Treatment experience for different risk groups of Kaposiform hemangioendothelioma.

Background: Kaposiform hemangioendothelioma (KHE) is a rare vascular tumor with a high risk of mortality. Few studies with large samples of KHE have been reported. KHE may develop into the Kasabach-Merritt phenomenon (KMP), which is characterized by thrombocytopenia and consumptive coagulopathy. The features of severe symptomatic anemia and life-threatening low platelets make the management of KHE associated with KMP challenging. Objective: The aim of this study was to examine the clinical characteristics of patients with KHE and discuss the treatment experience for different risk groups of KHE. Methods: Through a retrospective review of 70 patients diagnosed with KHE between 2017 and 2022 in our center, we classify lesions into three clinicopathological stages based on the tumor involving depth, and divided the severity of KHE into three levels by estimating clinicopathological stages and severity of thrombocytopenia. Treatments of different severity groups were estimated with sufficient data. Results: In our cohort, 27% were neonates, and KHE lesion occurred at birth in 84% of patients. There was a slight male predominance (32 girls and 38 boys). Common clinical characteristics included associated coagulation disorder (100%), locally aggressive cutaneous blue-purple mass (89%), thrombocytopenia (78%), and local pain or joint dysfunction (20%). The lower extremities were the dominant location (35%), followed by the trunk (29%), the maxillofacial region and neck (24%), and the upper extremities (10%). Of the total cohort, 78% developed KMP; the median age at which thrombocytopenia occurred was 27.8 days. The median platelet count of patients who were associated with KMP was 24,000/µL in our cohort. Ninety-two percent of patients were given surgery treatment and 89% of these patients were given high-dose methylprednisolone (5-6 mg/kg daily) before surgery. In 55 patients with KMP, 36% were sensitive to high-dose corticosteroid therapy. Patients from the low-risk group (eight cases) underwent operation, all of whom recovered without recurrence after a maximum follow-up of 5 years. Out of 26 patients from the high-risk group, 25 underwent surgery treatment, with 1 case undergoing secondary surgery after recurrence and 1 case taking sirolimus. Out of 36 cases from the extremely high-risk group, 32 underwent surgery (including 2 cases who underwent external carotid artery ligation and catheterization), 3 of whom underwent secondary operation after recurrence, and the remaining 4 cases took medicine. The mean length of having sirolimus was 21 months; two cases stopped taking sirolimus due to severe pneumonia. Two cases died at 1 and 3 months after discharge. Conclusions: Our study describes the largest assessment of high-risk patients with KHE who have undergone an operation to date, with 5 years of follow-up to track recovery, which provides invaluable knowledge for the future treatment of patients with KHE and KMP from different risk groups: Early surgical intervention may be the most definitive treatment option for most patients with KHE; multimodality treatment is the best choice for the extremely high-risk group.

Hemoporfin-mediated photodynamic therapy for the treatment of port-wine stain: A multicenter, retrospective study.

BACKGROUND: Hemoporfin-mediated photodynamic therapy (Hemoporfin-PDT) has been approved for port-wine stain (PWS) in China in 2017. This study evaluated the efficacy and safety of Hemoporfin-PDT for PWS in a real life setting and investigated factors that influence the efficacy. METHODS: A multicenter retrospective study included patients with PWS who underwent Hemoporfin-PDT in 29 hospitals across China and completed at least two months of follow-up. The efficacy was evaluated based on patien photographs. RESULTS: A total of 1679 patients were included. After the first and second sessions of Hemoporfin-PDT, 63.5 and 75.3% of patients responded, respectively. The response rate of purple-type PWS was significantly lower than that of pink-type PWS (OR: 0.71, 95% CI: 0.54-0.94, P < 0.05), and there was no significant difference between thick- and pink-type (OR: 0.72, 95% CI: 0.42-1.22, P > 0.05). The response rate of PWS on the limbs was significantly lower than that on the mid-face (OR: 0.35, 95% CI: 0.23-0.53, P < 0.0001), while no significant difference was observed between PWS on the peripheral part of the face, neck or other parts of the body and PWS on the mid-face (P > 0.05). The response rate was lower in male patients with an age > 3 years or ≤ 6 years (P < 0.05). Previous treatment history did not affect the efficacy (P > 0.05). Hemoporfin-PDT was well tolerated. CONCLUSION: Patients with PWS have a good response and good tolerance to Hemoporfin-PDT.

[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.

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.

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.

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.

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.

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.

[Management of Kasabach-Merritt syndrome by drug therapy and surgery].

OBJECTIVE: To summarize the characters of Kasabach-Merritt syndrome (KMS) and to evaluate the therapeutic effect of drug therapy combined with surgery. METHODS: From 2004 to 2010, 59 cases with KMS, who underwent drug therapy and surgery, were retrospectively studied. The average age of the patients, including 33 male and 26 female (male/female, 1.269/1), was 2.9 months (range, 7 days-2.5 years). 28 cases with maxillofacial lesions were treated with the ligation of external carotid artery and injection of carbonyldiamide and methylprednisolone. 31 cases with lesions at trunks and extremities were treated by excision of lesions. All the patients were followed up for 2.8 years (range, 6.5 months -7.3 years). Therapeutic outcomes were assessed by evaluating platelet counts,size of lesion, function of trunk and limb. RESULTS: 58 cases were cured except for one dead case. Emergency operation was given in 4 cases, and selective operation was performed in other cases (55 cases). The thrombocyte count, hemoglobin and blood coagulation function returned to normal within 1-2 weeks. The mental condition, appetite, body weight,sleeping were greatly improved one week after treatment. The size of the lesions decreased gradually after the management of ligation of external carotid artery including 18 cases within 6-12 months and 10 cases within 13-24 months. Long term follow-up studies indicated that there was no recurrent case, and the weight, height, immunity of the patients with good function activities were in keeping with the normal counterparts. CONCLUSIONS: The drug combined with surgery therapy is a very reliable management with high curative rate, short disease period and minimum side-effect.