Study of endocytosis receptor LRP1 in colon adenocarcinomas : associated clinical, pathological and molecular characteristics and prognosis impact

LRP1 (low-density lipoprotein receptor–related protein 1), un récepteur endocytaire multifonctionnel, a récemment été identifié comme pivot d’un réseau de biomarqueurs pour la prédiction pronostique de plusieurs types de cancers. Son rôle dans le cancer du côlon n'a pas été caractérisé. Notre travail porte sur l’étude de la relation entre expression de LRP1 et cancer du côlon.L'expression de l'ARNm LRP1 a été déterminée dans des échantillons d'adénocarcinome et de muqueuses coliques appariées, ainsi que dans les cellules stromales et tumorales obtenues après microdissection laser. Les associations clinicopathologiques et moléculaires ont été étudiées par immunohistochimie dans une série de cancer colique (n = 307). La présence de méthylation ou mutation du gène LRP1 et l'expression de miR-205 ont été évaluées et comparées aux niveaux d'expression de LRP1.L’ARNm de LRP1 est sous exprimé dans les cellules d'adénocarcinome colique par rapport à la muqueuse colique par rapport aux cellules stromales. La faible expression immunohistochimique de LRP1 dans les adénocarcinomes était associée à un âge plus élevé, à localisation droite, une perte d'expression de CDX2, une expression d'Annexine A10, un statut CIMP-H, MSI-H et BRAFV600E muté. Cette faible expression était associée à un mauvais pronostic, en particulier chez les patients de stade IV. Les mutations du gène LRP1 entrainaient une sous-expression de LRP1. L’expression était peu modifiée par miR-205. Le promoteur de LRP1 n'était jamais méthylé.La perte d'expression de LRP1 est associée à un profil clinico-pathologique et moléculaire particulier et à un un mauvais pronostic dans les cancers du côlon.LRP1 (low-density lipoprotein receptor–related protein 1), a multifunctional endocytic receptor, has recently been identified as a hub in a biomarker network for multi-cancer clinical outcome prediction. Its role in côlon cancer has not been characterized. Here, we investigate the relationship between LRP1 and colon cancer.LRP1 mRNA expression was determined in colon adenocarcinoma and paired colon mucosa samples, and in stromal and tumoral cells obtained after laser capture microdissection. The clinical potential was further investigated by immunohistochemistry in a population-based colon cancer series (n = 307). LRP1 methylation, mutation and miR-205 expression were evaluated and compared to LRP1 expression levels.LRP1 mRNA levels are significantly decreased in colon adenocarcinoma cells compared to colon mucosa and stromal cells. Low LRP1 immunohistochemical expression in adenocarcinomas was associated with higher age, right-sided tumor, loss of CDX2 expression, Annexin A10 expression, CIMP-H, MSI-H and BRAFV600E mutation. Low LRP1 expression correlates with poor clinical outcome, especially in stage IV patients. LRP1 expression was downregulated by LRP1 mutation. LRP1 expression was slightly modified by miR-205 expression. LRP1 promoter was never methylated.Loss of LRP1 expression is associated with peculiar clinocopathological and molecular characteristics and with worse colon cancer outcomes

Comparing histological activity indexes in UC

International audienceBACKGROUND:Assessment of disease activity in UC is important for designing an optimal therapeutic strategy. No single histology score is considered optimum. The aim of this study was to compare intraobserver reproducibility and the interobserver agreement of available histological UC activity indexes.METHODS:One hundred and two biopsy specimens (collected between 2003 and 2014) were scored blindly by three pathologists by determining Geboes, Riley, Gramlich and Gupta indexes and global visual evaluation (GVE). Intraobserver reproducibility and interobserver agreements for index and items of index were studied by intraclass correlation coefficient for quantitative parameter and by κ values and Krippendorff index for qualitative parameters. Relationship between indexes was studied by computation of Pearson's and Spearman's correlation coefficients.RESULTS:Geboes, Riley, Gramlich and Gupta indexes and GVE showed good intraobserver reproducibility and a good interobserver agreement. Histological items that showed the best interobserver agreement were 'erosion/ulceration or surface epithelial integrity' and 'acute inflammatory cells infiltrate/neutrophils in lamina propria'. The five scores were strongly correlated.CONCLUSIONS:Correlation between indexes is strong. Intraobserver reproducibility and interobserver agreement for all indexes is very good. Histological items that showed the best interobserver agreement are 'erosion/ulceration' and 'acute inflammatory cells infiltrate/neutrophils in lamina propria'

Deep learning for the prediction of the chemotherapy response of metastatic colorectal cancer: comparing and combining H&E staining histopathology and infrared spectral histopathology

International audienceColorectal cancer is a global public health problem with one of the highest death rates. It is the second most deadly type of cancer and the third most frequently diagnosed in the world. The present study focused on metastatic colorectal cancer (mCRC) patients who had been treated with chemotherapy-based regimen for which it remains uncertainty about the efficacy for all eligible patients. This is a major problem, as it is not yet possible to test different therapies in view of the consequences on the health of the patients and the risk of progression. Here, we propose a method to predict the efficacy of an anticancer treatment in an individualized way, using a deep learning model constructed on the retrospective analysis of the primary tumor of several patients. Histological sections from tumors were imaged by standard hematoxylin and eosin (HE) staining and infrared spectroscopy (IR). Images obtained were then processed by a convolutional neural network (CNN) to extract features and correlate them with the subsequent progression-free survival (PFS) of each patient. Separately, HE and IR imaging resulted in a PFS prediction with an error of 6.6 and 6.3 months respectively (28% and 26% of the average PFS). Combining both modalities allowed to decrease the error to 5.0 months (21%). The inflammatory state of the stroma seemed to be one of the main features detected by the CNN. Our pilot study suggests that multimodal imaging analyzed with deep learning methods allow to give an indication of the effectiveness of a treatment when choosing

Anti-tumoral and anti-angiogenic effects of low-diluted phenacetinum on melanoma

International audienceMelanoma is the most aggressive form of skin cancer and the most rapidly expanding cancer in terms of worldwide incidence. If primary cutaneous melanoma is mostly treated with a curative wide local excision, malignant melanoma has a poor prognosis and needs other therapeutic approaches. Angiogenesis is a normal physiological process essential in growth and development, but it also plays a crucial role in crossing from benign to advanced state in cancer. In melanoma progression, angiogenesis is widely involved during the vertical growth phase. Currently, no anti-angiogenic agents are efficient on their own, and combination of treatments will probably be the key to success. In the past, phenacetin was used as an analgesic to relieve pain, causing side effects at large dose and tumor-inducing in humans and animals. By contrast, Phenacetinum low-dilution is often used in skin febrile exanthema, patches profusely scattered on limbs, headache, or flushed face without side effects. Herein are described the in vitro, in vivo, and ex vivo anti-angiogenic and anti-tumoral potentials of Phenacetinum low-dilution in a B16F1 tumor model and endothelial cells. We demonstrate that low-diluted Phenacetinum inhibits in vivo tumor growth and tumor vascularization and thus increases the survival time of B16F1 melanoma induced-C57BL/6 mice. Moreover, Phenacetinum modulates the lung metastasis in a B16F10 induced model. Ex vivo and in vitro, we evidence that low-diluted Phenacetinum inhibits the migration and the recruitment of endothelial cells and leads to an imbalance in the pro-tumoral macrophages and to a structural malformation of the vascular network. All together these results demonstrate highly hopeful anti-tumoral, anti-metastatic, and anti-angiogenic effects of Phenacetinum low-dilution on melanoma. Continued studies are needed to preclinically validate Phenacetinum low-dilution as a complementary or therapeutic strategy for melanoma treatment

Automatic Identification of Paraffin Pixels on FTIR Images Acquired on FFPE Human Samples

International audienceThe transfer of mid-infrared spectral histopathology to the clinic will be possible provided that its application in clinical practice is simple. Rapid analysis of formalin-fixed paraffin-embedded (FFPE) tissue section is thus a prerequisite. The chemical dewaxing of these samples before image acquisition used by the majority of studies is in contradiction with this principle. Fortunately, the in silico analysis of the images acquired on FFPE samples is possible using extended multiplicative signal correction (EMSC). However, the removal of pure paraffin pixels is essential to perform a relevant classification of tissue spectra. So far, this task was possible only if using manual and subjective histogram analysis. In this article, we thus propose a new automatic and multivariate methodology based on the analysis of optimized combinations of EMSC regression coefficients by validity indices and KMeans clustering to separate paraffin and tissue pixels. The validation of our method is performed using simulated infrared spectral images by measuring the Jaccard index between our partitions and the image model, with values always over 0.90 for diverse baseline complexity and signal-to-noise ratio. These encouraging results were also validated on real images by comparing our method with classical ones and by computing the Jaccard index between our partitions and the KMeans partitions obtained on the infrared image acquired on the same samples but after chemical dewaxing, with values always over 0.84

Intraoral fibrolipoma: case report and review of literature

Introduction: Lipomas are benign soft tissue tumors, characterized by the presence of mature adipocytes in histopathology. Their development is slow and their etiologies are still controversial. Frequently subcutaneous, this type of lesion is rarely present in the oral cavity. Observation: A 67-year-old man consulted for a nodule on the inner face of his right cheek which had been developing for several years, with severe discomfort during chewing. The typical clinical aspect of this lesion suggested a lipoma. Magnetic resonance imaging (MRI) was performed before surgical excision in order to establish a differential diagnosis with a well-differentiated liposarcoma. Comments: The various imaging examinations, particularly MRI, combined with the analysis of the fat component and the morphology of the non-fat component (septa) enable us to define several categories of lesions likely to have a benign or malignant character. However, some lesions remain difficult to classify, and it is the histopathological examination along with, if necessary, immunohistochemistry (anti-MDM2 and/or anti-CDK4), which allows to confirm or not the malignancy of a lesion. Histological examination suggested a fibrolipoma. Conclusion: Although benign, the size of a fibrolipoma may can lead to significant functional and aesthetic discomfort for the patient. Surgical excision remains the treatment of choice

Collagen-Based Medical Device as a Stem Cell Carrier for Regenerative Medicine

Maintenance of mesenchymal stem cells (MSCs) requires a tissue-specific microenvironment (i.e., niche), which is poorly represented by the typical plastic substrate used for two-dimensional growth of MSCs in a tissue culture flask. The objective of this study was to address the potential use of collagen-based medical devices (HEMOCOLLAGENE®, Saint-Maur-des-Fossés, France) as mimetic niche for MSCs with the ability to preserve human MSC stemness in vitro. With a chemical composition similar to type I collagen, HEMOCOLLAGENE® foam presented a porous and interconnected structure (>90%) and a relative low elastic modulus of around 60 kPa. Biological studies revealed an apparently inert microenvironment of HEMOCOLLAGENE® foam, where 80% of cultured human MSCs remained viable, adopted a flattened morphology, and maintained their undifferentiated state with basal secretory activity. Thus, three-dimensional HEMOCOLLAGENE® foams present an in vitro model that mimics the MSC niche with the capacity to support viable and quiescent MSCs within a low stiffness collagen I scaffold simulating Wharton’s jelly. These results suggest that haemostatic foam may be a useful and versatile carrier for MSC transplantation for regenerative medicine applications

Identification of TAX2 peptide as a new unpredicted anti-cancer agent

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