Hemangiomas In Proliferative Phase Research Articles

PROPRANOLOL COMO TRATAMENTO DE PRIMEIRA LINHA DOS HEMANGIOMAS DA INFÂNCIA

Introdução: Os hemangiomas são os tumores vasculares mais frequentes da infância. Em aproximadamente 10% dos casos ocorrem complicações que obrigam a intervenção. O propranolol foi recentemente adicionado aos fármacos utilizados para o seu tratamento e tem vindo a revolucionar a atitude terapêutica perante os mesmos. O objectivo deste estudo é avaliar a eficácia e segurança do propranolol no tratamento dos hemangiomas da infância.Material e Métodos: Efectuamos um estudo descritivo dos doentes tratados com propranolol entre Março de 2010 e Março de 2013. Foram incluídos doentes com hemangiomas em fase proliferativa que apresentassem crescimento rápido, ulceração ou risco de compromisso funcional e/ou estético. O tratamento foi realizado em ambulatório e a dose administrada foi de 2mg/kg por dia. A resposta ao tratamento foi categorizada em completa, parcial ou ausente.Resultados: Foram tratados 22 doentes, com um total de 32 hemangiomas. As principais indicações para o tratamento foram o risco de compromisso estético (n=18) e funcional (n=9). Observou-se estabilização do crescimento dos hemangiomas em todos os casos, a regressão foi completa em 20 casos e parcial em três, o que corresponde a um sucesso terapêutico de 87%. Quatro doentes ainda se encontram em tratamento e em um caso foi necessário a interrupção precoce do fármaco por bradicardia.Discussão e Conclusão: Na grande maioria dos casos o propranolol provocou uma regressão rápida e sustentada dos hemangiomas, diminuindo assim a duração natural das lesões, com poucos efeitos secundários. Consideramos o propranolol o fármaco de primeira linha no tratamento dos hemangiomas da infância.

Knockdown of IGF2R suppresses proliferation and induces apoptosis in hemangioma cells in vitro and in vivo.

Insulin-like growth factor-II (IGF-II)/IGF2R signaling plays a pivotal role in cell growth, migration and differentiation in many malignancies. An individual with high IGF-II expression levels has a high risk of developing cancer, but IGF2R is often considered to be a tumor suppressor. To date, little has been reported about the role of IGF-II/IGF2R signaling in hemangiomas (HAs). Thus, uncovering the mechanisms of IGF-II/IGF2R signaling is very important to understanding the development of HAs. In the present study, the expression of IGF-II and IGF2R was investigated in 27 cases of HAs of different phases by immunohistochemistry. Through lentivirus-mediated IGF2R siRNA (Lv-siIGF2R) in HA-derived endothelial cells (HDECs), we observed the effects of IGF2R knockdown on the biological behavior of HA cells. We found that the expression of IGF-II and IGF2R was significantly increased in proliferating phase HAs, but decreased in involuting phase HAs. Furthermore, knockdown of IGF2R in vitro significantly diminished the proliferative activity and induced apoptosis and cycle arrest with decreased expression of PCNA, Ki-67, Bcl-2, Cyclin D1 and E and increased the expression of Bax in the proliferative phase HAs (HDEC and CRL-2586 EOMA cells). In addition, the tumor volumes in a subcutaneous HDEC nude mouse model treated with Lv-siIGF2R were significantly smaller than those of the control group. Taken together, our findings indicate that the expression of IGF-II and IGF2R is increased in proliferating phase HAs, and knockdown of IGF2R suppresses proliferation and induces apoptosis in HA cells in vitro and in vivo, suggesting that IGF2R may represent a novel therapeutic target for the treatment of human HAs.

Efficacy and safety of propranolol in treating infantile hemangiomas

[Objective] To evaluate the clinical efficacy and safety of propranolol in treating infantile hemangiomas.[Methods] Ninety children with hemangioma collected from July 2010 to November 2011 were recruited in this study.Oral propranolol was given at a dose of 1.5-2.0 mg/kg per day,and the dose was adjusted according to the growth of body weight.Patients were revisited every month for the observation of appearance of hemangioma.The following parameters,including blood glucose,alanine transarninase,aspartate aminotransferase,urea nitrogen,creatinine,creatine kinase,heart rate,blood pressure,electrocardiogram and ultrasound image of hemangioma,were monitored before and after the administration of propranolol.[Results] A rapid halt in haemangioma proliferation was seen in 91.1％ (82/91) of the patients within 24-48 hours after the administration of popranolol.After 1-10 months of treatment,haemangioma shrunk by 0-25％ with a lightening of lesional color in 8.0％ (7/88) of the patients,by 26％-50％ with an obvious lightening of lesional color in 39.8％ (35/88),by 51％-75％ with a marked lightening of lesional color in 26.1％ (23/88),and 26.1％ (23/88)of the patients achieved a shrinkage of more than 75％ or fading of lesional color.The 7-8 months of treatment leaded to the best outcome,followed by 5-6 months,3-4 months,and 1-2 months,of treatrnent.No rebound was observed in patients who stopped the treatment at 10 months to l year and 4 months of age.Usually during early stage of the therapy,some of the patients suffered from reduced diastolic blood pressure,sleep disorder,loose stools,hypoglycemia,cold extremities,bronchial hyperreactivity,elevated alanine transaminase/aspartate aminotransferase or creatine kinase isoenzyme,most of which were tolerable and relieved with or without symptomatic treatment.[Conclusion]s Propranolol can suppress the growth and accelerate the regression of hemangiomas in proliferative phase,and also can promote the subsidence of hemangiomas in regressive phase.The side effects of propranolol are usually mild,but still need close monitoring. Key words: Hemangioma; Propranolol; Infant

Progressive growth of infantile cutaneous hemangiomas is directly correlated with hyperplasia and angiogenesis of adjacent epidermis and inversely correlated with expression of the endogenous angiogenesis inhibitor, IFN-beta.

Cutaneous infantile hemangioma progresses through proliferation and involution phases. Since treatment with interferon, a negative regulator of angiogenesis, accelerates the involution phase, we hypothesized that cutaneous infantile hemangioma is associated with an imbalance between endogenous positive and negative regulators of angiogenesis. We examined 30 specimens of cutaneous hemangioma [proliferative phase (n=15), involuting phase (n=8), and involuted phase (n=7)] and control human skin (n=17), fixed in formalin and embedded in paraffin. Routine histology, immunohistochemistry, and an mRNA in situ hybridization technique were used to measure expression of the positive angiogenic molecules basic fibroblast growth factor (bFGF) and vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), and an endogenous inhibitor of angiogenesis, interferon-beta (IFN-beta). Proliferative phase hemangiomas expressed high levels of bFGF and VEGF/VPF but not IFN-beta (mRNA and protein). The epidermis directly overlying proliferating hemangiomas was hyperplastic, contained numerous dividing cells, and expressed bFGF and VEGF/VPF but not IFN-beta. Epidermis from normal individuals and epidermis directly overlying involuted tumors or at sites distant to the proliferating hemangioma was not hyperplastic and expressed normal levels of bFGF, VEGF/VPF, and IFN-beta. These data suggest that the proliferation of cutaneous hemangiomas and adjacent epidermis is associated with an imbalance between positive and negative angiogenic factors expressed by the neoplasm and adjacent normal tissue.

Increased Apoptosis Coincides with Onset of Involution in Infantile Hemangioma

Hemangioma is an endothelial cell tumor that grows rapidly during infancy and regresses slowly during childhood. However, little is known about the natural history of this common tumor. To gain insight into the cellular mechanisms that underlie the switch from uncontrolled growth to involution of endothelium, we investigated the extent of cellular apoptosis versus proliferation in hemangioma specimens that spanned the natural life cycle of the tumor. We analyzed apoptosis and cellular proliferation in frozen sections from 16 hemangioma specimens using the TUNEL assay to detect apoptotic cells and the Ki67 antigen to detect dividing cells. Apoptosis was low in proliferative phase hemangiomas but increased fivefold in involutive phase specimens obtained from children one to four years of age. Immunofluorescence double-labeling experiments showed that at least one third of the apoptotic cells were endothelial. As expected, cellular proliferation was high in specimens up to 2 years of age but decreased significantly thereafter. Apoptosis was consistently low in nine normal skin tissues (newborn to 4 years of age) obtained from discarded pathology specimens. These results suggest that increased apoptosis during the second year of life can offset cellular proliferation and may be involved in initiating regression of hemangioma.