Hajime Hirano

Adipose-derived stromal cells inhibit prostate cancer cell proliferation inducing apoptosis.

Mesenchymal stem cells (MSCs) have generated a great deal of interest in the field of regenerative medicine. Adipose-derived stromal cells (AdSCs) are known to exhibit extensive proliferation potential and can undergo multilineage differentiation, sharing similar characteristics to bone marrow-derived MSCs. However, as the effect of AdSCs on tumor growth has not been studied sufficiently, we assessed the degree to which AdSCs affect the proliferation of prostate cancer (PCa) cell. Human AdSCs exerted an inhibitory effect on the proliferation of androgen-responsive (LNCaP) and androgen-nonresponsive (PC3) human PCa cells, while normal human dermal fibroblasts (NHDFs) did not, and in fact promoted PCa cell proliferation to a degree. Moreover, AdSCs induced apoptosis of LNCaP cells and PC3 cells, activating the caspase3/7 signaling pathway. cDNA microarray analysis suggested that AdSC-induced apoptosis in both LNCaP and PC3 cells was related to the TGF-β signaling pathway. Consistent with our in vitro observations, local transplantation of AdSCs delayed the growth of tumors derived from both LNCaP- and PC3-xenografts in immunodeficient mice. This is the first preclinical study to have directly demonstrated that AdSC-induced PCa cell apoptosis may occur via the TGF-β signaling pathway, irrespective of androgen-responsiveness. Since autologous AdSCs can be easily isolated from adipose tissue without any ethical concerns, we suggest that therapy with these cells could be a novel approach for patients with PCa.

Incidence of urethral stricture after bipolar transurethral resection of the prostate using TURis: results from a randomised trial

To assess whether bipolar transurethral resection of the prostate (B‐TURP) using the TURis® system has a similar level of efficacy and safety to that of the traditional monopolar transurethral resection of the prostate (M‐TURP), and to evaluate the impact of the TURis system on postoperative urethral stricture rates over a 36‐month follow‐up period.

Novel Bladder Preservation Therapy with Osaka Medical College Regimen

PURPOSE We investigated the effect of balloon occluded arterial infusion of an anticancer agent (cisplatin/gemcitabine), used concomitantly with hemodialysis, which delivers an extremely high concentration of anticancer agent to the tumor site without systemic adverse effects, along with concurrent radiation (referred to as the Osaka Medical College regimen) in patients with advanced bladder cancer. MATERIALS AND METHODS A total of 329 patients (TisN0 16, T2N0 174, T3N0 77, T4N0 22 and TxN+ 40) were assigned to receive the Osaka Medical College regimen. Patients who did not achieve complete response underwent total cystectomy or secondary balloon occluded arterial infusion with an increased amount of cisplatin and/or gemcitabine. RESULTS The Osaka Medical College regimen allowed 83.6% (276 of 329) of patients in total and 93.6% (250 of 267) of patients with organ confined disease (including T3b) to achieve complete response. Of the patients with a complete response 96% (240 of 250) survived with a functional bladder without evidence of recurrent disease within a mean followup of 159 weeks. Although lymph node involvement, especially N2 stage, was selected as a significant risk factor for treatment failure and survival, it was noteworthy that 61.9% of patients with N1 disease achieved complete response and that the 5-year overall survival rate was 72.2%. No patients had grade III or more severe toxicities. CONCLUSIONS The Osaka Medical College regimen, a new bladder preservation strategy, can be curative not only in patients for whom cystectomy is indicated, but also in patients whose condition is not amenable to curative treatment because of disease stage, age or other factors, and for whom merely palliative therapy would otherwise seem the only option.

The Anti-Proliferative Effect of Boron Neutron Capture Therapy in a Prostate Cancer Xenograft Model

Purpose Boron neutron capture therapy (BNCT) is a selective radiation treatment for tumors that preferentially accumulate drugs carrying the stable boron isotope, 10B. BNCT has been evaluated clinically as an alternative to conventional radiation therapy for the treatment of brain tumors, and more recently, recurrent advanced head and neck cancer. Here we investigated the effect of BNCT on prostate cancer (PCa) using an in vivo mouse xenograft model that we have developed. Materials and Methods Mice bearing the xenotransplanted androgen-independent human PCa cell line, PC3, were divided into four groups: Group 1: untreated controls; Group 2: Boronophenylalanine (BPA); Group 3: neutron; Group 4: BPA-mediated BNCT. We compared xenograft growth among these groups, and the body weight and any motility disturbance were recorded. Immunohistochemical (IHC) studies of the proliferation marker, Ki-67, and TUNEL staining were performed 9 weeks after treatment. Results The in vivo studies demonstrated that BPA-mediated BNCT significantly delayed tumor growth in comparison with the other groups, without any severe adverse events. There was a significant difference in the rate of freedom from gait abnormalities between the BPA-mediated BNCT group and the other groups. The IHC studies revealed that BNCT treatment significantly reduced the number of Ki-67-positive cells in comparison with the controls (mean±SD 6.9±1.5 vs 12.7±4.0, p<0.05), while there was no difference in the number of apoptotic cells, suggesting that BPA-mediated BNCT reduced PCa progression without affecting apoptosis at 9 weeks post-treatment. Conclusions This study has provided the first preclinical proof-of-principle data to indicate that BPA-mediated BNCT reduces the in vivo growth of PCa. Although further studies will be necessary, BNCT might be a novel potential treatment for PCa.

Feasibility of Photodynamic Diagnosis for Challenging TUR- Bt Cases Including Muscle Invasive Bladder Cancer, BCG Failure or 2 nd -TUR

BACKGROUND Despite widely adopted standard methods for follow-up including cystoscopy plus cytology, recurrence rates of non muscle-invasive bladder cancer (NMIBC) have not improved over the past decades, still ranging from 60% through 70%. Hence, widely acceptable surveillance strategies with excellent sensitivity are needed. Early recurrence has led to the development of a novel cystoscopy technique utilizing photodynamic diagnosis (PDD). Although, no studies have evaluated the efficacy of PDD for patients of MIBC, BCG failure or 2nd-transurethelial resection (TUR). MATERIALS AND METHODS The present study was performed from October 2012 through May 2013. IRB approved 25 patients initially underwent a cystoscopy examination of white light and blue light followed by the resection of tumors identified. Resections were performed from bladder mucosa areas considered suspicious at PDD, along with PDD negative normal bladder mucosa area resected by random biopsy. Specimens were divided into two groups, PDD positive and negative. Primary endpoints were sensitivity and specificity. RESULTS A total of 147 specimens extracted from 25 patients were included in the analysis. Some 45 out of 92 PDD-positive specimens were confirmed to have bladder cancer, and 51 out of PDD-negative 55 specimens were confirmed to be cancer negative. The sensitivity of PDD was 91.8% (45/49) and specificity was 52.0% (51/98). The sensitivity:specificity was 89.5% (17/19) : 47.6% (30/63) in 12 2nd-TUR patients, 90.5% (19/21) : 61.1% (11/18) in seven MIBC patients, and 95.0% (19/20) : 48.5% (16/33) in eight failed BCG cases. CONCLUSIONS PDD-TURBT has high sensitivity to diagnose BC even for 2nd-TUR, MIBC or BCG failure cases.

E74-like factor inhibition induces reacquisition of hormone sensitiveness decreasing period circadian protein homolog 1 expression in prostate cancer cells ☆

Purpose Initiating as an androgen-dependent adenocarcinoma, prostate cancer (PCa) gradually progresses to a castrate-resistant disease following androgen deprivation therapy with a propensity to metastasize. Methods In order to resolve the mechanism of castrate-resistant PCa, we performed a cDNA-microarray assay of two PCa cell lines, LNCaP (androgen dependent) and C4-2 (androgen independent). Among them, we focused on a novel Ets transcription factor, E74-like factor 5 (ELF5), the expression level of which was extremely high in C4-2 in comparison with LNCaP both in the microarray analysis and real-time polymerase chain reaction analysis, and investigated the biological role in acquisition of androgen-refractory PCa growth. Results Western blot analysis and morphological analysis using confocal immunofluorescence microscopy demonstrated that ELF5 was expressed mainly in cytosol both in LNCaP and C4-2. Inhibition of ELF5 expression using ELF5-small interfering RNA in C4-2 induced decreased expression of androgen receptor corepressor, period circadian protein homolog 1, and MTT assay of C4-2 after ELF5 small interfering RNA transfection showed the same cell growth pattern of LNCaP. Conclusions Our in vitro experiments of cell growth and microarray analysis have demonstrated for the first time that decreased expression of period circadian protein homolog 1 due to ELF5 inhibition may induce the possibility of reacquisition of hormone sensitiveness of PCa cells. We suggest that ELF5 could be a novel potential target for the treatment of hormone-refractory PCa patients.

The effect of systematic conversion to generic Mycophenolate mofetil (MMF) in kidney transplantation;A single center clinical experience from Japan.

INTRODUCTION Recently, more and more generic drugs have been used for immunosuppressive drugs in the field of organ transplantation. Some reports have indicated that blood concentration of most generic drugs is difficult to maintain stability, and it may cause the difference in graft survival of transplanted organs between original drugs and generic drugs. In this article, we report the cases could not maintain blood concentration of generic drugs of mycophenolate mofetil (MMF). RESULTS In 4 cases out of 5 cases that we had to change original MMF to generic MMF, there were cases that blood concentration level was not stabilized. There were possibility that the lowered blood concentration level of MMF caused a rejection, in two cases. Mean MMF trough level was decreased from 3.6 ± 1.9 μg/mL to 0.6 ± 0.4 μg/mL. Due to the early detection, it did not become severe or failure of graft function, however, we cannot deny the possibilities that side effects were increased and rejection rose. In these cases, we discontinued to use the generic drugs thereafter due to unstable plasma concentration of MMF. DISCUSSION Some reports have indicated that failure to maintain plasma concentration of MMF leads to rejection. Therefore, maintenance of effective plasma concentration and prevention of rejection are essential to long-term graft survival in kidney transplant. CONCLUSION Generic drug formulations may exhibit differences in effects and absorption compared to the brand-name drug. If the generic drug should be used, patients should be closely monitored.

Dual Gas Treatment With Hydrogen and Carbon Monoxide Attenuates Oxidative Stress and Protects From Renal Ischemia-Reperfusion Injury

BACKGROUND Hydrogen (H2) and carbon monoxide (CO) gas are both reported to reduce reactive oxygen species and alleviate tissue ischemia-reperfusion (I-R) injury. The present study was conducted to evaluate the effects of a mixture of H2 gas and CO gas (dual gas) in comparison with hydrogen gas (H2: 2%) alone on I-R renal injury (composition of dual gas; N2: 77.8%; O2: 20.9%; H2: 1.30%; CO: 250 parts per million). METHODS Adult male Sprague-Dawley rats (body weight 250-280 g) were divided into 5 groups: (1) sham operation control, (2) dual gas inhalation (dual treatment) without I-R treatment, (3) I-R renal injury, (4) H2 gas alone inhalation (H2 treatment) with I-R renal injury, and (5) dual treatment with I-R renal injury. I-R renal injury was induced by clamping the left renal artery and vein for 45 minutes followed by reperfusion, and then contralateral nephrectomy was performed 2 weeks later. Renal function was markedly decreased at 24 hours after reperfusion, and thereafter the effects of dual gas were assessed by histologic examination and determination of the superoxide radical, together with functional and molecular analyses. RESULTS Pathologic examination of the kidney of I-R rats revealed severe renal damage. Importantly, cytoprotective effects of the dual treatment in comparison with H2 treatment and I-R renal injury were observed in terms of superoxide radical scavenging activity and histochemical features. Rats given dual treatment and I-R renal injury showed significant decreases in blood urea nitrogen. Increased expression of several inflammatory cytokines (tumor necrosis factor-α, interleukin-6, intracellular adhesion molecule-1, nuclear factor-κB, hypoxia inducible factor-1α, and heme oxygenase-1) was attenuated by the dual treatment. CONCLUSIONS Dual gas inhalation decreases oxidative stress and markedly improves I-R-induced renal injury.

A Kidney with Type II Damage to be Transplanted into a Patient Undergoing Treatment with Antiplatelet and Anticoagulant Medications

Background The number of cadaveric kidney transplants in our country as grown to nearly 300 cases per year, with the average waiting period for a healthy kidney being 16 years. In this report, we describe the graft survival time after transplantation of a cadaveric kidney that was first screened for damage. Case Presentation A 64-year-old man who had undergone dialysis for 17 years presented to our clinic to undergo kidney transplantation. He had undergone previous operations for aortic valve replacement and coronary artery bypass and had been using antiplatelet and anticoagulant drugs since 62 years of age. The kidney donor was a 34-year-old man who had died due to an acute subdural hematoma that developed after a fall. Despite attempts to administer first aid, the man was considered brain dead. The donor’s kidney was then inspected and was found to exhibit type II damage. Moreover, arteriography on the day of the donor’s hospital admission revealed leakage of contrast medium. The kidney capsule exhibited lacerations and damage to the renal parenchyma, but was transplanted without additional treatment using conventional techniques. There was an increase in ecchymoma around the kidney at post-operative day 4, but it was improved with conservative treatment. The transplanted kidney exhibited good function and the patient was discharged without complication. Conclusions To the best of our knowledge, the present case is the first report in our country involving the transplantation of a cadaveric kidney with renal parenchyma damage. Moreover, this case demonstrates the suitability of a kidney with type II damage to be transplanted into a patient undergoing treatment with antiplatelet and anticoagulant medications. There are many instances in which a type II-damaged kidney can be preserved using conventional techniques. Therefore, cadaveric kidneys that are screened based on a careful damage assessment represent a possible source for transplantation.

MP10-08 A PANEL OF MICRO-RNA SIGNATURE AS A TOOL FOR PREDICTING SURVIVAL OF PATIENTS WITH UROTHELIAL CARCINOMA OF THE BLADDER

99% of 23 million people in Taiwan. The National Health Insurance Research Database (NHIRD) was released for research purposes. A total of 868 CKD patients who received renal transplantation (RT) and 54,243 non-CKD controls matched for age, gender and index date were recruited from the NHIRD. The CKD patients with RT was also confirmed by the registry of catastrophic illness. The cancer incidence was identified through cross-referencing with the Cancer Registry Database. Risks were estimated as hazard ratios (HRs) and their 95% confidence intervals (CIs) by using a Cox proportional hazards model. RESULTS: For CKD patients with RT, a significant higher incidence rate ratio (IRR) of all cancer sites (IRR 1⁄4 3.79, 95% CI 1⁄4 3.12-4.62) was found. After the adjustment for age, sex and co-morbidities, we also observed a significantly increased cancer risk of 3.87 (HR 1⁄4 3.79, 95% CI 1⁄4 3.16-4.73). Especially, we found that CKD patients with RT have a significant increased IRR of bladder cancer (IRR 1⁄4 14.42, 95% CI 1⁄4 8.09-25.67). A greatly increased bladder cancer risk (HR 1⁄4 17.67, 95% CI 1⁄4 9.64-32.38) was found for CKD patients with RT after the adjustment for age, sex and co-morbidities. CONCLUSIONS: CKD patients have a higher risk of subsequent cancers, but the effect of therapeutic modalities such as RT on cancer risk is still unclear. Our finding is that CKD patients with RT have a significant increased risk of bladder cancer. Therefore, we should pay more attention to carry out effective treatments and implement an intensive follow-up to prevent CKD patients to progress to cancer.