50-Hz extremely low frequency electromagnetic fields enhance cell proliferation and DNA damage: possible involvement of a redox mechanism

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Epidermal growth factor receptor gene copy number in 101 advanced colorectal cancer patients treated with chemotherapy plus cetuximab

<p>Abstract</p> <p>Background</p> <p>Responsiveness to Cetuximab alone can be mediated by an increase of Epidermal Growth factor Receptor (EGFR) Gene Copy Number (GCN). Aim of this study was to assess the role of EGFR-GCN in advanced colorectal cancer (CRC) patients receiving chemotherapy plus Cetuximab.</p> <p>Methods</p> <p>One hundred and one advanced CRC patients (43 untreated- and 58 pre-treated) were retrospectively studied by fluorescence in situ hybridization (FISH) to assess EGFR-GCN and by immunohistochemistry (IHC) to determine EGFR expression. Sixty-one out of 101 patients were evaluated also for k-ras status by direct sequencing. Clinical end-points were response rate (RR), progression-free survival (PFS) and overall survival (OS).</p> <p>Results</p> <p>Increased EGFR-GCN was found in 60/101 (59%) tumor samples. There was no correlation between intensity of EGFR-IHC and EGFR-GCN (p = 0.43). Patients receiving chemotherapy plus Cetuximab as first line treatment had a RR of 70% (30/43) while it was 18% (10/56) in the group with previous lines of therapy (p < 0.0001). RR was observed in 29/60 (48%) of patients with increased EGFR-GCN and in 6/28 (21%) in those without (p = 0.02). At multivariate analyses, number of chemotherapy lines and increased EGFR-GCN were predictive of response; EGFR-IHC score, increased EGFR-GCN and number of chemotherapy lines were significantly associated with a significant better PFS. Response to therapy was the only prognostic predictive factor for OS. In the 60 patients analyzed for k-ras mutations, number of chemotherapy lines, increased EGFR-GCN and k-ras wild type status predicted a better PFS.</p> <p>Conclusion</p> <p>In metastatic CRC patients treated with chemotherapy plus Cetuximab number of chemotherapy lines and increased EGFR-GCN were significantly associated with a better clinical outcome, independent of k-ras status.</p

Age-dependent modifications of expression level of VEGF and its receptors in the inner ear

The mechanisms responsible for age-associated hearing loss are still incompletely characterized. In this study, we used a murine model of age-dependent hearing loss and evaluated whether this condition is associated with vascular modifications of the structures of the inner ear. We used old C57BL/6J mice that are affected by rapid and severe age-related hearing loss, and analyzed the expression pattern of vascular endothelial growth factor (VEGF), a prototypical angiogenic cytokine, and its receptors Flt-1 and Flk-1 in the inner ear. We report for the first time morphological and quantitative data about the expression of these crucial angiogenic molecules in the murine cochlea. We also show that in this animal model, cochlear VEGF expression is significantly reduced as a function of age. Our findings provide new evidence of possible interdependent relationships between aging, VEGF, and presbycusis, suggesting that vascular abnormalities might play a role in aging-associated hearing loss, with potentially important fundamental and clinical implications. (C) 2004 Elsevier Inc. All rights reserved

Efficacy and safety of chronomodulated irinotecan, oxaliplatin, 5‐fluorouracil and leucovorin combination as first‐ or second‐line treatment against metastatic colorectal cancer : results from the International EORTC 05011 Trial

The triplet combination of irinotecan, oxaliplatin and fluorouracil is an active frontline regimen in metastatic colorectal cancer, but scarce data exist on its use as salvage treatment. We aimed at assessing its safety and efficacy profiles with its circadian‐based administration (chronoIFLO5) as either first‐ or second‐line treatment, within the time‐finding EORTC 05011 trial. Five‐day chronoIFLO5 was administered every 3 weeks in patients with PS 0, 1 or 2. It consisted of chronomodulated irinotecan (180 mg/sqm), oxaliplatin (80 mg/sqm) and fluorouracil‐leucovorin (2800 and 1200 mg/sqm, respectively). For our study, toxicity and antitumour activity were evaluated separately in first‐ and second‐line settings. Primary endpoints included Grade 3‐4 toxicity rates, best objective response rate (ORR), progression‐free survival (PFS) and overall survival (OS). One‐hundred forty‐nine and 44 patients were treated in first‐line and second‐line settings, respectively, with a total of 1138 cycles with median relative dose intensities of about 90%. Demographics were comparable in the two groups. Thirty‐six (24.7%) and 10 (22.2%) patients experienced at least one episode of severe toxicity in first line and second line, respectively. Frontline chronoIFLO5 yielded an ORR of 62.3% [95% CI: 54.2‐70.4] and resulted in median PFS and OS of 8.7 months [7.5‐9.9] and 19.9 months [15.4‐24.5]. Corresponding figures in second line were 37.5% [22.5‐52.5], 6.7 months [4.8‐8.9] and 16.3 months [11.8‐20.8]. International and prospective evaluation revealed the favourable safety and efficacy profiles of chronoIFLO5, both as frontline and as salvage treatment against metastatic colorectal cancer. In particular, encouraging activity in second line was observed, with limited haematological toxicity

LIN28B Underlies the Pathogenesis of a Subclass of Ewing Sarcoma

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Age-related Histopathological Changes of the Stria Vascularis: An Experimental Model: Cambios histopat??logicos relacionados con la edad en la estr??a vascular: Un modelo experimental

The stria vascularis (SV) of 3-, 8- and 18-month-old C57 mice was examined with a fluorescence microscope in order to evaluate the capillary density and vessel diameter. The capillary density was significantly reduced in 18-month-old mice compared to 3-month-old (P&lt;0.001) and to 8-month-old (.P&lt;0.001) mice. The difference between 3- and 18-month-old mice was significant for the basal, middle and apical cochlear turns, while the difference between 8- and 18-month-old mice was significant only for the middle and basal turns. Vessel diameter within the whole SV was significantly reduced in all turns in 18-month-old mice (P&lt;0.01) versus 3-month-old animals, while vessel diameter was reduced only in the basal turn in 8-month-old versus 3-month-old mice. The results suggest that previously described histopathological changes in the organ of Corti of C57 mice may be related to modifications of strial capillaries

Gender effects of single nucleotide polymorphisms and miRNAs targeting clock-genes in metastatic colorectal cancer patients (mCRC)

The circadian system is composed of a set of clock-genes including PERIOD, CLOCK, BMAL1 and CRY. Disrupting this system promotes cancer development and progression. The expression levels of miR-206, miR-219, miR-192, miR-194 and miR-132 regulating clock-genes and three functional polymorphisms rs11133373 C/G, rs1801260 T/C, rs11133391 T/C in CLOCK sequence were associated with the survival of 83 mCRC patients (50 males and 33 females). Longer overall survival (OS) was observed in women compared to men, 50 versus 31 months. This difference was associated with rs11133373 C/C genotype (p = 0.01), rs1801260 T/C+C/C genotype (p = 0.06) and rs11133391 T/T genotype (p = 0.06). Moreover women expressing high levels (H) of miR-192 (p = 0.03), miR-206 (p = 0.003), miR-194 (p = 0.02) and miR-219 (p = 0.002) had a longer OS compared to men. In women longer OS was reinforced by the simultaneous presence of two or more H-miR, 58 months versus 15 months (p = 0.0008); in this group of women an OS of 87 months was reached with the additional presence of rs11133391T/T genotype (p = 0.02). In this study we identified a subgroup of female patients who seems to have a better prognosis. Personalized medicine should prospectively take into account both genetic and gender differences