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.

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.

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.

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.

[Analysis of the pain in extremities caused by intramuscular venous malformation and surgical treatments].

Objective: To analyze the pain caused by intramuscular venous malformation, so as to avoid misdiagnosis. Methods: We retrospectively analyzed 173 patients who received surgical treatments in our department between Jan.2012 to Dec.2014,with the main complaint of local pain and were diagnosed as intramuscular venous malformation. The mechanisms of the local pain, based on the image data, intra-operative findings, pathology reports and the comparison of the Visual Analogue Scale(VAS)data before and after operation were summarized. The surgical interventions included simple excision or excision + adhesiolysis or excision + adhesiolysis + nerve decompression. Results: The reasons of local pain can be divided into 4 categories:①lesion located in the tendon insertions;②lesion involving the local nerve, inducing the thickening and tensing of its epineurium and the increasing of its diameter;③lesion infiltrated to the periosteum;④phlebolith in it. All the 173 patients received surgical treatments and got varying degrees of relieving from local pain.63 patients got a decrease of the VAS by 5 or more, and 95 cases' VAS number decreased by 3-4,the rest 15 patients' VAS cut down by 1-2. Conclusions: Intramuscular venous malformation is an important reason for local pain and should not be neglected. Surgical treatment can be an effective method to remove the lesion and relieve local pain.

Promotion of Propranolol Delivery to Hemangiomas by Using Anti-VEGFR Antibody-Conjugated Poly(lactic-co-glycolic acid) Nanoparticles.

Infantile hemangiomas are the most common tumors affecting children. Although infantile hemangiomas are benign, they could result in morbidity and mortality. The only US Food and Drug Administration-approved drug for infantile hemangiomas is propranolol hydrochloride (Hemangeol™); however, its adverse effects and high frequency of administration hamper its clinical application. Vascular endothelial growth factor receptor (VEGFR) is crucial to the angiogenesis of infantile hemangiomas, and thus it is considered a valuable therapeutic target for infantile hemangiomas. To reduce the adverse effects and high administration frequency of propranolol, we developed propranolol-loaded nanoparticles conjugated with anti-VEGFR antibody (PNP-VEGFR) as a controlled- and targeted-release system to treat infantile hemangiomas. The characteristics, anti-hemangioma activity, and mechanisms of PNP-VEGFR were examined in vitro and in vivo. The developed PNP-VEGFR exhibited a small size (∼100 nm), drug encapsulation efficiency (∼60%), and sustained drug release for 8 days. PNP-VEGFR was efficiently bound to human umbilical vein endothelial cells and human hemangioma endothelial cells in a VEGFR-dependent manner, resulting in enhanced cytotoxic effects and stronger inhibition of VEGF expression, compared to that of the untargeted propranolol-loaded nanoparticles (PNP) and propranolol. Notably, the in vivo therapeutic effects of PNP-VEGFR in infantile hemangiomas were superior to that of propranolol and PNP, as reflected by significantly reduced hemangioma volume, weight, and microvessel density, without any noticeable behavioral changes or weight loss. PNP-VEGFR was shown to provide targeted delivery and sustained release of propranolol to infantile hemangiomas. Therefore, it represents a promising treatment for infantile hemangiomas.

[Surgical treatment of cervical giant cystic lymphangioma in children].

OBJECTIVE: To discuss the radical treatment of cervical giant cystic lymphangioma in Children and cosmetic result. METHODS: Twenty-five children with cervical giant cystic lymphangioma were retrospectively analyzed. The diameter of all the tumors was more than 10 cm. 24 cases underwent resection. The complication, therapeutic effect and cosmetic result were recorded. RESULTS: The tumors were all removed radically in all the cases. The patients were followed up for 1-5 years with no recurrence. Cosmetic result was satisfactory in 22 cases. Secondary operation was performed in 2 cases with satisfactory result. Complications included 5 cases of lymph leakage, 2 cases of poor wound healing, 1 case of infection and 2 cases of tongue edema. CONCLUSIONS: The cervical giant cystic lymphangioma in children can be resected radically with satisfactory result.

[Combined and sequential therapy for Kasabach-Merritt syndrome].

OBJECTIVE: To review and summarize the clinical characteristics and therapeutic approaches of Kasabach-Merritt syndrome (KMS). METHODS: The combined and sequential therapy was used to for 51 KMS infants between 2005 and 2009. And all cases were retrospectively analyzed. There were 27 males and 24 females with a median age of 1.8 months (range: 2 days to 2.5 years). Among them, lesions were located in maxillofacial (n = 20), truck (n = 4), upper extremities (n = 11) and lower extremities (n = 16). RESULTS: Among them, 47 of 51 patients were cured, 3 cases were effectively treated and only 1 patient died of multiple organ failure post-operation. Of the 51 cases, emergency surgery was given in 3 cases while other 48 cases were initially treated with methylprednisolone. The responses were varied: excellent and rapid improvement (n = 12); moderate response (n = 15) and total failure (n = 21). Immunoglobulin was used a second-line therapy for those (n = 21) unresponsive to steroid, with sensitive response (n = 5), effective response (n = 7) and invalid response (n = 9) respectively. And adjunct carbonyldiamide therapy was combined. Conservative treatment was tried in 14 patients. Then 11 curative cases and 3 effective cases were observed. The thrombocyte count in 4 cases returned to normal within 4 - 7 days, 5 cases within 8 - 14 days, and 2 cases within 15 - 28 days. In the remaining 3 cases, it normalized more than 28 days. The hemangiomas in 6 cases disappeared completely in 6 - 12 months and 8 cases disappeared in 13 - 24 months. 19 patients were treated with the ligation of external carotid artery, the insertion of a tube inside the lesion and the injections of carbonyldiamide and methylprednisolone. The platelet counts of 13 cases increased to normal in 4 - 7 days of the treatment, and 6 cases in 8 - 14 days. The tumors of 12 cases disappeared within 6 - 12 months, and 7 cases within 13 - 24 months. Combined surgical resection including emergency operation (n = 3) and selective operation (n = 15) was performed in 18 patients. And all cases except for one were cured. The platelet counts of that the hemangiomas of 10 cases were excised surgically completely increased rapidly and reached the normal range in post-operative 1 - 3 days. The counts of 8 cases after subtotal resection increased to normal within 8-14 days. CONCLUSION: A stepwise multimodal approach is recommended for the treatment of KMS. With a higher curative rate, it has minimal side effects.