Association of CD206 Protein Expression with Immune Infiltration and Prognosis in Patients with Triple-Negative Breast Cancer.

Background: Triple-negative breast cancers (TNBCs) have a worse prognosis, but might respond to immunotherapies. Macrophages are plastic cells that can adopt various phenotypes and functions. Although they are a major immune population in TNBCs, the relationship between tumor-associated macrophages (TAMs) and TNBC progression has been rarely explored, with controversial results. Methods: We evaluated the prognostic impact of TAMs, quantified by immunohistochemistry with anti-CD68, -IRF8, -CD163, and -CD206 antibodies, in a well-described cohort of 285 patients with non-metastatic TNBC. Results: CD68 (p = 0.008), IRF8 (p = 0.001), and CD163 (p < 0.001) expression positively correlated with higher tumor grade, while CD206 was associated with smaller tumor size (p < 0.001). All macrophage markers were associated with higher tumor-infiltrating lymphocyte numbers and PD-L1 expression. Univariate survival analyses reported a significant positive correlation between CD163+ or CD206+ TAMs and relapse-free survival (respectively: HR = 0.52 [0.28−0.97], p = 0.027, and HR = 0.51 [0.31−0.82], p = 0.005), and between CD206+ TAMs and overall survival (HR = 0.54 [0.35−0.83], p = 0.005). In multivariate analysis, there was a trend for an association between CD206+ TAMs and relapse-free survival (HR = 0.63 [0.33−1.04], p = 0.073). Conclusions: These data suggest that CD206 expression defines a TAM subpopulation potentially associated with favorable outcomes in patients with TNBC. CD206 expression might identify an immune TNBC subgroup with specific therapeutic options.

Mechanical signatures of human colon cancers.

Besides the standard parameters used for colorectal cancer (CRC) management, new features are needed in clinical practice to improve progression-free and overall survival. In some cancers, the microenvironment mechanical properties can contribute to cancer progression and metastasis formation, or constitute a physical barrier for drug penetration or immune cell infiltration. These mechanical properties remain poorly known for colon tissues. Using a multidisciplinary approach including clinical data, physics and geostatistics, we characterized the stiffness of healthy and malignant colon specimens. For this purpose, we analyzed a prospective cohort of 18 patients with untreated colon adenocarcinoma using atomic force microscopy to generate micrometer-scale mechanical maps. We characterized the stiffness of normal epithelium samples taken far away or close to the tumor area and selected tumor tissue areas. These data showed that normal epithelium was softer than tumors. In tumors, stroma areas were stiffer than malignant epithelial cell areas. Among the clinical parameters, tumor left location, higher stage, and RAS mutations were associated with increased tissue stiffness. Thus, in patients with CRC, measuring tumor tissue rigidity may have a translational value and an impact on patient care.

Prognostic Value of HER2-Low Expression in Non-Metastatic Triple-Negative Breast Cancer and Correlation with Other Biomarkers.

HER2-low breast cancer (i.e., HER 1+ or 2+, without gene amplification) is an emerging subtype for which very few data are available, especially within the triple-negative breast cancer (TNBC) group. Our aim was to evaluate HER2 expression and its prognostic value in a large retrospective series of patients with non-metastatic TNBC (median age: 57.7 years; range: 28.5-98.6). Among the 296 TNBC samples, 83.8% were HER2 0, 13.5% were HER2 1+, and 2.7% were HER2 2+ (HercepTestTM and 2018 ASCO/CAP guidelines for HER2 scoring). CK5/6 and/or EGFR-expressing androgen receptors and FOXA1-expressing tumors were classified as basal-like (63.8%) and molecular apocrine-like (MA, 40.2%), respectively. Compared with HER2 0 tumors, HER2 1+/2+ tumors exhibited a lower histological grade (1/2) (35.4% vs. 18.2%, p = 0.007) and MA profile (57.5% vs. 36.7%, p = 0.008). Moreover, patients with HER2 1+/2+ tumors were older (p = 0.047). After a median follow-up of 9.7 years, HER2 2+ tumors (compared with HER2 0/1+ tumors) were associated with worse relapse-free survival (RFS) (HR = 3.16, 95% CI [1.27; 7.85], p = 0.034) in a univariate analysis. Overall survival (OS) and RFS were not different in the HER2 0 and 1+/2+ groups. HER2 levels were not significantly associated with OS or RFS in a multivariate analysis.

Clinicopathological Correlates of γδ T Cell Infiltration in Triple-Negative Breast Cancer.

The prognostic impact of the different tumor-infiltrating lymphocyte (TIL) subpopulations in solid cancers is still debated. Here, we investigated the clinicopathological correlates and prognostic impact of TILs, particularly of γδ T cells, in 162 patients with triple-negative breast cancer (TNBC). A high γδ T cell density (>6.625 γδ T cells/mm2) was associated with younger age (p = 0.008), higher tumor histological grade (p = 0.002), adjuvant chemotherapy (p = 0.010), BRCA1 promoter methylation (p = 0.010), TIL density (p < 0.001), and PD-L1 (p < 0.001) and PD-1 expression (p = 0.040). In multivariate analyses, γδ T cell infiltration (cutoff = 6.625 γδ T cells/mm2) was an independent prognostic factor (5-year relapse-free survival: 63.3% vs. 89.8%, p = 0.027; 5-year overall survival: 73.8% vs. 89.9%, p = 0.031, for low vs. high infiltration). This prognostic impact varied according to the tumor PIK3CA mutational status. High γδ T cell infiltration was associated with better survival in patients with PIK3CA wild-type tumors, but the difference was not significant in the subgroup with PIK3CA-mutated tumors. Altogether, these data suggest that high γδ T cell infiltrate is correlated with immune infiltration and might represent a candidate prognostic tool in patients with TNBC.

Diversity of Tumor-Infiltrating, γδ T-Cell Abundance in Solid Cancers.

γδ T-cells contribute to the immune response against many tumor types through their direct cytolytic functions and their capacity to recruit and regulate the biological functions of other immune cells. As potent effectors of the anti-tumor immune response, they are considered an attractive therapeutic target for immunotherapies, but their presence and abundance in the tumor microenvironment are not routinely assessed in patients with cancer. Here, we validated an antibody for immunohistochemistry analysis that specifically detects all γδ T-cell subpopulations in healthy tissues and in the microenvironment of different cancer types. Tissue microarray analysis of breast, colon, ovarian, and pancreatic tumors showed that γδ T-cell density varies among cancer types. Moreover, the abundance of γδ tumor-infiltrating lymphocytes was variably associated with the outcome depending on the cancer type, suggesting that γδ T-cell recruitment is influenced by the context. These findings also suggest that γδ T-cell detection and analysis might represent a new and interesting diagnostic or prognostic marker.

Outcome after pancreatectomy for neuroendocrine neoplams according to the WHO 2017 grading system: A retrospective multicentric analysis of 138 consecutive patients.

AIM: The aim of this study was to evaluate the new World Health Organization (WHO) 2017 grading system and the others clinicopathological factors in pancreatic neuroendocrine tumor (panNET) operated patients. METHODS: Histological staging was based on the WHO 2017 grading system. Outcome after surgery and predictors of overall survival (OS) and disease free survival (DFS) were evaluated. RESULTS: A total of 138 patients underwent surgical resection with a severe morbidity and mortality rates of 14.5% and 0.7% respectively. Five years OS differed according to WHO 2017: 95% among 58 patients with NETG1, 82% in 68 patients with NETG2, 35% in 7 patients with NETG3 and 0% in 5 patients with NECG3 (P<0.0001). Independent predictors of worse OS were age>60 y.o (P=0.014), synchronous metastasis (P=0.005) and WHO 2017 with significant differences between NETG1 versus NETG2 (P=0.005), NETG3 (P<0.001) and NECG3 (P<0.001). Independent predictors of worse DFS were symptomatic NET (P=0.038), pN+ status (P=0.027) and WHO 2017 with significant differences between NETG1 versus NETG3 (P=0.014) and NECG3 (P=0.009). CONCLUSION: The WHO 2017 grading system is a useful tool for patient prognosis after panNET resection and the tailoring of therapeutic strategy. Surgery could provide good results in NETG3 patients.

Endoscopic management of 345 small rectal neuroendocrine tumours: A national study from the French group of endocrine tumours (GTE).

Introduction: Small rectal neuroendocrine tumours are good candidates for endoscopic resection provided that complete pathological resection (R0) is obtained and their risk of metastatic progression is low. We conducted a large multicentre nationwide study to evaluate the outcomes of the management of non-metastatic rectal neuroendocrine tumours ≤2 cm diagnosed endoscopically. Patients and methods: The medical records, the endoscopic and pathological findings of patients with non-metastatic rectal neuroendocrine tumours ≤2 cm managed from January 2000-June 2018 in 16 French hospitals, were retrospectively analysed. The primary objective was to describe the proportion of R0 endoscopic resections. Results: A total of 329 patients with 345 rectal neuroendocrine tumours were included, 330 (96%) tumours were managed by local treatments: 287 by endoscopy only and 43 by endoscopy followed by transanal endoscopic microsurgery. The final endoscopic R0 rate was 134/345 (39%), which improved from the first endoscopy (54/225, 24%), to the second (60/100, 60%) and the third endoscopy (20/26, 77%). R0 was associated with endoscopic technique (90% for advanced techniques, 40% for mucosectomy and 17% for polypectomy), but not with tumour or patient characteristics. Twenty patients had metastatic disease, which was associated with tumour size ≥10 mm (odds ratio: 9.1, 95% confidence interval (3.5-23.5)), tumour grade G2-G3 (odds ratio: 4.2, (1.5-11.7)), the presence of muscular (odds ratio: ∞, (11.9-∞)) and lymphovascular invasion (odds ratio: 57.2, (5.6-578.9)). Conclusions: The resection of small rectal neuroendocrine tumours often requires multiple procedures. Training of endoscopists is necessary in order to better recognise these tumours and to perform the appropriate resection technique.

ESM1 as a Marker of Macrotrabecular-Massive Hepatocellular Carcinoma.

PURPOSE: Macrotrabecular-massive hepatocellular carcinoma (MTM-HCC) is a novel morphological subtype of HCC associated with early relapse after resection or percutaneous ablation, independently of classical clinical and radiological prognostic factors. The aim of the present study was to identify immunohistochemical markers of MTM-HCC, to ease its diagnosis and implementation into clinical practice. EXPERIMENTAL DESIGN: To identify potential biomarkers of MTM-HCC, we first analyzed gene expression profiling data from The Cancer Genome Atlas study and further selected two candidate biomarkers. Performance of both biomarkers for diagnosis of MTM-HCC was further tested by immunohistochemistry in two independent series of 67 and 132 HCC biopsy samples. RESULTS: Analysis of RNA sequencing data showed that MTM-HCC was characterized by a high expression of neoangiogenesis-related genes. Two candidate biomarkers, Endothelial-Specific Molecule 1 (ESM1) and Carbonic Anhydrase IX (CAIX), were selected. In the discovery series, sensitivity and specificity of ESM1 expression by stromal endothelial cells for the detection of MTM-HCC were 97% (28/29), and 92% (35/38), respectively. Sensitivity and specificity of CAIX were 48% (14/29) and 89% (34/38). In the validation set, sensitivity and specificity of ESM1 for the identification of MTM-HCC were 93% (14/15) and 91% (107/117), respectively. Interobserver agreement for ESM1 assessment was good in both series (Cohen Kappa 0.77 and 0.76). CONCLUSIONS: Using a molecular-driven selection of biomarkers, we identified ESM1 as a reliable microenvironment immunohistochemical marker of MTM-HCC. The results represent a step toward the implementation of HCC morpho-molecular subtyping into clinical practice.

Current Management and Predictive Factors of Lymph Node Metastasis of Appendix Neuroendocrine Tumors: A National Study from the French Group of Endocrine Tumors (GTE).

OBJECTIVE: The primary endpoint was to analyze the predictive factors of lymph node involvement (LN+). BACKGROUND: Indications for additional right hemicolectomy (RHC) with lymph node (LN) resection after appendectomy for appendix neuroendocrine tumor (A-NET) remain controversial, especially for tumors between 1 and 2 cm in size. METHODS: National study including all patients with nonmetastatic A-NET diagnosed after January, 2010 in France. RESULTS: In all, 403 patients were included. A-NETs were: within tip (67%), body (24%) or base (9%) of the appendix; tumor size was < 1 cm (62%), 1 to 2 cm (30%), or >2 cm (8%); grade 1 (91%); mesoappendix involvement 3 mm (5%); lymphovascular (15%) or perineural (24%) invasion; and positive resection margin (8%). According to the European NeuroEndocrine Tumor Society (ENETS) recommendations, 85 patients (21%) should have undergone RHC. The agreement between ENETS guidelines and the multidisciplinary tumor board for complementary RHC was 89%. In all, 100 (25%) patients underwent RHC with LN resection, 26 of whom had LN+. Tumor size (best cut-off at 1.95 cm), lymphovascular and perineural invasion, and pT classifications were associated with LN+. Among the 44 patients who underwent RHC for a tumor of 1 to 2 cm in size, 8 (18%) had LN+. No predictive factor of LN+ (base, resection margins, grade, mesoappendix, lymphovascular, perineural involvement) was found in this subgroup of patients. CONCLUSIONS: In the largest study using the latest pathological criteria for completion RHC in A-NET, a quarter of patients had residual tumor. Further studies are warranted to demonstrate the survival impact of RHC in this setting.

Chromosomal Aberrations Associated with Sequential Steps of the Metastatic Cascade in Colorectal Cancer Patients.

BACKGROUND: Genomic information can help to identify colorectal tumors with high and low metastatic potential, thereby improving prediction of benefit of local and/or systemic treatment. Here we investigated chromosomal aberrations in relation to the different stages of the metastatic cascade: dissemination of tumor cells into the mesenteric vein, metastatic outgrowth in the liver, intravasation of the peripheral blood circulation, and development of further distant metastasis. METHODS: Peripheral and mesenteric blood from colorectal cancer patients (n = 72) were investigated for circulating tumor cells, and DNA extracted from their primary tumors was subjected to array comparative genomic hybridization profiling. The results were validated with an independent set of primary colorectal tumors (n = 53) by quantitative reverse transcription PCR. RESULTS: Mesenteric intravasation and liver metastasis were correlated with losses of chromosomes 16p (72%), 16q (27%), and 19 (54%), gain along 1q31 (45%) and 20q (60%), tumor cell infiltration into the peripheral blood circulation, and further distant metastasis with gain of chromosome 8q (59%) and 12 (47%, P < 0.01). Chromosome 12 gain was associated with poor overall survival in the initial (2.8 vs >7 years) and validation cohort (3.3 vs >6 years). The prospective study presented here is a hypothesis-generating study and confirmation with larger cohorts is required. CONCLUSIONS: This is the first study that investigated colorectal cancer in its different stages of metastasis in correlation with copy number changes of the primary tumor. This information might be helpful to identify patients with limited metastatic spread who may profit from liver metastasis resection and may lead to the discovery of new therapeutic targets.Microarray data have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GSE82228.

Diagnosis, Natural History and Treatment of Eosinophilic Enteritis: a Review.

PURPOSE OF REVIEW: To review recent findings regarding eosinophilic enteritis, including epidemiology, pathogenesis, natural history, and treatment. RECENT FINDINGS: A 2017 population-based study using a US healthcare system database identified 1820 patients with a diagnosis of eosinophilic enteritis among 35,826,830 individuals. The majority of patients with eosinophilic enteritis in this study were women (57.7%), Caucasian (77.5%), and adults (> 18 years of age) (83.5%). The overall prevalence of eosinophilic enteritis was estimated at 5.1/100,000 persons. Eosinophilic enteritis, also known as eosinophilic gastroenteritis, is a rare primary eosinophilic gastrointestinal disorder (EGID) of unknown etiology characterized by the presence of an intense eosinophilic infiltrate on histopathological examination of the intestinal mucosa. The etiology of eosinophilic enteritis remains unknown. However, there is evidence to support the role of allergens in the pathogenesis of this disorder, as children and adults with EGIDs often have positive skin testing to food allergens and a family history of allergic diseases. Recent studies unraveling the role of IgE-mediated but also delayed Th2-type responses have provided insight into the pathogenesis of this disease. Eosinophilic enteritis causes a wide array of gastrointestinal symptoms such as abdominal pain, diarrhea, nausea, vomiting, bloating, or ascites, and its diagnosis requires a high degree of clinical likelihood, given the nonspecific clinical presentation and physical examination findings. Oral corticosteroids are considered to be the mainstay of treatment and are generally used for a short period with good response rates. Antihistamine drugs and sodium cromoglycate have also been used to treat patients with eosinophilic enteritis. Preliminary studies have demonstrated the potential benefit of biological therapies targeting the eosinophilic pathway such as mepolizumab, an anti-IL5 antibody, or omalizumab, an anti-IgE monoclonal antibody. Eosinophilic enteritis is generally considered to be a benign disease without relapse, but up to 50% of patients may present a more complex natural history characterized by unpredictable relapses and a chronic course.

Macrotrabecular-massive hepatocellular carcinoma: A distinctive histological subtype with clinical relevance.

We recently identified a histological subtype of hepatocellular carcinoma (HCC), designated as "macrotrabecular-massive" (MTM-HCC) and associated with specific molecular features. In order to assess the clinical relevance of this variant, we investigated its prognostic value in two large series of patients with HCC treated by either surgical resection or radiofrequency ablation (RFA). We retrospectively included 237 HCC surgical samples and 284 HCC liver biopsies from patients treated by surgical resection and RFA, respectively. Histological slides were reviewed by pathologists specialized in liver disease, and the MTM-HCC subtype was defined by the presence of a predominant (>50%) macrotrabecular architecture (more than six cells thick). The main clinical and biological features were recorded at baseline. Clinical endpoints were early and overall recurrence. The MTM-HCC subtype was identified in 12% of the whole cohort (16% of surgically resected samples, 8.5% of liver biopsy samples). It was associated at baseline with known poor prognostic factors (tumor size, alpha-fetoprotein level, satellite nodules, and vascular invasion). Multivariate analysis showed that MTM-HCC subtype was an independent predictor of early and overall recurrence (surgical series: hazard ratio, 3.03; 95% confidence interval, 1.38-6.65; P = 0.006; and 2.76; 1.63-4.67; P < 0.001; RFA series: 2.37; 1.36-4.13; P = 0.002; and 2.19; 1.35-3.54; P = 0.001, respectively). Its prognostic value was retained even after patient stratification according to common clinical, biological, and pathological features of aggressiveness. No other baseline parameter was independently associated with recurrence in the RFA series. CONCLUSION: The MTM-HCC subtype, reliably observed in 12% of patients eligible for curative treatment, represents an aggressive form of HCC that may require more specific therapeutic strategies. (Hepatology 2018;68:103-112).

Epidermal Growth Factor Represses Constitutive Androstane Receptor Expression in Primary Human Hepatocytes and Favors Regulation by Pregnane X Receptor.

Growth factors have key roles in liver physiology and pathology, particularly by promoting cell proliferation and growth. Recently, it has been shown that in mouse hepatocytes, epidermal growth factor receptor (EGFR) plays a crucial role in the activation of the xenosensor constitutive androstane receptor (CAR) by the antiepileptic drug phenobarbital. Due to the species selectivity of CAR signaling, here we investigated epidermal growth factor (EGF) role in CAR signaling in primary human hepatocytes. Primary human hepatocytes were incubated with CITCO, a human CAR agonist, or with phenobarbital, an indirect CAR activator, in the presence or absence of EGF. CAR-dependent gene expression modulation and PXR involvement in these responses were assessed upon siRNA-based silencing of the genes that encode CAR and PXR. EGF significantly reduced CAR expression and prevented gene induction by CITCO and, to a lower extent, by phenobarbital. In the absence of EGF, phenobarbital and CITCO modulated the expression of 144 and 111 genes, respectively, in primary human hepatocytes. Among these genes, only 15 were regulated by CITCO and one by phenobarbital in a CAR-dependent manner. Conversely, in the presence of EGF, CITCO and phenobarbital modulated gene expression only in a CAR-independent and PXR-dependent manner. Overall, our findings suggest that in primary human hepatocytes, EGF suppresses specifically CAR signaling mainly through transcriptional regulation and drives the xenobiotic response toward a pregnane X receptor (PXR)-mediated mechanism.

[Hepatic myelolipoma: A rare entity, case report and review of the literature]. / Myélolipome hépatique : une entité rare, à propos d'un cas et revue de la littérature.

Hepatic myelolipoma is a rare entity with only 17 cases described in the literature. A 73mm right liver mass was fortuitously discovered in a 55-year-old man. The biopsy showed normal hepatic tissue adjacent to a normal medular like hematopoïetic tissue, showing trilieage hematopoieses, including myeloid cells, erythroid cells and megakaryocytic cells. The diagnosis of hepatic myelolipoma was proposed. This benign tumor was initially described in adrenal gland, which is the most common topography. No malignancy or bleeding complication has been described in its hepatical location. The diagnosis is histological due to non-specific radiological presentation; it allows to avoid a surgical treatment in relation to its excellent prognosis. The etiology is not well established; but some hypotheses are discussed: adrenal or medullar heterotopia, bone marrow embolism, myeloïd metaplasia.

Stricturing Crohn's disease-like colitis in a patient treated with belatacept.

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) modifying agents have been involved in the development of intestinal inflammation, especially therapeutic monoclonal antibodies directed against CTLA-4. Here we report the appearance of a severe stricturing Crohn's disease-like colitis in a patient with a kidney allograft who was treated with belatacept, a recombinant CTLA-4-Ig fusion protein.

Molecular Classification of Hepatocellular Adenoma Associates With Risk Factors, Bleeding, and Malignant Transformation.

BACKGROUND & AIMS: Hepatocellular adenomas (HCAs) are benign liver tumors that can be assigned to molecular subtypes based on inactivating mutations in hepatocyte nuclear factor 1A, activating mutations in ß-catenin, or activation of inflammatory signaling pathways. We aimed to update the classification system for HCA and associate the subtypes with disease risk factors and complications. METHODS: We analyzed expression levels of 20 genes and sequenced exon regions of 8 genes (HNF1A, IL6ST, CTNNB1, FRK, STAT3, GNAS, JAK1, and TERT) in 607 samples of 533 HCAs from 411 patients, collected from 28 centers mainly in France from 2000 and 2014. We performed gene expression profile, RNA sequence, whole-exome and genome sequence, and immunohistochemical analyses of select samples. Molecular data were associated with risk factors, histopathology, bleeding, and malignant transformation. RESULTS: Symptomatic bleeding occurred in 14% of the patients (85% of cases were female, median age, 38 years); 7% of the nodules were borderline between HCA and hepatocellular carcinoma, and 3% of patients developed hepatocellular carcinoma from HCA. Based on molecular features, we classified HCA into 8 subgroups. One new subgroup, composed of previously unclassified HCA, represented 4% of HCAs overall and was associated with obesity and bleeding. These tumors were characterized by activation of sonic hedgehog signaling, due to focal deletions that fuse the promoter of INHBE with GLI1. Analysis of genetic heterogeneity among multiple HCAs, from different patients, revealed a molecular subtype field effect; multiple tumors had different mutations that deregulated similar pathways. Specific molecular subtypes of HCA associated with various HCA risk factors, including imbalances in estrogen or androgen hormones. Specific molecular subgroup of HCA with ß-catenin and sonic hedgehog activation associated with malignant transformation and bleeding, respectively. CONCLUSIONS: Using sequencing and gene expression analyses, we identified a subgroup of HCA characterized by fusion of the INHBE and GLI1 genes and activation of sonic hedgehog pathway. Molecular subtypes of HCAs associated with different patients' risk factors for HCA, disease progression, and pathology features of tumors. This classification system might be used to select treatment strategies for patients with HCA.

Simultaneous trans-hepatic portal and hepatic vein embolization before major hepatectomy: the liver venous deprivation technique.

PURPOSE: To assess technical feasibility, safety, and efficacy of the liver venous deprivation (LVD) technique that combines both portal and hepatic vein embolization during the same procedure for liver preparation before major hepatectomy. MATERIALS AND METHODS: Seven patients (mean age:63.6y[42-77y]) underwent trans-hepatic LVD for liver metastases (n = 2), hepatocellular carcinoma (n = 1), intrahepatic cholangiocarcinoma (n = 3) and Klatskin tumour (n = 1). Assessment of future remnant liver (FRL) volume, liver enzymes and histology was performed. RESULTS: Technical success was 100 %. No complication occurred before surgery. Resection was performed in 6/7 patients. CT-scan revealed hepatic congestion in the venous-deprived area (6/7 patients). A mean of 3 days (range: 1-8 days) after LVD, transaminases increased (AST: from 42 ± 24U/L to 103 ± 118U/L, ALT: from 45 ± 25U/L to 163 ± 205U/L). Twenty-three days (range: 13-30 days) after LVD, FRL increased from 28.2 % (range: 22.4-33.3 %) to 40.9 % (range: 33.6-59.3 %). During the first 7 days, venous-deprived liver volume increased (+13.4 %) probably reflecting vascular congestion, whereas it strongly decreased (-21.3 %) at 3-4 weeks. Histology (embolized lobe) revealed sinusoidal dilatation, hepatocyte necrosis and important atrophy in all patients. CONCLUSION: Trans-hepatic LVD technique is feasible, well tolerated and provides fast and important hypertrophy of the FRL. This new technique needs to be further evaluated and compared to portal vein embolization. KEY POINTS: • Twenty-three days after LVD, FRL increased from 28.2 % (range:22.4-33.3 %) to 40.9 % (range:33.6-59.3 %) • During the first 7 days, venous-deprived liver volume increased (+13.4 %) • Venous-deprived liver volume strongly decreased (mean atrophy:229 cc; -21.3 %) at 3-4 weeks • Histology of venous-deprived liver revealed sinusoidal dilatation, hepatocyte necrosis and important atrophy.

Assessing the Impact of Mechanical Damage on Full-Thickness Porcine and Human Skin Using an In Vitro Approach.

For most xenobiotics, the rates of percutaneous absorption are limited by diffusion through the horny layer of skin. However, percutaneous absorption of chemicals may seriously increase when the skin is damaged. The aim of this work was to develop an in vitro representative model of mechanically damaged skins. The epidermal barrier was examined following exposure to a razor, a rotating brush, and a microneedle system in comparison to tape-stripping which acted as a reference. Excised full-thickness skins were mounted on a diffusion chamber in order to evaluate the effect of injuries and to mimic physiological conditions. The transepidermal water loss (TEWL) was greatly increased when the barrier function was compromised. Measurements were made for all the damaged biopsies and observed histologically by microscopy. On human and porcine skins, the tape-stripping application (0 to 40 times) showed a proportional increase in TEWL which highlights the destruction of the stratum corneum. Similar results were obtained for all cosmetic instruments. This is reflected in our study by the nonsignificant difference of the mean TEWL scores between 30 strips and mechanical damage. For a specific appreciation, damaged skins were then selected to qualitatively evaluate the absorption of a chlorogenic acid solution using fluorescence microscopy.

Analysis of Glycogen Synthase Kinase Inhibitors That Regulate Cytochrome P450 Expression in Primary Human Hepatocytes by Activation of ß-Catenin, Aryl Hydrocarbon Receptor and Pregnane X Receptor Signaling.

Cytochrome P450 (CYP) expression and activity are not homogeneous in the liver lobules. Indeed, CYPs are mainly expressed and induced in centrilobular hepatocytes. The wingless-type MMTV integration site family (WNT)/ß-catenin pathway was identified as a major regulator of this zonal organization. We have recently demonstrated that in primary human hepatocytes (PHHs), the expression of CYP2E1, CYP1A2, and aryl hydrocarbon receptor (AhR), but not of CYP3A4, is regulated by the WNT/ß-catenin pathway in response to WNT3a, its canonical activator. Here, we investigated whether glycogen synthase kinase 3ß (GSK3ß) inhibitors, which mimic the action of WNT molecules, could be used in PHHs to activate the ß-catenin pathway to study CYP expression. We assessed the activity of 6BIO (6-bromoindirubin-3'-oxime), CHIR99021 (6-((2-((4-(2,4-dichlorophenyl)-5-(4methyl-1H-imidazol-2-yl)pyrimidin-2-yl)amino)ethyl)amino) nicotinonitrile), and GSK3iXV (Pyridocarbazolo-cyclopentadienyl Ruthenium complex GSK3 inhibitor XV) that belong to structurally different families of GSK3ß inhibitors. Using small interfering RNAs, reporter gene assays, and molecular docking predictions, we demonstrated that GSK3ß inhibitors can activate the WNT/ß-catenin pathway in PHHs to regulate CYP2E1 expression. We also found that 6BIO and GSK3iXV are AhR full agonists that participate, through AhR signaling, to CYP1A2 induction. Conversely, CHIR99021 is an AhR partial agonist, and a pregnane X receptor ligand and partial agonist, thus regulating CYP1A2 and CYP3A4 gene expression in a ß-catenin-independent manner. In conclusion, GSK3ß inhibitors can activate the WNT/ß-catenin pathway in PHHs. Nevertheless, their role in CYP regulation should be analyzed with caution as these molecules can interact with xenosensors.

Dietary silicon-enriched spirulina improves early atherosclerosis markers in hamsters on a high-fat diet.

OBJECTIVE: The aim of this study was to investigate the effects of dietary silicon-enriched spirulina (SES) on atherosclerosis. METHODS: Hamsters (six per group) on a high-fat (HF) diet received SES or non-enriched spirulina (both at 57 mg/kg body weight) daily. This corresponded to 0.57 mg silicon/kg body weight daily. RESULTS: The HF diet induced dyslipidemia, insulin resistance, oxidative stress, and vascular dysfunction. Compared with the HF group, SES attenuated increases of lipemia and prevented insulin resistance (IR) (P = 0.001). SES protected against oxidative stress through a reduction of heart (P = 0.006) and liver (P < 0.0001) nicotinamide adenine dinucleotide phosphate-oxidase activity and by sparing the activity of superoxide dismutase (P = 0.0017) and glutathione peroxidase (P = 0.01861). SES decreased inflammation, lowering tumor necrosis factor-α (P = 0.0006) and interleukin-6 levels (P = 0.0112), decreasing polymorphonuclear cells and preventing nuclear factor-κB activity (P = 0.0259). SES corrected plasma level of monocyte chemoattractant protein-1 (P = 0.0380), which was increased by the HF diet. Finally, SES supplementation prevented vascular and endothelial functions assessed respectively by the contractile response to the agonist phenylephrine and the relaxation induced by acetylcholine. CONCLUSION: SES protects against metabolic imbalance, inflammation, oxidative stress, and vascular dysfunction induced by an HF diet, and could prevent the atherogenic processes. Synergistic effects between spirulina and silicon were observed.