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Could Thalidomide Be a Treatment Option for Arteriovenous Malformations?
Letter to the Editor Could Thalidomide Be a Treatment Option for Arteriovenous Malformations?
LETTER: e read with great interest the article by Pabaney et al.1 on the development of a de novo arteriovenous malformation (AVM) and their review of the literature. Besides their praiseworthy effort to collect and analyze all the sporadic literature reports, the authors are to be commended for trying to stress and explain the dynamic manifestation of AVMs. In this regard, they emphasize the potential role of vascular endothelial growth factor pathway activation induced by other factors or insults. In particular, in their case report, they infer that an ischemic event acted like a “second hit” to an existing genetic aberrancy. Their hypothesis is that after a stressing event, the cerebral endothelial structures may be subjected to the effect of an angiogenic niche, which could dynamically challenge the stability of the vascular architecture, leading to the development or enlargement of an AVM.
W
In our opinion, this is comparable to the pathophysiologic mechanism of hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber syndrome, in which an imbalance in growth factors secondary to a genetic haploinsufficiency could lead to an excessive proliferation and migration of endothelial cells resulting in the vascular walls being thinned and vessel maturation being reduced.2 HHT is known to be related to cerebral, often multiple, AVMs, and genetically modified HHT animal models have been employed for preclinical AVM studies, as the angioarchitecture of HHT-related AVMs is indistinguishable from sporadic AVMs.3,4 On the strength of this analogy, we report that a phase II clinical trial was published more recently on the use of low doses of thalidomide for the treatment of severe recurrent epistaxis in HHT.5 Thalidomide was introduced in the 1950s for pregnancy-related nausea and was subsequently withdrawn from the market because of teratogenic effects, but new insights on its immunomodulatory, anti-inflammatory, and antiangiogenic effects led the U.S. Food and Drug Administration to reapprove its use for erythema nodosum leprosum and multiple myeloma. Invernizzi et al.5 reported remarkable efficacy of this drug in inhibiting epistaxis with an oral regimen of 50 mg/day for 3 months, reporting only nonserious (grade I) adverse events. All the patients responded to treatment, and approximately one third of the patients maintained remission at 1 year follow-up, implying that the reduction in bleeding lasted past the discontinuation of the drug. On the basis of previous laboratory investigations showing that thalidomide inhibits proliferation and migration of endothelial cells while activating mural cells,6 the authors concluded that this drug regimen might have made HHT vessels firmer and less prone to breaking even at low doses.5 However, no drug has been clinically tested to date for the treatment of
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AVMs despite the fact that there are already preclinical data suggesting that an antievascular endothelial growth factor action may be an effective pharmacologic target.7 On a speculative basis, thalidomide could represent a new pharmacologic approach, if not to cure AVMs per se, to prevent rupture of AVMs. On clinical grounds, we know from the most extensive cohort of untreated patients from the Helsinki group that the cumulative 5-year rupture rate for grade IV and grade V AVMs is 40% for lesions manifesting with hemorrhage and only 10% for unruptured ones.8 We could then argue that the frail cytoarchitecture of high-grade AVMs is challenged especially in the first months after hemorrhage. The article by Pabaney et al.1 has strengthened our opinion about the “dynamic” pathophysiology of AVMs. Therefore, we are wondering: Could thalidomide act in cerebral AVMs as a potential reinforcing agent, a “stabilizer” of the endothelial structures, in particular, after the acute or subacute bleeding phases? We believe that a multicenter collaborative study should be encouraged, at least for AVMs deemed untreatable. Daniele Bongetta1,3, Cesare Zoia1, Elvis Lafe2, Paolo Gaetani1 From the 1Neurosurgery Unit and 2Neuroradiology Unit, Fondazione IRCCS Policlinico S. Matteo; and 3Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, Università degli Studi di Pavia, Pavia, Italy To whom correspondence should be addressed: Daniele Bongetta, M.D. [E-mail: [email protected]] http://dx.doi.org/10.1016/j.wneu.2016.10.068.
REFERENCES 1. Pabaney AH, Rammo RA, Tahir RA, Seyfried D. Development of de novo arteriovenous malformation following ischemic stroke: case report and review of current literature. World Neurosurg. 2016;96:608.e5-608.e12. 2. Sadick H, Hage J, Goessler U, Bran G, Riedel F, Bugert P, et al. Does the genotype of HHT patients with mutations of the ENG and ACVRL1 gene correlate to different expression levels of the angiogenic factor VEGF? Int J Mol Med. 2008;22: 575-580. 3. Komiyama M. Pathogenesis of brain arteriovenous malformations. Neurol Med Chir (Tokyo). 2016;56:317-325. 4. Matsubara S, Mandzia JL, ter Brugge K, Willinsky RA, Faughnan ME. Angiographic and clinical characteristics of patients with cerebral arteriovenous malformations associated with hereditary hemorrhagic telangiectasia. AJNR Am J Neuroradiol. 2000;21:1016-1020. 5. Invernizzi R, Quaglia F, Klersy C, Pagella F, Ornati F, Chu F, et al. Efficacy and safety of thalidomide for the treatment of severe recurrent epistaxis in hereditary haemorrhagic telangiectasia: results of a non-randomised, single-centre, phase 2 study. Lancet Haematol. 2015;2:e465-e473. 6. Lebrin F, Srun S, Raymond K, Martin S, van den Brink S, Freitas C, et al. Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia. Nat Med. 2010;16:420-428. 7. Walker EJ, Su H, Shen F, Degos V, Amend G, Jun K, et al. Bevacizumab attenuates VEGF-induced angiogenesis and vascular malformations in the adult mouse brain. Stroke. 2012;43:1925-1930. 8. Laakso A, Dashti R, Juvela S, Isarakul P, Niemelä M, Hernesniemi J. Risk of hemorrhage in patients with untreated Spetzler-Martin grade IV and V arteriovenous malformations: a long-term follow-up study in 63 patients. Neurosurgery. 2011;68:372-377 [discussion: 378].
99: 802, MARCH 2017 WORLD NEUROSURGERY
LETTER: e read with great interest the article by Pabaney et al.1 on the development of a de novo arteriovenous malformation (AVM) and their review of the literature. Besides their praiseworthy effort to collect and analyze all the sporadic literature reports, the authors are to be commended for trying to stress and explain the dynamic manifestation of AVMs. In this regard, they emphasize the potential role of vascular endothelial growth factor pathway activation induced by other factors or insults. In particular, in their case report, they infer that an ischemic event acted like a “second hit” to an existing genetic aberrancy. Their hypothesis is that after a stressing event, the cerebral endothelial structures may be subjected to the effect of an angiogenic niche, which could dynamically challenge the stability of the vascular architecture, leading to the development or enlargement of an AVM.
W
In our opinion, this is comparable to the pathophysiologic mechanism of hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber syndrome, in which an imbalance in growth factors secondary to a genetic haploinsufficiency could lead to an excessive proliferation and migration of endothelial cells resulting in the vascular walls being thinned and vessel maturation being reduced.2 HHT is known to be related to cerebral, often multiple, AVMs, and genetically modified HHT animal models have been employed for preclinical AVM studies, as the angioarchitecture of HHT-related AVMs is indistinguishable from sporadic AVMs.3,4 On the strength of this analogy, we report that a phase II clinical trial was published more recently on the use of low doses of thalidomide for the treatment of severe recurrent epistaxis in HHT.5 Thalidomide was introduced in the 1950s for pregnancy-related nausea and was subsequently withdrawn from the market because of teratogenic effects, but new insights on its immunomodulatory, anti-inflammatory, and antiangiogenic effects led the U.S. Food and Drug Administration to reapprove its use for erythema nodosum leprosum and multiple myeloma. Invernizzi et al.5 reported remarkable efficacy of this drug in inhibiting epistaxis with an oral regimen of 50 mg/day for 3 months, reporting only nonserious (grade I) adverse events. All the patients responded to treatment, and approximately one third of the patients maintained remission at 1 year follow-up, implying that the reduction in bleeding lasted past the discontinuation of the drug. On the basis of previous laboratory investigations showing that thalidomide inhibits proliferation and migration of endothelial cells while activating mural cells,6 the authors concluded that this drug regimen might have made HHT vessels firmer and less prone to breaking even at low doses.5 However, no drug has been clinically tested to date for the treatment of
802
www.SCIENCEDIRECT.com
AVMs despite the fact that there are already preclinical data suggesting that an antievascular endothelial growth factor action may be an effective pharmacologic target.7 On a speculative basis, thalidomide could represent a new pharmacologic approach, if not to cure AVMs per se, to prevent rupture of AVMs. On clinical grounds, we know from the most extensive cohort of untreated patients from the Helsinki group that the cumulative 5-year rupture rate for grade IV and grade V AVMs is 40% for lesions manifesting with hemorrhage and only 10% for unruptured ones.8 We could then argue that the frail cytoarchitecture of high-grade AVMs is challenged especially in the first months after hemorrhage. The article by Pabaney et al.1 has strengthened our opinion about the “dynamic” pathophysiology of AVMs. Therefore, we are wondering: Could thalidomide act in cerebral AVMs as a potential reinforcing agent, a “stabilizer” of the endothelial structures, in particular, after the acute or subacute bleeding phases? We believe that a multicenter collaborative study should be encouraged, at least for AVMs deemed untreatable. Daniele Bongetta1,3, Cesare Zoia1, Elvis Lafe2, Paolo Gaetani1 From the 1Neurosurgery Unit and 2Neuroradiology Unit, Fondazione IRCCS Policlinico S. Matteo; and 3Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, Università degli Studi di Pavia, Pavia, Italy To whom correspondence should be addressed: Daniele Bongetta, M.D. [E-mail: [email protected]] http://dx.doi.org/10.1016/j.wneu.2016.10.068.
REFERENCES 1. Pabaney AH, Rammo RA, Tahir RA, Seyfried D. Development of de novo arteriovenous malformation following ischemic stroke: case report and review of current literature. World Neurosurg. 2016;96:608.e5-608.e12. 2. Sadick H, Hage J, Goessler U, Bran G, Riedel F, Bugert P, et al. Does the genotype of HHT patients with mutations of the ENG and ACVRL1 gene correlate to different expression levels of the angiogenic factor VEGF? Int J Mol Med. 2008;22: 575-580. 3. Komiyama M. Pathogenesis of brain arteriovenous malformations. Neurol Med Chir (Tokyo). 2016;56:317-325. 4. Matsubara S, Mandzia JL, ter Brugge K, Willinsky RA, Faughnan ME. Angiographic and clinical characteristics of patients with cerebral arteriovenous malformations associated with hereditary hemorrhagic telangiectasia. AJNR Am J Neuroradiol. 2000;21:1016-1020. 5. Invernizzi R, Quaglia F, Klersy C, Pagella F, Ornati F, Chu F, et al. Efficacy and safety of thalidomide for the treatment of severe recurrent epistaxis in hereditary haemorrhagic telangiectasia: results of a non-randomised, single-centre, phase 2 study. Lancet Haematol. 2015;2:e465-e473. 6. Lebrin F, Srun S, Raymond K, Martin S, van den Brink S, Freitas C, et al. Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia. Nat Med. 2010;16:420-428. 7. Walker EJ, Su H, Shen F, Degos V, Amend G, Jun K, et al. Bevacizumab attenuates VEGF-induced angiogenesis and vascular malformations in the adult mouse brain. Stroke. 2012;43:1925-1930. 8. Laakso A, Dashti R, Juvela S, Isarakul P, Niemelä M, Hernesniemi J. Risk of hemorrhage in patients with untreated Spetzler-Martin grade IV and V arteriovenous malformations: a long-term follow-up study in 63 patients. Neurosurgery. 2011;68:372-377 [discussion: 378].
99: 802, MARCH 2017 WORLD NEUROSURGERY