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We previously reported a 35-gene expression classifier identifying four clear-cell renal cell carcinoma groups (ccrcc1 to ccrcc4) with different tumour microenvironments and sensitivities to sunitinib in metastatic clear-cell renal cell carcinoma. Efficacy profiles might differ with nivolumab and nivolumab–ipilimumab. We therefore aimed to evaluate treatment efficacy and tolerability of nivolumab, nivolumab–ipilimumab, and VEGFR-tyrosine kinase inhibitors (VEGFR-TKIs) in patients according to tumour molecular groups. This biomarker-driven, open-label, non-comparative, randomised, phase 2 trial included patients from 15 university hospitals or expert cancer centres in France. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0–2, and had previously untreated metastatic clear-cell renal cell carcinoma. Patients were randomly assigned (1:1) using permuted blocks of varying sizes to receive either nivolumab or nivolumab–ipilimumab (ccrcc1 and ccrcc4 groups), or either a VEGFR-TKI or nivolumab–ipilimumab (ccrcc2 and ccrcc3 groups). Patients assigned to nivolumab–ipilimumab received intravenous nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by intravenous nivolumab 240 mg every 2 weeks. Patients assigned to nivolumab received intravenous nivolumab 240 mg every 2 weeks. Patients assigned to VEGFR-TKIs received oral sunitinib (50 mg/day for 4 weeks every 6 weeks) or oral pazopanib (800 mg daily continuously). The primary endpoint was the objective response rate by investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1. The primary endpoint and safety were assessed in the population who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02960906, and with the EU Clinical Trials Register, EudraCT 2016-003099-28, and is closed to enrolment. Between June 28, 2017, and July 18, 2019, 303 patients were screened for eligibility, 202 of whom were randomly assigned to treatment (61 to nivolumab, 101 to nivolumab–ipilimumab, 40 to a VEGFR-TKI). In the nivolumab group, two patients were excluded due to a serious adverse event before the first study dose and one patient was excluded from analyses due to incorrect diagnosis. Median follow-up was 18·0 months (IQR 17·6–18·4). In the ccrcc1 group, objective responses were seen in 12 (29%; 95% CI 16–45) of 42 patients with nivolumab and 16 (39%; 24–55) of 41 patients with nivolumab–ipilimumab (odds ratio [OR] 0·63 [95% CI 0·25–1·56]). In the ccrcc4 group, objective responses were seen in seven (44%; 95% CI 20–70) of 16 patients with nivolumab and nine (50% 26–74) of 18 patients with nivolumab–ipilimumab (OR 0·78 [95% CI 0·20–3·01]). In the ccrcc2 group, objective responses were seen in 18 (50%; 95% CI 33–67) of 36 patients with a VEGFR-TKI and 19 (51%; 34–68) of 37 patients with nivolumab–ipilimumab (OR 0·95 [95% CI 0·38–2·37]). In the ccrcc3 group, no objective responses were seen in the four patients who received a VEGFR-TKI, and in one (20%; 95% CI 1–72) of five patients who received nivolumab–ipilimumab. The most common treatment-related grade 3–4 adverse events were hepatic failure and lipase increase (two [3%] of 58 for both) with nivolumab, lipase increase and hepatobiliary disorders (six [6%] of 101 for both) with nivolumab–ipilimumab, and hypertension (six [15%] of 40) with a VEGFR-TKI. Serious treatment-related adverse events occurred in two (3%) patients in the nivolumab group, 38 (38%) in the nivolumab–ipilimumab group, and ten (25%) patients in the VEGFR-TKI group. Three deaths were treatment-related: one due to fulminant hepatitis with nivolumab–ipilimumab, one death from heart failure with sunitinib, and one due to thrombotic microangiopathy with sunitinib. We demonstrate the feasibility and positive effect of a prospective patient selection based on tumour molecular phenotype to choose the most efficacious treatment between nivolumab with or without ipilimumab and a VEGFR-TKI in the first-line treatment of metastatic clear-cell renal cell carcinoma. Bristol Myers Squibb, ARTIC.

With limitations of conventional imaging and biopsy, accurate, non-invasive techniques to detect clear-cell renal cell carcinoma in patients with renal masses remain an unmet need. 89Zr-labelled monoclonal antibody ([89Zr]Zr-girentuximab) has high affinity for carbonic anhydrase 9, a tumour antigen highly expressed in clear-cell renal cell carcinoma. We aimed to evaluate [89Zr]Zr-girentuximab PET–CT imaging for detection and characterisation of clear-cell renal cell carcinoma. ZIRCON was a prospective, open-label, multicentre, phase 3 trial conducted at 36 research hospitals and practices across nine countries (the USA, Australia, Canada, the UK, Türkiye, Belgium, the Netherlands, Spain, and France). Patients aged 18 years or older with an indeterminate renal mass 7 cm or smaller (cT1) suspicious for clear-cell renal cell carcinoma and scheduled for nephrectomy received a single dose of [89Zr]Zr-girentuximab (37 MBq ±10%; 10 mg girentuximab) intravenously followed by abdominal PET–CT imaging 5 days (±2 days) later. Surgery was performed no later than 90 days after administration of [89Zr]Zr-girentuximab. Blinded central review, conducted by three independent readers, determined the histology from surgical samples. The coprimary endpoints, determined for each individual reader, were the sensitivity and specificity of [89Zr]Zr-girentuximab PET–CT imaging to detect clear-cell renal cell carcinoma, with histopathological confirmation as standard of truth. Analyses were on the full analysis set of patients, defined as patients who had evaluable PET–CT imaging and a confirmed histopathological diagnosis. The trial is registered with ClinicalTrials.gov, NCT03849118, and EUDRA Clinical Trials Register, 2018-002773-21, and is closed to enrolment. Between Aug 14, 2019, and July 8, 2022, 371 patients were screened for eligibility, 332 of whom were enrolled. 300 patients received [89Zr]Zr-girentuximab (214 [71%] male and 86 [29%] female). 284 (95%) evaluable patients were included in the primary analysis. The mean sensitivity was 85·5% (95% CI 81·5–89·6) and mean specificity was 87·0% (81·0–93·1). No safety signals were observed. Most adverse events were not or were unlikely to be related to [89Zr]Zr-girentuximab, with most (193 [74%] of 261 events) occurring during or after surgery. The most common grade 3 or worse adverse events were post-procedural haemorrhage (in six [2%] of 261 patients), urinary retention (three [1%]), and hypertension (three [1%]). In 25 (8%) of 300 patients, 52 serious adverse events were reported, of which 51 (98%) occurred after surgery. There were no treatment-related deaths. Our results suggest that [89Zr]Zr-girentuximab PET–CT has a favourable safety profile and is a highly accurate, non-invasive imaging modality for the detection and characterisation of clear-cell renal cell carcinoma, which has the potential to be practice changing. Telix Pharmaceuticals.

Background Only a few studies have compared the outcomes of robotic partial nephrectomy (RPN) and open partial nephrectomy (OPN). This study aimed to compare perioperative and oncologic outcomes of RPN and OPN. Methods The data of all patients who underwent partial nephrectomy from 2006 to 2014 in six academic departments of urology were retrospectively collected. Perioperative outcomes were compared between OPN and RPN patients. Cancer-specific survival (CSS) and recurrence-free survival (RFS) were estimated using the Kaplan–Meier method and compared using the log-rank test. Results The study included 1800 patients: 937 who underwent RPN and 863 who underwent OPN. The patients in the robotic group had smaller tumors (33.1 vs. 39.9 mm; p  < 0.001) but comparable RENAL scores (6.8 vs. 6.7; p  = 0.37). The complication rate was higher in the OPN group (28.6 vs. 18 %; p  < 0.001). The OPN patients had greater estimated blood loss (359.5 vs. 275 ml; p  < 0.001) and more frequent hemorrhagic complications (12.1 vs. 6.9 %; p  < 0.001). The robotic approach was associated with a shorter warm ischemia time (WIT 15.7 vs. 18.6 min; p  < 0.001) and a shorter hospital of stay (4.7 vs. 10.1 days; p  < 0.001). In the propensity score-weighted analysis, the inverse probability of treatment weighting adjusted odds ratio for the risk of complication after OPN versus RPN was 2.11 (95 % confidence interval, 1.53–2.91; p  < 0.001). After a median postoperative follow-up period of 13 months for OPN and 39 months for RPN ( p  < 0.001), CSS and RFS were similar in the two groups. In the multivariate analysis, RPN showed an impact on the occurrence of a complication but had no effect on WIT or RFS. Conclusion In this study, RPN was less morbid than OPN, with lower complications, less blood loss, and a shorter hospital of stay. The intermediate-term oncologic outcomes were similar in the two groups.

Purpose To assess the impact of 3D printed models of renal tumor on patient’s understanding of their conditions. Patient understanding of their medical condition and treatment satisfaction has gained increasing attention in medicine. Novel technologies such as additive manufacturing [also termed three-dimensional (3D) printing] may play a role in patient education. Methods A prospective pilot study was conducted, and seven patients with a primary diagnosis of kidney tumor who were being considered for partial nephrectomy were included after informed consent. All patients underwent four-phase multi-detector computerized tomography (MDCT) scanning from which renal volume data were extracted to create life-size patient-specific 3D printed models. Patient knowledge and understanding were evaluated before and after 3D model presentation. Patients’ satisfaction with their specific 3D printed model was also assessed through a visual scale. Results After viewing their personal 3D kidney model, patients demonstrated an improvement in understanding of basic kidney physiology by 16.7 % ( p  = 0.018), kidney anatomy by 50 % ( p  = 0.026), tumor characteristics by 39.3 % ( p  = 0.068) and the planned surgical procedure by 44.6 % ( p  = 0.026). Conclusion Presented herein is the initial clinical experience with 3D printing to facilitate patient’s pre-surgical understanding of their kidney tumor and surgery.

Background Renal Cell Carcinoma (RCC) is difficult to treat with 5-year survival rate of 10% in metastatic patients. Main reasons of therapy failure are lack of validated biomarkers and scarce knowledge of the biological processes occurring during RCC progression. Thus, the investigation of mechanisms regulating RCC progression is fundamental to improve RCC therapy. Methods In order to identify molecular markers and gene processes involved in the steps of RCC progression, we generated several cell lines of higher aggressiveness by serially passaging mouse renal cancer RENCA cells in mice and, concomitantly, performed functional genomics analysis of the cells. Multiple cell lines depicting the major steps of tumor progression (including primary tumor growth, survival in the blood circulation and metastatic spread) were generated and analyzed by large-scale transcriptome, genome and methylome analyses. Furthermore, we performed clinical correlations of our datasets. Finally we conducted a computational analysis for predicting the time to relapse based on our molecular data. Results Through in vivo passaging, RENCA cells showed increased aggressiveness by reducing mice survival, enhancing primary tumor growth and lung metastases formation. In addition, transcriptome and methylome analyses showed distinct clustering of the cell lines without genomic variation. Distinct signatures of tumor aggressiveness were revealed and validated in different patient cohorts. In particular, we identified SAA2 and CFB as soluble prognostic and predictive biomarkers of the therapeutic response. Machine learning and mathematical modeling confirmed the importance of CFB and SAA2 together, which had the highest impact on distant metastasis-free survival. From these data sets, a computational model predicting tumor progression and relapse was developed and validated. These results are of great translational significance. Conclusion A combination of experimental and mathematical modeling was able to generate meaningful data for the prediction of the clinical evolution of RCC.

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. We identified new splice variants of VEGF (VEGFXXX/NF) by bioinformatic analysis and molecular approaches, and we observed that VEGFXXX/NF stimulated angio/lymphangiogenesis and vascular permeability. High levels of VEGFXXX/NF correlated with shorter survival and resistance to anti‐angiogenic drugs (AAD) in patients with metastatic renal cancer. Thus, VEGFXXX/NF could serve as a relevant therapeutic target, a prognostic marker and a predictive marker for the efficacy of AAD.

PurposeRobot-assisted partial nephrectomy (RAPN) is a difficult procedure with risk of significant perioperative complications. The objective was to evaluate the impact of preoperative planning and intraoperative guidance with 3D model reconstructions on perioperative outcomes of RAPN.MethodsWe conducted a retrospective analysis of all patients who underwent RAPN for kidney tumor by three high-volume expert surgeons from academic centers. Clinical data were collected prospectively after written consent into the French kidney cancer network database UroCCR (CNIL-DR 2013-206; NCT03293563). Our cohort was divided into two groups: 3D-Image guided RAPN group (3D-IGRAPN) and control group. A propensity score according to age, pre-operative renal function and RENAL tumor complexity score was used. Both surgical techniques were compared in terms of perioperative outcomes.ResultsThe initial study cohort included 230 3D-IGRAPN and 415 control RAPN. Before propensity-score matching, patients in the 3D-IGRAPN group had a larger tumor (4.3 cm vs. 3.5 cm, P < 0.001) and higher RENAL complexity score (9 vs. 8, P < 0.001). Following propensity-score matching, there were 157 patients in both groups. The rate of major complications was lower for patients in the 3D-IGRAPN group (3.8% vs. 9.5%, P = 0.04). The median percentage of eGFR variation recorded at first follow-up was lower in the 3D-IGRAPN group (− 5.6% vs. − 10.5%, P = 0.002). The trifecta achievement rate was higher in the 3D-IGRAPN group (55.7% vs. 45.1%; P = 0.005).ConclusionThree-dimensional kidney reconstructions use for pre-operative planning and intraoperative surgical guidance lowers the risk of complications and improve perioperative clinical outcomes of RAPN.

Personalized 3D-printed kidney models could serve as valuable educational tools for patients undergoing robot-assisted partial nephrectomy (RAPN). These models facilitate patients' understanding of their pathology, surgical procedure, and anatomy. However, the costs associated with 'personalized' printing remain a barrier to their use. This study aims to thoroughly investigate the benefits of using a personalized 3D-printed kidney model as opposed to a generic 3D-printed kidney model as an educational tool for patients and as a communication tool for healthcare professionals. In this prospective single center study, 60 patients undergoing RAPN will be randomized to receive information based on their personalized 3D-printed tumoral kidney model or a generic 3D-printed tumoral kidney model. These models will accompany patients throughout their care pathway, from pre-operative consultations to the post-operative visit. The impact of these models on the management approaches of various healthcare professionals will also be examined. The data will be collected and analyzed using a mixed method, combining interviews (with patients and caregivers), observations during the presentation of the models and questionnaires (understanding of their pathology and the surgical procedure, Health-literacy, satisfaction). Three dimensional kidney models have the potential to play a central role in the preoperative information process and serve as an effective educational tool during the patient's social interactions with relatives and healthcare professionals. This study will evaluate the potential advantages of personalized 3D models of tumoral kidneys compared to their generic counterparts. The PERSONALIZE study was registered on ClinicalTrials.gov (NCT06379698) on the 5th of September 2023.

The announcement of a diagnosis can be a source of anxiety for patients. Managing this anxiety is a major challenge, in terms of quality of life but also for the use of anxiolytic and analgesic therapies. The use of 3D modeling technology in partial nephrectomy surgery has proved its worth as a surgical aid but it could also help patients to manage their own care, by reducing their anxiety and increasing their understanding of the disease and its treatment. We aim to test this hypothesis with a prospective multicenter trial. R3DP-A (Rein 3D - Anxiety) is an unblinded, multicenter, randomized, prospective, superiority-controlled trial. Participants are patients with kidney tumors treated by robot-assisted partial laparoscopic nephrectomy. The 234 patients (78x3 groups) from 6 French centers will undergo a pre-operative consultation dedicated to a personalized explanation of the surgical management and its risks. They will be randomized into three (1:1:1) groups corresponding to three types of support for consultation: use of a virtual 3D model of the kidney and its tumor; a printed 3D model; or the standard information sheet from the French Association of Urology (control group). Several self-questionnaires will be sent by the UroConnect® application and completed at different times during the study. The primary endpoint will be pre-operative anxiety (STAI-state questionnaire completed the day before surgery D-1). Secondary endpoints will be changes in anxiety levels between the pre-operative and post-operative consultations (between inclusion and D15 post-op), changes in health literacy and quality of life (HLSEU-Q16 and EQ-5D-5L questionnaires at inclusion and D15), feelings of understanding of the disease and its treatment at pre-operative period (Wake questionnaire at D-1), and consultation times. We aim to highlight a benefit of using a personalized 3D model on the anxiety level of patients undergoing partial nephrectomy surgery, as well as on their level of understanding of their pathology and its surgical treatment. The use of these models could be incorporated into current practice to improve patient experience throughout care.

Distant metastasis-free survival (DMFS) curves are widely used in oncology. They are classically analyzed using the Kaplan-Meier estimator or agnostic statistical models from survival analysis. Here we report on a method to extract more information from DMFS curves using a mathematical model of primary tumor growth and metastatic dissemination. The model depends on two parameters, α and μ , respectively quantifying tumor growth and dissemination. We assumed these to be lognormally distributed in a patient population. We propose a method for identification of the parameters of these distributions based on least-squares minimization between the data and the simulated survival curve. We studied the practical identifiability of these parameters and found that including the percentage of patients with metastasis at diagnosis was critical to ensure robust estimation. We also studied the impact and identifiability of covariates and their coefficients in α and μ , either categorical or continuous, including various functional forms for the latter (threshold, linear or a combination of both). We found that both the functional form and the coefficients could be determined from DMFS curves. We then applied our model to a clinical dataset of metastatic relapse from kidney cancer with individual data of 105 patients. We show that the model was able to describe the data and illustrate our method to disentangle the impact of three covariates on DMFS: a categorical one (Führman grade) and two continuous ones (gene expressions of the macrophage mannose receptor 1 (MMR) and the G Protein-Coupled Receptor Class C Group 5 Member A (GPRC5a) gene). We found that all had an influence in metastasis dissemination ( μ ), but not on growth ( α ).