Single-cell sequencing of facial adipose tissue unveils FKBP5 as a therapeutic target for facial infiltrating lipomatosis.

BACKGROUND: Facial infiltrating lipomatosis is characterized by excessive growth of adipose tissue. Its etiology is associated with somatic phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) variants, but the specific mechanisms are not yet fully understood. METHODS: We collected facial adipose tissue from both FIL patients and non-FIL individuals, isolated the stromal vascular fraction (SVF) and performed single-cell transcriptome sequencing on these samples. RESULTS: We mapped out the cellular landscape within the SVF, with a specific focus on a deeper analysis of fibro-adipogenic precursor cells (FAPs). Our analysis revealed that FAPs from FIL patients (FIL-FAPs) significantly overexpressed FK506 binding protein 51 (FKBP5) compared to FAPs from individuals without FIL. Further experiments indicated that FKBP5 is regulated by the PI3K-AKT signaling pathway. The overactivation of this pathway led to an increase in FKBP5 expression. In vitro experiments demonstrated that FKBP5 promoted adipogenic differentiation of FAPs, a process that could be hindered by FKBP5 knockdown or inhibition. Additionally, in vivo assessments confirmed FKBP5's role in adipogenesis. CONCLUSIONS: These insights into the pathogenesis of FIL underscore FKBP5 as a promising target for developing non-surgical interventions to manage the excessive adipose tissue growth in FIL.

Practical surgical technique using the SMISS approach for lip reduction in involuted lip infantile hemangiomas.

BACKGROUND: Lip infantile hemangiomas tend to show less volumetric regression and are more susceptible to visible sequelae in the involuted stage. Some of them still require surgical management after propranolol therapy. This study aimed to evaluate the efficacy and safety of the Stepwise, Multi-Incisional, and Single-Stage (SMISS) approach applied to lip reduction for those with involuted lip hemangiomas. METHODS: A retrospective review was performed to evaluate patients with lip hemangioma who received previous propranolol treatment and underwent the aforementioned procedure. Demographic characteristics, lesion morphology, and medical history were reviewed. The Visual Analog Scale was applied to assess the postoperative appearance. Complications within 12 months postoperatively were recorded. RESULTS: A total of 18 patients with lip hemangioma were eligible. All patients received oral propranolol therapy before surgery, with treatment duration ranging from 6.0 to 23.0 months. Their age at surgery ranged from 2.5 to 9.0 years. The median Visual Analog Scale scores were 8.0, ranging from 4.0 to 10.0. No severe complications were reported. CONCLUSIONS: This modified technique based on the SMISS approach has proven reliable and effective in improving the aesthetic outcome for involuted lip infantile hemangiomas. Practical surgical techniques still play an important part in the propranolol era.

Intralesional betamethasone versus oral propranolol for localized infantile hemangiomas of the lip.

Infantile hemangiomas (IHs) of the lips are associated with an increased risk of incomplete involution and ulceration, causing disfigurement. Treatment with oral propranolol (OPT) has credible efficacy but takes months to complete. Thus, this study aimed to investigate the efficacy of intralesional betamethasone injection (IBI) as an alternative treatment for protruding localized IHs of the lips. To investigate the efficacies of OPT and IBI, we designed a prospective, noninferiority, parallel-group study. The primary outcome assessed was treatment response rate. Secondary outcome assessments included lesion size changes and surgical rate. Additionally, complication rates and treatment durations of OPT and IBI were compared. The treatment response rate of IBI was not inferior to that of OPT (95.7% vs. 76.0%, respectively; a difference of 19.7%, 95% confidence interval [CI], -4.4% to 41.6%). The average surgical rate in the IBI group was significantly lower than that in the OPT group (8.7% vs. 40%, respectively; p = 0.012), and the average duration of treatment for IBI was shorter than that of OPT (2.1 months vs. 6.3 months, respectively; p < 0.001). There were no severe adverse drug events in either group. If not managed properly, small, localized lip IHs may cause disfigurement in a child. Our study demonstrated that IBI is as effective as OPT in treating protruding localized lip IHs. Moreover, IBI treatment has a shorter duration and lower surgical rate than OPT. With proper care, IBI is an effective treatment modality for small and localized lip IHs.

Usefulness of Ultrasound in Verrucous Venous Malformation: a Series of 103 Cases.

BACKGROUND: Verrucous venous malformation (VVM), previously called "verrucous hemangioma," is a rare type of vascular malformation. OBJECTIVE: Little is known about the ultrasonographic characteristics of VVM. The present study aimed to show the conventional US and elastographic features of a VVM. MATERIALS AND METHODS: The US findings in 103 patients with VVMs were retrospectively evaluated. RESULTS: On gray-scale ultrasound images, 98 (95.1%) lesions showed subcutaneous fat infiltration from skin across muscle to deep fascia. The other 5 (4.9%) sat in the subcutaneous layer with no skin involvement. Most (96.1%) lesions were hyperechoic. Furthermore, 71.8% of lesions were heterogeneous, 68.9% of which were with ill-defined margins. Calcifications and visible vessels were present in 5.7% and 10.7% of the VVM cases, respectively. By color Doppler ultrasound, all lesions were found with low vascular density and 4.9% showed enhanced blood flow after compression. Venous spectrum was observed in 67.0% of lesions. The elasticity score was 2.66 ± 0.48. CONCLUSION: Diagnosis of a VVM is challenging in the clinic. However, we found that most VVM lesions present distinctive ultrasound imaging characteristics. These ultrasound findings may well contribute to the accuracy of VVM diagnosis, especially in those with the absence of epidermal changes and the lack of dermal involvement.

CD146+ mural cells from infantile hemangioma display proangiogenic ability and adipogenesis potential in vitro and in xenograft models.

Objective: Infantile hemangioma (IH), the most common infantile vascular neoplasm, is uniquely characterized by rapid proliferation followed by slow spontaneous involution lasting for years. In IH lesions, perivascular cells are the most dynamic cell subset during the transition from the proliferation phase to the involution phase, and we aimed to systematically study this kind of cell. Methods and results: CD146-selective microbeads were used to isolate IH-derived mural-like cells (HemMCs). Mesenchymal markers of HemMCs were detected by flow cytometry, and the multilineage differentiation potential of HemMCs was detected by specific staining after conditioned culture. CD146-selected nonendothelial cells from IH samples showed characteristics of mesenchymal stem cells with distinct angiogenesis-promoting effects detected by transcriptome sequencing. HemMCs spontaneously differentiated into adipocytes 2 weeks after implantation into immunodeficient mice, and almost all HemMCs had differentiated into adipocytes within 4 weeks. HemMCs could not be induced to differentiate into endothelial cells in vitro. However, 2 weeks after implantation in vivo, HemMCs in combination with human umbilical vein endothelial cells (HUVECs) formed GLUT1+ IH-like blood vessels, which spontaneously involuted into adipose tissue 4 weeks after implantation. Conclusions: In conclusion, we identified a specific cell subset that not only showed behavior consistent with the evolution of IH but also recapitulated the unique course of IH. Thus, we speculate that proangiogenic HemMCs may be a potential target for the construction of hemangioma animal models and the study of IH pathogenesis.

Distribution of problematic localized facial infantile haemangiomas and their response to propranolol: a retrospective cohort study.

BACKGROUND: The distribution and response to propranolol of problematic facial infantile haemangiomas (IHs) has rarely been described in the literature. AIM: To map problematic facial IHs and observe their response to propranolol. METHODS: Eligible patients were categorized according to focal location and cohorts corresponding to these (buccal, medial, zygomatic, lateral and multiregional) were created. The primary efficacy variable was regression score ranging from 1 to 4, calculated using results of colour Doppler ultrasonography. RESULTS: In total, 104 patients met the inclusion criteria. There were 32 (30·8%) IHs located in the buccal area, 12 (11·5%) in the medial area, 49 (47·1%) in the lateral area and 1 (1·0%) in the zygomatic area, with 10 (9·6%) IH cases having multiregional lesions. We found that the distribution pattern of most IHs matched the surface projection of the trunk of the external carotid and the facial arteries. Further analysis showed that the median regression score in the buccal and medial groups were significantly lower than those in the lateral and multiregional groups. CONCLUSION: Treatment of buccal and medial haemangiomas tends to be more challenging and their distribution pattern mainly reflects the direction of the facial vessels.

Apelin Receptor Can Act as a Specific Marker and Promising Therapeutic Target for Infantile Hemangioma.

Infantile hemangioma (IH), the most common benign tumor in infancy, is generally sensitive to propranolol treatment. However, the challenge remains because resistance or recurrence could occur in some patients, and the mechanism or target of propranolol remains unknown. Therefore, advancement in the drug development is needed. In this study, we explored whether apelin receptor (APJ) can become a candidate target. We found that APJ is expressed only in endothelial cells of IH (HemECs) but not in other vascular anomalies, and its antagonist, ML221, can negatively regulate cellular viability and functions of HemECs. This inhibitory effect could be replicated in a murine hemangioma model. Importantly, in vitro experiments also indicated that ML221 failed to affect the proliferation or angiogenesis of normal endothelial cells or APJ-knockout HemECs. Through analysis of the phosphoantibody microarray data, ML221 was revealed to have an inhibitory effect on HemECs by suppressing the activation of mitogen-activated protein kinase/extracellular signal-regulated kinase pathway. These results verified the distinctive expression of APJ in IH and specific inhibition of HemEC activity caused by ML221. In addition, APJ was also detected in propranolol-resistant IH. Collectively, we propose that APJ can act as a specific marker and a promising therapeutic target for IH, which will facilitate further drug development.

Evaluation of Transdermal Transport and Concurrent Cutaneous Hydrolysis of Timolol Prodrug for the Treatment of Infantile Hemangiomas.

Infantile hemangiomas (IH) leave sequelae after involution. Topical application of timolol maleate (TM) is the mainstream treatment for superficial lesions but is limited by its low penetrable properties. We aimed to develop a superior skin permeation drug while maintaining the therapeutic properties of timolol. We predict that this drug will promote the involution of thick and deep IH lesions and avoid sequelae. We chemically modified drug structure to prepare butyryl timolol maleate (BT) prodrug and conducted in vitro and in vivo toxicity evaluations of BT with rat dorsal skin and normal skin cells. Skin permeation and absorption comparisons of TM and BT were conducted using rat and porcine skin models. Conversion efficiency of BT to timolol was also tested on human skin ex vivo. BT did not cause skin irritation on rat dorsal skin and exhibited low cytotoxicity overall. BT exhibited superior skin permeation ability compared with that of TM, whilst maintaining a low systemic absorbance. Further, BT was converted to timolol in human skin in a time-dependent manner. Noticeably, timolol accumulation in the skin from BT was higher than that from TM. Finally, BT demonstrated similar biocompatibility with TM in the IH tumor. BT enhances local delivery of timolol and its skin permeation. Using BT, we could eliminate thicker IH lesions that are prone to leave sequelae, and potentially help young children avoid dermal sequelae, disfigurement, and concomitant therapy.

Does Oral Propranolol Improve the Final Outcome of All Involuted Infantile Hemangiomas? A Matched Retrospective Comparative Study.

BACKGROUND: Oral propranolol can effectively activate and accelerate infantile hemangioma (IH) involution; however, could the final outcome of oral propranolol treatment for IHs commensurate that of spontaneous involution? OBJECTIVE: This study aimed to investigate the long-term therapeutic effect of oral propranolol for IHs. METHODS: We present an individual matching comparative study with (1) oral propranolol therapy for mixed and deep IHs on the lips, nose, and parotid and (2) lesion type- and lesion location-matched untreated IHs as controls. Patients' follow-up photographs were assessed by 3 surgeons blinded of their treatment. Outcome measures were the quantification of the degree of sequelae ranging from 1 to 4 and the age at which IH achieved involution arrest. RESULTS: Ten groups of oral propranolol and untreated patients with matched lesions were assessed. Average age at which lesions stabilized and reached no change in appearance was 1.7 years old and 6.3 years old for propranolol group and untreated group ( t = 5.663, P < 0.001). There was no significant difference in the quantified degree of sequelae for oral propranolol group and untreated group upon follow-up (1.60 vs 1.40, respectively; t = 1.259, P = 0.240). CONCLUSIONS: Oral propranolol therapy accelerates IH involution but does not have a superior effect than spontaneous involution on the overall outcome of problematic IHs.

The effect of 0.5% topical timolol cream on regression of superficial infantile haemangioma in the involuting phase: a prospective, randomized, self-controlled study.

BACKGROUND: Infantile haemangiomas are the most common benign tumours affecting infants. Over time, the tumours may involute to some extent. However, sequelae, such as telangiectasia or fibrofatty tissue, often occur following this condition, which may cause disfigurement and influence patients' psychosocial development. OBJECTIVE: This prospective, randomized, self-controlled study aimed to assess the effects of topical timolol (0.5%) on involuting infantile haemangiomas. MATERIALS & METHODS: Each involuting superficial infantile haemangioma (n = 29) was randomly divided into two regions; one region was treated with topical timolol (0.5%) cream, three times daily, and the other region was untreated. The comparative treatments continued for three months. Five independent assessors, blinded to the treatment regimen, judged the treated and untreated regions by comparing photographs before and after treatment. RESULTS: The topical timolol-treated tumour sections showed no difference compared with the untreated sites (p = 0.355) after three months of treatment, and by the end of the treatment, the untreated lesions showed significant differences relative to pre-treatment (p<0.001). CONCLUSION: Topical timolol was not observed to have any effect on the regression of infantile haemangiomas in the involuting phase.

A 7-year follow-up study on untreated deep or mixed facial infantile hemangioma in East-Asian patients: When propranolol was not yet an option.

Infantile hemangioma (IH) is a type of benign tumor that develops during infancy and spontaneously involutes after 1 year of age. Before the introduction of propranolol in 2008, some patients with IH were instructed to wait for the involution without treatment. This long-term follow-up study was conducted to assess the prognosis of East-Asian children with untreated deep or mixed facial IH. Skin sequelae were assessed by comparing images obtained during the patients' first and last visits in our clinic. Possible factors were assessed for their association with IH prognosis. The mean follow-up time was 7.4 years. Among the 48 patients with deep or mixed facial IH, 26 (54%) achieved complete involution without sequelae and 22 encountered various sequelae, including telangiectasia (36.3%), fibrofatty residue (68.2%), and scars (4%). The complete regression rate of deep or mixed IH occurring in the central facial region was significantly lower than for those in the perifacial region (33.3% vs 66.7%, respectively, χ2 , P = 0.025). Further, the most common sequelae in this area are fibrofatty residue.

Treatment of Congenital Melanocytic Nevi in the Eyelid and Periorbital Region With Ablative Lasers.

BACKGROUND: Congenital melanocytic nevi (CMN) that occur on the eyelid and periorbital region cause cosmetic disfiguring. Laser treatment has aroused interest as an alternative treatment method, and resurfacing lasers have shown promising results. OBJECTIVE: This study aimed to evaluate the efficacy and safety of carbon dioxide laser and erbium:yttrium aluminum garnet laser to treat CMN of the eyelid and periorbital region. METHODS AND MATERIALS: Twenty patients with CMN were included in this study and were treated with either the CO2 or erbium:yttrium aluminum garnet laser. Clinical efficacy outcomes were evaluated by visual assessment and L*a*b* color space evaluation at least 6 months after treatment. RESULTS: The average (SD) visual evaluation improvement, assessed on a 5-point scale, was 2.8 (1.27). The mean (SD) values of the relative L* improvement rate and blanching rate of the CMN lesion were 32.0% (47.9%) and 34.1% (36.2%), respectively. Spearman rank correlation coefficient between the objective and subjective evaluations was significant (P < 0.001). Three cases developed partial hypopigmentation. No patient developed hypertrophic scars. CONCLUSION: The outcomes after laser treatment were variable, although half of the patients achieved greater than 50% clearance. It provides an alternative to surgical excision for the removal of CMN in the difficult regions. Surgery excision is inevitable for some patients.

Location of infantile hemangioma is a predictor of volumetric sequelae after involution.

Although infantile hemangiomas (IH) spontaneously involute, some leave more volumetric sequelae than others. Identifying predictors of such sequelae would provide a management reference for IH lesions and help achieve favorable outcomes. Our objective is to explore the correlation between volumetric residue remaining after IH involution and its location and to identify other potential outcome predictors. All IH patients examined at our hospital from 2008 to 2011 were reviewed, and both the degree of volumetric residue after involution and the quantified degree of sequelae were obtained by comparing follow-up photographs with photographs of lesions at their maximum size. We discovered that for children with a defined age at the initial visit, lesions of the perifacial area achieved significantly more volumetric regression than lesions of the central facial (P < 0.0001) and chest areas (P = 0.0002). Perifacial lesions had a significantly higher aesthetic score than those on the central facial area (P < 0.0001), chest (P < 0.0001) and trunk/extremities (P = 0.0226) when the age at initial visit and lesion type were consistent. Our study reveals that lesion location and age at initial visit are contributing factors to volumetric sequelae and the aesthetics of the lesion after involution. The results of this study provide a reference to guide treatment decisions with the aim of achieving a favorable outcome.

Safety and Efficacy of Cosmetic Augmentation of the Nasal Tip and Nasal Dorsum With Expanded Polytetrafluoroethylene: A Randomized Clinical Trial.

IMPORTANCE: Expanded polytetrafluoroethylene (ePTFE) is a widely used alloplast, but studies of augmentation of the nasal tip and nasal dorsum with ePTFE are lacking. OBJECTIVE: To investigate whether attaching the conchal cartilage as shield grafts at the distal end of the graft can prevent extrusion and whether the use of ePTFE in the nasal tip can achieve a stable aesthetic outcome. DESIGN, SETTING, AND PARTICIPANTS: A randomized clinical trial was performed from April 1, 2006, to October 31, 2008. Follow-up was completed in 2012 and 2017. The study was conducted at the Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. One hundred fifty patients seeking rhinoplasty were recruited, and 129 were eligible for inclusion in the study. All the recruited patients were intent-to-treat populations who were randomized into 2 groups: an ePTFE-only group and an ePTFE with conchal cartilage group. INTERVENTIONS: Expanded PTFE was used for augmentation of the nasal tip and nasal dorsum in both groups. Conchal cartilage was placed above the distal end in the ePTFE with conchal cartilage group. MAIN OUTCOMES AND MEASURES: Preoperative and postoperative standard photographs were obtained. Postoperative satisfaction and complications were evaluated. RESULTS: Of the 129 patients (mean age [range], 28 years [21-45 years]; 6 male and 123 female) eligible for inclusion in this study, 76 (mean age [range], 31 years [22-45 years]; 4 male and 72 female) were available for follow-up (mean [range], 106.9 months [100-131 months]) through 2017, including 39 in the ePTFE-only group and 37 in the ePTFE with conchal cartilage group. Infection occurred in 2 patients (5%) in the ePTFE-only group vs 1 patient (3%) in the ePTFE with conchal cartilage group (infection rate [OR, 1.946; 95% CI, 0.169-22.413; P > .99]). Soft-tissue reaction occurred in 0 patients in the ePTFE-only group vs 1 patient (3%) in the ePTFE with conchal cartilage group (soft-tissue reaction rate [OR, 0.000; 95% CI, 0.000-8.538; P = .49]). Irregularity occurred in 0 patients in the ePTFE-only group vs 3 patients (8%) in the ePTFE with conchal cartilage group (irregularity rate [OR, 0.000; 95% CI, 0.000-1.066; P = .11]). Extrusion occurred in neither of the 2 groups. CONCLUSIONS AND RELEVANCE: A new technique using ePTFE alone for augmentation of the nasal tip and nasal dorsum achieved safe, attractive, and acceptable outcomes in nasal contouring and patient satisfaction. The use of conchal cartilage as a shield in the nasal tip is not necessary. LEVEL OF EVIDENCE: 1. TRIAL REGISTRATION: Chinese Clinical Trial Registry identifier: ChiCTR-INR-17011101.

Effects of Botulinum Toxin on Improving Facial Surgical Scars: A Prospective, Split-Scar, Double-Blind, Randomized Controlled Trial.

BACKGROUND: Early intervention might improve the quality of surgical scars. Botulinum toxin type A has been shown to improve surgical scars in the past decade. The purpose of this study was to evaluate the effect of botulinum toxin type A on surgical facial scars. METHODS: In this prospective, split-scar, double-blind, randomized controlled trial, 16 consecutive patients who underwent facial surgery between June and October of 2015 were enrolled. Botulinum toxin type A was injected randomly into half of each surgical wound closure immediately after surgery. The scars were assessed independently by two plastic surgeons at a 6-month follow-up visit using the Vancouver Scar Scale and the visual analogue scale. The scar width was also measured. RESULTS: Fourteen patients completed the study. The visual analogue scale score and scar width measurements revealed a significant improvement in appearance and narrower scars for the botulinum toxin type A-treated halves of the scars (p = 0.046 and p = 0.001, respectively). The mean Vancouver Scar Scale score was 4.68 for the botulinum toxin type A-injected group and 5.24 for the control group (p = 0.15). In addition, the Vancouver Scar Scale height score was significantly different between the two groups (p = 0.008). CONCLUSION: This study demonstrates that early postsurgical botulinum toxin injections can produce better, narrower, and flatter facial surgical scars. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

Treatment of Early-stage Extracranial Arteriovenous Malformations with Intralesional Interstitial Bleomycin Injection: A Pilot Study.

Purpose To assess the efficacy and safety of intralesional interstitial bleomycin injection in the treatment of early-stage (Schobinger stage I or II) extracranial arteriovenous malformations (AVMs). Materials and Methods This prospective study involved 34 patients with early-stage AVMs, as defined by the Schobinger staging system. The patients received intralesional interstitial bleomycin injected at a maximum dose of 15 000 IU or 1000 IU per kilogram of body weight for children who weighed less than 15 kg per procedure for a total of 6 months (once every month). Therapeutic outcome was evaluated by the degree of devascularization at angiography and the clinical outcome 3 months after the last treatment. Further follow-up was evaluated based on further clinical outcome. Adverse events were recorded according to the Society of Interventional Radiology classification. Results Of the 34 patients with early-stage AVM, 32 (mean age, 20.5 years; 24 female [75%]) completed the study. The results showed that 27 (84.4%, 95% confidence interval [CI]: 71.1, 97.7) patients were responsive to bleomycin injection, including nine (28.1%) with a complete response. Four (12.5%) patients showed no response, and one (3.1%) patient experienced worsening 3 months after the last treatment. During further follow-up (mean follow-up time, 20.7 months; range, 5-28 months), the outcome remained stable in 31 (96.9%) of the 32 patients. A major complication, anaphylactic shock, was observed in one (3.1%, 95% CI: 0, 9.5) patient. Common minor complications included hyperpigmentation, nausea, pruritus, and bullae. Conclusion Intralesional interstitial bleomycin injection is a feasible approach for early-stage AVMs and yields safe and effective outcomes. © RSNA, 2017.