Takuji Hayashi

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.

Preoperative serum sodium is associated with cancer‐specific survival in patients with upper urinary tract urothelial carcinoma treated by nephroureterectomy

To assess the impact of preoperative serum sodium concentration on the prognosis of patients with upper urinary tract urothelial carcinoma treated by nephroureterectomy.

Decreased fucosylated PSA as a urinary marker for high Gleason score prostate cancer

Fucosylation is an important oligosaccharide modification associated with cancer and inflammation. We investigated whether urinary fucosylated PSA (Fuc-PSA) levels could be used for the detection of high Gleason score prostate cancer. Urine samples were collected from men with abnormal digital rectal examination findings or elevated serum PSA levels, before prostate biopsy. Lectin-antibody ELISA was used to quantify the Lewis-type or core-type fucosylated PSA (PSA-AAL) and core-type fucosylated PSA (PSA-PhoSL) in the urine samples. Both types of urinary Fuc-PSA were significantly decreased in the men with prostate cancer compared with the men whose biopsies were negative for cancer (P = 0.026 and P < 0.001, respectively). Both were also significantly associated with the Gleason scores of the biopsy specimens (P = 0.001 and P < 0.001, respectively). Multivariate analysis showed that PSA density, urinary PSA-AAL, and urinary PSA-PhoSL were independent predictors of high Gleason score prostate cancer. The area under the receiver-operator characteristic curve (AUC) value for the prediction of cancers of Gleason score ≥ 7 was 0.69 for urinary PSA-AAL and 0.72 for urinary PSA-PhoSL. In contrast, the AUC value was 0.59 for serum PSA, 0.63 for PSA density, and 0.58 for urinary PSA. In conclusion, a decreased urinary Fuc-PSA level is a potential marker for the detection of high Gleason score prostate cancer.

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.

Serum monocyte fraction of white blood cells is increased in patients with high Gleason score prostate cancer

Systemic inflammation and immune responses are reported to be associated with progressive prostate cancer. In this study, we explored which among the fractions of white blood cell (WBC) and C-reactive protein (CRP) level were associated with high Gleason score prostate cancer. Prostate needle biopsy was performed in 966 men with suspicion of prostate cancer. We assessed age, serum prostate-specific antigen (PSA), prostate volume, WBC count, fractions of WBCs (neutrophils, lymphocytes, monocytes, basophils, and eosinophils), and CRP level before biopsy for associations with biopsy findings. Among all men, 553 (57.2%) were positive for prostate cancer including 421 with high Gleason score cancer (Gleason score ≥7). Age, PSA, PSA density (PSAD), serum monocyte fraction of WBC, monocyte-to-lymphocyte ratio (MLR), and CRP were significantly associated with high Gleason score cancer (p<0.01). Multivariate analysis showed that age, PSA, PSAD, and serum monocyte fraction were significantly associated with high Gleason score prostate cancer (p <0.01). In 571 patients with PSA of <10 ng/ml, age, PSA, PSAD, serum WBC count, neutrophil fraction, monocyte fraction, and MLR were significantly associated with high Gleason score prostate cancer (p<0.05). Multivariate analysis showed that age, PSAD, and serum monocyte fraction were significantly associated with high Gleason score prostate cancer (p<0.01). The monocyte fraction of WBCs was increased in patients with high Gleason score prostate cancer, suggesting an interaction of monocytes with the progression of prostate cancer.

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.