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.

Anti-angiogenic role of microRNA-23b in melanoma by disturbing NF-κB signaling pathway via targeted inhibition of NAMPT.

Aim: Melanoma is the major cause of death in patients inflicting skin cancer. We identify miR-23b plays an anti-angiogenic role in melanoma. Materials & methods: We collected tumor tissues from melanoma patients. Experiments in vivo and in vitro were designed to evaluate the role of miR-23b in melanoma. Results & conclusion: miR-23b was found to be downregulated in melanoma tissues, and associated with poor patient survival. Elevating miR-23b inhibited cell viability and colony formation, reduced pro-angiogenetic ability, and accelerated apoptosis in SK-MEL-28 cells. miR-23b targeted NAMPT. Disturbing NF-κB signaling pathway with ammonium pyrrolidinedithiocarbamate (an inhibitor of NF-kB signaling pathway) impeded acquired pro-angiogenetic ability of nicotinamide phosphoribosyl transferase-overexpressed SK-MEL-28 cells. MiR-23b is a prognostic factor in melanoma. This study provides an enhanced understanding of microRNA-based targets for melanoma treatment.

Propranolol suppresses HUVEC viability, migration, VEGF expression, and promotes apoptosis by downregulation of miR-4295.

Infantile hemangioma (IH) is a common benign tumor. Human umbilical vein endothelial cells (HUVECs) have the potential of stem cells, which has been widely used in vascular endothelial cell experiments. Oral propranolol was first reported to treat hemangioma in 2008. However, the role of propranolol in IH remains unclear. Therefore, in this study, we investigated the effects of propranolol on HUVECs in vitro, to explore the underlying mechanism of propranolol in IH. HUVECs were treated with 0.15, 1.5, and 15 µM of propranolol, and transfected with microRNA-4295 (miR-4295) mimic. Cell viability, migration, and apoptosis were examined using Cell Counting Kit-8, transwell assay, and flow cytometry analysis, respectively. In addition, the expressions and concentrations of miR-4295, vascular endothelial growth factor (VEGF), VEGF-A, FLT1, FLT2, and FOXF1 were assessed using real-time polymerase chain reaction, Western blot assay, and enzyme-linked immunosorbent assay. We found that 15 µM of propranolol decreased HUVEC viability the most. Then, cell migration and the concentrations of VEGF and VEGF-A were reduced, and apoptosis was increased when treated with propranolol. Meanwhile, the expressions of VEGF, VEGF-A, FLT1, FLT2, and FOXF1 were downregulated by propranolol exposure. Further study showed that miR-4295 expression was upregulated in IH tissues, and propranolol treatment downregulated miR-4295 expression in HUVECs. MiR-4295 overexpression alleviated the reductions of viability, migration, and factors expression, as well as the increase of apoptosis. Propranolol suppressed HUVEC viability, migration, the expression of VEGF, VEGF-A, FLT1/2, FOXF1, and promoted apoptosis via downregulation of miR-4295. This study lays a foundation for further study of the effect of propranolol on IH.

A Network Meta-Analysis of Non-Melanoma Skin Cancer (NMSC) Treatments: Efficacy and Safety Assessment.

The mainstream treatments for non-melanoma skin cancer (NMSC) include photodynamic therapy (PDT), surgery excision (SE), cryotherapy (CT), imiquimod (IM), radiotherapy (RT), 5-fluorouracil (FU), and vehicle (VE). Our network meta-analysis (NMA) was aimed at evaluating the efficacy and safety of these seven treatments and providing superior ones. After searching the trials from Embase and PubMed and screening with our criteria, we conducted the NMA with software R 3.2.3 and STATA 13.0. Complete lesion response (CLR), complete lesion clearance (CLC), cumulative recurrence probabilities (CRP), and adverse effects (AEs) were considered as outcomes and displayed as odds ratios (ORs) and 95% credible intervals (CrI). The surface under the cumulative ranking curve (SUCRA) was calculated to rank each treatment on each index. The consistency of direct and indirect evidence was also assessed by node-splitting and heat plot methods. Data from 18 trials with 3706 patients were included. Both IM and SE were demonstrated significantly higher CLR rate than VE (OR = 9.12, 95% CrI = 1.92-47.5; OR = 26.1, 95% CrI = 1.92-347; respectively), while only IM was proved to be statistically better than VE in CLC rate (OR = 7.03, 95% CrI = 1.51-32.8). No significant difference was observed concerning CRP, and IM was more likely to induce AEs than VE (OR = 4.44, 95% CrI = 1.58-13.9). The SUCRA results indicated that SE was the treatment with best ranking in the entire three efficacy indexes and a relatively high safety. Taking efficacy and safety into account, our study recommended SE as the optimal regimen for NMSC with high efficacy considering CLR, CLC, and CRP and moderate AEs when compared with other interventions. J. Cell. Biochem. 118: 3686-3695, 2017. © 2017 Wiley Periodicals, Inc.

Hedgehog/Gli1 signal pathway facilitates proliferation, invasion, and migration of cutaneous SCC through regulating VEGF.

Since hedgehog (HH)/Gli1 that contributes to cancer proliferation and metastasis has been masked for decades, the signaling pathway was investigated about its exact role in proliferation and metastasis of cutaneous squamous cell carcinoma (SCC). Sonic hedgehog homolog (Shh), GLI family zinc finger 1 (Gli1), and vascular endothelial growth factor (VEGF) expressions in cutaneous SCC tissues were analyzed with immunohistochemistry, and their correlations with cutaneous SCC patients' prognosis were conducted with Kaplan-Meier curve. Regarding in vitro studies, effects of the HH signaling pathway, and cyclopamine on patched 1 (Ptch1), smoothened/frizzled class receptor (Smo) and VEGF expressions were assessed in A431 cells based on western blot and quantitative real-time polymerase chain reaction (qRT-PCR). Besides, Cell Counting Kit-8 (CCK-8) assay was implemented to evaluate cell proliferation, while wound-healing assay and transwell assay were performed to assess cell migration and invasion, respectively. Mice models were also established to observe effects of Gli1 on tumor diversity and incidence during a period of 20 weeks. Positively expressed VEGF, Gli1, and Shh proteins in cutaneous SCC tissues were correlated with poor survival of patients (P < 0.05). Besides, Gli1 messenger RNA (mRNA) and VEGF mRNA were observed to be significantly over-expressed in A431 cells (P < 0.05), and they were associated with incremental cell proliferation, invasiveness, and migration, which can be reversed by the interference of VEGF siRNA. Furthermore, cyclopamine treatment could induce inhibition of cell proliferation, invasiveness, and migration and suppression of Smo, Gli1, and VEGF expressions. The mice models also confirmed that Gli1 could significantly induce rise of tumor incidence and tumor diversity, while cyclopamine statistically relieved this transformation (P < 0.05). Abnormal activation of the HH signaling pathway plays critical roles in development of cutaneous SCC either in vivo or in vitro.

Long noncoding RNA expression profile of infantile hemangioma identified by microarray analysis.

Infantile hemangioma (IH) is one of the most common vascular tumors of childhood. Long noncoding RNAs (lncRNAs) play a critical role in angiogenesis, but their involvement in hemangioma remains unknown. This study aimed to assess the expression profiles of lncRNAs in IH and adjacent normal tissue samples, exploring the biological functions of lncRNAs as well as their involvement in IH pathogenesis. The lncRNA expression profiles were determined by lncRNA microarrays. A total of 1259 and 857 lncRNAs were upregulated and downregulated in IH, respectively, at a fold change cutoff of 2.0 (p < 0.05); in addition, 1469 and 1184 messenger RNAs (mRNAs) were upregulated and downregulated, respectively (fold change cutoff of 2.0; p < 0.05). A total of 292 differentially expressed mRNAs were targeted by the lncRNAs with altered expression in hemangioma, including 228 and 64 upregulated and downregulated, respectively (cutoff of 2.0, p < 0.05). Gene ontology (GO) analyses revealed several angiogenesis-related pathways. An lncRNA-mRNA co-expression network for differentially expressed lncRNAs revealed significant associations of the lncRNAs MEG3, MEG8, FENDRR, and Linc00152 with their related mRNAs. The validation results of nine differentially expressed lncRNAs (MALAT1, MEG3, MEG8, p29066, p33867, FENDRR, Linc00152, p44557_v4, p8683) as well as two mRNAs (FOXF1, EGFL7) indicated that the microarray data correlated well with the QPCR results. Interestingly, MALAT1 knockdown induced apoptosis and S-phase cell cycle arrest in human umbilical vein endothelial cells (HUVECs). Overall, this study revealed the lncRNA expression profile of IH and that lncRNAs likely regulate several genes with important roles in angiogenesis.

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.

Does autologous fat grafting serve the need for reconstructive surgery in oral cancer patients? A prospective evaluation in cosmetic surgery patients.

BACKGROUND: The prevalence of cancer is growing daily. Oral cancer, which is primarily triggered by tobacco use, can have detrimental effects on facial appearance. Despite significant advances in the molecular underpinnings of cancer, surgery, chemotherapy and radiotherapy have become standard cancer treatment methods. These treatments remove the tumor but can significantly alter patient's appearance, which can impact their physical and mental wellbeing. The soft tissue augmentation technique of autologous fat grafting (AFG), commonly referred to as lipofilling, is frequently used in cosmetic and reconstructive surgery to promote facial rejuvenation and body form remodeling. The advantages of AFG include its biocompatibility, low immunogenicity and allergenicity, as well as its capability to heal wounds. OBJECTIVES: To explore the advantages of and patient satisfaction with the AFG technique as a potential facial restoration procedure in oral cancer patients. MATERIAL AND METHODS: We examined the effects of facial AFG in cosmetic surgery patients and investigated the prevalence of postoperative problems. Patient satisfaction and potential complications after autologous fat filling in different areas of the facial space were investigated using clinical evaluations, patient-reported outcomes and photographic assessments. RESULTS: All of the patients were satisfied with the results in terms of improved facial shape, skin glossiness, skin elasticity, ptosis, and facial expressions. More than 80% of the patients and surgeons reported overall satisfaction. CONCLUSIONS: Based on these findings, we hypothesize that the AFG approach may be beneficial as a reconstructive therapy for patients with oral cancer following treatment. This technique will improve the patient's physical appearance, confidence and mental wellbeing.

Topical propranolol for treatment of superficial infantile hemangiomas.

BACKGROUND: "Wait-and-see" is a common principle for most superficial infantile hemangiomas (IHs) because of their expected involution. Topical propranolol has recently been reported to be an effective treatment for superficial IHs. OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of 1% propranolol ointment in the treatment of superficial IHs. METHODS: A retrospective chart review was performed on 25 children (21 female and 4 male) with a median age of 4 months (range, 1-10 months). A total of 28 lesions were treated with 1% propranolol ointment. Topical propranolol was applied thrice daily for a mean duration of 21 weeks (range, 5-59 weeks). Changes in the size, texture, and color of the tumor were monitored and recorded at regular intervals. The treatment response was evaluated using a 3-point scale system: good, partial, and no response. Adverse effects after medication were evaluated and managed accordingly. RESULTS: Of the 28 hemangiomas, 16 (57%) demonstrated good response, 9 (33%) showed a partial response, and 3 (10%) had no response. Among all the IHs, 90% showed either good or partial responses to topical 1% propranolol ointment treatment. No systemic complication was observed in any of the patients. LIMITATIONS: This report is a retrospective uncontrolled study. CONCLUSIONS: Topical therapy with 1% propranolol ointment may be a safe and effective method for the treatment of superficial IHs and can be used as an adjuvant treatment measure during the wait-and-see period.

Identification of ACTA2 as a Key Contributor to Venous Malformation.

Objectives: Proteomics and high connotation functional gene screening (HCS) were used to screen key functional genes that play important roles in the pathogenesis of venous malformation. Furthermore, this study was conducted to analyze and explore their possible functions, establish a gene mutation zebrafish model, and perform a preliminary study to explore their possible pathogenic mechanisms in venous malformation. Methods: Pathological and normal tissues from patients with disseminated venous malformation were selected for Tandem Mass Tag (TMT) proteomics analysis to identify proteins that were differentially expressed. Based on bioinformatics analysis, 20 proteins with significant differential expression were selected for HCS to find key driver genes and characterize the expression of these genes in patients with venous malformations. In vitro experiments were then performed using human microvascular endothelial cells (HMEC-1). A gene mutant zebrafish model was also constructed for in vivo experiments to explore gene functions and pathogenic mechanisms. Results: The TMT results showed a total of 71 proteins that were differentially expressed as required, with five of them upregulated and 66 downregulated. Based on bioinformatics and proteomics results, five highly expressed genes and 15 poorly expressed genes were selected for functional screening by RNAi technology. HCS screening identified ACTA2 as the driver gene. Quantitative polymerase chain reaction (qPCR) and western blot were used to detect the expression of ACTA2 in the pathological tissues of patients with venous malformations and in control tissues, and the experimental results showed a significantly lower expression of ACTA2 in venous malformation tissues (P < 0.05). Cell assays on the human microvascular endothelial cells (HMEC-1) model showed that cell proliferation, migration, invasion, and angiogenic ability were all significantly increased in the ACTA2 over-expression group (P < 0.05), and that overexpression of ACTA2 could improve the inhibitory effect on vascular endothelial cell proliferation. We constructed an ACTA2-knockdown zebrafish model and found that the knockdown of ACTA2 resulted in defective vascular development, disruption of vascular integrity, and malformation of micro vein development in zebrafish. Further qPCR assays revealed that the knockdown of ACTA2 inhibited the Dll4/notch1 signaling pathway, Ephrin-B2 signaling pathway, and vascular integrity-related molecules and activated the Hedgehog signaling pathway. Conclusion: This study revealed that ACTA2 deficiency is an important factor in the pathogenesis of venous malformation, resulting in the disruption of vascular integrity and malformed vascular development. ACTA2 can be used as a potential biomarker for the treatment and prognosis of venous malformations.

Oral propranolol therapy in parotid hemangiomas: A retrospective comparison with other infantile hemangiomas.

BACKGROUND: The outcomes of propranolol treatment remain controversial for parotid hemangiomas, which may be inferior to outcomes for infantile hemangiomas (IHs) at other sites. METHODS: Patients with IHs treated with oral propranolol were retrospectively reviewed. Outcomes of propranolol therapy for parotid hemangiomas and other IHs were examined. Regression models were conducted to analyze the factors associated with the outcomes for parotid hemangiomas. RESULTS: Longer treatment duration was needed for parotid hemangiomas (p = 0.012) at a comparable efficacy and relapse rate as those of IHs at other sites. The higher efficacy was associated with early intervention before 4 months of age (OR = 5.2, p = 0.011), while, the lower relapse rate was associated with adequate treatment duration over 6 months (OR = 9.2, p = 0.010). CONCLUSIONS: With a longer propranolol treatment duration, parotid hemangiomas could achieve a comparable efficacy and relapse rate as other IHs. Early treatment initiation and adequate treatment duration benefited the outcomes.

Safety of intralesional injection of lauromacrogol combined with triamcinolone for infantile hemangiomas.

The efficacy of lauromacrogol injection therapy and intralesional triamcinolone for infantile hemangiomas (IH) has been well documented recently, but with an increase in serious or rare adverse reactions. The aim of this study is to investigate the safety concerns regarding intralesional injection of lauromacrogol combined with triamcinolone for IH and to study its effect on infant growth and development. A total of 1039 IH patients who were subjected to intralesional injection of lauromacrogol combined with triamcinolone in the Plastic Surgery Department of Shandong Provincial Hospital between 1 January 2015 and 31 May 2018 were enrolled in this study. When the dose of lauromacrogol and triamcinolone was less than 3.5 and 2.0 mg/kg respectively, no serious side-effects were observed. The adverse event rate reported was 7.7%. Among the 405 patients not subjected to propranolol before the last injection, the study included three modes of treatment response: regression (82.7%), stabilization (13.8%) and failure (3.5%). By comparing height and weight to the reference standards and also by comparisons between the same-sex groups, our results confirmed that there was no significant effect on children's height and weight, regardless of whether the injection therapy was combined with oral propranolol at the appropriate dose and with more than 4-week intervals. Intralesional injection of lauromacrogol combined with triamcinolone in the treatment of IH was highly safe and effective.

Circular RNA profile of infantile hemangioma by microarray analysis.

BACKGROUND: Circular RNAs (circRNAs) are a recently identified class of noncoding RNAs that participate in several physiological processes. However, the expression of circRNAs in infantile hemangioma (IH) remains unknown. METHODS: The profile of circRNAs was assessed by microarray in four pairs of IH and adjacent skin tissues. The expression of circRNAs was validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Furthermore, circRNA-microRNAs (miRNA)-mRNA networks were constructed using bioinformatics tools. RESULTS: 234 up- and 374 down- regulated circRNAs were identified in IH by microarray. Among them, the expression of two up-regulated circRNAs (hsa_circRNA_100933 and hsa_circRNA_100709) and one down-regulated circRNA (hsa_circRNA_104310) was confirmed by qRT-PCR. In addition, 3,019 miRNA response elements (MREs) of circRNAs were predicted, and two circRNA-miRNA-mRNA networks were constructed, including 100 and 94 target genes of hsa_circRNA_100933 and hsa_circRNA_104310, respectively. GO and pathway analysis showed that both networks participated in angiogenesis and vascular development-related biological processes. CONCLUSIONS: This is the first study to reveal the profiling of circRNAs in IH and pave the way for further characterization of the role of circRNAs in the pathogenesis of IH.

[Expression of mast cell tryptase in scar].

OBJECTIVE: To investigate the expression and distribution of mast cell tryptase (MCT) in scar, and to discuss the different MCT gene expression in keloid, hypertrophic scar and normal skin. METHODS: 20 samples of keloid, 20 samples of hypertrophic scar and 20 samples of normal skin were collected. The distribution of MCT was investigated by immunofluorescence histochemistry, and the MCT mRNA expression was detected by Relative Quantification real-time fluorescent PCR. RESULTS: MCT gene was mainly located in the collagen fiber bundles of the scar, especially in the superficial layer of scar. MCT mRNA expression was significantly higher in keloid than that in hypertrophic scar and normal skin (P < 0.01). Averagely, the MCT gene expression in keloid was 2.5 times and 5.4 times of that in hypertrophic scar and normal skin. CONCLUSIONS: MCT gene may play a role in the pathogenesis of scar.