Pierre Fouret

p63 Is Expressed in Basal and Myoepithelial Cells of Human Normal and Tumor Salivary Gland Tissues

p63 is essential for epithelial cell survival and may function as an oncogene. We examined by immunohistochemistry p63 expression in human normal and tumor salivary gland tissues. In normal salivary glands, p63 was expressed in the nuclei of myoepithelial and basal duct cells. Among 68 representative salivary gland tumors, 63 displayed p63 reactivity. In all tumor types differentiated towards luminal and myoepithelial lineages (pleomorphic adenomas, basal cell adenomas, adenoid cystic carcinomas, and epithelial-myoepithelial carcinomas), p63 was expressed in myoepithelial cells, whereas luminal cells were always negative. Similarly, in mucoepidermoid carcinomas, basal, intermediate, and squamous cells expressed p63, in contrast to luminal mucous cells. p63 reactivity was also restricted to basal cells in Warthin tumors and oncocytomas. Myoepitheliomas and myoepithelial carcinomas all expressed p63. The only five negative tumors were three of four acinar cell carcinomas and two of three adenocarcinomas. In conclusion, p63 is expressed in the nuclei of normal human salivary gland myoepithelial and basal duct cells. p63 expression is retained in the modified myoepithelial and basal cells of human salivary gland tumors, which suggests a role for p63 in oncogenesis of these complex tumors.

Extra-Cellular Signal-Regulated ERK-1/ERK-2 Pathway Activation in Human Salivary Gland Mucoepidermoid Carcinoma : Association to Aggressive Tumor Behavior and Tumor Cell Proliferation

Information on oncogenetic events accompanying salivary gland mucoepidermoid carcinoma is so far limited. Activation of extracellular signal-regulated kinases ERK-1 and ERK-2 is strongly correlated to cancer. Using an antibody specific for phosphorylated (active) ERK-1/ERK-2, we examined human salivary gland mucoepidermoid carcinoma samples by immunohistochemistry. The comparison in paired tumor and normal tissue samples showed that phosphorylated ERK-1/ERK-2 immunoreactivity was higher in tumor cells as compared to surrounding normal salivary parenchyma. ERK-1/ERK-2 phosphorylation was observed in approximately 39% of mucoepidermoid carcinomas. Those tumors where the ERK-1/ERK-2 pathway was activated had a more aggressive tumor behavior as compared to the group where this pathway was inactive. The association of ERK-1/ERK-2 phosphorylation to a worse prognosis was independent of histological grade. ERK-1/ERK-2 phosphorylation was associated with increased Ki67 and cyclin A indexes, which indicated that ERK-1/ERK-2 pathway activation increased tumor cell proliferation. There was no relationship between ERK-1/ERK-2 phosphorylation and HER-2/neu or p16/INK4a protein expression. In conclusion, ERK-1/ERK-2 pathway is active in salivary gland mucoepidermoid carcinoma and this activation is associated to a more aggressive tumor behavior and a higher proliferative activity. These data suggest that deregulation of ERK-1/ERK-2 pathway contributes to mucoepidermoid carcinoma phenotype and, possibly, represents a target for new anticancer drugs.

Prevalence and significance of rare RYR2 variants in arrhythmogenic right ventricular cardiomyopathy/dysplasia: results of a systematic screening.

BACKGROUND Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a genetic disease predominantly caused by desmosomal gene mutations that account for only ~50% of cases. Ryanodine receptor 2 (RYR2) gene mutations usually cause catecholaminergic polymorphic ventricular tachycardia but have been associated with a peculiar phenotype named ARVC2. OBJECTIVE We aimed to determine the prevalence and phenotype associated with RYR2 mutations in a large ARVC/D population. METHODS We analyzed the whole RYR2 coding sequence by Sanger sequencing in 64 ARVC/D probands without desmosomal gene mutations. RESULTS We have identified 6 rare missense variants: p.P1583S, p.A2213S, p.G2367R, p.Y2932H, p.V3219M, and p.L4670V. It corresponds to a 9% prevalence of rare RYR2 variants in the ARVC/D population (6 of 64 probands), which is significantly higher than the estimated frequency of rare RYR2 variants in controls (Fisher exact test, P = .03). Phenotypes associated with RYR2 variants were similar to desmosome-related ARVC/D, associating typical electrocardiographic abnormalities at rest, frequent monomorphic ventricular tachycardia, right ventricular dilatation, wall motion abnormalities, and fibrofatty replacement when histopathological examination was available. CONCLUSION In this first systematic screening of the whole coding region of the RYR2 gene in a large ARVC/D cohort without mutation in desmosomal genes, we show that putative RYR2 mutations are frequent (9% of ARVC/D probands) and are associated with a conventional phenotype of ARVC/D, which is in contrast with previous findings. The results support the role of the RYR2 gene in conventional ARVC/D.

Loss of Heterozygosity on the Short Arm of Chromosome 3 in Cervical Intra-Epithelial Neoplasia without Concomitant Cervical Carcinoma

Losses of heterozygosity on the short arm of chromosome 3p are common in cervical carcinomas in the 3p13-3p21 region, and can be observed in intra-epipthelial lesions accompanying cervical cancers. As a preliminary attempt to determine whether these losses can be observed in intra-epithelial cervical lesions without concomitant invasive carcinoma, we have used two microsatellite markers located at the two most frequently deleted segments of the 3p13-3p21 region. We have studied 36 cases of grade II and grade III cervical intra-epithelial neoplasias obtained by conisation biopsies and 30 cases of cervical carcinoma including 3 micro-invasive squamous cell carcinomas. We found loss of heterozygosity or microsatellite instability in 6 of 16 (38%) and 9 of 23 (39%) informative cases of cervical carcinoma at 3p13 and 3p21, respectively. Four of 27 (15%) cases of cervical intra-epithelial neoplasia showed loss of heterozygosity at 3p13, whereas loss of heterozygosity or microsatellite instability at 3p21 was found in 5 of 19 cases (26%). No relationship was found between 3p loss of heterozygosity and human papillomavirus infection. In conclusion, losses of heterozygosity at 3p13 and 3p21 occur in premalignant lesions without concomitant invasive lesions. The prevalence and precise extent of these losses should be established by a more extensive analysis.

Expression of Bcl-2 protein in human laryngeal keratoses.

Strong Bcl-2 immunostaining was detected in 2 of 21 samples of human laryngeal keratoses, one of which contained neither p53 gene mutation nor human papillomavirus sequences nor significant levels of p53 protein. The other 19 samples including 6 cases with moderate or strong p53 staining were Bcl-2-unreactive or had minimal Bcl-2 reactivity similar to that observed in normal samples. Minimal Bcl-2 staining in 5 samples with moderate or severe dysplasia was only seen in the adjacent nondysplastic area. Our study shows that (1) some laryngeal keratoses strongly express Bcl-2 protein, (2) Bcl-2 expression does not appear to be dependent on p53, and (3) moderate or severe dysplasias may occur despite a decline in Bcl-2 expression.

Large-vessel vasculitis in human immunodeficiency virus-infected patients

Objective: The objective of this study was to describe large‐vessel vasculitis (LVV) in patients with human immunodeficiency virus (HIV) infection. It is a retrospective single‐center study conducted between 2000 and 2015 through a university hospital of 11 HIV‐infected patients with LVV. Methods: The characteristics and outcome of 11 HIV‐infected patients with LVV (7 patients fulfilled international criteria for Takayasu arteritis, 5 patients had histologic findings of vasculitis, and 5 patients had imaging features of aortitis) were analyzed and compared with those of 82 patients with LVV but without HIV infection. Results: Concerning the HIV‐infected patients with LVV (n = 11), the mean age was 40 years (range, 36‐56 years), and 55% of patients were female. At diagnosis of LLV, the mean initial CD4 cell count was 455 cells/mm3 (range, 166‐837 cells/mm3), and the median HIV viral load was 9241 copies. Vascular lesions were located in the aorta (n = 7), in supra‐aortic trunks (n = 7), and in digestive arteries (n = 3). Inflammatory aorta infiltrates showed a strong expression of interferon‐&ggr; and interleukin 6. In HIV‐negative LVV patients (n = 82), the median age was 42 years, and 88% of the patients were women. Thirty patients had an inflammatory syndrome. Seventy patients had been treated with glucocorticosteroids and 57 with immunosuppressive treatments. Compared with their negative counterparts, HIV‐positive patients with LVV were more frequently male (P = .014), had more vascular complications (ie, Ishikawa score; P = .017), and had more frequent revascularization (P = .047). After a mean follow‐up of 96 months, four relapses of vasculitis were reported, and one patient died. Regardless of the HIV virologic response, antiretroviral therapy improved LVV in only one case. Conclusions: LVV in HIV‐infected patients is a rare and severe entity.

TTR sequencing should be considered ahead of hypertrophic cardiomyopathy in Afro-Americans

Background Amyloid cardiomyopathy is a polymorphic condition with heterogeneous prognosis. Whereas AL amyloid cardiomyopathy is the most frequent type of amyloid cardiopathy, transthyretin (TTR) amyloidosis is often under diagnosed. TTR gene sequencing may be easily performed although usually used after a histological proof of amyloidosis is obtained. We conducted a prospective study to evaluate the interest of TTR gene sequencing in hypertrophic cardiomyopathy with suspicion of amyloidosis before obtaining a histological proof of amyloidosis.