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NOTCH2-inactivating antibody inhibited tumor progression in vitro and in vivo.

NOTCH2 silencing inhibited tumor progression through decreased cell proliferation and invasion.

NOTCH2-induced cell invasion was blocked by downstream inhibition of canonical NOTCH2 signaling.

Purpose: Recent molecular analyses of bladder cancer open the door to significant advances in targeted therapies. NOTCH has been identified as a tumor suppressor in bladder cancer, but prior reports have focused on NOTCH1. Here we hypothesized that NOTCH2 is an oncogene suitable for therapeutic targeting in bladder cancer.Experimental design: We studied genomic aberrations of NOTCH, compared survival and tumor progression according to NOTCH2 expression levels, and studied NOTCH2 function in vitro and vivo.Results: We report a high rate of NOTCH2 copy number gain in bladder cancer. High NOTCH2 expression was identified especially in the basal subtype and in mesenchymal tumors. NOTCH2 activation correlated with adverse disease parameters and worse prognosis by immunohistochemistry. Forced overexpression of the intracellular domain of NOTCH2 (N2ICD) induced cell growth and invasion by cell-cycle progression, maintenance of stemness and epithelial-to-mesenchymal transition (EMT). These effects were abrogated by silencing of CSL, indicating that the effects were mediated through the canonical NOTCH signaling pathway. In an orthotopic xenograft model, forced overexpression of N2ICD increased growth, invasion, and metastasis. To explore the potential for therapeutic targeting of NOTCH2, we first silenced the receptor with shRNA and subsequently treated with a specific inhibitory antibody. Both interventions decreased cell growth, invasion, and metastasis in vitro and in the orthotopic xenograft model.Conclusions: We have demonstrated that NOTCH2 acts as an oncogene that promotes bladder cancer growth and metastasis through EMT, cell-cycle progression, and maintenance of stemness. Inhibition of NOTCH2 is a rational novel treatment strategy for invasive bladder cancer. Clin Cancer Res; 22(12); 2981–92. ©2016 AACR.

NOTCH2 overexpression promoted bladder cancer progression through increased proliferation and invasion.

The lists of antibodies, primers and patients characteristics and detailed information of methods were described in Supplementary Material and Methods.

In-hospital bleeding is associated with poor prognosis in patients with acute myocardial infarction (AMI). We sought to investigate whether a combination of pre-procedural blood tests could predict the incidence of in-hospital major bleeding in patients with AMI.A total of 1684 consecutive AMI patients who underwent primary percutaneous coronary intervention (PCI) were recruited and randomly divided into derivation (n = 1010) and validation (n = 674) cohorts. A risk-score model was created based on a combination of parameters assessed on routine blood tests on admission. In the derivation cohort, multivariate analysis revealed that the following 5 variables were significantly associated with in-hospital major bleeding: hemoglobin level 12 g/dL (odds ratio [OR], 3.32), white blood cell count10,000/μL (OR, 2.58), platelet count150,000/μL (OR, 2.51), albumin level 3.8 mg/dL (OR, 2.51), and estimated glomerular filtration rate 60 mL/min/1.73 mOur novel laboratory-based bleeding risk model could be useful for simple and objective prediction of in-hospital major bleeding events in patients with AMI.

Development of acute kidney injury (AKI) is associated with poor prognosis in patients with ST-segment elevation myocardial infarction (STEMI).This study sought to investigate whether a combination of pre-procedural blood tests could predict the incidence of AKI in patients with STEMI.A total of 908 consecutive Japanese patients with STEMI who underwent primary percutaneous coronary intervention within 48 hours of symptom onset were recruited and divided into derivation (n = 617) and validation (n = 291) cohorts. A risk score model was created based on a combination of parameters assessed on routine blood tests on admission.In the derivation cohort, multivariate analysis showed that the following 4 variables were significantly associated with AKI: blood sugar ≥200 mg/dL (odds ratio [OR]: 2.07), high-sensitivity troponin I1.6 ng/mL (upper limit of normal ×50) (OR: 2.43), albumin ≤3.5 mg/dL (OR: 2.85), and estimated glomerular filtration rate 45 mL/min/1.73 mOur novel laboratory-based model might be useful for early prediction of the post-procedural risk of AKI in patients with STEMI.

Background/aim Bladder cancer with histological variant (HV) has different morphological features from usual urothelial carcinoma (UC). The aim of this study was to evaluate the oncological outcomes of HV in patients with bladder cancer. Patients and methods We retrospectively evaluated data from 102 patients with UC of the bladder treated with radical cystectomy between 1998 and 2017. Pathological findings including HV were assigned by one dedicated pathologist. Recurrence-free survival (RFS) and cancer-specific survival (CSS) and overall survival (OS) were estimated by Cox regression models. Results In total, 26 patients (25.5%) had HV, and the most common variant was squamous differentiation, followed by glandular differentiation and a mixed variant consisted of squamous and glandular differentiation. The presence of HV was associated with RFS and CSS (p=0.018, p=0.036, respectively). Conclusion HV has more aggressive tumor biological features compared to those with pure UC. The presence of HV was associated with poor survival.

Low serum albumin (SA) on admission in patients with acute myocardial infarction (AMI) has been reported to be associated with adverse cardiovascular events. The relation between low SA and post-AMI bleeding events is presently unknown. We analyzed 1,724 patients with AMI enrolled in the HAGAKURE-ACS registry who underwent primary percutaneous coronary intervention from January 2014 to December 2018. To assess the influence of low SA at admission, patients were divided into 3 groups according to the albumin tertiles: the low SA group (3.8 g/100 ml), the middle SA (MSA) group (3.8 to 4.1 g/100 ml), and the normal SA (NSA) group (≥4.2 g/100 ml). The primary end point was the incidence of Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries moderate/severe bleeding. The cumulative 3-year incidence of the primary end point was significantly higher in the low SA group than in the MSA and NSA groups (30.8% and 11.9% vs 7.7%; p0.001). In the landmark analysis at 30 days, the cumulative incidences of the primary end point were also significantly higher in the low SA group than in the MSA and NSA groups, both within and beyond 30 days (20.1% and 6.1% vs 3.5%; p0.001, and 12.4% and 6.2% vs 4.5%; p0.001, respectively). After adjusting for confounders, the low SA group showed excess risk of bleeding events relative to NSA (hazard ratio 1.56; 95% confidence interval 1.06 to 2.30; p = 0.026), whereas risk of bleeding was neutral in MSA relative to NSA (hazard ratio 0.94; 95% confidence interval 0.63 to 1.34; p = 0.752). In conclusion, low SA at admission was independently associated with higher risk for bleeding events in patients with AMI undergoing percutaneous coronary intervention.

Few studies mention the necessity of antimicrobial prophylaxis (AMP) for transurethral resection of bladder tumor (TURBT) and the risk factors for postoperative urinary tract infections (UTIs) after TURBT. To evaluate the necessity of AMP and to detect the risk of UTIs, we examined the perioperative clinical factors. 687 patients who underwent TURBT between 2006 and 2017 at Hiroshima Prefectural Hospital were examined retrospectively. We defined the postoperative UTIs as febrile UTIs (≥ 38 °C). The AMP for the TURBT that we used was mostly cephalosporin generation 1. The association between the perioperative clinical/pathological factors and postoperative UTIs was assessed by logistic regression retrospectively. 21 patients (3.1%) suffered from postoperative UTIs, and almost all of them were successfully treated with the immediate administration of antibiotics. Univariate analysis showed that past pelvic radiotherapy (p = 0.024, odds ratio (OR) 6.00), tumor size (≥ 2cm) (p = 0.008, OR 3.38), age (≥ 75 years) (p = 0.036, OR 2.65), preoperative hospital stay (≥ 5 days) (p = 0.017, OR 3.76), asymptomatic pyuria (p = 0.038, OR 2.54) and bacteriuria (p = 0.044, OR 2.97) were all associated with postoperative UTIs. We demonstrated that AMP was effective for patients who underwent TURBT, and history of pelvic radiotherapy, high age, preoperative hospital stay and a certain tumor size were the risk factors as well as pyuria and bacteriuria of postoperative UTIs.

(Objective) The aim of this study is to investigate the treatment outcome of laparoscopic radical prostatectomy (LRP). (Patients and methods) The study cohort consisted of 926 hormone-naïve patients with localized prostate cancer who underwent LRP at the Hiroshima Endourological Association from January 2007 to December 2016. (Results) The mean age was 69.4 years, the mean initial PSA was 9.1 ng/ml, and the mean follow-up period was 40.3 months. The D'Amico Risk Classification was Low: 232 cases, Intermediate: 344 cases, and High: 350 cases. Nerve preservation was performed bilaterally for 138 patients and unilaterally for 181 patients. The mean operative time was 181.0 minutes and the mean estimated blood loss was 360.7 ml. As the number of experienced cases increased, the operative time was significantly shorter and the estimated blood loss was significantly decreased. According to Clavien-Dindo classification, the ratio of perioperative complication degree IIIa or above was 4.0% (37 cases). The pathological results were Gleason score (GS) ≤6: 174 cases, GS7: 514 cases, GS ≥8: 232 cases, pT2≥: 704 cases, pT3a: 172 cases, pT3b: 47 cases, pT4: 3 cases, pN0: 917 cases, and pN1: 9 cases. Positive surgical margins were found in 278 cases (30.0%). The biochemical recurrence-free survival rate at 5 years was 78.1%. In multivariate analysis, age (≥70 yrs), initial PSA (≥10 ng/ml), biopsy GS (GS ≥8), cancer positive core ratio at biopsy (≥30%), pT (pT≥3), pathological GS (GS≥8), positive surgical margin and total number of patients in the facility were predictive factors of postoperative biochemical PSA recurrence. Younger age and nerve preservation were found to be predictive factors for the early recovery of urinary continence after surgery, with 88% regaining urinary continence at 12 months after surgery. (Conclusion) This study revealed the clinical outcome and appropriate candidates for LRP in Japanese patients.

(Purpose) We report five cases of adrenal myelolipoma with surgical treatment, and analyze the patients' background and clinical courses. (Patients and methods) From 2004 to 2017, five patients diagnosed adrenal myelolipoma were underwent surgical treatment at our hospital. We investigate the patients' background and clinical courses retrospectively. (Results) Median age was 53 years old. Four of them were male and one was female. The tumor was located on the right side in four cases and the left side in one case. All cases were incidentally found by abdominal ultrasound or computer tomography (CT) during a medical check or image examination for other disease. Whereas all cases were asymptomatic, they have past history either hypertension, diabetes or obesity. The tumor size at the time of diagnosis was from 28 mm to 80 mm (median 58 mm). All tumors were nonfunctioning, and diagnosed by CT scan preoperatively. The median tumor size at the time of operation was 66 mm. (Conclusion) We report five cases of adrenal myelolipoma treated surgically. The opportunity of encountering this disease has been increasing as the recent improvement of diagnostic imaging such as CT, MRI, and etc. However, there is no widely-accepted treatment algorithm. We should manage them carefully, because spontaneous rupture of adrenal myelolipoma has been reported in some cases.

Background: In-hospital bleeding is associated with poor prognosis in patients with acute myocardial infarction (AMI). We sought to investigate whether a combination of pre-procedural blood tests could predict the incidence of in-hospital major bleeding in patients with AMI. Methods and Results: A total of 1684 consecutive AMI patients who underwent primary percutaneous coronary intervention (PCI) were recruited and randomly divided into derivation (n=1010) and validation (n=674) cohorts. A risk-score model was created based on a combination of parameters assessed on routine blood tests on admission. In the derivation cohort, multivariate analysis revealed that the following 5 variables were significantly associated with in-hospital major bleeding: hemoglobin level 10000/μL (OR, 2.58), platelet count < 150000/μL (OR, 2.51), albumin level < 3.8 mg/dL (OR, 2.51), and estimated glomerular filtration rate < 60 mL/min/1.73 m 2 (OR, 2.31). Zero to five points were given according to the number of these factors each patient had. Incremental risk scores were significantly associated with a higher incidence of in-hospital major bleeding in both cohorts ( P < 0.001). Receiver operating characteristic curve analysis of risk models showed adequate discrimination between patients with and without in-hospital major bleeding (derivation cohort: area under the curve [AUC], 0.807; 95% confidence interval [CI], 0.759 – 0.848; validation cohort: AUC, 0.793; 95% CI, 0.725 – 0.847). Conclusions: Our novel laboratory-based bleeding risk model could be useful for simple and objective prediction of in-hospital major bleeding events in patients with AMI