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Background: Lapatinib is a dual inhibitor of epidermal growth factor receptor (EGFR) and human EGFR-2 (HER-2) tyrosine kinases. This study investigated the pharmacodynamic and clinical effects of lapatinib in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).Methods: In total, 107 therapy-naive patients with locally advanced SCCHN were randomised (2 : 1) to receive lapatinib or placebo for 2-6 weeks before chemoradiation therapy (CRT). Endpoints included apoptosis and proliferation rates, clinical response, and toxicity.Results: Versus placebo, lapatinib monotherapy did not significantly increase apoptosis detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labelling or caspase-3 assays. A statistically significant decrease in proliferation using Ki67 assay was observed (P=0.030). In a subset of 40 patients that received 4 weeks of lapatinib or placebo, objective response rate (ORR) was 17% (n=4/24) vs 0% (n=0/16). In the lapatinib single-agent responders, all had EGFR overexpression, 50% had EGFR amplification, and 50% had HER2 expression by immunohistochemistry (including one patient with HER2 amplification). However, these patients showed variable modulation of apoptosis, proliferation, and phosphorylated EGFR on drug treatment. Following CRT, there was a statistically non-significant difference in ORR between lapatinib (70%) and placebo (53%). There was no clear correlation between changes in apoptosis or proliferation and response to chemoradiation. Mucosal inflammation, asthenia, odynophagia, and dysphagia were the most commonly reported adverse events with lapatinib.Conclusion: Short-term lapatinib monotherapy did not demonstrate apoptotic changes, but provided evidence of clinical activity in locally advanced SCCHN, and warrants further investigation in this disease. [ABSTRACT FROM AUTHOR]

Background: Imatinib induces responses and disease stabilisations in non-resectable patients with aggressive fibromatosis (AF). The precise target of imatinib in AF and predictive factors for response to treatment are unknown.Methods: We investigated factors potentially predictive of response to imatinib in a series of 40 patients with progressive AF included in a phase II trial of imatinib: we tested the presence of KIT exon 10 variant (M541L), the expression of imatinib-sensitive kinases and cell cycle proteins by immunohistochemistry (IHC), and other clinical and biological factors.Results: Of 10 patients for whom DNA could be extracted, 3 had a KIT exon 10 variant (30%), with no correlation with response or progression-free survival (PFS). The expression of other imatinib targets (PDGFRA/B, macrophage colony-stimulating factor receptor (M-CSFR)) and of downstream components of the cell cycle, cell proliferation and proliferation pathway (cyclin D1, ERK, MEK 1-2) did not correlate with PFS. Pre-treatment lymphopenia (<1500/microl) and tumour size >120 mm correlated with shorter PFS in univariate and multivariate analyses.Conclusion: Our findings show that a baseline biological characteristic of the patient is the major parameter influencing response to imatinib in aggressive fibromatosis. Tumour characteristics, including the presence of a KIT exon 10 M541L variant, may influence tumour control but this needs to be confirmed and better explained. [ABSTRACT FROM AUTHOR]

Studies the treatment for the disease cutaneous melanoma. Clinical diagnosis and histopathological assessment of the disease; Need for removal of cutaneous lesion instead of a biopsy; Description of therapeutic strategies followed for the disease.

Background Recent studies have shown that interleukin-2 (IL2) is less toxic when administered subcutaneously than intravenously. Moreover interferon a and Dacarbazine could increase the efficiency of IL2. Patients and methods Nineteen ambulatory patients with metastatic melanoma (I stage III and 18 stage IV) were treated with an association of dacarbazine 400 mg/m[sup2], interferon α[sub2a] (Roferon) 9 × 10[sup6] IU 3 times per week administered subcutaneously and recombinant interleukin-2 (IL-2) (Eurocetus) 3 × 10[sup6] IU five days per week for two weeks per month subcutaneously. The treatment consisted of 2 induction cures separated by a one-month interval followed by evaluation studies. Results At the end of the induction phase, 2 complete and 3 partial responses (response rate 26.2%) were observed. These responses were obtained in patients with sinus (1 case), skin (3 cases), lymph node (2 cases), bone (1 case) and liver (1 case) targets. The mean response period was 10 months for the 2 complete responses. No patients had grade 4 toxicity, and treatment was stopped for only one patient. Painful subcutaneous nodules frequently (23%) formed at the injection site. Conclusion The association of subcutaneously administered dacarbazine, interferon α and IL2 would thus seem of interest for the treatment of metastatic melanoma. Moreover, toxicity is tolerable and compatible with ambulatory treatment ensuring the patient a decent quality of life. [ABSTRACT FROM AUTHOR]

Interferons (IFNs) are very promising fluorouracil (FU) biochemical modulators. The pharmacological origin sustaining the FU-IFN synergistic interaction is not clearly understood. It was recently shown that alpha-IFN was associated with a dose-dependent decrease in FU clearance in treated patients. Dihydropyrimidine dehydrogenase (DPD) is the key regulating enzyme for FU catabolism. The effects on DPD exerted by both the IFN dose and the duration of exposure were evaluated in a panel of five human cancer cell lines. All cell lines investigated exhibited quantifiable DPD activity with inter-cell-line variability (0.118-0.318 nmol min-1 mg protein-1). A prolonged exposure to IFN (up to 5 days) was necessary to obtain a significant inhibition of DPD activity. A concentration-dependent significant decrease in DPD activity, reaching 50% of the initial activity determined for the highest IFN concentration (10(5) IU/ml), was demonstrated in all cell lines tested (5-day IFN exposure). For three cell lines, IFN potentiated the FU-induced growth inhibition in a concentration-dependent manner. Considering all cell lines and all IFN concentrations, it appears that globally, the greater the inhibition of DPD activity, the greater the FU potentiation (Spearman rank correlation on all cell lines, P = 0.011). [ABSTRACT FROM AUTHOR]

Tumor-tissue and plasma concentrations of platinum were studied prospectively in two groups of eight patients who were suffering from advanced non-small-cell lung cancer. Treatments including two different schedules of cisplatin administration (25 vs 100 mg/m2 on day 1) were compared. At 30 min after the beginning of the cisplatin infusion, blood samples and bronchoscopically obtained biopsy specimens were taken for determinations of platinum concentrations by means of flameless atomic absorption spectrophotometry. The procedure did not induce any complication. Total plasma platinum concentrations at 30 min were significantly lower (P less than 0.01) in patients receiving 25 mg/m2 (0.49 +/- 0.23 microgram Pt/ml) than in those receiving 100 mg/m2 (1.44 +/- 0.62 micrograms Pt/ml), whereas no significant difference was observed in tumor-tissue platinum concentrations (22.49 +/- 53.89 ng Pt/mg in patients receiving 25 mg/m2 vs 51.13 +/- 65.52 ng Pt/mg in those receiving 100 mg/m2). There was a weak correlation between simultaneous plasma and tumor-tissue platinum concentrations at 30 min. Tumor-tissue platinum concentrations seem to be poorly influenced by the cisplatin dose. This finding suggests a great interindividual variability of platinum tumor-diffusion properties in non-small-cell lung cancer. [ABSTRACT FROM AUTHOR]