Dermatologic surgey

Oxford, UK
International
IJD
Blackwell
1365-4632
45
Publishing,
Publishing
Journal Ltd,
of
Ltd.
Dermatology
2005

Treatment of keloids and hypertrophic scars with dermojet

injections of bleomycin: a preliminary study

Treatment
Saray
PHARMACOLOGY
and Gle
of keloids and
and hypertrophic
THERAPEUTICS
scars with intralesional bleomycin

Yasemin Saray, MD, and A. Tlin Gle, MD

From the Department of Dermatology,

Bakent University Faculty of Medicine,
Ankara, Turkey
Correspondence
Yasemin Saray, MD
Bakent University Faculty of Medicine
Department of Dermatology
5. Sokak, No. 48, 06490-Bahelievler
Ankara
Turkey
E-mail: yaseminsaray@hotmail.com
There was no funding source for this study,
and the authors had no conflict of interest.

Abstract
Background Numerous treatment modalities have been used to treat keloids and hypertrophic
scars, but the optimal treatment has not been established.
Objective The aim of this study was to determine the efficacy and safety of intralesional jet
injection of bleomycin as therapy for keloids and hypertrophic scars that are unresponsive to
intralesional steroid injection.
Methods The study included 14 patients with 15 keloids or hypertrophic scars that had not
responded to a minimum of three intralesional injections of triamcinolone acetonide. Multiple jet
injections of 0.1 ml of bleomycin (1.5 IU/ml) were administered to each lesion, with injection
sites spaced 0.5 mm apart. Injections were repeated each month. Scar height was measured,
and scar pliability and erythema were scored at baseline and then monthly during the treatment
and follow-up periods.
Patients self-assessments of subjective symptoms (pruritus and pain) were also scored.
Clinical improvement was defined primarily on the basis of scar height reduction (percentage
reduction from baseline), and was classified using the following scale: complete flattening
(100%), highly significant flattening (> 90%), significant flattening (75 90%), moderate
flattening (5075%), and minimal flattening (< 50%). Pre- and post-treatment mean values for
scar height, scar pliability, erythema, pruritus and pain were statistically compared.
Results The number of sessions required to successfully treat the lesions ranged from two to
six. Eleven lesions (73.3%) showed complete flattening, one (6.7%) showed highly significant
flattening, two (13.3%) showed significant flattening, and one scar (6.7%) showed moderate
flattening. The mean scar height was significantly lower, and the mean scores for scar pliability
and erythema were significantly better at the end of treatment (P < 0.001, P < 0.001 and
P < 0.001, respectively). The mean scores for pruritus and pain also improved significantly
(P < 0.001 and P = 0.01, respectively). The observed side-effects were hyperpigmentation (four
lesions) and skin atrophy (three lesions). No recurrences were noted during follow up (mean
duration of 19 months).
Conclusions Intralesional jet injection of bleomycin is an effective and safe method of treating
keloids and hypertrophic scars that are unresponsive to intralesional steroid therapy.

Introduction
Keloids and hypertrophic scars (HS) are abnormal healing
responses characterized by excessive accumulation of extracellular matrix, and by overabundant collagen formation in
particular.1 These lesions occur after a variety of cutaneous
injuries, including surgery,2 burns,3 dermal trauma,4 and
acne,5 and some even arise spontaneously.6 Keloids and HS
can cause physical disfigurement, restricted range of motion,
bothersome symptoms, and psychological problems, and yet
there is no consensus in the literature regarding appropriate
therapy.79 Several treatment modalities, such as intralesional
2005 The International Society of Dermatology

(IL) injections of corticosteroids10,11 or 5-fluorouracil,12 surgical

excision,13 cryotherapy,14 radiotherapy,15 pressure therapy,16
silicone gel sheeting,17 and laser treatment,18 have been used
with variable success. Lesion recurrence and lack of response
are the most common reasons for failure.
Bleomycin is an antineoplastic agent that has been used
successfully for many years as treatment for recalcitrant
plantar warts in dermatological practice.1922 The literature
contains only two reports on the efficacy of IL bleomycin
therapy for keloids and HS.23,24 In 1996, Bodokh and Brun23
conducted the first bleomycin study on 31 keloids and five
HS. After administering three to five IL injections of the drug
International Journal of Dermatology 2005, 44, 777 784

777

International Journal of Dermatology 2005, 44, 777 784

III
III
III
F
F
F
12
13
14

23
32
42

M
F
F
F
M
M
F
M
F
F
F
1
2
3
4
5
6
7
8
9
10
11

HS = hypertrophic scar; CF = complete flattening; SF = significant flattening; MF = moderate flattening; HSF = highly significant flattening.

No lesion at 24 mo. follow up

No lesion at 19 mo. follow up
No lesion at 18 mo. follow up
No lesion at 18 mo. follow up
No lesion at 16 mo. follow up
No lesion at 16 mo. follow up
No lesion at 19 mo. follow up
No lesion at 19 mo. follow up
No lesion at 17 mo. follow up
No lesion at 19 mo. follow up
No lesion at 21 mo. follow up
No lesion at 21 mo. follow up
No lesion at 24 mo. follow up
No lesion at 16 mo. follow up
No lesion at 19 mo. follow up
Atrophy, hyperpigmentation
None
Atrophy, hyperpigmentation
None
None
None
Atrophy
None
None
Hyperpigmentation
None
None
None
None
Hyperpigmentation
CF
CF
CF
CF
SF
CF
CF
CF
MF
CF
HSF
HSF
CF
CF
CF
4
3
4
3
5
5
3
2
6
4
5
5
3
2
3
36
24
72
18
96
60
54
24
84
70
60
60
42
120
12
Surgery
Vaccination
Sebaceous cyst
Surgery
Surgery
Surgery
Acne
Surgery
Sebaceous cyst
Surgery
Surgery
Surgery
Trauma
Surgery
Surgery
Presternal
Shoulder
Presternal
Shoulder
Presternal
Shoulder
Presternal
Arm
Presternal
Abdomen
Presternal
Presternal
Presternal
Back
Abdomen
Keloid
Keloid
Keloid
Keloid
Keloid
Keloid
Keloid
Keloid
Keloid
HS
Keloid
Keloid
HS
Keloid
Keloid
IV
II
IV
III
III
III
II
II
III
IV
III

Sex

48
32
29
25
73
16
26
18
31
29
32

Side effects
Degree of
flattening
with treatment
Number of
sessions
required
Scar
duration
(months)
Scar
etiology
Scar
location

Saray and Gle

Patient

Study design and intervention

An injectable solution of bleomycin was prepared by diluting 15
units of bleomycin (BLEOCINA ampoule, Nippon, Kayaku Co. Ltd,
Tokyo, Japan) in 10 ml of sterile saline (final concentration 1.5 IU/
ml). Initially, local anesthetic (2% prilocaine hydrochloride) was
administered at the lesion site. Then multiple injections of bleomycin solution (each 0.1 ml [0.15 IU]) were administered using a jet
injector (MadaJet XL, Mada Inc., Carlstadt, NJ). The injections
were spaced 0.5 mm apart, and the dose applied to each lesion
was 0.4 ml/cm2 (maximum volume per session 3.5 ml). Injections
were repeated every 4 weeks, and the total number of treatment
sessions depended on the cosmetic outcome of each lesion.

Scar
type

The study included 14 patients (10 females and four males) aged
16 73 years (mean age, 32.5 14.3 years) who had Fitzpatricks
skin phototypes II (n = 3), III (n = 8) and IV (n = 3). All subjects
gave informed consent to participate. The Institutional Review
Board approved this study. Eleven of the patients had single
keloids, two had single HS, and one (patient 11) had two keloids
in the presternal region. The mean duration of the 15 lesions was
55.5 30.5 months. We defined keloid as a red to brown, dense,
elevated fibrous tumor or plaque located at a site of previous
trauma and extending beyond the borders of the original wound.
Lesions that were similar but remained within the confines of the
original skin damage were considered to be HS. All lesions had
been unresponsive to at least three IL injections of triamcinolone
acetonide. In addition to IL steroid injections, some of the lesions
had also been treated with other treatment modalities (surgical
excision, pressure therapy or cryotherapy). Patients with scars that
had been present for less than 1 year were excluded from the
study. In order to eliminate confounding effects from other
therapies, cases were only included if at least 6 months had
passed since the previous treatment(s). Female subjects were
warned to practice strict birth control during the treatment period.
The subjects demographic characteristics and the clinical
features of the lesions are summarized in Table 1.

Skin
type

Patients and Methods

Age
(years)

within a 1-month period, they observed complete regression

in 69.4% of the lesions. In a more recent study,24 involving
13 patients, bleomycin was dripped onto the scars and the skin
was then punctured repeatedly with a needle to allow the
drug to penetrate the dermis. The results with this method
were also promising, as the authors reported a 53.8% rate of
complete regression.
Jet injectors are needle-free injectors used to deliver certain therapeutic agents, such as local anesthetics and corticosteroids.25
This method has also been used successfully to administer
bleomycin to warts.26
The aim of this study was to determine the safety and
efficacy of an IL jet injection of bleomycin as treatment for
keloids and HS that do not respond to IL steroid therapy.

Outcome

Dermatologic surgey Treatment of keloids and hypertrophic scars with intralesional bleomycin

Table 1 Patient demographic characteristics, clinical features of the scars, side effects of bleomycin treatment, and therapeutic outcome

778

2005 The International Society of Dermatology

Saray and Gle

Treatment of keloids and hypertrophic scars with intralesional bleomycin Dermatologic surgey

Follow up
After the therapy was completed, the patients were examined
monthly during follow up to determine the incidence of recurrence.
We defined recurrence as the appearance of a markedly elevated
and hardened lesion that had previously been categorized as
completely flattened (see parameter details later) after bleomycin
therapy.
The same physician (YS) evaluated all the patients at each visit
during the treatment and follow-up periods.

scar that gives way to pressure while offering moderate resistance;

3 = a firm scar that moves as a solid, inflexible unit; and
4 = banding that produces a rope of scar tissue with blanching.
3. Scar erythema: This parameter was graded according to
severity, with 0 = absent, 1 = mild, 2 = moderate, and 3 = severe.

Self-assessed symptoms
Patients were asked to grade their symptoms of pruritus and pain
using the above-mentioned three-tiered scale of severity.

Evaluation procedures
Findings for clinical parameters (scar height, erythema, pliability)
and patients symptoms (self-assessed pruritus and pain) were
recorded at baseline and then monthly during the treatment and
follow-up periods. Systemic side-effects of bleomycin were not
evaluated, but cutaneous side-effects were noted. Photographs
were taken at baseline and at every visit.

Statistical analysis
Pre- and post-treatment mean values for scar height, pliability,
erythema, pruritus, and pain were calculated and then compared
using the Students paired t-test. A P-value less than 0.05 was
considered statistically significant.

Clinical parameters
1. Scar height (thickness): Calipers were used to measure scar
height (the maximum vertical elevation of the scar above normal
skin) in millimeters. Percentage of scar flattening was defined as
the percentage reduction of scar height from baseline at the end of
treatment. Flattening was classified using the following scale:
complete flattening (100%), highly significant flattening (> 90%),
significant flattening (7590%), moderate flattening (50 7 5%),
and minimal flattening (< 50%).
2. Scar pliability: This was rated using a scale commonly used to
assess the functional mobility of burn scars:27 0 = normal skin;
1 = supple skin that yields with negligible resistance; 2 = a yielding

Treatment for the 15 lesions was completed in a range of two

to six sessions (mean, four sessions) (Table 1), and follow up
lasted from 16 to 24 months (mean, 19 months). The results
for the clinical parameters studied and the patients symptoms
at baseline and after completion of treatment are detailed in
Table 2.

Results

Clinical parameters

1. Scar height: All the treated scars were flattened to some

degree by the jet injections of bleomycin. At the end of treatment, 11 (73.3%) showed complete flattening (Figs 1, 2 and
3), one (6.7%) showed highly significant flattening (Fig. 4),

Table 2 Pre- and posttreatment scores for clinical findings in the keloids and hypertrophic scars, and for patient symptoms
Mean scores for lesion parameters

Mean scores for symptoms

Patient

Pretreatment / Posttreatment
Height (mm)

Pliability

Erythema

Pretreatment/Posttreatment
Pruritus

Pain

1
2
3
4
5
6
7
8
9
10
11
11
12
13
14
Mean
P value

3.6 / 0
3.8 / 0
4.2 / 0
2.2 / 0
3.5 / 0
3.8 / 0
3.2 / 0
4/0
3.9 / 1.8
2.9 / 0
5.4 / 1
5.5 / 0.8
3.6 / 0
1.8 / 0
2.1 / 0
3.56 / 0.26
< 0.001

2 /0
3 /0
3 /0
2 /0
2 /0
2 /0
3 /0
3 /0
3/1
4 /0
3 /0
3 /0
2 /0
3 /0
3 /0
2.7 / 0.06
< 0. 001

3/0
2/0
3/0
3/2
1/0
2/0
2/0
0/0
3/0
3/0
3/1
2/0
2/0
2/0
3/0
2.26 /0.13
< 0. 001

1/0
3/1
3/0
1/0
2/0
0/0
3/0
0/0
3/1
0/0
0/0
3/1
0/0
3/0
2/0
1.6 /0.2
< 0. 001

3/0
0/0
0/0
0/0
0/0
0/0
3/0
0/0
3/1
3/0
3/1
3/0
0/0
0/0
0/0
1.2 / 0.13
0.01

2005 The International Society of Dermatology

International Journal of Dermatology 2005, 44, 777784

779

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Dermatologic surgey Treatment of keloids and hypertrophic scars with intralesional bleomycin

Figure 1 (a) Keloid on the left shoulder of patient 4 and

(b) complete flattening and reduced erythema after treatment.

There was no recurrence in 18 months

two (13.3%) showed significant flattening, and one (6.7%)

showed moderate flattening (Table 1). The mean scar
height at the completion of the bleomycin treatment was
significantly lower than the baseline mean (0.26 mm vs.
3.56 mm, respectively; P < 0.001). In all cases, a drop in height
was observed even after the first treatment session, and the
degree to which the scar was flattened after all sessions
remained unchanged throughout follow up.
2. Scar pliability: The mean score for scar pliability at the
completion of bleomycin treatment was significantly
lower than the baseline score (0.06 vs. 2.7, respectively;
P < 0.001). All but one of the 15 scars was completely
softened (mean score of 0) at the end of therapy (Table 2).
All of the lesions exhibited significant softening after the first
treatment session, and no re-hardening was noted during
follow up.
3. Scar erythema: The mean erythema score after bleomycin
therapy was significantly lower than the baseline score (0.13
vs. 2.26, respectively; P < 0.001). At the end of the treatment, 13 scars showed no erythema and the other two
showed mild and moderate erythema, respectively (Table 2).
International Journal of Dermatology 2005, 44, 777 784

Saray and Gle

Figure 2 (a) Presternal keloid on patient 7, and (b) complete

flattening and significantly reduced erythema after treatment.

Dermal atrophy occurred as a late side-effect, but there was no
recurrence in 19 months

In most cases, reduction of erythema was first observed after

the second treatment session. All the lesions maintained their
improved color throughout follow up.
Symptoms

The mean post-treatment pruritus score was significantly

lower than the score at baseline (0.2 vs. 1.6, respectively; P <
0.001). The treatment resolved the pruritus completely in
eight of the 10 patients who reported this symptom at baseline. The mean post-treatment score for pain was also significantly lower than the pretreatment mean score (0.13 vs. 1.2,
respectively; P = 0.01). Six of the patients had varying degrees
of scar-associated pain at baseline. At the end of treatment,
four of these individuals reported total pain relief and two
reported partial relief (Table 2). All the subjects who complained of pruritus and/or pain reported that their symptoms
improved gradually and relatively late, usually after the third
injection.
2005 The International Society of Dermatology

Saray and Gle

Treatment of keloids and hypertrophic scars with intralesional bleomycin Dermatologic surgey

Figure 3 (a) Hypertrophic scar on the abdomen of patient 10,

and (b) complete flattening, significantly reduced erythema, and

hyperpigmentation surrounding the lesion after treatment.
There was no recurrence in 19 months

Side-effects

Seven of the 14 patients had mild to moderate local pain after

each injection. This lasted 5 7 days. All the scars showed
superficial ulceration and crusting at the sites of injection, and
these changes resolved spontaneously within 10 days. Hyperpigmentation (four lesions, Fig. 3b) and dermal atrophy (three
lesions, Fig. 2b) were noted as late side-effects (Table 1). Of
the four patients who developed hyperpigmentation, three
had skin phototype IV and one had skin phototype III. The
hyperpigmentation occurred in the healthy skin surrounding
these four scars, and it resolved within 2 months of treatment
with topical tretinoin. None of the cases of dermal atrophy
improved during follow up.
Discussion
In this study, we administered IL jet bleomycin treatment to
a total of 15 keloid and HS lesions. The therapy led to com 2005 The International Society of Dermatology

plete flattening of 73.3% of the scars, and highly significant

(6.7%), significant (13.3%), or moderate degrees of flattening (6.7%) in the reamainder of the lesions. All the scars
treated with this method showed greater than 50% reduction
in height after an average of four treatment sessions. Our
success rate (73.3% complete flattening) was higher than the
rates in the two previous reports that investigated bleomycin
therapy for keloids and HS. In the first of these studies,
Bodokh and Brun23 treated 31 keloids and five HS with three
to five IL bleomycin injections within a very short period
(1 month), and reported complete flattening in 69.4% of the
lesions. In the other study, Espana et al.24 treated 13 patients
by dripping bleomycin onto the scars and then puncturing the
surfaces in multiple places to allow the drug to penetrate.
They performed two to five sessions at 1- to 4-month intervals
and achieved complete flattening in seven cases (53.8%),
highly significant flattening in five cases (38.5%), and significant flattening in one case (7.7%).
In addition to height reduction, we also found that the jet
injections of bleomycin resulted in significant improvements
with respect to scar erythema and pliability. In most cases, the
first signs of positive response were decreased lesion height
and increased pliability of the scar tissue. These changes were
followed by reduction of erythema. Such findings are fairly
consistent with the results of Bodokh and Brun,23 who noted
rapid reduction of scar height and erythema within the initial
two bleomycin injection sessions. Espana et al.24 did not
mention details related to the timing or nature of the patients
initial response in their investigation.
Our findings demonstrate that treatment of keloids and
HS with jet-injected bleomycin not only improves cosmetic
appearance, but also relieves discomfort caused by pruritus
and pain. However, the above-mentioned previous reports23,24
both indicated that pruritus disappeared after the first two
sessions in all patients, whereas in most of our cases we noted
pruritus and pain relief after the third treatment session. The
earlier reports did not discuss pretreatment pain.
Concerning side-effects of IL bleomycin, four of our subjects
developed hyperpigmentation in the healthy skin surrounding the treated lesions. Our findings are in line with those of
Espana et al.,24 who detected slight residual hyperpigmentation in two patients with skin type III. In our series, we only
noted hyperpigmentation in patients with skin phototypes III
or IV. We suggest that this side-effect may be directly related
to dark skin color, as one would expect. We also observed
dermal atrophy in three of the 15 lesions in our series. Interestingly, this side-effect was not mentioned in the two previous studies.23,24 Our study did not assess systemic side-effects
of bleomycin, such as hepatotoxicity, pulmonary fibrosis, or
blood marrow suppression. These types of problems are
observed with the higher doses of bleomycin used in systemic
chemotherapy.28 To date, no systemic toxicity has been
reported with low doses of this drug.
International Journal of Dermatology 2005, 44, 777784

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Dermatologic surgey Treatment of keloids and hypertrophic scars with intralesional bleomycin

Saray and Gle

Figure 4 (a) Presternal keloids on patient 11, and (b) highly significant flattening and reduced erythema after treatment. The lesions

remained unchanged throughout 21 months of follow up

Our cases were evaluated for an average of 19 months after

treatment ended, and we observed no lesion recurrence during follow up. In contrast, Espana and coworkers24 followed
their patients for a range of 5 36 months and documented a
recurrence rate of 15.4%. The other bleomycin study by Bodokh
and Brun23 provided no data related to recurrence.23
Bleomycin is a cytotoxic antibiotic derived from Streptomyces verticellus. It has antitumoral, antibacterial and antiviral properties.28 The exact mechanism of action by which
bleomycin resolves keloids and HS is unclear, but several possible explanations have been postulated.23,24 Recent research29
on cultures of human dermal fibroblasts showed that bleomycin directly inhibits synthesis of collagen by these cells. The
same study demonstrated that this agent inhibits collagen
synthesis stimulated by transforming growth factor-beta 1, a
cytokine that has been detected at high levels in scar tissue.
Decreased apoptosis of fibroblasts has also been implicated as
a major factor in the etiopathogenesis of keloids and HS.30,31
Several investigations3234 have shown that bleomycin induces
apoptosis in mammalian cells. It has also been demonstrated
that an injection of bleomycin into warts causes apoptosis.35
Also, recent work3638 has indicated that keloids and HS have
International Journal of Dermatology 2005, 44, 777 784

higher concentrations of lysyl-oxidase, the cross-linking

enzyme involved in maturation of collagen, than normal skin.
One of these recent studies revealed that bleomycin reduces
lysyl-oxidase levels in cultures of human dermal fibroblasts.38
This is another possible mechanism for the therapeutic effect
of bleomycin on keloids and HS.
In this study, we tested a different method for introducing
bleomycin into keloid and HS lesions. Jet injectors are airpowered, high-pressure devices that deliver a therapeutic
agent to the dermis.25 This method has been used successfully
to administer several different agents. Various reports describe
jet injection of triamcinolone acetonide in the treatment of
keloids39 and hairless patches in cases of alopecia areata,40
and jet injection of bleomycin in the treatment of warts.26 We
chose this method of administration because the jet injector
delivers a controlled volume (one-tenth of a milliliter per
injection) to a depth of 5 mm and forms a circular injection
site of approximately 5 mm in diameter.25 Using this device,
bleomycin can be spread more uniformly throughout the
lesion. Smaller volumes of bleomycin are administered, but
even distribution of the drug in the scar tissue explains why
this method is successful. With the jet-injection method we
2005 The International Society of Dermatology

Saray and Gle

Treatment of keloids and hypertrophic scars with intralesional bleomycin Dermatologic surgey

were able to achieve excellent effect with a bleomycin dose of

0.4 ml / cm2, whereas the dose used by Espana et al. was 2 ml/
cm2.24 In the latter investigation, the method of administration did not allow precise control of the depth and volume of
bleomycin given. The distribution of the bleomycin was uneven, and larger volumes of bleomycin were used to treat the
scars. Low doses of this agent ensure that the significant
side-effects of higher doses, such as systemic toxicity, can be
avoided. Further, the jet-injection technique eliminates the
psychological and physical trauma of standard needle treatment. Also, the monthly jet injections we tested in our study
were better tolerated by patients than the treatments (three to
five needle injections within a month, or 40 punctures per
5 mm2 of lesion) used in previous bleomycin studies.23,24
In conclusion, IL bleomycin administered via a jet injector
appears to be a safe and effective method for treating keloids
and HS. We believe that effective distribution of bleomycin
throughout the lesion is responsible for our high success rate.
Nevertheless, the small number of patients investigated and
the absence of a control group are limitations of this study.
Placebo-controlled studies involving a larger sample size and
longer follow up are needed in order to list IL bleomycin via
a jet injector as a preferred treatment for keloids and HS.
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2005 The International Society of Dermatology

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