Stroke risk reduction in asymptomatic and symptomatic patients treated surgically: the effectiveness of carotid endarterectomy with patch graft angioplasty

From March 1980 to March 1987, 217 consecutive patients underwent 252 carotid revascularisations with routine use of continuous EEG monitoring and selective use of an intraluminal shunt for symptomatic (70%) or asymptomatic (30%) internal carotid artery (ICA) atherosclerotic stenosis. All carotid endarterectomies were routinely performed with a patch graft angioplasty. None of the patients suffered permanent or transient neurological deficits in the immediate postoperative period and none of them died. There was an 0.8% stroke rate and 0.4% mortality rate in the early postoperative course. Neurological assessment, Doppler and Echo doppler sonography of both the operated and the contralateral ICA was performed every 6 months. One-hundred and twenty-one patients (142 carotid revascularisations) operated on up to December 31st 1985 were reassessed in July 1986. The mean follow-up time was 35 months (range: 6 months to 6 years). New neurological symptoms were present in 7.4% of the patients; 2.5% of patients developed a stroke and 8.9% showed progression of stenosis in the contralateral ICA. One patient had a common carotid artery stenosis 2 years after surgery. Re-stenosis of the ICA was found in two patients who underwent re-operation without difficulty. The late mortality was 21.4% (11.9% of the overall series). In only two patients (7.6%) was stroke the cause of death.     

Comprehensive analysis of HPV infection,EGFR exon 20 mutations and LINE1 hypomethylation as risk factors for malignant transformation of sinonasal-inverted papilloma to squamous cell carcinoma

Different risk factors are suspected to be involved in malignant transformation of sinonasal papillomas and include HPV infection, tobacco smoking, occupational exposure, EGFR/KRAS mutations and DNA methylation alterations. In our study, 25 inverted sinonasal papillomas (ISPs), 5 oncocytic sinonasal papillomas (OSP) and 35 squamous cell carcinomas (SCCs) from 54 patients were genotyped for 10 genes involved in EGFR signalling. HPV-DNA detection was performed by in-situ hybridisation and LINE-1 methylation was quantitatively determined by bisulphite-pyrosequencing. High-risk HPV was observed only in 13% of ISP-associated SCC and in 8% of de novo-SCC patients. EGFR mutations occurred in 72% of ISPs, 30% of ISP-associated SCCs and 17% of de novo-SCCs. At 5-year follow-up, SCC arose in only 30% (6/20) of patients with EGFR-mutated ISPs compared to 76% (13/17) of patients with EGFR-wild-type ISP (p = 0.0044). LINE-1 hypomethylation significantly increased from papilloma/early stage SCC to advanced stage SCC (p = 0.03) and was associated with occupational exposure (p = 0.01) and worse prognosis (p = 0.09). In conclusion, our results suggest that a small subset of these tumours could be related to HPV infection; EGFR mutations characterise those ISPs with a lower risk of developing into SCC; LINE-1 hypomethylation is associated with occupational exposure and could identify more aggressive nasal SCC.     

Role for CXCR6 and its ligand CXCL16 in the pathogenesis of T-cell alveolitis in sarcoidosis

RATIONALE: Receptor expression dictates the spectrum of chemokine actions on immunocompetent cells. We have previously shown that the chemokine receptor CXCR3 is highly expressed by T-helper type 1 (Th1) cells infiltrating the lungs of patients with sarcoidosis. OBJECTIVES: The evaluation of the role of Bonzo/CXCR6 and its ligand CXCL16 in the pathogenesis of sarcoidosis. METHODS: Immunocompetent cells infiltrating sarcoid lung have been evaluated by flow cytometry, confocal microscopy, immunohistochemical and molecular analysis, and functional assays. MAIN RESULTS: Th1 cells isolated from the bronchoalveolar lavage of patients with sarcoidosis and T-cell alveolitis coexpressed CXCR3 and CXCR6. Immunohistochemical analysis of lung specimens has shown that CXCR6+ T cells infiltrated lung interstitium surrounding the central core of the granuloma. The CXCR6 ligand CXCL16 was abundantly expressed by macrophages infiltrating sarcoid tissue and/or forming the granuloma core. From a functional point of view, sarcoid Th1 cells were able to respond to CXCL10 and CXCL16 in migratory assay. In vitro kinetic studies demonstrated that, although CXCR3 was rapidly induced by interleukin (IL)-15 and IL-18, CXCR6 induction was slow (8 d) and mainly regulated by IL-15. CONCLUSIONS: T cells coexpressing CXCR3 and CXCR6 act coordinately with respective ligands and Th1 inflammatory cytokines in the alveolitic/granuloma phases of the disease.     

Circulating endothelial progenitor cells are reduced in peripheral vascular complications of type 2 diabetes mellitus

OBJECTIVES: We sought to establish whether a reduction in endothelial progenitor cells (EPCs) has a putative role in peripheral vascular disease (PVD) of type 2 diabetic patients. BACKGROUND: Peripheral vascular disease is a common and severe complication of diabetes mellitus. Impaired collateralization of diabetic vasculopathy has been extensively shown, but causes leading to its pathogenesis are not fully understood. Recently, EPCs have been found to contribute to vascular repair and angiogenesis. Diabetes has been associated with low levels of circulating EPCs, but no data are available in the literature on the relationship between EPCs and PVD in diabetes. METHODS: Flow cytometric analysis was used to quantify circulating progenitor cells (CPCs, CD34+) and EPCs (CD34+KDR+) in 51 patients and 17 control subjects. RESULTS: The CPCs and EPCs from diabetic patients were reduced by 33% and 40%, respectively, compared with healthy subjects (p < 0.001). An inverse correlation was found between the number of EPCs and the values of fasting glucose (r = -0.49, p = 0.006). Peripheral vascular disease was associated with a 47% reduction in EPCs (p < 0.0001) and EPC levels directly correlated with the ankle-brachial index (r = 0.70, p = 0.01). The subgroup of diabetic patients with PVD also had reduced CPCs by 32% (p = 0.037), whereas patients with ischemic foot lesions had the lowest levels of both EPCs and CPCs (p = 0.02). CONCLUSIONS: Our data demonstrate decreased EPC levels in diabetic patients and, for the first time, show that PVD is associated with an extensively low number of EPCs. Depletion of circulating EPCs in diabetic patients may be involved in the pathogenesis of peripheral vascular complications.     

Spontaneous resolution of p58/EB6 antigen restricted NK-type lymphoproliferative disease of granular lymphocytes: role of Epstein Barr virus infection

We describe a patient with a CD3⁻ lymphoproliferative disease of granular lymphocytes (LDGL) characterized by proliferation of CD3⁻CD16⁺ GL, restricted to the expression of p58/EB6 antigen and lacking the p58/GL183 antigen. Using PCR analysis we demonstrated the presence of EBV DNA in the peripheral blood mononuclear cells and purified CD16⁺ GL from the patient; a monoclonal episomic configuration of the virus could not be demonstrated with Southern blot analysis. The presence of EBV DNA was also detected by PCR in the serum; this finding was associated with a serological pattern consistent with a previous, already seroconverted, EBV infection. During a 4-year follow-up the lymphocytosis spontaneously disappeared; interestingly, in terms of the p58 antigen expression, we provided evidence of the reconstitution of a normal pattern of circulating NK subsets (i.e. p58/EB6⁺ p58/GL183⁻, p58/EB6⁺ p58/GL183⁺, p58/EB6⁻ p58/GL183⁻, p58/EB6⁻ p58/GL183⁺). At the time of resolution of lymphocytosis, EBV-PCR analysis still demonstrated the persistence of EBV DNA in peripheral blood mononuclear cells, but not in the patient's serum.   By indicating that inciting agents (in this case EBV) are involved in inducing the GL proliferation, our data contribute insights into the pathogenetic mechanisms accounting for in vivo GL accumulation in LDGL. It appears that a second, still unknown, event is required to determine the neoplastic transformation.     

Telomere length and telomerase levels delineate subgroups of B-cell chronic lymphocytic leukemia with different biological characteristics and clinical outcomes

Background

B-cell chronic lymphocytic leukemia is a clinically heterogeneous disease; some patients rapidly progress and die within a few years of diagnosis, whereas others have a long life expectancy with minimal or no treatment. Telomere length and telomerase levels have been proposed as prognostic factors; however, very few cases have been characterized for both parameters and no study has analyzed the prognostic value of the telomere/telomerase profile.

Design and Methods

One hundred and seventy-three cases of chronic lymphocytic leukemia were characterized for telomere lengths and telomerase levels by real-time polymerase chain reaction. Data were correlated with established prognostic markers, IGVH mutational status and chromosomal aberrations, and clinical outcome.

Results

Telomere lengths were inversely correlated with telomerase levels (r_s= −0.213; P=0.012), and most of the cases of chronic lymphocytic leukemia with high levels (above median) of telomerase had short (below median) telomeres (P=0.0001). Telomerase levels were higher and telomeres were shorter in unmutated IGVH cases than in mutated IGVH ones (P<0.0001). Chronic lymphocytic leukemias with 11q, 17p deletion or 12 trisomy had significantly higher levels of telomerase and shorter telomeres than those with no chromosomal aberration or the sole 13q deletion (P<0.001). Telomere length/telomerase level profiles identified subgroups of patients with different clinical outcomes (P<0.0001), even within the subsets of chronic lymphocytic leukemia defined by IGVH mutational status or chromosomal aberrations. Short telomere/high telomerase profile was independently associated with more rapid disease progression.

Conclusions

Comprehensive analyses of telomeres, telomerase, chromosomal aberrations, and IGVH mutational status delineate groups of chronic lymphocytic leukemias with distinct biological characteristics and clinical outcomes. The telomere/telomerase profile may be particularly useful in refining the prognosis of chronic lymphocytic leukemia patients with mutated IGVH and no high-risk chromosomal aberrations.