Exploration of the optimal time to discontinue propranolol treatment in infantile hemangiomas: A prospective study.

BACKGROUND: Relapse of infantile hemangiomas after withdrawal from propranolol treatment is common. Early withdrawal is believed to increase the risk of relapse. OBJECTIVE: The objective of this study was to determine the optimal time to discontinue propranolol treatment for infantile hemangiomas. METHODS: A prospective study conducted at a tertiary referral center. RESULTS: Compared to withdrawal after 1-month maintenance treatment, withdrawal after 3-month maintenance, corresponding achieving maximum regression of infantile hemangiomas, was associated with a lower major relapse rate (P = .041). The relapse (P = .055) and adverse event rates (P = .154) between the 2 withdrawal modes were not statistically significant. Compared with direct withdrawal, the relapse (P = .396), major relapse (P = .963), and adverse event rates (P = .458) of gradual withdrawal were not statistically different. Patients with/without relapse could be best distinguished according to whether withdrawal followed a 3-month maintenance and age >13 months (area under the receiver operating characteristic curve = 0.603). Patients with/without major relapse could be best distinguished according to whether withdrawal was accompanied by 3-month maintenance (area under the receiver operating characteristic curve = 0.610). LIMITATIONS: The limitations of this study are nonrandomization and single-center design. CONCLUSIONS: The optimal propranolol withdrawal time to avoid relapse is when the patient is aged >13 months and the lesion has maintained for 3 months after reaching maximum regression, while the optimal time to prevent major relapse is after 3 months of maintenance.

Mental Health of School-Aged Children Treated with Propranolol or Atenolol for Infantile Hemangioma and Their Parents.

BACKGROUND: Infants with infantile hemangioma (IH) have been effectively treated with propranolol or atenolol. Concerns were raised about the mental health of these children at school age, due to central nervous system effects of propranolol and visible nature of IH. OBJECTIVE: This study aimed to compare the mental health at school age of children treated with propranolol to children treated with atenolol for IHs and their parents. METHODS: This two-centered cross-sectional study included children aged ≥6 years and treated with either propranolol or atenolol for IH during infancy. Children's outcomes were performance-based affect recognition (Dutch version of the Developmental Neuropsychological Assessment-II [NEPSY-II-NL]), parent-reported emotional and behavioral functioning (Child Behavioral Checklist [CBCL]), and health-related quality of life (KIDSCREEN-27). Parents' outcome was parenting stress (Parenting Stress Questionnaire [OBVL]). RESULTS: Data of 105 children (36 propranolol, 69 atenolol; 6.0-11.8 years) were analyzed. Mental health outcomes did not differ between both ß-blocker groups. Although overall functioning was in line with norms, children presented specific problems concerning affect recognition, parent-reported attention, and social quality of life. Parents showed increased physical symptoms, depressive symptoms, and parent-child relationship problems. CONCLUSION: No difference in mental health at school age was found between children treated with propranolol or atenolol for IH. Although few overall mental health problems were found, specific problems require follow-up. Follow-up of children should be directed toward affect recognition, attention, and social functioning in daily life. Problems reported by parents could be ameliorated by mental health support during and after their infant's ß-blocker treatment.

Documented growth of an intracranial capillary hemangioma: A case report.

Intracranial capillary hemangiomas in adults are rare, and diagnosis can be challenging. Hemangiomas, in general (and particularly in the skin), are more often noted in the pediatric population. Due to the lack of imaging undertaken in the presymptomatic phase, the literature provides few clues on the rate of growth of these unusual tumors. Therefore, we report a case of a 64-year-old man with a medical history of Lyme disease who presented with exhaustion and confusion. Imaging demonstrated an intra-axial lesion with vascularity in the posterior right temporal lobe, raising the possibility of a glioma. Imaging two years prior revealed a very small lesion in the same location. The patient underwent a craniectomy, total resection of the lesion was completed, and his symptoms of confusion resolved. Biopsy revealed a capillary hemangioma composed of small vascular channels lined by endothelial cells and pericytes without smooth muscle. Features of glioma, vascular neoplasms or neuroborreliosis (cerebral Lyme disease) were not identified. Our case documents the growth over two years of a rare intracranial capillary hemangioma in an older adult male.

Clinical characteristics of infantile haemangioma in twins: a retrospective study.

BACKGROUND: Infantile hemangioma is one of the most common benign soft tissue tumors in infants. The pathogenesis of infantile hemangioma remains unclear and twin studies regarding its incidence may help clarify disease pathogenesis. Thus, this study aimed to analyze the clinical characteristics of infantile hemangioma in twin patients and discuss its clinical incidence. METHODS: We retrospectively analyzed the data of 83 pairs of twins with infantile hemangioma admitted to the Guangdong Provincial Women and Children Hospital and Henan Provincial People's Hospital between May 2016 and May 2022. Thirty-one pairs of twins among whom both developed infantile hemangioma and 52 pairs of twins among whom only one twin was affected were included. Analysis was performed using the Spearman correlation. Additionally, we analyzed the influence of factors such as sex, twin zygosity, preterm birth, birth weight, and assisted reproduction on the clinical characteristics of twins. RESULTS: We observed that disease occurrence in both twins correlated with assisted reproduction (χ2 = 13. 102, P < 0.05) and preterm birth (χ2 = 36.523, P < 0.05). Twin zygosity (χ2 = 0.716, P > 0.05) and total birth weight of twins (t=-3.369, P > 0.05) were not correlated with infantile hemangioma. However, among twins, the ones with lesser birth weight were more likely to develop infantile hemangioma. CONCLUSIONS: The clinical characteristics of infantile hemangioma in twins were consistent with their epidemiological characteristics. Female sex, preterm birth, less birth weight, and assisted reproduction increased the probability of morbidity in both twins. Analysis of the characteristics of infantile hemangioma in twins may assist further research and clinical treatment.

Rare complication - skin atrophy - after systemic conservative therapy of infantile hemangioma.

BACKGROUND: Hemangiomas, also called infantile hemangiomas (IH) or hemangiomas of infancy are the most frequently seen benign vascular tumors of infancy. Different types of hemangiomas are described in the literature. The current approach is to assess the risk and, if needed, first line treatment is to initiate systemic propranolol. CASE PRESENTATION: A 3-month-old Caucasian female patient was brought as an outpatient. The main complaint was an infantile hemangioma in the facial area, which as per the parents' story appeared within a week of birth like a small reddish line and it rapidly grew. Systemic propranolol was proposed as a first-line treatment and the adverse effects were explained. The parents, afraid of the side effects, wanted to explore other possibilities such as topical timolol, however, since it had no effect, propranolol was initiated in the end. Hemangioma was completely reduced in size; however, a skin defect was detected. As per the dermatologist's counsel, topical cream was initiated. The skin defect was reduced but not fully healed. The child is still being monitored periodically. CONCLUSION: After successful treatment of hemangioma, we identified a skin defect, which was very similar to steroid-induced skin atrophy. However, we cannot attribute this to a single factor. The only thing that can be concluded is that the subject needs a thorough studying, since rate of infantile hemangioma is high, and pediatricians need a clear management strategy of how to approach skin atrophy after successfully treating the hemangioma itself.

Intramedullary spinal capillary hemangioma with secondary neurulation defect in children.

Intramedullary spinal capillary hemangioma is a rare occurrence in pediatric patients, and only limited cases have been reported. This study presents the first two cases of spinal capillary hemangioma co-present with retained medullary cord and one case of spinal capillary hemangioma with lumbosacral lipomatous malformation. Previous literature on ten patients with this pathology was reviewed. We speculated pathogenesis, imaging features, and histopathologic findings of the disease.

An analysis of information about infantile hemangiomas on TikTok: A cross-sectional study.

The video app TikTok, a controversial platform, has increasingly been utilized for the dissemination of health-related topics. In this study, the quality of information on the top 50 most viewed TikTok videos on infantile hemangiomas (IHs) labeled #hemangioma was analyzed. The results showed that the videos were skewed toward more severe subtypes of IH, and most were directed at raising awareness about IH or combating stigmatizing attitudes toward birthmarks. Providers should be aware that social media applications such as TikTok are a commonly used venue for parents to cope and connect but may relay inaccurate or misleading information.

Basal cell carcinoma arising at the site of a previously irradiated infantile hemangioma.

We describe a case of a previously irradiated infantile hemangioma in a patient 1 year of age. At the age of 78, the patient presented with a pink, pearly plaque at the previously irradiated infantile hemangioma site and was found to have a nodular basal cell carcinoma. [Correction added on 30 August 2023, after first online publication: In the preceding sentence, patient age has been corrected in this version] This case highlights the rare, but long-term risks of radiation therapy for hemangiomas, but also presents an interesting historical vignette in dermatological treatments, with photographic documentation. It also represents the longest time interval between irradiation of an infantile hemangioma and the development of a basal cell skin cancer, 70 years in this case.

Critical role of Aquaporin-1 and telocytes in infantile hemangioma response to propranolol beta blockade.

Propranolol, a nonselective ß-adrenergic receptor (ADRB) antagonist, is the first-line therapy for severe infantile hemangiomas (IH). Since the incidental discovery of propranolol efficacy in IH, preclinical and clinical investigations have shown evidence of adjuvant propranolol response in some malignant tumors. However, the mechanism for propranolol antitumor effect is still largely unknown, owing to the absence of a tumor model responsive to propranolol at nontoxic concentrations. Immunodeficient mice engrafted with different human tumor cell lines were treated with anti-VEGF bevacizumab to create a model sensitive to propranolol. Proteomics analysis was used to reveal propranolol-mediated protein alteration correlating with tumor growth inhibition, and Aquaporin-1 (AQP1), a water channel modulated in tumor cell migration and invasion, was identified. IH tissues and cells were then functionally investigated. Our functional protein association networks analysis and knockdown of ADRB2 and AQP1 indicated that propranolol treatment and AQP1 down-regulation trigger the same pathway, suggesting that AQP1 is a major driver of beta-blocker antitumor response. Examining AQP1 in human hemangioma samples, we found it exclusively in a perivascular layer, so far unrecognized in IH, made of telocytes (TCs). Functional in vitro studies showed that AQP1-positive TCs play a critical role in IH response to propranolol and that modulation of AQP1 in IH-TC by propranolol or shAQP1 decreases capillary-like tube formation in a Matrigel-based angiogenesis assay. We conclude that IH sensitivity to propranolol may rely, at least in part, on a cross talk between lesional vascular cells and stromal TCs.

Long-Term Results of Oral Propranolol Treatment Protocol for Periocular Infantile Hemangioma: Should There Be Any Contraindication?

PURPOSE: The authors report long-term results of the oral propranolol treatment protocol for periocular infantile hemangioma regardless of conventional indications. METHODS: This is a retrospective study (2008-2018) on children with propranolol treatment protocol for periocular infantile hemangioma and last follow-up (FU) of ≥4 months after treatment and age of >24 months. After systemic evaluation, it was started with 0.5 and increased by 0.5 every 3 days to reach 2 mg/kg/day. If there was no good response, it would be gradually increased up to 3 mg/kg/day. Tapering (0.5 mg/kg/day every 4 weeks) was started when patients were on treatment for ≥6 months and ≥12 months old and there was no change in the infantile hemangioma size for ≥3 months. Rebound growth was based on the parents' report and would be treated by increasing the dose to at least 2 mg/kg/day for 3 months. FU was either in-person or via social media. Change in periocular infantile hemangioma size on the photos was scored by 3 masked observers (visual analog scale) and presented as excellent (≥50% reduction), good (1%-49%), fair (no change), and failure (enlarged). RESULTS: Forty-three patients were included. Orbital involvement was in 49%, ptosis in 58%, and risk of amblyopia in 63%. Mean treatment, tapering, and FU duration were 37, 13, and 74 months, respectively. Mean age at presentation, start of propranolol treatment protocol, tapering, stop, and last FU were 1.5, 5, 29, 42, and 78 months, respectively. Twenty-seven patients received 2, seven 2.5, and nine 3 mg/kg/day. Mean visual analog scale significantly increased from 43% (FU1) to 92% (last FU) when 97.6% of patients showed an excellent response. The remaining skin lesions were observed in 35%. No side effect was reported. CONCLUSIONS: Long-term results of the propranolol treatment protocol for periocular infantile hemangioma showed an excellent response in 97.6% of patients with no side effects. A residual skin lesion was observed in 1/3 of the patient.

Clinical efficacy and safety of two different hematoporphyrin monomethyl ether-mediated photodynamic therapy regimen in Chinese children with port-wine stain.

Hematoporphyrin monomethyl ether-photodynamic therapy (HMME-PDT) has achieved encouraging clinical outcomes in adult port-wine stain (PWS). Optimal treatment option for children with PWS was minimal. To compare whether the clinical effectiveness of HMME-PDT with the 5-min (fast) administration treatment regimen (FATR) was better than the 20-min (slow) administration treatment regimen (SATR) for PWS of children in vivo and in vitro. Thirty-four children with PWS were divided into two groups including FATR and SATR. The two groups received three times HMME-PDT, respectively. Treatment efficacy and safety were evaluated in vivo and in vitro. Erythema index (EI) was used to evaluate the clinical outcomes. Both FATR and SATR were effective and safe in children with PWS after HMME-PDT. There were significance differences between the two groups in reductions of EI after the second treatment (p < 0.001) and the third treatment (p < 0.001) with HMME-PDT. The serum HMME concentration reach the peak level at short time compare with SATR group. A significance increased superoxide levels were observed in FATR group compare to SATR groups in vitro (p < 0.05). Our study suggested that HMME-PDT was effective and safe for children with PWS, the therapy regimen with FATR was better in clinical efficacy than that of the SATR.

Sirolimus for diffuse intestinal infantile hemangioma with PHACE features: systematic review.

BACKGROUND: We report a 3-month-old female with cardiovascular anomalies and diffuse intestinal infantile hemangioma (IIH) of the small bowel suggesting possible diagnosis of PHACE syndrome (posterior fossa anomalies, hemangioma, arterial lesions, cardiac abnormalities/coarctation of the aorta, eye anomalies). The GI symptoms persisted under treatment with propranolol, whereas the addition of sirolimus led to regression of the IIH. METHODS: A systematic review was conducted using PubMed, EMBASE, and Ovid MEDLINE databases between 1982 and 2021. RESULTS: A total of 4933 articles were identified; 24 articles met inclusion criteria with 46 IIH cases. The most common GI presentations were unspecified GI bleed (40%) and anemia (38%). The most common treatments were corticosteroids (63%), surgical resection (32.6%), and propranolol (28%). Available outcomes were primarily bleeding arrest (84%). Nine cases (19.5%) were diagnosed with definite PHACE, 5 (11%) with possible PHACE, and 32 (69.5%) no PHACE. Our case presented with symptoms most consistent with those of possible PHACE and definite PHACE. No cases in this review underwent treatment with sirolimus. CONCLUSIONS: This is the first reported case of successful treatment of IIH with sirolimus. Our case, along with other patients who present with IIH and PHACE features, suggests consideration of IIH as a diagnostic criterion for PHACE syndrome. IMPACT: This is the first reported case in which sirolimus showed regression of an intestinal infantile hemangioma. This study serves to demonstrate the presentation, treatment, outcomes of intestinal infantile hemangioma, and correlation with PHACE. The potential correlation between intestinal infantile hemangioma and PHACE deserves more study in consideration of intestinal infantile hemangioma as a diagnostic criterion of PHACE.

Incidence and clinical factors associated with ulceration in infantile hemangiomas.

BACKGROUND: Ulceration is an important complication in infantile hemangiomas (IHs). Prior to the use of ß-blockers, the estimated incidence of this complication in a referral population was between 15% and 30%. The incidence and factors associated with ulceration have not been systematically studied since the emergence of ß-blocker therapy. OBJECTIVE: Examine the incidence and clinical predictors for ulceration in IHs. METHODS: Retrospective study at tertiary referral centers. RESULTS: Compared with a previous large pre-propranolol cohort study, ulceration occurred at a significantly lower incidence of 11.4%. Clinical factors associated with ulceration included partial segmental morphology, location in the diaper area, and size greater than 5 cm. Higher risk of ulceration in Black patients was observed, suggesting barriers to care including delayed diagnosis and referral to specialty care. LIMITATIONS: Retrospective design at tertiary referral centers. CONCLUSION: Compared with reports before the use of ß-blockers became widespread, the incidence of ulceration in IHs has decreased. However, it continues to be a relatively frequent complication of IH.

Lower socioeconomic status is associated with delayed access to care for infantile hemangioma: A cohort study.

BACKGROUND: Early specialist evaluation during rapid proliferative growth of complicated infantile hemangiomas (IHs) is crucial. Health disparities and barriers of access to care for children with IHs have not been examined. OBJECTIVE: To investigate whether socioeconomic status (SES) is associated with age at presentation to a subspecialist for IH evaluation. METHOD: A retrospective cohort study of 804 children presenting to a large academic hospital. The primary outcome was age at initial presentation. Covariates included demographic, socioeconomic, geographic, and clinical characteristics. Medicaid and the Children's Health Insurance Program were proxies for lower SES. Analysis of covariance, chi-square tests, and generalized ordered logistic regressions were performed. RESULTS: Children with lower SES had higher odds of presenting after 3 months of age (odds ratio, 2.11; 95% confidence interval, 1.31-3.38). In the subset that qualified for the institutional care management program (ICMP), no risk factors were associated with delayed presentation. LIMITATIONS: Use of insurance and economic distress as proxies for SES; exclusion of uninsured children, which may have resulted in underestimation of racioethnic effects; and examination of a single academic center, which may limit generalizability. CONCLUSIONS: Children with IHs and lower SES were more likely to present later to specialists, but those enrolled in an ICMP were not, suggesting that integrated ICMPs may mitigate disparities and delayed access to care for IHs among lower-SES populations.

Characteristics, Natural Course and Treatment of Intramuscular Capillary-type Haemangioma: A Systematic Literature Review.

Intramuscular capillary-type haemangiomas (ICTH) are rare vascular anomalies that can easily be misdiagnosed as other entities. A systematic review was performed of all cases of ICTH in the literature since its first description in 1972. An adjudication committee reviewed cases to include only ICTHs. Among 1,143 reports screened, 43 were included, involving 75 patients. The most frequent differential diagnosis was intramuscular venous malformations. The mean age of patients at diagnosis was 21.2 years. ICTH was mainly described as a gradually increasing mass (81.8%), painless (73.9%), that could occur anywhere in the body but most frequently on the head and neck (44.0%). Magnetic resonance imaging (MRI) was mainly used for diagnosis (69.1%) and displayed specific features. The most frequent treatment was complete surgical removal (73.9%), which could be preceded by embolization, and led to complete remission without recurrence in all but 1 case.

Prognostic Factors for Long-term Aesthetic Outcome of Infantile Haemangioma Treated with Beta-blockers.

Parents of infants treated with beta-blockers for infantile haemangioma are often concerned about the long-term aesthetic outcome. This cross-sectional study assessed the influence on the long-term aesthetic outcome of characteristics of the infantile haemangioma, the beta-blocker treatment, and the infant. The study included 103 children aged 6-12 years, treated with beta-blockers (propranolol or atenolol) for infantile haemangioma during infancy (age at treatment initiation ≤1 year) for ≥6 months. Dermatologists and parents scored the Patient Observer Scar Assessment Scale, and the child scored a visual analogue scale. Dermatologists identified whether telangiectasia, fibrofatty tissue, and atrophic scar tissue were present. The long-term aesthetic outcome of infantile haemangioma was judged more negatively by dermatologists and parents in case of a superficial component, ulceration, older age at treatment initiation, higher cumulative dose, and/or shorter follow-up time. According to children, infantile haemangioma located on the head had better aesthetic outcome than infantile haemangioma located elsewhere. Close monitoring, particularly of infantile haemangioma with a superficial component, is essential for early initiation of treatment, and to prevent or treat ulceration. These outcome data can support parental counselling and guide treatment strategy.

Long-term neurocognitive functioning of children treated with propranolol or atenolol for infantile hemangioma.

The purpose of this study was to compare long-term neurocognitive functioning (working memory, processing speed, and attention) between children who had been treated with either propranolol or atenolol for infantile hemangioma during infancy. All eligible children (n = 158) aged 6 years or older and treated with propranolol or atenolol as infants were invited to participate in this two-center cross-sectional study. The primary outcome was the Wechsler Intelligence Scale for Children-V Cognitive Proficiency Index (CPI), a measure of working memory, processing speed, and attention. Secondary outcomes were general intelligence, auditory, visuospatial, and narrative memory, as well as executive functioning and sleep. A total of 105 children, of whom 36 had been treated with propranolol (age 6.0-11.8 years, follow-up time 1.6-9.7 years, 19% male) and 69 had been treated with atenolol (age 6.9-9.7 years, follow-up time 4.5-8.4 years, 19% male), were analyzed. The CPI and other neurocognitive outcomes did not differ between the propranolol and atenolol groups and were in line with general population test norms. Post hoc analyses revealed lower CPI scores for males, both compared to participating females (10.3 IQ points, medium effect size) and compared to matched test norms (12.4 IQ points, medium effect size). CONCLUSIONS:  Long-term neurocognitive functioning did not differ between children treated with propranolol and those treated with atenolol for IH. Overall, propranolol and atenolol appear to be safe treatments for IH regarding long-term neurocognitive functioning. The substantially lower CPI scores in males warrant further investigation. TRIAL REGISTRATION:  Netherlands Trial Register, NL7703 https://www.trialregister.nl/trial/7703 What is Known: • Infants with infantile hemangioma are effectively treated with propranolol or atenolol. • Parents and professionals are concerned about long-term neurocognitive effects. WHAT IS NEW: • No long-term (≥ 6 years) differences in neurocognitive functioning were found between children treated with propranolol or atenolol. • Males treated with beta-blockers had substantially lower IQ scores than treated females and males from the general population, which is a matter of concern and should be considered when evaluating the risk/benefit ratio in less severe forms of infantile hemangioma.

Distribution of problematic localized facial infantile haemangiomas and their response to propranolol: a retrospective cohort study.

BACKGROUND: The distribution and response to propranolol of problematic facial infantile haemangiomas (IHs) has rarely been described in the literature. AIM: To map problematic facial IHs and observe their response to propranolol. METHODS: Eligible patients were categorized according to focal location and cohorts corresponding to these (buccal, medial, zygomatic, lateral and multiregional) were created. The primary efficacy variable was regression score ranging from 1 to 4, calculated using results of colour Doppler ultrasonography. RESULTS: In total, 104 patients met the inclusion criteria. There were 32 (30·8%) IHs located in the buccal area, 12 (11·5%) in the medial area, 49 (47·1%) in the lateral area and 1 (1·0%) in the zygomatic area, with 10 (9·6%) IH cases having multiregional lesions. We found that the distribution pattern of most IHs matched the surface projection of the trunk of the external carotid and the facial arteries. Further analysis showed that the median regression score in the buccal and medial groups were significantly lower than those in the lateral and multiregional groups. CONCLUSION: Treatment of buccal and medial haemangiomas tends to be more challenging and their distribution pattern mainly reflects the direction of the facial vessels.

Foam Sclerotherapy in the Treatment of Hemangiomas and Venous Malformations.

BACKGROUND: Sclerotherapy has achieved great success in treating most venous malformation (VM) lesions. OBJECTIVE: To compare the effects of foam sclerotherapy on infantile hemangioma and pyogenic granuloma (PG). In addition, we analyzed the data and outcomes of foam sclerotherapy for the VM. MATERIALS AND METHODS: Thirty-nine patients with hemangiomas and 83 patients with VMs were treated, and clinical outcomes, resolution, and complication rates were compared. Sclerotherapy data from the VM group were also analyzed. RESULTS: The average age of the patients and the distribution and tissue involvement of lesions among the 3 groups were significantly different ( p < .001). The average amount of sclerosing foam administered per session in VMs was significantly higher than that in the other 2 groups ( p < .0001) (whereas that in the PG group was lower than that in the infantile hemangioma group [ p < .0001]). However, the overall therapeutic efficacy and side effects in the 3 groups were not significantly different. For VMs, the frequency of ultrasound guided foam sclerotherapy and use of 3% polidocanol increased from superficial to deep lesions, whereas the use of 1% POL decreased ( p < .0001). CONCLUSION: Infantile hemangioma and PG treatments presented good results and minor adverse reactions comparable with those of VMs.

Hybrid lung lesions in children with segmental infantile hemangiomas, a new association?

Infantile hemangiomas (IHs) are the most common tumors of infancy and, in rare instances, can present in the setting of congenital structural anomalies or as part of syndromic disorders. In this study, we present three cases of children with segmental IHs born with concurrent pulmonary anomalies: congenital pulmonary airway malformations and bronchopulmonary sequestration. To date, no known association between these entities and hemangiomas has been described.