Biomarkers Associated with the Progression of Infantile Hemangioma: An Exploratory Study

Academic Background

Infantile Hemangioma (IH) is one of the most common benign tumors in infancy. Although most IH is not apparent at birth, it gradually manifests within the first month of life and undergoes a proliferative phase over approximately one year, followed by an involution phase. While most IH spontaneously regresses, some cases may lead to functional impairments or permanent scarring, especially when critical organs such as the eyes or airways are involved. Therefore, early identification and treatment of high-risk IH are crucial.

Currently, the Japanese Clinical Practice Guidelines for Vascular Anomalies (2017) recommend treatments such as oral propranolol or corticosteroids. However, early therapy may pose risks such as hypoglycemia, bradycardia, infection, and growth disturbances. Thus, determining which IH patients require early intervention is a significant clinical challenge. Since the pathogenesis of IH remains unclear, and there is a lack of biomarkers to predict tumor proliferation, researchers aimed to explore plasma cytokines as potential clinical markers to inform early treatment.

Source of the Paper

This research paper, titled “Biomarkers Associated with Progression of Infantile Hemangioma: Exploratory Study,” was co-authored by Ken Miyazaki, Kayo Kunimoto, and others from institutions such as Wakayama Medical University and Gifu University, Japan. The paper was published in the Journal of Dermatology in 2025, with the DOI 10.¹¹¹¹⁄₁₃₄₆-8138.17639. The study was funded by Maruho Co., Ltd.

Research Process

1. Study Design and Participants

The study was a multicenter, prospective, observational study aimed at exploring plasma cytokines as potential biomarkers for IH progression. A total of 46 IH patients were recruited, with 41 meeting the inclusion criteria forming the full analysis set (FAS). Participants were aged between 14 and 60 days after birth and had not received any IH treatment before the study began.

2. Sample Collection and Processing

Plasma samples were collected at three time points: - Baseline (14–60 days after birth) - Visit 1 (61–150 days after birth, proliferative phase) - Visit 2 (151–395 days after birth, involution phase)

At least 3 mL of blood was collected using EDTA-2Na as an anticoagulant, cooled on ice, and centrifuged (3000 rpm, 15 minutes). The plasma was then separated and stored at -80°C for subsequent analysis.

3. Cytokine Array Analysis

High-density antibody arrays (AAH-BLG-1; RayBiotech, Inc.) were used to screen 507 cytokines in plasma samples. This technology, based on biotin labeling, enables the simultaneous detection of multiple proteins. By analyzing plasma samples from 5 progressive and 5 non-progressive IH patients, 6 cytokines potentially associated with IH proliferation were identified.

4. ELISA Validation

To validate the cytokine array results, ELISA (enzyme-linked immunosorbent assay) was performed on plasma samples from the 41 FAS patients. Selected cytokines included growth differentiation factor 1 (GDF1), angiopoietin-related protein 7 (ANGPTL7), IL-7Rα, and Pentraxin3. ELISA results indicated that GDF1 and IL-7Rα levels were significantly associated with IH proliferation.

5. Clinical Assessment and Data Analysis

IH volume was measured via ultrasound, and changes in total lesion volume and target lesion volume were calculated. Statistical analysis employed ANCOVA (analysis of covariance) models to evaluate the relationship between cytokine levels and IH volume changes. Additionally, ROC (receiver operating characteristic) curves were used to determine cutoff values for GDF1 in predicting IH progression.

Key Findings

1. GDF1 as a Predictive Marker

The study found that baseline plasma GDF1 levels were inversely correlated with IH proliferation rates from baseline to Visit 1. Although this correlation did not reach statistical significance, GDF1 levels were significantly lower in patients with a fourfold or greater increase in volume (p=0.013). This suggests that GDF1 may serve as a potential predictive marker, particularly in identifying highly proliferative IH, with high specificity.

2. Role of IL-7Rα

Changes in plasma IL-7Rα levels showed a significant inverse correlation with changes in target lesion volume (p=0.0069). This indicates that the downregulation of IL-7Rα may play an important role in IH proliferation.

3. Role of Other Cytokines

Although cytokines such as ANGPTL7 and Pentraxin3 showed some correlation in preliminary analyses, they did not reach statistical significance in ELISA validation.

Conclusions and Implications

1. Scientific Value

This study is the first to explore plasma cytokines as biomarkers for IH progression. The discovery of GDF1 and IL-7Rα provides new insights into the pathogenesis of IH, particularly the potential of GDF1 in identifying highly proliferative IH.

2. Clinical Application Value

By measuring plasma GDF1 levels after birth, physicians can identify IH patients in need of early intervention more effectively, optimizing treatment plans and reducing unnecessary risks.

3. Highlights of the Study

• Innovation: First to use plasma cytokines as predictive markers for IH progression.
• Practicality: High specificity of GDF1 makes it a potential clinical tool.
• Multicenter Design: Enhances the reliability and generalizability of the findings.

Additional Valuable Information

The study reported three adverse events, including abnormal liver function, pallor, and hypoglycemia, none of which led to study discontinuation. Additionally, the research team developed an ELISA-based cytokine detection method, providing a technical reference for future related studies.

This study offers new perspectives on the early diagnosis and treatment of IH, with significant scientific and clinical implications. Future research could further explore the specific roles of GDF1 and IL-7Rα in IH pathogenesis and validate their predictive value in larger samples.