In vivo mechanisms by which tumors producing thrombospondin 1 bypass its inhibitory effects

Thrombospondin 1 (TSP1) is a multifunctional protein able to activate TGFβ and to inhibit angiogenesis in vivo. Although usually thought of as an inhibitor of tumor growth, TSP1 may sometimes be present at high levels during tumor progression, suggesting that tumors can eventually overcome their anti-tumor effects. Using a tet-repressible expression system, we demonstrate that murine TSP1 delayed the onset of tumor growth when produced in the tumor bed by rat fibrosarcoma tumor cells or by stromal fibroblasts coinjected with unmodified C6 glioma tumor cells. Yet upon prolonged exposure to TSP1, tumors came to grow at the same rate in the presence as in the absence of TSP1 and transplantation experiments showed that they had become insensitive to inhibition by TSP1 in both syngeneic and immune compromised hosts. Tumor resistance to TSP1 developed as a result of the in vivo outgrowth of pre-existing tumor cell variants that (1) secreted increased amounts of angiogenic factors that counterbalanced the inhibitory effect of TSP1 on neovascularization and (2) grew more efficiently in the presence of TSP1-activated TGFβ. These results indicate that prolonged and continuous local delivery of a single multifunctional angiogenesis inhibitor like TSP1 to fast-growing tumors can lead to tumor resistance in vivo by fostering the outgrowth of subpopulations that are a by-product of the genetic instability of the tumor cells themselves

Clinical value of circulating endothelial cells and circulating tumor cells in metastatic breast cancer patients treated first line with bevacizumab and chemotherapy.

International audienceBACKGROUND: We investigated whether circulating tumor cells (CTCs) and circulating endothelial cells (CECs) predict clinical outcome of first-line chemotherapy combined with bevacizumab in metastatic breast cancer patients. PATIENTS AND METHODS: In a French substudy of the MO19391 trial, CTC and CEC counts (CellSearch system) at baseline and changes after two cycles of treatment were correlated with time to progression (TtP). RESULTS: CTC and CEC levels were not correlated in the 67 patients included. At baseline, CTC positivity was a significant prognostic marker for TtP at a threshold of 3 CTC/7.5 ml (P /=45 years (P = 0.01), elevated lactate dehydrogenase (P < 0.01) and not with TtP at any threshold. Changes of CTC count during treatment were not a surrogate of TtP, with any of the model tested (threshold based or relative decrease in percent). However, increase in CEC count was associated with improved TtP, at the threshold of 20 CEC/4 ml (P < 0.01). CONCLUSION: Bevacizumab combined with first-line chemotherapy may modify the predictive value of CTC during treatment possibly due to impaired tumor cells intravasation through vessels endothelium. Variations in CEC levels appear to be a promising early surrogate marker of TtP under antiangiogenic treatment

: Cellules tumorales circulantes et cancer du sein

International audienceDue to recent technological progresses, Circulating Tumor Cells (CTC) are currently extensively studied in order to define their diagnostic, prognostic and predictive value. We review here the different detection techniques and their clinical results in breast cancer patients

Incidence of H1N1 2009 virus infection through the analysis of paired plasma specimens among blood donors, France.

BACKGROUND: Knowledge of the age-specific prevalence of seroprotection and incidence of seroconversion infection is necessary to complement clinical surveillance data and statistical models. It provides the basis for estimating the future impact of influenza A (H1N1pdm09) and implementing appropriate prevention and response strategies. METHODS: Using a cross-sectional design, two-stage stratified sampling and paired plasma samples, we estimated the age-specific prevalence of a protective level of H1N1pdm09 antibodies in the French adult population before and after the 2009/10 pandemic, and the proportion of those susceptible that seroconverted due to infection, from a single sample of 1,936 blood donors aged 20-70 years in mainland France in June 2010. Samples with a haemagglutination inhibition (HI) titre ≥1∶40 were considered seropositive, and seroconversion due to infection was defined as a 4-fold increase in titre in the absence of H1N1pdm09 vaccination or pre-pandemic seropositivity. RESULTS: Out of the 1,936 donors, 1,708 were included in the analysis. Seroprevalence before the pandemic was 6.7% (95% CI 5.0, 8.9) with no significant differences by age-group (p = 0.3). Seroprevalence afterwards was 23.0% (95% CI 17.7, 29.3) with 20-29 year olds having a higher level than older groups (p<0.001). Seroconversion due to infection was 12.2% (95% CI 6.9, 20.5). Younger age-group, vaccination against H1N1 and being seropositive before the pandemic were strongly associated with post-pandemic seropositivity. CONCLUSIONS: Before the 2009/2010 winter influenza season, only 6.7% of the French mainland population aged 20-70 had a level of antibodies usually considered protective. During the first pandemic wave, 12.2% of the population seroconverted due to infection and the seroprevalence after the wave rose to 23%, either due to prepandemic seropositivity, infection or vaccination. This relatively low latter figure contributed to an extension of target groups for influenza vaccination for the 2010/2011 season

Cross-Validation Study for Epidermal Growth Factor Receptor and KRAS Mutation Detection in 74 Blinded Non-small Cell Lung Carcinoma Samples: A Total of 5550 Exons Sequenced by 15 Molecular French Laboratories (Evaluation of the EGFR Mutation Status for the Administration of EGFR-TKIs in Non-Small Lung Carcinoma [ERMETIC] Project-Part 1).

International audienceINTRODUCTION:: The Evaluation of the epidermal growth factor receptor (EGFR) Mutation status for the administration of EGFR-Tyrosine Kinase Inhibitors in non-small cell lung Carcinoma (NSCLC) (ERMETIC) project part 1 assessed the accuracy of EGFR and KRAS mutations detection in NSCLC among 15 French centers. METHODS:: The 15 ERMETIC centers selected 74 NSCLC surgical specimens from previously untreated patients. Paraffin and paired frozen DNA were sequenced for EGFR exons 18 to 21 and KRAS exon 2 by an external molecular laboratory, yielding a gold standard. The 74 blinded paraffin DNAs were redistributed to the 15 ERMETIC laboratories for sequencing of a total of 5550 exons. Results were compared with the gold standard and between centers by discordance rates and kappa statistics. RESULTS:: The gold standard included 39 mutated samples with 22 EGFR and 17 KRAS mutated samples. Kappa statistics showed that 10, 6, and 6 of the 15 ERMETIC centers had a moderate to good kappa score, when compared with external laboratory for EGFR exon 19, EGFR exon 21, and KRAS exon 2, respectively. Kappa statistics showed moderate score between centers which increased to good for EGFR exon 19 mutation when removing 16 poor-quality samples with high nonamplificable rates. CONCLUSIONS:: Paraffin-embedded specimens may represent a suitable source of DNA for sequencing analyses in ERMETIC centers. EGFR exon 19 deletions were most accurately detected by ERMETIC centers. Ease and accuracy of results, depended more on the quality of sample than on the difference in molecular sequencing procedures between centers, emphasize the need of preanalytical quality control programs

Factors associated with seroconversion in those without pre-pandemic titre ≥1∶40 or vaccination against H1N1.

<p>Factors associated with seroconversion in those without pre-pandemic titre ≥1∶40 or vaccination against H1N1.</p

Prevalence of a titre ≥1∶40 before and after the pandemic by age group, France 2010.

<p>Seroprevalence before the pandemic was 6.7% (95% CI 5.0–8.9%) overall with no significant differences by age-group. Seroprevalence after the pandemic was 23.0% (95% CI 17.7, 29.3) overall with the 20–29 year age-group having a higher seroprevalence than older groups. The increase in seroprevalence was more marked in younger age-groups.</p