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Aflibercept-mediated early angiogenic changes in aggressive B-cell lymphoma

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Abstract

Purpose

Diffuse large B-cell lymphoma is the most common and one of the most aggressive lymphomas in adults. The standard, R-CHOP-based treatment needs improvement. There has been recent interest in anti-angiogenic therapy, but its cellular effects in lymphoma are little known.

Methods

In five aggressive B-cell lymphoma patients, we analyzed the microvessel and lymphoma cell changes after Aflibercept, an angiogenic inhibitor. Under ultrasonography, we performed two biopsies, one before any treatment and one two hours after Aflibercept, before R-CHOP. Using ultrasonography, immuno-histochemistry, double immuno-fluorescent staining, and electron microscopy, we compared the early changes induced by Aflibercept to the early changes induced by R-CHOP in three control patients.

Results

We identified microvessel damage in the five patients treated with Aflibercept but not in the three patients treated with R-CHOP. Two hours after Aflibercept, microvessel damage was focal, with severely damaged microvessel sections close to normal ones in the same area; different stages of microvessel damage were concomitantly found, with an increase in relative necrosis area in three cases. There was no difference in necrosis or relative microvessel area after R-CHOP. For lymphoma cells, the two biotherapies induced similar changes, with increase in apoptosis but not in proliferation.

Conclusion

We identified focal microvascular damage, necrosis, and apoptosis of lymphoma cells in aggressive B-cell lymphoma as soon as 2 h after Aflibercept. This suggests that there is more than one mechanism associated with the early effect of anti-angiogenic therapy in lymphoma.

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Acknowledgments

The authors would like to thank Raymond Barnhill, M.D Ph.D, for his critical review of the manuscript, Ms Stéphanie Lefrançois and Mr Sylvain Arien for the electron microscopy technique. MR is a recipient of Assistance Publique-Hôpitaux de Paris grant for cooperation with Hospital Universitario Fundación Santa Fe de Bogotá-Universidad de los Andes, Colombia. WL is a recipient of poste vert Inserm for Pole Franco-Chinois of Shanghai. This work was supported by Inserm, Université Paris VII, INCa, and ANR. Mrs Angela Swaine Verdier reviewed the English language of the manuscript.

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Authors and Affiliations

  1. Laboratoire de pathologie, U728, AP-HP-Hôpital Saint-Louis, 1, Avenue Claude Vellefaux, 75010, Paris, France

    Martha Romero, Josette Brière, Christophe Lebœuf, Li Wang & Anne Janin

  2. INSERM U728, 75010, Paris, France

    Martha Romero, Josette Brière, Cédric de Bazelaire, Christophe Lebœuf, Li Wang, Philippe Ratajczak, Eric de Kerviler, Catherine Thieblemont & Anne Janin

  3. Université de Paris, VII Diderot, 75010, Paris, France

    Martha Romero, Josette Brière, Cédric de Bazelaire, Christophe Lebœuf, Li Wang, Philippe Ratajczak, David Sibon, Eric de Kerviler, Catherine Thieblemont & Anne Janin

  4. Radiology Departement, AP-HP-Hôpital Saint-Louis, 75010, Paris, France

    Cédric de Bazelaire & Eric de Kerviler

  5. Hemato-Oncology Departement, AP-HP-Hôpital Saint-Louis, 75010, Paris, France

    David Sibon & Catherine Thieblemont

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  1. Martha Romero
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Correspondence to Anne Janin.

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Romero, M., Brière, J., de Bazelaire, C. et al. Aflibercept-mediated early angiogenic changes in aggressive B-cell lymphoma. Cancer Chemother Pharmacol 68, 1135–1143 (2011). https://doi.org/10.1007/s00280-011-1589-9

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  • DOI: https://doi.org/10.1007/s00280-011-1589-9

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