Cardiac resynchronization therapy allows the optimization of medical treatment in heart failure patients.

AIM: Cardiac resynchronization therapy (CRT) is recommended for selected patients with advanced heart failure (HF) despite optimal medical treatment. However, the doses of pharmaceuticals in this population are often limited by adverse effects. We compared the drug regimens of 21 patients before and 6 months after they underwent the implantation CRT systems. METHODS: We studied 17 men and four women (mean age=63.4 ± 11 years) presenting in New York Heart Association HF classes III-IV, and with a left ventricular ejection fraction (LVEF) ≤ 35% and cardiac dyssynchrony, who underwent implantation of CRT systems. RESULTS: At baseline, 52% of patients were treated with ß-adrenergic blockers (ß-B), though in optimal doses in only 19%. The introduction of (ß-B) was complicated by cardiogenic shock in three patients. At baseline, all patients were treated with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB), of whom 76% received optimal doses. After 6 months of CRT, ß-B were administered to 76% of patients, in optimaklon ACE or ARB but 75% of them were receiving maximal doses. After 6 months of CRT, ß blockers have been introduced in 72% of patients and maximal doses have been achieved in 60% of them. Maximal doses of ACE or ARB were reached in 95% of the study population. We noticed that systolic blood pressure was higher after implantation. There was also a significant improvement in functional status and left ventricular ejection fraction compared to baseline. CONCLUSION: CRT is an efficacious adjunctive device therapy to standard medical therapy for patients with heart failure and cardiac dyssynchrony. Its benefits are in addition to those afforded by standard pharmacological therapy. Achieving maximal doses of medical treatment and the possibility of introducing ß blockers after CRT prove that CRT and pharmacological treatment are complementary strategies and should not be considered as competitive.

[The role of B type natriuretic peptide in the assessment of post myocardial infarction prognosis]. / Place du BNP dans l'evaluation du pronostic au décours de l'infarctus du myocarde.

Recently cardiac peptides have received close attention as cardiovascular markers. Brain (B type) natriuretic peptide is a neurohormone synthesized predominantly in ventricular myocardium. Previous studies have shown that this hormone can provide prognostic information in patients with myocardial infarction. The aim of this review is to evaluate the impact of plasma levels of BNP on prediction of left ventricular ejection fraction and remodelling and major cardiac events after myocardial infarction.

[Syphilitic aortic aneurysm. A case report]. / Anévrysme aortique d'origine syphilitique. A propos d'un cas]

The incidence of tertiary syphilis has declined in recent years owing to the early recognition of the disease and use of antibiotics. As a result, syphilitic aortic aneurysms are rarely encountered nowadays. We report the case of a 65 years old man, who was admitted to our hospital in June 2004 for dyspnea, cough and chest discomfort. On physical examination, blood pressure was 130/80 mmHg with no significant laterality, pulse rate was 70 per minute and there was a decrease of breath sounds over the right lung. Laboratory findings revealed a slight elevation of the erythrocyte sedimentation rate. Serological studies for syphilis showed a positive venereal disease laboratory test (VDRL) at 1/32 and a positive Treponema pallidum hemagglutination test (TPHA) at 1/2560. The chest radiography showed a right para cardiac opacity measuring 16 x 12 cm. Fiber optic bronchoscopy showed an extrinsic compression of the right upper lobar bronchus. Gadolinium-enhanced magnetic resonance angiography and 16 multidetector-row spiral computed aortography showed a huge partially thrombosed saccular aneurysm of the ascending aorta measuring 132 mm in diameter. The circulating lumen measured 53 mm in its largest diameter. This aneurysm involved the innominate artery. There was no other arterial involvement. The patient was given a three week course of intravenous penicillin followed by a successful surgical procedure in September 2004 with ascending aortic replacement and innominate artery reimplantation. This case illustrates well a formerly common, but now extremely rare disease.

Expression of vascular endothelial growth factor mRNA in non-small-cell lung carcinomas.

The vascular endothelial growth factor (VEGF) has been shown to be strictly related to vascular permeability and endothelial cell growth under physiological and pathological conditions. In tumour development and progression, VEGF plays a pivotal role in the development of the tumoral vascular network, and useful information in the progression of human cancer can be obtained by analysing the vascular endothelial growth factor expression of the tumours. In this study, we investigated the vascular endothelial growth factor transcript expression in non-small-cell lung carcinomas to evaluate the significance of this factor in a group of cancers in which the vascular pattern has been shown to significantly affect progression. Surgical samples of 42 patients with NSCLC were studied using reverse transcription polymerase chain reaction (PCR) analysis and in situ hybridization. Thirty-three out of 42 cases (78.6%) showed VEGF transcript expression predominantly as transcripts for the secretory forms of VEGF (isoforms 121 and 165). In situ hybridization, performed on 24 out of 42 samples, showed that the VEGF transcript expression was in several cases present in the cytoplasm both of neoplastic and normal cells, even if the VEGF mRNA was less expressed in the corresponding non-tumoral part. The VEGF 121 expression was associated with hilar and/or mediastinal nodal involvement (P = 0.02), and, taken together, the VEGF isoforms were shown to significantly influence overall (P = 0.02) and disease-free survival (P = 0.03). As a regulator of tumour angiogenesis, VEGF may represent a useful indicator of progression and poor prognosis in non-small-cell lung carcinomas.

Thrombospondins I and II messenger RNA expression in lung carcinoma: relationship with p53 alterations, angiogenic growth factors, and vascular density.

Thrombospondin (TSP) is a Mr 450,000 multifunctional matrix glycoprotein that interferes with tumor growth, angiogenesis, and metastasis. It has recently been shown that TSP expression is enhanced by the product of the p53 gene and that a down-regulation of TSP may be observed when alterations of the p53 protein occur. Moreover, a number of studies have demonstrated a regulatory activity of p53 on human vascular endothelial growth factor (VEGF), although additional investigations will be necessary to understand their relationship. In non-small cell lung carcinoma (NSCLC), neoangiogenesis, p53 alterations, and VEGF expression seem to have meaningful implications in the development and progression of this type of cancer. The aim of this study is to identify and quantitate TSP I and TSP II mRNA in NSCLCs with respect to p53 alterations, angiogenic growth factor expression, and microvascular density. A series of 24 cases of NSCLC were analyzed. Eleven of 24 of the cases were positive for TSP II mRNA, whereas 8 of 24 showed TSP I mRNA expression. A significant inverse association was found between TSP I mRNA and fibroblast growth factor (FGF) protein expression (P = 0.00001). Tumors with low FGF protein expression (< or = 40% of positive cells) presented a number of TSP I cDNA molecules, significantly higher than tumors expressing high levels of FGF protein. No association was found between TSP mRNA expression and other angiogenic growth factors (i.e., VEGF) or tumoral neovascularization. On the contrary, tumors with high levels of FGF showed a higher number of microvessels (P = 0.05). By PCR-single-strand conformational polymorphism analysis, we observed aberrations of the p53 gene in 19 of the 24 tumor samples. No association was found between p53 alterations and TSP mRNA expression. Instead, an interestingly significant association was found between the presence of p53 mutations and high VEGF protein expression (P = 0.01) and neovascularization (P = 0.03). Highly vascularized tumors showed higher VEGF protein expression (r = 0.45; P = 0.02). These data support the concept that in NSCLC, p53 exerts an important role in the control of neoangiogenesis. This influence is probably mediated by VEGF. The inverse association we found between TSP I and basic FGF suggests a different role of TSP I and TSP II in the angiogenic "switch," supporting the hypothesis that especially TSP I may have a significant function in tumor angiogenesis.

Bcl2 and p53 regulate vascular endothelial growth factor (VEGF)-mediated angiogenesis in non-small cell lung carcinoma.

The aim of this study was to investigate the expression of p53 and bcl2 proteins in a series of 107 non-small cell lung cancers (NSCLC), and to relate such protein expression to neovascularisation and the expression of vascular endothelial growth factor (VEGF). Moreover, we analysed the prognostic impact of these biological parameters on overall survival, both in univariate and multivariate analyses. An inverse association was found between bcl2 expression and microvessel count (MVC; P = 0.0004) and bcl2 and VEGF (P = 0.007). In contrast, a significant association was found between p53 expression and MVC (P = 0.03) and p53 and VEGF expression (P = 0.04). In univariate analysis, nodal status (P < 0.000001), MVC (P < 0.000001), bcl2 (P = 0.002), p53 (P = 0.03) and VEGF expression (P < 0.000001) significantly affected overall survival, but in multivariate analysis only MVC and VEGF expression retained their prognostic influence. Our results suggest that bcl2 and p53 possibly control the development of tumour angiogenesis in NSCLC, with putative mediation by VEGF. Moreover, the important influence of angiogenesis in the progression of NSCLC is further highlighted.

Evaluation of epidermal growth factor-related growth factors and receptors and of neoangiogenesis in completely resected stage I-IIIA non-small-cell lung cancer: amphiregulin and microvessel count are independent prognostic indicators of survival.

We have determined the expression of transforming growth factor alpha (TGF alpha), amphiregulin (AR), CRIPTO, the epidermal growth factor receptor (EGFR), erbB-2, erbB-3, and tumor angiogenesis in a series of 195 patients with stage I-IIIA non-small cell lung cancer (NSCLC) treated with radical surgery to define their usefulness as prognostic indicators of survival. A variable degree of specific staining in cancer cells was observed for the three growth factors and for the three growth factor receptors in the majority of NSCLC patients. A statistically significant association between overexpression of TGF alpha, AR, and CRIPTO was observed. Enhanced expression of AR was significantly correlated with enhanced expression of erbB-2 and advanced T-stage. A direct association was also detected for overexpression of TGF alpha and of erbB-2 or erbB-3, respectively. Sex, tumor size, nodal status, stage, microvessel count, as a measure of neovascularization, and AR overexpression significantly correlated with overall survival at univariate analysis. In a Cox multivariate analysis, the only characteristics with an independent prognostic effect on OAS were microvessel count [relative hazard (RH), 6.61; P < 0.00001), nodal status (RH, 1.59; P = 0.0013), and AR overexpression (RH, 1.72; P = 0.02). These results suggest that evaluation of neoangiogenesis and of certain growth factors, such as AR, can be useful in addition to conventional pathological staging to select high-risk NSCLC patients who may benefit from post-surgical systemic therapies.

Vascular endothelial growth factor is associated with neovascularization and influences progression of non-small cell lung carcinoma.

Vascular endothelial growth factor (VEGF) plays a pivotal role in the development of neovascularization in both physiological and pathological processes, e.g., developmental and reproductive angiogenesis, proliferative retinopathies, and cancers. Several solid tumors produce ample amounts of VEGF, which stimulates proliferation and migration of endothelial cells, thereby inducing neovascularization by a paracrine mechanism. Recently, VEGF expression has been shown to significantly affect the prognosis of different kinds of human cancer. Because neoangiogenesis represents an important prognostic indicator of poor prognosis in non-small cell lung cancer (NSCLC), we investigated the influence of VEGF during progression of this type of cancer and its relationship to tumoral neovascularization. VEGF expression was significantly associated with new vessel formation (r = 0.44; P < 0.0001). Moreover, in univariate analysis, VEGF expression significantly affected overall and disease-free survival (P = 0.00003 and P = 0. 0004, respectively). Backward stepwise regression analysis indicated that VEGF expression was an independent prognostic factor in patients with NSCLC. These findings support the hypothesis that VEGF is an important angiogenic factor in primary NSCLC and may help in predicting the outcome of this group of cancers.

8-Chloro-cyclic AMP inhibits autocrine and angiogenic growth factor production in human colorectal and breast cancer.

8-Chloro-cyclic AMP (8-Cl-cAMP) is a cAMP analogue that specifically down-regulates type I protein kinase A, a signaling protein directly involved in cell proliferation and neoplastic transformation, and that causes growth inhibition in a variety of human cancer cell types. In this report, we have investigated the effects of 8-Cl-cAMP on the expression of several growth factors in human colon (GEO and LS174T) and breast (MDA-MB468) cancer cell lines. 8-Cl-cAMP treatment caused in the three cancer cell lines a significant dose- and time-dependent inhibition in the expression of various endogenous autocrine growth factors, such as transforming growth factor alpha, amphiregulin, and CRIPTO, and of two angiogenic factors, such as vascular endothelial growth factor and basic fibroblast growth factor, at both the mRNA and protein levels. Furthermore, 8-Cl-cAMP treatment markedly inhibited the ability of all three cell lines to invade a basement membrane matrix in a chemoinvasion assay. Finally, 8-Cl-cAMP-induced inhibition of GEO tumor growth in nude mice was accompanied by a significant suppression of transforming growth factor alpha, amphiregulin, CRIPTO, basic fibroblast growth factor, and vascular endothelial growth factor production by the tumor cells, and of neoangiogenesis, as detected by factor VIII staining of host blood cells. These results demonstrate that 8-Cl-cAMP is a novel anticancer drug that inhibits the production of various autocrine and paracrine tumor growth factors that are important in sustaining autonomous local growth and facilitate invasion and metastasis.

67-Kilodalton laminin receptor expression correlates with worse prognostic indicators in non-small cell lung carcinomas.

Tumor samples obtained from 72 patients resected for non-small cell lung cancer were stained immunohistochemically using an immunoperoxidase method and the MLuC5 monoclonal antibody specific for the 67-kDa laminin receptor. Sixty-one of 72 patients (84.7%) displayed a MLuC5-positive reaction, which was usually localized in both the inner surface of the plasmatic membranes and the cytoplasm of neoplastic cells. When we compared the laminin receptor expression with clinicopathological and biological parameters such as histotype, grading, T status, N status, ploidy, proliferative activity, vessel invasion, and p53 protein accumulation, the following results were observed: (a) the mean expression of the receptor was higher in the group of patients with metastatic nodal involvement than in those with uninvolved lymph nodes (P = 0.02); (b) a high Ki-67 score (>13% of positive cells) was observed in tumors with a higher mean value of laminin receptor (P = 0.004); (c) the tumors harboring neoplastic emboli in their vessels showed a higher laminin receptor immunoreactivity (P = 0.02); and (d) a borderline association was found between the high mean value of laminin receptor immunopositivity and p53 accumulation in neoplastic cell nuclei (P = 0.05). Our observations indicate that detection of high tissue levels of 67-kDa laminin receptor is associated with an invasive phenotype in non-small cell lung cancer and may provide further information in the biological characterization of this type of cancer.

Neoangiogenesis and p53 protein in lung cancer: their prognostic role and their relation with vascular endothelial growth factor (VEGF) expression.

Following up-regulation of an angiogenesis inhibitor by the wild-type p53 protein proven recently, we have analysed on the one hand the prognostic impact of microvessel count (MC) and p53 protein overexpression in non-small-cell lung carcinoma (NSCLC) progression and, on the other hand, the inter-relation between the microvascular pattern and the p53 protein expression. Moreover, we assessed the expression of vascular endothelial growth factor (VEGF), one of the pivotal mediators of tumour angiogenesis, in order to investigate its relation to p53 protein expression and MC. Tumours from 73 patients resected for NSCLC between March 1991 and April 1992 (median follow-up 47 months, range 32-51 months) were analysed using an immunohistochemical method. In univariate analysis, MC and p53 accumulation were shown to affect metastatic nodal involvement, recurrence and death significantly. Multiple logistic regression analysis showed an important prognostic influence of MC and nodal status on overall (P = 0.0009; P = 0.01) and disease-free survival (P = 0.0001; P = 0.03). Interestingly, a strong statistical association was observed between p53 nuclear accumulation and MC (P = 0.0003). The same inter-relationship was found in non-squamous histotype (P = 0.002). When we analysed the concomitant influence of MC and p53 expression on overall survival, we were able to confirm a real predominant role of MC in comparison with p53. With regard to VEGF expression, p53-negative and lowly vascularized tumours showed a mean VEGF expression significantly lower than p53-positive and highly vascularized cancers (P = 0.02). These results underline the prognostic impact of MC and p53 protein accumulation in NSCLC and their reciprocal inter-relationship, supporting the hypothesis of a wild-type p53 regulation on the angiogenetic process through a VEGF up-regulation.

Recurrence and death in non-small cell lung carcinomas: a prognostic model using pathological parameters, microvessel count, and gene protein products.

The 5-year survival rate of non-small cell lung carcinoma (NSCLC) has only marginally improved during the past two decades, despite advances in surgery and chemoradiotherapy. Major efforts are currently directed toward biological characterization of these tumors to define biomarkers able to add further prognostic information, thus improving new therapeutic protocols. We analyzed the predictive relevance of the microvessel count (MC), bcl-2 and p53 proteins, proliferative activity, and usual postsurgical parameters on recurrence and overall survival in a series of 70 patients with NSCLC. The expression of biological parameters (p53, bcl-2, proliferative activity, and MC) was detected using immunohistochemistry on paraffin-embedded and frozen sections from the tumors treated with surgical resection alone until relapse. In the univariate analysis, the histotype, tumor status, node status, p53, bcl-2, and MC have been shown to significantly affect progression and death. In the multiple logistic regression analysis, the MC (P < 0.000001), tumor status (P < 0.005), and node status (P < 0.0002) influenced the overall survival while prediction of relapse was strongly revealed by tumor status (P < 0.005), nodal metastatic involvement (P < 0.000001), and the assessment of the vascular count (P < 0.0004). These data have allowed the creation of a multivariate model which may add more information on risk of recurrence and death in patients with NSCLC and can form the basis for future randomized clinical trials.

Microvessel count predicts metastatic disease and survival in non-small cell lung cancer.

The growth of newly formed vessels, or neoangiogenesis, represents an important step in both physiological and pathological situations: in particular, tumour growth and metastasis require angiogenesis. Microvessel count (MC), which represents a measure of tumour angiogenesis, has been associated with metastatic spread in cutaneous, mammary, prostatic, head and neck, and early-stage lung cancer. In this study, the role of tumour angiogenesis as a prognostic indicator was examined in 253 primary non-small lung cancer (NSCLC) patients. Microvessels were counted by highlighting endothelial cells with anti-Factor VIII monoclonal antibody (Mab) in methacarn-fixed tumour samples. In univariat analysis, MC (P< 0.000001), sex (P=0.0036), histotype (P < 0.014), tumour status (P <0.007), and vessel invasion (P < 0.019) were significantly related to hilar and/or mediastinal nodal involvement. However, in the stepwise logistic regression analysis, MC (P<0.000003) retained the most important influence on nodal metastasis. The overall survival analysis calculated by the Kaplan-Meier method revealed that tumours with high MC ( > 25 vessels/field) were significantly associated with increased death risk (log-rank test P = 0.00067; Cox's test P = 0.00046; Gehan's Wilcoxon test P = 0.00108). In 94 patients, the development of metastatic disease during follow-up was significantly related to MC. Indeed, patients who developed metastasis during follow-up showed a higher MC, either as a dichotomous (P = 0.01) or as a continuous (P = 0.003) variable, than patients who had developed no metastasis at the time of the analysis. Moreover, in the stepwise logistic regression analysis, MC retained the most important influence on distant metastases.(ABSTRACT TRUNCATED AT 250 WORDS)