Carcinomes mammaires in situ, série rétrospective du centre des maladies du sein de l hôpital Saint Louis

L étude de la série rétrospective du Centre de maladies du sein de l hôpital Saint Louis s intéresse aux carcinomes mammaires in situ : les carcinomes canalaires in situ (CCIS ; 463 cas) et les carcinomes lobulaires in situ (CLIS ; 44 cas). Pour les CCIS, le suivi médian est de 6,3 ans. 43% des patientes ont été traitées par mastectomie, 44% par tumorectomie avec radiothérapie et 13% par tumorectomie seule (principalement des lésions = 2mm comme associées à un risque plus faible de récidive locale (comparées à des marges <1mm : HR = 0,29 ; IC95% 0,12-0,70 ; p=0,006) ; à l inverse, le traitement conservateur, en comparaison avec la mastectomie, était associé à un risque de récidive locale 2,38 fois plus élevé avec radiothérapie, et 2,46 fois plus élevée sans radiothérapie. La comparaison des groupes traités de manière conservatrice avec et sans radiothérapie ne retrouvait pas de différence sur le risque de récidive locale (HR=0,97 ; IC95% 0,54-1,74 ; p=0,91). Ainsi notre série suggère une possibilité de proposer une tumorectomie seule pour des lésions de bon pronostic. Pour les CLIS le suivi médian était de 4,3 ans. Ils ont tous bénéficié d une exérèse chirurgicale, 34% par mastectomie et 66% par tumorectomie. Le risque de récidive était de 19% avec une répartition équilibré en homo- et contro-latéral (4 récidives de chaque côté). L analyse des CLIS a été limitée du fait du faible effectif de notre série.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocSudocFranceF

Modification of position-effect variegation by competition for binding to Drosophila satellites

white-mottled (w(m4)) position-effect variegation (PEV) arises by translocation of the white gene near the pericentric AT-rich 1.688 g/cm(3) satellite III (SATIII) repeats of the X chromosome of Drosophila. The natural and artificial A•T-hook proteins D1 and MATH20 modify w(m4) PEV in opposite ways. D1 binds SATIII repeats and enhances PEV, presumably via a recruitment of protein partners, whereas MATH20 suppresses it. We show that D1 and MATH20 compete for binding to identical sites of SATIII repeats in vitro and that conditional MATH20 expression results in a displacement of D1 from pericentric heterochromatin in vivo. In the presence of intermediate levels of MATH20, we show that this displacement becomes selective for SATIII repeats. These results strongly suggest that the suppression of w(m4) PEV by MATH20 is due to a displacement of D1 from its preferred binding sites and provide additional support for a direct role of D1 in the assembly of AT-rich heterochromatin

Displacement of D1, HP1 and topoisomerase II from satellite heterochromatin by a specific polyamide

The functions of DNA satellites of centric heterochromatin are difficult to assess with classical molecular biology tools. Using a chemical approach, we demonstrate that synthetic polyamides that specifically target AT-rich satellite repeats of Drosophila melanogaster can be used to study the function of these sequences. The P9 polyamide, which binds the X-chromosome 1.688 g/cm(3) satellite III (SAT III), displaces the D1 protein. This displacement in turn results in a selective loss of HP1 and topoisomerase II from SAT III, while these proteins remain bound to the adjacent rDNA repeats and to other regions not targeted by P9. Conversely, targeting of (AAGAG)(n) satellite V repeats by the P31 polyamide results in the displacement of HP1 from these sequences, indicating that HP1 interactions with chromatin are sensitive to DNA-binding ligands. P9 fed to larvae suppresses the position-effect variegation phenotype of white-mottled adult flies. We propose that this effect is due to displacement of the heterochromatin proteins D1, HP1 and topoisomerase II from SAT III, hence resulting in stochastic chromatin opening and desilencing of the nearby white gene

The AT-Hook Protein D1 Is Essential for Drosophila melanogaster Development and Is Implicated in Position-Effect Variegation

We have analyzed the expression pattern of the D1 gene and the localization of its product, the AT hook-bearing nonhistone chromosomal protein D1, during Drosophila melanogaster development. D1 mRNAs and protein are maternally contributed, and the protein localizes to discrete foci on the chromosomes of early embryos. These foci correspond to 1.672- and 1.688-g/cm(3) AT-rich satellite repeats found in the centromeric heterochromatin of the X and Y chromosomes and on chromosomes 3 and 4. D1 mRNA levels subsequently decrease throughout later development, followed by the accumulation of the D1 protein in adult gonads, where two distributions of D1 can be correlated to different states of gene activity. We show that the EP473 mutation, a P-element insertion upstream of D1 coding sequences, affects the expression of the D1 gene and results in an embryonic homozygous lethal phenotype correlated with the depletion of D1 protein during embryogenesis. Remarkably, decreased levels of D1 mRNA and protein in heterozygous flies lead to the suppression of position-effect variegation (PEV) of the white gene in the white-mottled (w(m4h)) X-chromosome inversion. Our results identify D1 as a DNA-binding protein of known sequence specificity implicated in PEV. D1 is the primary factor that binds the centromeric 1.688-g/cm(3) satellite repeats which are likely involved in white-mottled variegation. We propose that the AT-hook D1 protein nucleates heterochromatin assembly by recruiting specialized transcriptional repressors and/or proteins involved in chromosome condensation

HER2-overexpressing breast cancer : Interim PET after two cycles of chemotherapy predicts the outcome of neoadjuvant treatment

International audienceBackground:Pathologic complete response (pCR) to neoadjuvant treatment (NAT) is associated with improved survival of patients with HER2+ breast cancer. We investigated the ability of interim positron emission tomography (PET) regarding early prediction of pathology outcomes.Methods:During 61 months, consecutive patients with locally advanced or large HER2+ breast cancer patients without distant metastases were included. All patients received NAT with four cycles of epirubicin+cyclophosphamide, followed by four cycles of docetaxel+trastuzumab. 18F-fluorodeoxyglucose (18F-FDG)-PET/computed tomography (CT) was performed at baseline (PET1) and after two cycles of chemotherapy (PET2). Maximum standardised uptake values were measured in the primary tumour as well as in the axillary lymph nodes. The correlation between pathologic response and SUV parameters (SUVmax at PET1, PET2 and ΔSUVmax) was examined with the t-test. The predictive performance regarding the identification of non-responders was evaluated using receiver operating characteristics (ROC) analysis.Results:Thirty women were prospectively included and 60 PET/CT examination performed. At baseline, 22 patients had PET+ axilla and in nine of them 18F-FDG uptake was higher than in the primary tumour. At surgery, 14 patients (47%) showed residual tumour (non-pCR), whereas 16 (53%) reached pCR. Best prediction was obtained when considering the absolute residual SUVmax value at PET2 (AUC=0.91) vs 0.67 for SUVmax at PET1 and 0.86 for ΔSUVmax. The risk of non-pCR was 92.3% in patients with any site of residual uptake >3 at PET2, no matter whether in breast or axilla, vs 11.8% in patients with uptake 3 (P=0.0001). The sensitivity, specificity, PPV, NPV and overall accuracy of this cutoff were, respectively: 85.7%, 93.8%, 92.3%, 88.2% and 90%.Conclusion:The level of residual 18F-FDG uptake after two cycles of chemotherapy predicts residual disease at completion of NAT with chemotherapy+trastuzumab with high accuracy. Because many innovative therapeutic strategies are now available (e.g., addition of a second HER2-directed therapy or an antiangiogenic), early prediction of poor response is critical.British Journal of Cancer advance online publication, 13 August 2013; doi:10.1038/bjc.2013.469 www.bjcancer.com

Vinorelbine thiotepa in metastatic breast cancer: a large real-life retrospective study

Vinorelbine thiotepa in metastatic breast cancer: a large real-life retrospective stud