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.

Summary of the application value of ultrasound imaging features in the clinical differential diagnosis of intramuscular capillary-type hemangioma and fibro-adipose vascular anomaly.

Objective: To investigate the value of ultrasonography as a diagnostic aid in differentiating intramuscular capillary-type hemangioma (ICTH) from fibro-adipose vascular anomaly (FAVA). Methods: A retrospective analysis was conducted of the clinical and ultrasound imaging data of 20 patients with ICTH and 45 patients with FAVA who were admitted to and pathologically confirmed in hospital between January 2013 and April 2023. The clinical and ultrasonographic appearances of the lesions in the two groups were compared and analyzed. A stepwise regression analysis was performed, and a joint diagnostic equation was constructed using the final variables selected. The receiver operating characteristic (ROC) curve and indicators, including sensitivity and specificity, were used to evaluate the efficacy of the joint diagnostic model. Results: The two groups of patients suffering from ICTH and FAVA presented a statistically significant difference (P< 0.05) in terms of 'age', 'lesion size', 'fascial tail sign', 'presence of a fatty-tissue-like hyperecho around the lesion', 'blood flow' and 'presence of straight blood capillaries within the lesion'. Finally, the variables 'fascial tail sign' and 'presence of straight blood capillaries within the lesion' were selected to construct the model. The constructed joint diagnostic model had a sensitivity value of 70.0% (95% CI: 59.00-81.00), a specificity value of 98.0% (95% CI: 94.70-100.00) and a ROC curve value of 0.908, indicating the high efficacy of the combined diagnosis method. Conclusions: Ultrasonography can be utilized to differentiate ICTH from FAVA, and the combined diagnosis method can further improve the technique's diagnostic efficacy.

Effect of interventional embolization based on absolute ethanol for peripheral arteriovenous malformations.

BACKGROUND: Interventional embolization schedules based on absolute ethanol are usually used for peripheral arteriovenous malformations (PAVMs), and clinicians often choose the scheme according to the classification. AIM: To evaluate different interventional embolization schedules based on absolute ethanol for PAVMs. METHODS: A retrospective study was performed of 165 patients with PAVMs treated with interventional embolization based on absolute ethanol in Henan Provincial People's Hospital from January 2018 to May 2021. PAVMs were classified as type II (n = 67), type III (n = 81) and type IV (n = 17) according to the Yakes classification system, including 123 maxillofacial, 13 trunk and 29 limbs. Effectiveness of embolization was based on PAVM devascularization on angiography: 100% (total), 90%~99% (near-total), 70%~90% (substantial), 30%~70% (partial) and 0%~30% (failure). RESULTS: PAVMs were classified as type II (n = 67), type III (n = 81) and type IV (n = 17) according to the Yakes classification system, including 123 maxillofacial (74.55%), 13 trunk (7.88%) and 29 limbs (17.58%). There are statistical differences in the angiographic outcomes among different Yakes classification and between different methods (P < 0.05), and there was a statistical difference in the failure rates among different Yakes classification (P < 0.05). CONCLUSIONS: PAVMs occur maxillofacial usually, and Type II can achieve better effect by spring coil and absolute ethanol, while Type III and Type IV have no ideal effect by Pingyangmycin + iodized oil + PVA + absolute ethanol and spring coil + absolute ethanol, respectively. Both the two happen to be complications, and wound accounts the highest.

Fibroadipose vascular anomaly: a clinicopathological study of 75 cases.

AIMS: Fibroadipose vascular anomaly (FAVA) is a complex vascular malformation that is likely to be under-recognised. In this study we aimed to report the pathological features and somatic PIK3CA mutations associated with the most common clinicopathological features. METHODS AND RESULTS: Cases were identified by reviewing the lesions resected from patients with FAVA registered at our Haemangioma Surgery Centre and unusual intramuscular vascular anomalies in our pathology database. There were 23 males and 52 females, who ranged in age from 1 to 51 years. Most cases occurred in the lower extremities (n = 62). The majority of the lesions were intramuscular, with a few disrupting the overlying fascia and involving subcutaneous fat (19 of 75), and a minority of the cases had cutaneous vascular stains (13 of 75). Histopathologically, the lesion was composed of anomalous vascular components that were intertwined with mature adipocytic and dense fibrous tissues and vascular components with: (a) clusters of thin-walled channels, some with blood-filled nodules and others with thin walls resembling pulmonary alveoli; (b) numerous small vessels (arteries, veins and indeterminate channels) - proliferative small blood vessels were often mixed with adipose tissue; (c) larger abnormal venous channels usually irregularly and sometimes excessively muscularised; (d) lymphoid aggregates or lymphoplasmacytic aggregates were usually observed; and (e) lymphatic malformations were sometimes seen as minor elements. All patients had their lessons subjected to PCR, and 53 patients had somatic PIK3CA mutations (53 of 75). CONCLUSIONS: FAVA is a slow-flow vascular malformation with specific clinicopathological and molecular characteristics. Its recognition is fundamental for its clinical/prognostic implications and for targeted therapy.

Radiomics-based machine learning approach in differentiating fibro-adipose vascular anomaly from venous malformation.

BACKGROUND: As a complex vascular malformation, fibro-adipose vascular anomaly was first proposed in 2014. Its overlap with other vascular malformations regarding imaging and clinical features often leads to misdiagnosis and improper management. OBJECTIVE: To construct a radiomics-based machine learning model to help radiologists differentiate fibro-adipose vascular anomaly from common venous malformations. MATERIALS AND METHODS: We retrospectively analyzed 178 children, adolescents and young adults with vascular malformations (41 fibro-adipose vascular anomaly and 137 common vascular malformation cases) who underwent MRI before surgery between May 2012 to January 2021. We extracted radiomics features from T1-weighted images and fat-saturated (FS) T2-weighted images and further selected features through least absolute shrinkage and selection operator (LASSO) and Boruta methods. We established eight weighted logistic regression classification models based on various combinations of feature-selection strategies (LASSO or Boruta) and sequence types (single- or multi-sequence). Finally, we evaluated the performance of each model by the mean area under the receiver operating characteristics curve (ROC-AUC), sensitivity and specificity in 10 runs of repeated k-fold (k = 10) cross-validation. RESULTS: Two multi-sequence models based on axial FS T2-W, coronal FS T2-W and axial T1-W images showed promising performance. The LASSO-based multi-sequence model achieved an AUC of 97%±3.8, a sensitivity of 94%±12.4 and a specificity of 89%±9.0. The Boruta-based multi-sequence model achieved an AUC of 97%±3.7, a sensitivity of 95%±10.5 and a specificity of 87%±9.0. CONCLUSION: The radiomics-based machine learning model can provide a promising tool to help distinguish fibro-adipose vascular anomaly from common venous malformations.

A Novel Human Acute Encephalitis Caused by Pseudorabies Virus Variant Strain.

BACKGROUND: Pseudorabies virus (PRV) is a common pathogen in multiple animal species, particularly in pigs. However, PRV infection in humans is rare and, to the best of our knowledge, PRV has never been isolated from human cases before. METHODS: Four acute encephalitis cases in humans were confirmed as PRV infection based on clinical symptoms, laboratory diagnosis, and metagenomic next-generation sequencing (mNGS). Cerebrospinal fluid (CSF) samples were collected and applied for virus isolation. Etiological and genetic characteristics of this PRV human isolate were further determined. RESULTS: The patients manifested respiratory dysfunction and acute neurological symptoms. The mNGS revealed PRV-specific nucleotide sequences in patients' CSF samples (7-6198 reads and 0.2446%-80.58% coverage). The PRV envelope glycoprotein B antibody, glycoprotein E antibody, and neutralizing antibody were positively detected. For the first time, a PRV strain, designated hSD-1/2019, was isolated and identified from a CSF sample, and transmission electron microscopy revealed that hSD-1/2019 had typical morphology similar to that of swine PRV. Phylogenetic analysis illustrated that hSD-1/2019 was genetically closest to those PRV variant strains currently circulating in pigs in China, and this strain showed similar etiological characteristics to Chinese PRV variant strains, while different from Chinese classical strain. Moreover, hSD-1/2019 showed high pathogenicity and induced acute neurological symptoms in pigs. CONCLUSIONS: A PRV strain was isolated from an acute human encephalitis case. This isolate showed close phylogenetic relationships and similar etiological characteristics to Chinese PRV variant strains, implying the great risk of PRV transmission from pigs to humans.

Propranolol inhibits proliferation and induces apoptosis of hemangioma-derived endothelial cells via Akt pathway by down-regulating Ang-2 expression.

Hemangioma is one of the commonest benign vascular tumors among children. Propranolol is the first-line therapeutic drug for hemangioma. However, the effects and mechanisms of propranolol in hemangioma have not been thoroughly elaborated. In this study, the effects and mechanisms of propranolol were explored using hemangioma-derived endothelial cells (HemECs). The expression of GLUT1 were determined by immunofluorescence staining. qRT-PCR assay was conducted to detect the mRNA expressions of angiopoietin-2 (Ang-2) and Tie-2. Western blot assay was carried out to measure the protein levels of Ang-2, Tie-2, protein kinase-B (Akt) and phospholyrated-Akt (p-Akt). Cell proliferation was assessed by Cell Counting Kit-8 (CCK-8) assay and Western blot of Ki67 protein level. Cell apoptosis was measured by flow cytometry analysis and Western blot of Bax and Bcl-2 levels. We found that propranolol inhibited proliferation and induced apoptosis in human umbilical vein endothelial cells (HUVECs) and HemECs. Moreover, propranolol inhibited the expressions of Ang-2 and Tie-2 in HUVECs and HemECs. Functional analysis revealed that Ang-2 attenuated the effects of propranolol on HemEC proliferation and apoptosis. Mechanistical analysis showed that propranolol inhibited the Akt pathway by regulating Ang-2 expression in HemECs. Futhermore, inhibition of the Akt pathway attenuated the effects of Ang-2 on proliferation and apoptosis in HemECs. In conclusion, propranolol inhibited proliferation and induced apoptosis of HemECs via Akt pathway by down-regulating Ang-2 expression, which contributes to our understanding on the pathogenesis of hemangioma and promotes the development of therapeutic approaches for hemangioma.

LncRNA-MALAT1 promotes tumorogenesis of infantile hemangioma by competitively binding miR-424 to stimulate MEKK3/NF-κB pathway.

AIMS: Infantile hemangioma (IH) is the most common vascular neoplasm in infant and young children. Long non-coding RNAs (lncRNAs) are known to be associated with IH. This study aims to investigate the role and underlying mechanism of lncRNA-MALAT1 in IH. MAIN METHODS: qRT-PCR was used to quantify the expressions of MALAT1, miR-424, and MEKK3 in IH tissues. The cell proliferation, apoptosis, migration, invasion, and tube formation ability were assessed by MTT assay, colony formation assay, flow cytometric analysis, transwell assay and tube formation assay, respectively. The interaction among MALAT1, miR-424 and MEKK3 was evaluated by luciferase reporter assay. Immunohistochemistry (IHC) and Western blotting were utilized to evaluate the expression levels of MEKK3, Ki-67 and NF-κB pathway-related proteins both in vitro and in vivo. KEY FINDINGS: In IH tissues, MALAT1 and MEKK3 were overexpressed while miR-424 was down-regulated. Silencing MALAT1 or overexpression of miR-424 significantly inhibited the IH cell proliferation, migration and tube formation, but promoted the cell apoptosis. Knockdown of MALAT1 suppressed the expression of MEKK3 and inactivated the IKK/NF-κB pathway by sponging miR-424. Overexpression of MEKK3 in HemEcs reversed the impact of knockdown of MALAT1 and overexpression of miR-424 on the cell proliferation, apoptosis, migration, invasion and tube formation rate. The tumor xenografts experiments demonstrated that silencing MALAT1 significantly inhibited the tumor growth in vivo and Ki-67 in the tumor tissues was also significantly suppressed. SIGNIFICANCE: MALAT1 promoted the IH progression through inhibiting miR-424 to activate MEKK3-mediated IKK/NF-κB pathway, suggesting that MALAT1, miR-424 and MEKK3 could be used as potential targets to improve IH treatment efficiency.

The sustained and targeted treatment of hemangiomas by propranolol-loaded CD133 aptamers conjugated liposomes-in-microspheres.

We previously developed propranolol-encapsulated liposomes-in-microspheres (PLIM) to realize the sustained propranolol release for the treatment of hemangiomas. However, the liposomes released from the microspheres still lacked specificity for CD133-positive hemangioma-derived stem cells (HemSCs) which are considered to be the seeds of hemangiomas. Therefore, we hereby encapsulated propranolol-loaded CD133 aptamers conjugated liposomes in poly(lactic-co-glycolic acid (PLGA) microspheres to develop propranolol-loaded CD133 aptamers conjugated liposomes-in-microspheres (PCLIM), to realize the aim of the sustained and targeted therapy of hemangiomas. The evaluation of the release of propranolol from PCLIM was carried out, and the cytotoxic effect and angiogenic growth factor expression inhibitory ability of PCLIM were performed in HemSCs. The in vivo hemangioma inhibitory ability of PCLIM was also investigated in nude mice with subcutaneous human hemangiomas. PCLIM possessed a desired size of 29.2 µm, drug encapsulation efficiency (25.3%), and a prolonged drug release for 40 days. Importantly, PCLIM could inhibit HemSCs proliferation and the protein expression of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor-A (VEGF) in HemSCs to a greater extent compared with PLIM. In nude mice bearing hemangioma xenograft, PCLIM showed the best therapeutic efficacy towards hemangiomas, as reflected by remarkably decreased hemangioma volume, weight and microvessel density (MVD). Thus, our results demonstrated that PCLIM realized the sustained and targeted treatment of hemangiomas, resulting in remarkable inhibition of hemangiomas.

Linc00152 knockdown inactivates the Akt/mTOR and Notch1 pathways to exert its anti-hemangioma effect.

AIMS: Infantile hemangioma (IH) is one of the most common benign vascular tumors occurred in infants. Linc00152 is a kind of long non-coding RNAs (lncRNAs) and acts as a tumor oncogene. Recent study reported that Linc00152 is highly expressed in clinical IH tissues. However, the exact biological roles have not yet been investigated. The aim of the present study was to investigate the oncogenic roles of Linc00152 in IH and the underlying mechanism in vitro. MAIN METHODS: The expressions of Linc00152 in IH tissues and hemangioma-derived endothelial cells (HemECs) were determined using quantitative real time-PCR (qRT-PCR) analysis. The expressions of Akt/mTOR and Notch1 pathways related proteins were detected using western blot analysis. Cell proliferation was assessed by detecting Ki67 expression and CCK-8 assay. Cell apoptosis was evaluated by detecting apoptotic rate, caspase-3/7 activity, and Bcl-2 and Bax expression. KEY FINDINGS: The results demonstrated Linc00152 was up-regulated in clinical IH tissues and HemECs. Knockdown of Linc00152 in HemECs suppressed the activation of Akt/mTOR and Notch1 signaling pathways and caused reduction in cell proliferation and Ki67 expression in HemECs. Besides, Linc00152 knockdown resulted in a significant increase in apoptotic rate, caspase-3/7 activity, and Bax expression level, as well as a decrease in Bcl-2 expression level. However, the effects of Linc00152 knockdown on cell proliferation and apoptosis were mitigated by overexpression of Akt or Notch1. SIGNIFICANCE: Knockdown of Linc00152 suppressed HemECs proliferation and induced apoptosis via inhibiting Akt/mTOR and Notch1 signaling pathways.

Urea-modulated UT-B urea transporter internalization is clathrin- and caveolae-dependent in infantile hemangioma-derived vascular endothelial cells.

The aim of this study was to investigate the manner of urea-modulated UT-B urea transporter (UT) internalization in infantile hemangioma-derived vascular endothelial cells (HemECs). The immunohistochemistry assay was performed to identify infancy hemangioma-derived endothelial cell line (XPTS-1) cells. Cell toxicity was detected with the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay. Quantitative real-time polymerase chain reaction and Western blot analysis were measured to analyze the expression of UT-B. UT-B internalization was observed by confocal microscopy. The clathrin inhibitor chlorpromazine (CPZ) and caveolin endocytic disrupter methyl-ß-cyclodextrin (MßCD) were used in XPTS-1 cells transfected with UT-B-GFP to repress endocytosis. Urea-promoted UT-B expression in a concentration-dependent manner in an infantile XPTS-1 cell line. CPZ and MßCD significantly inhibited UT-B protein internalization. The pretreatment of UT-B-GFP cells with adaptor protein2 (AP2)-µ2-siRNA and caveolin-siRNA significantly inhibited UT-B protein internalization. Our findings suggested that urea-mediated UT-B UT internalization is clathrin and caveolae dependent in infantile HemECs.

Knockdown of inhibitor of differentiation 1 suppresses proliferation and induces apoptosis by inactivating PI3K/Akt/mTOR signaling in hemangioma-derived endothelial cells.

Hemangioma (HA) is one of the commonest benign vascular neoplasms of infancy. Inhibitor of differentiation 1 (ID-1) has been reported to be an oncogene in multiple cancers. However, the role of ID-1 and its molecular mechanism in HA progression have not been elucidated. In the present study, we found that ID-1 expression at mRNA and protein levels was up-regulated in HA-derived endothelial cells (HDECs). Knockdown of ID-1 inhibited proliferation, facilitated apoptosis, and enhanced propranolol cytotoxicity in HDECs. Knockdown of ID-1 decreased the protein levels of phospholyrated protein kinase-B (Akt) and phospholyrated mammalian target of rapamycin (mTOR). Inhibition of PI3K/Akt/mTOR pathway by LY294002 abrogated ID-1-mediated pro-proliferation and anti-apoptosis effects in HDECs. In conclusion, knockdown of ID-1 suppressed proliferation and promoted apoptosis by inactivating phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR signaling in HDECs, shedding light on the function of ID-1 in HA progression and highlighting the therapeutic value of ID-1 for HA.

Retrospective study on the outcomes of infantile tufted angioma complicated by Kasabach-Merritt Phenomenon.

OBJECTIVE: To analyze the clinical characteristics and treatment of pediatric tufted angiomas(TA)complicated by Kasabach-Merritt Phenomenon (KMP). METHOD: A retrospective analysis was conducted on the clinical data and follow-up data of 13 patients diagnosed with TA complicated by KMP. Five male and 8 female patients with an average age of 5.7 months (range, 29 days to 1 year) were treated with surgery between January 2009 and June 2012. According to the size and location of lesions and the degree of thrombocytopenia, complete or subtotal resection was performed. The median follow-up period was 3.4 years (range, 1.7 years to 5.2 years). Therapeutic outcomes were evaluated by platelet count and lesion size. RESULTS: Curative treatment of KMP is defined as restoration of normal hemostasis and elimination of tumor cells. Twelve patients achieved curative treatment and one died of multiple organ failure after operation. Ten patients received complete resection and three patients received incomplete resection. Thrombocyte count, hemoglobin and blood coagulation were respectively restored to normal levels within 1-3 days and 1-2 weeks post complete resection operation. One of the three patients who received subtotal resection operation died. In the other two patients, the platelet count fluctuated over time but remained above 60 × 109 /L, a significantly higher level than the preoperational level. Residual lesions slowly disappeared after continuous medication 3-6 months post operation. CONCLUSION: Early surgical treatment of patients with TA complicated with KMP resulted in significantly higher curative rate and reduced side-effects of drugs.

Propranolol inhibits proliferation and invasion of hemangioma-derived endothelial cells by suppressing the DLL4/Notch1/Akt pathway.

Infantile hemangioma (IH) is one of the most common benign vascular tumors of infancy. Propranolol has been recently introduced for the treatment of IH. However, the mechanism of protective effect has not been fully understood. In this study, hemangioma-derived endothelial cells (HemECs) were isolated and treated with propranolol. The cell viability was measured by MTT assay, and the cell cycle arrest was detected using flow cytometry. Cell invasion was determined using transwell assay. The expressions of matrix metalloproteinase (MMP)-2, MMP-9, Delta-like 4 (DLL4), Notch1, Akt, p-Akt, and vascular endothelial growth factor (VEGF) were detected using western blot. HemECs were incubated with recombinant human DLL4 (rhDLL4) to investigate the role of DLL4/Notch1 in the effect of propranolol. The results showed that propranolol inhibited cell viability of HemECs in a time-dependent manner. Propranolol suppressed cell proliferation of HemECs by arresting cell progression at G0/G1 phase. Propranolol inhibited the invasion ability of HemECs and reduced the expression levels of MMP-2 and MMP-9 in HemECs. Besides, propranolol treatment blocked the DLL4/Notch1 and Akt signaling and inhibited VEGF expression in HemECs. Treatment with rhDLL4 activated the Akt signaling and attenuated the effect of propranolol on HemECs. Our data indicated that propranolol inhibited the cell proliferation and invasion of HemECs. The effect was possibly involved in the DLL4/Notch1/Akt signaling pathway.

Significant inhibition of infantile hemangioma growth by sustained delivery of urea from liposomes-in-microspheres.

Infantile hemangioma (IH) is a benign pediatric tumor, and rapid growth of IH can result in serious morbidity and even mortality. Only one drug Hemangeol™ (propranolol hydrochloride oral solution) has been approved for the treatment of IH, whereas patients suffer from its adverse effects and high frequency of administration. We have used urea, an organic compound and a normal body metabolite, in the treatment of IH for 20 years, and demonstrated that urea is an effective and well-tolerated treatment for IH. To reduce the daily administration of urea, we firstly utilized urea-loaded liposomes-in-microspheres (ULIM) as a novel topical controlled release system to realize the sustained release of urea. ULIM were fabricated from the encapsulation of urea-loaded liposomes in poly(lactic-co-glycolic acid)-b-poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) microspheres. The characteristics, activity and mechanism against IH of ULIM were examined in vitro and in vivo. ULIM were of a desired particle size (~62.4 µm), drug encapsulation efficiency (~51.5%) and sustained drug release for 40 days. ULIM inhibited the proliferation of hemangioma endothelia cells (HemECs) and expression of vascular endothelial growth factor-A in HemECs. The therapeutic effect of ULIM in IH was better than propranolol, urea, urea-loaded liposomes and urea-loaded microspheres in vivo, as reflected by markedly decreased hemangioma weight, volume and microvessel density. None of the treated mice showed behavioral changes, severe side­effects and weight loss. Our results suggest that use of ULIM is a potential and safe approach with which to locally and efficiently deliver urea to hemangioma, and is a promising alternative to propranolol in the treatment of IH.

Clinical significance of galectin-3 expression in malformed hepatic venous tissue.

BACKGROUND & OBJECTIVES: Hepatic venous malformation gradually develops over time and exhibits the malignant biological behaviours of being locally invasive, causing morphological and functional damage to local tissue, and may even cause systemic coagulopathy. Studies show that galectin-3(Gal-3) expression is closely associated with local invasion of malignant tumours. In this study an attempt was made to assess the clinical significance of Gal-3 in local invasion during hepatic venous malformation in patients. METHODS: Gal-3 protein and its mRNA expression were examined using immunohistochemistry and in situ hybridization in a total of 126 patients with hepatic venous malformation. For control tissue, 20 cases of normal tissue distal to surgical margins were also examined. In addition, the association between Gal-3 expression and pathological parameters was analyzed in hepatic venous malformation patients. RESULTS: Gal-3 mRNA positivity was observed in 65.08 per cent (82/126) of hepatic venous malformation tissue samples, which was higher than the rate of 20 per cent (4/20) (P <0.05) seen in control tissues. Gal-3 protein positivity was observed in 58.73 per cent (74/126) of hepatic venous malformation tissue samples, which was higher than the rate of 15 per cent (3/20) (P <0.05) seen in the normal tissue. Gal-3 expression was not significantly associated with age or gender. However, there was a significant association between Gal-3 positivity and lesion size, local invasion depth, and involvement with the hepatic vein and the portal system. INTERPRETATION & CONCLUSIONS: Local tissue invasion and destruction by hepatic venous malformation may be related to the upregulation of Gal-3. Gal-3 expression and the development of venous malformation may be related and needs to be studied further.

Continuous delivery of propranolol from liposomes-in-microspheres significantly inhibits infantile hemangioma growth.

PURPOSE: To reduce the adverse effects and high frequency of administration of propranolol to treat infantile hemangioma, we first utilized propranolol-loaded liposomes-in-microsphere (PLIM) as a novel topical release system to realize sustained release of propranolol. METHODS: PLIM was developed from encapsulating propranolol-loaded liposomes (PLs) in microspheres made of poly(lactic-co-glycolic acid)-b-poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) copolymers (PLGA-PEG-PLGA). The release profile of propranolol from PLIM was evaluated, and its biological activity was investigated in vitro using proliferation assays on hemangioma stem cells (HemSCs). Tumor inhibition was studied in nude mice bearing human subcutaneous infantile hemangioma. RESULTS: The microspheres were of desired particle size (~77.8 µm) and drug encapsulation efficiency (~23.9%) and achieved sustained drug release for 40 days. PLIM exerted efficient inhibition of the proliferation of HemSCs and significantly reduced the expression of two angiogenesis factors (vascular endothelial growth factor-A [VEGF-A] and basic fibroblast growth factor [bFGF]) in HemSCs. Notably, the therapeutic effect of PLIM in hemangioma was superior to that of propranolol and PL in vivo, as reflected by significantly reduced hemangioma volume, weight, and microvessel density. The mean hemangioma weight of the PLIM-treated group was significantly lower than that of other groups (saline =0.28 g, propranolol =0.21 g, PL =0.13 g, PLIM =0.03 g; PLIM vs saline: P<0.001, PLIM vs propranolol: P<0.001, PLIM vs PL: P<0.001). The mean microvessel density of the PLIM-treated group was significantly lower than that of other groups (saline =40 vessels/mm2, propranolol =31 vessels/mm2, PL =25 vessels/mm2, PLIM =11 vessels/mm2; PLIM vs saline: P<0.001, PLIM vs propranolol: P<0.01, PLIM vs PL: P<0.05). CONCLUSION: Our findings show that PLIM is a very promising approach to locally and efficiently deliver propranolol to the hemangioma site leading to a significant inhibition of infantile hemangioma.

PLGA nanoparticles with CD133 aptamers for targeted delivery and sustained release of propranolol to hemangioma.

AIM: To develop propranolol-loaded poly(lactic-co-glycolic acid) nanoparticle with CD133 aptamers (PPN-CD133) to treat infantile hemangioma. MATERIALS & METHODS: The antihemangioma activity and mechanism of PPN-CD133 were evaluated. RESULTS & CONCLUSION: PPN-CD133 are of desired size (143.7 nm), drug encapsulation efficiency (51.8%) and sustained drug release for 8 days. PPN-CD133 could effectively bind to CD133+ hemangioma stem cells, resulting in enhanced cytotoxic effect and reduced expression of angiogenesis factors in hemangioma stem cells. The therapeutic effect of PPN-CD133 in hemangioma was superior to that of untargeted PPN and propranolol in vivo, as reflected by reduced hemangioma volume, weight and microvessel density. PPN-CD133 represents a very promising approach to locally and efficiently deliver propranolol leading to significant inhibition of infantile hemangioma.