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International audience; BACKGROUND: Intratumor heterogeneity (ITH) is a key feature in clear cell renal cell carcinomas (ccRCCs) that impacts outcomes such as aggressiveness, response to treatments, or recurrence. In particular, it may explain tumor relapse after surgery in clinically low-risk patients who did not benefit from adjuvant therapy. Recently, single-cell RNA sequencing (scRNA-seq) has emerged as a powerful tool to unravel expression ITH (eITH) and might enable better assessment of clinical outcomes in ccRCC. OBJECTIVE: To explore eITH in ccRCC with a focus on malignant cells (MCs) and assess its relevance to improve prognosis for low-risk patients. DESIGN, SETTING, AND PARTICIPANTS: We performed scRNA-seq on tumor samples from five untreated ccRCC patients ranging from pT1a to pT3b. Data were complemented with a published dataset composed of pairs of matched normal and ccRCC samples. INTERVENTION: Radical or partial nephrectomy on untreated ccRCC patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Viability and cell type proportions were determined by flow cytometry. Following scRNA-seq, a functional analysis was performed and tumor progression trajectories were inferred. A deconvolution approach was applied on an external cohort, and Kaplan-Meier survival curves were estimated with respect to the prevalence of malignant clusters. RESULTS AND LIMITATIONS: We analyzed 54 812 cells and identified 35 cell subpopulations. The eITH analysis revealed that each tumor contained various degrees of clonal diversity. The transcriptomic signatures of MCs in one particularly heterogeneous sample were used to design a deconvolution-based strategy that allowed the risk stratification of 310 low-risk ccRCC patients. CONCLUSIONS: We described eITH in ccRCCs, and used this information to establish significant cell population-based prognostic signatures and better discriminate ccRCC patients. This approach has the potential to improve the stratification of clinically low-risk patients and their therapeutic management. PATIENT SUMMARY: We sequenced the RNA content of individual cell subpopulations composed of clear cell renal cell carcinomas and identified specific malignant cells the genetic information of which can be used to predict tumor progression.

Resume Le carcinome renal a stroma leiomyomateux (CRSL) est une entite histopathologique rare et encore peu decrite. Nous rapportons ici un cas unique presentant des zones en metaplasie osseuse, survenu chez un homme de 31 ans recemment diagnostique d’une sclerose tubereuse de Bourneville (STB) avec mutation TSC2. Une nephrectomie partielle a ete realisee. Microscopiquement, la composante epitheliale est d’architecture papillaire et alveolaire, avec des cellules au cytoplasme clair a eosinophile, et des noyaux en position basale. Elle est entouree d’un abondant stroma musculaire lisse avec une metaplasie osseuse focale. Les cellules tumorales expriment l’anhydrase carbonique (CAIX), les cytokeratines CK7 et CK20, et le CD10, sans expression de TFE3. Cette entite emergente a la particularite d’etre fortement associee a la STB, justifiant son depistage.

International audience; CONTEXT: The advent of immune check inhibitors (ICIs) has tremendously changed the prognosis of metastatic renal cell carcinoma (mRCC), adding an unseen substantial overall survival benefit. These agents could be administered alone or in combination with anti-vascular endothelial growth factor (anti-VEGF) therapies. So far, treatment allocation is based only on clinical stratification risk models. OBJECTIVE: Herein, we aimed to report the different molecular classifications reported in the first-line treatment of mRCC and discuss the awaited clinical implications in terms of treatment selection. EVIDENCE ACQUISITION: Medline database as well as European Society for Medical Oncology (ESMO)/American Society of Clinical Oncology (ASCO) conference proceedings were searched to identify biomarker studies. Inclusion criteria comprised randomized and nonrandomized clinical trials that included patients treated in the first line of mRCC setting, patients treated with anti-VEGF therapies or ICIs, biological modeling, and available survival outcomes. EVIDENCE SYNTHESIS: Four classification models were identified with subsequent clinical implications: Beuselinck model (34 gene signatures), IMmotion150, Hakimi, and JAVELIN 101 model. Tumor profiling shows distinct outcomes when treated with one or other combination. Patients are clustered into two gene signatures: angiogenic and proinflammatory (as per JAVELIN). The first is more likely to respond to therapy that includes anti-VEGF agents, while the best outcomes are obtained with an ICI combination with the second. CONCLUSIONS: The findings presented here were mostly derived from ancillary registered studies of new drugs in the setting of mRCC. Further validation is needed, which sets new paradigms for investigation in clinical research based on tumor biology for treatment allocation and not only on clinical stratification tools. PATIENT SUMMARY: First-line treatment of metastatic kidney includes immunotherapy alone or in combination with antiangiogenic therapy. However, clinical practice demonstrated that the "one treatment fits all" strategy might not be the best approach. In fact, recent studies showed that the addition of immunotherapy agents will not benefit all patients equally, and some still respond either equally to or better than anti-vascular endothelial growth factor alone. This review revealed biomarker modeling that impacts treatment selection. Recent tumor profiling into "angiogenic signature" more sensitive to angiogenic agents versus "immune signature" more likely to achieve the best response with immunotherapy should be validated. Tumor biology features might be more powerful than clinical classification for a tailored treatment approach.

International audience; Aims First described in 2014, renal cell carcinoma (RCC) with TFEB amplification (6p21) is a rare molecular subgroup whose diagnosis is challenging. The prognosis and therapeutic implications remain unclear. Methods We report here the clinical, histological, immunohistochemical, and genetic features of nine novel cases. The pathological and immunohistochemical features were centrally reviewed by expert uropathologists. Fluorescence in situ hybridisation (FISH) confirmed the diagnosis and comparative genomic hybridisation (CGH) was performed to determine quantitative genomic alterations. We also performed an exhaustive review of the literature and compiled our data. Results TFEB-amplified RCC were locally advanced, with initial lymph node involvement in one case and liver metastasis in another case. They were high-grade eosinophilic tumours with papillary/pseudopapillary architecture, frequent positivity for melanocytic markers, and frequent PDL1 expression. FISH demonstrated high-level TFEB amplification in six cases. One case showed concomitant TFEB translocation. CGH analysis identified complex alterations with frequent losses of 1p, 2q, 3p, 6p, and frequent 6p and 8q gains. VEGFA coamplification was identified in all cases with a lower level than TFEB. The prognosis was poor, with five patients having lymph node or distant metastases. Conclusion TFEB-amplified RCC is a rare molecular subgroup with variable morphology whose diagnosis is confirmed by FISH analysis. The complex alterations identified by CGH are consistent with an aggressive clinical behaviour. The coamplification of VEGFA and the expression of PDL1 could suggest a potential benefit from antiangiogenics and targeted immunotherapy in combination for these aggressive tumours.

Introduction Cases of osteonecrosis of the jaw have been reported by dental surgeons to the pharmacovigilance center in Rennes, France, occurring among patients treated with palbociclib, a cyclin-dependent kinase 4/6 inhibitor. Although this event was not expected with the drug, a safety signal was raised. Describing a local case series, the aim of our study was to identify specific patterns that might suggest a triggering role for these drugs, and to discuss pathophysiological hypotheses. Materials and methods A retrospective case series of patients exposed to cyclin-dependent kinase 4/6 inhibitors between 2016 and 2020 with a diagnosis of osteonecrosis of the jaw at the Rennes Dental Care Center was analyzed. The descriptive analysis was conducted on patient demographics, breast cancer characteristics, osteonecrosis of the jaw, biological data, and exposure to cyclin-dependent kinase 4/6 inhibitors. Results We identified eight cases, most of them at stages 0–1 (62.5%). Four patients were still exposed to palbociclib at the time of diagnosis and four had discontinued the treatment before the diagnosis. Chronological imputability could not be excluded given the drug’s half-life and the variable intervals of dental monitoring from one patient to another. All patients had at least one dental osteonecrosis risk factor (including dental extraction, dentures, and denosumab exposure at the time of diagnosis). Neutropenia and mucositis were not systematically reported at the time of diagnosis. The anatomopathological characteristics were nonspecific. Conclusion We did not identify a specific pattern that could suggest a triggering role of palbociclib in the development of ONJ.

Objectives: The objective of this study was to assess the impact of complete transurethral resection of bladder tumors (TURBTs) before radical cystectomy on pathological and oncological outcomes of patients with muscle-invasive bladder cancer (MIBC) and high-risk non-MIBC. Materials and Methods: The charts of all patients who underwent radical cystectomy for bladder cancer in 2 academic departments of urology between 1996 and 2016 were retrospectively reviewed. Patients were divided into 2 groups according to the completeness of the last endoscopic resection before radical cystectomy: macroscopically complete transurethral resection (complete) or macroscopically incomplete transurethral resection (incomplete). The primary end point was the recurrence-free survival (RFS). Secondary end points included cancer-specific survival (CSS) and rates of pT0 and downstaging. Results: Out of 486 patients included for analysis, the TURBT immediately preceding radical cystectomy was considered macroscopically complete in 253 patients (52.1%) and incomplete in 233 patients (47.9%). In multivariate analysis, macroscopically complete TURBT was the strongest predictor of both pT0 disease (OR = 3.1; p = 0.02) and downstaging (OR = 7.1; p < 0.0001). After a median follow-up of 41 months, macroscopically complete TURBT was associated with better RFS (5-year RFS: 57 vs. 37%; p < 0.0001) and CSS (5-year CSS: 70.8 vs. 54.5%; p = 0.002). In multivariate analysis adjusting for multifocality, weight of endoscopic resection specimen, cT4 stage on preoperative imaging, interval between endoscopic resection and radical cystectomy, neoadjuvant chemotherapy, pT stage, and associated carcinoma in situ, macroscopically complete endoscopic resection remained the main predictor of better RFS (HR = 0.4; p = 0.0003) and the only preoperative factor associated with CSS (HR = 0.5; p = 0.01). Conclusion: A macroscopically complete TURBT immediately preceding radical cystectomy may improve pathological and oncological outcomes in patients with MIBC and high-risk MIBC.

International audience; Background With the development of precision oncology, Molecular Tumor Boards (MTB) are developing in many institutions. However, the implementation of MTB in routine clinical practice has still not been thoroughly studied. Material and methods Since the first drugs approved for targeted therapies, patient tumor samples were centralized to genomic testing platforms. In our institution, all tumor samples have been analyzed since 2014 by Next Generation Sequencing (NGS). In 2015, we established a regional MTB to discuss patient cases with 1 or more alterations identified by NGS, in genes different from those related to drug approval. We conducted a retrospective comparative analysis to study whether our MTB increased the prescriptions of Molecular Targeted Therapies (MTT) and the inclusions of patients in clinical trials with MTT, in comparison with patients with available NGS data but no MTB discussion. Results In 2014, 86 patients had UGA, but the results were not available to clinicians and not discussed in MTB. During the years 2015 and 2016, 113 patients with an UGA (unreferenced genomic alteration) were discussed in MTB. No patients with an UGA were included in 2014 in a clinical trial, versus 2 (2%) in 2015-2016. 13 patients with an UGA (12%) were treated in 2015-2016 with a MTT whereas in 2014, no patient (p = 0.001). Conclusions In this retrospective analysis, we showed that the association of large-scale genomic testing and MTB was feasible, and could increase the prescription of MTT. However, in routine clinical practice, the majority of patients with UGA still do not have access to MTT.

Computer-assisted pathology is one of the biggest challenges in the medicine of the future. However, artificial intelligence is struggling to gain acceptance in the broader medical community due to data security issues, lack of trust in the machine, and poor data availability. Here, we develop a tumor delineation algorithm with only eight whole slide images of ovarian cancer to demonstrate the feasibility of an artificial intelligence application created from only a few data, finely annotated and with optimal processing. We test the model on seventeen other slides from the same hospital. The predictions are similar to the ground truth annotations made by an expert pathologist, with a mean DICE score of 0.90 [0.85 - 0.93]. The results on slides from another hospital are consistent, suggesting that the model is generalizable and that its performance does not suffer from different data acquisition. This study demonstrates the feasibility of a contouring algorithm based on a reduced dataset well optimized, going against the commonly accepted idea that a phenomenal amount of data is paramount. This study paves the way for other medical applications, especially for rare pathologies with limited available data.

PURPOSE Emerging evidence suggests a correlation between the tumor mutational burden (TMB) and the response to programmed cell death-1 protein (PD-1) monotherapy across multiple cancer types. In skin cancers, as high TMB is mostly because of ultraviolet (UV) exposure, we hypothesized a correlation between the primary melanoma cutaneous location according to sun exposure and response to anti–PD-1 monotherapy. METHODS The aim of this study was to analyze, in advanced melanoma, the relationship between TMB, locations according to sun exposure, and response to PD-1 inhibitors. We conducted a prospective multicentric analysis, by sequencing the most recent metastatic sample before PD-1 inhibitors using FoundationOne assay. RESULTS One hundred two patients were included, with TMB available for 94 cases. In univariate and multivariate linear regression, TMB was significantly associated with sun-exposed areas of the primary melanoma location and with age (coefficients of the association with log-TMB: non-UV location, –1.05; chronic sun-exposed area, 1.12; P value for the location, < 10–5; age, 0.021 per year, P value for age, .002). Molecular UV signature present on the metastatic site was associated with higher TMB (P = .003). Melanomas bearing a high TMB had a higher probability of response to PD-1 inhibitors compared with melanomas with a low TMB, with a dose-dependent effect following an exponential curve and a negative odds ratio of 0.40 (95% CI, 0.20 to 0.72, P = .004) between log-TMB and 6-month progression. CONCLUSION Cumulative sun exposure related to skin location and molecular UV signature present on the metastatic site appear to be relevant biomarkers directly linked to TMB. Because TMB is not yet available to all for routine clinical use, the location of the primary melanoma in a sun-exposed area may play an important role in clinical decisions regarding therapeutic choice., The location of the primary melanoma in a sun-exposed area can help choosing first-line advanced melanoma treatment.

We report the case of a patient with exceptional survival over 8 years after left trisectionectomy combined with portal vein and hepatic artery resection and reconstruction for advanced perihilar cholangiocarcinoma. Such extended hepatectomy with vascular resection is the only way to obtain free tumor margin. It can be performed with acceptable morbidity and mortality and it is the only hope to prolong survival.

The dynamics of metastatic evolution in clear cell renal cell carcinoma (ccRCC) are complex. We report a case study where tumour heterogeneity resulting from clonal evolution is a frequent feature and could play a role in metastatic dissemination.We used an integrative multiomics strategy combining genomic and transcriptomic data to classify fourteen specimens from spatially different areas of a kidney tumour and three non-primary sites including a vein thrombus and two adrenal metastases.All sites were heterogeneous and polyclonal, each tumour site containing two different aggressive subclonal populations, with differentially expressed genes implicated in distinct biological functions. These are rare primary metastatic samples prior to any medical treatment, where we showed a multiple metastatic seeding of two subclonal populations.Multiple interdependent lineages could be the source of metastatic heterogeneity in ccRCC. By sampling metastases, patients with resistance to therapies could benefit a combination of targeted therapies based on more than one aggressive clone.

International audience; Tyrosine kinase inhibitors have revolutionized the treatment of patients with gastrointestinal stromal tumors (GISTs). Nevertheless, some GISTs do not contain any targetable KIT or PDGFRA mutations classically encountered in this field. Novel approved therapies targeting TRK chimeric proteins products of NTRK genes fusions consist in a promising approach to treat some patients with GISTs lacking any identified driver oncogenic mutation in KIT, PDGFRA or BRAF genes. Thus, an adequate testing strategy permitting to diagnose the rare NTRK-rearranged GISTs is required. In this work, we studied about the performances of pan-TRK immunohistochemistry (IHC) and NTRK1/2/3 fluorescent in situ hybridization in a series of 39 GISTs samples. Among 22 patients with GISTs lacking KIT or PDGFRA mutations, BRAFV600E IHC permitted to diagnose 2/22 (9%) BRAFV600E-mutated GISTs and, among the 20 KIT, PDGFRA, and BRAF wild type tumors, 1/20 (5%), NTRK3-rearranged tumor was diagnosed using NTRK3 fluorescent in situ hybridization. Pan-TRK IHC using EPR17341 and A7H6R clones was negative in this NTRK3-rearranged sample. Pan-TRK IHC was frequently positive in NTRK not rearranged tumors without (24 samples analyzed) or with (15 samples analyzed) KIT or PDGFRA mutations with major discrepancies between the 2 IHC clones (intraclass correlation coefficient of 0.3042). Given the new therapeutic opportunity offered by anti-TRK targeted therapies to treat patients with advanced cancers including GISTs, it is worth to extend molecular analysis to NTRK fusions testing in KIT, PDGFRA, and BRAF wild type GISTs. Pan-TRK IHC appears not relevant in this field but performing a simple NTRK3 fluorescent in situ hybridization test consists in a valuable approach to identify the rare NTRK3-rearranged GISTs treatable using anti-TRK therapies.

International audience; Renal cell carcinoma is the third type of urologic cancer and has a poor prognosis with 30% of metastatic patients at diagnosis. The antiangiogenics and targeted immunotherapies led to treatment remodeling emphasizing the role of the tumour microenvironment. However, long-term responses are rare with a high rate of resistance. New strategies are emerging to improve the efficacy and the emerging drugs are under evaluation in ongoing trials. With the different treatment options, there is an urgent need to identify biomarkers in order to predict the efficacy of drugs and to better stratify patients. Owing to the limitations of programmed death-ligand 1 (PD-L1), the most studied immunohistochemistry biomarkers, and of the tumor mutational burden, the identification of more reliable markers is an unmet need. New technologies could help in this purpose.

International audience; Renal cell carcinoma with leiomyomatous stroma (RCCLS) is an emerging entity frequently associated with tuberous sclerosis complex (TSC). We described herein a series of RCCLS in TSC patients at pathological and cytogenetic levels. Three male patients with TSC and RCCLS were identified between 2000 and 2019 at the University Hospital of Rennes. Histologically, the architecture was tubulo-papillary with thick bundles of smooth muscle cells. The tumor cells showed clear cytoplasm with eosinophilic globules. The immunohistochemical profile was identical with an intense positivity of CK7, CAIX, and CD10 and a heterogeneous positivity of CK20. SDHB was low but positive and TFE3 was not expressed. Comparative genomic hybridization (CGH) did not show any quantitative chromosome abnormality. No recurrence was observed with a median follow-up of 4 years. RCCLS in TSC patients has morphological, immunohistochemical, and cytogenetic distinct features that could constitute a distinct entity and a sentinel manifestation for the diagnosis of TSC.

To compare the short-term outcomes of robot-assisted partial nephrectomy (RPN) and laparoscopic partial nephrectomy (LPN) when performed by highly experienced surgeons.A prospective multicenter study was conducted, including the 50 last patients having undergone LPN and RPN for T1-T2 renal tumors in two institutions between 2013 and 2016, performed by two different surgeons with an experience of over 200 procedures each in LPN and RPN, respectively, at the beginning of the study. Perioperative parameters and functional and oncological outcomes were collected and compared between the LPN and RPN groups.The laparoscopic approach was associated with a longer warm ischemia time (15.7 versus 23 minutes; P .001) and hospital stay (3.6 versus 4.6 days; P = .01). Conversely, estimated blood loss was significantly higher in the RPN group (381 mL versus 215 mL; P .001), but transfusion rates were similar between the two groups (8% versus 6%; P = .33). In the RPN group, three patients (6%) required conversion to open partial nephrectomy and three patients (6%) required a conversion to radical nephrectomy (RN), while no conversion was needed in the LPN group. There were no differences in terms of perioperative complications, and change in renal function was comparable in the two groups postoperatively. Positive surgical margin rates were similar in the RPN and LPN groups (2% versus 6%; P = .36). After a median follow-up of 19 and 14 months in the RPN and LPN groups, respectively (P = .38), recurrence-free survivals did not differ significantly (P = .94).In this series, perioperative and short-term oncological and functional outcomes appeared broadly comparable between RPN and LPN when performed by highly experienced surgeons.

Objective To evaluate the impact of fellows’ involvement on the peri-operative outcomes of robot-assisted partial nephrectomy (RAPN). Materials and Methods We analysed 216 patients who underwent RAPN for a small renal tumour. We stratified our cohort into two groups according to the involvement of a fellow surgeon during the procedure: expert surgeon operating alone (expert group) and fellow operating under the supervision of the expert surgeon (fellow group). Peri-operative data were compared between the two groups. Linear and logistic regression analyses were performed to assess the impact of fellows’ involvement on peri-operative and postoperative outcomes. Trifecta and margins ischaemia complications (MIC) score achievement rates were used to assess the quality of surgery in both the expert and fellow groups. Trifecta was defined as a combination of warm ischaemia time

Resume Introduction Le pheochromocytome composite est une tumeur medullosurrenalienne rare associant un pheochromocytome et une tumeur neuroblastique. Nous presentons le cas d’un pheochromocytome composite decouvert chez un patient atteint d’une neurofibromatose de type 1. Observation Il s’agissait d’un patient de 61 ans presentant des episodes de sueurs associes a des palpitations et une hypertension arterielle moderee. Biologiquement, le dosage des derives methoxyles urinaires etait eleve. L’imagerie montrait une tumeur intra-surrenalienne heterogene. A l’examen histologique, la tumeur etait composee d’un pheochromocytome et d’un ganglioneurome, faisant porter le diagnostic de pheochromocytome composite. Il s’agit d’une tumeur frequemment associee a la neurofibromatose de type 1, la mutation germinale du gene NF1 pouvant etre impliquee dans sa physiopathologie. Conclusion Le pheochromocytome composite est une tumeur rare dont la composante pheochromocytome est suspectee cliniquement mais dont le diagnostic est anatomopathologique. Le pronostic reste mal connu du fait de la rarete de ces tumeurs.

Objectifs L’objectif de cette etude etait d’explorer les facteurs biologiques predictifs de la progression apres nephrectomie pour carcinome des cellules renales (CCR) a haut risque non metastatique en utilisant les tumeurs collectees des patients inclus en France dans l’essai randomise S-TRAC ( NCT00375674 ). Methodes Nous avons analyse les tumeurs de la cohorte francaise du STRAC qui comprenait 44 cas de CCR qui ont ete recueillis dans six centres. L’objectif principal etait d’explorer les facteurs biologiques predictifs de la progression (definis comme SSP) au sunitinib. L’analyse a large spectre, y compris l’immunohistochimie, la fluorescence in situ d’hybridation (FISH), d’hybridation genomique comparative (CGH) et de transcriptomique des analyses ont ete effectuees sur les tumeurs. Resultats L’analyse de la densite vasculaire a montre un stroma vasculaire de type 1 correspondant a une densite vasculaire elevee a ete associee a une progression (p Fig. 1 ). La perte de poly bromo-1 a montre un profil distinct : une tumeur agressive hautement avec un profil angiogenique marque (surexpression du facteur de croissance endothelial vasculaire et stroma vasculaire immature de type 2), pas d’expression PD1 ou PDL1, et statut de type sauvage (WT) du gene VHL. Il y avait 27 regions chromosomiques gagnees chez les patients presentant une progression (sur les chromosomes 7 et 16, et dans une moindre mesure 8, 12, 17, 19, 20 correspondant a 605 genes associes) et 10 regions perdues chez ces memes patients sur les chromosomes 8 et 9, et dans une moindre mesure 2 et 21 correspondant a 25 genes associes. Conclusion Nous avons constate qu’un phenotype angiogenique defini par une forte densite vasculaire avec un stroma vasculaire de type 2 etait un facteur predictif de la resistance au sunitinib. Quel que soit le traitement recu (sunitinib ou placebo) les gains et de pertes chromosomiques et d’alterations genomiques, y compris la perte de PBRM1 etaient associees a un plus mauvais pronostic.

Resume Introduction L’objectif de ce travail etait d’analyser l’evolution des pratiques et des resultats de la nephrectomie partielle (NP) avec l’acquisition du robot Da Vinci ® . Materiels et methodes Il s’agit d’une etude monocentrique retrospective portant sur 280 patients traites par NP pour une tumeur renale de janvier 2006 a mai 2013. Le nombre de NP, les caracteristiques tumorales, et les resultats perioperatoires ont ete etudies sur 3 periodes en fonction de la voie d’abord majoritairement utilisee : 2006–2008 (NP ouverte), 2008–2010 (NP laparoscopique) puis 2010-2013 (NP robot-assistee). Resultats Le ratio NP/nephrectomies a evolue avec une augmentation significative du nombre de NP par rapport au nombre de nephrectomies elargies ( p = 0,002). Aucun changement significatif de la taille tumorale moyenne n’a ete observe ( p = 0,42) au cours de l’etude mais la proportion de tumeurs complexes (RENAL score ≥ 10) a augmente de facon significative au cours des trois dernieres annees (10,7 % ; 18,6 % et 33,2 % ; p = 0,04). Le temps de clampage a augmente passant de 23 minutes en 2006–2008 a 26 minutes en 2008–2010, puis diminue durant l’ere robotique passant a 14,5 minutes ( p p = 0,003). Conclusion Dans cette serie monocentrique, la chirurgie robotique a contribue au developpement et a l’amelioration des resultats de la chirurgie renale conservatrice. Niveau de preuve 4.

The idiopathic myointimal hyperplasia of mesenteric veins is a rare pathology, affecting recto-sigmoid and mimicking clinically an inflammatory chronic disease of the bowel. Only about fifteen cases have been reported in the literature. This lesion is characterized by a myointimal thickening of the mesenteric veins, without inflammatory infiltrate of the vascular wall, differentiating it from vasculitis. We present here the case of a 48-year-old man, in whom the diagnosis of ulcerative colitis then digestive vasculitis had first been raised.

International audience; BACKGROUND: Long-term responders (LTRs) are defined by at least 18 months of response to sunitinib in metastatic clear-cell renal cell carcinoma (ccRCC). Well-described by clinical studies, the phenotype of these tumors has never been explored.PATIENTS AND METHODS: In a retrospective and multicenter study, 90 ccRCCs of patients with metastatic disease were analyzed. Immunohistochemistry (carbonic anhydrase IX, vascular endothelial growth factor, c-MET, programmed death-ligand 1 [PD-L1], and PD-1) and VHL status were performed. Progression-free survival and overall survival were calculated from sunitinib introduction and from progression. LTRs and their corresponding tumors were compared with others using univariate and multivariate analysis.RESULTS: Twenty-eight patients were LTRs. They had a median progression-free survival of 28 months versus 4 months for other patients (P < .001). Similarly, LTRs had a median overall survival of 49 months versus 14 months (P < .001), even from progression (median, 21 vs. 7 months; P = .029). They were associated with a favorable or intermediate risk (International Metastatic Renal Cell Carcinoma Database Consortium model) (P = .007) and less liver metastasis (P = .036). They experienced more frequent complete or partial responses at the first radiologic evaluation (P = .035). The corresponding ccRCCs were associated with less nucleolar International Society for Urological Pathology grade 4 (P = .037) and hilar fat infiltration (P = .006). They were also associated with low PD-L1 expression (P = .02). Only the International Metastatic Renal Cell Carcinoma Database Consortium model and PD-L1 expression remained significant after multivariate analysis (P = .014 and P = .029, respectively).CONCLUSION: Primary tumor characteristics of LTRs were studied for the first time and demonstrated a different phenotype. Interestingly, they were characterized by low expression of PD-L1, suggesting a potentially lower impact of targeted immunotherapy in these patients.

Renal cell carcinomas (RCC) are divided in several subtypes, characterized by morphological and histological features, protein expression patterns and genetics criteria. The main subtypes include Clear cell renal cell carcinoma (CCRCC), Papillary RCC (PRCC), Chromophobe RCC (ChRCC), oncocytoma, TFE3 and TFEB Translocation renal cell carcinoma (TRCC). In most cases, RCC can be easily classified according to histological criteria and immunohistochemistry. Nevertheless, the subtyping process can be more complex in some cases: differential diagnosis (CCRCC or TFE3 TRCC, PRCC or TFE3 TRCC, oncocytic tumors corresponding to ChRCC or oncocytoma), molecular confirmation (TFEB TRCC) and unclassified RCC. Complementary analyses are required such as fluorescence in situ hybridization (FISH) for the detection of chromosomal abnormalities associated to each subtype. In this aim, this study assessed the performance of FISH analysis in the histological classification of 359 RCC exhibiting unusual histological characteristics and/or occurring in young people. FISH probes were selected according to the histological features of each tumor. FISH analysis contributed to the histological classification in 73% of the RCC (261/359). Conversely, FISH did not contribute to the diagnosis in 19% of the cases (69/359) and a hybridization failure was observed for the remaining tumors (8%; 29/359). Considering the different RCC subtypes, FISH analysis was highly efficient to confirm the histological diagnosis of CCRCC, PRCC, and TFE3 TRCC and to identify abnormalities of the TFEB gene. However, this strategy showed some limitations for the diagnosis of oncocytic tumors and unclassified RCC, suggesting that additional molecular assays should be evaluated in these cases.

To evaluate the impact of accidental surgical incision into the tumour (ASIT) on oncological outcomes in patients undergoing RPN for a malignant tumour. A retrospective review of our prospectively maintained database was performed to identify all patients who underwent RPN for a localized RCC between June 2010 and July 2016. We stratified our cohort into two groups according to the presence of an ASIT. Perioperative data were compared between the two groups. Logistic regression analyses were used to assess the variables associated with ASIT. Recurrence-free survival was estimated using the Kaplan–Meier method and compared between groups with the log-rank test. A total of 234 patients were identified. 32 (14%) ASIT were observed. Patients’ characteristics were similar in the two groups. Most of intraoperative outcomes were comparable between the two groups, but patients in the ASIT group had greater EBL (475 vs. 300 mL; p = 0.01). In multivariate analysis, tumour size (p = 0.02), RENAL score (p = 0.02), EBL (p = 0.05) and low surgeon experience (p = 0.03) were all predictive factors of ASIT. 15 (6%) of recurrences were observed over a median follow-up of 36 months. There was no difference in recurrence-free survival between the two groups (p = 0.57). In our experience, accidental surgical incision into the tumour during RPN was a common event that did not appear to compromise oncological outcome.

International audience; Risk stratification for kidney sparing procedures (KSP) to treat upper tract urothelial carcinoma (UTUC) is a major issue. A non-systematic Medline/PubMed literature search was performed using the terms "upper tract urothelial carcinoma" with different combinations of keywords to review the current knowledge on this topic. Original articles, reviews and editorials in English language were selected based on their clinical relevance. Available techniques for KSP include segmental ureterectomy and endoscopic resection through a percutaneous or flexible ureteroscopic access. These approaches were traditionally restricted to patients with imperative indications. Current recommendations suggest that selected patients with normal contralateral kidney should also be candidates for such treatments. Modern imaging and endoscopy have improved to accurately stage and grade the tumor while various prognostic clinical factors and biomarkers have been proposed to identify tumor with aggressive features and worse outcomes. Several predictive models using different combinations of such baseline characteristics may help clinicians in clinical decision making. However, risk-adapted based approach that has been proposed in recent guidelines to identify patients who are more likely to benefit from KSP only relies on few clinical and pathological factors. Despite growing understanding of the disease, treatment of UTUC remains challenging. Further efforts and collaborative multicenter studies are mandatory to improve risk stratification to decide and promote optimal KSP in UTUC. These efforts should focus on the integration of promising biomarkers and predictive tools in clinical decision making.

Resume Introduction L’objectif etait de rapporter les resultats perioperatoires et oncologiques de la cystectomie radicale robot assistee dans une serie monocentrique prospective francaise, et d’evaluer l’impact de l’experience sur les donnees perioperatoires. Materiels et methodes Entre mars 2012 et janvier 2016, 41 patients operes d’une cystectomie robot-assistee pour une TVIM dans un centre par un meme operateur ont ete inclus prospectivement. Les donnees perioperatoires et oncologiques ont ete recueillies. Les survies sans recidive, specifique et globale ont ete estimees selon la methode de Kaplan-Meier. L’impact de l’experience sur les resultats perioperatoires a ete evalue en utilisant le test de correlation de Spearman. Resultats L’âge moyen etait de 67,7 ans (± 10,6). Une chimiotherapie neoadjuvante avait ete realisee dans 73,2 % des cas. La duree d’intervention et les pertes sanguines moyennes etaient respectivement de 319,5 minutes (± 85,3) et 662,5 mL (± 360,9). Huit patients (19,5 %) ont necessite une transfusion durant l’intervention, et une conversion a ete necessaire dans 3 cas (7,3 %). Une enterocystoplastie a ete realisee dans 26,8 % des cas (intracorporelle dans 54,5 % des cas), et un conduit ileal dans 73,2 %. Le nombre de ganglions preleves par curage etait en moyenne de 17,7 (± 9,3). Un patient avait des marges positives (2,3 %). La duree moyenne d’hospitalisation etait de 13,2 jours (± 9,8). Le taux de complications postoperatoires etait de 46,3 %. Apres un suivi median de 16 mois, les survies globale et specifique estimees etaient respectivement de 62 et 76,1 % a 2 ans. La survie sans recidive estimee a 2 ans etait de 67,6 %. Les resultats perioperatoires s’amelioraient avec l’experience, avec une diminution significative de la duree operatoire ( p = 0,04) et une augmentation significative du nombre de ganglions par curage ( p = 0,05). Conclusion Dans cette serie monocentrique, la cystectomie robot-assistee etait associee a des resultats perioperatoires et oncologiques satisfaisants malgre la courbe d’apprentissage. Les resultats perioperatoires s’amelioraient avec l’experiences. Des resultats a long terme sont necessaires pour confirmer ces donnees. Niveau de preuve 4.

International audience; Objectives: To assess the impact of a prolonged follow-up schedule using computed tomography scan on oncological outcomes after radical cystectomy for bladder cancer. Methods: A single-center retrospective study was carried out. All patients who underwent a radical cystectomy for bladder cancer between 1992 and 2012 were included. The protocol for postoperative oncological follow up included a thoracoabdominal computed tomography scan twice per year for 2 years and then annually for life. The patients with tumor recurrence were divided into two groups: asymptomatic recurrences and recurrences diagnosed because of symptoms. Cancer-specific survivals were estimated using the Kaplan–Meier method and compared with the log–rank test. Cox proportional hazards regression models were used to determine the predictive factors of cancer-specific survival. Results: Overall, 331 patients were included in this analysis, and, of them, 48.5% had a cancer recurrence after a median follow up of 52.6 months. A total of 30 of these recurrences were diagnosed at routine follow up among asymptomatic patients (18.8%). A total of 50% of recurrences occurred during the first 6 months and 75% during the first year. Just 10 of the recurrences (6.3%) appeared more than 3 years after radical cystectomy. The 5-year cancer-specific survival was higher in patients with asymptomatic recurrences (15.7% vs 32.1%), but this difference was not statistically significant (P = 0.10). On multivariate analysis, detection of asymptomatic recurrence reached statistical significance (HR 0.55; P = 0.04). Conclusion: Routine computed tomography scan surveillance after radical cystectomy for bladder cancer might provide a survival benefit. The risk of recurrence beyond 3 years seems to be low, and further studies are required to determine the role of routine computed tomography scan in the follow up beyond this timeframe. © 2016 The Japanese Urological Association

Objectifs Evaluer la performance de l’analyse de texture pour predire la survie sans progression (SSP) et la survie globale (SG) chez les patients atteints d’un carcinome renal a cellules claire metastatique (CCRm) traites par nivolumab. Methodes Il s’agit d’une etude retrospective monocentrique qui a analyse les donnees cliniques et radiomiques de patients atteints de CCRm traites par nivolumab. L’analyse radiomique des lesions metastatiques a ete effectuee sur des scanners injectes obtenus dans le mois precedant l’administration du traitement. Les caracteristiques de texture liees a l’histogramme de niveau de gris, a la cooccurrence de niveau de gris, aux caracteristiques de la matrice de longueur d’onde, aux caracteristiques du modele autoregressif et a la caracteristique des ondelettes de Haar ont ete extraites. Des analyses de regression de Cox penalisees ont ete effectuees pour identifier des predicteurs de la SSP et SG. Resultats Au total, 48 patients ont ete analyses. Les survies medianes sans progression et globale etaient de 5,7 et 13,8 mois. Trente-neuf patients ont eu une progression et 27 sont decedes. L’analyse de regression penalisee a identifie trois parametres radiomiques comme predicteurs potentiels de la SSP : l’asymetrie, S.2.2. Correlat et S.1.1. SumVarnc. L’analyse multivariee a montre que l’asymetrie (HR [IC95 %] = 1,49 [1,21–1,85], p Conclusion Les resultats de cette etude preliminaire suggerent que la radiomique pourrait etre un outil d’imagerie quantitative prometteur permettant de predire les resultats oncologiques des patients ayant un CCRm traites par nivolumab.

Background Little is known about the predictive value of surgeon’s judgement to estimate perioperative outcomes following robotic partial nephrectomy (RPN). Objective To evaluate the accuracy of surgeon’s intuition to estimate perioperative outcomes of patients undergoing RPN and compare its predictive value with that of objective scoring systems. Design, setting, and participants We prospectively analysed 100 consecutive patients who underwent RPN. Outcome measurements and statistical analysis RENAL, PADUA, and MAP scores were calculated based on preoperative imaging. The surgeon gave a subjective estimation of the technical difficulty and the risk of postoperative complications of RPN immediately before and after surgery using a visual analogue scale (VAS). Correlation between scores, VAS, estimated blood loss (EBL), operative time (OT), and warm ischaemia time (WIT) were examined. Logistic regression analyses were performed to identify the best predictors of overall complications. Receiver operating characteristic (ROC) curve analysis was used to assess the accuracy of VAS and scoring systems to predict trifecta achievement. Results and limitations RENAL, PADUA, and MAP scores significantly correlated with surgeon’s pre- and postoperative VAS evaluation, with the RENAL score showing the strongest correlation (r = 0.49 and r = 0.34, respectively). Pre- and postoperative VAS scores had the strongest correlation with EBL (r = 0.48 and r = 0.59, respectively), OT (r = 0.44 and r = 0.65, respectively), and WIT (r = 0.37 and r = 0.47, respectively). In multivariate analysis adjusted for anticoagulant/antiplatelet treatment, body mass index, surgeon’s experience, and Charlson comorbidity index, only surgeon’s prediction could significantly predict overall complications (odds ratio = 5.42, p Conclusions Surgeon’s clinical assessment is a good predictor of perioperative outcomes of RPN and seems to perform better than conventional scores. Patient summary In this report, we found that surgeon’s clinical feeling can better predict perioperative morbidity of robotic partial nephrectomy than conventional radiological scores.

Low-grade eosinophilic unclassified renal cell carcinoma is a rare kidney tumor recently described, not included in the WHO classification, which is very close to oncocytoma. It is unknown to most pathologists and clinicians. From a histopathological point of view, this tumor is composed of oncocytic cells arranged in a diffuse and solid pattern, without cell nests, that makes it possible to differentiate it from oncocytoma, and expresses cytokeratin 7 (CK7) heterogeneously. We report a case with a cranial vault metastasis, and present the features to differentiate this entity from oncocytoma. Furthemore, we discuss about unclassified renal cell carcinomas with oncocytic cells.

International audience; INTRODUCTION: Clear cell renal cell carcinomas (ccRCCs) are highly metastatic tumors with metastases detected at diagnosis (synchronous) or during follow-up (metachronous). To date, there have been no reports comparing primary ccRCC of patients with synchronous and metachronous metastases, who are different in terms of prognosis. Determining whether there is a phenotypic difference between these 2 groups could have important clinical implications. PATIENTS AND METHODS: In a retrospective consecutive cohort of 98 patients with ccRCC, 48 patients had metastases, including 28 synchronous and 20 metachronous presentations, with a follow-up of 10 years. For each primary tumor in these metastatic patients, pathologic criteria, expression of vascular endothelial growth factor, partitioning-defective 3, CAIX, and programmed death ligand 1 as detected by immunohistochemistry, and complete VHL status were analyzed. Univariate analysis was performed, and survival was assessed using Kaplan-Meier curves compared by log-rank test. RESULTS: Compared with primary ccRCC in patients with metachronous metastases, primary ccRCC in patients with synchronous metastases were significantly associated with a poorer Eastern Cooperative Oncology Group performance (P = .045), higher pT status (P = .038), non-inactivated VHL gene (P = .01), sarcomatoid component (P = .007), expression of partitioning-defective 3 (P = .007), and overexpressions of vascular endothelial growth factor (> 50%) (P = .017) and programmed death ligand 1 (P = .019). Patients with synchronous metastases had a worse cancer-specific survival than patients with metachronous metastases even from metastatic diagnosis (median survival, 16 months vs. 46 months, respectively; P = .01). CONCLUSION: This long-term study is the first to support the notion that synchronous m-ccRCC has a distinct phenotype. This is probably linked to the occurrence of oncogenic events that could explain the worse prognosis. These particular patients with metastases could benefit from specific therapy.

International audience; PURPOSE OF REVIEW: Upper tract urothelial carcinoma (UTUC) is a relatively rare and poorly investigated disease. The objective of this review was to discuss recent advances in genomics and their implication regarding prognosis and treatment. RECENT FINDINGS: UTUC were compared with urothelial carcinoma of the bladder (UCB) at genomic and transcriptomic levels. Molecular studies focused on identifying new prognostic biomarkers that were often initially described in UCB and extrapolated to UTUC. Some of them could be interesting to improve the management of UTUC. SUMMARY: Recent studies improved our understanding of UTUC as a distinct entity compared with UCB. Although UTUC shares many of the same genomic alterations with UCB, some key differences have been identified as oncogenic drivers of these cancers. This better comprehension of genomics could lead to new prognostic markers that may refine UTUC treatment.

International audience; Background: Clear cell renal cell carcinoma (ccRCC) is highly metastatic. Cabozantinib, an anti-angiogenic tyrosine kinase inhibitor that targets c-MET, provided interesting results in metastatic ccRCC treatment.Objective: To understand better the role of c-MET in ccRCC, we assessed its status in a population of patients with metastatic ccRCC. Patients and Methods For this purpose, tumor samples were analyzed for c-MET expression by immunohistochemistry (IHC), for c-MET copy number alterations by fluorescence in situ hybridization (FISH), and for c-MET mutations by next generation sequencing (NGS) in a retrospective cohort of 90 primary ccRCC of patients with metastases treated by first-line sunitinib. The expression of c-MET was correlated with pathological, immunohistochemical (VEGFA, CAIX, PD-L1), clinical, and molecular criteria (VHL status) by univariate and multivariate analyses and to clinical outcome using Kaplan-Meier curves compared by log-rank test.Results: Of ccRCC, 31.1% had low c-MET expression (absent to weak intensity by IHC) versus 68.9% with high expression (moderate to strong intensity). High expression of c-MET was associated with a gain in FISH analysis (p=0.0284) without amplification. No mutations were detected in NGS. Moreover, high c-MET expression was associated with lymph node metastases (p=0.004), sarcomatoid component (p=0.029), VEGFA (p=0.037), and PD-L1 (p=0.001) overexpression, the only factor that remained independently associated (p

International audience; Clear cell renal cell carcinoma (ccRCC) is an aggressive tumor that is characterized in most cases by inactivation of the tumor suppressor gene VHL. The VHL/HIF/VEGF pathway thus plays a major role in angiogenesis and is currently targeted by anti-angiogenic therapy. The emergence of resistance is leading to the use of targeted immunotherapy against immune checkpoint PD1/PDL1 that restores antitumor immune response. The correlation between VHL status and PD-L1 expression has been little investigated. In this study, we retrospectively reviewed 98 consecutive cases of ccRCC and correlated PD-L1 expression by immunohistochemistry (IHC) with clinical data (up to 10-year follow-up), pathological criteria, VEGF, PAR-3, CAIX and PD-1 expressions by IHC and complete VHL status (deletion, mutation and promoter hypermethylation). PD-L1 expression was observed in 69 ccRCC (70.4%) and the corresponding patients had a worse prognosis, with a median specific survival of 52 months (p = 0.03). PD-L1 expression was significantly associated with poor prognostic factors such as a higher ISUP nucleolar grade (p = 0.01), metastases at diagnosis (p = 0.01), a sarcomatoid component (p = 0.04), overexpression of VEGF (p = 0.006), and cytoplasmic PAR-3 expression (p = 0.01). PD-L1 expression was also associated with dense PD-1 expression (p = 0.007) and with ccRCC with 0 or 1 alteration(s) (non-inactivated VHL tumors; p = 0.007) that remained significant after multivariate analysis (p = 0.004 and p = 0.024, respectively). Interestingly, all wild-type VHL tumors (no VHL gene alteration, 11.2%) expressed PD-L1. In this study, we found PD-L1 expression to be associated with noninactivated VHL tumors and in particular wild-type VHL ccRCC, which may benefit from therapies inhibiting PD-L1/PD-1.