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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

XLSX file - 172K, List of genes that have been reported previously to be involved in translocations.

PDF file - 135K, Supplementary Figure 1. Flow chart for patient selection and different tested performed.

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.

Purpose: Translocation renal cell carcinoma (tRCC) is a rare subtype of kidney cancer involving the TFEB/TFE3 genes. We aimed to investigate the genomic and epigenetic features of this entity.Experimental Design: Cytogenomic analysis was conducted with 250K single-nucleotide polymorphism microarrays on 16 tumor specimens and four cell lines. LINE-1 methylation, a surrogate marker of DNA methylation, was conducted on 27 cases using pyrosequencing.Results: tRCC showed cytogenomic heterogeneity, with 31.2% and 18.7% of cases presenting similarities with clear-cell and papillary RCC profiles, respectively. The most common alteration was a 17q gain in seven tumors (44%), followed by a 9p loss in six cases (37%). Less frequent were losses of 3p and 17p in five cases (31%) each. Patients with 17q gain were older (P = 0.0006), displayed more genetic alterations (P < 0.003), and had a worse outcome (P = 0.002) than patients without it. Analysis comparing gene-expression profiling of a subset of tumors bearing 17q gain and those without suggest large-scale dosage effects and TP53 haploinsufficiency without any somatic TP53 mutation identified. Cell line–based cytogenetic studies revealed that 17q gain can be related to isochromosome 17 and/or to multiple translocations occurring around 17q breakpoints. Finally, LINE-1 methylation was lower in tRCC tumors from adults compared with tumors from young patients (71.1% vs. 76.7%; P = 0.02).Conclusions: Our results reveal genomic heterogeneity of tRCC with similarities to other renal tumor subtypes and raise important questions about the role of TFEB/TFE3 translocations and other chromosomal imbalances in tRCC biology. Clin Cancer Res; 19(17); 4673–84. ©2013 AACR.

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

PDF file - 62K

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.

XLSX file - 39K, List of somatic mutations discovered in exome sequencing in MITF/TFE TRCC cases.

PDF file - 498K, Coordinate of the exonic breakpoint of the novel KHSRP/TFE3 translocation.

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.

Purpose:MITF/TFE translocation renal cell carcinoma (TRCC) is a rare subtype of kidney cancer. Its incidence and the genome-wide characterization of its genetic origin have not been fully elucidated.Experimental Design: We performed RNA and exome sequencing on an exploratory set of TRCC (n = 7), and validated our findings using The Cancer Genome Atlas (TCGA) clear-cell RCC (ccRCC) dataset (n = 460).Results: Using the TCGA dataset, we identified seven TRCC (1.5%) cases and determined their genomic profile. We discovered three novel partners of MITF/TFE (LUC7L3, KHSRP, and KHDRBS2) that are involved in RNA splicing. TRCC displayed a unique gene expression signature as compared with other RCC types, and showed activation of MITF, the transforming growth factor β1 and the PI3K complex targets. Genes differentially spliced between TRCC and other RCC types were enriched for MITF and ID2 targets. Exome sequencing of TRCC revealed a distinct mutational spectrum as compared with ccRCC, with frequent mutations in chromatin-remodeling genes (six of eight cases, three of which were from the TCGA). In two cases, we identified mutations in INO80D, an ATP-dependent chromatin-remodeling gene, previously shown to control the amplitude of the S phase. Knockdown of INO80D decreased cell proliferation in a novel cell line bearing LUC7L3–TFE3 translocation.Conclusions: This genome-wide study defines the incidence of TRCC within a ccRCC-directed project and expands the genomic spectrum of TRCC by identifying novel MITF/TFE partners involved in RNA splicing and frequent mutations in chromatin-remodeling genes. Clin Cancer Res; 20(15); 4129–40. ©2014 AACR.

XLSX file - 12K, List of fusion transcripts identified in our dataset with validation accuracy.

PDF file - 130K, Supplementary Figure 3. A) Gene Set enrichment Analysis (GSEA) showing enrichment of mitosis pathways in cases with 17q gain. B, Ingenuity Pathway Analysis of genes expressed differently between samples with partial 17q gain and without it showing activation of ICOS-ICOSL signaling in T helper cells and activation of the CTLA4 signaling pathway.

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

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

XLSX file - 185K, List of fusion transcripts identified in TCGA cohort, including the number of reads identified spanning the fusion junction.

PDF file - 86K, Supplementary Table 1. Clinicopathologic characteristics of patients with confirmed Translocation RCC Supplementary Table 2: Clinicopathological features of TFE3 overexpressing renal cell carcinoma with no TFE3 translocation identified. Supplementary Table 3: List of upstream regulators predicted to be activated or inhibited in two cases of translocation renal cell carcinoma with concomitant 17q gain and 17p loss as compared to two cases with balanced karyotype.

XLSX file - 20K, Clinicopathological features of MITF/TFE TRCC samples selected in our cohort for RNA and exome sequencing.

XLSX file - 10K, List of all ccRCC included from the TCGA with the identified translocations in each sample.

PDF file - 79K, Material and Methods describing the TCGA dataset with the RNAseq and exome-sequencing analysis.

PDF file - 166K, Supplementary Figure 2. A, virtual karyotyping of the UOK109 cell line shows the following copy number alterations: +2, +5q,+7,-8p,+8q,-9p,+16, which are consistent with pRCC karyotyping. B, virtual karyotyping of the UOK146 cell line shows 3p loss, 9 p loss, 17 p loss and 17 gain. C, conventional karyotyping of the UOK146 cell line shows the following alterations: M1 = del(1p), M2 = del(3p), M3 = del(6q), M4 = i(17q), and M5 = t(X;1)(p11.2;q21.2). D, FISH result for TFE3 split in the novel MDA-92 cell line.

Resume Introduction L’epidemiologie du cancer de prostate (CaP) en Guyane francaise (GF) n’est pas bien documentee. Elle differe de celle relevee aux Antilles en raison d’une population plus jeune, moins exposee aux pesticides agricoles mais ayant une plus grande difficulte d’acces aux soins et a l’information medicale. Materiel Les taux d’incidence et de mortalite disponibles dans le registre des cancers du departement sont etudies et rapportes pour la periode 2010–2014. Les caracteristiques des 242 series de biopsies prostatiques realisees entre janvier 2017 et octobre 2019 a Kourou pour suspicion clinique et/ou biologique (PSA > 4 ng/mL) de CaP sont decrites. Resultats L’incidence du CaP en GF est de 94,4°/°°°° et la mortalite specifique de 16,9°/°°°°. Parmi les biopsies, 77,7 % (188/242) sont positives avec un PSA moyen de 72,6 ng/mL (1–4000) a un âge moyen de 66 ans (50–89), 34 % (64/188) avec un TR anormal, 12,3 % (23/188) avec un PSA > 50 ng/mL et 28,2 % (53/188) avec un score de Gleason ≥ 8. Conclusion Malgre une population jeune, une exposition moins forte qu’aux Antilles aux facteurs de risque environnementaux et un taux de metissage important, le diagnostic precoce du CaP en GF est encore un defi a relever. Les taux d’incidence et de mortalite observes suggerent a la fois une sous declaration des cas et une prise en charge trop tardive ce qui est confirme par les caracteristiques anatomopathologiques defavorables des cancers diagnostiques et par les taux eleves de PSA au moment du diagnostic. Niveau de preuve 3.

Von Hippel-Lindau (VHL) disease is the main cause of inherited clear-cell renal cell carcinoma (ccRCC) and is caused by germline mutations in the VHL tumor suppressor gene. Bi-allelic VHL alterations lead to inactivation of pVHL, which plays a major role by downstream activation of the hypoxia inducible factor (HIF) pathway. Somatic VHL mutations occur in 80% of sporadic ccRCC cases and the second most frequently mutated gene is polybromo 1 (PBRM1). As there is currently no data regarding PBRM1 involvement in VHL disease-associated ccRCC, the aim of the present study was to assess the PBRM1 mutational status, and PBRM1 and HIF expression in VHL disease-associated ccRCC series compared with a sporadic series. PBRM1 gene was screened by Sanger sequencing for 23 VHL-disease-associated ccRCC and 22 sporadic ccRCC cases. Immunohistochemical studies were performed to detect the expression of PBRM1, HIF1 and HIF2 for all cases. In VHL-associated tumors, 13.0% (n=3/23) had PBRM1 somatic mutations and 17.4% (n=4/23) had a loss of PBRM1 nuclear expression. In sporadic cases, 27.3% (n=6/22) showed PBRM1 somatic mutations and 45.5% (n=10/22) had a loss of PBRM1 nuclear expression. Loss of PBRM1 was associated with an advanced tumor stage. HIF1-positive tumors were observed more frequently in the VHL-associated ccRCC than in the sporadic series. Furthermore, in the VHL cohort, PBRM1 expression appeared to be associated more with HIF1 than with HIF2. Given that hereditary tumors tend to be less aggressive, these results would suggest that co-expression of PBRM1 and HIF1 may have a less oncogenic role in VHL-associated ccRCC.

Transcription factor E3-rearranged renal cell carcinoma (TFE3-RCC) has heterogenous morphologic and immunohistochemical (IHC) features.131 pathologists with genitourinary expertise were invited in an online survey containing 23 questions assessing their experience on TFE3-RCC diagnostic work-up.Fifty (38%) participants completed the survey. 46 of 50 participants reported multiple patterns, most commonly papillary pattern (almost always 9/46, 19.5%; frequently 29/46, 63%). Large epithelioid cells with abundant cytoplasm were the most encountered cytologic feature, with either clear (almost always 10/50, 20%; frequently 34/50, 68%) or eosinophilic (almost always 4/49, 8%; frequently 28/49, 57%) cytology. Strong (3+) or diffuse (>75% of tumour cells) nuclear TFE3 IHC expression was considered diagnostic by 13/46 (28%) and 12/47 (26%) participants, respectively. Main TFE3 IHC issues were the low specificity (16/42, 38%), unreliable staining performance (15/42, 36%) and background staining (12/42, 29%). Most preferred IHC assays other than TFE3, cathepsin K and pancytokeratin were melan A (44/50, 88%), HMB45 (43/50, 86%), carbonic anhydrase IX (41/50, 82%) and CK7 (32/50, 64%). Cut-off for positive TFE3 fluorescent in situ hybridisation (FISH) was preferably 10% (9/50, 18%), although significant variation in cut-off values was present. 23/48 (48%) participants required TFE3 FISH testing to confirm TFE3-RCC regardless of the histomorphologic and IHC assessment. 28/50 (56%) participants would request additional molecular studies other than FISH assay in selected cases, whereas 3/50 participants use additional molecular cases in all cases when TFE3-RCC is in the differential.Optimal diagnostic approach on TFE3-RCC is impacted by IHC and/or FISH assay preferences as well as their conflicting interpretation methods.

Failure rates after first-line treatment of localized prostate cancer (PCa) treatment remain high. Improvements to patient selection and identification of at-risk patients are central to reducing mortality. We aimed to determine if cancer aggressiveness correlates with androgen levels in patients undergoing radical prostatectomy for localized PCa. We performed a prospective, multicenter cohort study between June 2013 and June 2016, involving men with localized PCa scheduled to undergo radical prostatectomy. Clinical and hormonal patient data (testosterone deficiency, defined by total testosterone (TT) levels

Resume Introduction L’influence de l’allongement du delai entre les biopsies de prostate et le traitement par prostatectomie radicale pour les patients presentant un cancer de prostate localise est controverse. L’objectif de cette etude etait d’etablir un delai limite entre biopsies de prostate et prostatectomie radicale au-dela duquel les risques d’upgradging et de recidive biochimique seraient majores. Materiel et methode Entre janvier 2013 et janvier 2017, une analyse retrospective des donnees cliniques, biologiques et histologiques de 513 patients ayant eu une prostatectomie radicale pour cancer de prostate localise a ete effectuee dans un centre unique. Le critere de jugement principal etait l’evaluation du risque de recidive biochimique par la difference entre les scores post-biopsies USCF-CAPRA et post-chirurgical CAPRA-S. Le critere de jugement secondaire etait l’evaluation de l’upgrading par la difference entre le score de Gleason sur biopsies et sur piece operatoire. Les risques de recidive biochimique et d’upgrading ont ete compares par test de Student en fonction de differents delais entre biopsies prostatiques et prostatectomie radicale. Les delais les plus courts pour lesquels une difference significative etait retrouvee ont ete rapportes. Resultats Dans cette etude, 513 patients ont ete inclus. L’âge median au moment de la biopsie etait de 65 ans (IQR : 60–69). Le PSA median pre-operatoire etait de 7,30 ng/mL (IQR : 5,60–9,94). Le delai median entre les biopsies et la chirurgie etait de 108 jours (IQR : 86–141). Pour la cohorte entiere, le risque de recidive biochimique apres prostatectomie radicale etait significativement plus eleve au-dela d’un seuil de 90 jours (p = 0,039). Aucun seuil n’a ete retrouve pour les patients Gleason 6(3 + 3). Un seuil de 90 jours a ete retrouve pour les patients Gleason 7(3 + 4) (p = 0,038). Les patients Gleason ≥ 8 presentait plus d’upgrading au-dela d’un seuil de 60 jours (p = 0,040). Conclusion Notre etude a montre qu’au-dela d’un delai de 3 mois, le risque de recidive biochimique apres prostatectomie radicale etait significativement plus eleve pour les cancers de prostate localises. Ce delai semblait pouvoir etre allonge chez les patients a faible risque, alors qu’il paraissait devoir etre conserve pour les risques intermediaires, et reduit a 2 mois pour les risques eleves. Niveau de preuve 4.

International audience; Curcumin is a natural polyphenolic compound known for its numerous pharmacological properties. However, its low water solubility and instability at neutral pH are serious drawbacks preventing its use as an oral drug. Well‐defined amphiphilic poly(ethylene glycol)‐block‐poly(ethoxyethyl glycidyl ether) (PEG‐b‐PEEGE) block copolymers carrying acid‐labile acetal groups are synthesized by anionic ring‐opening polymerization and investigated as potential pH‐sensitive nano‐carriers for delivery of curcumin to cancer cells. The nanoparticles, resulting from copolymer self‐assembly in aqueous media, are characterized by dynamic light scattering and cryo‐transmission electron microscopy. The nanoparticles’ stabilities are evaluated in three different phosphate buffers (pH = 7.2, 6.4, and 5.3). The stability decreases at lower pH and a complete disappearance of the nanoparticles is noticed after 4 days at pH 5.3. Curcumin is encapsulated in hydrophobic core of mPEG40‐b‐PEEGE25 nanoparticles allowing significant enhancements of curcumin solubility in water and lifetime at neutral pH. In vitro curcumin release is studied at different pH by UV‐spectroscopy and high‐performance liquid chromatography (HPLC). The cytotoxicity of curcumin and curcumin encapsulated in micelles is evaluated by cell viability 3‐(4,5‐Dimethyl‐2‐thiazolyl)‐2,5‐diphenyl‐2H‐tetrazolium bromide (MTT) assay on MDA‐MB‐231 human breast cancer cells

An association between HIV infection and cervical cancer, a major public health issue worldwide, has been reported. The aim of this study was to estimate the prevalence of human papillomavirus (HPV) infection and the distribution of HPV genotypes in HIV-infected women living in French Antilles and Guiana and to determine HIV-related characteristics associated with HPV infection. This cross-sectional study included 439 HIV-infected women who were followed between January 2011 and May 2014. Variables related to HIV infections were collected, and cervical samples were analysed to determine HPV genotypes. The median age of the population was 46 years. Estimated prevalence of HPV and high-risk (HR)-HPV infection were 50.1% IC95 [45.4-54.7] and 42% IC95 [37.3-46.6], respectively. HR-HPV 16, 52, 53 or intermediate risk-HPV-68 were found in 25% to 30% of the HPV-infected patients. Gynaecological screening revealed abnormal cervical smear in 24% and 42% of HR-HPV-negative and HPV-positive women, respectively (p = 0.003). Approximately 90% of women were on antiretroviral therapy (ART). Demographic characteristics associated with a higher prevalence of HPV infection included alcohol consumption. Regarding HIV-related characteristics, current therapy on ART, its duration, and undetectable plasma concentrations of RNA-HIV1 were associated with a lower risk of HPV infection. Infection rate with HR-HPV was higher than what is commonly reported in HIV-negative women worldwide and was more likely in women with incomplete HIV suppression. These results highlight the need for supporting adherence to ART, cervical cytology, HPV testing and HPV vaccination.

Von Hippel-Lindau (VHL) disease is a rare auto-somal dominant syndrome that is the main cause of inherited clear-cell renal cell carcinoma (ccRCC), which generally occurs in the form of multiple recurrent synchronized tumors. Affected patients are carriers of a germline mutation in the VHL tumor suppressor gene. Somatic mutations of this gene are also found in sporadic ccRCC and numerous pan-genomic studies have reported a dysregulation of microRNA (miRNA) expression in these sporadic tumors. In order to investigate the molecular mechanisms underlying the pathogenesis of VHL-associated ccRCC, particularly in the context of multiple tumors, the present study characterized the mRNA and miRNA transcriptome through an integrative analysis compared with sporadic renal tumors. In the present study, two series of ccRCC samples were used. The first set consisted of several samples from different tumors occurring in the same patient, for two independent patients affected with VHL disease. The second set consisted of 12 VHL-associated tumors and 22 sporadic ccRCC tumors compared with a pool of normal renal tissue. For each sample series, an expression analysis of miRNAs and mRNAs was conducted using microarrays. The results indicated that multiple tumors within the kidney of a patient with VHL disease featured a similar pattern of miRNA and gene expression. In addition, the expression levels of miRNA were able to distinguish VHL-associated tumors from sporadic ccRCC, and it was identified that 103 miRNAs and 2,474 genes were differentially expressed in the ccRCC series compared with in normal renal tissue. The majority of dysregulated genes were implicated in 'immunity' and 'metabolism' pathways. Taken together, these results allow a better understanding of the occurrence of ccRCC in patients with VHL disease, by providing insights into dysregulated miRNA and mRNA. In the set of patients with VHL disease, there were few differences in miRNA and mRNA expression, thus indicating a similar molecular evolution of these synchronous tumors and suggesting that the same molecular mechanisms underlie the pathogenesis of these hereditary tumors.

Objectifs Les patients originaires d’Afrique subsaharienne ont une incidence et une mortalite par cancer de prostate plus eleve que les hommes caucasiens. L’objectif de cette etude etait d’evaluer les resultats anatomopathologiques d’une cohorte afro-antillaise diagnostiquee d’un cancer de prostate sur biopsies de prostate, et de les comparer a une cohorte de France metropolitaine a majorite caucasienne. Methodes Une etude retrospective comparative bicentrique a ete realisee entre un centre Martiniquais et un centre Parisien entre 2008 et 2016. Les donnees cliniques, biologiques et pathologiques etaient recueillies au diagnostic. Les biopsies etaient realisees selon le schema standard de 12 prelevements systematises. Le critere de jugement principal etait la classification de la societe internationale de pathologie urologique (ISUP) pour le score de Gleason. Le critere de jugement secondaire etait le taux de detection du cancer de prostate par les biopsies. Toutes les biopsies ont ete relues par le meme anatomopathologiste. Une analyse multivariee a ete realisee par regression lineaire. Resultats Sur les 1880 patients ayant beneficie de biopsies de prostate dans la cohorte afro-caribeenne, 945 ont eu un diagnostic de cancer de la prostate (50,3 %), et 500 patients sur 945 dans la cohorte metropolitaine (33,8 %). Les patients afro-antillais etaient plus âges (moyenne : 68,5 ans vs 67,5 ans, p = 0,028), avaient un stade clinique plus eleve (13,2 % vs 5,2 % cT3-4, p Tableau 1 , Tableau 2 et Fig. 1 ). Conclusion Les patients afro-antillais ne presentaient pas de resultats anatomopathologiques plus defavorable au diagnostic que les patients metropolitains, apres analyse multivariee. Les patients afro-antillais atteints de cancer de prostate pourraient s’attendre au meme pronostic que les patients caucasiens, au meme stade de la maladie, dans des centres presentant des conditions equivalentes d’acces aux soins.

Resume Objectifs La prise en charge des pieces de prostatectomie totale et leur analyse histopathologique sont essentielles pour confirmer le diagnostic et evaluer l’histo-pronostic des cancers de la prostate. Materiel et methodes Une revue de la litterature a ete effectuee a partir de la base de donnees PubMed, en privilegiant les articles recents (5 ou 10 dernieres annees), a partir des mots cles suivants : prostate cancer ; prostatectomy ; specimen ; handling ; pathology ; tumor staging ; Gleason score ; surgical margin ; prognosis ; frozen section ; lymph node ; biomarkers. Une attention particuliere a ete portee sur la prise en charge des prelevements et la caracterisation des criteres histo-pronostiques. Resultats La prise en charge des pieces de prostatectomie totale et des produits de curage ganglionnaire est actuellement standardisee selon des criteres internationaux. L’evaluation des facteurs histo-pronostiques principaux, que sont le score de Gleason, le stade pathologique et le statut des limites d’exerese, a beaucoup evoluee ces dernieres annees permettant une prediction accrue du risque de recidive apres traitement chirurgical. Conclusion La standardisation de la prise en charge et du compte rendu anatomopathologique de la prostatectomie totale represente un prealable a l’uniformisation des approches therapeutiques. Cette standardisation a un role crucial dans la stratification des malades atteints d’un cancer de la prostate et la personnalisation du traitement.

Purpose: MITF/TFE translocation renal cell carcinoma (TRCC) is a rare subtype of kidney cancer. Its incidence and the genome-wide characterization of its genetic origin have not been fully elucidated. Experimental Design: We performed RNA and exome sequencing on an exploratory set of TRCC (n = 7), and validated our findings using The Cancer Genome Atlas (TCGA) clear-cell RCC (ccRCC) dataset (n = 460). Results: Using the TCGA dataset, we identified seven TRCC (1.5%) cases and determined their genomic profile. We discovered three novel partners of MITF/TFE (LUC7L3, KHSRP, and KHDRBS2) that are involved in RNA splicing. TRCC displayed a unique gene expression signature as compared with other RCC types, and showed activation of MITF, the transforming growth factor β1 and the PI3K complex targets. Genes differentially spliced between TRCC and other RCC types were enriched for MITF and ID2 targets. Exome sequencing of TRCC revealed a distinct mutational spectrum as compared with ccRCC, with frequent mutations in chromatin-remodeling genes (six of eight cases, three of which were from the TCGA). In two cases, we identified mutations in INO80D, an ATP-dependent chromatin-remodeling gene, previously shown to control the amplitude of the S phase. Knockdown of INO80D decreased cell proliferation in a novel cell line bearing LUC7L3–TFE3 translocation. Conclusions: This genome-wide study defines the incidence of TRCC within a ccRCC-directed project and expands the genomic spectrum of TRCC by identifying novel MITF/TFE partners involved in RNA splicing and frequent mutations in chromatin-remodeling genes. Clin Cancer Res; 20(15); 4129–40. ©2014 AACR.

Purpose: Papillary renal cell carcinomas (pRCC) are the most common nonclear cell RCC subtype. Germline mutations of the MET oncogene at 7q31 have been detected in patients with hereditary type I pRCC and in 13% of sporadic type I pRCC. Recent report of MET inhibition strengthened the role of c-Met inhibition across pRCC. Experimental Design: We collected 220 frozen samples of sporadic pRCC through the French RCC Network and quality controlled for percentage of malignant cells >70%. Gene expression was assessed on 98 pRCC using human whole-genome Agilent 8 × 60K arrays. Copy number alterations were analyzed using Agilent Human 2 × 400K and 4× 180K array for type II pRCC and comparative genomic microarray analysis method for type I pRCC. MET gene sequencing was performed on type I pRCC. Results: MET expression level was high across all pRCC. We identified copy number alterations (gain) in 46% of type II pRCC and in 81% of type I pRCC. Correlation between DNA copy number alterations and mRNA expression level was highly significant. Eleven somatic mutations of MET gene were identified amongst 51 type I pRCC (21.6%), including 4 new mutations. We validated LRRK2 cokinase as highly correlated to MET expression. Conclusion: The present report expands the role of MET activation as a potential target across all pRCC subtypes. These data support investigating MET inhibitors in pRCC in correlation with MET activation status. Clin Cancer Res; 20(13); 3411–21. ©2014 AACR.

Objectifs Le cancer testiculaire est la premiere cause de cancer chez l’homme âge de 20 a 34 ans. Les tumeurs germinales non seminomateuses metastatiques sont traites par un curage lombo-aortique lorsqu’il persiste des masses residuelles apres chimiotherapie. L’abord cœlioscopique s’associe a une reduction des complications per- et perioperatoire. L’objectif de notre etude est d’etudier la faisabilite et les resultats oncologiques du curage lombo-aortique par voie cœlioscopique. Methodes Il s’agit d’une etude retrospective mono-operateur de novembre 2000 a novembre 2017 portant sur une serie de 107 patients. Les voies d’abords etaient cœlioscopiques transperitoneales et retroperitoneales. Les curages etaient unilateraux ou bilateraux. Les tumeurs germinales seminomateuses ont ete exclues de l’etude. L’ensemble des images radiologiques ont ete relues. Parmi les patients, 73,5 % presentaient une tumeur germinale mixte. Les stades 2a, 2b, 2c representaient respectivement 21,5 %, 28 %, 11,2 % des patients. Les stades 3 representaient 24,3 % des patients. Les patients de pronostics bon, intermediaire, mauvais representaient respectivement 71,1 %, 15,9 %, 13 %. La taille mediane selon le grand axe de la masse residuelle etait de 30 mm [10–134]. Resultats La duree mediane de suivi etait de 46,9 mois [1 ; 203]. Un abord transperitoneale et retroperitoneale etait realise chez 31,7 % et 66,3 % des patients. Le curage etait unilaterale dans 74,7 % des cas avec une duree operatoire mediane de 186 minutes [90–540] et bilaterale dans 25,2 % et une duree operatoire mediane de 254 minutes [138–489]. Le taux de conversion etait de 6,5 %. Parmi les patients, 17,2 % ont presente des complications postoperatoires precoces. La duree mediane d’hospitalisation etait de 4 jours [1 ; 26]. Des ejaculations antegrades etaient presentes chez 71,1 % des patients. Parmi les patients, 7,7 % ont presente une recidive tumorale, 2,8 % dans le template. L’intervalle de recidive median etait de 9,5 mois [1–20]. Au terme du suivi 94,4 % des patients etaient consideres vivant sans maladie. Conclusion Le curage lombo-aortique par voie cœlioscopique, realise dans un centre expert, est une technique faisable offrant une faible morbidite et de tres bons resultats oncologiques.

Introduction The sub Comittee prostate of the CCAFU established guidelines for diagnostic, treatment, evaluation and standart of care of prostate cancer. Methods Guidelines 2010 were updated based on systematic literature search performed by the sub-Comittee in Medline and PubMed databases to evaluate references, levels of evidence and grade of recommandation. Results Pathological examination of the tissue specimens was defined specifically for Gleason score according to ISP 2005 recommandations. Prostate and pelvis RMN became the reference in terms of radiological exam. Individual and early diagnosis of prostate cancer was defined and role of PSA was precised. Active surveillance became one of the standart of care of low-risk tumors, radical prostatectomy remained one of the options for all risk group tumors, length of hormonotherapy in association with radiotherapy was precised according to the risk group. Side effects of hormonotherapy treament needed specific supervision ; hormonotherapy had no indication in case of non metastatic tumors and intermittent hormonotherapy in metastatic tumors. New hormonal drugs in pre and post chemotherapy and bone target drugs opened new therapeutics pathways. Conclusion From 2010 to 2013, standarts of care of prostate cancer were modified because of results of prospective studies and new therapeutics. They allowed precise treatments for each specific clinical situation. In the future, multidisciplinary treatments for high risk tumors, time of adjuvant treatment and sequencies of new hormonal treatment had to be defined.

What's known on the subject? and What does the study add? Local relapse of renal cell carcinoma following radical nephrectomy is rare, and surgical removal provides the only opportunity for cure. Open surgery has been established as the usual approach for these tumours. It is, however, associated with significant morbidity. Our study describes the largest series of laparoscopic treatment of local relapse of renal cell carcinoma with the longest follow-up. We show that the laparoscopic approach is feasible in expert centres. It provides faster recovery and fewer complications with satisfactory oncological outcomes in selected patients. Objective To assess the feasibility and oncological outcomes of laparoscopic treatment for local relapse of renal cell carcinoma. Patients and Methods Nine patients were treated by a pure laparoscopic approach for local recurrence of a renal tumour between 2005 and 2011 by a single surgeon (HB), following an initial open radical nephrectomy for the primary tumour. Clinical and histopathological data were collected prospectively and analysed retrospectively. Seven patients were treated by a transperitoneal approach and two patients had a retroperitoneal approach. Results Relapse occurred within a mean time of 83 months (7–168) following nephrectomy. Recurrent tumour size varied from 2.5 to 4.5 cm. All surgeries were performed laparoscopically without need for conversion. Mean operative duration was 144 min (40–240), mean estimated blood loss was 430 mL (50–1300) and mean hospital stay was 4.5 days (3–6). Three patients had Clavien grade I intraoperative complications. Late complications were noted in two patients (Clavien I and IIIb). Pathology confirmed clear cell carcinoma in all patients with an absence of sarcomatoid features and negative surgical margins. Three patients had neoadjuvant treatment and two patients had adjuvant treatment. In all, 67% of patients were disease free with a mean follow-up period of 3 years. Conclusions Surgical removal of isolated local recurrence remains the only possibility of cure in patients with renal cell carcinoma. We demonstrated that the laparoscopic approach is a safe and feasible alternative treatment option for selected cases with low morbidity and satisfactory oncological outcomes.

Background and Purpose— Carotid bulb diaphragm (CBD) has been described in young carotid ischemic stroke (CIS) patients, especially in blacks. However, the prevalence of CBD in CIS patients is unknown, and whether CBD is a risk factor for CIS remains unclear. We assessed the association between CBD and incident CIS in a population-based study. Methods— We selected all young ( Results— CIS associated with ipsilateral CBD incidence was 3.8 per 100 000 person-years (95% confidence interval, 1.4–6.1). Prevalence of ipsilateral CBD was 23% in all CIS and 37% in undetermined CIS patients. When restricted to undetermined CIS, CBD prevalence was 24 times higher than that in controls (adjusted OR, 24.1; 95% confidence interval, 1.8–325.6). Conclusions— CBD is associated with an increased risk of ipsilateral CIS in young Afro-Caribbean population.

Adenosine and inosine are both key intracellular energy substrates for nucleotide synthesis by salvage pathways, especially during ischemic stress conditions. Additionally they both possess cell protective and cell repair properties. The objective of this study is to detect potential advantages of the combination of adenosine and inosine versus each drug alone, in terms of ventricular function, infarct size reduction and angiogenesis. Myocardial ischemia was created in rodents and treated with adenosine, inosine or their combination. Results of experiments showed that the combination of both drugs significantly reduced infarct size and improved myocardial angiogenesis and ventricular function. The two compounds, while chemically similar, use different intracellular pathways, allowing for complementary biological activities without overlapping. The drug combination at specific 1 : 5 adenosine : inosine dose ratio demonstrated positive cardiologic effects, deserving further evaluation as an adjunct to reperfusion techniques during and after acute coronary syndrome. The association of adenosine and inosine may contribute to reduce myocardial infarction morbidity and mortality rates.

Objectifs L’interpretation histologique des pieces de prostatectomie radicale a pour but de confirmer la presence d’un adenocarcinome prostatique, d’en preciser la stadification : pTNM, score de Gleason et etat des marges d’exerese chirurgicale. Ces criteres sont parfois sujets a des interpretation individuelles inter-pathologistes avec des coefficient kappa variant de 0,2 a 0,9. Nous rapportons les resultats de la lecture centralisee des foyers index (plus haut stade et/ou de plus haut grade) des pieces de prostatectomie radicale de l’etude ANDROCAN. Methodes Les pathologistes des centres ayant participe a l’etude ANDROCAN ont transmis pour relecture centralise les lames du foyer index des pieces de prostatectomies radicales (1494 cas sur les 1516 inclus). Les deux pathologistes experts en uropathologie (VM, CR) ont relus de maniere anonymes les lames transmises et ont precise pour chaque cas le score de Gleason, le stade pTNM (2010) et l’etat des marges. En cas de discordance entre les deux relecteurs, une troisieme lecture au microscope a double tete a ete effectuee afin d’obtenir un consensus. Le coefficient de correlation Kappa a ete calcule pour evaluer la reproductibilite interobservateur. Resultats La concordance dans l’interpretation du score de Gleason exact (n = 1211) est de 36,5 % (Kappa = 0,035) avec une sous-evaluation du score dans 24,8 % des cas et une surevaluation du score dans 27,2 % des cas. En regroupant les cas en score de Gleason ≤ 6 ; 3 + 4 ; 4 + 3 et ≥ 8 (n = 1190), la concordance est de 36,8 % (Kappa = 0,025). La concordance pour la predominance de grade 4 et/ou 5 a ete de 57 % (Kappa = –0,003). L’analyse du stade pathologique effectuee dans 1342 cas retrouve une concordance dans 93,5 % des cas (Kappa = 0,86) avec une sous-evaluation du stade dans 2.2 % et une surevaluation du stade dans 4,2 % des cas. L’analyse des marges evaluable pour 1144 cas a montre une concordance dans 96,5 % des cas avec une sous-estimation des marges dans 5,8 % et une sur-estimation dans 16,6 % des cas (Kappa = 0,92) Tableau 1 , Tableau 2 . Conclusion Nos resultats montrent qu’en termes d’analyse interobservateur les pathologistes ayant participe a cette etude ont des coefficient de correlation excellents pour l’evaluation du stade et des marges, superieurs a ceux rapportes dans la litterature (Kappa = 0,58–0,82) mais que l’evaluation du SG et du pourcentage de grade 4/5 reste encore problematique.

Aims To report clinicopathological and genomic characteristics of (ccpRCC), a rare, recently characterized renal tumour entity. Methods and results Twenty-four renal tumours identified as ccpRCC were collected. Data from comparative genomic hybridization on microarrays (array-CGH) were obtained for seven of these. Most tumours (58%) occurred in the absence of renal disease. Mean patient age was 58.1 years. Tumours were small (mean size: 2.4 cm) and classified as pT1. Histological characteristics consisted of tubules and papillae lined by a single layer of small clear cells harbouring low-grade nuclei (Fuhrman grades 1 or 2). Architectural variations, with compact areas (41% of cases) and a micro- or macrocystic pattern (67% of cases) were observed frequently. Immunostaining demonstrated diffuse, strong expression of cytokeratin 7 and vimentin, whereas CD10, racemase, RCC antigen, translocation factor E3, TFE3 and translocation factor EB were consistently negative. In seven tumours, array-CGH detected no chromosomal imbalances. Conclusions Clear-cell papillary renal cell carcinoma (ccpRCC) were differentiated from other renal neoplasms by a specific constellation of histopathological and immunohistochemical features, without characteristic genomic imbalances. Clinical, histopathological and genomic data suggested that these tumours have a low potential for malignancy.

Resume En 2009, le cancer de la prostate a fait l’objet de nombreuses communications dans les congres internationaux d’urologie, d’oncologie et de radiotherapie. L’evenement majeur a ete la presentation des resultats des etudes de depistage de masse europeenne ERSPC et americaine PLCO. Plusieurs communications concernent la prevention, l’histoire naturelle de la maladie et les nouveaux marqueurs tumoraux comme le PCa3 et le gene de fusion TMPRSS2 : ERG. L’hormonotherapie adjuvante a ete evaluee chez les patients a haut risque de recidive. L’association hormonotherapie-radiotherapie permettrait de reduire la recidive biologique, la mortalite specifique et la mortalite globale des patients porteurs d’une tumeur localement avancee. Le THI pourrait etre une option chez les patients metastatiques hormono-sensibles. L’interet du denosumab et du toremifene a ete evalue dans la prevention du risque fracturaire sous hormonotherapie. Le mecanisme de proliferation tumorale en situation d’echappement hormonal a ete precise et 2 nouvelles molecules l’abiraterone et le MDV 3100 apparaissent prometteuses.

Resume Tres peu d’etudes ont ete publiees concernant les resultats de la prostatectomie totale (PT) chez le patient âge. Les rares donnees disponibles suggerent que l’âge avance n’augmente pas le taux de mortalite ou de morbidite postoperatoire, sous reserve d’une selection etroite des patients. De meme, les resultats carcinologiques de la PT sont comparables entre les patients de plus de 70 ans et les patients plus jeunes. Seul le risque d’incontinence semble accru, avec un impact potentiel sur la qualite de vie. Il n’existe pas d’etude comparant les differents traitements curatifs du cancer de la prostate (PT, radiotherapie externe, curietherapie, surveillance active) dans la population âgee. Le benefice en termes de survie ne peut etre precise.

Prostate cancer (PaC) is a significant health problem. Elderly have the highest incidence of the disease as age is its strongest risk factor. Despite its complications, the use of androgen suppression in aging patients with prostate cancer has become extremely frequent with probable excess. However, some of these complications carry specific mortality and all of them have a negative impact on quality of life. It is critical to perform a geriatric assessment, concerning physical, mental and social items, before to consider androgen suppression in this population. Indications of androgen suppression for the treatment of prostate cancer follow the guidelines of CCAFU. Delayed treatment deserves a special attention when possible. Treatment modalities are no specific to the elderly, but complications have to be anticipated with preventive measures. Intermittent androgen suppression should be considered with caution. Close follow up will focus on the diagnosis of adverse effects of androgen suppression.

Resume L’hydatidose est une anthropozoonose largement repandue, touchant le foie, le poumon et d’autres organes. Nous decrivons ici le cas de volumineux kyste hydatique retroperitoneal, localisation particulierement rare, dont le diagnostic a ete pose grâce a des prelevements sanguins et des investigations radiologiques. Une incision de greffe renale etendue en sous-costale droit a ete effectuee. La paroi du kyste a ete partiellement excisee. Le patient a recu en pre-, per-, et postoperatoire de l’albendazole en comprimes a la dose de 15 mg/kg par jour. La dose totale a ete administree pendant trois semaines (une semaine avant et deux semaines apres la chirurgie) avec une surveillance biologique hepatique. Lors du bilan d’une masse retroperitoneale, le diagnostic de kyste hydatique doit etre garde a l’esprit, notamment chez les patients provenant de regions d’endemie. Ces kystes peuvent etre traites efficacement par chirurgie.