Multimodal In Vivo Imaging of Tumorigenesis and Response to Chemotherapy in a Transgenic Mouse Model of Mammary Cancer

International audiencePurpose: Transgenic mice expressing the polyoma middle T oncoprotein (PyMT) in the mammary epithelium were explored by multimodal imaging to monitor longitudinally spontaneous tumor growth and response to chemotherapy.Procedures: Positron emission tomography (PET) with 2-deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG) and 3'-deoxy-3'-[ 18 F]fluorothymidine ([ 18 F]FLT), single photon emission tomography (SPECT) with [ 99m Tc]TcO 4 ([ 99m Tc]TEC), X-ray computed tomography, and fluorescent confocal endomicroscopy (FCE) images were acquired during tumor progression in female PyMT mice. Imaging with [ 18 F]FDG and [ 99m Tc]TEC was also performed in untreated, doxorubicin-treated, and docetaxel-treated PyMT mice. Total tumor volumes were quantified. Tumors were collected and macroscopic and histological examinations were performed. Results: All PyMT mice developed multifocal tumors of the mammary epithelium that became palpable at 8 weeks of age (W8). Computed tomography (CT) detected tumors at W14, while a clear tumoral uptake of [ 99m Tc]TEC and [ 18 F]FDG was present as early as W6 and W8, respectively. No contrast between mammary tumors and surrounding tissue was observed at any stage with [ 18 F]FLT. FCE detected an angiogenic switch at W10. Lung metastases were not clearly evidenced by imaging. Doxorubicin and docetaxel treatments delayed tumor growth, as shown by [ 18 F]FDG and [ 99m Tc]TEC, but tumor growth resumed upon treatment discontinuation. Tumor growth fitted an exponential model with time constant rates of 0.315, 0.145, and 0.212 week−1 in untreated, doxorubicin, and docetaxel groups, respectively.Conclusions: Molecular imaging of mammary tumors in PyMT is precocious, precise, and predictive. [18F]FDG-PET and [99mTc]TEC SPECT monitor tumor response to chemotherapy

Comprehensive clinical and molecular analyses of neuroendocrine carcinomas of the breast

Neuroendocrine breast carcinomas represent a rare subtype of breast cancer. Their definition, prevalence, and prognosis remain controversial in the literature. The 2012 WHO classification of breast cancer categorizes neuroendocrine carcinomas into three morphologically distinct subtypes: well-differentiated neuroendocrine tumors, poorly differentiated neuroendocrine carcinomas, and invasive breast carcinomas with neuroendocrine differentiation. We aimed to gain insight into the clinical, morphologic, phenotypic, and molecular features of 47 neuroendocrine breast carcinomas. Targeted next-generation sequencing by an AmpliSeq 22 cancer gene hotspot panel and the Prosigna assay were performed on 42/47 and 35/47 cases, respectively. Average age at diagnosis was 69 years. All tumors were estrogen receptor-positive and the large majority expressed progesterone receptor (89%), GATA3 (98%), FOXA1 (96%), and CK8/18 (98%). There was an almost equal distribution of luminal A (52%) and B (48%) carcinomas. Almost half of the cohort (49%) displayed a high risk of recurrence score with the Prosigna test. Patients with a neuroendocrine carcinoma had a shorter disease-free survival compared with those affected by carcinomas of no special type matched for age, size, grade, and estrogen receptor status. No significant differences were observed in terms of overall survival. Stratification of neuroendocrine carcinomas using the 2012 WHO criteria did not reveal statistically significant differences among the distinct categories (well-differentiated neuroendocrine tumors, poorly differentiated neuroendocrine carcinomas, and invasive breast carcinomas with neuroendocrine differentiation), in terms of either progression-free or overall survival. Our targeted sequencing analysis found three cases (7%) harboring a PIK3CA mutation, and in three other cases (7%) TP53 mutations were detected. This study showed that neuroendocrine breast carcinoma is a distinct subtype of luminal carcinoma with a low rate of PIK3CA mutations and with an aggressive clinical behavior. An accurate identification of neuroendocrine differentiation may be useful to better tailor patient adjuvant therapy within luminal carcinomas.Modern Pathology advance online publication, 8 September 2017; doi:10.1038/modpathol.2017.107

Substances prioritaires DCE : Etude de détermination de facteurs de bioaccumulation (BAF) sur les mollusques en milieu marin

Pour permettre d’évaluer la qualité chimique des masses d’eau en utilisant les résultats de la surveillance opérée sur les bivalves via le ROCCH ou le RINBIO, il est nécessaire de transposer les seuils existants applicables dans les eaux marines en seuils « mollusques » et ainsi d’adapter les NQE eau marine (Normes de Qualité Environnementale) en VGE mollusques (Valeur Guide Environnementale). Cette adaptation nécessite d’utiliser des facteurs de conversion eau-biote : les facteurs de bioconcentration (BCF) ou les facteurs de bioaccumulation (BAF) spécifiques de couples substance-espèce. Les BAF sont les facteurs à privilégier autant que possible car plus représentatifs de ce qui se passe dans le milieu avec notamment la prise en compte des différentes voies d’exposition des organismes aquatiques aux contaminants, i.e. la voie directe (eau) et la voie trophique (ingestion de proies contaminées). Cette démarche de détermination de VGE mollusques est engagée par Ifremer - OFB depuis 2015, et plusieurs étapes ont été réalisées : proposition de VGE mollusques (1) sur la base de données existantes, élaboration d’une méthodologie de détermination de BAF pour les mollusques en milieu marin afin d’acquérir des données BAF terrain. Cette étude de détermination des BAF sur les mollusques en milieu marin a été conduite entre 2016 et 2019, elle concerne 27 substances prioritaires : 3 composés métalliques et 24 substances organiques. Sept sites ont été échantillonnés en parallèle sur les matrices eau marine et mollusques. Suivant les points, les mollusques échantillonnés étaient des moules sauvages (ou d’élevage) et / ou des moules encagés, et deux sites disposaient en plus d’huîtres encagées. Les concentrations dans l’eau marine ont été mesurées sur eau brute et / ou eau filtrée. En dépit des nombreuses difficultés logistiques rencontrées, cette étude souligne d’un point de vue technique, l’intérêt de la SBSE (Stir Bar Sorptive Extraction), pour la recherche de certaines substances organiques dans l’eau marine, la pertinence de rechercher ces substances sur eau brute mais également sur eau filtrée. Cette étude permet de disposer de résultats acquis en parallèle à la fois sur moules encagées, sur moules sauvages ou d’élevage et de mesurer des BAF pour 10 substances : Cd, Ni, Pb, anthracène, PBDE, DDT total, HCH, naphtalène, octylphénol, TBT, permettant d’affiner les VGE mollusques