Reliability of sentinel node procedure for lymph node staging in prostate cancer patients at high risk for lymph node involvement.

AIM: To investigate the reliability of a sentinel node (SN) procedure for nodal staging in prostate cancer (PCa) patients at high risk for lymph node (LN) involvement. MATERIAL AND METHODS: Seventy-four patients with localized prostate adenocarcinoma, who were clinically node-negative and had a risk of LN involvement of ≥ 10% (Partin tables), were prospectively enrolled. Upon intraprostatic 99mTc-nanocolloid injection, they underwent planar scintigraphy and SPECT imaging. Surgical removal of the SN, located by means of a gamma probe, was completed with a superextended LN dissection (seLND) as a reference and followed by radical prostatectomy. RESULTS: In total, 470 SN (median 6, IQR 3-9) were scintigraphically detected of which 371 (median 4, IQR 2-6) were located by gamma probe and selectively removed during surgery (79%). Histopathology confirmed LN metastases in 37 patients (50%) having 106 affected LN in total (median number per patient 2, IQR 1-4). Twenty-eight patients were node positive (N+) based on the analysis of the resected SN. However, the seLND that was performed as a reference revealed nine additional N+ patients resulting in a sensitivity of 76% (28/37). In total, 15 of 37 patients (41%) had metastases in SN only and could have been spared seLND to remove all affected nodes. CONCLUSION: We found a relatively low sensitivity when addressing the SN procedure for nodal staging in PCa patients at high risk for LN involvement. Importantly, only less than half of the N+ patients could have been spared a seLND to remove all affected lymphoid tissue.

VEGFR1 single nucleotide polymorphisms associated with outcome in patients with metastatic renal cell carcinoma treated with sunitinib - a multicentric retrospective analysis.

BACKGROUND: There are no validated markers that predict outcome in metastatic renal cell cancer (mRCC) patients treated with sunitinib. Recently, single nucleotide polymorphism (SNP) rs9582036 in VEGFR1 has been proposed as a predictor of progression-free survival (PFS) and overall survival (OS) to bevacizumab in patients with pancreatic cancer and rs7993418 in VEGFR1 as predictor for PFS in mRCC-patients treated with bevacizumab. Here, we aim to study the impact of these SNPs in mRCC patients treated with sunitinib. METHODS: We included patients with mRCC treated in 15 institutions in France and Belgium. Patients received sunitinib as first-line targeted therapy. We assessed response, time-to-tumor progression (TTP), OS, and clinical and biochemical parameters associated with outcome. We genotyped rs9582036 and rs7993418 as well as three other surrounding SNPs in VEGFR1: rs9554320, rs9554316 and rs9513070. Association between SNPs and treatment outcome were studied by univariate analysis and by multivariate Cox regression using relevant clinical factors associated with TTP and OS as covariates. FINDINGS: Ninety-one patients were included. We found that mRCC patients with the CC-variant in rs9582036 in VEGFR1 have a poorer response rate (RR) (0% vs. 46%, p = 0.028), a poorer PFS (10 vs. 18 months, p = 0.033 on univariate and 0.06 on multivariate analysis) and a poorer OS (14 vs. 31 months, p = 0.019 on univariate and 0.008 on multivariate analysis) compared to patients with the AC- and AA-genotypes. mRCC patients with the AA-variant in rs9554320 in VEGFR1 have a poorer PFS (12 vs. 21 months, p = 0.0066 on univariate and 0.005 on multivariate analysis) and a poorer OS (22 vs. 34 months, p = 0.019 on univariate and 0.067 on multivariate analysis) compared to patients with the AC- and CC-genotypes. Interpretation. mRCC patients with the CC-genotype in VEGFR1 SNP rs9582036 have a poorer response rate, PFS and OS when treated with sunitinib. These findings are in agreement with the association of rs9582036 and outcome observed in bevacizumab treated pancreatic cancer patients. Prospective validation of this SNP is warranted.

A possible role for microRNA-141 down-regulation in sunitinib resistant metastatic clear cell renal cell carcinoma through induction of epithelial-to-mesenchymal transition and hypoxia resistance.

PURPOSE: We identified microRNA driven mechanisms in clear cell renal cell carcinoma associated with the tumor response to the multitargeted receptor tyrosine kinase inhibitor sunitinib. MATERIALS AND METHODS: We performed screening genome-wide microRNA real-time quantitative polymerase chain reaction on 20 freshly frozen clear cell renal cell carcinoma tissue samples of patients who received sunitinib as first line targeted therapy. Nine patients with progressive disease within 6 months after initiating therapy were considered poor responders and 11 with at least 1-year progression-free survival were considered good responders. We studied microRNA-141 function in vitro by stable up-regulation of microRNA-141, quantification of target gene expression and cell viability in normoxic and hypoxic conditions. Relative expression in clinical and cell line samples was determined by real-time quantitative polymerase chain reaction. Localization of microRNA-141 and its targets was assessed by microRNA in situ hybridization and immunohistochemistry. Hypoxia induced cytotoxicity was assessed by a luminescence adenosine triphosphate detection assay. RESULTS: Compared to good responders, microRNA-141 was significantly down-regulated in tumors of poor responders to sunitinib. This seemed spatially linked to epithelial-to-mesenchymal transition in vivo. Reintroduction of microRNA-141 in vitro reversed epithelial-to-mesenchymal transition and decreased cell viability in hypoxic conditions. CONCLUSIONS: In our study microRNA-141 down-regulation driven epithelial-to-mesenchymal transition in clear cell renal cell carcinoma was linked to an unfavorable response to sunitinib therapy. Reintroduction of microRNA-141 in vitro led to epithelial-to-mesenchymal transition reversal and increased sensibility to a hypoxic environment. Future experiments should be done in vivo to see whether microRNA-141 driven reversal of epithelial-to-mesenchymal transition could affect the efficacy of sunitinib treatment.

Single incision mini-sling versus a transobutaror sling: a comparative study on MiniArc and Monarc slings.

INTRODUCTION AND HYPOTHESIS: A retrospective, dual-center, cohort study on the single incision MiniArc sling and the transobturator Monarc sling in the treatment of stress urinary incontinence is presented. We hypothesized that both systems would perform equally well. METHODS: One hundred thirty-one (MiniArc n = 75, Monarc n = 56) consecutive patients were evaluated. Evaluation was performed by cough stress test (CST), daily pad use, IIQ-7, UDI-6, and a 0-5 visual analog scale for quality of life. The 1-year data are presented. RESULTS: Six weeks after surgery, 91% of the patients in both populations had a negative CST. At 1 year, 85% of the MiniArc group and 89% of the Monarc group (p = 0.60) maintained a negative CST. QoL, symptom scores, and number of pads improved significantly and were comparable in both groups. Complication rates were similar. CONCLUSIONS: These results suggest that MiniArc sling and Monarc sling are equally effective in the treatment of stress incontinence at 1 year follow-up.

Expression of a Distinct Set of Chemokine Receptors in Adipose Tissue-Derived Stem Cells is Responsible for In Vitro Migration Toward Chemokines Appearing in the Major Pelvic Ganglion Following Cavernous Nerve Injury.

INTRODUCTION: Adipose tissue-derived stem cells (ADSCs) herald tremendous promise for clinical application in a wide range of injuries and diseases. Several preclinical reports demonstrate their efficacy in the treatment of cavernous nerve (CN) injury-induced erectile dysfunction in rats. It was recently illustrated that these effects were established as a result of ADSC migration to the major pelvic ganglion (MPG) where these cells induced neuroregeneration in loco. AIMS: The study aims to identify chemotactic factors in the MPG following injury and to match upregulated chemokines to their respective receptors in human ADSC on the genomic, structural, and functional levels. METHODS: Quantitative real-time polymerase chain reaction, fluorescence-activated cell sorting (FACS), intracellular FACS, immunofluorescence microscopy, migration assays, and calcium imaging were used in this study. MAIN OUTCOME MEASURES: The main outcomes are chemokine expression in the MPG following CN injury, and the functional and structural presence of chemokine receptors in ADSC. RESULTS: CCR4, CX3CR1, and XCR1 are functionally and structurally present in human ADSC, and are activated by the chemokines CCL2, CX3CL1, and XCL1 respectively, which are upregulated in the MPG following CN injury. CXCR4 and its ligand CXCL12 (SDF1) are likely no major homing factors for ADSC. Expression of chemokine receptor mRNA in ADSC did not necessarily translate into receptor presence at the cell surface and/or functional activation of these receptors. Most of the expressed chemokine receptors were detected in the intracellular compartment of these cells. CONCLUSIONS: We identified the ligand/chemokine receptor pairs CCL2/CCR4, CX3CL1/CX3CR1, and XCL1/XCR1 as potentially responsible for ADSC homing toward the MPG following CN injury. The intracellular localization of various chemokine receptors likely indicates redirecting of chemokine receptors to the cell surface under specific cellular conditions. Furthermore, modification of expression of these receptors at the genomic level may potentially lead to improved migration toward injury sites and thus enhancement of treatment efficacy. Albersen M, Berkers J, Dekoninck P, Deprest J, Lue TF, Hedlund P, Lin C-S, Bivalacqua TJ, Van Poppel H, De Ridder D, and Van der Aa F. Expression of a distinct set of chemokine receptors in adipose tissue-derived stem cells is responsible for in vitro migration toward chemokines appearing in the major pelvic ganglion following cavernous nerve injury. Sex Med 2013;1:3-15.

Glycaemic control and perioperative organ protection.

The concept of stress hyperglycaemia as an adaptive, beneficial response in critical illness has recently been challenged. Two large prospective randomized controlled trials in the Leuven University Hospital surgical and medical ICUs demonstrated that maintenance of normoglycaemia with intensive insulin therapy substantially prevents morbidity and reduces mortality. Strict normoglycaemia is required to gain most clinical benefit. With this therapy the risk of hypoglycaemia increased, but without inducing obvious clinical sequellae. Other studies have been used to advocate against implementation of intensive insulin therapy by showing lack of benefit or questioning safety. However, these studies are inconclusive on this subject, due to problems of not reaching normal glucose levels clearly separated from the standard glycaemic group or lack of statistical power. Clearly, future studies should be adequately powered and comply with the study protocol in order to confirm the survival and other clinical benefits of intensive insulin therapy.