1. correspondence
negative predictive value.1 It should be noted that Constantinos Christopoulos, M.D., Ph.D.
plasma levels of imatinib in patients given high Vasiliki Dimakopoulou, M.D.
doses of the drug exceed those of the no-effect Evangelos Rotas, M.D.
level in the study of rat fertility. We also disagree Amalia Fleming General Hospital
with the specific reservations expressed by the 15127 Athens, Greece
cgchristopoulos@yahoo.gr
correspondents. The time relationship was rea­
sonable, with oligomenorrhea occurring a few 1. Andrade RJ. Evaluation ofMI, Pachkoria K, Borraz Y, Hidalgo
R,
García-Cortés M, Lucena
Naranjo Adverse Drug Reactions
months after the increase in the dose of imatinib. Probability Scale in causality assessment of drug-induced liver
There were no other exposures, and no alterna­ injury. Aliment Pharmacol Ther 2008;27:780-9.
tive causes were found on routine investigation of 2. Hutt KJ, McLaughlin EA, Holland MK. Kit ligand and c-Kit
have diverse roles during mammalian oogenesis and folliculo­
amenorrhea. Finally, the hypothesis of an etiolog­ genesis. Mol Hum Reprod 2006;12:61-9.
ic link between imatinib and ovarian insufficiency 3. Nilsson EE, Detzel C, Skinner MK. Platelet-derived growth
is biologically plausible, since pathways involving factor modulates the primordial to primary follicle transition.
Reproduction 2006;131:1007-15.
kinases targeted by imatinib appear to play criti­ 4. Carlsson IB, Laitinen MP, Scott JE, et al. Kit ligand and c-Kit
cal roles in the survival and maturation of folli­ are expressed during early human ovarian follicular develop­
ment and their interaction is required for the survival of follicles
cles and oocytes.2-4 in long-term culture. Reproduction 2006;131:641-9.
Propranolol for Severe Hemangiomas of Infancy
To the Editor: Despite their self-limited course, conal orbital involvement, as well as an
infantile capillary hemangiomas can impair vital intracervical mass causing compression and tra­
or sensory functions or cause disfigurement. Cor­ cheal and esophageal deviation (see the Supple­
ticosteroids are the first line of treatment for mentary Appendix). Ultrasonography showed
problematic infantile capillary hemangiomas1,2; increased cardiac output, and treatment with
other options include interferon alfa3 and vin­ propranolol, at a dose of 2 mg per kilogram of
cristine.1 We have observed that propranolol can body weight per day, was initiated. Seven days
inhibit the growth of these hemangiomas. Our later, the child was able to open his eye sponta­
preliminary data from 11 children are summa­ neously, and the mass near the parotid gland was
rized in Table 1 in the Supplementary Appendix, considerably reduced in size. Prednisolone was
available with the full text of this letter at www. discontinued at 4 months of age, without any
nejm.org. regrowth of the hemangioma; at 9 months of
The first child had a nasal capillary heman­ age, the eye opening was satisfactory, and no
gioma. Despite corticosteroid treatment, the le­ major visual impairment was noted.
sion was stabilized but obstructive hypertrophic After written informed consent had been ob­
myocardiopathy developed, so the patient was tained from the parents, propranolol was given
treated with propranolol. The day after the initia­ to nine additional children who had severe or
tion of treatment, the hemangioma changed from disfiguring infantile capillary hemangiomas (see
intense red to purple, and it softened. The corti­ Table 1 in the Supplementary Appendix). In all
costeroids were tapered, but the hemangioma patients, 24 hours after the initiation of treat­
continued to improve. When the corticosteroids ment, we observed a change in the hemangioma
were discontinued, no regrowth of the hemangi­ from intense red to purple; this change was as­
oma was noted. When the child was 14 months sociated with a palpable softening of the lesion.
of age, the hemangioma was completely flat. After these initial changes, the hemangiomas
The second child had a plaque-like infantile continued to improve until they were nearly flat,
capillary hemangioma involving the entire right with residual skin telangiectasias. Ultrasound ex­
upper limb and part of the face (Fig. 1). At 1 month aminations in five patients showed an objective
of age, a subcutaneous component developed, regression in thickness associated with an in­
and despite corticosteroid treatment, the hem­ crease in the resistive index of vascularization of
angioma continued to enlarge. Magnetic reso­ the hemangioma (Table 1 in the Supplementary
nance imaging revealed intraconal and extra­ Appendix).
n engl j med 358;24 www.nejm.org june 12, 2008 2649
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2. The n e w e ng l a n d j o u r na l of m e dic i n e
A B
C D
Infantile capillary hemangiomas are composed are involved: basic fibroblast growth factor (bFGF)
of a complex mixture of clonal endothelial cells and vascular endothelial growth factor (VEGF)1;
ICM AUTHOR Labreze RETAKE 1st
associated with pericytes, dendritic cells, and histologic studies have shown that both endo­
REG F FIGURE 1a-d 2nd
mast cells.1 Regulators of hemangioma growth thelial and interstitial cells are actively dividing
CASE TITLE
3rd
Revised
and involution are poorly understood. During the in this phase. During the involution phase, apop­
EMail Line 4-C
SIZE
growth phase, two major proangiogenic factors tosis has been shown.1 Potential explanations for
Enon ARTIST: mst H/T H/T
FILL Combo 33p9
AUTHOR, PLEASE NOTE:
Figure has been redrawn and type has been reset.
2650 Please check carefully.
n engl j med 358;24 www.nejm.org june 12, 2008
The New35824
JOB: England Journal of Medicine
ISSUE: 6-12-08
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3. correspondence
Christine Léauté-Labrèze, M.D.
Figure 1 (facing page). Photographs of Patient 2 before
and after Treatment with Propranolol. Eric Dumas de la Roque, M.D.
Panel A shows the patient at 9 weeks of age, before Thomas Hubiche, M.D.
treatment with propranolol, after 4 weeks of receiving Franck Boralevi, M.D., Ph.D.
systemic corticosteroids (at a dose of 3 mg per kilogram Bordeaux Children’s Hospital
of body weight per day for 2 weeks and at a dose of 5 mg 33 076 Bordeaux, France
per kilogram per day for 2 weeks). Panel B shows the christine.labreze@chu-bordeaux.fr
patient at 10 weeks of age, 7 days after the initiation of Jean-Benoît Thambo, M.D.
propranolol treatment at a dose of 2 mg per kilogram
Haut-Lévêque Heart Hospital
per day while prednisolone treatment was tapered to
33 600 Pessac, France
3 mg per kilogram per day. Spontaneous opening of
the eye was possible because of a reduction in the size Alain Taïeb, M.D.
of the subcutaneous component of the hemangioma. Bordeaux Children’s Hospital
Panel C shows the patient at 6 months of age, while 33 076 Bordeaux, France
he was still receiving 2 mg of propranolol per kilogram
per day. Systemic corticosteroids had been discontinued The authors report applying for a patent for the use of beta-
at 2 months of age. No subcutaneous component of blockers in infantile capillary hemangiomas. No other potential
conflict of interest relevant to this letter was reported.
the hemangioma was noted, and the cutaneous com-
ponent had considerably faded. The child had no visual
1. Frieden IJ, Haggstrom AN, Drolet BA, Mancini AJ, Fried­
impairment. Panel D shows the child at 9 months of lander SF, Boon L. Infantile hemangiomas: current knowledge,
age. The hemangioma had continued to improve, and future directions: proceedings of a research workshop on infan­
the propranolol treatment was discontinued. tile hemangiomas, April 7-9, 2005, Bethesda, Maryland, USA.
Pediatr Dermatol 2005;22:383-406.
2. Bennett ML, Fleischer AB Jr, Chamlin SL, Frieden IJ. Oral
corticosteroid use is effective for cutaneous hemangiomas: an
the therapeutic effect of propranolol — a nonse­ evidence-based evaluation. Arch Dermatol 2001;137:1208-13.
lective beta-blocker — on infantile capillary hem­ 3. Ezekowitz RAB, Phil CBD, Mulliken JB, Folkman J. Inter­
angiomas include vasoconstriction, which is im­ feron alfa-2a therapy for life-threatening hemangiomas of in­
fancy. N Engl J Med 1992;326:1456-63. [Errata, N Engl J Med
mediately visible as a change in color, associated 1994;330:300, 1995;333:595-6.]
with a palpable softening of the hemangioma; 4. D’Angelo G, Lee H, Weiner RI. cAMP-dependent protein ki­
decreased expression of VEGF and bFGF genes nase inhibits the mitogenic action of vascular endothelial
growth factor and fibroblast growth factor in capillary endothe­
through the down-regulation of the RAF–mito­ lial cells by blocking Raf activation. J Cell Biochem 1997;67:353-
gen-activated protein kinase pathway4 (which ex­ 66.
plains the progressive improvement of the hem­ 5. Sommers Smith SK, Smith DM. Beta blockade induces apop­
tosis in cultured capillary endothelial cells. In Vitro Cell Dev
angioma); and the triggering of apoptosis of Biol Anim 2002;38:298-304.
capillary endothelial cells.5 Copyright © 2008 Massachusetts Medical Society.
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