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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
                                             The New England Journal of Medicine
                Downloaded from nejm.org on March 6, 2012. For personal use only. No other uses without permission.
                              Copyright © 2008 Massachusetts Medical Society. All rights reserved.
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
          Downloaded from nejm.org on March 6, 2012. For personal use only. No other uses without permission.
                        Copyright © 2008 Massachusetts Medical Society. All rights reserved.
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.




                                               instructions for letters to the editor

  Letters to the Editor are considered for publication, subject to editing and abridgment, provided they do not contain material
  that has been submitted or published elsewhere. Please note the following: •Letters in reference to a Journal article must not
  exceed 175 words (excluding references) and must be received within 3 weeks after publication of the article. Letters not
  related to a Journal article must not exceed 400 words. All letters must be submitted over the Internet at http://authors.nejm.org.
  •A letter can have no more than five references and one figure or table. •A letter can be signed by no more than three authors.
  •Financial associations or other possible conflicts of interest must be disclosed. (Such disclosures will be published with the
  letters. For authors of Journal articles who are responding to letters, this information appears in the published articles.)
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  We cannot acknowledge receipt of your letter, but we will notify you when we have made a decision about publication. Letters
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  to provide prepublication proofs. Submission of a letter constitutes permission for the Massachusetts Medical Society, its
  licensees, and its assignees to use it in the Journal’s various print and electronic publications and in collections, revisions, and
  any other form or medium.




                                      n engl j med 358;24  www.nejm.org  june 12, 2008                                                    2651
                                             The New England Journal of Medicine
                Downloaded from nejm.org on March 6, 2012. For personal use only. No other uses without permission.
                              Copyright © 2008 Massachusetts Medical Society. All rights reserved.

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Angiomas, pediatrics

  • 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 The New England Journal of Medicine Downloaded from nejm.org on March 6, 2012. For personal use only. No other uses without permission. Copyright © 2008 Massachusetts Medical Society. All rights reserved.
  • 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 Downloaded from nejm.org on March 6, 2012. For personal use only. No other uses without permission. Copyright © 2008 Massachusetts Medical Society. All rights reserved.
  • 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. instructions for letters to the editor Letters to the Editor are considered for publication, subject to editing and abridgment, provided they do not contain material that has been submitted or published elsewhere. Please note the following: •Letters in reference to a Journal article must not exceed 175 words (excluding references) and must be received within 3 weeks after publication of the article. Letters not related to a Journal article must not exceed 400 words. All letters must be submitted over the Internet at http://authors.nejm.org. •A letter can have no more than five references and one figure or table. •A letter can be signed by no more than three authors. •Financial associations or other possible conflicts of interest must be disclosed. (Such disclosures will be published with the letters. For authors of Journal articles who are responding to letters, this information appears in the published articles.) •Include your full mailing address, telephone number, fax number, and e-mail address with your letter. Our Web site: http://authors.nejm.org We cannot acknowledge receipt of your letter, but we will notify you when we have made a decision about publication. Letters that do not adhere to these instructions will not be considered. Rejected letters and figures will not be returned. We are unable to provide prepublication proofs. Submission of a letter constitutes permission for the Massachusetts Medical Society, its licensees, and its assignees to use it in the Journal’s various print and electronic publications and in collections, revisions, and any other form or medium. n engl j med 358;24  www.nejm.org  june 12, 2008 2651 The New England Journal of Medicine Downloaded from nejm.org on March 6, 2012. For personal use only. No other uses without permission. Copyright © 2008 Massachusetts Medical Society. All rights reserved.