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Treatment Response of Keloidal and Hypertrophic Sternotomy Scars
Comparison Among Intralesional Corticosteroid, 5-Fluorouracil, and 585-nm Flashlamp-Pumped Pulsed-Dye Laser Treatments
Woraphong Manuskiatti, MD;
Richard E. Fitzpatrick, MD
Arch Dermatol. 2002;138:1149-1155.
ABSTRACT
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Objective To compare the clinical response of keloidal and hypertrophic scars
after treatment with intralesional corticosteroid alone or combined with 5-fluorouracil
(5-FU), 5-FU alone, and the 585-nm flashlamp-pumped pulsed-dye laser (PDL).
Design Prospective, paired-comparison, randomized controlled trial.
Setting A private ambulatory laser facility.
Patients Ten patients with previously untreated keloidal or hypertrophic median
sternotomy scars at least 6 months after surgery that were considered problematic
by the patients.
Interventions Five segments were randomly treated with 4 different regimens: (1) laser
radiation with a 585-nm PDL (5 J/cm2); (2) intralesional triamcinolone
acetonide (TAC) (20 mg/mL); (3) intralesional 5-FU (50 mg/mL); and (4) intralesional
TAC (1 mg/mL) mixed with 5-FU (45 mg/mL). One segment of each scar received
no treatment and served as a control.
Main Outcome Measures Scar height, erythema, and pliability were evaluated before and every
8 weeks after treatment. Patients' subjective evaluations were tabulated.
Histologic sections of segments were examined in 1 biopsy sample per segment
at week 32.
Results There was a statistically significant clinical improvement in all treated
segments. No significant difference in treatment outcome vs method of treatment
was noted. However, intralesional formulas resulted in faster resolution than
the PDL: scar induration responded better to intralesional formulas, scar
texture responded better to the PDL, and scar erythema responded the same
as the control with all treatments. Adverse sequelae, including hypopigmentation,
telangiectasia, and skin atrophy, were observed in 50% (5/10) of the segments
that received corticosteroid intralesionally alone. No long-term adverse sequelae
were demonstrated in the segments treated with other modalities.
Conclusions Clinical improvement of keloidal and hypertrophic scars after treatment
with intralesional corticosteroid alone or combined with 5-FU, 5-FU alone,
and PDL seemed comparable, with the exceptions of the incidence of adverse
reactions, which were most common with intralesional corticosteroid. Intralesional
5-FU is comparable to the other therapies.
INTRODUCTION
KELOIDS AND hypertrophic scars that develop as a result of an exaggerated
proliferation of dermal fibroblasts after skin injury are characterized by
excess accumulation of collagen in the wound.1
Despite the disfigurement, symptoms, and psychological impact of these abnormal
wound responses, the literature offers little consensus about appropriate
therapy. Laser therapy, surgical removal, radiation therapy, silicone cream
or gel application, cryosurgery, intralesional injection of various agents
(eg, triamcinolone acetonide [TAC], an interferon, and 5-fluorouracil [5-FU]),
and occlusive dressing have all been used either alone or in various combinations
with variable but largely transient success.2-10
It has been difficult to assess the efficacy of the existing treatment
modalities because there have been limited numbers of controlled, comparative
studies of the effectiveness of various treatment methods in improving the
appearance or symptoms of these scars. In the present study, we compared the
clinical responses of keloidal and hypertrophic sternotomy scars to treatment
with pulsed-dye laser (PDL), intralesional TAC alone or combined with 5-FU,
and 5-FU alone.
PATIENTS AND METHODS
PATIENTS
Ten patients (6 women and 4 men) aged 25 to 74 years with skin phototypes
I (n = 1), II (n = 5), III (n = 2), and VI (n = 2) were enrolled in the study
after providing informed consent. All participants had a median sternotomy
scar of at least 6 months' duration that was not healing to their satisfaction,
and none had received previous treatment.
STUDY DESIGN AND INTERVENTION
Each scar was divided equally into 5 segments, with an untreated area
of 1 cm between individual treated segments to avoid the global effect of
PDL and intralesional formulas on the adjacent treated segments and to have
a well-defined segment for observation of each treatment modality. Before
treatment, each scar was mapped with a permanent marker on a flexible, transparent
sheet using natural landmarks such as moles, lentigines, or other anatomic
sites as references. Five segments of each scar were randomly treated with
4 different regimens: (1) laser irradiation with a 585-nm PDL (Photogenica
V; Cyanosure Inc, Bedford, Mass) at an energy density of 5 J/cm2
with a 7-mm spot without cooling for 6 treatment sessions at 4-week intervals
(the detailed technique of scar treatment with PDL has been previously described11-12 and involves a single pass of spots
overlapping 10%-20%); (2) intralesional TAC (Kenalog; Westwood-Squibb, Buffalo,
NY) at a concentration of 20 mg/mL every 4 weeks for a total of 6 treatments;
(3) intralesional 5-FU (Roche, Nutley, NJ) at a concentration of 50 mg/mL
for a total of 10 treatments (every 2 weeks for the first 8 treatments and
every 4 weeks for the last 2 treatments); and (4) intralesional TAC (1 mg/mL)
mixed with 5-FU (45 mg/mL) for a total of 10 treatments (every 2 weeks for
the first 8 treatments and every 4 weeks for the last 2 treatments). No local
or topical anesthesia was used in conjunction with any treatment. The injection
technique has been described in detail in a previous study4
and involves injection into the center of the scar mass using a 30-gauge needle.
One segment of each scar received no treatment and served as a control. The
assignment of modality per segment was sequentially rotated from superior
to inferior in each patient to adjust for effects of location. Immediate treatment
reactions and adverse sequelae on all treated segments were also observed
at every follow-up visit.
EVALUATION PROCEDURE
Scar Height, Erythema, and Pliability
A dial caliper (Mitutoyo Corporation, Kawasaki, Japan) was used to determine
scar height by measuring the maximum vertical elevation of the scar above
normal skin. Scar erythema was measured using a handheld colorimeter (ChromaMeter
CR-200; Minolta, Ramsey, NJ). A higher erythema value indicates increased
saturation toward red.13 The mean of 3 measurements
obtained from each area under study was used. Scar pliability was rated according
to a standard scale used to assess functional mobility of the scar related
to contracture and the elastic texture of the scar.14
Patient Self-assessment
At the end of the study (week 32), self-assessment of overall scar improvement
was subjectively graded by patients as being completely clear (100% improvement)
or was placed in a category of 25% increments compared with a standardized
photograph taken before treatment.
Histologic Examination
Punch biopsy samples were obtained from 2 representative patients at
week 32: 2 from the PDL- and TAC-treated segments of one patient and 2 from
the TAC + 5-FU and control segments of another patient. Each biopsy sample
stained with hematoxylin-eosin was examined for the pattern, arrangement,
and characteristics of collagen bundles and fibroblasts and the vascularity
features of individually treated segments.
STATISTICAL ANALYSIS
Mean values for scar height, erythema, and pliability were considered
significant at P<.05. The percentage of scar flattening
and lightening was defined as the percentage of scar height and erythema reduction
after treatment compared with baseline height and erythema, respectively.
Repeated-measures analysis of variance and standard 2-tailed, paired t test analyses were performed between means of scar height
and erythema of baseline, control, and all treated segments and were used
to compare the percentage of flattening and lightening. Scar pliability of
baseline, control, and all treated segments was also compared using Friedman
and Wilcoxon signed rank tests. The mean scar height, erythema, and pliability
values of each treated segment (PDL, TAC alone, TAC + 5-FU, and 5-FU alone)
and the control segment were also compared based on the aforementioned statistical
formulas at each follow-up visit.
RESULTS
BASELINE CHARACTERISTICS OF SCARS
Mean scar duration at the onset of treatment was 7 months (range, 6.0-11.5
months). In all median sternotomy scars, there were no statistically significant
differences in thickness, erythema, and pliability for any segments from all
patients.
SCAR HEIGHT
All hypertrophic portions of the treated segments showed significant
flattening compared with baseline and control segments in all patients (Figure 1 and Figure 2). Laser-irradiated segments showed significant flattening
compared with baseline at week 16 (4 weeks after the fourth treatment, P = .01) and compared with control segments at week 32
(12 weeks after the sixth treatment, P = .005). The
TAC-treated segments showed significant flattening compared with baseline
at week 8 (4 weeks after the second injection, P
= .003) and compared with control segments at week 16 (4 weeks after the fourth
injection, P = .02). Segments treated with 5-FU showed
significant flattening compared with baseline at week 8 (2 weeks after the
fourth injection, P = .02) and compared with control
segments at week 16 (2 weeks after the eighth injection, P = .003). The TAC + 5-FU–treated segments showed significant
flattening compared with baseline at week 8 (2 weeks after the fourth injection, P = .004) and compared with control segments at week 8
(2 weeks after the fourth injection, P = .02).
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Figure 1. Hypertrophic median sternotomy
scar at week 0 (A) and week 32 (B). A, Pulsed-dye laser–irradiated segment.
B, Triamcinolone acetonide–treated segment. C, 5-fluorouracil–treated
segment. D, Triamcinolone acetonide– and 5-fluorouracil–treated
segment. E, Control segment.
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Figure 2. Scar height of the treated segments
showed significant flattening compared with baseline and control segments
in all patients. TAC indicates triamcinolone acetonide; 5-FU, 5-fluorouracil.
Error bars represent SDs.
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Scar flattening was maintained at all subsequent follow-up visits through
week 32 in all treated segments. Control segments showed a slight increase
in scar height at week 32 compared with baseline. No statistically significant
difference in the mean scar height of all treated segments vs each other was
noted at all follow-up visits through week 32. However, there was a trend
toward all intralesional formula therapies providing a greater percentage
improvement compared with laser treatment (Figure 3).
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Figure 3. The degree of scar erythema was
significantly reduced with all treatments compared with baseline except triamcinolone
acetonide (TAC). 5-FU indicates 5-fluorouracil. Error bars represent SDs.
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ERYTHEMA
Compared with baseline, the degree of scar erythema was significantly
reduced at week 32 (12 weeks after the sixth treatment) at the laser-irradiated
segments (P = .02), at week 16 (2 weeks after the
eighth injection) at the 5-FU–treated (P =
.01) and control (P = .03) segments, and at week
24 (2 weeks after the tenth injection) at the TAC + 5-FU–treated segments
(Figure 1 and Figure 4). However, there was no significant difference in the degree
of erythema at the TAC-treated segments at baseline vs all follow-up visits.
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Figure 4. Scar pliability of the hypertrophic
portions of scars vs baseline was improved at all intralesional-treated segments.
TAC indicates triamcinolone acetonide; 5-FU, 5-fluorouracil. Error bars represent
SDs.
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In this study, only the red tone representing the scar erythema was
recorded by the colorimeter. Isolated telangiectatic vessels would not be
expected to have a predictable measurable impact on this measurement. In addition,
there was mild hypopigmentation in 2 of 10 patients after receiving 2 and
6 TAC injections, respectively. This might have an effect on the recorded
measurement as well.
No significant differences in scar erythema were shown among treatment
modalities at all follow-up visits through the end of the study. There also
was no significant difference in degree of erythema lightening between each
treated segment and the control segments.
PLIABILITY
All patients showed significant softening of the hypertrophic portions
of their scars vs baseline at all intralesional-treated segments (Figure 5). Significant softening was initially
seen as early as week 8 at TAC-treated (4 weeks after the second injection, P = .02) and TAC + 5-FU–treated (2 weeks after the
fourth injection, P = .02) segments and by week 16
(2 weeks after the eighth injection, P = .02) at
5-FU–injected segments. No statistically significant softening of the
laser-irradiated segments vs baseline was seen, whereas significant softening
of the control segments vs baseline was initially noted at week 24 (P = .046), but it was not maintained through the week 32
follow-up visit.
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Figure 5. Percentage of flattening. TAC
indicates triamcinolone acetonide; 5-FU, 5-fluorouracil. Error bars represent
SDs.
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IMMEDIATE TREATMENT REACTION AND ADVERSE SEQUELAE
Mild to moderate discomfort or pain described as similar to the sensation
of a rubber band snapping was reported in 90% (9/10) of the patients during
laser pulsing at the PDL-treated segments, whereas mild to moderate pain during
injection was noted in 100% (10/10) of the patients at the TAC-, 5-FU–,
and TAC + 5-FU–treated segments. There was no difference in the initial
pain of injection of TAC vs 5-FU, but a burning discomfort from 5-FU was reported
to last 30 minutes to several hours. Spots of purpura were seen at the 5-FU
and TAC + 5-FU injection sites in 20% to 30% (2/10 to 3/10) of the patients
at each follow-up visit. One of the 10 patients developed localized superficial
tissue slough at the TAC + 5-FU injection site after the first treatment visit,
but this reaction was not observed after the subsequent treatments. Purpuric
discoloration was seen at the laser-irradiated segments of all patients. Erosion
secondary to blistering was observed on some areas treated with laser in 2
patients with skin phototype VI.
Adverse sequelae, including hypopigmentation (20%, 2/10), telangiectasia
(20%, 2/10), and skin atrophy (10%, 1/10), were seen in 50% (5/10) of the
segments that received TAC injection alone. Some of these adverse effects
were initially noted as early as week 8 (4 weeks after the second injection),
and all persisted through 32-week follow-up. No persistent adverse sequelae
were demonstrated in segments treated with the other modalities.
PATIENT SELF-ASSESSMENT
Figure 6 summarizes the percentage
of improvement using each treatment modality as assessed by patients at the
end of the study (week 32). Fifty percent improvement or higher was rated
by 80% (8/10) of the patients at the laser-irradiated segments, 100% (10/10)
at the TAC-treated segments, 100% (10/10) at the 5-FU–treated segments,
and 90% (9/10) at the TAC + 5-FU–treated segments. Control segments
were graded as less than 50% improvement by 60% (6/10) of the patients. An
improvement in skin texture toward that of adjacent normal skin was also noted
in all laser-irradiated segments but in no other segments.
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Figure 6. Patient self-assessment of improvement
for each treatment modality at the end of the study (week 32). TAC indicates
triamcinolone acetonide; 5-FU, 5-fluorouracil.
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HISTOLOGIC FINDINGS
At the week 32 follow-up visit, 4 biopsy specimens were obtained from
2 of the 10 patients: 2 from a laser- and a TAC-treated segment of one patient
and 2 from a TAC + 5-FU–treated and a control segment of another patient
(Figure 7). There were subtle differences
among the treated segments but a more dramatic difference between all treated
areas and the control segment. The thick condensed collagen bundles of the
untreated segment particularly contrast with the finer, more loosely woven
fibers of the treated segments.
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Figure 7. Histologic findings from 2 representative
patients. A and B, Pulsed-dye laser–irradiated segment. Note the significantly
finer and loosely interwoven collagen bundles parallel to the epidermis in
the more superficial locations and the more dense and larger bundles in the
deeper dermis. The vessels are significantly smaller throughout (original
magnification x40). C and D, Triamcinolone acetonide–treated segment.
Note the dense and thick collagen bundles throughout the dermis, although
less condensed than in the control. Predominant visibility and number of vessels
stream through the collagen throughout (original magnification x40).
E and F, Triamcinolone acetonide– and 5-fluorouracil–treated segment.
Fine interwoven collagen with small dark nuclei of fibroblasts are in the
upper dermis, and more condensed and larger collagen bundles with more plump
fibroblasts are in the deeper dermis (original magnification x40). G
and H, Control segment. Note the thick condensed bundles of collagen with
large oval basophilic fibroblasts in the middle to lower dermis and the finer
bundles of collagen in the superficial dermis (original magnification x40).
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COMMENT
Although the basis for keloid and hypertrophic scar formation has not
been fully delineated, an imbalance of matrix degradation and collagen biosynthesis
resulting in excess accumulation of collagen in the wound has been postulated
to be the primary biochemical features of these skin lesions.3, 15
Fibroblasts construct new extracellular matrix components, initiate collagen
synthesis, and provide wound edge tension through contractile proteins, actin,
and desmin. Keloid- and hypertrophic scar–derived fibroblasts produce
increased amounts of collagen per cell compared with normal fibroblasts.16 Thus, suppression of the overwhelming and uncontrolled
fibroblast activity in keloids and hypertrophic scars may be essential in
therapeutic approaches to this abnormal wound response.
The efficacy of corticosteroid injections in the treatment of keloids
and hypertrophic scars has been well established. Suppressive mechanisms of
corticosteroids on wound healing include (1) interruption of the inflammatory
process by inhibition of inflammatory cell migration and phagocytosis, (2)
a vasoconstriction effect resulting in disruption of the oxygen and nutrient
supply to the wound, and (3) antimitotic activity on fibroblasts and keratinocytes,
which may be the most important mechanism.17
The most commonly used corticosteroid is TAC. The dosage and treatment interval
have arbitrarily varied from 10 to 40 mg/mL administrated at intervals of
4 to 6 weeks for several months or until the scar is flattened. Although intralesional
TAC administration has shown clinical efficacy, the outcome has been uncertain
and associated with multiple adverse effects, including atrophy, telangiectasia,
and pigmentary changes.15, 18 Recently,
the combined used of intralesional TAC and 5-FU in the treatment of inflamed
hypertrophic scars has been reported to be effective and can avoid these potential
complications.4 5-Fluorouracil, a pyrimidine
antimetabolite, has been used as an adjunct to glaucoma filtering surgery,
a procedure in which inhibition and prevention of postoperative scarring is
essential for achieving surgical success.5, 16
5-Fluorouracil inhibits fibroblast proliferation in vitro7
and in vivo.8 Long-term follow-up studies9-10 of the ophthalmic surgery using 5-FU
confirm its efficacy and safety.
The effectiveness of PDL in the treatment of keloids and hypertrophic
scars has been well documented11, 19
and has been thought to be mediated by selective damage of the microvasculature
of the scar.20 A fluence-dependent inhibition
of hypertrophic scar implants in mice was proportional to the fluence from
6 to 10 J/cm2 using a candela PDL. In contrast, previous clinical
studies11, 21 on the PDL treatment
of scars noted no significant difference in the treatment outcome vs minor
variations in fluence used (6.0-7.5 J/cm2). Similarly, our recent
controlled study12 noted no statistically significant
fluence dependence of the clinical improvement of keloidal and hypertrophic
median sternotomy scars after PDL treatment. However, a trend toward better
response with lower fluence was observed. A dose-response study22
of treatment of striae distensae demonstrated enhanced response at lower fluence.
This response was speculated to be mediated by stimulation of elastic tissue.22
A recent study23 of the efficacy of the
585-nm PDL in treatment of hypertrophic scars showed that the clinical improvement
in scar sections treated with 4 PDL irradiations at 8-week intervals was no
different than that in control sections. Several factors were postulated to
affect this difference in clinical results from other previous studies: differences
in the range of patient skin phototypes, a tendency for partial spontaneous
resolution of scars less than 1 year old in previous studies, and a global
effect of PDL on the adjacent sections used as a control in the recent study.23 This was in contrast to an average improvement in
nonfacial scars of 81% after 2 treatments with PDL reported by Goldman
and Fitzpatrick.11 This positive result is
confirmed by the present study as there was statistically significant flattening
of the scars at the PDL-irradiated segments vs baseline as early as week 16
(4 weeks after the fourth treatment) and vs the control at week 32 (12 weeks
after the sixth treatment). In addition, a significantly higher percentage
of scar flattening was noted after more than 2 treatments. Therefore, multiple
sequential treatments may be essential for achieving a better clinical response.
The increase in epidermal melanin in dark-skinned individuals is a competitive
chromophore to the hemoglobin at the 585-nm wavelength of the PDL. Four patients
with darker skin (2 patients with skin phototype III and 2 with skin phototype
VI) were also included in the present study. Although the number of patients
was too small to assess the statistical difference in clinical improvement
compared with fair-skinned patients (skin phototypes I and II), the mean scar
height of these type III and VI patients was also substantially decreased
at the PDL-irradiated segments. A global effect of PDL on adjacent nontreated
scar tissue might explain the indifference in clinical improvement between
PDL-treated and adjacent control sections reported in the study by Wittenberg
et al23 as we also observed this improvement
effect at the adjacent nontreated segments in our patients.
The improvement in skin texture of scars treated with PDL is an interesting
observation because it adds a significant cosmetic element to the improvement
seen. Textural changes such as this are thought to be the result of collagen
remodeling and are the basis of the improvement seen with treatment of photoaged
skin with nonablative resurfacing.24-27
It is not surprising that this effect would be observed with this treatment
as well.
The average time to onset of action of scar flattening of all intralesional
formulas was comparable and was seen at an earlier follow-up period than that
of PDL (week 8 vs week 16). However, the number of treatments required for
achieving the onset of this therapeutic response varied from 2 treatments
at 4-week intervals with TAC to 4 treatments at 2-week intervals with 5-FU
and TAC + 5-FU to 4 treatments at 4-week intervals at the PDL-irradiated segments.
Onset of action of scar softening was seen as early as week 8 at the TAC-
and TAC + 5-FU–treated segments and at week 16 at the 5-FU–treated
segments. Although no significant scar softening was noted at the 5 J/cm2 PDL-irradiated segments, there was a trend toward pliability score
reduction after each treatment session. The study by Alster and Williams19 and our recent study12
also found statistically significant improvement in scar pliability after
treatment with PDL at fluences of 3 and 7 J/cm2. The fact that
scar pliability was a subjective evaluation might affect the accuracy of its
assessment. All treatment modalities provided significant improvement in scar
height and pliability but not scar erythema. In addition, the improvement
was sustained through the week 32 follow-up visit (10-12 weeks after the last
treatment). Because the natural history of spontaneous improvement of scars
during the first 6 to 12 months after integumental injury, especially in terms
of erythema,2 may complicate the interpretation
of treatment evaluation, it was not surprising that there was no significant
improvement in scar erythema noted with any treatment modalities compared
with controls. These particular scars were all of 6 to 12 months' duration,
a time during which improvement is to be expected.
All intralesional formulas seemed to have comparable effectiveness in
scar flattening and had a trend toward a higher degree of effectiveness than
laser treatment. However, because the treatment of scars is often undertaken
for at least some cosmetic concerns, the treatment should be free of adverse
sequelae in addition to being judged effective. Transient burning sensation
or discomfort was the most common immediate adverse effect reported by all
patients at the TAC + 5-FU– and 5-FU–treated segments, and purpuric
discoloration usually lasting 7 to 10 days was seen in all patients at the
laser-irradiated segments. At week 32, adverse sequelae were seen only at
the TAC-treated segments in half of the patients, whereas no adverse effects
were found at the segments treated with the other modalities. Atrophy, telangiectasia,
and hypopigmentation are not acceptable adverse effects for most patients.
Inactive fibroblasts were seen on all the biopsy specimens obtained
at laser-, TAC-, and TAC + 5-FU–treated segments. The tissue vascularity
of the laser-irradiated segment was particularly less prominent than that
of the TAC-treated segment. This hypervascular state of the TAC-treated segment
may result from the adverse effect of the intralesional corticosteroid, which
presents clinically in the form of telangiectasia. The TAC-treated segment
seemed to have altered tissue effects throughout the depth of the specimen,
which is probably because of the depot effect and diffusion of action.
In summary, clinical improvement of keloidal and hypertrophic scars
was seen after treatment of hypertrophic and keloidal sternotomy scars with
intralesional corticosteroid alone or combined with 5-FU, 5-FU alone, and
585-nm PDL; overall, the end results were comparable. Use of the intralesional
formulas provided a more rapid response, but intralesional corticosteroid
therapy is much more likely to cause adverse effects. Use of intralesional
5-FU is a reasonable alternative. The histologic findings of each treatment
reflect the clinical findings. Management of these lesions should be individualized
according to the patient's desires and expectations. Some patients may not
respond to any single treatment modality, and the use of multiple treatment
modalities may be the best approach for maximizing therapeutic success.
AUTHOR INFORMATION
Accepted for publication November 28, 2001.
Corresponding author and reprints: Richard E. Fitzpatrick, MD, Dermatology
Associates and Cosmetic Laser Associates of San Diego County Inc, 9850 Genesee
Ave, Suite 480, La Jolla, CA 92037 (e-mail: fitzskin{at}pacbell.net).
From Dermatology Associates and Cosmetic Laser Associates of San Diego
County Inc, La Jolla, Calif. Dr Manuskiatti is now with the Department of
Dermatology, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
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