Region-Guided CycleGANs for Stain Transfer in Whole Slide Images

International audienceIn whole slide imaging, commonly used staining techniques based on hematoxylin and eosin (H&E) and immunohistochemistry (IHC) stains accentuate different aspects of the tissue landscape. In the case of detecting metastases, IHC provides a distinct readout that is readily interpretable by pathologists. IHC, however, is a more expensive approach and not available at all medical centers. Virtually generating IHC images from H&E using deep neural networks thus becomes an attractive alternative. Deep generative models such as CycleGANs learn a semantically-consistent mapping between two image domains, while emulating the textural properties of each domain. They are therefore a suitable choice for stain transfer applications. However, they remain fully unsupervised, and possess no mechanism for enforcing biological consistency in stain transfer. In this paper, we propose an extension to CycleGANs in the form of a region of interest discriminator. This allows the CycleGAN to learn from unpaired datasets where, in addition, there is a partial annotation of objects for which one wishes to enforce consistency. We present a use case on whole slide images, where an IHC stain provides an experimentally generated signal for metastatic cells. We demonstrate the superiority of our approach over prior art in stain transfer on histopathology tiles over two datasets. Our code and model are available at https://github.com/jcboyd/miccai2022-roigan

Surveillance biologique des expositions professionnelles aux agents chimiques. Recommandation de bonne pratique.

National audienceCes recommandations de bonne pratique sur la surveillance biologique des expositions professionnelles aux agents chimiques ont pour finalité de guider le médecin dans sa décision de mettre en place une telle surveillance, le choix des modalités de son exécution, l'interprétation et la restitution tant individuelles que collectives et les modalités de collecte et de conservation des données en vue de leur exploitation collective à visée de prévention

Recommandations de bonne pratique pour la surveillance biologique de l’exposition professionnelle aux agents chimiques (SBEP) : recommandations de la Société française de médecine du travail, associée à la Société française de toxicologie analytique et à la Société de toxicologie clinique

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Regorafenib: Antitumor Activity upon Mono and Combination Therapy in Preclinical Pediatric Malignancy Models.

The multikinase inhibitor regorafenib (BAY 73-4506) exerts both anti-angiogenic and anti-tumorigenic activity in adult solid malignancies mainly advanced colorectal cancer and gastrointestinal stromal tumors. We intended to explore preclinically the potential of regorafenib against solid pediatric malignancies alone and in combination with anticancer agents to guide the pediatric development plan. In vitro effects on cell proliferation were screened against 33 solid tumor cell lines of the Innovative Therapies for Children with Cancer (ITCC) panel covering five pediatric solid malignancies. Regorafenib inhibited cell proliferation with a mean half maximal growth inhibition of 12.5 μmol/L (range 0.7 μmol/L to 28 μmol/L). In vivo, regorafenib was evaluated alone at 10 or 30 mg/kg/d or in combination with radiation, irinotecan or the mitogen-activated protein kinase kinase (MEK) inhibitor refametinib against various tumor types, including patient-derived brain tumor models with an amplified platelet-derived growth factor receptor A (PDGFRA) gene. Regorafenib alone significantly inhibited tumor growth in all xenografts derived from nervous system and connective tissue tumors. Enhanced effects were observed when regorafenib was combined with irradiation and irinotecan against PDGFRA amplified IGRG93 glioma and IGRM57 medulloblastoma respectively, resulting in 100% tumor regressions. Antitumor activity was associated with decreased tumor vascularization, inhibition of PDGFR signaling, and induction of apoptotic cell death. Our work demonstrates that regorafenib exhibits significant antitumor activity in a wide spectrum of preclinical pediatric models through inhibition of angiogenesis and induction of apoptosis. Furthermore, radio- and chemosensitizing effects were observed with DNA damaging agents in PDGFR amplified tumors

Recommandations de bonne pratique pour la surveillance biologique de l’exposition professionnelle aux agents chimiques (SBEP)

International audienceObjectifLa biométrologie est un outil indispensable à l’évaluation et à la traçabilité individuelle et collective des expositions à des agents chimiques, mais reste sous-utilisée en France. Ces recommandations visent à rappeler le rôle de chacun des acteurs impliqués et à guider le médecin du travail dans sa décision de mettre en place une SBEP, dans la stratégie d’exécution ainsi que dans l’interprétation et la restitution des résultats

Antitumor activity of regorafenib <i>in vivo</i> against various subcutaneous pediatric tumor xenografts.

<p>Animals bearing subcutaneous RMS-1 rhabdomyosarcoma, STA-ET-1 and EW7 Ewing sarcoma, SJ-N-B8 and SK-N-AS neuroblastoma xenografts were treated orally with regorafenib at 10 mg/kg/d (light blue; R-10) and/or 30 mg/kg/d (dark blue, R-30), or with vehicle (grey, C) for a minimum of 21 days; treatment periods are indicated by bars above the graphs. (A) Graphs show arithmetic means ± standard error of mean (SEM) of tumor volumes. (B) Times to reach 5 times the initial volume (V_i) of 3–14 tumors per group is displayed as box plot, + represents means and error bars minimum to maximum values. Statistical significance was estimated by Mann-Whitney or Kruskal-Wallis tests, ****p<0.0001 ***<0.001, **<0.01., *<0.05.</p

Regorafenib activity alone and in combination against patient-derived tumor models is mediated by anti-angiogenic effects and induction of cell death.

<p>Paraffin-embedded sections of IGRG93 (left column), IGRM57 (central column) and NEM14 (right column) tumors, harvested at Day 3 post-treatment initiation, were stained immunohistochemically with anti-CD34 and anti-cleaved caspase 3 antibodies and histologically with Hematoxylin-Eosin-Saffron (HES). (A) Microvessel area and (B) apoptosis index are presented as means ± SEM of 3 controls and regorafenib 30 mg/kg/d treated tumors each (*p<0.05; Mann-Whitney). Due to extensive necrosis only one sample could be evaluated in the combination group of the IGRG93 study. For IGRM57, the assessment of viable tumor by excluding necrotic areas was estimated on HES stained sections. (C) Total lysates from individual tumors were subjected to Western blotting for expression analyses of phosphorylated (p-) and non-phosphorylated PDGFRA, PDGFRB, AKT and ERK1/2. β-actin was used as reference. C: control, R: regorafenib; X: omitted sample due to limited availability of tumor 1; RT: irradiation, Iri: irinotecan.</p

Anti-tumor activity of regorafenib alone and in combination against pediatric xenografts

<p>CR, complete regression; PR, partial regression; TGD, tumor growth delay; TGI, tumor growth inhibition; 5xVi, Time to reach five time initial tumor volume; TD, tumor doubling time; TFS, tumor free survivor at day 120; ns, non-significant; Statistical analysis was performed using the non-parametric Mann-Whitney test for experiments with 2 treatment groups and the Kruskal-Wallis test for those with more than 2 groups</p><p>Anti-tumor activity of regorafenib alone and in combination against pediatric xenografts</p

Inhibition of proliferation of pediatric solid tumor cell lines <i>in vitro</i> by regorafenib.

<p>33 ITCC pediatric rhabdomyosarcoma (A), Ewing sarcoma (B), neuroblastoma (C), medulloblastoma (D) and osteosarcoma (E) cell lines were exposed to regorafenib at the indicated concentrations and cell viability was measured after 72 hours by MTS assay. The adult <i>RET</i> mutated TT thyroid cancer cell line is included as reference. Dose-response to regorafenib of all cell lines is plotted as the percentage of relative cell viability compared to untreated controls.</p