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Objectif : évaluer de façon rétrospective la pertinence du schéma décisionnel proposé par le centre de lutte contre le cancer (CLCC) de Lyon pour la prise en charge des hyperplasies canalaires atypiques (HCA) sur une série de patientes de l’Institut Curie (IC), et définir un sous-groupe de patientes à l’égard duquel l’abstention chirurgicale serait concevable. Matériel et méthodes : nous avons recensé toutes les patientes avec un diagnostic d’HCA sur une macrobiopsie stéréotaxique de microcalcifications de février 2011 à décembre 2015 à l’IC, et confronté les résultats histologiques de la biopsie et de la pièce d'exérèse. L’arbre décisionnel permettant de classer les patientes dans une catégorie « abstention » ou « chirurgie » était fondé sur trois critères : taille des microcalcifications, nombre de foci d’HCA sur la macrobiopsie et qualité de l’exérèse macrobiopsique. Résultats : l’analyse a porté sur 98 cas. Il y avait 44 % de cancer manqués dans la catégorie "chirurgie". Ce taux était de 5% dans la catégorie « abstention », ce qui ne différait pas significativement du taux de sous-estimation de 2% de l'étude de Lyon (p>0,64). Deux facteurs étaient significativement associés à la malignité : la taille du foyer de microcalcifications et le nombre de foci d’HCA. Conclusion : les résultats de notre étude sont similaires à l’étude de Lyon, insuffisants cependant pour appliquer son arbre décisionnel de prise en charge. En attendant les résultats d’une étude prospective en cours, l’attitude chirurgicale reste préconisée, associée à une surveillance clinique et mammographique annuelle en raison du risque majoré de cancer du sein chez ces patientes.

International audience; OBJECTIVE: Vulvar intraepithelial neoplasia (VIN) and vulvar Paget disease are managed with either vulvectomy, destructive treatments (laser, antimitotic drugs) or immunostimulants. All these options are associated with functional complications. The purpose of this study was to evaluate the surgical technique consisting of skinning vulvectomy with split-thickness skin graft, and its effect on overall quality of life and sexual function. METHODS: A retrospective study was conducted on thirteen patients who underwent skinning vulvectomy with split-thickness skin graft between 1999 and 2009. Overall quality of life and sexual function were assessed with the Medical Outcome Study Short Form 36 (MOS SF-36) and Female Sexual Function Index (FSFI), respectively. RESULTS: The median age of patients was 54 (range: 33-77) years. Three patients had Paget disease and 10 patients had VIN lesions. The excision margins were clear in 46% of cases. The incidence of occult cancer was 31%. The mean follow-up period was 77 (±35) months. Four patients experienced a relapse of their intraepithelial disease. The mean disease-free survival was 58 (±44) months. There was no significant difference in MOS SF-36 scores between the study population and the general population. The patients assessed with the FSFI regained normal sexual function after the surgical procedure. CONCLUSION: Skinning vulvectomy with split-thickness skin graft is a feasible technique yielding good results in terms of quality of life and sexual function. It enables occult cancer to be diagnosed in patients with VIN or Paget disease.

Objective: Carcinoma in situ (OS) is associated with increased risk of progression when found with high-grade non-muscle-invasive bladder cancer, yet its impact is less clear in the upper urinary tract. In the current study, we evaluated the impact of concomitant CIS on recurrence-free survival and cancer-specific survival following radical nephroureterectomy for upper tract urothelial carcinoma (UTUC). Materials and methods: A multi-institutional retrospective cohort of 1,387 patients undergoing radical nephroureterectomy was identified. Concomitant CIS was defined as the presence of CIS in association with another pathologic stage; patients with CIS alone were excluded from the analysis. The presence of concomitant CIS served as the exposure variable with disease recurrence and cancer-specific mortality as the outcomes. Organ-confined disease was defined as AJCC/UICC stage II or lower. Results: Concomitant CIS was identified in 371 of 1,387 (26.7%) patients and was significantly more common in patients with a previous bladder cancer history, high grade, and high stage tumors. In a multivariable analysis, concomitant CIS was a predictor of disease recurrence (HR = 1.25, P = 0.04) and cancer specific mortality (HR = 1.34, P = 0.05) for patients with organ-confined UTUC, but not in the entire cohort. Other prognostic variables, such as grade, stage, lymphovascular invasion, and lymph node status, were associated with poorer overall and recurrence-free survival for all patients. Conclusion: The presence of concomitant CIS in patients with organ-confined UTUC is associated with a higher risk of recurrent disease and cancer-specific mortality. This information may be useful in refining surveillance protocols and in more appropriate selection of patients for adjuvant chemotherapy. (C) 2012 Elsevier Inc. All rights reserved.

International audience; OBJECTIVES: To study the prognostic impact of muscularis mucosae (MM) invasion for pT1 bladder cancer treated by transurethral resection (TUR) and adjuvant Bacille Calmette-Guerin (BCG) intravesical immunotherapy. METHODS: Sixty-six patients treated by BCG intravesical instillations were substaged into pT1a and pT1b, regarding Muscularis Mucosae invasion. Tumor grade, associated carcinoma in situ (CIS), multifocality, tumoral size up to 3cm, BCG maintenance were noted. With a mean follow-up of 50.5±38 months, we studied recurrence, progression, overall and specific survival. Cox's model method was used for multivariate analysis. RESULTS: Tumor recurrence was observed in 30±7% and 43±10% (P=0.29) and tumor progression in 16.3±5% and 39±10% (P=0.04) for pT1a and pT1b. The rate of progression was higher (P=0.04) and progression free survival was decreased (P=0.04) for pT1b. Specific death rates were 11±5% and 21±9% (P=0.28), median overall survival was 80.9 [1.5-92] and 48.2 [12-93] months for pT1a and pT1b. Overall and specific survival weren't different between the two populations (P=0.38; P=0.3). Cystectomy rates were 2.3±2% and 30±9% for pT1a and PT1b (P=0.0006). For pT1a patients, recurrence (P=0.8) or progression rates (P=0.64) were no different regarding BCG maintenance immunotherapy but pT1b population had a better progression free survival with BCG maintenance than without (P=0.0051). Only CIS had prognostic value in multivariate analysis. CONCLUSIONS: Tumors with Muscularis Mucosae invasion have a higher risk of progression and BCG failure. Maintenance immunotherapy should be given to improve results with these patients.

International audience; The glial cell line-derived neurotrophic factor (GDNF) has multiple functions that promote cell survival, proliferation and migration in different cell types. The experimental over-expression of GDNF in mouse testis leads to infertility and promotes seminomatous germ cell tumours in older animals, which suggests that deregulation of the GDNF pathway may be implicated in germ cell carcinogenesis. GDNF activates downstream pathways upon binding to its specific co-receptor GDNF family receptor-a 1 (GFRA1). This complex then interacts with Ret and other co-receptors to activate several intracellular signalling cascades. To explore the involvement of the GDNF pathway in the onset and progression of testicular germ cell tumours, we analysed GFRA1 and Ret expression patterns in seminoma samples. We demonstrated, via immunohistochemistry, that GFRA1, but not Ret, is over-expressed in in situ carcinoma (CIS) and in intratubular and invasive seminoma cells compared with normal human germ cells. Functional analysis of the GDNF biological activity was performed on TCam-2 seminoma cell line. Reverse transcription-PCR (RT-PCR) and immunohistochemical analyses demonstrate that TCam-2 cells express both GFRA1 and Ret mRNA, but only GFRA1 was detected at the protein level. In TCam-2 cells, although GDNF is not mitogenic, it is able to induce migration, as demonstrated by a Boyden chamber assay, possibly through the Src and MEK pathways. Moreover, GDNF promotes invasive behaviour, an effect dependent on pericellular protease activity, possibly through the activity of matrix metalloproteinases. GFRA1 over-expression in CIS and seminoma cells, along with the functional analyses in TCam-2 cells, suggests an involvement of the GDNF pathway in the progression of testicular germ cell cancer.

International audience; The present investigation was conducted first to determine whether correlation exists between VEGF-A and -B mRNA levels and clinicopathological parameters and to assess their prognostic value in bladder cancer, then to clarify the expression level and biological significance of VEGF-A isoforms. Total RNA was isolated from 37 specimens of bladder cancer. Northern blot analysis revealed that VEGF-B mRNA was not expressed either in normal urothelium or in bladder cancer and detected three VEGF-A transcripts of 5.2, 4.5 and 1.7 kb in length, respectively. The VEGF-A transcript levels were greater in cancer tissues than in normal urothelium. They were significantly higher in pT2-T4 than in pTa and pT1 urothelial tumors and thus, were correlated to the pathologic stage. Contrary to the 4.5 kb transcript, elevated expression of the 5.2 and 1.7 kb transcripts was correlated with the histologic grade and the presence of carcinoma in situ. Patients with higher VEGF-A mRNA levels had a significantly shorter survival without progression compared to those with lower levels. Three VEGF-A splice variants were detected by southern blotting namely, VEGF121, 165 and 189. The expression intensity of each isoform was evaluated by quantitative real-time RT-PCR in 20 new fresh frozen recent tumors. VEGF121 and VEGF165 were expressed at the similar level. On the contrary, they were significantly more expressed than VEGF189 (p

International audience

International audience; RATIONALE: The outcome of precancerous bronchial lesions is not well known, and their management is subject to controversy. Many molecular alterations are present in preinvasive lesions, but none has been assessed to predict the evolution of the lesions. OBJECTIVES: To analyze the outcome of high-grade precancerous lesions according to their molecular profile. METHODS: Twenty-three severe dysplasia and 31 carcinoma in situ (CIS) lesions in 37 patients were monitored using repeated autofluorescence bronchoscopy over a 12-year period. Microdissection and polymerase chain reaction analysis were performed on paraffin tissue sections to assess loss of heterozygosity (LOH) and microsatellite instability on chromosome 3p, 5q, and 9p. Histology and molecular status at baseline were compared between 7 lesions that became invasive, 11 that relapsed after treatment, 17 that were eradicated with local treatment, and 19 that spontaneously regressed. MEASUREMENTS AND MAIN RESULTS: Ninety-four percent of lesions that progressed or relapsed were CIS at baseline, whereas 79% of spontaneously regressing lesions were severe dysplasia (P < 0.0001). 3p and 9p LOH was more frequent in CIS than in severe dysplasia (P = 0.03). In the whole group of lesions as well as in the CIS group, 3p LOH was strongly associated with progression (P < 0.0001 and P = 0.02, respectively). Microsatellite instability was not associated with the outcome of the lesions. A therapeutic strategy based on the presence of 3p or 9p LOH would have led to overtreatment of six lesions but would have missed only 1 among the 18 progressing lesions. CONCLUSIONS: Baseline histology and 3p LOH analysis appear to be useful in predicting the outcome of high-grade precancerous lesions.

International audience; OBJECTIVE: To assess the prevalence of and factors associated with squamous intraepithelial lesions and condyloma [human papillomavirus (HPV)-related lesions) in HIV-infected patients. DESIGN: A cross-sectional study in a tertiary-care university hospital conducted in 516 consecutive outpatients. INTERVENTION: A systematic examination for macroscopic HPV-related lesions through anoscopy with histological confirmation, evaluation of dysplasia and HPV typing. Sexual behaviours were assessed using a semi-directive questionnaire. RESULTS: Of 473 patients examined, (200 homosexual men, 123 heterosexual men, 150 women), 108 (23%) had histologically confirmed anal HPV-related lesions (36, 15 and 11% of the respective populations), including 51 (47%) with only endoanal localization. Among these 108 patients, histological dysplasia of grades I or II and grade III were noted in 59 and two patients, respectively, invasive endoanal cancer in one; three patients also had high-risk oncogenicity HPV without dysplasia. Independent identified associated factors of HPV-related condyloma were the number of incidents of sexual intercourse per month [odds ratio (OR) 1.04; 95% confidence interval (CI) 1.01-1.06], CD4 cell count below 200 x 10 cells/l (OR 3.22; 95% CI 1.37-7.60), history of anal HPV lesion (OR 4.57; 95% CI 2.13-9.81), and receptive anal intercourse (OR 2.30; 95% CI 1.11-4.77). The two latter factors remained associated with histological dysplasia (OR 2.82; 95% CI 1.38-5.76 for history of anal condyloma, and OR 4.29; 95% CI 2.18-8.44 for receptive anal intercourse). CONCLUSION: The high rate of condyloma and histological dysplasia seen argues for a systematic screening for these lesions in HIV-infected individuals.

International audience; PURPOSE: To evaluate survival and prognostic factors of 108 patients with clinically or mammographically detected ductal carcinoma in situ (DCIS), treated from 1980 to 1996 by complete local excision followed by external irradiation. PATIENTS AND METHODS: The median age was 51 (range 37-80). All the patients underwent surgery consisting of a wide resection of the mammary gland harbouring the tumour. The surgical specimens were sent to the pathologists to get information on histology and margin clearance; all the slides were reviewed by one of us to assess the tumoral diameter. External beam therapy was delivered within 8 weeks after surgery. The prescribed irradiation dose was 50 Gy in 25 fractions to be given in 5 weeks. The median duration of follow-up was 93 months (range 40-173). RESULTS: There were nine patients with local recurrence (8.3%); three patients had local recurrence of DCIS and six patients developed invasive breast cancer. The treatment of local recurrence consisted of mastectomy with or without axillary dissection (eight cases) and quadrantectomy (one case). The 5-year and 10-year ipsilateral recurrence-free rate was respectively 92 and 89%. The 10-year cause specific survival was 100%. In univariate analysis, size>or=10 mm, age

International audience; The genome of a novel human papillomavirus (HPV) type, HPV74, was cloned from an iatrogenically immunosuppressed woman with persisting low-grade vaginal intraepithelial neoplasia. HPV74 was found to be phylogenetically related to the low-risk HPV types 6, 11, 44, and 55. HPV74 or a variant of this type was found in specimens from three additional immunosuppressed women but not in about 3,000 anogenital specimens from immunocompetent patients.