CEA,CA19-9, circulating DNA and circulating tumour cell kinetics in patients treated for metastatic colorectal cancer (mCRC)

Background We previously reported that CEA kinetics are a marker of progressive disease (PD) in metastatic colorectal cancer (mCRC). This study was specifically designed to confirm CEA kinetics for predicting PD and to evaluate CA19-9, cell-free DNA (cfDNA), circulating tumour DNA (ctDNA) and circulating tumour cell (CTC) kinetics.Methods Patients starting a chemotherapy (CT) with pre-treatment CEA > 5 ng/mL and/or CA19.9 > 30 UI/mL were prospectively included. Samples were collected from baseline to cycle 4 for CEA and CA19-9 and at baseline and the sixth week for other markers. CEA kinetics were calculated from the first to the third or fourth CT cycle.Results A total of 192 mCRC patients were included. CEA kinetics based on the previously identified >0.05 threshold was significantly associated with PD (p < 0.0001). By dichotomising by the median value, cfDNA, ctDNA and CA19-9 were associated with PD, PFS and OS in multivariate analysis. A circulating scoring system (CSS) combining CEA kinetics and baseline CA19-9 and cfDNA values classified patients based on high (n = 58) and low risk (n = 113) of PD and was independently associated with PD (ORa = 4.6, p < 0.0001), PFS (HRa = 2.07, p < 0.0001) and OS (HRa = 2.55, p < 0.0001).Conclusions CEA kinetics alone or combined with baseline CA19-9 and cfDNA are clinically relevant for predicting outcomes in mCRC.Trial registration number {"type":"clinical-trial","attrs":{"text":"NCT01212510","term_id":"NCT01212510"}}NCT01212510.Subject terms: Colon cancer, Genetic markers     

The L1 major capsid protein of HPV16 differentially modulates APC trafficking according to the vaccination or natural infection context

Human papillomavirus (HPV) infection, particularly type 16, is causally associated with cancer of the uterine cervix. The progression of cervical lesions suggests that viral antigens are not adequately presented to the immune system. The aim of this study was to determine whether HPV16 viral particles can influence the trafficking of human DC/Langerhans cells (LC), either by direct interactions with DC or following incubation with human normal keratinocytes that are in close contact with LC in the squamous epithelium. We first demonstrated that HPV16 L1 major capsid protein, when self-assembled into virus-like particles (VLP), is able to induce in DC an over-expression of CXC receptor 4 (CXCR4) via the activation of the NF-κB signaling pathway and to enhance DC motility in the presence of CXCL12, suggesting an ability to migrate towards lymph nodes. We also showed that conditioned media of HPV16 VLP-treated keratinocytes induce a lower LC migration than those from untreated keratinocytes and that prostaglandin E2 (PGE(2)), detected in HPV16 VLP-treated keratinocyte supernatants, may reduce LC recruitment into the squamous epithelium. Taken together, our data demonstrate that HPV16 VLP may differentially regulate the immune protective response according to their target cells.     

Devic disease with brainstem lesions

We describe a patient who suffered from an unusually severe form of neuromyelitis optica with a hyperacute time-course evolution requiring mechanical ventilation within 3 days. The patient died after 72 days and autopsy showed major spinal cord, optic nerve, and brainstem necrosis, and multifocal necrotic lesions on the cerebellum and cerebral white matter.     

A large collection of integrated genomically characterized patient-derived xenografts highlighting the heterogeneity of triple-negative breast cancer

Triple-negative breast cancer (TNBC) represents 10% of all breast cancers and is a very heterogeneous disease. Globally, women with TNBC have a poor prognosis, and the development of effective targeted therapies remains a real challenge. Patient-derived xenografts (PDX) are clinically relevant models that have emerged as important tools for the analysis of drug activity and predictive biomarker discovery. The purpose of this work was to analyze the molecular heterogeneity of a large panel of TNBC PDX (n = 61) in order to test targeted therapies and identify biomarkers of response. At the gene expression level, TNBC PDX represent all of the various TNBC subtypes identified by the Lehmann classification except for immunomodulatory subtype, which is underrepresented in PDX. NGS and copy number data showed a similar diversity of significantly mutated gene and somatic copy number alteration in PDX and the Cancer Genome Atlas TNBC patients. The genes most commonly altered were TP53 and oncogenes and tumor suppressors of the PI3K/AKT/mTOR and MAPK pathways. PDX showed similar morphology and immunohistochemistry markers to those of the original tumors. Efficacy experiments with PI3K and MAPK inhibitor monotherapy or combination therapy showed an antitumor activity in PDX carrying genomic mutations of PIK3CA and NRAS genes. TNBC PDX reproduce the molecular heterogeneity of TNBC patients. This large collection of PDX is a clinically relevant platform for drug testing, biomarker discovery and translational research.     

Cadmium induces direct morphological changes in mesangial cell culture

The cadmium produced by industrial and agricultural practice represents a major environmental pollutant which may induce severe damage, especially in the kidney where cadmium accumulates. While cadmium is known to severely impair renal tubular functions, glomerular structures are also potential targets. The present study investigated the effects of cadmium on glomerular mesangial cell cultures after short- and long-term exposures, requiring for each endpoint specific culture conditions. After 30 min exposure to 1 microM CdCl(2), used as non-lethal concentration, 0.14 ng/microg proteins of cadmium was internalized by the cells as evaluated by atomic emision spectrometry and induced a significant, cell surface reduction (8.9+/-1.9%). These morphological changes could be correlated to smooth muscle alpha-actin disorganization, without quantitative change in its protein expression level as evaluated by Western-blot and Northern-blot analysis (SMAmRNA/28sRNA, 1.78 CdCl(2) vs. 1.42 control). For longer exposure times, in complex medium, cadmium uptake was efficient (0.36 ng/microg proteins) and induced changes in the actin cytoskeleton with no loss of cell membrane integrity. This study suggests that cultured mesangial cells provide an alternative model to study the effect of cadmium, and underlines the importance of using well-defined conditions to study further intracellular mechanisms.     

Effect of reduced maternal protein intake in pregnancy in the rat on the fatty acid composition of brain,liver, plasma,heart and lung phospholipids of the offspring after weaning

Reduced protein intake during pregnancy decreased maternal hepatic and plasma docosahexaenoic acid concentrations and impaired docosahexaenoic acid accumulation into fetal brain in the rat. The present study investigated whether restriction of maternal protein intake during pregnancy in the rat alters membrane phospholipid fatty acid composition in the offspring after weaning. Female rats (six per group) were mated and fed diets containing either 180 or 90 g protein/kg throughout pregnancy. Mothers were transferred to standard chow after delivery and the litters reduced to eight pups. Weaning was at 28 d and pups were killed 5 to 6 d later. Tissue weights or membrane total phosphatidylcholine (PC) and phosphatidylethanolamine (PE) concentrations in the offspring did not differ between dietary groups. There were significant differences between the 180 and 90 g/kg groups in liver, brain, lung and heart fatty acid composition that differed between tissues and phospholipid classes. For example, docosahexaenoic and arachidonic acid concentrations were 23 and 10 % lower respectively in hepatic PC, but not PE, in the 90 g/kg group. In brain, docosahexaenoic acid concentration was 17 % lower in PC, but not PE, while arachidonic acid content was 21 % greater in PE but unchanged in PC. The greatest differences were in unsaturated fatty acids, which suggests alterations to desaturase activities and/or the specificity of phospholipid biosynthesis. These results suggest that restricted maternal protein intake during pregnancy results in persistent alterations to membrane fatty acid content.     

Nutritional and plasmatic antioxidant vitamins status of ultra endurance athletes

OBJECTIVE: The "Marathon des Sables" (MDS) is a competition known to induce oxidative stress. Antioxidant vitamins prevent exercise-induced oxidative damages. The purpose of this study was to evaluate daily intake and plasma level of the main antioxidant vitamins (alpha-tocopherol, vitamin C, beta-carotene and retinol) in 19 male athletes who participated in this competition. METHODS: Data collected before the beginning of the competition included daily dietary intake using a 7-day food record and plasma biochemical measurements (alpha-tocopherol, vitamin C, beta-carotene and retinol). RESULTS: First, total energy intake was obviously lower than the energetic intake usually observed in well-trained endurance athletes. Second, antioxidant vitamins intake was also insufficient. Indeed, the intake was lower than the French Dietary Reference Intakes (DRI) for this population in 18 subjects for vitamin E and 6 subjects for vitamin C, beta-carotene and Retinol Equivalent. As a significant relationship was found between total energy intake and the intake of vitamin E (r = 0.73; p < 0.001) and vitamin C (r = 0.78; p < 0.001), the low total energy intake contributed partially to the insufficient antioxidant vitamins intake. The dietary questionnaire analysis also revealed a low intake of vegetable oils, fruits and vegetables. However, plasma concentrations of these antioxidant vitamins were similar to the literature data observed in athletes. CONCLUSION: This study evidenced obvious insufficient energy intake in ultra endurance athletes associated with a low antioxidant vitamin intake.     

Atypical epithelial hyperplasia of the breast: state of the art

Introduction: Atypical epithelial hyperplasia (AEH) of the breast is considered benign histological lesions with breast cancer risk. This review focuses on clinical signification and management of AEH that remains controversial.

Areas covered: A review of published studies was performed using medline database. In this review, we fully describe the current evidence available. In particular, we describe 1) data from immunohistochemistry and molecular studies that suggest AEH is a precursor of breast cancer; 2) epidemiological studies demonstrate low rate of breast cancer in women with AEH; 3) surgical excision is necessary after diagnosis of AEH, such as lobular carcinoma in situ or atypical ductal hyperplasia, on core needle biopsy; 4) although current recommendations are evolving to fewer (if not no) excisions for flat epithelial with atypia and classic lobular neoplasia found on percutaneous biopsy (without radiologic indications for excision).

Expert commentary: HEA management steel need prospective evidences, but recent retrospective data give some clue for less invasive management for some of HEA.