a significant difference between both groups with regard to lymph node metastasis (15% vs 42%, P = 0.01). Moreover, bladder function in Group B patients improved to the same extent as the preoperative rate three months postoperatively. These data were similar to the results in Group A. With regard to overall survival, the 5-year survival rate was 98.1% (95% confidence interval (CI) 87.8-99.7) in Group A and 86.7% (95% CI 71.7-96.7) in Group B ( P > 0.1). METHODS: We retrospectively identified 86 patients with cervical cancer who underwent NSRH at Osaka Medical College from May 2009 to November 2016. NAC was performed via balloon occluded arterial infusion. We extracted data on the patient's stage of progress, tumor volume, histological subtype, bleeding volume, urodynamic study results, and postoperative complications. The data were divided into two groups - those patients who received NAC and those who did not - and then compared. CONCLUSIONS: According to our analysis, NSRH surgery after NAC via balloon occluded arterial infusion brings beneficial results to patients with bulky IB2 to IIB cervical cancers., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no conflicts of interest.

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.

Purpose: To evaluate factors affecting the success rate of stone fragmentation and stone-free rate after extracorporeal shockwave lithotripsy (SWL) in treatment of upper urinary tract stones., Materials and Methods: A total of 121 patients with upper urinary tract calculi underwent SWL treatment., Results: Success rate of stone fragmentation after SWL was 73.6% (89/121). In 89 patients who had success of breaking stones, 71 patients were followed up for the assessment of stone-free status, of whom 51 (71.8%) patients were stone-free at 3-month follow-up. Among four prognostic factors, including body mass index (BMI), stone size, stone position, and hydronephrosis, BMI and stone position had a significant impact on the success rate of stone fragmentation (P = .04 and U1: P = .0108, respectively). Among five prognostic factors of BMI, stone size, stone position, hydronephrosis, and times of SWL treatments, stone size was the only factor with significant impact on the stone-free rate (middle: P = .0229)., Conclusion: Our study suggests that stone fragmentation and stone-free rate after SWL treatment for upper urinary tract stones can be predicted.

A 31-year-old man visited another hospital with a chief complaint of a solid mass in the left scrotum. The diagnosis was a skin cancer of the scrotum, and he was referred to our hospital. We performed surgical resection of the mass, left testis, and bilateral superfical inguinal nodes. Histopathological findings revealed leiomyosarcoma of the scrotum. He is free of disease at 16 months after the operation.

Cisplatin-based chemotherapy has been widely used in a neoadjuvant as well as adjuvant setting. Furthermore, trimodal approaches including complete transurethral resection of the bladder tumor followed by combined chemotherapy and radiation have generally been performed as bladder preservation therapy. However, none of the protocols have achieved a 5-year survival rate of more than 70%. Additionally, the toxicity of chemotherapy and/or a decreased quality of life due to urinary diversion cannot be ignored, as most patients with bladder cancer are elderly. We therefore newly developed the novel trimodal approach of "combined therapy using balloon-occluded arterial infusion of anticancer agent and hemodialysis with concurrent radiation, which delivers an extremely high concentration of anticancer agent to the site of a tumor without systemic adverse effects ("Osaka Medical College regimen" referred to as the OMC regimen). We initially applied the OMC regimen as neoadjuvant chemotherapy for locally advanced bladder cancer. However, since more than 85% of patients with histologically-proven urothelial cancer achieved complete response with no evidence of recurrence after a mean follow-up of 170 (range 21-814) weeks, we have been applying the OMC-regimen as a new approach for bladder sparing therapy. We summarize the advantage and/or disadvantage of chemotherapy in neoadjuvant as well as adjuvant settings, and show the details of our newly developed bladder sparing approach OMC regimen in this review., (© 2011 The Japanese Urological Association.)

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Gamma-aminobutyric acid (GABA) was first discovered as an inhibitory neurotransmitter in the central nervous system (CNS) and has been reported to have a variety of functions, including regulation of cell division, cell differentiation and maturation, and to be involved in the development of certain cancers outside the CNS. In the present study, using the human renal cell carcinoma cell line Caki-2, we demonstrated that GABA stimulation significantly increased the expression of MMP-2 and -9 and subsequently increased the invasive activity of the cancer cells. Because MAPK signaling is one of the key regulators of MMP expression, we further evaluated MAPK signaling after stimulation with GABA. It was found that GABA stimulation promoted the phosphorylation of MAPKs, including ERK1/2, JNK, and p38. ERK1/2 phosphorylation was sustained for up to 12 h, while phosphorylation of JNK and p38 returned to the endogenous level by 30 min. It was noteworthy that the ras/raf/MEK/ERK pathway inhibitor PD98059 attenuated GABA-induced MMP-9 expression and that both PD98059 and MMP inhibitors attenuated the GABA-induced invasive activity of Caki-2 cells. Moreover, data obtained by depletion of the MEK/ERK pathway using interfering RNA transfection of Caki-2 cells clearly corroborated the above results, as both MMP-9 expression and GABA-induced invasive ability were decreased significantly. We also demonstrated that the GABA-induced increase in invasive ability via ERK1/2 up-regulation was mediated mainly through the GABA-B receptor. These results indicate that GABA stimulation promotes cancer cell invasion and that the effect is partly due to ERK1/2-dependent up-regulation of MMPs.

Background: A unique immunosuppressant, FTY720, selectively induces apoptosis in activated lymphocytes, but not in other hematopoietic cells. The potential that this unique mechanism could provide anticancer potential by inducing apoptosis in the human renal cancer cell line, ACHN, which is resistant to cisplatin, and its molecular pathway was investigated., Materials and Methods: The difference in drug susceptibility to FTY720 between cancer cells and non-cancer cells was examined by MTT assay and flow cytometry. Apoptosis assay, including TUNEL staining, electron microscopy and DNA electrophoresis, was performed and the molecular pathway of FTY720 was evaluated by real time RT-PCR and Western blot. The in vivo effect of FTY720 was evaluated using a murine zenograft model., Results: The susceptibility to FTY720 was significantly higher in ACHN cancer cells than in normal renal tubular cells (HK-2) at a concentration of less than 30 microM, while the susceptibility to cisplatin was even higher in HK-2 than in ACHN. Cancer cells treated with FTY720 showed findings typical of apoptosis with highly condensed nuclear chromatin and fragmented nuclei. The molecular analysis revealed that FTY720-induced apoptosis was mediated by a Fas-independent, Bcl-associated signal transduction pathway, and that inhibition of extracellular signal-regulated kinase (ERK) activity was involved in its underlying mechanism of action. FTY720 treatment significantly prevented in vivo tumor growth without any severe adverse reactions, while cisplatin treatment did not inhibit tumor growth despite exhibiting severe side-effects., Conclusion: FTY720 may be a promising candidate for a new anticancer therapy of renal cancer.

Background: Transforming growth factor beta (TGF-beta) facilitates metastasis during the advanced stages of cancer. Smad6, Smad7, and c-Ski block signaling by the TGF-beta superfamily proteins through different modes of action. We used adenovirus-mediated gene transfer of these natural inhibitors in a mouse model of breast cancer to examine the roles of TGF-beta superfamily signaling in tumor growth and metastasis., Methods: We systemically administered, by intravenous injection, adenoviruses (AdCMV) containing the mouse cDNAs for Smad7, Smad6, c-Ski, the c-Ski mutant c-Ski (ARPG), or LacZ (control) to nude mice (>19 mice/group) bearing tumors derived from mouse mammary carcinoma JygMC(A) cells, which spontaneously metastasize to lung and liver, and examined their effects on survival and metastasis. High-throughput western blotting analysis was used to examine the expression levels for 47 signal transduction proteins in JygMC(A) cells and primary tumors. We also investigated the proliferation, migration, and invasion of JygMC(A) cells that stably overexpressed Smad6 or Smad7. Nonparametric comparisons were done by Kruskal-Wallis H statistic and Wilcoxon's rank sum tests. Parametric comparisons were done by one-way analysis of variance or two-sided unpaired Student's t tests. All statistical tests were two-sided., Results: Control mice bearing tumors derived from JygMC(A) cells showed many metastases to the lung and liver; all animals died by 50 days after cell inoculation. By contrast, mice treated with AdCMV-Smad7 or AdCMV-c-Ski demonstrated a dramatic decrease in metastasis and statistically significantly longer survival than control mice (Smad7 versus LacZ: medium survival = 55 days versus 41 days, difference = 14 days [95% confidence interval {CI} = 6 days to 22 days], P < .001), whereas mice treated with AdCMV-Smad6 or AdCMV-c-Ski (ARPG) did not. Expression of Smad7 in JygMC(A) cells was associated with increased expression of major components of adherens and tight junctions, including E-cadherin, decreased expression of N-cadherin, and decreases in the migratory and invasive abilities of the JygMC(A) cells., Conclusion: Smad7 inhibits metastasis, possibly by regulating cell-cell adhesion. Systemic expression of Smad7 may be a novel strategy for the prevention of metastasis of advanced cancers.

We investigated expression of gamma-aminobutyric acid (GABA), glutamate decarboxylase, and matrix metalloproteinase (MMP) in the prostates of patients with cancer or benign prostatic hypertrophy by immunohistochemical study. Marked expression of GABA, glutamate decarboxylase 67, and MMPs was observed in the prostates of cancer patients with metastasis (n = 72) and lymph node metastasis, although only sparse expression was noted in those of cancer patients without metastasis (n = 76) or patients with benign prostatic hypertrophy (n = 152). We then investigated the influence of GABA stimulation on in vitro MMP production and the invasive ability of cancer cells using human prostate cancer cell line C4-2. The production of MMPs increased significantly in cancer cells after a 24-h incubation with GABA. Cell invasion assay using a BioCoat Matrigel Invasion Chamber kit revealed that GABA stimulation significantly promoted the invasive ability of cancer cells and that addition of MMP inhibitor GM6001 significantly decreased GABA-induced migration. This may indicate the involvement of MMP activity in GABA-induced cancer cell invasion. We further analyzed the transmission pathway by performing GABA receptor modulation. The GABA(B) receptor agonist baclofen significantly increased MMP production as well as invasive ability. Moreover, blockade of the GABA(B) receptor pathway using GABA(B) receptor antagonist CGP 35348 significantly inhibited GABA-induced MMP production and invasive ability in cancer cells, whereas GABA(A) receptor modulation did not influence MMP production or the invasive ability of cancer cells. Thus, increased expression of GABA may be implicated in cancer metastasis by promoting MMP production in cancer cells, and the GABA(B) receptor pathway may be involved in the process.

A 72-year-old Japanese man presented with a painless swollen left scrotal mass with elevated levels of serum alpha-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 alpha-fetoprotein or prostate specific antigen 26 months after the orchiectomy.

A 58-year-old man presented with dysuria at the Osaka Medical College Hospital in November 1996. Laboratory examination revealed elevated serum prostate-specific antigen (PSA) to > 100 ng/mL. Adenocarcinoma of the prostate with metastasis to the bone was diagnosed after a biopsy of the prostate and bone scintigraphy; hormonal therapy was administered. Although bone metastasis was well controlled and the serum PSA level declined to within normal levels (2.0 ng/mL), several painless nodules were found on the penile glans. Biopsy of the nodules showed that the penile tumor was a metastasis from the prostate cancer. The patient underwent partial penectomy for relief from penile pain. The serum PSA level showed no elevation 3 months after the partial penectomy, suggesting that careful observation of prostate cancer patients is necessary, even when oseous metastasis is well controlled and serum PSA levels are kept within normal ranges by hormonal therapy. The case also indicates that urologists should consider the possibility of metastasis to the penis from prostate cancer.

A 77-year-old man with a low grade fever persisting for 30 days consulted a local physician. A computed tomographic scan of the abdomen showed a mixed density mass on the left adrenal gland. He was referred to our hospital for further examination. Hormonal assay demonstrated a slightly high level of noradrenalin in the serum (18 pg/ml) and vanillyl mandelic acid in the urine (6.2 ng/ml). Magnetic resonance imaging revealed a heterogeneous mass lesion 3 cm in diameter with a high signal intensity on both T1 and T2 weighted images. Angiography showed a hypovascular mass in the supra-renal region suggesting an adrenal tumor or malignancy. Left adrenalectomy combined with en bloc nephrectomy was performed because of severe adhesion. Histologic evaluation showed hematoma without malignant cells due to idiopathic adrenal hemorrhage.

A 52-year-old male visited our department for a painless swelling from the right side of the anus to the right scrotum that he first noticed 5 years earlier. Palpation revealed a small fist-sized elastic solid mass with a smooth surface from the central area to the inferior pole of the right scrotum. This mass was clearly demarcated from the contents of the scrotum and not adherent to the scrotal skin. A diagnosis of a tumorous lesion in the scrotum was made, and the tumor was resected. Histopathological examination demonstrated a scrotal epidermoid cyst. To our knowledge, this is the 17th case reported in Japan.