Transcript Interferon alfa-2a

Medical Care
hemangioma
and
complications
Dr.F.Iraji
Medical Care
The vast majority of infantile hemangiomas do 
not require any medical or surgical
intervention.[9] Medical care of clinically
significant hemangiomas has been limited to
a few medications, including
glucocorticosteroids (topical, intralesional,
and oral), interferon alfa, and, rarely,
vincristine and topical imiquimod.[46] Betablockers, most specifically propranolol,[47]
have serendipitously been shown to induce
involution of infantile hemangiomas.[48, 49, 50, 51]
Medical Care
The vast majority of infantile hemangiomas do
not require any medical or surgical
intervention. Medical care of clinically
significant hemangiomas has been limited to
a few medications, including
glucocorticosteroids (topical, intralesional,
and oral), interferon alfa, and, rarely,
vincristine and topical imiquimod.Betablockers, most specifically propranolol, have
been shown to induce involution of infantile
hemangiomas
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Medical Care
An expert panel has developed 
provisional recommendations for the use
of propranolol, including in patients with
PHACE syndrome (posterior fossa
abnormalities, hemangioma, arterial
lesions, cardiac abnormalities/aortic
coarctation, and eye abnormalities).
PHACE syndrome is associated with a
higher risk of neurologic and cognitive
impairment.
Medical Care
When to treat complicated infantile 
hemangiomas
Contraindications and pretreatment 
evaluation protocols
Formulation, target dose, and frequency of
dosing
Initiation in infants 
Cardiovascular monitoring 
Ongoing monitoring 
Prevention of hypoglycemia 
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Medication Summary
The goals of pharmacotherapy for 
infantile hemangiomas are to reduce
morbidity and mortality and to prevent
complications. Note that only propranolol
oral solution (Hemangeol) is approved for
treatment of infantile hemangiomas by
the FDA.
corticosteroids
Oral and intralesional corticosteroids are 
effective at slowing the growth and
decreasing the size of proliferating
infantile hemangiomas. corticosteroids
have been shown to inhibit VEGF-A
expression and subsequent proliferation in
hemangioma stem cells in a murine
hemangioma model.Evidence indicates
that corticosteroids block estradiol
receptors in hemangiomas in vitro.
corticosteroids
Response vary widely, from less than 40% 
to greater than 90%, depending on dose,
duration of treatment, and age at which
corticosteroid therapy is initiated
corticosteroids
Corticosteroid therapy should be 
administered during the proliferative
phase because it has a negligible effect
on involuting and otherwise stable
infantile hemangiomas. The oral route
generally is preferred over intralesional
therapy; however, the location, size,
patient age, and physician experience
factor into the decision-making process.
corticosteroids
Prednisolone decreases inflammation by
suppressing the migration of
polymorphonuclear leukocytes and
reducing capillary permeability
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Propranolol
Propranolol oral solution (Hemangeol) 
was approved by the FDA in March 2014.
Approval was based on the results from a
dose-ranging study of 460 infants aged 35
days to 5 months with proliferating
hemangiomas.
Propranolol
Beta-blockers, most specifically 
propranolol and more recently topical
timolol, have been in use since mid 2008
for infants with severe or disfiguring
hemangiomas.
Propranolol
Several reports in the literature describe 
efficacy for life- and sight-threatening airway
and retro-orbital hemangiomas, respectively.
Some have been treated with the beta-1
selective blocker, acebutolol. However, most
infants reported have been treated with the
nonselective blocker, propranolol, at a dose
of 2-3mg/kg/d in 2-3 divided doses. Duration
of therapy varies from 2-10 months.
Propranolol
As early as 24 hours after the initiation of 
therapy, many infantile hemangiomas
have begun to change from intense red
to purple, with evidence of softening.
Most continue to improve until nearly flat
and with significantly diminished color.
Propranolol
A retrospective study of 39 children in 
France with infantile hemangiomas of the
head and neck concluded that
propranolol treatment effectively
lightened and reduced hemangiomas,
especially as first-line treatment started
during proliferative growth (mean age, 4.1
m; mean duration, 8.5 m).
Propranolol
some hypothesize that local vasoconstriction 
may be a factor, which is based on the early
color change and softening of the lesion. One
study has demonstrated that nonspecific and
beta2-selective blockers (eg, propranolol)
triggered apoptosis of capillary endothelial
cells in adult rat lung tissue, suggesting a
similar mechanism may be plausible for
hemangioma endothelial cells.
Propranolol
No protocol for initiating propranolol therapy 
in infants with hemangiomas is universally
accepted.Therapy should be approached
with extreme caution in neonates and infants
who generally do not have preexisting venous
hypertension or any other hemodynamic
disorder. Of particular note, infants with
hemangiomas associated with PHACE
syndrome with cerebrovascular anomalies
are at higher risk for cerebral vascular
accidents and therefore should not receive
beta-blockers.
Provisional guidelines for
initiation
Exclude infants with evidence of the 
following:
Bronchospasm 
- Cardiac disease 
- CNS vascular anomalies (suspected 
PHACE syndrome, large cervicofacial
hemangiomas
Provisional guidelines for
initiation
Baseline laboratory tests and evaluation: 
- Blood glucose level 
- Blood pressure check 
- Electrocardiography (variable) 
- Echocardiogram (if considering PHACE 
syndrome or other clinical indications)
- Pediatric cardiology consultation for 
evaluation and dosing recommendations
(if any concerning findings)
Monitoring
Monitor for 24-72 hours;
Monitoring 1 hour after administration 
(dosing) includes the following:
- Blood pressure check 
- Heart rate check (hold dose for heart 
rate at < 100 beats per min)
Monitoring
- Blood glucose level (due to potential 
blocking of liver glycogen phosphorylase):
Recommended that young infants feed
every 3-4 hours to decrease risk of
hypoglycemia.
- Temperature determination to evaluate 
for hypothermia
Observation for
bronchospasm
At home, parents should observe for signs 
of lethargy, poor feeding, and/or
bronchospasm.
Blood pressure and heart rate should be 
evaluated intermittently at the
pediatrician's office.
Discontinuation
Consider gradual taper over 2 weeks, 
rather than abrupt discontinuation.
Cardiac hypersensitivity may occur 24-48
hours after propranolol is discontinued.
The mechanism
Propranolol is a nonselective beta- 
adrenergic receptor blocking agent
possessing no other autonomic nervous
system activity. It is indicated for
treatment of proliferating hemangioma
requiring systemic therapy. Available as
an oral solution (4.28 mg/mL).
interferon alfa-2a
interferon alfa-2a was found to induce 
regression of Kaposi sarcoma. This led to its
use in treating other vascular lesions (eg,
hemangiomas). Interferon alfa inhibits
endothelial cell migration and proliferation
and specific growth factors (eg, endothelial
growth factor, fibroblast growth factor).
Numerous studies have demonstrated the
efficacy of interferon alfa-2a and interferon
alfa-2b in treating infantile hemangiomas.
interferon alfa-2a
Because interferon alfa-2a works by a 
different mechanism, it can be used in
lesions that are unresponsive to steroids. In
fact, unlike steroids, it does not require
that administration occur during the
proliferation phase to be effective.
interferon alfa-2a
The onset of action is slower than that of 
corticosteroids, usually requiring several
weeks; this makes it less attractive for use
in acute life- or sight-threatening
situations. Interferon alfa-2a should be
used only if steroid, beta-blocker, and
other potentially toxic therapies fail.
significant adverse
The most significant adverse event limiting
its use in hemangiomas is potentially
irreversible spastic diplegia; while most
infants have displayed significant
recovery of spasticity of lower extremities,
it appeared permanent in other infants.A
meta-analysis of interferon use in children
revealed all cases of neurological
dysfunction occurred when interferon was
used prior to the patient’s first birthday
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Interferon alfa-2a (Roferon-A)
Interferon alfa-2a is a protein product 
manufactured by recombinant DNA
technology. Its mechanism of antitumor
activity is not clearly understood;
however, direct antiproliferative effects
against malignant cells and modulation of
host immune response may play
important roles. Interferon alfa-2a may be
given topically, systemically, and
intralesionally.
Interferon alfa-2b
Interferon alfa-2b is a protein product 
manufactured by recombinant DNA
technology. Indications are adult hairy
cell leukemia, malignant melanoma,
condyloma acuminata, AIDS-related
Kaposi sarcoma, and certain forms of
chronic viral hepatitis. Interferon alfa-2b
has also used to treat children with these
conditions and, most recently, infants with
life-threatening hemangiomas
Imiquimod cream
It purportedly works by stimulation of toll-like
receptor 7 (TLR-7) and increases local
interferon alpha and gamma, through
which it may exert antiangiogenic effects
Imiquimod cream
In a mouse model, imiquimod-treated 
vascular tumors showed decreased tumor
cell proliferation, increased tumor
apoptosis, and increased expression of
tissue inhibitor of matrix
metalloproteinase-1, with decreased
activity of matrix metalloproteinase-9,
both of which are observed in the natural
involution of infantile hemangiomas.
Imiquimod (Aldara cream)
Imiquimod is an immune response 
modifier indicated condyloma
acuminata, actinic keratoses, and
superficial basal cell carcinoma in adults.
It is not approved by FDA for use in
children.
Becaplermin 0.01% gel
(Regranex Gel)
A few reports in the literature (Metz, 2004) 
suggest this is helpful for ulcerated
infantile hemangiomas, especially those in
the diaper area. Data are limited and no
placebo-controlled trial have been
published to date. Seven infants with
refractory ulcerated infantile
hemangiomas experienced healing 3-21
days after initiating therapy.
Management : Venous Malformation
demonstrated significant patient satisfaction with
sclero-therapy with tetradecyl sulfate (Sotrdecol)
combined with conservative ablation.
It is important to know that in most cases 
sclerosant therapy is purely an adjunct to proper
surgical ablation.

Management : Arterial or A-V Malformation
High flow lesions can have turbulent blood flow, 
introducing the risk of consumption
coagulopathies. Therefore proper pre-operative
hematological studies have to be carried out.
Pre-ablation selective arterial embolization has 
improved the surgical success rates for arterial
and A-V Malformations, especially the intraosseous ones.
Management : Arterial or AV Malformation
The goal of embolization is to decrease flow in the 
malformation while avoiding disruption of flow through
proximal feeders.
Any surgical intervention should follow within 24 to 48 
hours of embolization, and never later than 10 days. It is
believed that collateral flow to the malformation develops
soon after embolization and that delaying surgery increases
the possibility of intra-operative bleeding and
postoperative recurrence.
The goal of surgery should be total excision of the
malformation.
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Complications
Ulceration 
Ulceration occurs in 10-15% of infantile 
hemangiomas, especially combined superficial
and deep lesions. The cause of ulceration is not
clear but may be a result of outstripped blood
supply to the overlying skin or secondary to the
action of certain cytokines.
Ulceration usually occurs in tense, rapidly 
proliferating hemangiomas and occurs more
commonly in the anogenital region, lip, and chest,
although any site may develop an ulcer..
Ulceration
The ulcerations are extremely painful and
result in scar formation upon healing,
which may take months. A white
discoloration seen early in the course
(usually within the first 3 months of life),
mimicking that seen in early involution,
may herald an impending ulceration,
particularly in segmental infantile
hemangiomas

Secondary infection
Secondary infection can occur, but cellulitis, 
abscess, and bacteremia are rare.
While intermittent bleeding is common, serious 
hemorrhage appears to be rare. Lifethreatening arterial hemorrhage has been
reported in at least 7 infants, mostly
complicating segmental hemangiomas of the
head and neck. Closer observation and
imaging studies to assess underlying
vasculature may be helpful in very high-risk
cases.
Treatment for ulcerated
Treatment for ulcerated hemangiomas 
includes topical or oral antibiotics, bioocclusive dressings (especially
hydrocolloid dressings), pulsed-dye laser
surgery, becaplermin gel (human
recombinant platelet-derived growth
factor), and external compression therapy
(especially helpful for limb lesions).
Treatment for ulcerated
Pulsed-dye laser surgery has been 
reported to be effective for ulcerated
superficial hemangiomas and often
decreases pain, even before the ulcer
has reepithelialized. Medical therapy to
hasten hemangioma involution with
glucocorticosteroids or beta-blockers can
also be helpful for recalcitrant ulcers.
Airway obstruction
Airway obstruction is a rare complication 
of hemangiomas; upper lip lesions very
seldom obstruct both nasal passages. This
can be a problem for young infants who
are obligate nose breathers.
Airway obstruction
Cervical parapharyngeal or palatal 
hemangiomas can cause acute or
subacute obstruction.
Insidious signs and symptoms, such as 
sleep apnea, cor pulmonale, or even
failure to thrive, can be associated with
hemangiomas in the upper aerodigestive
tract.
Airway obstruction
Laryngeal (often referred to as subglottic)
hemangiomas present early (6-8 wk) with
symptoms of inspiratory or biphasic stridor,
especially with feeding or crying. Cough,
cyanosis, or hoarseness may be
associated findings.

Airway obstruction
The diagnosis is confirmed by direct 
laryngoscopy, MRI, soft tissue
anteroposterior neck radiographs, or
esophagography.
Prompt consultation with a pediatric 
otolaryngologist should be sought for all
suspected cases.
Treatment
includes systemic corticosteroids or 
interferon alfa, as well as excisional or
laser surgery. Tracheostomy is sometimes
necessary until the hemangioma
involutes.
Airway obstruction
Upper airway hemangiomas appear to
be associated more commonly with
superficial cutaneous hemangiomas
involving the mandibular branch of the
trigeminal nerve (beard area
hemangiomas).They can occur without
cutaneous involvement.

Visual obstruction
Visual obstruction should be considered 
whenever a hemangioma involves the eyelids
or periorbital tissues.
Hemangiomas can lead to visual deprivation 
amblyopia by 3 separate mechanisms:
physical obstruction of the visual axis,
astigmatism from direct pressure on the
anterior segment from eyelid involvement
(upper eyelid is more common than lower
eyelid), and unilateral myopia.
Visual obstruction
Strabismus can result either secondary to
amblyopia or from paralysis of the
extraocular muscles infiltrated by an
orbital hemangioma.

Visual obstruction
A pediatric ophthalmologist should 
evaluate all children with periorbital
hemangiomas using refraction with
retinoscopy, with upper eyelid lesions
rquiring the most frequent observation.
Other complications
Diffuse neonatal hemangiomatosis is a 
potentially life-threatening condition
characterized by numerous cutaneous
hemangiomas accompanied by visceral
hemangiomas. When more than 10
cutaneous hemangiomas are present, the risk
of visceral lesions rises. The liver and
gastrointestinal tract are affected most often,
although any organ can be involved.
Congestive heart failure is a cause of early
mortality because of increased vascular
volume.
Other complications
Evaluation should include an imaging 
study of the liver (eg, liver scanning, MRI,
ultrasonography) and stool guaiac tests to
rule out intestinal bleeding from gut
hemangiomas. Systemic corticosteroids
and/or interferon alfa and conventional
surgery are possible treatments.
Kasabach-Merritt
phenomenon (KMP)
is marked by platelet sequestration and 
severe thrombocytopenia associated
with a rapidly proliferating vascular
neoplasm. This often is accompanied by a
potentially fatal, generalized bleeding
disorder. KMP is heralded by rapid
enlargement, edema of the surrounding
tissues, and accompanying purpura.
Kasabach-Merritt
phenomenon (KMP
Evidence suggests that most cases of KMP are
associated with kaposiform
hemangioendothelioma or tufted angioma
and not infantile hemangiomas, as previously
believed.The early reports of KMP were
described in lesions in which a clinical, not
histological, diagnosis was made. Systemic
corticosteroids are not usually effective, but
vincristine has been effective in several cases
of KMP caused by kaposiform
hemangioendotheliomas and tufted
angiomas.

PHACE syndrome
Patients with PHACE syndrome present 
with hemangiomas and one or more
extracutaneous congenital anomalies.
Reports have also described intracranial
invasion of associated infantile
hemangiomas.
PHACE syndrome
is an acronym denoting posterior fossa 
abnormalities (most characteristically DandyWalker malformation and other forms of brain
hypoplasia), hemangiomas (cervicofacial,
segmental/> 5 cm in diameter), arterial
anomalies (especially carotid, cerebral, and
vertebral), cardiac anomalies (especially
coarctation of the aorta), eye abnormalities,
and, rarely, midline ventral abnormalities
(sternal clefting or supraumbilical raphe).
Segmental infantile
hemangiomas
Segmental infantile hemangiomas involving the 
perineal area may be associated with other
underlying congenital anomalies as delineated in
the PELVIS or SACRAL syndromes.The acronymic
PELVIS syndrome describes the association of a
perineal hemangioma with any of the following:
external genital malformations,
lipomyelomeningocele, vesicorenal abnormalities,
imperforate anus, or skin tag. SACRAL syndrome is
spinal dysraphism with anogenital, cutaneous,
renal, and urologic anomalies, associated with an
angioma of lumbosacral localization.
lumbosacral hemangioma
An isolated midline lumbosacral 
hemangioma may be a cutaneous
marker for underlying occult spinal
dysraphism, the most common being an
intraspinal lipoma with resultant tethered
cord. Spinal imaging should be performed
in these cases.
lumbosacral hemangioma
Symptoms may not occur for several 
years and which infants require corrective
surgery has been debated, because as
many as 10% of the population have
asymptomatic tethering of the spinal
cord. The decision should be left to a
neurosurgeon with experience with this
condition.
consumptive hypothyroidism
Rarely, infantile hemangiomas have been 
implicated in cases of consumptive
hypothyroidism. This was initially reported with
hepatic hemangiomas; however, this has also
been reported with bulky cutaneous infantile
hemangiomas.This phenomenon appears be
secondary to high activity of the type 3
iodothyronine deiodinase enzyme in hemangioma
tissue, which is responsible for degradation of T4 to
reverse T3 (rT3). One case reported also
demonstrated increased production of a
thyrotropinlike hormone from a hepatic
hemangioma.Thyroid function tests should be
ordered.
Psychosocial problems
Psychosocial problems associated with 
disfiguring facial hemangiomas can be
significant.During infancy and early
childhood, parents often have reactions of
loss and grief. Parental feelings of disbelief,
panic, or fear often are associated with the
rapid growth of these lesions. The variability in
the natural course, in regard to timing and
completeness of resolution, adds to parental
anxiety.
Psychosocial problems
Parental stress is heightened by strangers who 
stare, startle, or raise questions about
causality, such as trauma (especially implied
or suspected child abuse), infection, or
cancer. Psychosocial stigmatization can be
problematic for both parents and patients
with disfiguring facial hemangiomas. Lesions
that result in significant facial or obvious
disfigurement should be addressed before the
child starts school.
Prognosis
The prognosis for most uncomplicated 
infantile hemangiomas is very good, with
complete involution of 50% by age 5 years,
70% by age 7 years, and 90% by age 9 years.
Despite resolution of the vascular component,
residual skin changes are observed in roughly
50% of cases. Of hemangiomas that have
involuted by age 6 years, 38% still have
residual evidence with scar formation,
telangiectasia, or redundant or anetodermic
skin.
Prognosis
Hemangiomas that take longer to 
involute have a higher incidence of
permanent cutaneous residua. Eighty
percent of lesions that complete
involution after age 6 years may exhibit
significant cosmetic deformities. An
increased incidence of permanent
residua exists when the lip, nasal tip,
eyelid, and ear are involved.
Patient Education
Educating parents about the variable
natural history, prognosis, risks, and
benefits of potential treatments and
possible complications is essential.
