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Biomedical subjects

Stefano Margaritora

Publications and source records attributed to Stefano Margaritora.

At least 19 recordsLinked to original sources
PubMed2006

Multimodality treatment of unresectable stage III non-small cell lung cancer: interim analysis of a phase II trial with preoperative gemcitabine and concurrent radiotherapy.

OBJECTIVE: We report the preliminary results of a phase II trial undertaken to determine the feasibility and efficacy of gemcitabine and concurrent radiotherapy in patients with inoperable stage III non-small cell lung cancer. METHODS: Between February 2001 and June 2003, a total of 46 patients (37 male and 9 female, median age 64 years) with clinical stage III non-small cell lung cancer (41 cIIIA and 5 cIIIB) were enrolled in a combined chemoradiation protocol with gemcitabine as the chemotherapeutic agent. Gemcitabine (350 mg/m2) was administered weekly for 5 consecutive weeks as a 30-minute intravenous infusion before radiotherapy (total dose 50.4 Gy, 1.8 Gy/d). Toxicity was routinely assessed. Those patients with disease judged to be resectable at restaging underwent surgery. RESULTS: Toxicity was moderate, with the exception of 1 grade 3 thrombocytopenia. All but 5 patients were available for restaging. No complete responses were observed. Thirty-four patients (82.9%) had partial responses, 5 (12.2%) had stable disease, and 2 (4.9%) had progressive disease. Twenty-nine of 46 patients (63%, 27 cIIIA and 2 cIIIB) underwent surgery. Radical resection was possible in all cases. Surgery included 17 lobectomies, 4 bilobectomies, and 8 pneumonectomies. There were no deaths. Morbidity was 13.8% (4/29). Pathologic downstaging to stage 0 or I was observed in 18 patients (39%, 18/46). After a median follow-up of 13 months (range 2-28 months), 24 of the patients who had undergone operation (86.2%) were alive, with a median disease-free survival of 16 months. Overall 2-year survival was 66.1%, with a significant difference between resected and unresected disease (82% vs 36%, P = .0002). CONCLUSION: The results of this induction trial confirm the feasibility and the efficacy of gemcitabine with concurrent radiotherapy.

Aged↗
PubMed2005

Tumor necrosis factor enhances SN38-mediated apoptosis in mesothelioma cells: the role of nuclear factor-kappaB pathway activation.

BACKGROUND: Despite the best and most aggressive, often integrated, standard therapeutic approaches for mesothelioma, overall survival remains very poor. The actual failure points out clearly the need for the development of novel therapy. One of the promising paths of experimentation is artificial induction of apoptosis. A therapeutic strategy that relies on the down-regulation of BCL-XL inhibition nuclear factor kappaB (NF-kappaB) with a combination of SN38 and tumor necrosis factor (TNF) was studied in human mesothelioma cell lines (MSTO-221H, IST-MES1, IST-MES2, MPP89, H28, H513, H2052, and H290). METHODS AND RESULTS: Cell proliferation (clonogenic assay) was inhibited strongly by the combination of TNF and SN38. Examining the persistence of the NF-kappaB complexes using an electrophoretic mobility-shift assay, it appeared that they still were present at 24 hours in TNF-treated cells. In SN38-treated cells, NF-kappaB complexes persisted for 6 hours. In cells that were treated with combined SN38 and TNF, NF-kappaB complexes disappeared quickly and became undetectable at 6 hours. In flow cytometry analysis, only cells that were treated with combined SN38 and TNF demonstrated significant cellular accumulation in the sub-G0-G1 phase, suggesting a specific induction of apoptosis. Morphologic examination (4,6-diamidino-2-phenylindole staining and electron microscopy) and internucleosomal DNA fragmentation (gel ladder) confirmed rigorously the induction of apoptosis. CONCLUSIONS: Because of NF-kappaB inhibition with the combination of SN38 and TNF, the expression of BCL-XL (both the protein [Western blot analysis] and the mRNA [reverse transcriptase-polymerase chain reaction analysis]) was down-regulated, cytochrome c was released into the cytoplasm, caspase 3 was activated (Western blot analysis), and, consequently, apoptosis was triggered. The authors hope that the results of the current study may contribute to the design and implementation of a novel therapeutic approach that improves patients' responses to treatment for mesothelioma.

Apoptosis↗
PubMed2005

Farnesyltransferase inhibitors and human malignant pleural mesothelioma: a first-step comparative translational study.

It is known that the potential clinical use of farnesyltransferase inhibitors (FTI) could be expanded to include cancers harboring activated receptor tyrosine kinases. Approximately 70% of malignant pleural mesotheliomas (MPM) overexpress epidermal growth factor receptors (EGFR) and a subset express both EGFR and transforming growth factor alpha (TGF-alpha), suggesting an autocrine role for EGFR in MPM. We checked on MPM cells (10 human cell lines, 11 primary cultures obtained by human biopsies, and 7 short-term normal mesothelial cell cultures) concerning the following: (a) the relative overexpression of EGFR (Western blotting, flow cytometry, immunohistochemistry), (b) the relative expression of EGFR ligands (EGF, amphiregulin, TGF-alpha, ELISA), (c) the relative increase of the activated form of Ras (Ras-bound GTP) after EGF stimulation (Ras activation assay), (d) the efficacy of five different FTIs (HDJ2 prenylation, cell cytotoxicity, and apoptosis using ApopTag and gel ladder). EGFR was overexpressed in MPM cells compared with normal pleural mesothelial cells in equivalent levels as in non-small cell lung cancer cells A459. MPM cells constitutively expressed EGFR ligands; however, Ras activation was attenuated at high EGF concentrations (100 ng/mL). Growth of MPM cells was substantially not affected by treatment with different FTIs (SCH66336, BMS-214662, R115777, RPR-115135, and Manumycin). Among these, BMS-214662 was the only one moderately active. BMS-214662 triggered apoptosis in a small fraction of cells (not higher than 30%) that was paralleled by a slight decrease in the levels of TGF-alpha secreted by treated MPM cells. Our data highlighted the concept that the same signaling pathway can be regulated in different ways and these regulations can differ between different cells of different origin.

Alkyl and Aryl Transferases↗
PubMed2005

Gene expression signature for angiogenic and nonangiogenic non-small-cell lung cancer.

Angiogenesis is regarded as essential for tumour growth. However, we have demonstrated that some other aggressive non-small-cell lung carcinomas (n-SCLC) do not have angiogenesis. In this study, using cDNA microarray analysis, we demonstrate that angiogenic and nonangiogenic tumour types can be distinguished by their gene expression profiles. Tissue samples from 42 n-SCLC patients were obtained with consent. In all, 12 tumours were nonangiogenic and 30 angiogenic. The two groups were matched by age, sex, smoking and tumour stage. Total RNAs were extracted followed by microarray hybridization and image scan procedure. Data were analysed using GeneSpring 5.1 software. A total of 62 genes were found to be able to separate angiogenic from nonangiogenic tumours. Nonangiogenic tumours have higher levels of genes concerned with mitochondrial metabolism, mRNA transcription, protein synthesis and the cell cycle. Angiogenic tumours have higher levels of genes coding for membrane vesicles, integrins, remodelling, angiogenesis and apoptosis. These results further support our first finding that nonangiogenic lung tumours are fast-growing tumours filling the alveoli in the absence of vascular remodelling. We raise the hypothesis that in nonangiogenic tumours, hypoxia leads to a higher activation of the mitochondrial respiratory chain, which allows tumour growth without triggering angiogenesis.

Carcinoma, Non-Small-Cell Lung↗
PubMed2004

Alpha7-nicotinic acetylcholine receptors affect growth regulation of human mesothelioma cells: role of mitogen-activated protein kinase pathway.

This study presents data suggesting that both human mesothelioma (cell lines and human mesothelioma biopsies) and human normal mesothelial cells express receptors for acetylcholine and that stimulation of these receptors by nicotine prompted cell growth via activation of nicotinic cholinergic receptors. Thus, these data demonstrate that: (a) human mesothelioma cells and human biopsies of mesothelioma as well as of normal pleural mesothelial cells express functionally alpha-7 nicotinic acethlycholine receptors, evaluated by alpha-bungarotoxin-FITC binding, receptor binding assay, Western blot, and reverse transcription-PCR; (b) choline acetyltransferase immunostaining is present in mesothelioma cells; (c) mesothelioma cell growth is modulated by the cholinergic system in which agonists (i.e., nicotine) has a proliferative effect, and antagonists (i.e., curare) has an inhibitory effect, evaluated by cell cloning, DNA synthesis and cell cycle; (d) nicotine induces Ca(+2) influx, evaluated by [(45)Ca(2+)] uptake, and consequently activation of mitogen-activated protein kinase pathway (extracellular signal-regulated kinase and p90(RSK) phosphorylation), evaluated by Western blot; and (e) apoptosis mechanisms in mesothelioma cells are under the control of the cholinergic system (nicotine antiapoptotic via induction of nuclear factor-kappaB complexes and phosphorylation of Bad at Ser(112); curare proapoptotic via G(0)-G(1) arrest p21(waf-1) dependent but p53 independent). The involvement of the nonneuronal cholinergic system in mesothelioma appears reasonable and open up new therapeutic strategies.

Apoptosis↗
PubMed2004

Pulmonary inverted Schneiderian papilloma.

Pulmonary inverted Schneiderian papilloma (ISP) is a very rare entity. We herein describe a case that, for its clinical and pathologic features, proved to be challenging.

Humans↗
PubMed2004

Non-small cell lung cancer: from cytotoxic systemic chemotherapy to molecularly targeted therapy.

Surgery is the only method of cure in lung cancer. Seldom its application with radical intent is possible. Despite the efforts aimed at integrating all the therapeutic strategies, the overall outcome of the management of this disease remains disappointing. For this reason, in the last three decades, thousands of preclinical and clinical attempts have been realised in order to investigate any possible way to cure this disease and significant steps forward have been made on the basis of the increasing "molecular knowledge" in the so called "post-genomic era". Particularly the impressive step forward in the biological characterization of cancer as a result of genetic/epigenetic multistep process has brought in a multitude of variables with staggering classification potentialities. "Benchside" and "bedside" scientists have assembled in functional teams to move the common efforts "translationally" to bridge basic and clinical research for a mutual synergistic enhancement. This paper represents the effort of a lung cancer focused translational research team made up of molecular biologists, medical oncologists and thoracic surgeons to achieve a comprehensive, but simple, review of the current status of the shift from cytotoxic to molecularly targeted therapy in lung cancer treatment potentially useful in the planning of translational research trials.

Angiogenesis Inhibitors↗