A group of novel VEGF splice variants as alternative therapeutic targets in renal cell carcinoma.

The efficacy of anti-angiogenic treatment by targeting VEGF/VEGF receptors in metastatic clear cell renal cell carcinoma (ccRCC) varies from patient to patient. Discovering the reasons behind this variability could lead to the identification of relevant therapeutic targets. Thus, we investigated the novel splice variants of VEGF that are less efficiently inhibited by anti-VEGF/VEGFR targeting than the conventional isoforms. By in silico analysis, we identified a novel splice acceptor in the last intron of the VEGF gene resulting in an insertion of 23 bp in VEGF mRNA. Such an insertion can shift the open-reading frame in previously described splice variants of VEGF (VEGFXXX ), leading to a change in the C-terminal part of the VEGF protein. Next, we analysed the expression of these alternatively spliced VEGF new isoforms (VEGFXXX/NF ) in normal tissues and in RCC cell lines by qPCR and ELISA, and we investigated the role of VEGF222/NF (equivalent to VEGF165 ) in physiological and pathological angiogenesis. Our in vitro data demonstrated that recombinant VEGF222/NF stimulated endothelial cell proliferation and vascular permeability by activating VEGFR2. In addition, VEGF222/NF overexpression enhanced proliferation and metastatic properties of RCC cells, whereas downregulation of VEGF222/NF resulted in cell death. We also generated an in vivo model of RCC by implanting RCC cells overexpressing VEGF222/NF in mice, which we treated with polyclonal anti-VEGFXXX/NF antibodies. VEGF222/NF overexpression enhanced tumour formation with aggressive properties and a fully functional vasculature, while treatment with anti-VEGFXXX/NF antibodies slowed tumour growth by inhibiting tumour cell proliferation and angiogenesis. In a patient cohort from the NCT00943839 clinical trial, we investigated the relationship between plasmatic VEGFXXX/NF levels, resistance to anti-VEGFR therapy and survival. High plasmatic VEGFXXX/NF levels correlated with shorter survival and lower efficacy of anti-angiogenic drugs. Our data confirmed the existence of new VEGF isoforms that could serve as novel therapeutic targets in patients with RCC that are resistant to anti-VEGFR therapy.

Evolution of Day-Case Holmium Laser Enucleation of the Prostate Success Rate Over Time.

Objectives: To describe the evolution of day-case success rate over the years and to identify predictive factors for prolonged hospitalization or readmissions. Methods: Retrospective review of all consecutive day-case holmium laser enucleation of the prostate (HoLEP) performed by a single surgeon between January 2013 and February 2019 using a prospective database. Day-case success was defined as discharge within less than 12 hours from admission without any readmission within 48 hours after discharge. Protocol for day-case treatment included systematic bladder catheter insertion with continuous irrigation for ∼2 hours and catheter removal on postoperative day 1. Patients were reached by phone on postoperative day 1 to ensure voiding. For the descriptive statistics, an analysis of variance was performed. Univariate and multivariate analyses were used to identify risk factors. Results: A total of 266 patients were retrieved and dispatched as follows: group 1 (n = 88) from January 2013 to July 2015, group 2 (n = 89) from August 2015 to June 2017, and group 3 (n = 89) from July 2017 to February 2019. The overall success rate was 80.5% (214/266) over the study period. It significantly improved over time from 70% in group 1 to 84% in group 2 and 87% in group 3 (p = 0.014). In the meantime, the operating time and the total energy delivered to the tissue decreased from 77 minutes in the first group to 60.4 minutes in the second group and 55.4 minutes in the third group (p < 0.001), and from 95.2 kJ in the first group to 84 kJ in the second group and 77.9 kJ in the third group (p = 0.041). On multivariate analysis, the only risk factor significantly associated with day-case failure was prostate volume greater than 90 cc (odds ratio = 2.041, p = 0.047). Conclusion: Day-case HoLEP is a reliable and safe procedure with a high success rate. The surgeon's experience seems to be crucial to improve perioperative outcomes, but prostate volume greater than 90 cc remains associated with higher failure rates.

Neoadjuvant targeted molecular therapies in patients undergoing nephrectomy and inferior vena cava thrombectomy: is it useful?

OBJECTIVE: To assess the effect of neoadjuvant targeted molecular therapies (TMTs) on size and level of inferior vena cava tumor thrombi and to evaluate their impact on surgical management. METHODS: We retrospectively analyzed the data of 14 patients treated for a clear cell renal cell carcinoma with inferior vena cava thrombi by neoadjuvant TMT before nephrectomy. Clinical, pathological and perioperative data were gathered retrospectively at each institution. The primitive tumor size and the thrombus size were defined by computed tomography before TMT. The tumor thrombus level was defined according to the Novick's classification. RESULTS: Before TMT, thrombus level was staged I for 1 (7%), II for 10 (72%) and III (21%) for 3 patients. First-line therapy was sunitinib in 11 cases and sorafenib in 3 cases. Median therapy duration was two cycles (1-5). Three patients experienced major adverse effects (grade III) during TMT. Following TMT, 6 (43%) patients had a measurable decrease, 6 (43%) had no change, and 2 (14%) had an increase in the thrombus. One patient (7%) had a downstage of thrombus level, 12 (85%) had stable thrombi, and 1 (7%) had an upstage. Regarding primary tumor, 7 (50%), 5 (36%) and 2 (14%) patients had a decrease, stabilization and an increase in tumor size, respectively. CONCLUSION: Neoadjuvant TMT appears to have limited effects on renal tumor thrombi. This retrospective study failed to demonstrate a significant impact of neoadjuvant TMT on surgical management of clear cell renal cell carcinoma with inferior vena cava tumor thrombi.