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Sepsis is a potentially fatal condition triggered by systemic inflammatory response to infection. Due to the heightened immune reactivity and multi-organ pathology, treatment options are limited and several clinical trials have not produced the desired outcome, hence the interest in the discovery of novel therapeutic strategies. The polyphenol resveratrol (RSV) has shown promise against several pathological states, including acute and chronic inflammation. In this study, we evaluated its therapeutic potential in a murine model of sepsis and in patients undergoing transrectal ultrasound biopsy. RSV was able to inhibit lipopolysaccharide (LPS) stimulated inflammatory responses through blocking Phospholipase D (PLD) and its downstream signaling molecules SphK1, ERK1/2 and NF-κB. In addition, RSV treatment resulted in the downregulation of MyD88, an adaptor molecule in the TLR4 signaling pathway, and this effect at least in part, involved RSV-induced autophagy. Notably, RSV protected mice against polymicrobial septic shock induced upon cecal ligation and puncture, and inhibited pro-inflammatory cytokine production by human monocytes from transrectal ultrasound (TRUS) biopsy patients. Together, these findings demonstrate the immune regulatory activity of RSV and highlight its therapeutic potential in the management of sepsis.

INTRODUCTION AND OBJECTIVE:Drinking mineral water has shown some benefit in reducing urinary stone recurrences in some studies. Our pilot study in 10 healthy subjects revealed significant reduction...

INTRODUCTION AND OBJECTIVE:Apalutamide (ARN-509) exert near total antagonist activity at androgen receptors and is approved for treatment of M0 CRPC. ARN-509 as neoadjuvant treatment in organ confi...

INTRODUCTION AND OBJECTIVES:The NEAR trial is a phase II single arm study of neoadjuvant apalutamide (ARN-509) and radical prostatectomy (RP) in the treatment of D’Amico intermediate and high-risk ...

Objective and background To describe the steps for ureteroscopic laser incision and drainage of an obstructive parapelvic renal cyst. Renal cysts are benign lesions of the kidney which represent more than 70% of asymptomatic renal masses. Majority of simple or minimally complex cysts do not require further follow-up or therapy upon diagnosis. However, in 2 - 4% of the cases, these simple renal cysts can become symptomatic due to enlargement, development of complications such as haemorrhage, infection, rupture or obstructive uropathy. Various interventions have been described which include open surgery, percutaneous aspiration with or without sclerosing agent, laparoscopic decortication, percutaneous ablation, retrograde endoscopic marsupialization and even robotic-assisted laparoscopic decortication. Patient and Method 67-year-old man had an asymptomatic right renal cyst which progressively enlarged to the extent that it caused obstructive uropathy. Computed tomography (CT) scan showed an obstructive 9 cm right parapelvic renal cyst. We performed laser incision and drainage of the cyst with semi-rigid ureteroscope under general anaesthesia. The cyst was identified endoscopically and confirmed with fluoroscopy prior to incision with holmium laser using 200-um fibre. Results The cyst was drained successfully and two double J ureteric stents were placed into upper pole calyx and cyst cavity, to ensure adequate drainage and reduce reflux into the cyst cavity. The operative time was 30 minutes. There was no complication and the patient is discharged on postoperative day two. Postoperative CT scans showed complete resolution of the hydronephrosis with no recurrence. Conclusion Overall, in the reported literatures, the symptomatic success rate is 83 – 100% and the average radiologic success rate is 90%. Ureteroscopic laser incision and drainage of obstructive or symptomatic benign renal cyst in selected cases offers the patient the advantages of endoscopic surgery with shorter hospital stay, rapid recovery, minimal trauma and excellent outcome.

Aims We hypothesised that CD1d expression in renal cell carcinoma (RCC) may play a role in modifying the host immune response. Our aims were to investigate the expression of CD1d and to correlate this with histopathology and clinical outcomes in a cohort study of patients with RCC. Methods Gene expression and tissue microarray studies on a panel of RCC tissue were performed. Clinicopathological correlation was analysed using χ 2 /Fisher9s exact test. Relapse-free survival, cancer-specific survival and overall survival were calculated for both CD1d high and low expressors. Survival outcomes were estimated with the Kaplan–Meier method and compared using Cox regression analysis. Results Gene expression microarray showed significant expression of CD1d in RCC versus normal renal tissue. By immunohistochemistry, we found that CD1d expression significantly associated with tumour stage/grade, higher relapse rates, poorer cancer-specific and overall survival. Conclusions CD1d expression on RCC correlated with aggressive disease and poorer clinical outcomes.

Recently, several genome-wide association studies have demonstrated a cumulative association of 5 polymorphic variants in chromosomes 8q24 and 17q with prostate cancer (CaP) risk in Caucasians, particularly those harboring aggressive clinicopathologic characteristics. The purpose of this study was to evaluate the influence of these variants on CaP susceptibility in Singaporean Asian men.We performed a case-control study in 289 Chinese CaP patients and 412 healthy subjects (144 Chinese, 134 Malays, and 134 Indians), and examined the association of the 5 single nucleotide polymorphisms (SNPs) with CaP.In the healthy subjects, rs16901979 A-allele frequency was highest amongst Chinese (0.32) compared with Malays (0.13; P0.0001) or Indians (0.09; P0.0001); rs6983267 G-allele was highest in Indians (0.51) compared with Chinese (0.42; P = 0.041) or Malays (0.43; P = 0.077); whereas rs1859962 G-allele frequency was highest amongst Indians (0.56) compared with Chinese (0.40; P = 0.0002) or Malays (0.38; P0.0001). Individuals with the rs4430796 TT genotype were at increased CaP risk in the Chinese via a recessive model (odds ratios (OR) = 1.56, 95% CI = 1.04-2.33). Significant associations were observed for rs4430796 TT with Gleason scores of ≥ 7 (OR = 1.76, 95% CI = 1.14-2.73) and prostate-specific antigen (PSA) levels of ≥ 10 ng/ml at diagnosis (OR = 1.63, 95% CI = 1.01-2.63), as well as for rs6983267 GG with stage 3-4 CaPs (OR = 1.91, 95% CI = 1.01-3.61). A cumulative gene interaction influence on disease risk, which approximately doubled for individuals with at least 2 susceptibility genotypes, was also identified (OR = 2.18, 95% CI = 1.10-4.32).This exploratory analysis suggests that the 5 genetic variants previously described may contribute to prostate cancer risk in Singaporean men.

Sorafenib, a multikinase inhibitor, is currently used as monotherapy for advanced renal cell carcinoma (RCC). However, adverse effects associated with its use have been experienced by some patients. In this study, we examined the antitumor and antiangiogenic activities of low-dose sorafenib in combination with the MEK inhibitor AZD6244 (sorafenib/AZD6244) in a preclinical model of RCC. Primary RCC 08-0910 and RCC 786-0 cells as well as patient-derived RCC models were used to study the antitumor and antiangiogenic activities of sorafenib/AZD6244. Changes of biomarkers relevant to angiogenesis and cell cycle were determined by western immunoblotting. Microvessel density, apoptosis and cell proliferation were analyzed by immunohistochemistry. Treatment of RCC 786-0 cells with sorafenib/AZD6244 resulted in G1 cell cycle arrest and blockade of serum-induced cell migration. Sorafenib/AZD6244 induced apoptosis in primary RCC 08-0910 cells at low concentrations. In vivo addition of AZD6244 to sorafenib significantly augmented the antitumor activity of sorafenib and allowed dose reduction of sorafenib without compromising its antitumor activity. Sorafenib/AZD6244 potently inhibited angiogenesis and phosphorylation of VEGFR-2, PDGFR-β and ERK, p90RSK, p70S6K, cdk-2 and retinoblastoma. Sorafenib/AZD6244 also caused upregulation of p27, Bad and Bim but downregulation of survivin and cyclin B1. These resulted in a reduction in cellular proliferation and the induction of tumor cell apoptosis. Our findings showed that AZD6244 and sorafenib complement each other to inhibit tumor growth. This study provides sound evidence for the clinical investigation of low-dose sorafenib in combination with AZD6244 in patients with advanced RCC.

Natural killer (NK) lymphomas occurring more frequently in the Far East and South America respond poorly to anthracycline-based regimens. Here we report an in vivo NK lymphoma xenograft (NK-S1) derived from the testicular metastasis of a patient with an extranodal NK lymphoma (nasal type). The NK-S1 xenograft, established in severe combined immune deficient (SCID) mice retained the same imunophenotypic features as the original tumor. NK-S1 disseminated intra-abdominally to the testis, intestine and liver. Although doxorubicin, rapamycin, bevacizumab, rapamycin-doxorubicin, and bevacizumab-doxorubicin had no effects on the growth of subcutaneous NK-S1 xenografts, intraperitoneal (IP) delivery of cyclophosphamide caused complete tumor regression; this tumor regression was associated with apoptosis, upregulation of activated caspase-3, and cleaved Poly(ADP-ribose) polymerase (PARP). In an IP model of NK lymphoma, cyclophosphamide also prolonged the survival of mice and potently inhibited tumor dissemination and ascites formation. Our data suggest that the NK-S1 xenograft is a useful tool for screening preclinical drugs, and cyclophosphamide may be a useful drug for the treatment of this disease.

// Prashant Kumar 1,* , Sayantani Nandi 1,* , Tuan Zea Tan 2,* , Siok Ghee Ler 3 , Kee Seng Chia 4 , Wei-Yen Lim 5 , Zentia Butow 6 , Dimitrios Vordos 6 , Alexandre De laTaille 6 , Muthafar Al-Haddawi 1 , Manfred Raida 7 , Burkhard Beyer 8 , Estelle Ricci 9 , Marc Colombel 9 , Tsung Wen Chong 10 , Edmund Chiong 11 , Ross Soo 12 , Mi Kyoung Park 13 , Hong Koo Ha 14,** , Jayantha Gunaratne 3,4,** and Jean Paul Thiery 1,2,7,** 1 Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore 2 Cancer Science Institute, National University of Singapore, Singapore 3 Quantitative Proteomics Group, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 4 Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 5 Saw Swee Hock School of Public Health, National University of Singapore, Singapore 6 CHU Hopital Henri Mondor, Department of Urology, Creteil, France 7 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 8 Department of Urology, Section for Translational Prostate Cancer Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 9 Service d’Urologie et Chirurgie de la Transplantation, Hopital Edouard Herriot, Lyon, France 10 Department of Urology, Singapore General Hospital, Singapore 11 Department of Urology, University Surgical Cluster, National University Health System (NUHS), Singapore 12 Haematology-Oncology Research Group, Department of Haematology-Oncology, National University Cancer Institute (NCIS), National University Hospital, Singapore 13 Institute of Microelectronics (IME), A*STAR, Singapore 14 Department of Urology, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea * These authors are co-first authors ** These authors are co-senior authors Correspondence to: Jean Paul Thiery, email: // Keywords : transitional bladder carcinoma, urine biomarkers, receiving operating characteristics, combination model Received : December 08, 2014 Accepted : March 19, 2015 Published : April 15, 2015 Abstract Transitional bladder carcinoma (BCa) is prevalent in developed countries, particularly among men. Given that these tumors frequently recur or progress, the early detection and subsequent monitoring of BCa at different stages is critical. Current BCa diagnostic biomarkers are not sufficiently sensitive for substituting or complementing invasive cystoscopy. Here, we sought to identify a robust set of urine biomarkers for BCa detection. Using a high-resolution, mass spectrometry-based, quantitative proteomics approach, we measured, compared and validated protein variations in 451 voided urine samples from healthy subjects, non-bladder cancer patients and patients with non-invasive and invasive BCa. We identified five robust biomarkers: Coronin-1A, Apolipoprotein A4, Semenogelin-2, Gamma synuclein and DJ-1/PARK7. In diagnosing Ta/T1 BCa, these biomarkers achieved an AUC of 0.92 and 0.98, respectively, using ELISA and western blot data (sensitivity, 79.2% and 93.9%; specificity, 100% and 96.7%, respectively). In diagnosing T2/T3 BCa, an AUC of 0.94 and 1.0 was attained (sensitivity, 86.4% and 100%; specificity, 100%) using the same methods. Thus, our multiplex biomarker panel offers unprecedented accuracy for the diagnosis of BCa patients and provides the prospect for a non-invasive way to detect bladder cancer.

In selected cases, RIRS management of calyceal diverticula and its related problems has been shown to be more efficacious than ESWL monotherapy and avoids the potential complications and discomfort of percutaneous and laparoscopic procedures. The advent of the Holmium laser energy source, with innovations such as the flexible ureteroscope and the tipless stone basket, have expanded the role of RIRS in the management of calyceal diverticula and associated problems. Presently, RIRS is the initial treatment choice for the management of low to moderate stone burdens that are contained in calyceal diverticula or trapped behind any narrowed intrarenal segment (e.g., infundibular stenosis). If repair of the stenotic segment is not successful, thereby excluding stone treatment, then under the same anesthesia, the patient undergoes a percutaneous antegrade renal surgery. The authors feel that the percutaneous approach as a first choice is more suitable for posteriorly located diverticula with a large stone burden. In selected cases of anteriorly located diverticula with large stone burdens, the laparoscopic approach is more expedient.

Item does not contain fulltext CONTEXT: Although an ever-increasing number of patients are being incidentally diagnosed with small renal masses, there is still a sizable portion of patients with renal cell carcinoma (RCC) who present with locally advanced or metastatic disease. Those with locally advanced disease present a challenge because they may be difficult to distinguish from those with organ-confined disease at the time of diagnosis. However, this distinction is important because they may require a different management strategy. These advanced RCC patients include those with venous tumour thrombi, extracapsular tumour extension, adjacent organ involvement, as well as nodal disease. EVIDENCE ACQUISITION: A thorough literature search of the following terms was undertaken: advanced renal cell carcinoma, renal cell carcinoma venous tumour thrombi, renal cell carcinoma extra-capsular extension, renal cell carcinoma nodal metastasis, and locally recurrent renal cell carcinoma. An international expert panel convened by the International Consultation on Urologic Diseases and the European Association of Urology reviewed these articles. EVIDENCE SYNTHESIS: Review of the available literature allowed for assessment of the level of evidence for the diagnosis, management, and therapy of locally advanced RCC with the ultimate goal of providing a synthesis of this information with a consensus statement from leaders in the field. CONCLUSIONS: Despite the advances in prognostic markers and targeted molecular therapies for RCC, currently the only curative treatment for locally advanced RCC is aggressive surgical resection.

Prostate cancer is the third most common cancer in Singaporean men. Compared to Western countries, the prostate cancer incidence is lower in Asian countries but recent data suggest that incidence is increasing, especially in rapidly urbanized countries. Recent studies provide evidence that methylated genes can be useful and promising molecular biomarkers for detection of prostate cancers. The aim of our study is to identify a panel of global gene methylation signatures that are unique and specific for different phases of prostate cancer development and different prostate cancer phenotypes. This may thus differentiate cancers from non-cancers, and aggressive cancers from indolent ones. We have profiled methylation of genes using the Illumina's GoldenGate Methylation System. The Standard GoldenGate Methylation Cancer Panel I (Illumina Inc, San Diego, CA) spans 1,505 CpG loci selected from 807 genes that have been shown in literature to play important roles in cancer. Methylation levels of candidate genes were quantified in 28 benign tissues without prostate cancer, 52 tissues of Gleason score 3+3, 66 tissues of Gleason score 4+x and 37 tissues of Gleason score 5+x. DNA used for the assays were obtained from laser capture microdissected paraffin embedded archival tissues. Interestingly, our results showed that 28 different CpG loci were methylated in Gleason 3+3 prostate cancer tissues compared to benign prostatic hyperplasia tissues that were used as controls. In addition, methylation levels in prostate cancer samples of high Gleason index (4+x and 5+x) were significantly higher than the paired prostate cancer samples of low Gleason index (3+3) in at least 10 candidate genes. These genes include VIM (p-value 3.59E-08), ASCL2 (p-value 1.71E-09), DAB2IP (p-value 6.55E-08) and FRZB (p-value 6.44E-08). Together with bioinformatics and quantitative methylation-specific PCR, we identified a set of potentially phenotype-specific gene methylation signatures in Asian men. Our studies contributed to the improvement of diagnostic capability for prostate cancer beyond available tumour markers such as PSA as it is a more sensitive molecular correlate. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3210. doi:10.1158/1538-7445.AM2011-3210

To directly compare the models-the UCLA-Integrated Scoring System (UISS) and the Leibovich models-using various survival endpoints. Several Phase III trials of adjuvant therapy in renal cell carcinoma (RCC) have been initiated after advances in targeted therapy. To select patients at high risk of relapse and mortality, 2 aforementioned prognostic models have been incorporated into these trials. These models have not been compared previously.A retrospective study of 355 patients with unilateral nonmetastatic clear cell RCC undergoing nephrectomy between 1990 and 2006 at the Singapore General Hospital was undertaken. Performance of the UISS and the Leibovich models, as well as corresponding trial inclusion criteria, was directly compared using log-likelihood statistics. Adequacy and concordance indices were also calculated. Study endpoints tested were overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS).Likelihood ratio testing demonstrated a significant benefit in prediction when adding the Leibovich model to the UISS model in all outcomes tested, with no benefit using the converse approach (OS: P=.002 vs P=.27; CSS: P=.0001 vs P=.57; DFS: P=0.0001 vs P=.30). Benefit was seen primarily in disease-free survival when adding the Leibovich trial criteria to UISS trial criteria, with no benefit using the converse approach (OS: P=.16 vs P=.27; CSS: P=.17 vs P=.11; DFS: P=.01 vs P=.26).Both the Leibovich model and trial criteria are superior to the UISS model and trial criteria, respectively, in estimating survival outcomes in patients with nonmetastatic clear cell RCC after nephrectomy.

Introduction Although metastatic carcinoma in the presence of an occult primary tumor is well recognized, underlying reasons for the failure of the primary tumor to manifest are uncertain. Explanations for this phenomenon have ranged from spontaneous regression of the primary tumor to early metastasis of the primary tumor before manifestation of a less aggressive primary tumor. We report a case of 'prechronous' metastasis arising from clear cell renal cell carcinoma, where metastatic disease initially manifested in the absence of a primary renal tumor, followed by aggressive growth of the primary renal lesion. Case presentation A 43-year-old Malay man initially presented to our facility with fever and cough. He subsequently underwent surgical resection of a 9 cm right-sided lung mass found on radiological examination. Histology showed a high-grade clear cell tumor with sarcomatoid differentiation, suggestive of a metastasis from clear cell renal cell carcinoma. However, no concurrent renal lesions were noted on computed tomographic evaluation at that time. Then, four months after lung resection, he presented with a subcutaneous mass in the left loin, as well as right loin discomfort. Computed tomography scanning revealed a 10 cm right renal mass, with renal vein and inferior vena cava invasion, as well as recurrent disease in the right thorax. Histological examination of the excised subcutaneous mass revealed a high-grade carcinoma consistent with clear cell renal cell carcinoma. Conclusions This is the first reported case of prechronous metastasis of renal cell carcinoma, with metastatic disease manifesting prior to the development of the primary lesion. The underlying mechanism is uncertain, but our patient's case provides anecdotal support for the early dissemination model of metastasis.