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Bladder cancer occurs mainly in older adults and surgery is not always possible when there are geriatric conditions and comorbidities. Trimodal treatment (TMT) combining trans-urethral resection of bladder tumour (TURBT) followed by concurrent chemoradiation (CRT) would be a curative alternative in such patients.All consecutive patients 75 years of age and older with non-metastatic muscle-invasive bladder cancer (MIBC) treated with TMT by Georges Pompidou European Hospital team were retrospectively analysed. Induction CRT combined hypofractionated twice-daily radiotherapy targeting bladder and pelvis to a total dose of 24 Gy (Gy) with concurrent platinum salt and 5-fluorouracil. Consolidation CRT to a total dose of 44 Gy was proposed to patients with biopsy-proven complete response after induction phase and those with persistent tumour underwent salvage cystectomy. We assessed using Kaplan-Meier method overall survival (OS), cancer specific survival (CSS), invasive recurrence-free survival (IRFS), metastasis-free survival (MFS), survival with bladder preserved (SBP), and toxicities. With a Cox model for OS and the Fine Gray method of competing risk for secondary endpoints, we analysed in univariate (u) and multivariate (m) analysis the impact of tumour characteristics and patient profiles: gender, age, age-adjusted Charlson comorbidity index, polypharmacy, and malnutrition.From 1988 to 2017, 85 patients were included. After induction, complete response rate was 83.5%. With a median follow-up of 63 months, 5 year-OS, CSS, IRFS, MFS and SBP were 61.0%, 77.6%, 71%, 82.9%, and 70.2% respectively. A persistent tumour after induction impacted SBP (SHRm 3.61; p = 0.004), CSS (SHRm 3.27; p = 0.023), and MFS (SHRm 3.68; p = 0.018). Late grade 3 urinary and gastrointestinal toxicities were 3.5% and 1.2%.We report here the largest series of bladder preservation over 75 years in a curative intent. Outcomes and tolerance in selected older adults compared favourably with surgical series and with CRT studies using classical fractionation.

Supplemental Table 4-6. Table S4: Detail for each sample of the PBRM1 and VHL-mutation status. NA stands for Not Available. Table S5: For each data type, clinical, transcriptome, methylome or SNP array, sensitity and specificity of the two predictors: PD vs (PR+SD) and PR vs (PD+SD) in the training and validation sets. The 'N()' columns indicate the numbers of each responder type. Table S6: List of the 27 genes firstly used by the classifier to predict the subtypes ccrcc2, ccrcc3 and the joint subtype ccrcc14 and list of the 8 genes used by the second classifier to assign the ccrcc14 samples to the two subtypes ccrcc1 and ccrcc4.

Supplemental Figure 7-10. Figure S7: Summary of the results obtained on the TCGA data; Figure S8: Survival analysis of the patients included in the TCGA according to our classification ccrcc 1 to 4; Figure S9: Illustration of the gradient assumption defined by subtype order

This file contains the legends for the 7 supplementary figures

Purpose: Selecting patients with metastatic clear-cell renal cell carcinoma (m-ccRCC) who might benefit from treatment with targeted tyrosine kinase inhibitors (TKI) is a challenge. Our aim was to identify molecular markers associated with outcome in patients with m-ccRCC treated with sunitinib.Experimental Design: We performed global transcriptome analyses on 53 primary resected ccRCC tumors from patients who developed metastatic disease and were treated with first-line sunitinib. We also determined chromosome copy-number aberrations, methylation status, and gene mutations in von Hippel–Lindau and PBRM1. Molecular data were analyzed in relation with response rate (RR), progression-free survival (PFS), and overall survival (OS). Validation was performed in 47 additional ccRCC samples treated in first-line metastatic setting with sunitinib.Results: Unsupervised transcriptome analysis identified 4 robust ccRCC subtypes (ccrcc1 to 4) related to previous molecular classifications that were associated with different responses to sunitinib treatment. ccrcc1/ccrcc4 tumors had a lower RR (P = 0.005) and a shorter PFS and OS than ccrcc2/ccrcc3 tumors (P = 0.001 and 0.0003, respectively). These subtypes were the only significant covariate in the multivariate Cox model for PFS and OS (P = 0.017 and 0.006, respectively). ccrcc1/ccrcc4 tumors were characterized by a stem-cell polycomb signature and CpG hypermethylation, whereas ccrcc3 tumors, sensitive to sunitinib, did not exhibit cellular response to hypoxia. Moreover, ccrcc4 tumors exhibited sarcomatoid differentiation with a strong inflammatory, Th1-oriented but suppressive immune microenvironment, with high expression of PDCD1 (PD-1) and its ligands.Conclusions: ccRCC molecular subtypes are predictive of sunitinib response in metastatic patients, and could be used for personalized mRCC treatment with TKIs, demethylating or immunomodulatory drugs. Clin Cancer Res; 21(6); 1329–39. ©2015 AACR.

Supplemental Figure 1-3. Figure S1: Expression of immune modulators among the 4 molecular subgroups and normal Samples; Figure S2: Expression of cell-type specific metagenes among the different subgroups and normal samples; Figure S3: CD8+ cell infiltration according to the molecular ccRCC subtype classification.

Supplementary Figure and Table Legends. Legends of all supplemental Figures and Tables

Supplemental Figure 4-6. Figure S4: Characterisation of the ccRCC molecular subtypes: methylation status and Benporath polycomb signature; Figure S5: Cytogenetic characterization of the ccRCC molecular subtypes; Figure S6: Characterization of the ccRCC molecular subtypes: Myc methylation and (target) amplification

Figure S1 : Heterogeneous distribution of various subpopulations of intratumor CD8+T cells defined by the differential expression of PD1 and Tim-3 using an in situ multiparametric immunofluorescence technique. Figure S2: PD-1 and Tim-3 co-expression on CD8+T cells (in situ IF analyzis) correlates with clinical parameters of RCC aggressiveness Figure S3 : Relationships between the total number of intratumor T cells and subpopulations of CD8+T cells and Progression Free Survival Figure S4: Heterogeneous distribution of various subpopulations of tumor-infiltrating CD8+T cells defined by the differential expression of PD1 and Tim-3 analyzed by cytometry Figure S5: Patients who co-expressed PD-1 and Tim-3 on CD8+T cells more often exhibited clear cell RCC histology Figure S6: Tim-3 expression was decreased on PD-1+CD8+T cells after treatment with collagenase Figure S7 : PD-1 and Tim-3 expression on renal cell carcinoma by in situ immunofluorescence analysis Figure S8 : Blockade experiments with anti-PD-1 and anti-Tim-3 on bulk TIL

Supplemental Table 7-10. Table S7: Area under the ROC curve or c-index for the predictive and prognostic markers presented in Table 1 and Figures 3A, 3B and 3C. Table S8: P-values of the pathway enrichment analysis for the genes differentially expressed, the genes differentially methylated and the genes differentially methylated and anti-correlated to expression data in the four unsupervised subgroups. Table S9: List of the recurrent chromosomal aberrations characterizing ccrcc4-samples with a sensitivity and a specificity greater than 0.65. Table S10: Correlation of the centroids of our classification in four subtypes with the Brannon classification in three subgroups ccA, ccB and cluster_3 and the subtypes predicted in the TCGA cohort

Inhibitory receptors expressed by T cells mediate tolerance to tumor antigens, with coexpression of these receptors exacerbating this dysfunctional state. Using the VectraR automated multiparametric immunofluorescence technique, we quantified intratumoral CD8+ T cells coexpressing the inhibitory receptors PD-1 and Tim-3 from patients with renal cell carcinoma (RCC). A second validation cohort measured the same parameters by cytometry. The percentage of tumor-infiltrating CD8+ T cells coexpressing PD-1 and Tim-3 correlated with an aggressive phenotype and a larger tumor size at diagnosis. Coexpression of PD-1 and Tim-3 above the median conferred a higher risk of relapse and a poorer 36-month overall survival. Notably, other CD8+T-cell subsets did not exert a similar effect on overall survival. Moreover, only the PD-1+Tim-3+ subset of CD8+ T cells exhibited impaired function after stimulation. Our findings establish intratumoral Tim-3+PD1+CD8+ T cells as critical mediators of an aggressive phenotype in RCC. Use of the Vectra tool may be useful to identify similarly critical prognostic and predictive biomarkers in other tumor types and their response to immunotherapy. Cancer Res; 77(5); 1075–82. ©2016 AACR.

Table S1: Baseline clinical characteristics of the 87 primary clear cell RCC patient selected for multiparametric immunofluorescence in situ analysis Table S2: Baseline clinical characteristics of the 42 primary RCC patient with analysis of fresh tumor TIL Table S3 : List of antibodies used for cytometry and in situ immunofluorescence Table S4: Correlation between the total number (Nb) of CD8+T cells and those expressing Tim-3 and/or PD-1 and the Fuhrman grade and UISS. Table S5 : RCC patients characteristics in the prospective cohorts Table S6 : RCC patients characteristics in the retrospective cohorts

This file contains supplementary figures showing prostate tumor kinetics (Fig S1) and histology (Fig S2) for the two mouse models, the validation of regimens (Fig S3 and S4), the effects of diets (Fig S5) and aging (Fig S6) on cancer hallmarks, and the results of cell studies complementary to main Figures 3 and 4.

International audience; Background: 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.Methods: 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.Findings: 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.Interpretation: 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.

International audience; The presence of intratumoral tertiary lymphoid structures (TLS) is associated with positive clinical outcomes and responses to immunotherapy in cancer. Here, we used spatial transcriptomics to examine the nature of B cell responses within TLS in renal cell carcinoma (RCC). B cells were enriched in TLS, and therein, we could identify all B cell maturation stages toward plasma cell (PC) formation. B cell repertoire analysis revealed clonal diversification, selection, expansion in TLS, and the presence of fully mature clonotypes at distance. In TLS+ tumors, IgG- and IgA-producing PCs disseminated into the tumor beds along fibroblastic tracks. TLS+ tumors exhibited high frequencies of IgG-producing PCs and IgG-stained and apoptotic malignant cells, suggestive of anti-tumor effector activity. Therapeutic responses and progression-free survival correlated with IgG-stained tumor cells in RCC patients treated with immune checkpoint inhibitors. Thus, intratumoral TLS sustains B cell maturation and antibody production that is associated with response to immunotherapy, potentially via direct anti-tumor effects.

Background: New predictive biomarkers are needed to accurately predict metastasis-free survival (MFS) and cancer-specific survival (CSS) in localized prostate cancer (PC). Keratin-7 (KRT7) overexpression has been associated with poor prognosis in several cancers and is described as a novel prostate progenitor marker in the mouse prostate. Methods: KRT7 expression was evaluated in prostatic cell lines and in human tissue by immunohistochemistry (IHC, on advanced PC, n = 91) and immunofluorescence (IF, on localized PC, n = 285). The KRT7 mean fluorescence intensity (MFI) was quantified in different compartments by digital analysis and correlated to clinical endpoints in the localized PC cohort. Results: KRT7 is expressed in prostatic cell lines and found in the basal and supra-basal compartment from healthy prostatic glands and benign peri-tumoral glands from localized PC. The KRT7 staining is lost in luminal cells from localized tumors and found as an aberrant sporadic staining (2.2%) in advanced PC. In the localized PC cohort, high KRT7 MFI above the 80th percentile in the basal compartment was significantly and independently correlated with MFS and CSS, and with hypertrophic basal cell phenotype. Conclusion: High KRT7 expression in benign glands is an independent biomarker of MFS and CSS, and its expression is lost in tumoral cells. These results require further validation on larger cohorts.

Laparoscopic living-donor nephrectomy (LLDN) is the gold-standard procedure for kidney procurement. Ipsilateral orchialgia has barely been described. Some authors reported that ligation of gonadal vein (GV) above iliac vessel bifurcation could prevent orchialgia. We aimed to assess incidence and duration of orchialgia after LLDN in male donors despite distal ligation of GV.Patients who underwent LLDN from 2014 to 2017 were included. Standard procedure consisted in distal ligation of GV, close to the renal vein confluence and proximal ureteral ligation. Patients' demographics, per-operative data, and post-operative consultation reports were retrospectively reviewed. Orchialgia and scrotal symptoms were assessed through a non-validated questionnaire by phone interview.Sixty-nine donors were included. Orchialgia incidence and testicular swelling were 31.9% (n = 22) and 15.9% (n = 11), respectively. Median symptom duration was 15.5 months. Orchialgia led to medical consultation in 41.7% (n = 10) of cases. All patients declared having been informed, prior to donation, about possible residual pain but not specifically orchialgia.Orchialgia after LLDN affects more than 30% of donors, despite distal ligation of GV and led less than 50% of them to medical consultation, suggesting a large underestimation in clinical practice. Emphasis should be put on this complication during pre-donation information.

Clear-cell renal cell carcinoma (ccRCC) possesses an unmet medical need, particularly at the metastatic stage, when surgery is ineffective. Complement is a key factor in tissue inflammation, favoring cancer progression through the production of complement component 5a (C5a). However, the activation pathways that generate C5a in tumors remain obscure. By data mining, we identified ccRCC as a cancer type expressing concomitantly high expression of the components that are part of the classical complement pathway. To understand how the complement cascade is activated in ccRCC and impacts patients' clinical outcome, primary tumors from three patient cohorts (n = 106, 154, and 43), ccRCC cell lines, and tumor models in complement-deficient mice were used. High densities of cells producing classical complement pathway components C1q and C4 and the presence of C4 activation fragment deposits in primary tumors correlated with poor prognosis. The in situ orchestrated production of C1q by tumor-associated macrophages (TAM) and C1r, C1s, C4, and C3 by tumor cells associated with IgG deposits, led to C1 complex assembly, and complement activation. Accordingly, mice deficient in C1q, C4, or C3 displayed decreased tumor growth. However, the ccRCC tumors infiltrated with high densities of C1q-producing TAMs exhibited an immunosuppressed microenvironment, characterized by high expression of immune checkpoints (i.e., PD-1, Lag-3, PD-L1, and PD-L2). Our data have identified the classical complement pathway as a key inflammatory mechanism activated by the cooperation between tumor cells and TAMs, favoring cancer progression, and highlight potential therapeutic targets to restore an efficient immune reaction to cancer.

To identify predictive preoperative factors of the presence of teratoma in retroperitoneal lymph node dissection specimens.We performed a 20 years multicenter retrospective analysis of all patients who underwent retroperitoneal lymph node dissection for residual masses after chemotherapy (PC-RPLND). Patients had undergone PC-RPLND after chemotherapy for advanced testicular cancer. The histologic components of the primary tumor were compared with those of the residual masses using logistic regression.A total of 469 NSGCT patients underwent PC-RPLND (complete data available for 211). By PC-RPLND, necrosis was found in 84 cases, teratoma in 102 cases, and viable tumor in 25 cases. The univariate and multivariate analyses showed that teratoma (P = 0.001 and P = 0.002, respectively) and yolk sac tumor (P = 0.009 and P = 0.035, respectively) in orchiectomy specimens were statistically significant predictors of the presence of teratoma in retroperitoneal lymph nodes.PC-RPLND is the standard treatment for any supracentimetric residual lesion. This procedure is associated with a high morbidity, and almost half patients are overtreated. The presence of teratoma and yolk sac tumor in the orchiectomy specimen were independent significant predictors of teratoma in retroperitoneal masses. J. Surg. Oncol. 2016;114:992-996. © 2016 Wiley Periodicals, Inc.

Inhibitory receptors expressed by T cells mediate tolerance to tumor antigens, with coexpression of these receptors exacerbating this dysfunctional state. Using the VectraR automated multiparametric immunofluorescence technique, we quantified intratumoral CD8

The principal surgical complication feared in a patient under anti-angiogenic targeted therapy is gastrointestinal perforation. It is therefore important to be alert to situations "potentially at risk" of perforation: diverticulitis, carcinomatosis, intra-abdominal abscess, history of external radiotherapy, colonoscopy in the 4 weeks preceding the treatment, inflammatory disease and gastrointestinal mucosal ulceration, colonic stent, NSAID. It is essential to make an early diagnosis, and for treatment to be conservative if possible, with nasogastric aspiration without surgery. Surgical treatment is only offered in the event of worsening or failure of medical treatment. The time periods between surgery and the initiation of anti-angiogenic treatment vary according to the medication. With bevacizumab: major surgery: 4 weeks; 6 weeks if the patient has comorbidities. Minor surgery (e.g. dental extraction): wait for the wound to heal. With insertion of a PAC, bevacizumab can be administered the day after the insertion if necessary. With TKI: it is recommended to wait for the scar to heal in cases of major surgery. There is no specific recommendation for mTOR inhibitors. The time periods between termination of an anti-angiogenic treatment and scheduling of surgery also vary depending on the medication. With bevacizumab: 6 to 8 weeks for scheduled surgery. In the event of emergency surgery, the surgeon must be aware of an increased risk of post-operative complications. With TKI, 2 days for sorafenib, and 4 days for sunitinib. There is no specific recommendation for mTOR inhibitors.

BACKGROUND AND OBJECTIVES: Cystinuria is an autosomal recessive disorder affecting renal cystine reabsorption; it causes 1% and 8% of stones in adults and children, respectively. This study aimed to determine epidemiologic and clinical characteristics as well as comorbidities among cystinuric patients, focusing on CKD and high BP. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This retrospective study was conducted in France, and involved 47 adult and pediatric nephrology and urology centers from April 2010 to January 2012. Data were collected from 442 cystinuric patients. RESULTS: Median age at onset of symptoms was 16.7 (minimum to maximum, 0.3-72.1) years and median diagnosis delay was 1.3 (0-45.7) years. Urinary alkalinization and cystine-binding thiol were prescribed for 88.8% and 52.2% of patients, respectively, and 81.8% had at least one urological procedure. Five patients (1.1%, n=4 men) had to be treated by dialysis at a median age of 35.0 years (11.8-70.7). Among the 314 patients aged ≥16 years, using the last available plasma creatinine, 22.5% had an eGFR≥90 ml/min per 1.73 m(2) (calculated by the Modification of Diet in Renal Disease equation), whereas 50.6%, 15.6%, 7.6%, 2.9%, and 0.6% had an eGFR of 60-89, 45-59, 30-44, 15-29, and

Although radical nephrectomy is still practiced in many patients with large renal tumors, oncology and nephrology arguments for kidney-sparing approach for small renal masses has taken over this first. Indeed, partial nephrectomy provides equivalent oncologic results while preserving renal function and thereby limit morbidity and cardiovascular mortality related to chronic kidney disease. In addition, patients who develop kidney cancer often have medical comorbidities that may affect renal function, such as diabetes and hypertension. Histological examination of renal tissue adjacent to the tumor showed significant pathological changes in the majority of patients. For elderly patients or patients with comorbidities, active surveillance allows kidney-sparing approach with extremely low rates of progression and metastasis of cancer disease. Despite these significant advances in understanding for the treatment of small renal masses, partial nephrectomy remains underused. Better management must take into account the preservation of renal function in order to increase overall survival. A strategy for the systematic evaluation of renal function in patients with CR, with multidisciplinary staff (nephrologist urologist and oncologist), is therefore highly desirable.

La frequence du cancer du rein (RCC), 3 % des cancers humains, augmente dans les pays industrialises, laissant supposer l’intervention de facteurs toxiques (xenobiotiques et/ou alimentation, trichlorethylene, tabagisme et obesite). Le RCC survient le plus souvent sous forme sporadique mais est egalement retrouve dans un contexte familial : la maladie de von Hippel-Lindau (VHL). L’existence, d’une part, d’une grande heterogeneite intra- et inter-familiale dans le contexte du VHL et, d’autre part, la susceptibilite variable a des carcinogenes chimiques dans les formes sporadiques, laisse supposer, en outre, la participation de genes modificateurs conditionnels. Afin d’identifier des sous-groupes d’individus particulierement exposes ou, au contraire, proteges du fait de certains genotypes, nous avons collecte une serie de 460 tumeurs et de patients appartenant a 79 familles VHL et developpe un outil informatique, l’« universal mutation database » (UMD) pour les mutations du gene VHL, permettant de rechercher des correlations. Les mutations du gene VHL a l’origine a la fois des RCC sporadiques et de la maladie de VHL sont de nature differente : 1) dans les tumeurs sporadiques, 83 % des mutations du gene VHL sont des mutations aboutissant a un decalage du cadre de lecture (deletion, insertion, non-sens = « frameshift »). Les 17 % restant comprennent des transversions (3/4) et des transitions (1/4). Cette proportion elevee de transversions suggere fortement l’implication de substances carcinogenes (fumee de tabac) dont l’impact est largement conditionne par la variabilite genetique de l’activite des enzymes de biotransformation ; 2) pour les formes familiales, les mutations de type faux sens predominent dans 65 % des cas. Cette difference permet de definir un facteur pronostique de developper un RCC pour les patients VHL en fonction de la nature de la mutation germinale dont ils sont porteurs. Afin de reperer les genotypes conferant un risque eleve en presence de substances potentiellement carcinogenes, nous avons etabli le genotype des patients pour 8 genes (une cinquantaine de genotypes) impliques dans le metabolisme des xenobiotiques. Cette etude fait apparaitre une relation significative entre le developpement d’un RCC et des combinaisons d’alleles comprenant : CYPIA1 ("variant"), NAT2 et NAT1 (acetyleurs lents) et GSTM1 (allele nul). D’eventuelles associations entre les genotypes "a risque" et le profil des mutations somatiques observees chez les patients, mais aussi a differents stades tumoraux, pourraient aider a 1) preciser la nature de certains profils de mutagenese en relation avec l’activite ou la deficience de telle ou telle enzyme du metabolisme des xenobiotiques et sous l’effet de tel ou tel carcinogene ; 2) montrer que, dans le contexte du VHL, certaines combinaisons d’alleles de ces differents genes conferent un risque particulier de developper certains types de tumeur. Ainsi, suivre "a la trace" des substances potentiellement carcinogenes, a la fois par l’empreinte laissee au niveau de l’ADN, ainsi qu’a travers les alleles conditionnellement deleteres de genes participant a leur detoxication, devrait permettre une meilleur prevention grâce a une alimentation personnalisee pour les individus presentant ces genotypes.

Knowledge of the very long-term consequences of kidney donors has not been previously reported extensively. The 398 persons who had donated a kidney between 1952 and 2008 at Necker hospital were contacted. Among the 310 donors who were located, the survival probabilities for this population were similar to those of the general population and end stage renal disease incidence was 581 per million population per year. All located donors still alive were asked to complete a medico-psychosocial questionnaire and give samples for serum creatinine and urinary albumin assays. Among the 204 donors who responded to the questionnaire, mean eGFR was 64.4±14.6ml/min per 1.73m(2) and mean microalbuminuria was 27.0±83mg/g. Most donors never regretted the donation and consider that it has no impact on their professional or social lives. Among the 59 donors who gave a kidney more than 30years ago (mean 40.2years, range 30-48years) had a mean eGFR of 67.5±17.4μmol/l, a mean microalbuminuria level of 44.8±123.2mg/g and none was dialyzed. In conclusion, living kidney donation does not impact survival, kidney function, medical condition or psychological or social status over the very long-term.

International audience; OBJECTIVE: To identify, in a large multicentre series of incidental renal tumours, the key factors that could predict cancer-related deaths, as such tumours have a better outcome than symptomatic tumours and selected patients are increasingly being included in watchful-waiting protocols. PATIENTS AND METHODS: Data from 3912 patients were extracted from three international kidney-cancer databases. Age, gender, Eastern Cooperative Oncology Group (ECOG) performance status (PS), Tumour-Node-Metastasis (TNM) stage, tumour size, Fuhrman grade, and final pathology were recorded. Benign tumours and malignant lesions with incomplete information were excluded from final analysis. RESULTS: The mean (SD) age of the patients was 60.6 (12.2) years and the mean tumour size 5.5 (3.5) cm. Most tumours were malignant (90.2%) and of low stage (T1-T2, 71.7%) and low grade (G1-G2, 72.4%). There were nodal and distant metastases in 5.7% and 13% of the patients. In all, 525 (14.4%) patients died from cancer; in this group, tumours were >4 cm in 88.2% and had nodal or distant metastases in 20.2% and 49.3%, respectively. Multivariable analysis showed that tumour size >4 cm, ECOG PS >or=1, TNM stage and Fuhrman grade were independent predictors of cancer-related death. CONCLUSION: A significant proportion of incidental renal tumours can lead to the death of the patient. Standard prognostic variables for renal cell carcinoma appear to remain valid for this subset of patients. A watchful-waiting strategy should not be recommended if the tumour diameter is >4 cm, if biopsy confirms high-grade tumours, or if there is an impaired ECOG PS, or computed tomography findings suggest the presence of advanced T stage.

To prospectively assess the value of frozen section examination during conservative surgery for renal cell carcinoma (RCC) in exclusively elective indications and to evaluate the reality of safety margins.From 1997 to 2001, 220 conservative procedures for RCC were performed in our department, including 104 elective lumpectomies, 61 of which were studied prospectively. The mean age of these 61 patients was 59.4 years (range: 34.2 to 78.5). The mean tumour diameter was 32 mm (range: 12 to 50). Tumours were peripheral in 51 cases and in a juxtahilar position in 10 cases. Resection margins were evaluated macroscopically by the surgeon, and the specimen was systematically sent for frozen section examination. Incomplete margins, i.e. negative but with no safety margin, were distinguished from positive margins on the final histological examination. The thickness of the safety margins was measured on the cortical and deep extremities of the operative specimen. The mean follow-up was 78.5 months (range: 52 to 101).Histological types of RCC comprised conventional clear cell (n = 42), tubulopapillary (n = 17) and chromophobe (n = 2), stage pT1 (n = 57) and pT2 (n = 4), and grade 1 (n = 16), 2 (n = 35) and 3 (n = 10). No positive margins were detected. The mean thickness of the safety margin was 7 mm peripherally and 2 mm in depth with no correlation between these two values. Surgeons concluded on the presence of 51 complete margins and 10 incomplete margins versus 53 and 8 on histological examination, respectively. Frozen section examination never modified the course of the operation. All patients were alive and recurrence free at last follow-up.Macroscopic evaluation of resection margins by the surgeon is precise and usually avoids the need for frozen section. However when the margins are considered to be incomplete by the surgeon, frozen section examination is mandatory to avoid positive margins, which must remain the main objective of conservative surgery.

The Association Française d 'Urologie conducted a national epidemiological study in 1997. Using our database, we compared our results, up-dated the epidemiological data and evaluated the differences observed over a period of 15 years.844 patients operated for kidney tumour between 1985 and 2000 were analysed and 810 were included in this study. Survival analysis was performed according to the Kaplan-Meier method. Relative risks were determined by the Log-Rank test and multivariate analysis was performed with the Cox regression model. The limit of significance was 0.05.The mean age at the time of diagnosis was 59.6 years (range: 14.6-90.2). Most tumours were discovered incidentally by ultrasound. The mean tumour diameter was 61.7 mm (range: 20-230). The most frequent surgical operation was radical nephrectomy, but there was a tendency towards an increasing number of conservative operations. Histology revealed 94% of renal cell carcinomas, with 73% of conventional cell carcinomas. The mean follow-up was 49 months (range: 0-197) and 5-year and 10-year survival rates were 74.9 months and 62.6 months, respectively. Multivariate statistical analysis confirmed the prognostic significance of N and M stage, Fuhrman grade, histological type, as well as renal capsule invasion.Our data largely confirm those of the last national study conducted in 1997 as well as those of the international literature. Kidney tumours are increasingly discovered incidentally, but tumour size and the age of patients remain stable, while the number of conservative procedures continues to increase each year In addition to the usual prognostic factors, we found that renal capsule invasion was an independent prognostic factor.