Therapeutic effect of high‐frequency ultrasound‐assisted dye laser on hemangioma and its influence on serum HIF‐1α in patients

Abstract Background To analyze the therapeutic effect of high‐frequency ultrasound (HFU)‐assisted dye laser on hemangioma patients and changes in serum hypoxia‐inducible factor‐1α (HIF‐1α). Methods A total of 20 patients diagnosed with hemangioma in our hospital from January 2013 to March 2018 were selected, including 12 males and eight females. All patients were treated with HFU‐assisted dye laser. The site and type of hemangioma and age distribution of patients were collected, and changes in data and area of hemangioma and serum HIF‐1α before and after treatment were analyzed. Results The vascular condition of hemangioma in all patients was significantly improved at 7, 14, and 30 days after treatment. Gray‐scale ultrasound displayed that the tumor area was reduced by more than 50%. After treatment, the serum HIF‐1α level declined obviously after treatment compared with that before treatment, showing a statistically significant difference (P < 0.05). Conclusion HFU‐assisted dye laser can effectively reduce the tumor area, decrease the serum HIF‐1α level, and improve the prognosis in the treatment of hemangioma.

on the wavelength, pulse characteristics, and fluence (energy output). A dye laser employs an organic dye mixed in a solvent as the lasing medium. The dyes include rhodamine, fluorescein, coumarin, stilbene, umbelliferone, tetracene, and malachite green while the solvents used contain water, glycol, ethanol, methanol, hexane, cyclohexane, and cyclodextrin. The dye solution is usually circulated at high speeds, to promote the dye molecules into the state of being ready to emit stimulated radiation. Pulsed dye lasers produce pulses of visible light at a wavelength of 585 or 595 nm with pulse durations of the order of 0.45-40 ms, which can be combined with radiofrequency to enhance effects. 5 With the constant development of laser medicine, HFU-assisted dye laser has many advantages in the treatment of hemangioma, such as small trauma and low risk of scar after treatment. 6 Hemangioma not only affects the appearance, but also leads to a variety of local or systemic complications, such as ulceration, bleeding, and even infection on local surface. Hemangioma located in special sites probably results in dyspnea and diminution of vision, thus threatening the life. 7 The main principle of treatment of hemangioma with HFU-assisted dye laser is the target chromophore. The target chromophore of hemangioma is the oxidized hemoglobin in blood vessels, and the laser can make oxyhemoglobin generate heat through absorbing light energy, thus causing vascular injury. 8,9 With the constant development of laser medical technology, HFUassisted dye laser has promoted the treatment of hemangioma.

| General materials
A total of 20 patients diagnosed with hemangioma in our hospital from January 2013 to March 2018 were selected, including 12 males and 8 females aged 3 months to 35 years old with an average age of (17.05 ± 15.17) years old. The type and site of hemangioma and age distribution of all patients were recorded (Table 1). All patients enrolled were treated with 595 mm dye laser therapy in our hospital using the 595 mm pulsed dye laser therapeutic instrument provided by Medical Laser Company, USA. Conditions of patients were recorded before and after HFU therapy. Before treatment, all patients were informed of the mechanism, main efficacy, and possible side effects of HFU-assisted dye laser (pain during treatment, redness, swelling, and itching immediately after the procedure that may last a few days after treatment, blistering, changes in skin pigmentation, bruising a bacterial infection) and asked to be reviewed within the stipulated time after treatment.
Before treatment, informed consent was obtained from patients and their families, and related files were signed. color changing from dark to light after radiation indicated the appropriate energy density. In case that hemangioma showed the dotted structure and could be fully overlapped, and hemangioma was located around the eye or in the eyelid, patients were asked to wear the eye shield before treatment to protect the eyes. After treatment, erythromycin ointment was applied locally, followed by sun protection, cleaning, etc. At 1 week, 2 weeks, and 1 month after treatment, patients were reviewed, and HFU detection was performed for changes in the area of hemangioma, the number of blood vessels in hemangioma, peak flow velocity (V max ) of main artery, and changes in the blood resistance index (RI).

| Statistical methods
Statistical Product and Service Solutions (SPSS) 19.0 software was used for data processing. Data were collected and expressed as (̄̄ ± s), and t test was adopted for the sample mean. P < 0.05 suggested that the difference was statistically significant.

| Main data of hemangioma detected via HFU before treatment
In hemangioma in different sites before treatment, there were abundant blood flow signals, a large number of blood vessels, and higher V max of main artery (Table 2).

| Main data of hemangioma detected via HFU at 7 days after treatment
In hemangioma in different sites at 7 days after treatment, blood flow signals weakened, and the number of blood vessels and V max of main artery declined compared with those before treatment (Table 3).

| Main data of hemangioma detected via HFU at 14 days after treatment
In hemangioma in different sites at 14 days after treatment, there were basically no or very weak blood flow signals, and the number of blood vessels and V max of main artery obviously declined (Table 4).

| Main data of hemangioma detected via HFU at 1 month after treatment
At 1 month after treatment, blood flow signals of hemangioma could be detected only in the forehead, upper abdomen, waist, and hip, while blood flow signals, blood vessels, and V max of main artery were not detected in other sites (Table 5).

| Changes in the area of hemangioma under HFU after treatment
Gray-scale ultrasound displayed that the area of hemangioma in different sites was reduced by more than 50%. Except 1 case of largearea hemangioma below the chin that needed longer-term follow-up or would be treated with other means eventually, the recovery of hemangioma in other sites was significant (Table 6).

| Changes in the mean percentage of decline in echo area of hemangioma under HFU after treatment
The mean percentages of decline in echo area of nevus telangiectaticus, capillary hemangioma, and cavernous hemangioma were significantly increased at 14 days after treatment compared with those at 7 days after treatment and also obviously increased at 1 month after treatment compared with those at 7 and 14 days after treatment, displaying statistically significant differences (P < 0.05) ( Table 7).

| Changes in serum HIF-1α before and after treatment
The level of serum HIF-1α was remarkably decreased after treatment compared with that before treatment, and it was lower at 14 days after treatment than that at 7 days after treatment and also lower at 1 month after treatment than that at 7 and 14 days after treatment, showing statistically significant differences (P < 0.05) ( Table 8).

| D ISCUSS I ON
Hemangioma is a kind of vascular disease of congenital or acquired developmental anomaly of blood vessels, which is generally caused by abnormal proliferation of vascular endothelial cells and pericytes. 10 15 In the past, common therapeutic methods for hemangioma included local skin grafting, isotope therapy, local injection of hormone, and local electrocoagulation, 5 which was less targeted, and had a therapeutic scope far beyond the focus, large trauma, and stronger inflammatory response later. 16 In the late repair of these therapeutic methods, fibrous protein is often formed, resulting in a high risk of scar formation. 17 With the further development of ultrasonic laser technique, HFU-assisted dye laser, as a special targeted intensive treatment, has offered more possibilities for the universal aesthetic requirements. 18 HFU laser therapy is strongly targeted at oxyhemoglobin in the blood, the probability of occurrence of inflammatory response is low after treatment, and it causes very little damage to deep tissues with a low risk of scar formation after treatment. 18 Out data indicated that, in different sites of hemangioma, the blood flow signals as well as the number of blood vessels and V max of main artery gradually declined. At 1 month after treatment, blood flow signals of hemangioma could be detected only in the forehead, upper abdomen, waist, and hip, while blood flow signals, blood vessels, and V max of main artery were not detected in other sites. We propose that the efficacy of 595 mm dye laser therapy may depend on the severity of the disease while the actual efficacy is likely to have certain correlation with the site of hemangioma according to a retrospective study indicating that the early treatment of superficial hemangioma contributes to excellent clearance rate and only few adverse effects. 19 In this study, it was found that the blood flow signals, the number of blood vessels and the area of hemangioma were dramatically decreased after treatment. However, there were also some adverse reactions in the treatment of hemangioma with HFU-assisted dye laser. In this study, there were 2 cases of allergic reaction, 1 case of pigment loss and 1 case of skin tightening after treatment with HFU-assisted dye laser, and the injury could be effectively reduced by appropriate energy and pulse width. Serum HIF-1α is a regulatory factor with a decisive effect in hypoxic tumor cells. The severer the environmental hypoxia is, the more stable HIF-1α will be, thereby helping enhance stability and proliferation capacity of tumor cells. 19 Some studies have demonstrated that the stronger the expression of nuclear antigen in tumor cells is, the higher the level of HIF-1α will be, the synthesis and secretion of HIF-1α are promoted by tumor cells due to hypoxia, and the level is closely related to angiogenesis. 20,21

| CON CLUS ION
Results of this study revealed that the level of serum HIF-1α sharply declined after treatment of hemangioma with HFU-assisted dye laser, confirming the treatment effect of ultrasonic laser therapy on hemangioma.