Yoshiyuki Yamamoto

Clinical characteristics and risk factors for septic shock in patients receiving emergency drainage for acute pyelonephritis with upper urinary tract calculi

BackgroundAcute pyelonephritis (APN) is a common complication of ureteral obstruction caused by urolithiasis, and it can be lethal if it progresses to septic shock. We investigated the clinical characteristics of patients undergoing emergency drainage and assessed risk factors for septic shock.MethodsA retrospective study was performed of 98 patients (101 events) requiring emergency drainage at our urology department for obstructive APN associated with upper urinary tract calculi from January 2003 to January 2011. Clinical characteristics were summarized, and risk factors for septic shock were assessed by logistic regression analysis.ResultsObjective evidence of sepsis was found in 64 (63.4%) events, and 21 events (20.8%) were categorized as septic shock. Ninety-six patients recovered, but 2 patients died of septic shock. Multivariate analysis revealed that age and the presence of paralysis were independent risk factors for septic shock.ConclusionsAPN associated with upper urinary tract calculi is a severe disease that should be treated with caution, particularly when risk factors are present.

Laparoscopic resection of primary retroperitoneal mucinous cystadenoma by retroperitoneal approach

Primary retroperitoneal mucinous cystadenoma (RMC) is rare, and usually forms a huge mass in retroperitoneal space. We report the successful resection of RMC retroperitoneoscopically with a SAND balloon catheter (Hakko Medical, Tokyo, Japan). A 29-year-old woman presented with left lower abdominal pain and gross hematuria. On physical examination, an elastic soft tumor was palpable on her left upper abdomen. Contrast-enhanced computed tomography showed a large cystic mass without solid components that measured 18 ¥ 13 ¥ 12 cm in the retroperitoneal space and a displaced left kidney (Fig. 1a). Cystic mass was homogeneous, thinwalled and unilocular with no calcifications. Laboratory data were unremarkable and tumor markers including CEA, CA125 and CA19-9 were normal. Preoperative diagnosis was lymphangioma or mucinous cystadenoma. Differential diagnosis was pancreatic pseudocyst, and needle aspiration was carried out. The aspirated cystic content was mucinous and clear, and its amylase level was normal. Cytology of cystic content was benign. Laparoscopic resection of the tumor by retroperitoneal approach was carried out. A 12-mm trocar was placed just below the tip of the 12th rib as a camera port. The second 12-mm trocar was inserted just below the costal arch on the posterior axillary line, and the third 5-mm trocar was inserted just below the costal arch on the anterior axillary line. The tumor was identified under the lateroconal fascia. The SAND balloon catheter was inserted 2 cm above the anterior superior iliac spine and the tumor was punctured by the SAND balloon catheter (Fig. 1b,c). A total of 540 mL of intracystic mucinous contents were aspirated without gross spillage, and the SAND balloon catheter continued to be used to pull the tumor. The tumor was removed through the 12-mm port. Pathological examination showed that the cyst wall consisting of fibrous tissues was lined by a single layer of columnar epithelium containing mucus, and there was no evidence of malignancy (Fig. 1d). Pathological diagnosis was benign mucinous cystadenoma. The patient was free of recurrence 6 months after surgery.

Role of adjuvant chemotherapy for lymph node-positive upper tract urothelial carcinoma and the prognostic significance of C-reactive protein: A multi-institutional, retrospective study

To analyze the role of adjuvant chemotherapy in lymph node‐positive patients with upper tract urothelial carcinoma undergoing radical nephroureterectomy, and identified the prognostic adjuvant chemotherapy parameters.

High-Fat Diet-Induced Inflammation Accelerates Prostate Cancer Growth via IL6 Signaling

Purpose: High-fat diet (HFD) could induce prostate cancer progression. The aim of this study is to identify mechanisms of HFD-induced prostate cancer progression, focusing on inflammation. Experimental Design: We administered HFD and celecoxib to autochthonous immunocompetent Pb-Cre+;Pten(fl/fl) model mice for prostate cancer. Tumor growth was evaluated by tumor weight and Ki67 stain, and local immune cells were assessed by flow cytometry at 22 weeks of age. Cytokines which correlated with tumor growth were identified, and the changes of tumor growth and local immune cells after inhibition of the cytokine signals were evaluated in the mice. IHC analyses using prostatectomy specimens of obese patients were performed. Results: HFD accelerated tumor growth and increased the myeloid-derived suppressor cells (MDSCs) fraction and M2/M1 macrophage ratio in the model mice. Celecoxib-suppressed tumor growth, and decreased both local MDSCs and M2/M1 macrophage ratio in HFD-fed mice. HFD-induced tumor growth was associated with IL6 secreted by prostatic macrophages, as were phosphorylated STAT3 (pSTAT3)-positive tumor cells. Anti-IL6 receptor antibody administration suppressed tumor growth, and decreased local MDSCs and pSTAT3-positive cell fractions in HFD-fed mice. The tumor-infiltrating CD11b-positive cell count was significantly higher in prostatectomy specimens of obese than those of nonobese patients with prostate cancer. Conclusions: HFD increased MDSCs and accelerated prostate cancer tumor growth via IL6/pSTAT3 signaling in the mice. This mechanism could exist in obese patients with prostate cancer. IL6-mediated inflammation could be a therapeutic target for prostate cancer. Clin Cancer Res; 24(17); 4309–18. ©2018 AACR.

Peripheral blood monocyte count reflecting tumor-infiltrating macrophages is a predictive factor of adverse pathology in radical prostatectomy specimens.

Tumor‐infiltrating macrophages, which are thought to be derived from blood monocytes, interact with tumor cells to promote cancer progression. The aim of this study was to assess the association of peripheral blood monocyte count with pathological findings and local tumor‐infiltrating macrophages in prostatectomy specimens.

Expression level of CXCL7 in peripheral blood cells is a potential biomarker for the diagnosis of renal cell carcinoma

There are no blood biomarkers for the diagnosis of renal cell carcinoma (RCC) in routine clinical use. We focused on the gene expression profile of peripheral blood cells obtained from RCC patients to discover novel biomarkers for RCC diagnosis. Using microarray analysis and quantitative verification, CXCL7 was shown to be significantly upregulated in the peripheral blood cells of RCC patients. Importantly, aberrant CXCL7 expression was confirmed even in peripheral blood cells obtained from early stage (pT1a) RCC patients, and the expression level of CXCL7 in peripheral blood cells was a potential independent biomarker for the diagnosis of RCC by receiver operating characteristic curve analysis (sensitivity, 70.0%; specificity, 64.0%; area under the curve = 0.722; multiple logistic regression analysis: odds ratio, 1.07; 95% confidence interval, 1.03–1.11; P = 0.0004). Moreover, CXCL7 expression in peripheral blood cells significantly decreased after resection of the primary tumor. CXCL7 is more highly expressed in PBMCs than in neutrophils from both healthy controls and RCC patients. Interestingly, CXCL7 expression in PBMCs from healthy volunteers was significantly elevated following coculture with RCC cells compared to those cocultured with normal cells as a control. These results suggest that aberrant CXCL7 expression in peripheral blood cells is induced by RCC cells and may serve as a novel biomarker in the diagnosis of RCC.

MP88-04 THE CLINICAL UTILITY OF ABSOLUTE COPY NUMBER AND FRAGMENT SIZE OF PLASMA CIRCULATING CELL-FREE DNA AS NOVEL BIOMARKERS IN RENAL CELL CARCINOMA PATIENTS

INTRODUCTION AND OBJECTIVES: Metabolomics offers the ability to exploit the unique metabolic dysregulation inherent in known pathways of renal cell carcinoma pathogenesis to help guide clinical management. While metabolomic pathways and signatures have been studied of a variety of cancers, the signature of urine of patients with RCC has not been well established. We consequently interrogated distinct urinary pathway-level metabolic shifts in patients following surgical excision of renal masses to differentiate metabolic profiles of highrisk clear cell RCC (ccRCC) from indolent and benign tumors. METHODS: Patients undergoing surgery for non-metastatic RCC were enrolled in an IRB-approved, institutional biorepository and donated urine samples prior to surgery. Patients0 pathology was indexed as high-risk (HR), defined as high-grade (Grade III-IV) and/or locally-advanced (pT3 or higher) ccRCC; indolent, defined as pT1-T2 and low-grade (Grade I-II) ccRCC; or benign. Capillary electrophoresis mass spectrometry was utilized to process urine samples in a highthroughput fashion to identify distinctive metabolomic profiles indicative of the three pathologies. Sixty-nine targeted metabolites were detected and quantified; principal components analysis and heatmaps were generated. Differences were analyzed using Welch0s t-test. RESULTS: A total of 66 urine specimens were included in our analysis: 30 (45.4%) were from patients with HR RCC, 19 (28.8%) from patients with indolent disease, and 17 (25.8%) from patients with benign pathology. Patients with indolent lesions had higher concentrations of the following unique amino acids compared to benign lesions (p<0.01): Phe (þ42.4%), Tyr (þ52.2%), Trp (þ42.7%) and Lys (þ66%). Concentrations of several unique metabolites differed between benign and HR RCC lesions (p<0.01): Hypoxanthine (-42%), Threonic Acid (þ26%), EAP (þ133%), and Glycerol-3-phosphate (þ110%). HR RCC had smaller concentrations of the following metabolites versus indolent lesions (p<0.01): Betaine (-63%), Hydrouracil (-36%), N-Ac Gln (-56%), Histidine (-42%), and 2-aminoisobutyrate (-47%). CONCLUSIONS: Given the prevalent metabolic rearrangements in RCC, use of urinary metabolomics represents a promising biomarker that can not only distinguish ccRCC from benign tumors, but also risk-stratify dangerous cancers from indolent ones by identifying specific metabolic profiles.

Increased level and fragmentation of plasma circulating cell-free DNA are diagnostic and prognostic markers for renal cell carcinoma

Background Reliable biomarkers for renal cell carcinoma (RCC) have yet to be found. Circulating cell-free DNA (cfDNA) is an emerging resource for the diagnosis and prognosis of various cancers. This study aims to identify novel blood biomarkers for RCC. Materials And Methods Plasma cfDNA was extracted from RCC patients (n = 92) and healthy controls (n = 41). Levels of cfDNA were determined using quantitative real-time PCR of ACTB as the target gene, and cfDNA fragment size was measured using a microfluidics-based platform. Diagnostic potential was assessed using receiver operating characteristic (ROC) and logistic regression analysis, and prognostic potential was evaluated using log-rank test. Results Median levels of cfDNA from RCC patients were significantly higher than those from healthy controls (3803 vs 2242 copies/ml, p < 0.001). Median fragment sizes of cfDNA in RCC patients were shorter than those in healthy controls (170 vs 171 bp, p = 0.052). To evaluate level of cfDNA as a diagnostic tool for RCC, ROC curve analysis revealed a sensitivity of 63.0% and a specificity of 78.1%. Multivariate analysis indicated that age, gender and the level of cfDNA were significantly associated with the presence of RCC (p < 0.001, p = 0.013, p < 0.001, respectively). Additionally, shorter cfDNA fragment size was negatively associated with progression-free survival (p = 0.006). Conclusions Our study demonstrates the diagnostic and prognostic potential of plasma cfDNA as a biomarker for RCC.

MP99-06 HIGH FAT DIET-INDUCED INFLAMMATION ACCELERATES TUMOR PROGRESSION IN MICE MODEL FOR PROSTATE CANCER

retention at DSB sites in prostate cancer cells, and also impaired recruitment of Ku70/Ku80 to DSB sites. The impaired recruitment of Ku70 and Ku80 proteins to DNA damage sites upon ELL2 knockdown was rescued by re-expression of an ELL2 transgene insensitive to siELL2. CONCLUSIONS: This study suggests that ELL2 is an important factor mediating androgen protection of DNA damage via Ku70/Ku80 in prostate cancer cells.

MP73-02 IMMUNOLOGICAL CLASSIFICATION IN RENAL CELL CARCINOMA BASED ON IMMUNOCHECKPOINT MOLECULES: THE RELATIONSHIP WITH TUMOR AGGRESSIVENESS AND THE PRESENCE OF INTRA-TUMOR DIVERSITY

INTRODUCTION AND OBJECTIVES: Immune checkpoint inhibitors-based therapy is rapidly developing into an effective treatment option for a surprising range of cancers. Despite the autoimmune or inflammatory immune-mediated adverse effects which have been seen, the responses and overall survival benefits exhibited thus far warrant further clinical development. Lycorine, an alkaloid extracted from plants in the Amaryllidaceae family, which showed a strong anticancer effect by inducing cell lysis of various carcinomas. This study investigated the effectiveness of a combination therapy of lycorine and anti-CTLA-4 in a mouse model of renal cell carcinoma (RCC). METHODS: We investigated the anti-tumor efficacy of lycorine in various RCC cell lines including Caki-1, ACHN, KPK-1 and Renca through XTT proliferation, scratch motility, migration and invasion assays. We also discuss that mechanism underlying this anticancer potential with flow cytometry and western blot. Furthermore, luciferase-expressing Renca cells were implanted in the left kidney and the lung of BALB/c mice to develop a RCC metastatic mouse model for investigated the combination therapy effect of lycorine and antiCTLA-4. RESULTS: We confirmed the anticancer potential of lycorine in vitro as observed time-dependent inhibition in several RCC cell lines. Moreover, lycorine suppressed the migratory and invasive abilities of Renca cells. The possible mechanism underlying this anticancer potential was cell cycle profile arrest. Lycorine and anti-CTLA-4 additively decreased tumor weight, lung metastasis, and luciferin-stained tumor images. Importantly, these effects were dependent on significantly suppressing regulatory T-cells while upregulating effector T-cells. CONCLUSIONS: Herein, as we know, it’s the first report that lycorine in combination with anti-CTLA-4 inhibited orthotopic and metastatic tumors by downregulating Treg, which was accompanied with upregulation of effector T-cells. Our findings suggest and indicate lycorine as a potent candidate for treating RCC and will serve as an excellent aid for developing a better treatment strategy for the use of immune checkpoint inhibitors in RCC.