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Am J Pathol. 2015 Feb;185(2):356-71. doi: 10.1016/j.ajpath.2014.10.021. Epub 2014 Dec 11.

Chemotherapy-induced pulmonary hypertension: role of alkylating agents.

Author information

1
Faculty of Medicine, Université Paris-Sud, Faculté de Médecine, Hôpital de Bicêtre, Le Kremlin-Bicêtre, Paris, France; INSERM U999, Pulmonary Arterial Hypertension: Pathophysiology and Therapeutic Innovation, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, Paris, France.
2
Faculty of Medicine, Université Paris-Sud, Faculté de Médecine, Hôpital de Bicêtre, Le Kremlin-Bicêtre, Paris, France; INSERM U999, Pulmonary Arterial Hypertension: Pathophysiology and Therapeutic Innovation, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, Paris, France; Assistance Publique des Hôpitaux de Paris (AP-HP), the Reference Center for Severe Pulmonary Hypertension, Pneumology and Respiratory Intensive Care Service, Hôpital de Bicêtre, Le Kremlin-Bicêtre, Paris, France.
3
Respiratory Division, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.
4
Faculty of Medicine, Université Paris-Sud, Faculté de Médecine, Hôpital de Bicêtre, Le Kremlin-Bicêtre, Paris, France; INSERM U999, Pulmonary Arterial Hypertension: Pathophysiology and Therapeutic Innovation, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, Paris, France; AP-HP, Pharmacy Service, Département Hospitalo-Universitaire Thorax Innovation, Hôpital Antoine Béclère, Clamart, France.
5
Faculty of Medicine, Université Paris-Sud, Faculté de Médecine, Hôpital de Bicêtre, Le Kremlin-Bicêtre, Paris, France; INSERM U999, Pulmonary Arterial Hypertension: Pathophysiology and Therapeutic Innovation, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, Paris, France; Pathology Service, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, Paris, France.
6
Department of Pediatrics, University of Colorado at Denver, Aurora, Colorado.
7
Faculty of Medicine, Université Paris-Sud, Faculté de Médecine, Hôpital de Bicêtre, Le Kremlin-Bicêtre, Paris, France; INSERM U999, Pulmonary Arterial Hypertension: Pathophysiology and Therapeutic Innovation, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, Paris, France. Electronic address: frederic.perros@inserm.fr.

Abstract

Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) characterized by progressive obstruction of small pulmonary veins and a dismal prognosis. Limited case series have reported a possible association between different chemotherapeutic agents and PVOD. We evaluated the relationship between chemotherapeutic agents and PVOD. Cases of chemotherapy-induced PVOD from the French PH network and literature were reviewed. Consequences of chemotherapy exposure on the pulmonary vasculature and hemodynamics were investigated in three different animal models (mouse, rat, and rabbit). Thirty-seven cases of chemotherapy-associated PVOD were identified in the French PH network and systematic literature analysis. Exposure to alkylating agents was observed in 83.8% of cases, mostly represented by cyclophosphamide (43.2%). In three different animal models, cyclophosphamide was able to induce PH on the basis of hemodynamic, morphological, and biological parameters. In these models, histopathological assessment confirmed significant pulmonary venous involvement highly suggestive of PVOD. Together, clinical data and animal models demonstrated a plausible cause-effect relationship between alkylating agents and PVOD. Clinicians should be aware of this uncommon, but severe, pulmonary vascular complication of alkylating agents.

PMID:
25497573
DOI:
10.1016/j.ajpath.2014.10.021
[Indexed for MEDLINE]

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