Sociedade Brasileira de Dermatolodia Surgical & Cosmetic Dermatology

IR PARA

ISSN-e 1984-8773

Volume 5 Number 1


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Original Article

Keloid treatment using postoperative radiotherapy with electron beams: a comparative randomized study of two methods

Tratamento de queloides usando radioterapia pósoperatória com elétrons: estudo comparativo e randomizado com dois esquemas

Batista de Oliveira Junior1, Silvana Artioli Schellini1, Joel Carlos Lastória1, Lídia Raquel de Carvalho1, Hamilton Ometto Stolf1, Ana Laura Paludetto de Oliveira1

Professor and Coordinator at the
Radiotherapy Department of the Hospital
das Clínicas da Faculdade de Medicina de
Botucatu da Universidade Estadual
Paulista (Unesp)—Botucatu (SP), Brazil1, Professor, Department of Ophthalmology,
Hospital das Clínicas da Faculdade de
Medicina de Botucatu da Universidade
Estadual Paulista (Unesp)2, Associate Professor, Department of
Dermatology and Radiotherapy of the
Faculdade de Medicina de Botucatu da
Universidade Estadual Paulista (Unesp)3, Professor, Department of Biostatistics at
the Instituto Básico da Universidade
Estadual Paulista (Unesp)4, Professor, Department of Dermatology
and Radiotherapy of the Faculdade de
Medicina de Botucatu da Universidade
Estadual Paulista (Unesp)5, Academician at the Faculdade de Medicina
da Universidade José do Rosário Vellano
(Unifenas)—Alfenas (MG), Brazil6

Received on: 20 October 2012
Approved on: 2 February 2013

The present study was carried out at
theHospital Universitário da Faculdade de
Medicina de Botucatu da Universidade
Estadual Paulista (Unesp)—Botucatu (SP),
Brazil.

Financial support: None
Conflict of interest: None

 

Abstract

Introduction: While several keloid treatment modalities exist, they all offer disappointing results when performed in isolation. The combination of surgical excision and post-operative irradiation with electron beams is effective in improving the quality of scars and reducing the recurrence rate of the condition. Objective: To assess, on a comparative basis, the prospects for cure, and also side effects in the irradiated areas of two treatment methods using electron beams. Methods: A prospective, comparative and randomized clinical study was carried out at the Faculdade de Medicina de Botucatu-UNESP, in Botucatu (SP), Brazil, between 2008 and 2010. The study included patients who were post-operative after their treatment for the resection of keloids. The study population was divided into groups G1 and G2, having received radiotherapy treatment with electrons from a linear accelerator at 30 Gy/10 fractions and 32 Gy/16 fractions, respectively. The patients were followed up with for 18 months. Results were assessed through the observation of two independent evaluators and the distribution of a questionnaire to study participants. Results: Forty-three patients were investigated (21 in G1 and 22 in G2). 52.4% showed good results in G1, with a recurrence rate of 47.6%. In G2, 91% showed good results, with a 9% recurrence rate. Conclusion: The 32 Gy/16 fractions method was proved to be superior to the 30 Gy/10 fractions method, resulting in a better therapeutic response and fewer side effects.

Keywords: KELOID, ELECTRONS, RADIOTHERAPY

INTRODUCTION

Healing is a process;one that is complex, multicellular, and defined by its progression. In the skin, its objective is to restore the body''''''''s protective barrier, which corresponds to the dermal integument. This process involves coordinated efforts of several cell types including keratinocytes, fibroblasts, endothelial cells, macrophages and platelets. 1

The migration, infiltration, proliferation, and differentiation of these cells will lead to an inflammatory response, new tissue formation, and eventually to the closure of the wound through the healing process. 1

This complex process is performed and regulated by an equally complex signaling network involving a great number of growth factors, cells, and cellular mediators. 1

The following are particularly important: epidermal growth factors family (EGF); transforming growth beta factors family (TGF-beta); fibroblast growth factors family (FGF-beta), vascular endothelial growth factor (VEGF), connective tissue growth factor (CTGF); tumor necrosis alpha growth factor family. 1

Failures in the regulatory sequences, in growth factors, and in keratinocyte-fibroblast interactions—with the consequent senescence and apoptosis—may lead to the keloid formation process. 2

Describing keloids for the first time in 1806, Alibert refers to growth resembling the projection of branches, which had the appearance of a crab''''''''s claw, hence the term keloid, from the Greek khele, which means the claw of a crab. 3

A keloid is an abnormal, elevated, and irregularly shaped scar, which extends beyond the incision or injury in the skin due to excessive accumulation of collagen in the dermis during the conjunctive tissue''''''''s repair process. 4

Despite the improvement in the knowledge of molecular and cellular events involved in the formation of keloids, these lesions'''''''' pathogenesis remains poorly understood, hampering its prevention and treatment. 4

The fact that these lesions occur more frequently in certain kinds of individuals is widely known. People of African and Asian ethnicities are more affected than Caucasians. 5

In an observational study assessing the maturation of the scar, Bond et al. concluded that the cellular proliferation rate varies according to several parameters, such as age, for example. They suggested that the maturation rate is higher in individuals younger than 30 years old, who have a delayed maturation of the scar. 6

It is known that human mesenchymal cells may be involved or have an enhancement role in the pathogenesis of keloids by differentiating themselves, directing the lesion''''''''s formation and progression. 7

Keloids are formed by a population of polyclonal fibroblasts that are intrinsically normal but respond to an abnormal extracellular signal, causing excessive production of collagen in the extracellular matrix. 8

The high consumption rate and insufficient diffusion of oxygen can possibly contribute to the keloids'''''''' pathophysiology.9 The tension on the suture is an important condition associated with the formation of keloids.10

De Felice et al. described an alteration in the mechanism which determines the regulation of apoptosis, during the healing process.11

Analyzing biological differences between fibroblasts in the central and peripheral areas of keloids, Lu et al. concluded that differences in the cell cycle and the expression of p53 protein might explain the different growth characteristics of the central and peripheral keloids. Sixty percent of the fibroblasts of the peripheral parts of keloids are in the G2 and S phases of the cell cycle. On the other hand, most of the fibroblasts derived from the keloids'''''''' center were in the G0 and G1 phases. The expression of the p53 protein was considerably greater in fibroblasts derived from central parts.12

The main causes for the formation of keloids are: surgery, lacerations, tattoos, burns, injections, bites, vaccines, piercing, dermatoses, laser assisted hair removal, induced trauma, and other spontaneous causes.

In 2006, Leventhal et al. published a meta-analysis involving 70 sets of various treatment modalities for keloids with the rate of primary improvement expected to level at 60%. Most treatments offer minimal probability of improvement.13

There are several treatment modalities that, isolated, have produced disappointing results. The most common are: bleomycin, 13 corticosteroids injection,14 interferon,14 5-fluorouracil (5-FU),15 imiquimod,16 laser therapy,17 silicone gel,18 liquid nitrogen,17 photodynamic therapy (PDT),19 mitomycin C,20 simvastatin, 21 vitamin D,22 acupuncture 23 intradermal tacrolimus,24 and radiotherapy (RT). 25

The variety of treatment modalities suggests that there is not a satisfactory therapy, resulting in frustration for both patients and physicians.6

There are various forms of adjuvant RT for surgically resected keloids: conventional X-Ray 26, beta therapy,27 singledose RT,28 electron beam RT.25

The electron beam radiotherapy is superior to conventional X-Ray irradiation in the treatment of keloids due to better distribution of the dose in the tissue.26

The combined treatment of surgical excision and postoperative irradiation with electrons is effective for the scar''''''''s quality and reducing the rate of recurrence, with a minimum follow up of 2.5 years.25

In an assessment of the effective biological dose for postoperative RT in the prevention of keloid, Kal and Veen concluded that the optimal dose is 30Gy BED (biological equivalent dose).29

The action mechanism of irradiation on conjunctive tissue with cell hyperplasia at the expense of fibroblasts is based on the inhibition of proliferation and stimulation of differentiation of those cells.30

Comparative assessments allow for the stating that the electron beam RT is better than betatherapy for the treatment of operated keloids due to a better distribution of the dose in the tissue.27

Keloids should be treated with electrons in doses tailored by location, with the greatest beamed in high-risk sites.31

In the 1970s, high-energy linear accelerators became increasingly available for clinical use due to the possibility of functioning with photons of various electron energies. The commercial development of these machines was immediate, largely due to the clinical experience in many health centers that showed that in some often encountered situations, there is no alternative treatment for the electron beam based therapy.

The most frequent clinically-used energy range for electrons is 6 to 20Mev (million electron volts). At these energy levels, the electron beam can be used for treating superficial tumors (located less than 5cm deep) with a sharp decrease in dose, and in the tumor.

The main applications of the electron beam are: treatment of skin and lip cancer, irradiation of the thoracic wall in breast cancer, administration of reinforcement dose (boost) in nodules or surgical bed, treatment of head and neck cancer, and irradiation of internal mammary chain, among others.

Electron beam irradiation provides several advantages in terms of dose uniformity regarding the target-volume, with minimal doses being administered to deeper adjacent tissues.27

When an electron beam travels through a medium, energy is continually degraded up until the electrons achieve thermal energy levels, when surrounding atoms capture them.

Thus continuous loss of energy occurs through linear energy transfer (LET), whose value is 2Mev per centimeter (cm) in the range of 4 to 20Mev.

That path is denominated reach, which is specific for each energy level. (Figure 1)

For this reason, electrons are used for the treatment of superficial or semi-deep lesions without irradiating the tissue that is beyond reach.

It is known that the type of scarring that occurs in keloids can suffer from the action of physical processes such as irradiation.

It is also known that irradiation has a positive effect on the reduction of keloids, with different treatment schemes and varying doses having been reported.

In a previous study, Oliveira Junior et al. 27 observed that the production of collagen continued to take place beyond the stipulated time of radiotherapy (eight days) in cases of recurring keloids, suggesting that more prolonged treatments could have more positive results.

In this manner, new therapeutic schemes must be tested— the reason that motivated the present research.

The present study was aimed at comparatively assessing two treatment schemes that use electron beams, as regards their probability for cure and side effects in the area of application. In addition, this study evaluates the opinions of keloids bearers 18 months after receiving treatment with a program of a total dose of 32Gy divided in 16 fractions.

METHODS

A comparative, prospective, and randomized clinical study was carried out at the Faculdade de Medicina de Botucatu / UNESP, from the period of 2008-2010.

The research protocol was reviewed by the Research Ethics Committee of the institution, having been approved on October 6, 2008 and registered under the number 414/08-CEP.

All patients were fully informed regarding their participation in the study and about the need for photographic documentation, and signed a term of informed consent and an authorization for the purposes of filming, photographing, publicly presenting and publishing the study material.

The research method was designed with an aim at comparing two treatment regimens using equivalent doses, nevertheless with different exposure times for the RT treatment, adjuvant to the surgical excision of keloids.

The representative sample for the study was composed of 60 patients of both genders who had undergone the procedure no more than 72 hours before the assessment.

The patients included in the study were divided into two groups by drawing lots that randomly assigned the RT scheme to be used:
Group 1 (G1): was considered as the control group. Composed of patients who underwent the 10 fractions scheme, with a total dose of 30Gy;
Group 2 (G2): was considered the study group. It was composed of patients who underwent the 16 fractions scheme, with a total dose of 32Gy.

Both groups received treatment with 4Mev energy electrons, produced by a 2,100C Linear Accelerator (Varian, USA).

The study patients were enrolled in the study and observed at 3, 6, and 18 months after the completion of the treatment.

Patients of both genders and without age limit, who had undergone complete resection of keloids and were into the post-operative period for no more than 72 hours, were included in the study.

Those excluded from the final study, being considered non-participants were those who:
- had undergone the surgical procedure more than 72 hours before the assessment
- had undergone previous laser or cryotherapy-based surgeries
- had undergone surgery using the shaving technique
- were using compressive dressings whose volume was able to produce significant absorption of the irradiation beam (Braun dressing)
- experienced healing by second intention due to dehiscence of the surgical suture
- underwent only a partial surgical procedure (i.e. there was exeresis of the center of the lesion only)
- underwent suture with great tension on the borders of the incision and with possibility of dehiscence

The surgery consisted of removing the keloid following conventional methods:
a) marking of the limits of the lesion with surgical ink (bright green). Next, a 1mm safety margin of normal skin was preserved;
b) incision and excision of keloids up until the subcutaneous level, using cold blade scalpel (number 15: Free Bac manufacturer);
c) hemostasis with bipolar electrocautery (WemEletrocirurgical operator SS-200A);
d) free skin graft when necessary;
e) edge-to-edge primary suture, using 4.0 nylon monofilament thread (B. Braum) in the chest wall and dorsum, and 5.0 nylon monofilament (Brasuture) in other body sites;
f) dressing with a micropore grid, kept for 72 hours;
g) cleansing of surgical wound site daily with water and soap.

Patients were positioned in the linear accelerator''''''''s stretcher, according to the location of the surgical scar and taking into account that the scar''''''''s plane must be perpendicular to the central axis of the irradiation beam. In flat scars, location is simple. In scars with small curvatures care must be taken in order to prevent that one extremity does not end up being farther than the other from the plane perpendicular to the beam, as the air layer in the farther side can significantly lessen the beam. In cases of lesions in the posterior region of the ear, it is necessary to traction them in order to perform irradiation.

With more extensive scarring it is necessary to divide the application into two or more fields, always observing the correct separation so as to avoid the overlapping (entailing overdose), or excessive separation (entailing subdose).

The duration of the exposure depends on the field''''''''s size, application''''''''s distance and the prescribed daily dose. In general, it varies from one to two minutes for each field, when using the Clinac 2100 C-Varian.

There was no previous preparation with creams or ointments before or after the RT sessions.

When patients use micropore dressing—usually in the first or second post-operative day—there is no need to remove it, since its presence does not interfere with the beam irradiation.

The evaluation parameters were: a) patient''''''''s characteristics regarding gender, age group, skin phototype, and affected body site, b) observation of clinical parameters in the treated area. The assessment was carried out by two physician evaluators, who were members of the Radiotherapy Department and had participated in the treatment of the patients. Assessments were also carried out by the authors at 3, 6, and 18 months, when a questionnaire on the patient''''''''s degree of satisfaction was distributed. Other assessments were carried out using the previously taken photographic records and inquiries made by the patients themselves. Consensus meetings were held when necessary; c) assessment of patients'''''''' degree of satisfaction regarding the aesthetic and symptomatic aspects, through a questionnaire given by the team members who took part in the evaluation of the clinical parameters. The questionnaire was distributed 18 months after the end of treatment, and considered the following criteria: unsatisfied (recurrence> 50%, with symptoms); satisfied (recurrence =50%, without symptoms); very satisfied (no recurrence, no symptoms).

The questionnaire was developed by the researcher and contained open and closed questions about: difficulty of adhering to the proposed treatment, guidance on the treatment, side effects, and satisfaction. It was given to 21 individuals in G1 and 22 in G2 (Tables 1, 2 and 3).

The results were statistically evaluated through the Chisquare test.

STATISTICAL ANALYSIS

The data obtained in the evaluation of photographs and from the questionnaire were transferred to an Excel spread sheet, having received statistical treatment. The Chi-square test was used to verify the association between the groups and the results of the evaluation.

RESULTS

During the study period, 64 patients who had undergone surgery to remove keloids were referred for evaluation of the inclusion and exclusion criteria. Sixty patients were considered as having fulfilled the criteria, and were included in the study.

The reasons for non-inclusion were: presence of dehiscence (two), infection (one) and pregnancy (one). When a patient had more than one problem, he or she was excluded.

Of the 60 patients included in the study, 17 were absent at follow-up visits, and were unreachable thereafter—mostly due to changes of address or phone number and limited access by the municipalities'''''''' Social Services (generally in rural areas).

The results presented refer to patients who completed the observation period (set at18 months).

Survey participants were of both genders (33 women (52%) and 31 men (48%)).

Regarding the age groups, 50% were 20-30 years old, 37% were older than 30 years old, and 13% were younger than 20 years old, meaning that most patients were young.

Analyzing the photographic records and employing the Fitzpatrick skin phototype classification, 12.9% of patients were classified as type III while 87.1% were classified as types IV, V, or VI.

The distribution of cases according to the affected body site is shown in Table 1. It is possible to observe that 23% of survey participants had lesions in the thoracic region, 14% in the upper limb, 19% on the back, 16% in the abdomen, 21% in the head and neck, and 7% in the lower limb.

Regarding the findings related to parameters of clinical observation one week after the completion of the treatment, both G1 and G2 individuals presented mild erythema or epilation that developed into hyperpigmentation in the irradiated area, with a later asymptomatic, dry desquamation (more frequent in G1), variable for each individual, which disappeared in the first three months without the need to treat side effects with other methods. These were the only side effects observed in the area that received radiation treatment.

Table 2 shows the results of the answers to the questionnaires applied by the independent evaluators, regarding the response to the treatment.

Recurrences were observed in 12 patients after the treatment (Table 3). They occurred mainly when the lesions were located in the thorax, limbs, and abdomen—body sites in which the suture threads opposed the skin''''''''s tension lines. (Figure 2)

The iconographic sequence (Figure 3) shows the results that were considered satisfactory after the application of adjuvant radiotherapy, combined with surgical treatment.

The answers to the questionnaires applied by the independent evaluator are depicted in Graphs 1 and 2.

As for the reaction to RT, six G1 patients and one G2 patient reported having reaction, edema, and/or erythema. (Graph 1)

The degree of patient satisfaction assessed through questionnaires revealed that 10 G1 patients were dissatisfied, as compared to two G2 patents. (Graph 2) In G1, 47.6% of patients were dissatisfaction, and 52.4% were satisfied or very satisfied.

In G2, those results were 9% and 91%, respectively. (Graph 3)

DISCUSSION

The idea of conducting the present study arose from the necessity of obtaining a solution for a problem known for many centuries—the treatment of keloids—and for which there is still no definitive solution, despite the existence of various therapeutic modalities, none of which alone is considered effective.13

From the RT modalities that may be used as an adjuvant to surgery, the most widely used was the beta-therapy with Strontium-90 plates. 13 The results obtained in this way are inferior to those obtained with the electron based treatment proposed by Akita et al. 25, with a 3.5-year follow-up and corroborated by Oliveira Jr. et al., who followedup with the patients for a 10 year period.27

A previous study by Oliveira Jr et al.27 confirmed that electron beam RT is better than beta-therapy in terms of results for the treatment of keloids. Nevertheless, the scheme that was proposed at the time also resulted in a number of unfavorable cases, suggesting at the end of the study that a diverse therapeutic scheme, more prolonged, with a greater number of applications and a similar biological dose, could have greater success. That was the main reason for the choice of the treatment implemented in the present study.

Thus, the critical purpose of the authors was to become acquainted with the response to the treatment with the previously employed Linear Accelerator Clinac 2100 (Varian), using a 4Mev energy intensity in 16 applications (total dose of 32Gy).27

The group used as the control (for comparing the new suggested dose) was the same used in the previous study,27 which had received an equivalent biological dose of 30Gy.

The observation period for the evaluation of the response was 18 months as recommended in other studies, in protocols of post-operative radiotherapy for keloids. Evaluations were also carried out in the third and sixth months. 30-32

The sample size was initially estimated at 30 individuals for each group. Due to the fact that the present is a clinical study involving actual people, the loss of follow-up was expected, and in fact happened to 8 G1 individuals and 9 G2 individuals.

It is important to note that most of the patients had already undergone treatment, being bearers of keloids whose volume and location could influence the degree of response to the treatment. The majority of patients in the present study''''''''s series were of African descent (87.1%) according to the Fitzpatrick classification, corresponding with the literature 5,33, which has a great number of citations describing dark-skinned individuals as more predisposed to develop this type of lesion.

That datum was not considered variable in the present study, since the classification of skin color is not always a simple task, due to the various hues that exist in the Brazilian population as a result of racial miscegenation.

Although the present study is a clinical study, all possible variables (such as how to establish criteria for inclusion and exclusion, to have the surgical procedures performed by a small number of professionals who used the same surgical technique, systematizing the assessment and implementation of the treatment, and having an independent evaluator—without participation in the choice of treatment—to apply the questionnaire to patients) were controlled.

The questionnaire was considered very important.34,35 Often a physician''''''''s evaluation is different from a patient''''''''s perception, since the physician intuitively seeks the resolution of the lesion, while a simple reduction can already be seen as positive by the patient and vice versa—a scenario which was also confirmed by the present research.

Another variable that could have been part of the study would be the morphometric assessment of lesions throughout the observation period. At the beginning of the study, the introduction of systematized photographs with a standardized camera, lighting, and technique, always taken by the same professional, had this intention. These measurements would confirm the reduction of lesions according to the established treatment. Nonetheless, irregular and sometimes protruding lesions, located in areas of continuity toward other surfaces—such as those located in the ear lobe, for example—hinder this task, which has been abandoned. Another important point was the possible variation of the distance between the camera and the patient, which could induce error or assessment bias.

The application of radiotherapy was performed soon after the surgical exeresis, which is necessary because the keloid, once formed, is not radiosensitive, as the collagen does not respond to the irradiations regardless of the dose used. The electron radiotherapy adjuvant to surgery, however has presented low recurrence rates (in the magnitude of 23%),27 which can be considered an encouraging result. One patient gave up the treatment after the consultation and scheduling of the surgery because she was pregnant, being informed that she should not undergo radiotherapy.

An individual bearing keloid in the left submandibular region presented two seromas during radiotherapy treatment. The seromas were drained and did not prevent the continuity of the treatment. The cause of the development of seroma was not determined.

The keloid problem can extend far beyond the local aspect of the lesion. One teenager had developed a keloid on the right shoulder, adopting an antalgic posture for years due to the pain, and then developing scoliosis.

The only side effect observed in all patients was the hyperpigmentation of the irradiated area, which followed the occurrence of erythema and / or variable epilation in each patient. That effect is minimal when compared to the pain during freezing and permanent hypopigmentation from cryosurgery, as well as when compared to the atrophy, hypopigmentation and inhibition of the healing process in intralesional injection of corticosteroids. Regarding the use of corticosteroids in the treatment, there is reference to Cushing syndrome in the literature. 36 It is important to note that the hyperpigmentation was transient, being more frequent in the 3-month assessment after the treatment and in G1, which received a greater daily dose (300cGy versus 200cGy in G2).

Recurrences observed in the study took place in body sites whose suture lines opposed the skin''''''''s tension lines. These observations agree with Akaishi et al. 10 and Bux''''''''s 37, with tension areas being more prone to the development of keloid lesions.

Aligned with Ogawa et al.,31 it was possible to observe that some keloids, such as those located in the lower lobe of the ear, responded to the treatment with a 30Gy/10 fractions dose, and other in locations, with a 32Gy/16 fractions dose, meaning that the lesion''''''''s location can have an influence in the response to the treatment. However, due to several factors (especially the draw of patient groups), it was not possible to pair the groups with respect to that parameter, with most of the individuals bearinglesions in the chest and abdomen falling into G1 and those bearing lesions in the head and neck falling into G2.

Except for in the therapy that used the electron beam, the distribution of doses according to the application depth is not homogeneous, given that some lesions may be more elevated. The radiotherapy using electron beam from linear accelerators can optimize the distribution of the doses in the relevant volume, with the choice of the most appropriate energy for each thickness to be irradiated.

Recurrences occurred in 9% of G2 individuals and in 47.6% of G1, particularly in those who presented a greater probability of an unfavorable outcome as a result of lesions being located in extension areas. The observation carried out during the present study leads to the belief that in places of great tension, surgery should be performed using the flap technique in an attempt to minimize the tension, which could bring more positive results after radiotherapy.

In patients who had a recurrence of keloids under the scheme proposed for G2 (32Gy / 16 fractions), the authors believe that the results could be improved by increasing both the dose and the duration of the treatment. As a future perspective, the authors intend to continue the study in order to refine the results, since the scheme tested in the present study in G2 (consisting of surgery and adjuvant therapy with 32Gy in 16 fractions), knowingly causes no side effects nor radio-induced carcinoma. 38,39 A new study, using the scheme 36Gy / 20 fractions and 12GY / 4 fractions, once a week (totaling eight weeks), is being proposed.

The benefits of treatment by applying electron beams to post-operative keloid lesions are therefore undeniable. With a refinement of the surgical technique, the dose and fractionation, always respecting the location, can drive even better results.

CONCLUSIONS

The combination of surgery and electron beam RT as an adjuvant treatment, applied in the immediate post-operative period in keloids is a well tolerated treatment modality, with minimal side effects and lower recurrence rates arising from the scheme 32Gy/16 fractions, when applied five days a week.

The side effects observed were transient hyperpigmentation and desquamation of the irradiated area, disappearing in about three months.

Regarding the opinions of the patients who underwent the treatment with radiotherapy in the scheme 32Gy / 16 fractions, 45.5% were very satisfied and 45.5% were satisfied, while only 9% were dissatisfied.

Acknowledgements:
We thank the collaborators Gabriela Fontes Carreira and William Barbosa da Silva, from the Centro de Estudos do Hospital Amaral Carvalho for the typing and diagramming.

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