therapy had no noticeable liver or skin hemangiomas after nine months of receiving the last dose. the infant that received four rounds of therapy had no detectable hemangiomas after six months of receiving the last dose. those who were involved in the case reports suggest that it is a requirement to have assertive and forceful treatment. they concluded that cyclophosphamide is safe for diffuse neonatal hemangiomatosis. propranolol propranolol, a beta-blocker medication, has undoubtedly replaced corticosteroids as the preferred first line treatment of therapy for infantile hemangiomas after a dramatic shift in the management of ih since 2008. the reasons for the change to propranolol include its efficacy and safety as being superior to those of oral corticosteroids. more studies have been done to assess the treatment of beta-blockers, both systemic and topical, for treating infants with ih. recently, the topical beta-blocker timolol, a medication for eye treatment, has been offered as an alternative medication for smaller ih. although more infants are treated with propranolol instead of oral corticosteroids, more research is needed to fully understand the treatment and management of ih with propranolol. although the exact mechanism of action of beta-blockers for treating ih is not fully known, it can be hypothesized that beta-blockers work to inhibit growth of the hemangiomas by vasoconstriction, apoptosis induction, and the recruitment of endothelial progenitor cells (epcs) where the marks are located. beta-adrenergic receptors are found and expressed on the endothelial cells present in ih which induce vasodilation and increased blood flow. inhibiting these receptors leads to vasoconstriction which can reduce blood flow to the site of the hemangioma and the size of the hemangioma. blocking the beta-receptors can also initiate apoptosis of the endothelial cells to decrease the symptoms of the hemangioma and decrease the movement of epcs to sites that are predisposed to the formation of the hemangiomas. one study looked at the use of propranolol, a beta-blocker medication, for treating infantile hepatic hemangiomas. the study followed 8 infants with infantile hepatic hemangiomas under three classifications: focal, multifocal, or diffuse. 4 infants had multifocal hepatic injuries (4 to 20 injuries) and 4 infants had diffuse injuries (more than 20 injuries).the diffuse ihh are life-threatening because they can induce heart failure. systemic steroids were given as first-line treatment for the infants with heart failure, but were stopped due to inefficacy or lack of improvement of ihh. the infants were given propranolol and a majority saw improvement in their condition. the first three infants saw undetectable injuries after 1 month of propranolol, and the other infants saw a decrease in size of the injuries of 50% after 2 to 4 months. one infant also saw a reduction in overall liver size. propranolol greatly improved symptoms for the 8 infants with infantile hepatic hemangiomas, with a range of responses from significant improvement to complete resolution of the injuries. another case report involving the use of propranolol was performed on a neonatal that had multiple hemangiomas on the skin, scalp, lips, brain, liver, lungs, kidney, and bones. the neonatal was also diagnosed with cerebral palsy. initially, prednisolone was given as a first line treatment at 4 mg/kg/day for four weeks from 27 to 55 postnatal days. this therapy was not effective, and the medical team switched to administering propranolol 2 mg/kg/day for two weeks. after the two week treatment, the hemangiomas decreased in size and had no acute hemorrhage. the use of propranolol was also found not to be associated with any severe adverse effects. the newborn baby was discharged with a four-month supply of propranolol to be administered at home. after the four-month course, the newborn baby was examined, and the size of the hemangiomas on the scalp, neck, skin, bones, brain, and kidney had decreased in size and number. the hemangiomas on the liver persisted but the ones on the lungs disappeared. at 10 months of age, the cerebral palsy was found to have improved. although corticosteroids are the first line treatment option, the success rates are only 30-60%. that is why there are alternative second line treatment options, like propranolol. there is no established dosing at this time due to lack of studies. but, it is recommended to be on propranolol therapy for at least seven months post birth to minimize any further replication of the hemangiomas. an additional study noted the effectiveness of propranolol in 3 infants with infantile hepatic hemangiomas and skin hemangiomas. two of the infants had cardiovascular complications and the other infant had hypothyroidism. all of the infants were given oral propranolol and saw a decrease in symptoms of the both hepatic and skin hemangiomas. the results of the study also observed a decrease in cardiovascular symptoms as well as thyroid requirement. propranolol has been recognized to decrease the growth of the hemangiomas and rapidly improve symptoms. it has been used for many decades for the treatment of hypertension and arrhythmias, with less attention on treatment of ih. side effects of propranolol that could arise include hypotension, hypoglycemia, restlessness, decreased appetite, and bradycardia. there is still much research needed to identify optimal dosing of propranolol, indications, and safety, but propranolol is noted to be a promising first-line treatment method for individuals with ih. radiotherapy radiotherapy helps get rid of blood vessels that are not fully developed due to fast reproduction. however, getting rid of these types of blood vessels have negative effects such as damaging other organs in the body. thus, this is no longer an option for therapy. surgery surgery is an effective option, but has high mortality rates. the mortality rate is 20%. future directional treatments mtor inhibitors other medications are currently being considered as treatment for diffuse neonatal hemangiomatosis. mtor inhibitors, an inhibitor that is normally used for post-organ transplantation, has previously been used for vascular anomalies. mtor is controlled by phosphoinositide 3-kinase which is essential in cell function. given its immunosuppressive, antiangiogenic, and antiproliferative characteristics, it could slow down disease progression. for example, the mtor inhibitor, sirolimus, can be used to treat diffuse neonatal hemangiomatosis. it is important to note that diffuse neonatal hemangiomatosis therapy requires a multidisciplinary team approach due to its perplexing, rare properties. interferon alpha-2a the use of interferon alpha-2a in infants that are resistant to corticosteroid treatment is an ongoing study of effectiveness and appropriateness of therapy. interferon alpha-2a is an anti-viral medication. it was studied among 20 neonatal and infant subjects that had life-threatening hemangiomas and were not responding positively to corticosteroid treatment. they were given daily subcutaneous injections of interferon alfa-2a 3 million units/0.5ml. the duration of treatment varied based on clinical response. there were no serious side effects observed and fever was the most common side effect which was promptly treated with acetaminophen. on average, 7.8 months of treatment were necessary to reduce the size of the hemangiomas at least 50% or more. vincristine (vcr) the use of vcr is proposed in the setting of infants with severe hemangiomas with complications and that are unresponsive to corticosteroid treatment. vcr is a vinca alkaloid and works by binding to the tubulin in tumor cells and causes cell destruction. it also limits the development of new blood vessels that is induced by vascular endothelial growth factor (vegf). the typical dosing of vcr is 1 mg/m2 slow intravenous injection. in the beginning phases of treatment, the injections are administered weekly and then tapered based on how the hemangiomas are responding and the presence/lack of accompanying symptoms. the decision to stop therapy is made when the hemangiomas have disappeared or have significantly decreased in size and if the accompanying symptoms have gone away. the length of therapy ranges from 1.5–8 months, with positive responses being observed after one month of therapy. there hasn't been any documented regrowth of hemangiomas after cessation of therapy with vcr. the common side effects tend to be mild and include constipation, stomach pain, acid reflux, and anemia. if the infant is suffering from anemia as a side effect, it is not recommended to administer erythropoietin because it can cause replication of cells and hemangiomas on the face can develop as a result.