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A total of 739 patients underwent RARP as initial treatment for PCa from November 2011 to October 2018. Data on BCR status, clinical and pathological parameters were collected from the clinical records. After excluding cases with neoadjuvant and/or adjuvant therapies, presence of lymph node or distant metastasis, and positive SM, a total of 537 cases were eligible for the final analysis. The median follow-up of experimental cohort was 28.0 (interquartile: 18.0–43.0) months. We identified the presence of International Society of Urological Pathology grade group (ISUP-GG) ≥ 4 (Hazard ratio (HR) 3.20, 95% Confidence Interval (95% CI) 1.70–6.03, P < 0.001), lymphovascular invasion (HR 2.03, 95% CI 1.00–4.12, P = 0.049), perineural invasion (HR 10.7, 95% CI 1.45–79.9, P = 0.020), and maximum tumor diameter (MTD) > 20 mm (HR 1.9, 95% CI 1.01–3.70, P = 0.047) as significant factors of BCR in the multivariate analysis. We further developed a risk model according to these factors. Based on this model, 1-year, 3-year, and 5-year BCR-free survival were 100%, 98.9%, 98.9% in the low-risk group; 99.1%, 94.1%, 86.5% in the intermediate-risk group; 93.9%, 84.6%, 58.1% in the high-risk group. Internal validation using the bootstrap method showed a c-index of 0.742 and an optimism-corrected c-index level of 0.731. External validation was also carried out using an integrated database derived from 3 other independent institutions including a total of 387 patients for the final analysis. External validation showed a c-index of 0.655. In conclusion, we identified risk factors of biochemical failure in patients showing negative surgical margin after RARP and further developed a risk model using these risk factors. [ABSTRACT FROM AUTHOR]

The IL-2 receptor α chain (IL-2Rα/CD25) is constitutively expressed on double-negative (DN2/DN3 thymocytes and regulatory T cells (Tregs) but induced by IL-2 on T and natural killer (NK) cells, with Il2ra expression regulated by a STAT5-dependent super-enhancer. We investigated CD25 regulation and function using a series of mice with deletions spanning STAT5-binding elements. Deleting the upstream super-enhancer region mainly affected constitutive CD25 expression on DN2/DN3 thymocytes and Tregs, with these mice developing autoimmune alopecia, whereas deleting an intronic region decreased IL-2–induced CD25 on peripheral T and NK cells. Thus, distinct super-enhancer elements preferentially control constitutive versus inducible expression in a cell type–specific manner. The mediator-1 coactivator colocalized with specific STAT5-binding sites. Moreover, both upstream and intronic regions had extensive chromatin interactions, and deletion of either region altered the super-enhancer structure in mature T cells. These results demonstrate differential functions for distinct super-enhancer elements, thereby indicating previously unknown ways to manipulate CD25 expression in a cell type–specific fashion. Editor's summary: Regulation of the gene encoding IL-2Rα (CD25) has been studied extensively to understand discrete patterns of expression on lymphocyte subsets, including the influence of Il2ra super-enhancer elements. Spolski et al. undertook an exhaustive investigation of CD25 regulation and function using a panel of mice bearing different deletions within Il2ra super-enhancer elements that modulate binding of STAT5. Deletion of the upstream super-enhancer region markedly affected constitutive CD25 expression on double-negative (DN)2/DN3 thymocytes and Tregs and resulted in the development of mice with autoimmune alopecia. By contrast, deletion of an intronic region reduced IL-2–driven CD25 expression on peripheral NK and T cells. The upstream and intronic regions also exhibited chromatin interactions, and deletions resulted in changes in super-enhancer structures in mature T cells. These findings highlight roles of different super-enhancer elements in controlling CD25 expression. —Christiana Fogg [ABSTRACT FROM AUTHOR]

Monocytic acute myeloid leukemia (AML) responds poorly to current treatments, including venetoclax-based therapy. We conducted in vivo and in vitro CRISPR-Cas9 library screenings using a mouse monocytic AML model and identified SETDB1 and its binding partners (ATF7IP and TRIM33) as crucial tumor promoters in vivo. The growth-inhibitory effect of Setdb1 depletion in vivo is dependent mainly on natural killer (NK) cell-mediated cytotoxicity. Mechanistically, SETDB1 depletion upregulates interferon-stimulated genes and NKG2D ligands through the demethylation of histone H3 Lys9 at the enhancer regions, thereby enhancing their immunogenicity to NK cells and intrinsic apoptosis. Importantly, these effects are not observed in non-monocytic leukemia cells. We also identified the expression of myeloid cell nuclear differentiation antigen (MNDA) and its murine counterpart Ifi203 as biomarkers to predict the sensitivity of AML to SETDB1 depletion. Our study highlights the critical and selective role of SETDB1 in AML with granulo-monocytic differentiation and underscores its potential as a therapeutic target for current unmet needs. [Display omitted] • CRISPR-Cas9 screens identify SETDB1 and its cofactors as tumor promoters in vivo • SETDB1 mediates H3K9me3 at the ERV enhancers to repress inflammation and NKG2D ligands • SETDB1 depletion in granulo-monocytic AMLs enhances their sensitivity to NK cell response Chang et al. perform CRISPR-Cas9 library screens and identify SETDB1 and its binding partners as key players in suppressing the NK cell-mediated immune surveillance against acute myeloid leukemia with granulocytic and monocytic differentiation, highlighting SETDB1 as a selective and promising therapeutic target in this disease. [ABSTRACT FROM AUTHOR]

Clonal hematopoiesis of indeterminate potential (CHIP) is an age‐associated phenomenon characterized by clonal expansion of blood cells harboring somatic mutations in hematopoietic genes, including DNMT3A, TET2, and ASXL1. Clinical evidence suggests that CHIP is highly prevalent and associated with poor prognosis in solid‐tumor patients. However, whether blood cells with CHIP mutations play a causal role in promoting the development of solid tumors remained unclear. Using conditional knock‐in mice that express CHIP‐associated mutant Asxl1 (Asxl1‐MT), we showed that expression of Asxl1‐MT in T cells, but not in myeloid cells, promoted solid‐tumor progression in syngeneic transplantation models. We also demonstrated that Asxl1‐MT–expressing blood cells accelerated the development of spontaneous mammary tumors induced by MMTV‐PyMT. Intratumor analysis of the mammary tumors revealed the reduced T‐cell infiltration at tumor sites and programmed death receptor‐1 (PD‐1) upregulation in CD8+ T cells in MMTV‐PyMT/Asxl1‐MT mice. In addition, we found that Asxl1‐MT induced T‐cell dysregulation, including aberrant intrathymic T‐cell development, decreased CD4/CD8 ratio, and naïve‐memory imbalance in peripheral T cells. These results indicate that Asxl1‐MT perturbs T‐cell development and function, which contributes to creating a protumor microenvironment for solid tumors. Thus, our findings raise the possibility that ASXL1‐mutated blood cells exacerbate solid‐tumor progression in ASXL1‐CHIP carriers. [ABSTRACT FROM AUTHOR]

Although the albumin-to-globulin ratio (AGR) is a promising biomarker, no study has investigated its prognostic significance for advanced urothelial carcinoma (UC). This study conformed to the REporting recommendations for tumor MARKer prognostic studies (REMARK) criteria. We retrospectively reviewed 176 patients with advanced UC treated with pembrolizumab between 2018 and 2020. We evaluated the associations between pretreatment clinicopathological variables, including the AGR and performance status (PS), with progression-free survival, cancer-specific survival, and overall survival. The Cox proportional hazards model was used for univariate and multivariable analyses. The AGR was dichotomized as < 0.95 and ≥ 0.95 based on receiver operating characteristic curve analysis. After excluding 26 cases with missing data from the total of 176 cases, 109 (73%) patients experienced disease progression, 75 (50%) died from UC, and 6 (4%) died of other causes (median survival = 12 months). Multivariate analyses identified PS ≥ 2 and pretreatment AGR < 0.95 as independent poor prognostic factors for all endpoints. Furthermore, a prognostic risk model incorporating these two variables achieved a relatively high concordance index for all endpoints. This is the first report to evaluate the significance of AGR in advanced UC. Pretreatment AGR < 0.95 may serve as a prognostic marker for advanced UC treated with pembrolizumab. [ABSTRACT FROM AUTHOR]

Background: There has been a limited number of reports on the significance and risk factors of urethrovesical anastomotic urinary leakage (AUL) following robot-assisted radical prostatectomy (RARP). We aimed to analyze the clinical significance of AUL and evaluated its risk factors.Methods: We conducted a multi-institutional study to review patients with prostate cancer undergoing RARP in three centers (The University of Tokyo Hospital, Mitsui Memorial Hospital, and Chiba Tokushukai Hospital). "Positive AUL" was defined as urinary extravasation at the anastomosis detected by post-operative cystogram and was further categorized into minor or major AUL. Univariate and multivariate analyses were performed to identify predictors of AUL. Postoperative continence rates and time to achieve continence were also analyzed.Results: A total of 942 patients underwent RARP for prostate cancer in 3 centers. Of these patients, a cystogram after the RARP procedure was not performed in 26 patients leaving 916 patients for the final analysis. AUL was observed in 56 patients (6.1%); 34 patients (3.7%) with minor AUL and 22 patients (2.4%) with major AUL. Patients with major AUL exhibited a significantly longer time to achieve continence than those without major AUL. Multivariate analysis demonstrated that longer console time (≥ 184 min) was significantly associated with overall AUL, and higher body mass index (≥ 25 g/kg2) was a significant predictor of both major and overall AUL.Conclusions: The presence of major AUL was associated with the achievement of urinary continence, suggesting clinical relevance of its diagnosis by postoperative cystogram. A selective cystogram has been proposed for high-risk cases. Furthermore, identification of the risk factors of AUL will lead to optimal application. [ABSTRACT FROM AUTHOR]

Background: A previous comparative study in Japan has demonstrated that the two consecutive UroVysion tests are useful tools to detect the presence of bladder cancer during follow-up after transurethral resection, but they also presented their high rates of false-positive results. Here, we aimed to evaluate the relationship between the UroVysion tests and subsequent intravesical recurrence. Methods: In the previous study, patients without bladder cancer during the first analysis showed the same examination set repeated 3 months later as the second analysis. In this follow-up study, 326 patients showed negative findings confirmed on cystoscopy during the second UroVysion test. Recurrence-free survival was assessed using a median follow-up of 27 months. Results: In the two consecutive UroVysion tests, 214 patients (65.6%) showed negative UroVysion results in both tests, whereas 91 presented a positive result on either tests and 21 patients presented positive results in both tests. During the follow-up, 40 patients (12.3%) had an intravesical recurrence with non-muscle-invasive bladder cancer. The recurrence rates in patients with negative results in both tests, those with one positive result in either tests, and those with positive results in both tests were 8.4%, 16.5%, and 33.3%, respectively. The multivariate analysis indicated that the history of bladder cancer and the consecutive UroVysion test pattern were independent risk factors for recurrence. Conclusions: Our data confirmed the effectiveness of two consecutive UroVysion tests in predicting intravesical recurrence after TURBT. Further prospective studies would help determine an appropriate interval for cystoscopy follow-up. [ABSTRACT FROM AUTHOR]

This open‐label, phase I dose‐finding study evaluated the gonadotropin‐releasing hormone antagonist, TAK‐385, in Japanese patients with nonmetastatic prostate cancer. In a two‐part design, patients received daily oral TAK‐385 at doses of 320 (loading, day 1)/80 (maintenance, day 2 and thereafter), 320/120, 320/160, or 360/120 mg for 28 days in a dose‐escalation phase (part A, n = 13), and at 320/80 or 320/120 mg for up to 96 weeks in a randomized expansion phase (part B, n = 30). Primary endpoint in both parts was safety, including dose‐limiting toxicity in part A. Secondary endpoints included pharmacokinetics, pharmacodynamics, and prostate‐specific antigen concentration. Ten (77%) patients in part A and all patients in part B experienced an adverse event; hot flush (part A, n = 4; part B, n = 15), viral upper respiratory tract infection (part A, n = 1; part B, n = 10), and diarrhea (part B, n = 8) were most frequent. No dose‐limiting toxicities were observed (part A). In 12 evaluable patients (part A), TAK‐385 was rapidly absorbed after a single loading dose; on day 28 (maintenance dose), median steady‐state Tmax was ~1‐2 hours and mean t1/2z was 67‐79 hours. All doses rapidly reduced testosterone concentrations to castration levels within 1 week. Durable reductions in prostate‐specific antigen of >90% from baseline were observed through 96 weeks. TAK‐385 appeared tolerable and resulted in sustained reductions in testosterone to castration levels at all doses. The lowest loading/maintenance dose required for a clinical effect was 320/80 mg. ClinicalTrials.gov: NCT02141659. [ABSTRACT FROM AUTHOR]

Background: We evaluated the use of UroVysion fluorescence in situ hybridization tests to detect the intravesical recurrence of bladder cancer during follow-up after a transurethral resection of bladder tumor (TURBT).Methods: In this prospective, blinded, comparative study, 486 patients treated by TURBT within the prior 2 years were registered at 12 centers. Urine cytology and UroVysion tests were performed once or twice at a central testing laboratory. For the patients with no suspicious findings of bladder cancer in the first analysis, the same examination set was repeated 3 months later as the second analysis. Totals of 468 and 399 patients were eligible for the first and second analyses, respectively. We determined the sensitivity and specificity of two consecutive UroVysion tests.Results: Bladder cancers were identified in 44 patients at the first analysis. The UroVysion test had 50.0% (95% CI 35.2-64.8%) sensitivity and 72.4% (68.3-76.8%). Urine cytology had 4.5% (0.0-10.7%) sensitivity and 99.8% (99.3-100.0%) specificity. The concordant rate of the first and second UroVysion test results was 72% (kappa coefficient 0.157). Interestingly, the patients with two consecutive positive UroVysion test results had the highest cancer detection rate (14.8%), which is greater than those of the patients with a positive result in either (7.2%) or neither (1.2%) of the two tests at the 3-month follow-up.Conclusions: The UroVysion test provided higher sensitivity than urine cytology to detect bladder cancer during post-TURBT follow-up. Two consecutive UroVysion tests might be a better indicator to predict intravesical recurrence. [ABSTRACT FROM AUTHOR]

Decitabine (DAC) is clinically used to treat myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Our genome-wide CRISPR-dCas9 activation screen using MDS-derived AML cells indicates that mitotic regulation is critical for DAC resistance. DAC strongly induces abnormal mitosis (abscission failure or tripolar mitosis) in human myeloid tumors at clinical concentrations, especially in those with TP53 mutations or antecedent hematological disorders. This DAC-induced mitotic disruption and apoptosis are significantly attenuated in DNMT1-depleted cells. In contrast, overexpression of Dnmt1, but not the catalytically inactive mutant, enhances DAC-induced mitotic defects in myeloid tumors. We also demonstrate that DAC-induced mitotic disruption is enhanced by pharmacological inhibition of the ATR-CLSPN-CHK1 pathway. These data challenge the current assumption that DAC inhibits leukemogenesis through DNMT1 inhibition and subsequent DNA hypomethylation and highlight the potent activity of DAC to disrupt mitosis through aberrant DNMT1-DNA covalent bonds. [Display omitted] • Genomic screen identifies mitotic regulation as a key decitabine resistance pathway • Clinical doses of decitabine induce extensive mitotic disruption in myeloid tumors • Decitabine-induced covalent binding of DNMT1 to DNA causes mitotic disruption • Inhibition of ATR-CHK1 synergizes with decitabine by impairing mitotic fidelity Yabushita et al. perform a genome-wide CRISPR activation screen to identify core regulators of resistance to decitabine in myeloid tumors. This screen reveals the potent activity of clinical-dose decitabine to disrupt mitosis via DNMT1-DNA adducts, challenging the prevailing notion that DNA demethylation is the primary mechanism of action of decitabine. [ABSTRACT FROM AUTHOR]

Tribbles pseudokinase 1 (Trib1) is a negative regulator of CCAAT/enhancer binding protein α (C/EBPα) and is known to induce granulopoiesis while suppressing monocyte differentiation. Loss of Trib1 was previously shown to increase the neutrophil population in the spleen but lead to M2‐like macrophage reduction. Because M2 macrophages are anti‐inflammatory and promote tissue repair by producing fibrogenic factors, we investigated liver fibrosis in Trib1‐deficient mice. Interestingly, loss of Trib1 suppressed fibrosis in the CCl4‐induced chronic liver injury model. Trib1 knockout increased neutrophils but had a minimal effect on the macrophage population in the liver. Hepatic expressions of neutrophil matrix metalloproteinases (Mmp)8 and Mmp9 were increased, but the production of fibrogenic factors, including transforming growth factor β1, was not affected by loss of Trib1. These results suggest that neutrophils are responsible for the suppression of fibrosis in Trib1‐deficient liver. Consistently, transplantation of Trib1‐deficient bone marrow cells into wild‐type mice alleviated CCl4‐induced fibrosis. Furthermore, expression of chemokine (C‐X‐C motif) ligand 1 (Cxcl1) by adeno‐associated viral vector in the normal liver recruited neutrophils and suppressed CCl4‐induced fibrosis; infusion of wild‐type neutrophils in CCl4‐treated mice also ameliorated fibrosis. Using recombinant adeno‐associated virus‐mediated expression of Mmp8 and Mmp9 alleviated liver fibrosis. Finally, neutrophil depletion by infusion of Ly6G antibody significantly enhanced CCl4‐induced fibrosis. Conclusion: While neutrophils are well known to exacerbate acute liver injury, our results demonstrate a beneficial role of neutrophils in chronic liver injury by promoting fibrolysis. (Hepatology Communications 2018;2:703‐717) [ABSTRACT FROM AUTHOR]

MicroRNA142 (MIR142) is a target of chromosome translocations and mutations in human B-cell lymphomas. We analyzed an aggressive B-cell lymphoma carrying t(8;17)(q24;q22) and t(6;14)(p21;q32), and sought to explore the role(s) of MIR142 in lymphomagenesis. t(8;17)(q24;q22) involved MYC on 8q24 and pri-MIR142 on 17q22. MYC was activated by a promoter substitution by t(8;17)(q24;q22). t(8;17)(q24;q22) was an additional event after t(6;14) (p21;q32), which caused the over-expression of CCND3. Southern blot analyses revealed that the MIR142 locus was deleted from the affected allele, whereas Northern analyses showed over-expression of MIR142 in tumor cells. Although previous studies reported an over-expression of mutations in MIR142 in B-cell lymphomas, limited information is available on the functions of MIR142 in lymphomagenesis. Therefore, we generated bone marrow transplantation (BMT) and transgenic (Eμ/mir142) mice, which showed enforced expression in hematopoietic progenitor cells and B cells, respectively. BMT mice showed decreased numbers of all lineage-positive cells, particularly B cells, in peripheral blood. Eμ/mir142 mice showed decreased numbers of IgM-positive splenocytes, and exhibited altered B-cell phenotypic changes induced by lipopolysaccharide. Our results suggest that over-expression of MIR142 alters B-cell differentiation, implying multi-step lymphomagenesis together with MYC activation and CCND3 over-expression. [ABSTRACT FROM AUTHOR]

Background: Resection of metastatic lesions (metastasectomy) is performed for highly selected patients with metastatic urothelial carcinoma (mUC). This study aimed to identify the clinicopathologic factors associated with oncologic outcome for patients who underwent metastasectomy for mUC. Methods: This analysis included 37 UC patients who underwent metastasectomy with curative intent at nine Japanese hospitals. The primary end point was cancer-specific survival. The Kaplan-Meier method with the log-rank test and the multivariable Cox proportional hazards model addressed the relationship between clinical characteristics and survival. Results: Metastasectomy was performed for pulmonary ( n = 23), nodal ( n = 7), and other ( n = 7) metastases. The median survival time was 35.4 months (interquartile range [IQR] 15.5, not reached) from the detection of metastasis and 34.3 months (IQR 13.1, not reached) from metastasectomy. The 5-year cancer-specific survival rate after detection of metastasis was 39.7%. In the multivariate analysis, the time from primary surgery to detection of metastasis (time-to-recurrence [TTR]) of 15 months or longer (hazard ratio [HR] 0.23; p = 0.0063), no symptoms of recurrence (HR 0.23; p = 0.0126), and serum C-reactive protein (CRP) levels lower than than 0.5 mg/dl (HR 0.24; p = 0.0052) were significantly associated with better survival. Conclusions: Long-term survival could be achieved for some patients with mUC who underwent metastasectomy. Lung and lymph nodes were predominant sites for metastasectomy. Symptoms, TTR, and CRP value were identified as associated with survival and should be taken into account when metastasectomy is considered. [ABSTRACT FROM AUTHOR]

Purpose: Small cell carcinoma of the urinary bladder (SCCB) is known for its aggressive clinical features and poor prognosis. No prognostic factor has been established so far. The aim of this study was to assess the significance of possible prognostic factors, including serum neuron-specific enolase (NSE), an established biomarker for small cell lung carcinoma. Methods: We retrospectively reviewed 31 patients with primary SCCB treated at our eight affiliate institutions between 2001 and 2014. The association of various clinicopathological factors at diagnosis, including the serum NSE value, with cancer-specific survival (CSS) was assessed. The log-rank test and Cox proportional hazards model were used for univariate and multivariate analyses, respectively. Results: Nineteen (61.3 %) died of SCCB during the follow-up, with a median survival time of 12.7 months. Prognostic factors were analyzed for the 25 patients after excluding six with missing data. Univariate analysis demonstrated that stage (extensive disease) and serum NSE ≥25 ng/ml were significantly associated with worse CSS. Multivariate analysis identified increased serum NSE value as a sole independent predictor of CSS (hazard ratio 18.52, p = 0.0022). Conclusions: Serum NSE value at diagnosis was an independent prognostic factor for primary SCCB and may serve as a useful biomarker in the management of SCCB. [ABSTRACT FROM AUTHOR]

Background: Several prognostic models predicting survival of patients with metastatic urothelial carcinoma (UC) have been developed; however, of them, the first model by Bajorin in 1999 is still the most representative and widely used, and validations of newer models are lacking. This study aimed to validate three major prognostic models for metastatic UC constructed based on clinical trials. Methods: We reviewed 200 patients with metastatic UC who received first-line chemotherapy at our five affiliate institutions between 2003 and 2011. Using this multi-institutional cohort, we validated the following models: the 'Bajorin model,' a model consisting of visceral metastasis and performance status; the 'Apolo model,' a nomogram including visceral metastasis, performance status, albumin and hemoglobin; and the 'Galsky model,' a nomogram including leukocyte count, number of sites of visceral metastases, site of primary tumor, performance status and lymph node metastasis. Harrell's c-index was calculated for each model. Cox proportional hazards regression model was used for multivariate analysis. Results: Among 200 patients, 171 (85.5 %) died during the follow-up, with a median survival of 12.0 months. Multivariate analysis demonstrated ECOG performance status, visceral metastasis and leukocyte count to be independent predictors of overall survival. C-index results (95 % confidence interval) were Bajorin: 0.86 (0.74-0.95); Apolo: 0.89 (0.78-0.98); and Galsky: 0.82 (0.69-0.93). Conclusions: All models were demonstrated to have high external validities in real-world patients, and of them, the 'Apolo model' achieved the highest c-index in the present population. Further studies with larger populations are needed for establishment of the next standard model. [ABSTRACT FROM AUTHOR]

Mature NK cells are heterogeneous as to their expression levels of cell surface molecules. However, the functional differences and physiological roles of each NK-cell subset are not fully understood. In this study, we report that based on the Ly6C expression levels, mature C57BL/6 murine NK cells can be subdivided into Ly6Clow and Ly6Chigh subsets. Ly6Chigh NK cells are in an inert state as evidenced by the production of lower levels of IFN-γ and granzyme B, and they exhibit poorer proliferative potential than Ly6Clow NK cells. In addition, adoptive transfer experiments revealed that Ly6Chigh NK cells are derived from Ly6Clow NK cells in the steady state. These results strongly suggest that Ly6Chigh NK cells are resting cells in the steady state. However, in vitro, Ly6Chigh NK cells become Ly6Clow NK cells with strong effector functions upon stimulation with IL-15. Moreover, Ly6Chigh NK cells also revert to Ly6Clow NK cells in vivo upon injection of the IL-15 inducers polyI:C and CpG. Taken together, these results demonstrate the plasticity of mature NK cells and suggest that Ly6Chigh NK cells are a reservoir of potential NK cells that allow effective and strong response to infections. [ABSTRACT FROM AUTHOR]

'LEOPIN ROYAL®' (LER), a non-prescription health-promoting medication in Japan, is a preparation containing six natural medicines, namely, aged garlic extract, ginseng, oriental bezoar, velvet antler, cuscuta seed and epimedium herb. To determine the effect of LER on symptoms of aging in males, we conducted an open-labeled, randomized clinical trial using Kampo (mainly kamishoyosan) as a control. Forty-nine male patients (age, 62.7 (SD 11.8) years) with mild or more pronounced symptoms of aging were enrolled and randomly assigned to the LER ( n = 24) or Kampo group ( n = 25) for 6 months. The Aging Males' Symptoms (AMS) scale and the International Index of Erectile Function with 5 questions (IIEF-5) were tested at baseline, and after 3 and 6 months of administration of the medications. In the AMS scale, the somatic and psychological sub-scores and total score decreased depending on the time course in both groups. However, the decrease in the slope of the LER group was greater than that of the Kampo group. There was a significant difference between the groups and the group and month interaction (G × M), as revealed by a linear mixed model analysis ( p < 0.05). The IIEF-5 score increased in the LER group ( p = 0.02 with regard to G × M). In conclusion, the present results indicate that LER is possibly superior to mainly kamishoyosan on the rate of improvement of symptoms of aging, including erectile dysfunction, in males. [ABSTRACT FROM AUTHOR]

Objectives Quinazoline-based α1-adrenoceptor antagonists are known to inhibit prostate tumor growth through induction of apoptosis. We investigated the effect of a naphthalene-based α1-adrenoceptor antagonist, naftopidil, on prostate cancer incidence, apoptosis of prostatic cell and transforming growth factor-β signaling. Methods Prescription records were linked to pathological data for men who continued naftopidil ( n = 766) or tamsulosin ( n = 1015) for 3 months or longer between 2003 and 2010. Prostate cancer incidence was analyzed by log-rank test and the Cox proportional hazards model. Apoptosis and cell cycle arrest in human tissues were assessed by immunohistochemical detection of Bcl2 and p21, respectively. Growth inhibition and apoptosis treatment with naftopidil and tamsulosin were assessed in cancer cell lines. Interference with transforming growth factor-β signaling was examined by western blot analysis. Results Prostate cancer incidence was significantly lower in men who received naftopidil for 3 months or longer compared with tamsulosin ( P = 0.035). Multivariate analysis confirmed a decreased hazard ratio, 0.46, for naftopidil use ( P = 0.013), which was more evident with longer treatment. Immunohistochemical positivity for Bcl2, a marker for resistance to apoptosis, was less frequently detected in prostate cancer cells of men who received naftopidil compared with tamsulosin ( P < 0.05). Naftopidil inhibited cancer cell growth, induced apoptosis and blocked Smad2 phosphorylation activated by transforming growth factor-β in cell lines, with a half maximal inhibitory concentration of 1.1 µmol/L. Conclusions Naftopidil seems to reduce prostate cancer incidence, possibly by inducing apoptosis, preferentially in cancer cells, and blocking transforming growth factor-β signaling. [ABSTRACT FROM AUTHOR]

Study Type - Harm (case series) Level of Evidence 4 What's known on the subject? and What does the study add? The common clinical practice for advanced prostatic adenocarcinoma is combination therapy of zoledronic acid (ZA) and docetaxel (TAX). Little is known about the consequences of this combination therapy with regard to osteonecrosis of the jaw (ONJ). This study shows that the combination therapy of ZA and TAX increases the risk of ONJ and that tooth extraction and leukopenia induced by TAX are the risk factors. OBJECTIVE To determine whether docetaxel (TAX) can increase the risk of osteonecrosis of the jaw (ONJ) in patients with prostatic adenocarcinoma (PC) receiving zoledronic acid (ZA), a bisphosphonate (BP) used in the treatment of patients with cancer., MATERIALS AND METHODS The medical records of 111 patients with PC who received ZA between September 2006 and March 2011 at our institutions were reviewed to assess the incidence and risk factors for ONJ., RESULTS Nine patients (8.1%) developed ONJ during a median follow-up of 14.5 months., Using univariate analysis we found that TAX chemotherapy ( P = 0.037, hazard ratio [HR] 6.611), tooth extraction during ZA therapy ( P < 0.001, HR 11.254), and high prostate-specific antigen level ( P = 0.019, HR 8.008) at the start of ZA were predictive factors., Using multivariate analysis we found that TAX chemotherapy ( P = 0.011, HR 56.35), steroid use ( P = 0.044, HR = 17.795), and tooth extraction ( P = 0.039, HR 7.471) were independent predictors., Among those receiving TAX chemotherapy, multivariate analysis identified tooth extraction ( P = 0.009) and nadir WBC counts <1000/µL during TAX chemotherapy ( P = 0.030) as independent risk factors., CONCLUSION Tooth extraction and nadir WBC counts <1000/µL were found to be risk factors for ONJ in metastatic prostate cancer treated with ZA and TAX combination therapy, showing that leukopenia is an important factor in the development of ONJ. [ABSTRACT FROM AUTHOR]

MicroRNA-125b-1 (miR-125b-1) is a target of the chromosomal translocations t(11;14)(q24;q32) and t(2;11)(p21;q23), which are found in human B-lymphoid and myeloid malignancies, respectively. These translocations result in overexpression of mature miR-125b, consisting of 22 nucleotides. To analyze the role of miR-125b-1 in leukemogenesis, we created a bone marrow transplantation model using a retrovirus vector containing GFP expression elements. Sole transduction of miR-125b-1 into bone marrow cells resulted in expansion of hematopoietic cells expressing GFP. Compared with cells lacking GFP expression, we observed that GFP(+)/CD11b(+) or GFP(+)/Gr(-)1(+) cells were increased in the bone marrow and spleen. Although previous studies reported sole induction of miR-125b-induced leukemia, we did not find leukemic transformation in our model. Transduction of miR-125b-1 did accelerate myeloid tumors induced by a C-terminal mutant of CAAT-enhancer binding protein (C/EBPα-C(m)), a class II-like mutation. As miR-125b has been shown to hasten the development of leukemia in a BCR/ABL-transduced animal model, our present results support the conclusion that overexpression of miR-125b cooperates with other genetic alterations in the pathogenesis of myeloid malignancies. [ABSTRACT FROM AUTHOR]

MicroRNA- 125b- 1 ( miR- 125b- 1) is a target of the chromosomal translocations t(11;14)(q24;q32) and t(2;11)(p21;q23), which are found in human B-lymphoid and myeloid malignancies, respectively. These translocations result in overexpression of mature miR-125b, consisting of 22 nucleotides. To analyze the role of miR- 125b- 1 in leukemogenesis, we created a bone marrow transplantation model using a retrovirus vector containing GFP expression elements. Sole transduction of miR- 125b- 1 into bone marrow cells resulted in expansion of hematopoietic cells expressing GFP. Compared with cells lacking GFP expression, we observed that GFP/CD11b or GFP/Gr1 cells were increased in the bone marrow and spleen. Although previous studies reported sole induction of miR-125b-induced leukemia, we did not find leukemic transformation in our model. Transduction of miR- 125b- 1 did accelerate myeloid tumors induced by a C-terminal mutant of CAAT-enhancer binding protein (C/EBPα-C), a class II-like mutation. As miR-125b has been shown to hasten the development of leukemia in a BCR/ABL-transduced animal model, our present results support the conclusion that overexpression of miR-125b cooperates with other genetic alterations in the pathogenesis of myeloid malignancies. [ABSTRACT FROM AUTHOR]

Objectives: To show the characteristics and therapeutic trends of renal trauma in Japan using a nationwide database. Methods: All renal trauma cases from the Diagnosis Procedure Combination database during 6 months of each year from 2006 to 2008 were included in the analysis. The following variables were considered: demographics, ambulance use, comorbid trauma, interventions, mechanism of injury and the Abbreviated Injury Scale. Patients were divided into two groups by trauma range: limited to rib, abdomen and pelvis (group A) or more extended (including supradiaphragmatic regions or lower extremities; group B). Rib fracture impact was assessed as a predictor of comorbid organ trauma. The incidences of angioembolization failure and nephrectomy were also evaluated. Results: A total of 1505 renal trauma cases (1014 and 491 in groups A and B, respectively) were identified. Comorbid trauma in the liver, spleen and lumbar/pelvic fractures were 7.4%, 5.6% and 5.1% in group A and 24.0%, 11.2% and 17.5% in group B, respectively. The rates of angioembolization (and its failure proportion), nephrectomy, transfusion and mortality were 7.9% (12.5%), 3.3%, 15.6% and 1.1% in group A, and 17.1% (11.9%), 2.6%, 28.3% and 8.1% in group B, respectively. Risks of coincident traumas in the liver, spleen and pelvic fracture were 2.23, 2.35 and 2.72 times higher if a rib fracture was observed. The incidences of renal trauma and nephrectomy (per 100 000 person-years) were estimated as 2.06 and 0.063, respectively. Conclusions: Angioembolization failure is not rare, and nephrectomy is an important last resort. Patients with comorbid rib fracture should be explored for coincident traumas. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study is to assess the association between lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) using the Core Lower Urinary Tract Symptom Score (CLSS) and the International Index of Erectile Dysfunction (IIEF)-5 questionnaires. Methods: A total of 220 consecutive treatment-naive men completed the International Prostate Symptom Score (IPSS), CLSS, and IIEF-5 questionnaires. The clinical diagnoses were benign prostate hyperplasia (BPH, n = 58), prostatic cancer ( n = 51), prostatitis ( n = 28), overactive bladder wet (OAB wet, n = 16), other diagnoses ( n = 39), and controls ( n = 28). Simple statistics and predictability of low IIEF-5 score were examined. Results: The total IIEF-5 score significantly correlated with both the IPSS and CLSS questionnaires ( p = 0.0001). Among IPSS and CLSS symptoms, factors other than daytime frequency and incomplete emptying showed significant correlation with the total IIEF-5 score. A multivariate regression model indicated nocturia and urethral pain as independent factors for low IIEF-5 scores. Conclusion: Urethral pain was identified as an independent factor for erectile dysfunction. The extraction of pain symptoms using CLSS questionnaire may be useful to evaluate LUTS in men with pelvic health problems. [ABSTRACT FROM AUTHOR]

Study Type - Therapy (symptom prevalence) Level of Evidence 2a What's known on the subject? and What does the study add? The International Prostate Symptom Score (IPSS) has been most commonly used for the symptom assessment of men with lower urinary tract symptoms (LUTS). However, LUTS in men are so variable that they may not be fully captured by the IPSS questionnaire alone. This study has demonstrated that the Core Lower Urinary Tract Symptom Score (CLSS) questionnaire, which addresses 10 important symptoms, is an appropriate initial assessment tool for LUTS in men with various diseases/conditions. OBJECTIVE • International Prostate Symptom Score (IPSS) has been commonly used to assess lower urinary tract symptoms (LUTS). We have recently developed Core Lower Urinary Tract Symptom Score (CLSS). The aim of this study is to compare IPSS and CLSS for assessing LUTS in men. PATIENTS AND METHODS • Consecutive 515 men fulfilled IPSS and CLSS questionnaires. • IPSS QOL Index was used as the QOL surrogate. • The clinical diagnoses were BPH ( n = 116), BPH with OAB wet ( n = 80), prostate cancer ( n = 128), prostatitis ( n = 68), underactive bladder ( n = 8), others ( n = 72), and controls (e.g., occult blood) ( n = 42). • Simple statistics and predictability of poor QOL (QOL Index 4 or greater) were examined. RESULTS • All symptom scores were significantly increased in symptomatic men compared with controls. Scores of corresponding symptoms of two questionnaires were significantly correlated ( r = 0.58-0.85, all P < 0.0001). • A multivariate regression model to predict poor QOL indicated nine symptoms (daytime frequency, nocturia, urgency, urgency incontinence, slow stream, straining, incomplete emptying, bladder pain and urethral pain) as independent factors. • The hazard ratios for bladder pain ( 2.2) and urgency incontinence ( 2.0) were among the highest. • All the nine symptoms are addressed in CLSS, while three symptoms (urgency incontinence, bladder, and urethral pain) are dismissed in IPSS. CONCLUSION • CLSS questionnaire is more comprehensive than IPSS questionnaire for symptom assessment of men with various diseases/conditions, although both questionnaires can capture LUTS with possible negative impact on QOL. [ABSTRACT FROM AUTHOR]

Transforming growth factor-β (TGF-β)-stimulated clone-22 (TSC-22), also called TSC22D1-2, is a putative tumor suppressor. We previously identified TSC-22 downstream of an active mutant of fms-like tyrosine kinase-3 (Flt3). Here, we show that TSC-22 works as a tumor suppressor through inhibiting Ras/Raf signaling. Notably, TSC-22 was upregulated by Ras/Raf activation, whereas its upregulation was inhibited by concurrent STAT5 activation. Although TSC-22 was normally retained in the cytoplasm by its nuclear export signal (NES), Ras/Raf activation caused nuclear translocation of TSC-22, but not TSC22D1-1. Unlike glucocorticoid-induced leucine zipper (GILZ/TSC22D3-2) previously characterized as a negative regulator of Ras/Raf signaling, TSC-22 failed to interact physically with Ras/Raf. Importantly, transduction with TSC-22, but not TSC22D1-1, suppressed the growth, transformation and tumorigenesis of NIH3T3 cells expressing oncogenic H-Ras: this suppression was enhanced by transduction with a TSC-22 mutant lacking NES that had accumulated in the nucleus. Collectively, upregulation and nuclear translocation of TSC-22 played an important role in the feedback suppression of Ras/Raf signaling. Consistently, TSC22D1-deficient mice were susceptible to tumorigenesis in a mouse model of chemically-induced liver tumors bearing active mutations of Ras/Raf. Thus, TSC-22 negatively regulated Ras/Raf signaling through a mechanism different from GILZ, implicating TSC-22 as a novel suppressor of oncogenic Ras/Raf-induced tumors. ( Cancer Sci 2012; 103: 26-33) [ABSTRACT FROM AUTHOR]

Objectives: The efficacy of docetaxel (TAX) chemotherapy for corticosteroid-refractory refractory prostate cancer (CRPC) is uncertain. Materials and methods: We retrospectively reviewed outcomes of 51 men with corticosteroid-refractory CRPC treated at our institute. Of them, 24 men had received only dexamethasone (DEX) before the approval of TAX (historical control). The remaining 27 men who had already become DEX refractory on the approval of TAX underwent TAX plus DEX. Results: The median overall survival for men treated with TAX plus DEX (17.6 months) was significantly longer than men with DEX (8.1 months, P = 0.021). On univariate analysis, performance status, lactate dehydrogenase (LDH), alkaline phosphatase (ALP), prostate specific antigen (PSA), and TAX therapy were significant factors for overall survival. Of these, performance status and TAX therapy remained as the significant factor on multivariate analysis. No significant benefit was detected for men with advanced disease such as poorer performance status, elevated LDH, elevated ALP, or high PSA. Grades 3, 4 toxicities including anemia (19%), leukocytopenia (26%), and neutropenia (26%) were found in TAX cases. Conclusions: Our results suggest that TAX would be a vital option for DEX refractory CRPC possibly with more efficacy for less advanced stages. [ABSTRACT FROM AUTHOR]

Objective: We have recently developed the core lower urinary tract symptom score (CLSS) questionnaire to readily address 10 important lower urinary tract symptoms (LUTS). The aim of the present study was to evaluate the performance of the CLSS in women compared with the International Prostate Symptom Score (IPSS) and Overactive Bladder Symptom Score (OABSS). Methods: Three hundred and eighteen treatment-naïve consecutive female patients, including 48 controls, completed the three questionnaires. Quality of life (QOL) was determined as per the IPSS QOL Index. The clinical diagnoses were overactive bladder ( n = 69), mixed incontinence ( n = 42), stress incontinence ( n = 17), pelvic organ prolapse ( n = 56), interstitial cystitis ( n = 31), bacterial cystitis ( n = 16), underactive bladder ( n = 16), and 'other' ( n = 23). Simple statistics and the relationship between symptom scores and poor QOL (QOL Index ≥4) were examined. Results: All symptom scores were significantly increased in symptomatic women. The CLSS described the symptom profiles of patients with distinct conditions. The scores of corresponding symptoms on the three questionnaires were significantly correlated ( r = 0.51-0.85; all P < 0.0001). Multivariate logistic regression modeling proved five CLSS symptoms (daytime frequency, nocturia, urgency incontinence, straining, and urethral pain) as independent predictors of poor QOL, with hazard ratios ranging from 2.0 to 4.2. The IPSS included only two (urgency and straining) significant symptoms. Conclusions: The IPSS alone does not fully evaluate female LUTS, with a possible negative impact on QOL. Using the CLSS questionnaire would enable a simple and comprehensive assessment of female LUTS. [ABSTRACT FROM AUTHOR]

Objectives: To explore whether Lys262Arg polymorphism of the Cytochrome P450 2B6 (CYP2B6) gene could act as a genetic marker for prostate cancer risk among Japanese men. Methods: A total of 350 patients with sporadic prostate cancer and 328 controls were examined. A single nucleotide polymorphism with non-synonymous amino acid change located at Lys262Arg of the CYP2B6 gene was genotyped using a TaqMan assay. Results: The frequency of the Arg/Arg genotype among prostate cancer patients was significantly higher than that among the controls ( P = 0.027). The frequency of the G allele of the Lys262Arg polymorphism was also significantly higher in prostate cancer patients than in the controls (30.4% vs 24.8%, P = 0.025). Patients with the Lys/Arg plus Arg/Arg genotypes carried a low Gleason score more frequently than those with the Lys/Lys genotype ( P = 0.042). The frequency of the G allele of the Lys262Arg polymorphism was significantly higher in the low Gleason score group than that in the high Gleason score group (34.3% vs 26.8%, P = 0.038). Conclusions: Lys262Arg polymorphism of the CYP2B6 gene may be a genetic marker for evaluating the risk of sporadic prostate cancer in native Japanese men. [ABSTRACT FROM AUTHOR]

The POU transcription factor human Skn-1a (hSkn-1a) specifically promotes the proliferation of keratinocytes and enhances their differentiation. We examined the effects of hSkn-1a on cervical cancer cell lines of epithelial origin, in which the differentiation program is interrupted. From HeLa/Tet-On, a clone that can be induced to make hSkn-1a by doxycycline (HeLa/hSkn-1a) was prepared and characterized. Shortly after the induction, the cells expressed cytokeratin 10 (K10), a major marker protein in differentiating keratinocytes. While maintained for several days in the presence of doxycycline, the HeLa/hSkn-1a cells showed a slightly prolonged time of population doubling, the occasional appearance of flat cells with lowered DNA synthesis, and a low level of apoptotic DNA fragmentation. In SiHa and HeLa S3 cultures, K10 mRNA and apoptotic DNA fragmentation were detected at 48?h after infection with an adenoviral vector capable of expressing hSkn-1a. A colony inhibition assay showed that the growth of HeLa S3, SiHa, CaSki, and C-33A cells was repressed, as seen from the decreased number and average size of the drug-resistant colonies at 2 or 3 weeks after transfection with a plasmid that can express hSkn-1a and neomycin resistance gene. These results suggest that the expression of hSkn-1a represses the growth of the cervical cancer cells through the partial resumption of the differentiation pathway followed by slow suppression of cell replication and apoptosis.Oncogene (2004) 23, 5014-5022. doi:10.1038/sj.onc.1207653 Published online 12 April 2004 [ABSTRACT FROM AUTHOR]

Information on the annual Editorial Board Meeting held by "International Journal of Urology" (IJU) Editorial Board in Yokohama, Japan on April 21, 2012 is presented. Topics include the performance of the journal, a report by the publisher John Wiley & Sons Inc. (Wiley-Blackwell) and the review process of the journal. The meeting featured several speakers such as doctor Rajeev Kumar, the publishers and editors of the journal.

The article focuses on the report of the Editorial Board meeting of the periodical "International Journal of Urology," (IJU) which was held during the annual meeting of the Japanese Urological Association (JUA) in Nagoya, Japan on April 22, 2011. The author refers to submissions to the journal from all over the world, with Asian countries including Japan, China and India listing among the highest contributors. Also mentioned is IJU's impact factor (IF) and the increasing online access.

A letter to the editor is presented regarding the case of a 74-year-old man who developed bladder endometriosis after undergoing a long-term estrogen therapy for prostate cancer.

The author reflects on the issue of the association between cerebro- and cardiovascular disorders (CCVD) and aortic calcification index or maximum intima media thickness in long-term hemodialytic patients. He notes that the study design is retrospective and the number of patients enrolled is small. Moreover, the author suggests that a large cohort study will be required to determine the exact relationship between the parameters and the development of CCVD.

Objectives To evaluate the prognostic significance of the pretreatment neutrophil-to-lymphocyte ratio in patients with metastatic urothelial carcinoma who underwent salvage chemotherapy. Methods We reviewed 200 metastatic urothelial carcinoma patients who received salvage chemotherapy at our five affiliate institutions between 2003 and 2011. The associations of pretreatment clinicopathological factors, including neutrophil-to-lymphocyte ratio, with cancer-specific survival and overall survival from the start of chemotherapy were assessed. Cox proportional hazards model was used for multivariate analysis. Results A total of 15 cases with missing data were excluded. Among the remaining 185 patients, 157 died during follow up, with a median survival of 13.0 months. Multivariate analysis showed that the pretreatment neutrophil-to-lymphocyte ratio ≥3, Eastern Cooperative Oncology Group performance status ≥2 and liver metastasis were independent poor prognostic factors, both for cancer-specific survival and overall survival. A prognostic model predicting overall survival was constructed based on the number of these three variables (0, 1 and ≥ 2). The classified patients showed significantly different overall survival (each P < 0.0001, log-rank test), with Harrell's concordance index as high as 0.81. Conclusions Pretreatment neutrophil-to-lymphocyte ratio elevation was an independent poor prognostic factor for metastatic urothelial carcinoma undergoing salvage chemotherapy. Our newly constructed prognostic model including the pretreatment neutrophil-to-lymphocyte ratio proved to be an excellent discriminator of overall survival. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular disease is a frequent cause of death in peritoneal dialysis patients. Biocompatible peritoneal dialysis solutions with neutral pH have been anticipated to reduce cardiovascular disease more than conventional peritoneal dialysis solutions with low pH, but it remains unclear which factors at peritoneal dialysis initiation increase cardiovascular risk in patients using biocompatible peritoneal dialysis solutions. This study was undertaken to investigate which clinical factors at peritoneal dialysis initiation, including peritoneal transport status, are associated with cardiovascular event in patients using biocompatible peritoneal dialysis solution.Methods: This retrospective cohort study of peritoneal dialysis patients using biocompatible solutions with neutral pH assessed relations of clinical parameters at peritoneal dialysis initiation to cardiovascular event during the subsequent five years.Results: Of 102 patients who started peritoneal dialysis, cardiovascular event occurred in 18. Age, history of cardiovascular disease before peritoneal dialysis initiation, hemoglobin, serum albumin, C-reactive protein, peritoneal permeability defined by the ratio of dialysate to plasma creatinine concentration at 4 hr (D/Pcre) in peritoneal equilibration test (PET), number of patients in each PET category defined by D/Pcre, and peritoneal protein clearance significantly differed between patients with and without cardiovascular event. For patients divided according to PET category using Kaplan-Meier method, the group of high average to high peritoneal transporters exhibited significantly high incidence of cardiovascular event and mortality compared with the groups of low and low-average peritoneal transporters (Log rank; p=0.0003 and 0.005, respectively). A Cox proportional hazards model showed independent association of PET category classification with cardiovascular event.Conclusions: Peritoneal permeability expressed as PET category at peritoneal dialysis initiation is an independent cardiovascular risk factor in peritoneal dialysis patients using biocompatible peritoneal dialysis solution with neutral pH. Greater peritoneal permeability at peritoneal dialysis initiation might reflect subclinical vascular disorders. [ABSTRACT FROM AUTHOR]