DNA double-strand breaks (DSBs) are considered as one of the primary causes of cancer but their induction by hydrogen peroxide (H 2 O 2 ) is still controversial. In this work, we studied whether the high levels of H 2 O 2 produced in the thyroid to oxidize iodide could induce DNA modifications. Scores of DNA damage, in terms of strand breaks, were obtained by comet assay (alkaline condition for single-strand breaks (SSBs) and neutral condition for DSBs). We demonstrated that in a rat thyroid cell line (PCCl3), non-lethal concentrations of H 2 O 2 (0.1-0.5 mmol/l) as well as irradiation (1-10 Gy) provoked a large number of SSBs (w2-3 times control DNA damage values) but also high levels of DSBs (1.2-2.3 times control DNA damage values). We confirmed the generation of DSBs in this cell line and also in human thyroid in primary culture and in pig thyroid slices by measuring phosphorylation of histone H2AX. L-Buthionine-sulfoximine, an agent that depletes cells of glutathione, decreased the threshold to observe H 2 O 2 -induced DNA damage. Moreover, we showed that DNA breaks induced by H 2 O 2 were more slowly repaired than those induced by irradiation. In conclusion, H 2 O 2 causes SSBs and DSBs in thyroid cells. DSBs are produced in amounts comparable with those observed after irradiation but with a slower repair. These data support the hypothesis that the generation of H 2 O 2 in thyroid could also play a role in mutagenesis particularly in the case of antioxidant defense deficiency.

The effectiveness of granulocyte and granulocyte-macrophage colony-stimulating factor (G-CSF and GM-CSF) in the treatment of febrile neutropenic cancer patients remains controversial. To assess their role in this condition, we conducted a systematic review of randomised trials published as full papers. A methodological evaluation using a specifically designed quality scale was performed before meta-analysis. Eleven trials were eligible, 8 of which were meta-analysable. The median quality score for the 11 pooled trials was 58.3% (range: 33.3%-68.8%). No significant quality difference was observed between positive (colony-stimulating factor more effective) and negative trials ( P=0.36). No quality difference was observed between the 8 meta-analysable studies and the 3 others, with respective median scores of 59.3% and 50%. No advantage was detected for the use of CSF in terms of mortality from febrile neutropenia, with a relative risk of 0.71 (95% CI 0.44-1.15). The relative risk was 0.66 (95% CI 0.39-1.13) in the G-CSF subgroup and 0.97 (95% CI 0.34-2.79) in the GM-CSF subgroup. Aggregation of the results on infection-related mortality, length of stay in hospital, fever and of neutropenia duration, antibiotic therapy adaptation and duration, superinfection rate and toxicity was not possible owing to the lack of adequate data in the publications. On the basis of this review, we cannot recommend the routine use of G-CSF or GM-CSF in established febrile neutropenia.

In the 1990s, chemotherapy has been shown able to improve survival of patients presenting with advanced non-small cell lung cancer (NSCLC, 1995). The survival benefit was obtained with first-generation active cytostatic agents -mainly ifosfamide, vinblastine, vindesine, mitomycin (MMC) -in combination with cisplatin (Donnadieu et al, 1991). New active drugs -the second generation -have appeared during the last decade, including gemcitabine, paclitaxel, docetaxel, vinorelbine and irinotecan. Their role in addition or in place of the first-generation agents, which should not be considered as obsolete for the unique reason that they are older and less fashionable, has yet to be defined (Meert et al, 1999).In this context, we have performed a systemic review of the literature about the role of one of the first-generation drugs, mitomycin (MMC), in the management of NSCLC. In order to determine if it is worthy to further conduct trials with that agent, we have searched answers to the 3 following questions: (1) is MMC an active drug against NSCLC? (2) does MMC improve the results when added to other active agents? (3) is MMC useful for salvage therapy? We have performed this investigation by using a methodology similar to that we have already used to conduct evidencebased medicine analyses of the literature. MATERIAL AND METHODSTo be eligible for the systematic review, a trial had to fulfil the following criteria: to deal only with NSCLC, to have been published as a full paper in the English or French language, to have a prospective design and to assess the effect of MMC in a randomized trial or in a first-line or second-line phase II trial according to the studied question.Trials were identified by an electronic search (Medline) in addition to the use of the personal bibliography of one of the authors and by consulting the references reported in the selected articles.Each trial was read and assessed for methodology by 12 investigators, including 11 physicians and 1 biostatistician. Each investigator independently extracted the data from the articles and disagreements were resolved by consensus. Randomized trials were evaluated for methodology by 2 quality scores calculated on the basis of the data reported in the publications: the score proposed by Chalmers et al (1981) and used by Marino in two meta-analyses (Marino et al, 1994(Marino et al, , 1995; and the score proposed by the ELCWP (European Lung Cancer Working Party) (Mascaux et al, 2000). Phase II trials were assessed by the ELCWP score for phase II studies (Meert et al, 1999).The result of a phase III trial was considered as conclusive if the P value for the statistical test comparing the survival distributions between arms for the overall patients populations was <0.05 in favour of the experimental arm. The trial was then called 'positive'. In the other situations (statistically significant survival benefit for the control arm or non-statistically significant difference in survival distributions), it was called 'negative'.The association between the quality s...

We studied gene expression profiles in two mouse models of human thyroid carcinoma: the Tg-RET/PTC3 (RP3) and Tg-E7 mice. RP3 fusion gene is the most frequent mutation found in the first wave post-Chernobyl papillary thyroid cancers (PTCs). E7 is an oncoprotein derived from the human papillomavirus 16 responsible for most cervical carcinoma in women. Both transgenic mice develop thyroid hyperplasia followed by solid differentiated carcinoma in older animals. To understand the different steps leading to carcinoma, we analyzed thyroid gene expression in both strains at different ages by microarray technology. Important biological processes were differentially regulated in the two tumor types. In E7 thyroids, cell cycle was the most up-regulated process, an observation consistent with the huge size of these tumors. In RP3 thyroids, contrary to E7 tumors, several human PTC characteristics were observed: overexpression of many immune-related genes, regulation of human PTC markers, up-regulation of EGF-like growth factors and significant regulation of angiogenesis and extracellular matrix remodeling-related genes. However, similarities were incomplete; they did not concern the overall gene expression and were not conserved in old animals. Therefore, RP3 tumors are partial and transient models of human PTC. They constitute a good model, especially in young animals, to study the respective role of the biological processes shared with human PTC and will allow testing drugs targeting these validated variables.

The purpose of this study was to use the microarray technology to define expression profiles characteristic of thyroid autonomous adenomas and relate these findings to physiological mechanisms. Experiments were performed on a series of separated adenomas and their normal counterparts on Micromax cDNA microarrays covering 2400 genes (analysis I), and on a pool of adenomatous tissues and their corresponding normal counterparts using microarrays of 18 000 spots (analysis II). Results for genes present on the two arrays corroborated and several gene regulations previously determined by Northern blotting or microarrays in similar lesions were confirmed. Five overexpressed and 24 underexpressed genes were also confirmed by real-time RT-PCR in some of the samples used for microarray analysis, and in additional tumor specimens. Our results show: (1) a change in the cell populations of the tumor, with a marked decrease in lymphocytes and blood cells and an increase in endothelial cells. The latter increase would correspond to the establishment of a close relation between thyrocytes and endothelial cells and is related to increased N-cadherin expression. It explains the increased blood flow in the tumor; (2) a homogeneity of tumor samples correlating with their common physiopathological mechanism: the constitutive activation of the thyrotropin (TSH)/cAMP cascade; (3) a low proportion of regulated genes consistent with the concept of a minimal deviation tumor; (4) a higher expression of genes coding for specific functional proteins, consistent with the functional hyperactivity of the tumors; (5) an increase of phosphodiesterase gene expression which explains the relatively low cyclic AMP levels measured in these tumors; (6) an overexpression of antiapoptotic genes and underexpression of proapoptotic genes compatible with their low apoptosis rate; (7) an overexpression of N-cadherin and downregulation of caveolins, which casts doubt about the use of these expressions as markers for malignancy.Oncogene (2005) 24, 6902-6916.