Transactivation of HER2 by vasoactive intestinal peptide in experimental prostate cancer. Antagonistic action of an analog of growth-hormone-releasing hormone

Receptors for vasoactive intestinal peptide (VIP) and the human epidermal growth factor family of tyrosine kinase receptors (HER) are potent promoters of cell proliferation, survival, migration, adhesion and differentiation in prostate cancer cell lines. In this study, we analyzed the cross-talk between both classes of receptors through the regulation of HER2 transactivation and expression by VIP. Three growth-hormone-releasing hormone analogs endowed with antagonistic activity for VIP receptors (JV-1-51, -52, and -53) abrogated the autocrine/paracrine stimuli of VIP on androgen-independent PC3 cells in the absence or the presence of 10% fetal bovine serum. Semiquantitative and real-time quantitative RT-PCR together with Western blotting showed increased expression levels of both mRNA and proteins for HER2 and HER3 in PC3 and androgen-dependent LNCaP prostate cancer cells as compared to non-neoplastic RWPE-1 cells. VIP (100 nM) stimulated the expression levels of both HER2 and HER3 in PC3 cells in a time-dependent manner. Whereas these effects were relatively slow, VIP rapidly (0.5 min) increased HER2 tyrosine phosphorylation. This pattern of HER transactivation was blocked by H89, a protein kinase A (PKA) inhibitor, as well as by the specific VIP antagonist JV-1-53, indicating the involvement of VIP receptors and PKA activity in phosphorylated HER2 formation. These findings support the merit of further studies on the potential usefulness of VIP receptor antagonists and both HER2 antibodies and tyrosine kinase inhibitors for prostate cancer therapy.Ministerio de Educación y CienciaComunidad de MadridFundación para la Investigación en Urologí

Assessing the accuracy and generalizability of the preoperative and postoperative Karakiewicz nomograms for renal cell carcinoma : results from a multicentre European and US study

WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The preoperative and postoperative Karakiewicz models for RCC are considered among the best prognostic tools available for clinical counseling. Nevertheless, their predictive acuracy was externally validated only in two papers: by the same author and in an independent sample of Asian patients. However, these models have not been externally validated in truly independent multicentre series of patients. Our study demonstrated that these models 1) provide robust prognostic information; 2) were robustly built; 3) are useful also in population far from the original series. The present results are the first to show the validity and generalizability of Karakiewicz nomograms, which are based on surgical series from European centres, for large-, mid- and small-volume European and American centres. OBJECTIVE: To assess the accuracy and generalizability of the pre- and postoperative Karakiewicz nomograms for predicting cancer-specific survival (CSS) in patients with renal cell carcinoma (RCC). PATIENTS AND METHODS: This retrospective study included 3231 patients from European and US centres, who were treated by radical or partial nephrectomy for RCC between 1992 and 2010. Prognostic scores for each patient were calculated and the primary endpoint was CSS. Discriminating ability was assessed by Harrell's c-index for censored data. The 'validation by calibration' method proposed by Van Houwelingen was used for checking the calibration of covariate effects. Calibration was graphically explored. RESULTS: Local and systemic symptoms were present in 23.2% and 9.1% of the patients, respectively. The median follow-up (FU) was 49 months. At the last FU, 408 cancer-related deaths were recorded, Kaplan-Meier estimates of CSS (with 95% confidence intervals [CIs]) at 5 and 10 years were 0.86 (0.84-0.87) and 0.77 (0.75-0.80), respectively. Both nomograms discriminated well. Stratified c-indices for CSS were 0.784 (95% CI 0.753-0.814) for the preoperative nomogram, and 0.842 (95% CI 0.816-0.867) for the postoperative one, with a significant difference between the two values (P < 0.001). The covariate-based predictions on our data for both nomograms were valid. The calibration plots showed no relevant departures from ideal predictions. CONCLUSIONS: The results suggest that the postoperative Karakiewicz nomogram discriminates substantially better than the preoperative one. These nomogram-based predictions may be used as benchmark data for pretreatment and postoperative decision-making in patients at various stages of RCC

Results of a comparative study analyzing octogenarians with renal cell carcinoma in a competing risk analysis with patients in the seventh decade of life

Objectives: To analyze clinicopathological features and survival of surgically treated patients with renal cell carcinoma (RCC)≥80 years of age in comparison with patients between the ages of 60 and 70 years. Materials and methods: The data for 2,516 patients with a median follow-up of 57 months were retrieved from a multinational database (Collaborative Research on Renal Neoplasms Association [CORONA]), including data for 6,234 consecutive patients with RCC after radical or partial nephrectomy. Comparative analysis of clinicopathological features of 241 octogenarians (3.9% of the database) and 2,275 reference patients between the ages of 60 and 70 years (36.5%) was performed. Multivariable regression analysis adjusted for competing risks was applied to identify the effect of advanced age on cancer-specific mortality (CSM) and other-cause mortality (OCM). Furthermore, instrumental variable analysis was employed to reduce residual confounding by unmeasured parameters. Results: Significantly more women were present (50% vs. 40%, P = 0.004), and significantly less often nephron-sparing surgery was performed in octogenarians compared with the reference group (11% vs. 20%, P&lt;0.001). Although median tumor size and stages did not significantly defer, older patients less often had advanced or metastatic disease (N+/M1) (4.6% vs. 9.6%, P = 0.009). On multivariable analysis, higher CSM (hazard ratio = 1.48, P = 0.042) and OCM rates (hazard ratio = 4.32, P&lt;0.001) were detectable in octogenarians (c-indices = 0.85 and 0.72, respectively). Integration of the variable age group in multivariable models significantly increased the predictive accuracy regarding OCM (6%, P&lt;0.001), but not for CSM. Limitations are based on the retrospective study design. Conclusions: Octogenarian patients with RCC significantly differ in clinical features and display significantly higher CSM and OCM rates in comparison with their younger counterparts

Do we need new high-risk criteria for surgically treated renal cancer patients to improve the outcome of future clinical trials in the adjuvant setting? : results of a comprehensive analysis based on the multicenter CORONA database

Background: Since there is still an unmet need for potent adjuvant strategies for renal cancer patients with high progression risk after surgery, several targeted therapies are currently evaluated in this setting. We analyzed whether inclusion criteria of contemporary trials (ARISER, ASSURE, SORCE, EVEREST, PROTECT, S-TRAC, ATLAS) correctly identify high-risk patients. Methods: The study group comprised 8873 patients of the international CORONA-database after surgery for non-metastatic renal cancer without any adjuvant treatment. Patients were divided into potentially eligible high-risk and assumable low-risk patients who didn't meet inclusion criteria of contemporary adjuvant clinical trials. The ability of various inclusion criteria for disease-free survival (DFS) prediction was evaluated by Harrell's c-index. Results: During a median follow-up of 53 months 15.2% of patients experienced recurrence (5-year-DFS 84%). By application of trial inclusion criteria, 24% (S-TRAC) to 47% (SORCE) of patients would have been eligible for enrollment. Actual recurrence rates of eligible patients ranged between 29% (SORCE) and 37% (S-TRAC) opposed to &lt;10% in excluded patients. Highest Hazard Ratio for selection criteria was proven for the SORCE-trial (HR 6.42; p &lt; 0.001), while ASSURE and EVEREST reached the highest c-index for DFS prediction (both 0.73). In a separate multivariate Cox-model, two risk-groups were identified with a maximum difference in 5-year-DFS (94% vs. 61%). Conclusion: Results of contemporary adjuvant clinical trials will not be comparable as inclusion criteria differ significantly. Risk assessment according to our model might improve patient selection in clinical trials by defining a high-risk group (28% of all patients) with a 5 year-recurrence rate of almost 40%

Results of a comparative study analyzing octogenarians with renal cell carcinoma in a competing risk analysis with patients in the seventh decade of life

Objectives: To analyze clinicopathological features and survival of surgically treated patients with renal cell carcinoma (RCC)≥80 years of age in comparison with patients between the ages of 60 and 70 years. Materials and methods: The data for 2,516 patients with a median follow-up of 57 months were retrieved from a multinational database (Collaborative Research on Renal Neoplasms Association [CORONA]), including data for 6,234 consecutive patients with RCC after radical or partial nephrectomy. Comparative analysis of clinicopathological features of 241 octogenarians (3.9% of the database) and 2,275 reference patients between the ages of 60 and 70 years (36.5%) was performed. Multivariable regression analysis adjusted for competing risks was applied to identify the effect of advanced age on cancer-specific mortality (CSM) and other-cause mortality (OCM). Furthermore, instrumental variable analysis was employed to reduce residual confounding by unmeasured parameters. Results: Significantly more women were present (50% vs. 40%, P = 0.004), and significantly less often nephron-sparing surgery was performed in octogenarians compared with the reference group (11% vs. 20%, P<0.001). Although median tumor size and stages did not significantly defer, older patients less often had advanced or metastatic disease (N+/M1) (4.6% vs. 9.6%, P = 0.009). On multivariable analysis, higher CSM (hazard ratio = 1.48, P = 0.042) and OCM rates (hazard ratio = 4.32, P<0.001) were detectable in octogenarians ( c-indices = 0.85 and 0.72, respectively). Integration of the variable age group in multivariable models significantly increased the predictive accuracy regarding OCM (6%, P<0.001), but not for CSM. Limitations are based on the retrospective study design. Conclusions: Octogenarian patients with RCC significantly differ in clinical features and display significantly higher CSM and OCM rates in comparison with their younger counterparts

Prostate Tumor Volume Measurement with Combined T2-weighted Imaging and Diffusion-weighted MR: Correlation with Pathologic Tumor Volume1

Combined T2-weighted and diffusion-weighted MR imaging performed by using an apparent diffusion coefficient cutoff value of 0.0016 mm2/sec is significantly more accurate than T2-weighted imaging alone in the measurement of tumor volume in the peripheral zone of the prostate