Nephron-sparing ureteroscopic surgery vs. radical nephroureterectomy: comparable survival-outcomes in upper tract urothelial carcinoma.

PURPOSE: This study investigates the utility of ureteroscopic surgery (URS) as an alternative to radical nephroureterectomy (RNU) in managing upper tract urothelial carcinoma (UTUC), with a focus on survival outcomes and re-evaluation of current the European Association of Urology guidelines criteria. METHODS: We conducted a retrospective, multi-institutional review of 143 UTUC patients treated with URS (n = 35) or RNU (n = 108). Clinicopathological factors were analyzed, and survival outcomes were assessed using Kaplan-Meier analysis and Cox proportional-hazards models. RESULTS: The median follow-up period was 27 months. Overall survival (OS) and radiographic progression-free survival (rPFS) were comparable between the URS and RNU groups (OS: HR 2.42, 95% CI 0.63-9.28, P = 0.0579; rPFS: HR 1.82, 95% CI 0.60-5.47, P = 0.1641). URS conferred superior renal function preservation. In patients characterized by factors such as radiographically invisible lesions, negative cytology, pTa stage, low-grade tumors, and multiple lesions, the OS outcomes with URS were comparable to those with RNU as follows: radiographically invisible lesions (P = 0.5768), negative cytology (P = 0.7626), pTa stage (P = 0.6694), low-grade tumors (P = 0.9870), and multiple lesions (P = 0.8586). CONCLUSION: URS offers survival outcomes similar to RNU, along with better renal function preservation, especially in low-risk UTUC patients. These findings underscore the urgency of re-evaluating the current EAU guidelines and encourage further research into determining the ideal patient selection for URS in UTUC treatment.

Taurodeoxycholic acid and valine reverse obesity-associated augmented alloimmune responses and prolong allograft survival.

Obesity initiates a chronic inflammatory network linked to perioperative complications and increased acute rejection rates in organ transplantation. Bariatric surgery is the most effective treatment of obesity recommended for morbidly obese transplant recipients. Here, we delineated the effects of obesity and bariatric surgery on alloimmunity and transplant outcomes in diet-induced obese (DIO) mice. Allograft survival was significantly shorter in DIO-mice. When performing sleeve gastrectomies (SGx) prior to transplantation, we found attenuated T cell-derived alloimmune responses resulting in prolonged allograft survival. Administering taurodeoxycholic acid (TDCA) and valine, metabolites depleted in DIO-mice and restored through SGx, prolonged graft survival in DIO-mice comparable with SGx an dampened Th1 and Th17 alloimmune responses while Treg frequencies and CD4+ T cell-derived IL-10 production were augmented. Moreover, in recipient animals treated with TDCA/valine, levels of donor-specific antibodies had been reduced. Mechanistically, TDCA/valine restrained inflammatory M1-macrophage polarization through TGR5 that compromised cAMP signaling and inhibited macrophage-derived T cell activation. Consistently, administering a TGR5 agonist to DIO-mice prolonged allograft survival. Overall, we provide novel insights into obesity-induced inflammation and its impact on alloimmunity. Furthermore, we introduce TDCA/valine as a noninvasive alternative treatment for obese transplant patients.

CTLA4-Ig prolongs graft survival specifically in young but not old mice.

Elderly organ transplant recipients have remained underrepresented in clinical trials, despite representing a rapidly growing population. Here, we assessed age-specific effects of CTLA4-Ig (cytotoxic T-lymphocyte antigen 4-Ig), a fusion protein blocking costimulatory signaling between antigen-presenting cells and T cells through CD28. Cardiac allografts in young mice (2-3 months) treated with CTLA4-Ig survived indefinitely, whereas 80% of old recipients (18 months) had lost their graft after 100 days. CTLA4-Ig was also significantly less effective in older recipients of skin transplants. CTLA4-Ig reduced CD4+ central memory and effector memory T cells and diminished systemic interferon-gamma levels only in young recipients. These differences corresponded to a reduced expression of CD28 on antigen-experienced CD4+ T cells in old mice. In support, adoptive transfer of old CD4+ T cells that were transfected with a lentiviral vector inducing constant expression of CD28 accelerated the rejection of allogeneic skin grafts in young RAG2-/- recipient mice. Regulatory T cells (Tregs), in contrast, demonstrated an increased expression of CD28 with aging and CTLA4-Ig treatment in old recipients resulted in reduced frequencies, compromised proliferation, and diminished suppressive capacity of Tregs. These findings may prove to have unique clinical consequences for immunosuppression in the growing population of elderly transplant recipients.

Recipient sex and estradiol levels affect transplant outcomes in an age-specific fashion.

Sex-specific influences have been shown for a variety of diseases. Whether donor or recipient sex and sex hormone levels impact alloimmune responses remains unclear. In unifactorial and multifactorial analyses of more than 400 000 SRTR listed kidney transplant patients, we found that younger female recipients had an inferior death-censored graft survival that was independent of donor sex. In contrast, graft survival was superior in older female recipients, suggesting the impact of recipient sex hormones over chromosomal sex mismatches. Those clinical changes were delineated in experimental skin and heart transplant models showing a prolongation of graft survival in ovariectomized young female recipients. In contrast, graft survival was comparable in ovariectomized and naïve old female recipients. Young ovariectomized mice showed reduced amounts and a compromised T cell proliferation. Deprivation of female hormones dampened the production of interferon (IFN)-γ and interleukin (IL)-17+ by CD4+ T cells while augmenting systemic counts of Tregs. Increasing estradiol concentrations in vitro promoted the switch of naïve CD4+ T cells into Th1 cells; high physiological estradiol concentrations dampening Th1 responses, promoted Tregs, and prolonged graft survival. Thus, clinical observations demonstrate age-specific graft survival patterns in female recipients. Estrogen levels, in turn, impact the fate of T cell subsets, providing relevant and novel information on age- and sex-specific alloimmunity.

Distinct effect of body mass index by sex as a prognostic factor in localized renal cell carcinoma treated with nephrectomy ~ data from a multi-institutional study in Japan ~.

BACKGROUND: We assessed the prognostic value of body mass index (BMI) in Asian patients with localized RCC who underwent nephrectomy. METHODS: A total of 665 patients who underwent nephrectomy for localized RCC were enrolled in the present study and divided into the two BMI groups: i.e., BMI < 25 in 463 (69.6%) and BMI > 25 in 202 (30.4%) patients. RESULTS: In total, there were 482 (72.5%) males and 183 (27.5%) females. Five-year cancer-specific survival (CSS) rates were significantly higher in increased BMI than the lower BMI group (97.1 and 92.5%: P = 0.007). When stratified by sex, significantly longer CSS in higher BMI was confirmed in males (5-year CSS of 92.7% in BMI < 25 and 98.1% in BMI > 25, p = 0.005), while there was no difference in CSS between BMI groups for female patients. Multivariable analysis exhibited that higher BMI was an independent predictor for favorable CSS in male (cox model: p = 0.041, Fine & Gray regression model: p = 0.014), but not in the female. Subgroup analysis for CSS revealed that favorable CSS with higher BMI was observed in patient subgroups of age < 65 (p = 0.019), clear cell histology (p = 0.018), and tumor size > 4 cm, p = 0.020) as well as male (p = 0.020). CONCLUSION: Our findings collected from the multi-institutional Japanese dataset demonstrated longer survival in patients with higher BMI than lower BMI for non-metastatic RCC treated with nephrectomy. Intriguingly, this finding was restricted to males, but not to females.

Targeting of intragraft reactive oxygen species by APP-103, a novel polymer product, mitigates ischemia/reperfusion injury and promotes the survival of renal transplants.

Inflammatory responses associated with ischemia/reperfusion injury (IRI) play a central role in alloimmunity and transplant outcomes. A key event driving these inflammatory responses is the burst of reactive oxygen species (ROS), with hydrogen peroxide (H2 O2 ) as the most abundant form that occurs as a result of surgical implantation of the donor organ. Here, we used a syngeneic rat renal transplant and IRI model to evaluate the therapeutic properties of APP-103, a polyoxalate-based copolymer molecule containing vanillyl alcohol (VA) that exhibits high sensitivity and specificity toward the production of H2 O2 . We show that APP-103 is safe, and that it effectively promotes kidney function following IRI and survival of renal transplants. APP-103 reduces tissue injury and IRI-associated inflammatory responses in models of both warm ischemia (kidney clamping) and prolonged cold ischemia (syngeneic renal transplant). Mechanistically, we demonstrate that APP-103 exerts protective effects by specifically targeting the production of ROS. Our data introduce APP-103 as a novel, nontoxic, and site-activating therapeutic approach that effectively ameliorates the consequences of IRI in solid organ transplantation.

Adjuvant chemotherapy improves overall survival in patients with localized upper tract urothelial carcinoma harboring pathologic vascular invasion: a propensity score-matched analysis of multi-institutional cohort.

OBJECTIVE: Whether adjuvant chemotherapy (AC) for patients with upper tract urothelial carcinoma (UTUC) offers survival benefit is still controversial. To explore the impact of AC on overall survival (OS) of cN0M0 UTUC patients, we conducted a propensity score-matched analysis using the regression model, including pathologic features such as lymphatic and vascular invasion. METHODS: A multi-institutional cohort of 413 UTUC patient record was used. Propensity score matching was performed to reduce bias by potential confounding factors for survival, including pathologic features from the specimen of radical nephroureterectomy (RNU), RESULTS: Ninety-eight patients were identified as pair-matched groups (49 patients in RNU and 49 patients in RNU + AC). Kaplan-Meier curves demonstrated that a 5-year OS rate of 72.7% for patients treated with RNU + AC was significantly higher than 51.6% for those treated with RNU (p = 0.0156). On multivariate analysis, pathologic vascular invasion (HR 3.41, 95% CI 1.24-10.66, p = 0.0166) and administration of AC (HR 0.45, 95% CI 0.19-0.98, p = 0.0438) still remained as the significant predictors for OS. In patients with pathologic vascular invasion (51 of 98 patients), a significantly longer OS in RNU + AC groups was observed (median OS of 30 and 70 months in RNU and RNU + AC groups, respectively: p = 0.0432), whereas there was no significant difference in the OS between RNU (median OS: not reached) and RNU + AC (median OS: not reached) groups in patients without the invasion (p = 0.4549). CONCLUSION: The result indicates a significant benefit for OS by the administration of AC, and pathologic vascular invasion in the specimen of RNU could help the patient selection to better predict the effect of AC.

MicroRNA-143/Musashi-2/KRAS cascade contributes positively to carcinogenesis in human bladder cancer.

It has been well established that microRNA (miR)-143 is downregulated in human bladder cancer (BC). Recent precision medicine has shown that mutations in BC are frequently observed in FGFR3, RAS and PIK3CA genes, all of which correlate with RAS signaling networks. We have previously shown that miR-143 suppresses cell growth by inhibiting RAS signaling networks in several cancers including BC. In the present study, we showed that synthetic miR-143 negatively regulated the RNA-binding protein Musashi-2 (MSI2) in BC cell lines. MSI2 is an RNA-binding protein that regulates the stability of certain mRNAs and their translation by binding to the target sequences of the mRNAs. Of note, the present study clarified that MSI2 positively regulated KRAS expression through directly binding to the target sequence of KRAS mRNA and promoting its translation, thus contributing to the maintenance of KRAS expression. Thus, miR-143 silenced KRAS and MSI2, which further downregulated KRAS expression through perturbation of the MSI2/KRAS cascade.

The CANLPH Score, an Integrative Model of Systemic Inflammation and Nutrition Status (SINS), Predicts Clinical Outcomes After Surgery in Renal Cell Carcinoma: Data From a Multicenter Cohort in Japan.

BACKGROUND: A myriad of studies have demonstrated the clinical association of systemic inflammatory and nutrition status (SINS) including C-reactive protein/albumin ratio (CAR), the neutrophil/lymphocyte ratio (NLR), and the platelet/hemoglobin ratio (PHR). This study aimed to investigate the predictive value of the score integrating these variables (CANLPH) in patients with renal cell carcinoma (RCC). METHODS: Using cohort data from a multi-institutional study, 757 of 1109 patients were retrospectively analyzed. The optimal cutoff value for outcome prediction of continuous variables in CAR, NLR, and PHR was determined and the CANLPH score was then calculated as the sum score of 0 or 1 by the cutoff value in each ratio. RESULTS: The median follow-up time was 76 months for the patients who survived (n = 585) and 31 months for those who died (n = 172). The Youden Index offered an optimal cutoff of 1.5 for CAR and 2.8 for NLR, and a higher value from the cutoff was assigned as a score of 1. The cutoff value of the PHR was defined as 2.1 for males and 2.3 for females. The patients were assigned a CANLPH score of 0 (47.2%), 1 (31.3%), 2 (13.1%), or 3 (8.5%). In the multivariate analysis, the CANLPH score served as an independent predictor of cancer-specific mortality in both localized and metastatic RCC. CONCLUSION: The score was well-correlated with clinical outcome for the RCC patients. Because this score can be concisely measured at the point of diagnosis, physicians may be encouraged to incorporate this model into the treatment for RCC.

Mast cells regulate CD4+ T-cell differentiation in the absence of antigen presentation.

BACKGROUND: Given their unique capacity for antigen uptake, processing, and presentation, antigen-presenting cells (APCs) are critical for initiating and regulating innate and adaptive immune responses. We have previously shown the role of nicotinamide adenine dinucleotide (NAD+) in T-cell differentiation independently of the cytokine milieu, whereas the precise mechanisms remained unknown. OBJECTIVE: The objective of this study is to further dissect the mechanism of actions of NAD+ and determine the effect of APCs on NAD+-mediated T-cell activation. METHODS: Isolated dendritic cells and bone marrow-derived mast cells (MCs) were used to characterize the mechanisms of action of NAD+ on CD4+ T-cell fate in vitro. Furthermore, NAD+-mediated CD4+ T-cell differentiation was investigated in vivo by using wild-type C57BL/6, MC-/-, MHC class II-/-, Wiskott-Aldrich syndrome protein (WASP)-/-, 5C.C7 recombination-activating gene 2 (Rag2)-/-, and CD11b-DTR transgenic mice. Finally, we tested the physiologic effect of NAD+ on the systemic immune response in the context of Listeria monocytogenes infection. RESULTS: Our in vivo and in vitro findings indicate that after NAD+ administration, MCs exclusively promote CD4+ T-cell differentiation, both in the absence of antigen and independently of major APCs. Moreover, we found that MCs mediated CD4+ T-cell differentiation independently of MHC II and T-cell receptor signaling machinery. More importantly, although treatment with NAD+ resulted in decreased MHC II expression on CD11c+ cells, MC-mediated CD4+ T-cell differentiation rendered mice resistant to administration of lethal doses of L monocytogenes. CONCLUSIONS: Collectively, our study unravels a novel cellular and molecular pathway that regulates innate and adaptive immunity through MCs exclusively and underscores the therapeutic potential of NAD+ in the context of primary immunodeficiencies and antimicrobial resistance.

Carboplatin Enhances the Activity of Human Transient Receptor Potential Ankyrin 1 through the Cyclic AMP-Protein Kinase A-A-Kinase Anchoring Protein (AKAP) Pathways.

Carboplatin, an anticancer drug, often causes chemotherapy-induced peripheral neuropathy (PN). Transient receptor potential ankyrin 1 (TRPA1), a non-selective cation channel, is a polymodal nociceptor expressed in sensory neurons. TRPA1 is not only involved in pain transmission, but also in allodynia or hyperalgesia development. However, the effects of TRPA1 on carboplatin-induced PN is unclear. We revealed that carboplatin induced mechanical allodynia and cold hyperalgesia, and the pains observed in carboplatin-induced PN models were significantly suppressed by the TRPA1 antagonist HC-030031 without a change in the level of TRPA1 protein. In cells expressing human TRPA, carboplatin had no effects on changes in intracellular Ca2+ concentration ([Ca2+]i); however, carboplatin pretreatment enhanced the increase in [Ca2+]i induced by the TRPA1 agonist, allyl isothiocyanate (AITC). These effects were suppressed by an inhibitor of protein kinase A (PKA). The PKA activator forskolin enhanced AITC-induced increase in [Ca2+]i and carboplatin itself increased intracellular cyclic adenosine monophosphate (cAMP) levels. Moreover, inhibition of A-kinase anchoring protein (AKAP) significantly decreased the carboplatin-induced enhancement of [Ca2+]i induced by AITC and improved carboplatin-induced mechanical allodynia and cold hyperalgesia. These results suggested that carboplatin induced mechanical allodynia and cold hyperalgesia by increasing sensitivity to TRPA1 via the cAMP-PKA-AKAP pathway.

Recall features and allorecognition in innate immunity.

Alloimmunity traditionally distinguishes short-lived, rapid and nonspecific innate immune responses from adaptive immune responses that are characterized by a highly specific response initiated in a delayed fashion. Key players of innate immunity such as natural killer (NK) cells and macrophages present the first-line defence of immunity. The concept of unspecific responses in innate immunity has recently been challenged. The discovery of pattern recognition receptors (PRRs) has demonstrated that innate immune cells respond in a semi-specific fashion through the recognition of pathogen-associated molecular patterns (PAMPs) representing conserved molecular structures shared by large groups of microorganisms. Although immunological memory has generally been considered as exclusive to adaptive immunity, recent studies have demonstrated that innate immune cells have the potential to acquire memory. Here, we discuss allospecific features of innate immunity and their relevance in transplantation.

Preoperative Measurement of the Modified Glasgow Prognostic Score Predicts Patient Survival in Non-Metastatic Renal Cell Carcinoma Prior to Nephrectomy.

PURPOSE: The modified Glasgow Prognostic Score (mGPS) by measurement of serum C-reactive protein and albumin levels has been shown to provide prognostic value in various cancer types. The purpose of this study was to evaluate whether preoperative assessment of the mGPS predicts patient survival outcome in renal cell carcinoma (RCC). MATERIALS AND METHODS: Clinicopathological and follow-up data in 219 RCC patients, all of whom underwent curative or non-curative nephrectomy, were collected. Overall survival (OS) and cancer-specific survival (CSS) after nephrectomy were evaluated, and univariate and multivariate analyses were conducted to assess the predictive value of the variables, including the mGPS. RESULTS: During the median follow-up of 57 months, 53 patients (24.2%) were deceased within 22 months of the median OS. The 5-year OS rate from nephrectomy was 85.9 and 18.8% in non-metastatic (n = 195) and metastatic (n = 24) patients, respectively. Increasing mGPS was associated with shorter OS in non-metastatic patients (2-year OS rate of 98.2% in mGPS0, 73.3% in mGPS1, and 44.4% in mGPS2; hazard ratio [HR] 9.96, 95% confidence interval [CI] 4.88-20.13, p < 0.001), whereas no significant difference in OS according to the mGPS was seen in metastatic patients (HR 2.01, 95% CI 0.79-5.16, p = 0.137). On multivariate analysis, the mGPS remained as an independent predictor for OS (HR 5.24, 95% CI 1.39-19.77, p = 0.015) and CSS (HR 4.69, 95% CI 1.13-20.96, p = 0.034) in non-metastatic RCC patients. CONCLUSIONS: The mGPS appeared to be a reliable, preoperatively defined predictive marker with widely standardized protocol in non-metastatic RCC, and should therefore be considered in treatment decision making for RCC patients.

A Novel Combination RNAi toward Warburg Effect by Replacement with miR-145 and Silencing of PTBP1 Induces Apoptotic Cell Death in Bladder Cancer Cells.

Bladder cancer is one of the most difficult malignancies to control. We explored the use of a novel RNA-interference method for a driver oncogene regulating cancer specific energy metabolism by the combination treatment with a small interfering RNA (siRNA) and a microRNA. After transfection of T24 and 253JB-V cells with miR-145 and/or siR-PTBP1, we examined the effects of cell growth and gene expression by performing the trypan blue dye exclusion test, Western blot, Hoechst 33342 staining, reverse transcription polymerase chain reaction (RT-PCR), and electron microscopy. The anti-cancer effects of xenograft model mice with miR-145 and/or siR-PTBP1 were then assessed. The combination treatment induced the deeper and longer growth inhibition and reduced the levels of both mRNA and protein expression of c-Myc and polypyrimidine tract-binding protein 1 (PTBP1) more than each single treatment. Notably, the combination treatment not only impaired the cancer specific energy metabolism by inhibiting c-Myc/PTBP1/PKMs axis but also inactivated MAPK/ERK and PI3K/AKT pathways examined in vitro and in vivo. Furthermore, the combination treatment induced apoptosis or autophagy; but, in some cells, apoptotic cell death was accompanied by autophagy, because the condensation of chromatin and many autophagosomes were coexistent. This combination treatment could be a novel RNA-interference strategy through the systemic silencing of the Warburg effect-promoting driver oncogene PTBP1 in bladder cancer cells.

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.

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

OBJECTIVES: 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. PATIENTS AND METHODS: A total of 136 patients with benign prostatic obstruction were randomised to undergo either B-TURP using the TURis system or conventional M-TURP, and were regularly followed for 36 months after surgery. The primary endpoint was safety, which included the long-term complication rates of postoperative urethral stricture. The secondary endpoint was the follow-up measurement of efficacy. RESULTS: In peri-operative findings, no patient in either treatment group presented with transurethral resection syndrome, and the decline in levels of haemoglobin and hematocrit were similar. The mean operation time was significantly extended in the TURis treatment group compared with the M-TURP group (79.5 vs 68.6 min; P = 0.032) and postoperative clot retention was more likely to be seen after M-TURP (P = 0.044). Similar efficacy findings were maintained throughout 36 months, but a significant difference in postoperative urethral stricture rates between groups was detected (6.6% in M-TURP vs 19.0% in TURis; P = 0.022). After stratifying patients according to prostate volume, there was no significant difference between the two treatment groups with regard to urethral stricture rates in patients with a prostate volume ≤ 70 mL (3.8% in M-TURP vs 3.8% in TURis), but in the TURis group there was a significantly higher urethral stricture rate compared with the M-TURP group in patients with a prostate volume >70 mL (20% in TURis vs 2.2% in M-TURP; P = 0.012). Furthermore, the mean operation time for TURis was significantly longer than for M-TURP for the subgroup of patients with a prostate volume > 70 mL (99.6 vs 77.2 min; P = 0.011), but not for the subgroup of patients with a prostate volume ≤ 70 mL. CONCLUSION: The TURis system seems to be as efficacious and safe as conventional M-TURP except that there was a higher incidence of urethral stricture in patients with larger preoperative prostate volumes.

[Idiopathic Lumbar Hernia: A Case Report].

A 68-year-old woman, complained of an indolent lump about 60 × 70 mm in size in the left lower back. We conducted a computed tomography scan, which exhibited a hernia of Gerota'sfascia-commonly called superior lumbar hernia. In the right lateral position, the hernia contents were observed to attenuate, hence only closure of the hernial orifice was conducted by using Kugel patch, without removal of the hernia sack. Six months after the surgery, she has had no relapse of the hernia. Superior lumbar hernia, which occurs in an anatomically brittle region in the lower back, is a rare and potentially serious disease. The urologic surgeon should bear in mind this rarely seen entity.

[A CASE OF ADVANCED BLADDER NEUROENDOCRINE CARCINOMA (SMALL CELL CARCINOMA) SIGNIFICANTLY IMPROVED BY LOW DOSE OF ORAL TEGAFUR-URACIL].

A 81-old-woman underwent a transurethral resection of bladder tumor (TURBT) at a nearby hospital in April 2011. The diagnosis was invasive urothelial carcinoma, G3 with a component of bladder small cell carcinoma, T1 or more. She was recommended to visit our hospital for combined modality therapy of bladder cancer, but she refused the treatment for over one year. In May 2012, she came to our hospital with the chief complaint of pain at urination. Cystoscopy revealed non-papillary sessile tumor in the top of the bladder, and CT scan demonstrated the presence of the right obturator lymph nodes swollen up to 1.2 cm in size. The second TURBT was performed and the diagnosis was bladder small cell carcinoma (pT3N2M0) according to urothelial cancer guidelines of the Japanese Urological Association (JUA). Because she strongly refused hospitalization anymore, we started daily oral intake of low dose Tegafur-Uracil (100 mg) for the treatment. After one month, the serum Neuron-Specific Enolase (NSE; tumor maker of small cell cancer) level was elevated to 27.6 ng/ml and the right obturator lymph node was enlarged up to 1.9 cm. Therefore, the Trgafur-Uracil dose was increased to 200 mg daily. After then, the serum NSE level was decreased to 15.5 ng/ml following reduction in size of the obturator lymph nodes with partial response in December 2013. After two years of follow-up period, her regular urine test showed normal findings, and no apparent recurrence was detected on urinary bladder with MRI and Cystoscopy. This is a case of advanced bladder small cell carcinoma significantly improved by oral administration of Tegafur-Uracil 200 mg/day for over 2 years.

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-ß 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-ß 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.

Single session of high-intensity focused ultrasound for localized prostate cancer: treatment outcomes and potential effect as a primary therapy.

PURPOSE: To investigate the treatment outcomes of a single-session high-intensity focused ultrasound (HIFU) using the Sonablate(®) for patients with localized prostate cancer. METHODS: Biochemical failure was defined according to the Stuttgart definition [a rise of 1.2 ng/ml or more above the nadir prostate-specific antigen (PSA)] and the Phoenix definition (a rise of 2 ng/ml or more above the nadir PSA). Disease-free survival rate was defined using the Phoenix criteria and positive follow-up biopsy. RESULTS: A total of 171 patients were identified. Fifty-two (30.4 %) patients were identified to be with D'Amico low risk, 47 (27.5 %) with intermediate risk, and 72 (42.1 %) with high risk. In the median follow-up time of 43 months, there was 44 (25.7 %) and 36 (21.1 %) patients experienced biochemical failure for Stuttgart and Phoenix definition with mean (±SD) time to failure of 17.8 ± 2.1 and 19.4 ± 2.3 months, respectively. A total of 44 (25.7 %) patients were diagnosed as disease failure. Cox multivariate analysis revealed PSA nadir level (PSA cutoff = 0.2 ng/ml; HR = 9.472, 95 % CI 4.527-19.820, p < 0.001) and D'amico risk groups [HR = 3.132 (95 % CI 1.251-6.389), p = 0.033] were the predictor for failure in single-session HIFU. CONCLUSIONS: Single-session HIFU treatment using the Sonablate(®) seems to be potentially curative approach. When treated carefully with neoadjuvant hormonal therapy or preoperative transurethral resection of the prostate, higher-risk disease might be able to choose this minimally invasive procedure as primary therapy.