Identification by MicroRNA Analysis of Environmental Risk Factors Bearing Pathogenic Relevance in Non-Smoker Lung Cancer.

MicroRNA and DNA adduct biomarkers may be used to identify the contribution of environmental pollution to some types of cancers. The aim of this study was to use integrated DNA adducts and microRNAs analyses to study retrospectively the contribution of exposures to environmental carcinogens to lung cancer in 64 non-smokers living in Sicily and Catania city near to the Etna volcano. MicroRNAs were extracted from cancer lung biopsies, and from the surrounding lung normal tissue. The expression of 2549 human microRNAs was analyzed by microarray. Benzo(a)Pyrene-DNA adducts levels were analyzed in the patients' blood by HPLC-fluorescence detection. Correlations between tetrols and environmental exposures were calculated using Pearson coefficients and regression variable plots. Compared with the healthy tissue, 273 microRNAs were downregulated in lung cancer. Tetrols levels were inversely related both with the distance from Etna and years since smoking cessation, but they were not significantly correlated to environmental exposures. The analysis of the microRNA environmental signatures indicates the contribution of environmental factors to the analyzed lung cancers in the following decreasing rank: (a) car traffic, (b) passive smoke, (c) radon, and (d) volcano ashes. These results provide evidence that microRNA analysis can be used to retrospectively investigate the contribution of environmental factors in human lung cancer occurring in non-smokers.

Relationship between the miRNA Profiles and Oncogene Mutations in Non-Smoker Lung Cancer. Relevance for Lung Cancer Personalized Screenings and Treatments.

Oncogene mutations may be drivers of the carcinogenesis process. MicroRNA (miRNA) alterations may be adaptive or pathogenic and can have consequences only when mutation in the controlled oncogenes occurs. The aim of this research was to analyze the interplay between miRNA expression and oncogene mutation. A total of 2549 miRNAs were analyzed in cancer tissue-in surrounding normal lung tissue collected from 64 non-smoking patients and in blood plasma. Mutations in 92 hotspots of 22 oncogenes were tested in the lung cancer tissue. MicroRNA alterations were related to the mutations occurring in cancer patients. Conversely, the frequency of mutation occurrence was variable and spanned from the k-ras and p53 mutation detected in 30% of patients to 20% of patients in which no mutation was detected. The prediction of survival at a 3-year follow up did not occur for mutation analysis but was, conversely, well evident for miRNA analysis highlighting a pattern of miRNA distinguishing between survivors and death in patients 3 years before this clinical onset. A signature of six lung cancer specific miRNAs occurring both in the lungs and blood was identified. The obtained results provide evidence that the analysis of both miRNA and oncogene mutations was more informative than the oncogene mutation analysis currently performed in clinical practice.

Oxaliplatin-Based Chemotherapy in Patients with Metastatic Colorectal Cancer Aged at Least 75 Years: A Post-Hoc Subgroup Analysis of Three Phase II Trials.

Patients older than 75 years of age are usually excluded from metastatic colorectal cancer studies based on a combination chemotherapy containing oxaliplatin. Our group conducted three phase II trials in elderly patients in recent years. A post-hoc subgroup analysis of 67 patients aged at least 75 years was included in this study. Oxaliplatin was combined with capecitabine in two trials and with uracil-tegafur (UFT) plus folinic acid in the third trial. In one study, bevacizumab was also added to chemotherapy. The median age of patients was 77 years, and all had a good performance status (0 to 1). The observed overall response rate was 45%, comparable to younger patients (51%, p = 0.49). The estimated median progression-free survival (PFS) time and overall survival (OS) time were 8.7 and 19.3 months, respectively. These results did not significantly differ from those in younger patients (8.0 months for PFS (p = 0.58) and 19.7 months for OS (p = 0.94), respectively). The most common grade 3-4 adverse events included diarrhea (13%), fatigue (13%), peripheral neuropathy (10%), and neutropenia (7%). Moreover, the toxicity was never statistically different from that in younger patients. The efficacy of oxaliplatin-based combination was maintained in fit elderly patients ≥75 years.

Phase II trial of oxaliplatin and tegafur/uracil and oral folinic acid for advanced or metastatic colorectal cancer in elderly patients.

OBJECTIVES: Colorectal cancer is usually diagnosed in elderly patients. Since there is clear evidence that such patients are under-treated and under-represented or even excluded from clinical studies and there are no reliable and prospective data on the feasibility and efficacy of an oxaliplatin (L-OHP)-based chemotherapy in this setting, we have tested the L-OHP plus oral uracil/tegafur (UFT) and oral folinic acid (FA) combination as first-line therapy in patients with advanced or metastatic colorectal cancer (MCRC) aged 70 or older. PATIENTS AND METHODS: Forty-seven patients with advanced or MCRC, aged over 70, were treated with L-OHP 65 mg/m(2) as an intravenous 3-hour infusion on day 1 and 8 plus UFT 300 mg/m(2) and FA 90 mg in 3 divided doses given orally on days 1-14 for each 3-week cycle. Patients were followed by a geriatric and a quality of life (QoL) assessment with specific scales and EORTC-QLQ-C30 questionnaire. RESULTS: All patients were assessable for toxicity and 45 for response to treatment. Complete response was achieved in 2 patients (4%) and partial response in 22 (47%) [overall response rate, 51%; 95% confidence interval (CI): 40.7-61.2%]; 18 patients (38%) had stable disease, and 5 (11%) had disease progression. The median duration of response was 8 months (range, 3-19+ months). After a minimum follow-up of 17 months, the median time to disease progression and the median overall survival were 8.0 (95% CI: 6.7-9.3%) and 14.1 (95% CI: 11.0-17.1%) months, respectively. Regimen safety was manageable. Most adverse events were mild to moderate, and this did not result in QoL impairment. The most common grade 3-4 treatment-related adverse events were diarrhea (17%), neutro- and thrombocytopenia (2%), laryngeal spasm (2%), and peripheral neuropathy (12.7%). No treatment-related deaths occurred. CONCLUSIONS: These results confirmed that this tested chemotherapy combination is active with acceptable tolerability and QoL maintenance in elderly patients with advanced or MCRC.