| Background:Vascular anomalies are common benign tumors and malformations. Although they are benign lesions, vascular anomalies of the maxillofacial and cervical regions can cause serious damage to appearance and are likely to affect pronunciation and eating.Moreover, they can cause bleeding, asphyxia and life-threatening conditions due to airway and digestive tract obstructions.Based on imaging and hemodynamics, vascular anomalies are divided into low-flow malformations (capillary deformity, venous malformation and lymphatic deformity) and high-flow malformations (artery malformation and arteriovenous malformation).Based on morphology, hemangioma is divided into three types:capillary hemangioma, cavernous hemangioma and cirsoid angioma.Hemangioma and vascular malformations are two types of pathological changes characterized by completely different clinical manifestations, durations and outcomes. Vascular malformation is non-neoplastic developmental anomalies of congenital vascular structures, without abnormal endothelial cell proliferation.lt does not undergo spontaneous regression but progresses with patients’growth and development, impairing tissue structure and function. In contrast, hemangioma is the most common type of congenital benign neoplastic or tumor-like diseases in infants, with abnormal vascular endothelial cell proliferation, and 80%of hemangioma undergoes spontaneous regression.Hemangioma can occur in any part of the body, often in the skin and subcutaneous tissue, followed by oral mucosa, muscle, bone and other organs, including the brain, liver and heart.Approximately 60%of hemangioma occurs in the head and neck, followed by torso (25%) and limbs (15%).It not only affects the appearance but also causes multiple complications, such as ulcer, hemorrhage and infection.Hemangioma occurs more commonly in women.It mainly develops in newborns and one-year-old children.In children with hemangioma, mosquito bite-shaped red dots are often found at birth or 2 weeks to 1 month after birth.These dots rapidly grow, forming bright red macules or papular masses that present as one or several bright red, purple, protrusive, soft lobulated masses, with clear borders and different diameters even up to several centimeters.These masses are not easy to fade away in response to pressure.The tumors are often bright red and protrusive; they often look like strawberries and have been called the "strawberry angioma" or "capillary hemangioma" in the past.According to the Mulliken diagnostic criteria, hemangioma is divided into the hyperplasia period and the retreat period.Hemangiomas usually grow the fastest in children under 1 year old, and the proliferation period lasts for 6 to 12 months.The first year is the proliferation period, in which there are two growth peaks (1 month and 6 months after birth). Hemangiomas grow the largest when children are around 1 year old.Afterward, they undergo a stable phase of slow growth until they gradually fade.However, complete retreat usually requires several years. Spontaneous regression completion often has sequelaes, such as flabby skin, pigmentation, scar formation and fiber adipose tissue deposition. Hemangiomas in special sites (such as the eyelids or trachea) may compress the ambient organs and can even be life-threatening.Lesions located in the nose, eyelids, the ear pinna and lips can cause corresponding dysfunction and serious threat to the quality of life, in addition to hairdressing defects, deformity and ill-tempered hemorrhage tendency in the face, leading to substantial trauma and psychological burden for the patients and their family members.In a few severe cases, hemangioma may rapidly progress, causing serious appearance and function obstacles and even life-threatening conditions. Therefore, hemangioma with no regression or incomplete regression or in special parts requires prompt and accurate aggressive therapy.At present, the treatment of hemangioma has no unified regime.The methods mainly include:1) waiting and observation; 2) cryotherapy; 3) laser treatment; 4) radiation and radionuclide therapy; 5) injections; 6) interventional therapy; 7) copper needle therapy; 8) surgery; 9) topical drags and; 10) oral drug therapy. Long-term follow-up has confirmed that the efficacy of these methods is not satisfactory. Cryotherapy can cause hyperplastic or atrophic scars, pigmentation and pigment drops.Laser therapy causes scarring and is inefficient when treating large-area and thick lesions. It can even cause massive hemorrhage. Thus, laser therapy must be conducted discreetly under strict construction. Radiation and radionuclide therapy tends to cause atrophic scars in the site of hemangioma and leads to desquamation in the skin.It does not exclude the cancerous likelihood of atrophic tissue.Moreover, the atrophic scars caused by radiation and radiation isotope treatment may cause potential harm to children with hemangioma. Thus, radiation should be avoided if possible. Another method injects hardener into the hemangioma, leading to local vessel lumen embolism and endothelial cell necrosis, therefore achieving therapeutic effects.This method can cause significant local stimulation and trauma and is at risk for infection, tissue necrosis and scarring due to local tumor necrosis after treatment. Thus, it has been less applied.A fever reaction can occur 6 to 12 h after pingyangmycin injection. It is likely that pingyangmycin inhibits the release of endogenous pyrogens. Therefore, dexamethasone is mixed into pingyangmycin suspension to effectively prevent the fever reaction. Due to the inefficacy of local injections of hormone in treating severe hemangioma, local injections of pingyangmycin are recommended. Interventional therapy is often used in treating visceral hemangioma, such as liver hemangioma. Copper needle therapy is now rarely used because of copper atomic absorption and corresponding toxic effects. In principle, for limited or more strictly regional hemangioma, surgical resection is reliable and safe, and it may achieve a radical cure.The scars derived from freezing, laser therapy and hemangioma regression can also be surgically repaired.For larger ranged hemangioma, the type, scope, level and blood supply of hemangioma should be determined before surgery. Secondary repair can be conducted if there is excessive hemorrhage, it is hard to clean the resection or primary repair is difficult.Topical imiquimod drug therapy is especially suitable for treating the medium and small hemangioma located in hidden parts of the body. Oral hormone therapy has been the first-line treatment for severe large-area, multiple-site hemangioma. It is mainly suitable for larger-area, multiple-site or aggressive hemangioma and for the life-threatening hemangioma, concurrent with congestive heart failure, debilitating coagulant function obstacle, thrombocytopenia and severe viscera function damages (such as harm to vision or breathing). However, specific therapeutic doses of oral hormone, drug time and the method of decreasing dosage are difficult to follow, and oral hormone can cause some temporary but serious complications, including individual personality change, fungal infections, hypertension, Cushing’s syndrome and gastrointestinal malaise. In summary, there are various therapeutic methods for treating hemangioma, and they involve many factors. The choice of the therapeutic method should depend on the circumstances. Currently, there is not a method that applies to all cases.It should be emphasized that the objective of treatment is not only to eliminate lesions but also to protect healthy normal tissue and appearance.In 2008, the French doctor Leaute-Labreze and collegues accidentally discovered that propranolol can promote nasopharyngeal hemangioma retreat and published their findings in the New England journal of Medicine.They started the precedent of using propranolol to treat infant hemangioma.In recent years, propranolol has started to be used in clinical applications to treat infant hemangioma and has achieved distinct curative effect. However, related domestic reports are rare. Moreover, the molecular mechanism of the therapeutic effect of propranolol on hemangioma is rarely reported domestically or overseas.The etiology and pathogenesis of hemangioma is still not completely clear.The current main theory is the imbalance between angiogenesis factors and inhibitory factors. Major angiogenesis factors, including vascular endothelial growth factor (VEGF) and basic fibroblast factor (bFGF), are considered active angiogenesis factors that promote vascular endothelial cell proliferation.Matrix metal proteinase-9 (MMP-9) expression in hemangioma endothelial cells is significantly higher than that in normal tissues, and in hemangioma endothelial cells, its expression is significantly higher during proliferation than during degeneration. Therefore, this study was designed to explore the effect of propranolol in treating hemangioma during the hyperplasia period in the clinical setting and to provide information for the further study of the etiology and pathogenesis of hemangioma. By intervention, we examined clinical manifestations of children patients with hemangioma during the hyperplasia period and investigated the variations in the serum and urine levels of several important factors during the hyperplasia period, providing theoretical basis for the treatment of this disease.Purpose:1) To investigate the clinical efficacy of oral propranolol in the treatment of proliferative hemangioma; 2) the variation of serum VFGF level during the treatment of proliferative hemangioma with oral propranolol; 3) the variation of serum MMP-9 level during the treatment of proliferative hemangioma with oral propranolol; 4) the correlation between serum VEGF and MMP-9 levels during the treatment of proliferative hemangioma with oral propranolol; 5) the variation of serum bFGF level during the treatment of proliferative hemangioma with oral propranolol; 6) the variation of urine bFGF level during the treatment of proliferative hemangioma with oral propranolol; 7) the correlation between bFGF level and treatment efficacy after the treatment of proliferative hemangioma with oral propranolol and; 8) the clinical characteristics during the treatment of proliferative hemangioma with oral propranolol and the safety and efficacy of oral propranolol. Methods:Assay 1:Based on Mulliken’s diagnostic criteria of hemangioma, the subjects in this study were patients suffering from proliferative hemangioma who were admitted to the Department of Orthopedic Surgery of Shandong Provincial Hospital belonging to Shandong University from April 2010 to November 2010.There were 53 subjects, and their mean age was 6.5 months (ranging from 2 to 6.5 months).The size of hemangiomas was larger than 1.0cm (ranging from 1.0 to 8.9cm) in all cases, and none of the subjects had received treatment before admission.All of the infants underwent routine tests, including routine blood test, tests for hepatonephric function, an ECG, serum glucose, heart rate (HR), blood pressure (BP) and B-type ultrasonography. Infants were administered with oral propranolol (Tianjin Lisheng pharmaceutical Factory, Batch No.H12020151), and all test results were in accordance with the requirements.The initial dose was 0.5mg/kg/day, delivered in 3 doses,8 hours apart, and the dose was gradually increased to 2.0mg/kg/day over a week.HR and BP were measured before every dose and 30 minutes after every dose.If the BP was lower than the normal level or other severe side effects occurred after administration, drug administration was discontinued.Blood samples were collected before the dose and at 4 and 8 weeks after the drug therapy was started.The double antibody sandwich-ELISA (DAS-ELISA) technique was used to determine the VEGF and MMP-9 levels in serum samples before the dose and at 4 and 8 weeks after the drug therapy was started. All data were processed and analyzed to investigate the clinical efficacy of oral propranolol in the treatment of proliferative hemangioma.Assay 2:According to Mulliken, the diagnostic criteria of hemangioma, the subjects in this study were patients suffering from proliferative hemangioma who were admitted to the Department of Orthopedic Surgery of Shandong Provincial Hospital belonging to Shandong University from April 2010 to November 2010.There were 82 subjects (53 patients with proliferative hemangioma and 29 patients with hemangioma in the involuting stage), including 24 patients with vascular malformation and 30 patients with a pigmented nevus, serving as controls.The mean age was 6.5 months (ranging from 2 to 6.5 months). The hemangiomas were all larger than 1.0cm (ranging from 1.0 to 8.9cm), and none of the subjects had received treatment before admission.All of the infants underwent routine tests, including routine blood test, tests for hepatonephric function, an ECG, serum glucose, HR, BP and B-type ultrasonography.Infants were administered oral propranolol (Tianjin Lisheng pharmaceutical Factory, Batch No.H 12020151), and all test results were in accordance with the requirements.The initial dose was 0.5mg/kg/day, delivered in 3 doses,8 hours apart, and the dose was gradually increased to 2.0mg/kg/day over a week.HR and BP were measured before every dose and 30 minutes after every dose.If the BP was lower than the normal level or other severe side effects occurred after administration, drug administration was discontinued.Blood samples and urine specimens were collected before the dose and at 4 and 8 weeks after the drug therapy was started.The bFGF level in serum samples and urine specimens was determined using the DAS-ELISA technique, before the dose and at 4 and 8 weeks after the drug therapy was started.All data were processed and analyzed to investigate the clinical efficacy of oral propranolol in the treatment of proliferative hemangioma.Assay 3:The subjects in this study were 82 patients with hemangioma, including 53 patients with proliferative hemangioma and 29 patients with hemangioma in the involuting stage.This assay investigated the clinical characteristics of the patients with proliferative hemangioma, the clinical characteristics before and after the treatment with oral propranolol and the clinical characteristics and body mass index after drug discontinuance.Results:Assay 1:There were 53 infants with proliferating hemangioma.In 7 of these cases, drug therapy had to be discontinued because of diarrhea or hypotension.Among these 7 cases, 5 had therapy discontinued during the first 4 weeks, and 2 had therapy discontinued during the second 4 weeks.The effective rate of the treatment of proliferating hemangioma increased with oral propranolol.lt reached 20%after 8 weeks of treatment, which was remarkably higher than the response rate (P<0.01).Serum VEGF levels declined after 4 and 8 weeks of treatment with oral propranolol. There was a statistically significant difference before and after 8 weeks of treatment (P< 0.05); however, there was no statistically significant difference before and after 4 weeks of treatment (P>0.05), and no statistically significant difference was observed between 4 and 8 weeks after treatment (P>0.05);Serum MMP-9 level declined after 4 and 8 weeks of treatment with oral propranolol. There was a statistically significant difference before and after 8 weeks of treatment (P< 0.05);however, there was no statistically significant difference before and after 4 weeks of treatment (P>0.05), and no statistically significant difference was observed between 4 and 8 weeks after treatment (P>0.05);A positive correlation was observed between MMP-9 level and VEGF level.(r=0.9997,P<0.01)Assay 2:There were 53 infants with proliferating hemangioma.In 7 of these cases, drug therapy had to be discontinued because of diarrhea or hypotension, of these 7,5 had the therapy discontinued during the first 4 weeks, and 2 had it discontinued during the second 4 weeks.There were 29 infants with proliferating hemangioma in the involuting stage, of which 4 had the therapy discontinued during the first 4 weeks, and 1 had it discontinued during the second 4 weeks.There were 30 infants serving as controls.All in all, there was no statistically significant difference in sex in any group (P>0.05).During the treatment of proliferating hemangioma with oral propranolol, the bFGF levels in patients’serum and urine were significantly higher than those in control samples before treatment (P<0.01).Serum bFGF levels declined after 4 and 8 weeks of treatment with oral propranolol. There was a statistically significant difference before and after 8 weeks of treatment (P<0.05); however, there was no statistically significant difference before and after 4 weeks of treatment (P>0.05), and no statistically significant difference was observed between 4 and 8 weeks after treatment (P>0.05).Urine bFGF level declined after 4 and 8 weeks of treatment with oral propranolol.There was a statistically significant difference before and after 8 weeks of treatment (P<0.05); however, there was no statistically significant difference before and after 4 weeks of treatment (P>0.05), and no statistically significant difference was observed between 4 and 8 weeks after treatment (P>0.05).During the treatment of hemangioma in the involuting stage with oral propranolol, there was no statistically significant difference in either serum or urine bFGF level before treatment and after 4 or 8 weeks of treatment (P>0.05).During the treatment of vascular malformation patients with oral propranolol, there was no statistically significant difference in either serum or urine bFGF level before treatment and after 4 or 8 weeks of treatment (P>0.05).Assay 3:Before the treatment with oral propranolol, patients with proliferating hemangioma were provided with comprehensive health care to make sure that their heart and lung features were normal.2) To decrease the side effect, the maximal dose for the treatment of proliferating hemangioma with oral propranolol was no more than 2mg/kg/d.3) To avoid the rebound effect of propranolol, the treatment continued until the end of hemangioma proliferation or tumor regression without further proliferation, and the dose gradually decreased until a complete withdrawal.Conclusion:1) In the treatment of proliferating hemangioma with oral propranolol, the effective rate was remarkably high, and the side effect was not significant; 2) Oral propranolol showed no significant efficacy on hemangioma in the involuting stage; 3) Oral propranolol also showed no significant efficacy on vascular malformation; 4) After the treatment with oral propranolol, serum VEGF, MMP-9, bFGF and urine bFGF levels decreased, indicating that propranolol can be used for treating proliferating hemangioma; 5) The mechanism for treating proliferating hemangioma with oral propranolol is related to serum VEGF, MMP-9, bFGF and urine bFGF levels; 6) To elucidate the mechanism for treating proliferating hemangioma with oral propranolol, further investigation with a larger sample and longer follow-up time is warranted. |
