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The Index for Facial Angiofibromas (IFA), a novel scoring system for angiofibromas, has been validated in patients with tuberous sclerosis complex (TSC). The objective of this analysis was to further validate the IFA using data from a clinical trial of topical sirolimus in patients with TSC. This was an analysis of photographs from a Phase III trial conducted in Japan (NCT02635789). Patients (n = 62) were randomized 1:1 to receive sirolimus or placebo gel for 12 weeks. Changes in angiofibromas were independently assessed using the primary composite endpoint, the Facial Angiofibroma Severity Index (FASI), and the IFA. Thresholds for a clinically meaningful change in IFA score were evaluated using receiver operating characteristic (ROC) analysis. The IFA scores had good-to-excellent inter-assessor reliability, very high intra-assessor reliability, and could be used to evaluate the distribution of disease severity at baseline. High correlations were observed between the categorized change from baseline in IFA scores and the primary composite endpoint (Kendall's coefficient of concordance, W = 0.8655, p < 0.0001), and between the change from baseline in IFA and FASI scores (Kendall's coefficient of concordance, W = 0.745, p < 0.0001). By ROC analysis, an optimal IFA cut-off point of 1.667 was determined to distinguish patients with markedly improved or improved angiofibromas from those with slightly improved or unchanged angiofibromas (area under the curve 0.937) as determined by the primary composite endpoint. The IFA score is potentially clinically useful because of its high validity and reliability. A decrease in score from baseline of ≥1.667 may be considered clinically meaningful., (© 2024 The Authors. The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

Objective: This article assesses the efficacy, safety, pharmacology, and clinical applications of topical sirolimus 0.2% gel for the treatment of tuberous sclerosis complex (TSC)-associated facial angiofibromas., Data Sources: A review of the literature was conducted using the Medline (PubMed) and EMBASE databases using the keywords topical sirolimus, rapamycin, Hyftor , and tuberous sclerosis ., Study Selection and Data Extraction: Articles written in English and relevant to the topic were included., Data Synthesis: In the phase 2 trial, the mean improvement factor, a composite measure of improved tumor size and redness, was achieved in all patient groups ( P < 0.001) with significant responses among the adult and pediatric subgroups at week 12. There were no serious adverse events recorded. In the phase 3 trial, 60% of participants responded to treatment in the sirolimus group compared with 0% in the placebo group with different response rates between the adult and pediatric subgroups at week 12. Sirolimus gel had no serious adverse events, and dry skin was the most common adverse reaction. Patients who had completed the 12-week trials were then enrolled in a long-term trial; angiofibromas had response rates of 78.2% to 0.2% sirolimus gel., Relevance to Patient Care and Clinical Practice in Comparison to Existing Drugs: Topical sirolimus 0.2% is a first-in-class, newly Food and Drug Administration (FDA)-approved, mammalian target of rapamycin (mTOR) inhibitor that is a promising and safe, noninvasive alternative to surgical procedures for TSC-associated angiofibromas., Conclusions: Topical sirolimus 0.2% gel is a moderately effective treatment for TSC-associated facial angiofibromas with an adequate safety profile., Competing Interests: Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr SRF has received research, speaking and/or consulting support from AbbVie, Accordant, Almirall, Alvotech, Amgen, Arcutis, Arena, Argenx, Biocon, Boehringer Ingelheim, Bristol-Myers Squibb, Dermavant, Eli Lilly and Company, Eurofins, Forte, Galderma, Helsinn, Janssen, Leo Pharma, Micreos, Mylan, Novartis, Ono, Ortho Dermatology, Pfizer, Regeneron, Samsung, Sanofi, Sun Pharma, UCB, Verrica, Voluntis, and vTv Therapeutics. He is founder and part owner of Causa Research and holds stock in Sensal Health.

Aims: Topical rapamycin is used to reduce facial angiofibromas in patients with tuberous sclerosis (TSC). In the absence of a commercially available preparation, numerous formulations have been tested clinically, although only in the short term., Methods: The pharmacy at Angers University Hospital (France) produced a cream formulation that was administered to people presenting this genetic disease. We conducted a questionnaire-based survey among 79 patients with TSC about their perceptions regarding the short-, medium- and long-term efficacy and safety of a topical rapamycin preparation in relation to facial angiofibromas., Results: This formulation was very well tolerated and its efficacy was sustained over the long term with a mean treatment duration of 33 months (extremes 1-60). Efficacy was rated ≥ 8/10 by 67.1% of patients while safety was rated ≥ 8/10 by 84.8% of patients., Conclusion: This survey supports the safety and efficacy of topical rapamycin in the short-, medium- and long-term in the treatment of facial angiofibromas in a cohort of 79 patients with TSC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Background: Facial angiofibromas (FAs) are a major feature of tuberous sclerosis complex (TSC). Topical rapamycin can successfully treat FAs. A new stabilized cream formulation that protects rapamycin from oxidation has been developed in 0.5% and 1% concentrations., Objectives: To assess the efficacy and safety of a novel, stabilized topical rapamycin cream formulation., Methods: This multicentre double-blind randomized placebo-controlled dose-response phase II/III study with a parallel design included participants aged 6-65 years with FAs of mild or moderate severity according to the Investigator's Global Assessment (IGA) scale. Participants were randomized to one of three treatment arms: topical rapamycin 0.5%, topical rapamycin 1% or placebo. Treatment was applied once daily for 26 weeks. Safety and efficacy measures were assessed at days 14, 56, 98, 140 and 182. The primary endpoint was the percentage of participants achieving IGA scores of 'clear' or 'almost clear' after 26 weeks of treatment. Secondary measures included Facial Angiofibroma Severity Index (FASI) and participant- and clinician-reported percentage-based improvement. Safety measures included the incidence of treatment-emergent adverse events and blood rapamycin concentration changes over time., Results: Participants (n = 107) were randomized to receive either rapamycin 1% (n = 33), rapamycin 0.5% (n = 36) or placebo (n = 38). All treated participants were included in the final analysis. The percentage of participants with a two-grade IGA improvement was greater in the rapamycin 0.5% treatment group (11%) and rapamycin 1% group (9%) than in the placebo group (5%). However, this was not statistically significant [rapamycin 0.5%: odds ratio (OR) 1.71, 95% confidence interval (CI) 0.36-8.18 (P = 0.50); rapamycin 1%: OR 1.68, 95% CI 0.33-8.40 (P = 0.53)]. There was a statistically significant difference in the proportion of participants treated with rapamycin cream that achieved at least a one-grade improvement in IGA [rapamycin 0.5%: 56% (OR 4.73, 95% CI 1.59-14.10; P = 0.005); rapamycin 1%: 61% (OR 5.14, 95% CI 1.70-15.57; P = 0.004); placebo: 24%]. Skin adverse reactions were more common in patients following rapamycin application (64%) vs. placebo (29%)., Conclusions: Both rapamycin cream formulations (0.5% and 1%) were well tolerated, and either strength could lead to clinical benefit in the treatment of FA., Competing Interests: Conflicts of interest: P.A. and L.B. are employees of AFT Pharmaceuticals Ltd. I.S. is a shareholder and director of clinical research of AFT Pharmaceuticals Ltd. H.A. is a shareholder and managing director of AFT Pharmaceuticals Ltd and the named inventor on a patent for a rapamycin cream composition. P.B. has received financial support for conference travel and/or speaker honoraria from Novartis, Biogen, Roche and PTC Therapeutics. K.R. has received honoraria for educational symposia, advisory boards and/or consultancy work from Eisai, LivaNova, Medlink Neurology, Novartis and UCB Australia Ltd. Her institution has supported clinical trials for Biogen Idec Research, Eisai, Epigenyx Therapeutics, GW Research, Janssen-Cilag, Longboard Pharmaceuticals, Marinus Pharmaceuticals, Medicure International, LivaNova, Neurocrine Biosciences, Noema Pharma, Novartis, SK Lifesciences, Takeda Pharmaceutical Company, UCB Australia, UCB Biopharma and Zogenix. C.M., A.F., Y.-H.L., M.I., E.M.-A., D.T., S.T.D., J.J., M.N., P.B., H.N.P., K.H., K.R., S.S., M.M.T., D.B. and B.P. were investigators at NCT03826628 study sites., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous syndrome causing hamartomatous growths in multiple organs. Facial angiofibromas occur in up to 80% of patients and can be highly disfiguring. Treatment for these lesions is challenging. Recently, topical rapamycin has been proposed as an effective option to treat angiofibromas but a commercially available compound has not yet been developed in Europe. We conducted a retrospective review with the aim to update the current data on the use of topical rapamycin in the treatment of angiofibromas in TSC, focusing on the optimal concentration and trying to establish which vehicle should be preferred. Thirty-nine reports describing the use of topical rapamycin in the treatment of angiofibromas in TSC were considered, involving a total of 483 patients. An improvement of the lesions has been shown in over 90% of subjects, particularly if the treatment was started at early stages. Several different formulations (ointment, gel, solution and cream) with a wide range of concentrations (0.003%-1%) were proposed, of which a pharmacological analysis has also been performed. Topical rapamycin can be considered an effective and safe option for the treatment and the prevention of facial angiofibromas in younger patients, but the best formulation has yet to be established. Our review demonstrates that ointment and gel should be preferred, but it is not clear which concentration is optimal. However, according to this study, the 0.1% concentration represents the first choice. Long-term and comparative studies between topical rapamycin formulations are required in order to establish which treatment has a better outcome and lower recurrence rate., (© 2022 European Academy of Dermatology and Venereology.)

Background: Juvenile nasopharyngeal angiofibroma (JNA) is a rare but potentially life-threatening fibrovascular tumor that is seen almost exclusively in adolescent males and usually presents with symptoms of nasal obstruction or severe epistaxis. The current gold standard of treatment consists of complete surgical resection; however, this is inherently challenging because of the tumor's invasive nature and a substantial risk of intraoperative hemorrhage. Flutamide, an anti-androgen antineoplastic agent, has been used preoperatively in attempts to reduce tumor volume allowing for surgical resection with more conservative procedural techniques and reduce intraoperative blood loss., Methods: A literature review of PubMed and CINAHL was used to identify and analyze 29 male patients with JNA to determine the efficacy of the preoperative use of flutamide., Results: Our analyses indicate that flutamide may be effective as a neoadjuvant agent by reducing tumor volume prior to resection in some patients but seemed to be more effective in the early stages of JNA without advanced tumor invasion. However, individual tumor response to flutamide was variable. Additionally, postpubertal patients seemed to demonstrate a greater reduction in tumor volume with flutamide compared to their prepubertal counterparts. Dosing regimen and side effects associated with flutamide therapy are also discussed., Conclusion: Flutamide may be an effective neoadjuvant therapy in some cases of juvenile nasopharyngeal angiofibroma, but larger scale, case-control studies are likely needed to further expand on this conclusion. Postpubertal males with early-stage disease seemed to be the population that may benefit most from this treatment protocol., (© 2021 the International Society of Dermatology.)

Facial angiofibromas are one of the dermatological hallmarks of tuberous sclerosis complex. Facial angiofibromas often lead to disfigurement and cosmetic concerns, which has a serious negative effect on the quality of life of the patients. There are no guidelines or consensus on the management of facial angiofibromas up to now. We report a patient with extensive facial angiofibromas treated with the combination of photodynamic therapy and ultrapulse carbon dioxide laser, achieving satisfying results. We suggest this might be a promising therapeutic option for facial angiofibromas in tuberous sclerosis complex., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Tuberous sclerosis complex (TSC) is an autosomal-dominant disorder characterized by hamartomatous tumors of the skin, kidneys, brain, and lungs. TSC is caused by mutations in the TSC1 and TSC2 genes, which result in hyperactivation of the mTOR, leading to dysregulated cell growth and autophagy. Rapamycin (sirolimus) shrinks TSC tumors, but the clinical benefits of sirolimus are not sustained after its withdrawal. In this study, we studied the cellular processes critical for tumor formation and growth, including cell proliferation and cell size. TSC2 -/- and TSC2 +/- cells were isolated from TSC skin tumors and normal-appearing skin, respectively. Cells were incubated with sirolimus for 72 hours. Withdrawal of sirolimus from TSC2 -/- cells resulted in a highly proliferative phenotype and caused cells to enter the S phase of the cell cycle, with persistent phosphorylation of mTOR, p70 S6 kinase, ribosomal protein S6, and 4EB-P1; decreased cyclin D kinase inhibitors; and transient hyperactivation of protein kinase B. Sirolimus modulated the estrogen- and autophagy-dependent volume of TSC2 -/- cells. These results suggest that sirolimus may decrease the size of TSC tumors by reducing TSC2 -/- cell volume, altering the cell cycle, and reprogramming TSC2-null cells., (Published by Elsevier Inc.)

Facial angiofibromas are benign tumors characteristic of tuberous sclerosis complex. The disease involves the mTOR pathway and the cutaneous manifestation responds to topical treatment with sirolimus (SIR). However, there are no approved topical SIR products and extemporaneous formulations have been sub-optimal. The aims of this study were (i) to develop aqueous formulations of SIR loaded in polymeric micelles prepared using D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and (ii) to use the cutaneous biodistribution method, in conjunction with a new statistical approach, to investigate the feasibility of SIR delivery to the viable epidermis. Optimized micelle solutions and hydrogels (0.2%) were developed and stable at 4 °C for at least 6 and 3 months, respectively. Cutaneous delivery experiments (infinite and finite dose) using porcine skin demonstrated that both formulations increased SIR cutaneous bioavailability as compared to the control (ointment 0.2%). Moreover, studies with the micellar hydrogel 0.2% demonstrated SIR deposition in the viable epidermis with no transdermal permeation. These encouraging results confirmed that polymeric micelles enabled development of aqueous SIR formulations capable of targeted epidermal delivery. Furthermore, the cutaneous biodistribution provided a detailed insight into drug bioavailability in the different skin compartments that could complement/explain clinical observations of formulation efficacy., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Facial angiofibromas may be present since early childhood in individuals with tuberous sclerosis complex (TSC), causing substantial cosmetic disfigurement. Current therapies are partially effective, but they are uncomfortable, produce scarring, and are especially expensive., Objective: The aim of the present study was to evaluate the efficacy of oral everolimus for TSC-associated angiofibromas., Methods: This retrospective study included TSC patients being treated with oral everolimus for subependymal giant cell astrocytomas (SEGAs) and angiomyolipomas (AMLs). We recorded the changes in facial angiofibromas. Changes in the Angiofibroma Grading Scale (AGS) indicators were recorded according to erythema, average lesion size, lesion density, and percent involvement on the forehead, nose, cheeks, and chin. The scores were recorded before and after the administration of oral everolimus., Results: Twenty-one patients being treated with oral everolimus were enrolled in this study. The mean age was 20.5 years (range 11-44 years, 4 males, and 17 females). The mean dose of oral everolimus was 3.6 mg/day. Clinically meaningful and statistically significant improvement was observed in erythema (p = 0.001), average lesion size (p < 0.001), lesion density (p < 0.001), and percent involvement (p < 0.001). Changes in the AGS findings were statistically significant on the forehead (p = 0.001), nose (p < 0.001) cheeks (p < 0.001), and chin (p = 0.004)., Conclusion: Everolimus shows evident improvement and is approved for TSC-associated SEGAs and AMLs. The current study demonstrated the efficacy of oral everolimus in reducing facial angiofibromas, showing the parallel benefits of the treatment protocol for TSC., (© 2020 S. Karger AG, Basel.)

Tuberous sclerosis complex (TSC) is an autosomal-dominant disorder that causes the formation of hamartomatous tumors such as facial angiofibromas (FAs). We present a combination of surgical debulking via shave biopsy, curettage, and electrocautery followed by application of sirolimus ointment 1% to the nose to treat FAs in the setting of TSC. This novel approach achieved an optimal therapeutic response in our patient with minimal recurrence of FAs after 1 year of follow-up.

Background: The efficacy of topical rapamycin is well documented for tuberous sclerosis complex (TSC)-related facial angiofibromas (FAs). Calcitriol has been shown to lessen skin fibrosis and may be therapeutically beneficial to FAs., Objectives: To evaluate whether topical rapamycin-calcitriol combination is an effective and safe treatment for TSC-related FAs., Methods: Fifty-two patients with TSC with FAs were enrolled in this prospective study including three 12-week periods. In period 1, either topical rapamycin 0·1% or calcitriol 0·0003% single-agent therapy vs. their combination was applied in a double-blind, left-right-randomized, split-face comparison. The primary outcome was the reduction of modified Facial Angiofibroma Severity Index (mFASI) at week 12. In period 2, the patients were reassigned to use on both cheeks the ointment that resulted in the better primary outcome in period 1. The treatment was discontinued in period 3 (week 25-36) and a follow-up mFASI was scored to evaluate the degree of recurrence., Results: The mean changes in mFASI at week 12 compared with baseline were -0·92, -0·44 and -1·09 for rapamycin (P ≤ 0·001), calcitriol (P = 0·039) and rapamycin-calcitriol combination (P ≤ 0·001), respectively. Although rapamycin-calcitriol combination and rapamycin had similar statistically significant decreases of mFASI at week 12, rapamycin-calcitriol combination resulted in faster improvement in erythema, greater reduction of papule elevation and longer durability after discontinuing treatment than rapamycin alone. The treatments were well tolerated., Conclusions: This randomized clinical trial demonstrates that topical rapamycin-calcitriol combination therapy is an effective and safe regimen for TSC-related FAs. What is already known about this topic? Facial angiofibromas (FAs) cause substantial psychological distress in individuals with tuberous sclerosis complex (TSC), but invasive procedural treatments are not applicable to all patients. Topical rapamycin has been demonstrated as an effective and safe treatment regimen for TSC-related FAs. What does this study add? Compared with baseline (day 0), both topical rapamycin 0·1% and rapamycin 0·1%-calcitriol 0·0003% combination ointment achieved statistically significant reductions in modified Facial Angiofibroma Severity Index at week 12. Compared with rapamycin alone, extended use of the rapamycin-calcitriol combination regimen until week 24 showed more effectiveness in decreasing papule elevation and could maintain a longer therapeutic effect after treatment discontinuation. Linked Comment: Lee. Br J Dermatol 2020; 183:604-606., (© 2020 British Association of Dermatologists.)

Background: Tuberous sclerosis complex (TSC) is a rare autosomal dominant disorder forming hamartomas throughout the body. Facial angiofibromas (FAs) occur in 75% of TSC patients, which are often enlarged, impairing the appearance of the face, and reducing the patient's quality of life (QOL). The aim of this study was to characterize the impact of topical sirolimus treatment on the health-related QOL in patients with FA associated with TSC., Methods: We investigated a total of 33 patients who received sirolimus gel treatment for FA associated with TSC and assessed the changes in the health-related QOL using the Medical Outcomes Study 36-Item Short Form (SF-36) Health Survey. SF-36 surveys were performed before and after 3 months of treatment. The conditions of the patients after using the sirolimus gel were categorized into the following three categories: "improved," "unchanged," and "aggravated." Adverse events were investigated using the CTCAE v5.0-JCOG., Results: The median age of the patients was 25 (range 14-55) years. After 3 months of sirolimus gel treatment, three scale scores of the SF-36, vitality (VT), social function (SF), and mental health (MH), were significantly improved compared to before the treatment. The VT and SF in patients who had improved FA were significantly better than those in the other patients. There were no significant differences in any scale scores between patients with and without adverse events at 3 months after the initiation of sirolimus gel treatment., Conclusions: This is the first report regarding improved health-related quality of life in patients treated with sirolimus gel for FA associated with TSC by using the SF-36. The three scale scores associated with mental health were significantly improved compared to before the treatment. The health-related QOL in patients receiving sirolimus gel treatment is more strongly affected by the treatment efficacy than adverse events. Sirolimus gel treatment improves the health-related QOL in patients with FA associated with TSC.

Juvenile nasopharyngeal angiofibroma (JNA) is a pathologically benign yet locally aggressive and destructive tumor that develops in the choana and nasopharynx. Historical treatment of JNA has included embolization, surgical resection, and radiation. Here, we describe three patients who received therapy with the mTOR inhibitor sirolimus with improvement in clinical symptoms, imaging, and overall well-being., (© 2020 Wiley Periodicals, Inc.)

Objectives: In recent years, various formulations containing rapamycin, mainly petrolatum-based, have been tested on facial angiofibromas in tuberous sclerosis. They are often poorly tolerated due to irritation and bleeding. In addition, their effectiveness was insufficient in young adults. The objective of this study was to develop and characterise a hydro-alcoholic gel containing solubilised rapamycin. The stability of the product stored at 4°C was evaluated over 1 year., Methods: Two different 0.1% rapamycin gels were formulated with or without α-tocopherol and urea. Different methods were used to characterise the gels: HPLC, gas chromatography, pH, visual observation and optical microscopy. A physico-chemical and microbiological stability study was also conducted for 1 year at 4°C., Results: Gels were physically and microbiologically stable after 1 year at 4°C: organoleptic characteristics and pH unchanged, no significant decrease in rapamycin was observed, tocopherol droplet size was constant and rheological behaviour was not altered., Conclusions: This study describes a new gel formulation to improve skin penetration using various excipients to promote skin tolerance. This study provides, for the first time, detailed stability data for a hydro-alcoholic rapamycin gel., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

The facial angiofbromas due to tuberous sclerosis complex produced significant social and emotional distress for affected individuals, but there is no specific therapeutic strategy up to now. Herein, we report a case of facial angiofibromas successfully treated by 5-aminolaevulinic acid-mediated photodynamic therapy (ALA-PDT) with no recurrence for 6 years, thus providing a promising therapeutic option., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Systemic mammalian target of rapamycin (mTOR) inhibitors are currently used in many dermatologic indications. Their topical use is recent and poorly codified., Objective: To provide an overview of the topical use of mTOR inhibitors in dermatologic conditions and evaluate their efficacy and safety., Methods: A literature search was performed in January 2017. Reports of all studies investigating the use of topical mTOR inhibitors in any dermatology diseases were included. The exclusion criteria were systemic use and mucosal administration., Results: We included 40 studies with a total of 262 patients. In all, 11 dermatologic conditions were found, the most frequent being angiofibromas linked to tuberous sclerosis complex (157 patients). Topical mTOR inhibitors were significantly more efficient than placebo for angiofibromas (relative risk, 2.52; 95% confidence interval, 1.27-5.00; I 2  = 0%). The median concentration of sirolimus was 0.1%, with a median treatment duration of 12 weeks. Topical mTOR inhibitors were well tolerated, with only mild or moderate local side effects (mostly irritative) reported. Blood level of sirolimus was not detected in 90% of patients., Limitations: High heterogeneity in most studies., Conclusion: This systematic review supports the efficacy of topical sirolimus for angiofibromas linked to tuberous sclerosis complex, with only local side effects reported. Other indications require further research., (Copyright © 2018 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Facial angiofibroma is the characteristic symptom and also a major diagnostic criterion for Bourneville-Pringle disease. The centrofacially localized hamartomatous tumours start to appear in early childhood, and progress over time. Facial angiofibromas represent a significant cosmetological problem for the patients and a therapeutic challenge for the physician. Beside the traditional invasive treating methods, topical sirolimus is a new, promising and well-tolerated treatment modality. Several studies and case reports have been published on this new therapeutic approach, but recommendation for the optimal sirolimus concentration still does not exist. We report here two cases when children were successfully treated with topical sirolimus. Orv Hetil. 2019; 160(13): 516-520.

Background: Nonsteroidal androgen receptor blockers like flutamide have been described as an adjuvant treatment for preoperative shrinkage of extensive juvenile nasopharyngeal angiofibroma. We present a case of cerebrospinal fluid (CSF) leak due to flutamide-induced tumor shrinkage., Case Report: A 15-year-old male with a prior diagnosis of juvenile nasopharyngeal angiofibroma stage IIIB on preoperative flutamide for 3.5 weeks presented with altered sensorium, meningeal signs, and clear watery nasal discharge consistent with CSF leak. Computed tomogram of the head revealed air in the ventricle and repeat contrast-enhanced magnetic resonance imaging showed significant tumor shrinkage in the area of the anterior skull base. This patient had an atypical pattern of tumor extension into the anterior skull base through the roof of posterior ethmoid and sphenoid sinus, which are inherently weak areas of the skull base, thereby predisposing the CSF leak on tumor shrinkage., Conclusion: CSF leak is a rare complication following flutamide therapy, especially if large areas of the anterior skull base are involved., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Juvenile nasopharyngeal angiofibroma (JNA) is a highly vascularized and locally aggressive tumor that typically presents in adolescent males. The molecular biology of this tumor remains understudied. We sought to identify differentially expressed genes in the JNA transcriptome through messenger RNA sequencing of primary fibroblasts from 2 tumor explants and tonsil tissue from tumor-free subjects. In total, 1088 significant, differentially expressed genes were identified with 749 upregulated and 339 downregulated. Pathway analysis identified a number of activated signaling pathways, most notably, the vascular endothelial growth factor (VEGF) pathway (adjusted overlap P = .03). VEGF-A showed a 4.4-fold upregulation in JNA samples. In addition, the angiogenic receptor, fibroblast growth factor receptor 2 (FGFR2), was not present in tumor-free samples but increased in JNA. We validate these findings with immunohistochemistry, demonstrating upregulation of VEGF and FGFR2 in patient sections. Inhibition of the VEGF or FGFR signaling axes may have therapeutic potential in the treatment of JNA.

Importance: Facial angiofibromas occur in approximately 75% of individuals with tuberous sclerosis complex (TSC), causing substantial morbidity and disfigurement. Current therapies are partially effective, uncomfortable, produce scarring, and need repeating to treat recurrence., Objective: To evaluate the efficacy and safety of topical rapamycin for TSC-related facial angiofibromas., Design, Setting, and Participants: This prospective, multicenter, randomized, double-blind, vehicle-controlled trial with 6 monthly clinic visits enrolled 179 patients with TSC-related facial angiofibromas not treated within 6 months from May 2012 to March 2014 in 9 clinical sites in the United States and 1 in Australia., Interventions: Patients were randomized (1:1:1) to topical formulation containing 0.3 g per 30 g (1%) rapamycin, 0.03 g per 30 g (0.1%) rapamycin, or vehicle alone. Participants applied 1.0 mL to designated areas daily at bedtime., Main Outcomes and Measures: Angiofibroma Grading Scale (AGS) change from baseline scored from photographs by independent masked dermatologists. Safety analyses included adverse events (AEs) and serum rapamycin levels., Results: All 179 patients randomized (99 [55.3%] female) comprised the primary analysis population (59 in the 1% rapamycin group, 63 in the 0.1% rapamycin group, and 57 in the vehicle-only group). The mean age was 20.5 years (range 3-61 years). Clinically meaningful and statistically significant improvement in facial angiofibromas was observed for both 1% and 0.1% rapamycin relative to the vehicle-only control group, and for 1% vs 0.1% rapamycin, with most of the improvement realized within the first month. At 6 months, AGS mean improvement for 1% rapamycin was 16.7 points compared with 11.0 for 0.1% rapamycin and 2.1 points for vehicle only (P < .001 for 1% and 0.1% vs vehicle only). Compared with baseline, end-of-treatment photos were rated "better" for 81.8% of patients in the 1% rapamycin group, compared with 65.5% for those in the 0.1% rapamycin group and 25.5% for those in the vehicle-only group (P < .001, all 3 pairwise comparisons). Topical rapamycin was generally well-tolerated, with no measurable systemic absorption. Apparent drug-related adverse effects were limited to 10% or less incidence of application site discomfort and/or pain, pruritus, erythema, and irritation. Nearly all AEs were mild, with no drug-related moderate, severe, or serious events., Conclusions and Relevance: Topical rapamycin appears effective and safe for treatment of TSC-related facial angiofibromas. In this trial, the preferred dose was 1% once daily. Future studies are needed to evaluate prophylactic, early, and long-term use of topical rapamycin, durability of response, and combination therapy with oral mammalian target of rapamycin (mTOR) inhibitors., Trial Registration: ClinicalTrials.gov Identifier: NCT01526356.

Importance: Most patients with tuberous sclerosis complex (TSC), an autosomal-dominant disorder that is caused by the constitutive activation of mammalian target of rapamycin, experience disfigurement caused by skin lesions involving facial angiofibromas. Many have been left untreated because of a lack of therapeutic options that are less invasive than surgery or laser treatment., Objective: To confirm the efficacy and safety of sirolimus gel, 0.2%, for treatment of patients with angiofibromas and/or skin lesions., Design, Setting, and Patients: Multicenter, randomized clinical trial at 9 centers in Japan from December 2015 to October 2016 including 62 children and adults with TSC., Interventions: Patients who developed angiofibromas were randomly assigned, in a 1:1 ratio, to receive sirolimus gel, 0.2%, or placebo, each applied topically twice daily for 12 weeks., Main Outcomes and Measures: The primary end point was composite improvement in the size and color of angiofibromas in photographs at week 12 of treatment. It was assessed by an independent review committee comprising 3 blinded dermatologists who categorized patient results into the following 6 categories: "markedly improved," "improved," "slightly improved," "unchanged," "slightly aggravated," and "aggravated.", Results: Sixty-two patients (27 pediatric and 35 adult; 34 [55%] female; mean [SD] age, 22.5 [11.9] years) were enrolled and randomly assigned to receive sirolimus gel, 0.2% (30 patients), or placebo (32 patients). The response rates of angiofibromas at weeks 4, 8, and 12 of treatment were 0 each in the placebo group in contrast to 20% (95% CI, 8%-39%; P = .01), 43% (95% CI, 26%-63%; P < .001), and 60% (95% CI, 41%-77%; P < .001), respectively, in the sirolimus group. None of the 31 assessable patients in the placebo group were rated improved or better, and 26 of them (84%) were rated unchanged. In contrast, 5 (17%) and 13 (43%) patients in the sirolimus group were rated markedly improved and improved, respectively. Adverse events were mild to moderate and were observed in 27 (90%) and 22 (69%) patients in the sirolimus and placebo groups, respectively; however, none of the trial participants discontinued treatment. Acute pancreatitis developed as a serious adverse event in 1 patient in the sirolimus group, and the patient recovered soon after hospitalization without discontinuing treatment., Conclusions and Relevance: Sirolimus gel, 0.2%, demonstrated a significant clinical benefit for patients with TSC involving angiofibromas, thus providing a promising therapeutic modality., Trial Registration: ClinicalTrials.gov Identifier: NCT02635789.

Background: Recent reports have suggested that the topical formulation of sirolimus is effective in treating facial angiofibromas in tuberous sclerosis complex (TSC). Here, we determined the safety and efficacy of 0.2% topical sirolimus for the treatment of facial angiofibroma and compared its effects based on age., Method: This was a retrospective study which involved 36 TSC patients with facial angiofibromas who were treated with 0.2% sirolimus ointment. Its effect was evaluated using the Facial Angiofibroma Severity Index (FASI). In order to observe its comparative effect based on patient age, a subgroup analysis was performed, between the adult group (> 18 years old) and the pediatric group (≤18 years old)., Results: The total FASI as well as its subcategories (erythema, size, and extent) showed statistically significant improvements after the topical treatment with 0.2% sirolimus ointment (FASI before treatment: 7.2 ± 1.1, FASI after treatment: 4.4± 1.4, p < 0.001). Among the subcategories of FASI, the erythema was most significantly reduced with the fastest response to the treatment. In a subgroup analysis, the pediatric group showed significantly greater improvements in FASI (improvement of FASI in the pediatric group = 49.7 ± 12.2%, adult group = 27.9 ± 15.6%, p < 0.001). The serial improvement analysis also showed that the pediatric group achieved a consistently greater improvement in FASI at all visits. Its 1-year application in 3 patients demonstrated a continuous maintenance effect. No significant adverse effects were observed., Conclusion: 0.2% sirolimus ointment is safe and effective for facial angiofibromas. Considering its higher efficacy in younger patients, an early initiation of the treatment is recommended., (© 2018 S. Karger AG, Basel.)

Background/objectives: Tuberous sclerosis complex (TSC) is a genetic disorder and facial angiofibromas are disfiguring facial lesions. The aim of this study was to analyze the clinical and genetic features of TSC and to assess the treatment of facial angiofibromas using topical sirolimus in Chinese children., Methods: Information was collected on 29 patients with TSC. Genetic analyses were performed in 12 children and their parents. Children were treated with 0.1% sirolimus ointment for 36 weeks. Clinical efficacy and plasma sirolimus concentrations were evaluated at baseline and 12, 24, and 36 weeks., Results: Twenty-seven (93%) of the 29 patients had hypomelanotic macules and 15 (52%) had shagreen patch; 11 of the 12 (92%) who underwent genetic analysis had gene mutations in the TSC1 or TSC2 gene. Twenty-four children completed 36 weeks of treatment with topical sirolimus; facial angiofibromas were clinically undetectable in four (17%). The mean decrease in the Facial Angiofibroma Severity Index (FASI) score at 36 weeks was 47.6 ± 30.4%. There was no significant difference in the FASI score between weeks 24 and 36 (F = 1.00, p = 0.33). There was no detectable systemic absorption of sirolimus., Conclusion: Hypomelanotic macules are often the first sign of TSC. Genetic testing has a high detection rate in patients with a clinical diagnosis of TSC. Topical sirolimus appears to be both effective and well-tolerated as a treatment of facial angiofibromas in children with TSC. The response typically plateaus after 12 to 24 weeks of treatment., (© 2017 Wiley Periodicals, Inc.)

Importance: Inhibitors of mammalian target of rapamycin complex 1, such as sirolimus, effectively target skin lesions in tuberous sclerosis complex (TSC). However, systemic treatment causes adverse effects, and topical sirolimus has shown promise in the treatment of facial angiofibromas., Objective: To evaluate the efficacy, safety, and optimal concentration of a topical sirolimus gel vs placebo for treatment of facial angiofibromas in TSC., Design, Setting, and Participants: A double-blind, placebo-controlled, parallel-group, dose-escalation, phase 2 randomized clinical trial using 3 sirolimus gel concentrations was performed at Osaka University Hospital, Osaka, Japan. Thirty-six patients with TSC and facial angiofibromas, including 18 aged 3 to 18 years (children) and 18 aged 19 to 65 years (adults), were enrolled from December 10, 2013, to July 17, 2014. Analysis was by intention to treat., Interventions: The adult and child groups were each subdivided into 3 groups (n = 12 each) and randomized to receive sirolimus gel concentrations of 0.05%, 0.1%, or 0.2% or placebo using a web-response system in a 2:1 fashion. The medication was applied to the patient's lesions twice per day for 12 weeks. Each patient underwent assessment at 2, 4, 8, and 12 weeks during treatment and at 4 weeks after discontinuation of the treatment (16 weeks)., Main Outcomes and Measures: The primary end point, planned before starting data collection, was an improvement factor, represented as a variable composed of tumor size reduction and a lessening of the redness of the 3 target tumors at 12 weeks relative to baseline., Results: All 36 patients (13 male and 23 female; median age, 40 years; range, 6-47 years) completed the study analyses. The improvement factor was statistically significant in all active treatment groups receiving 0.2% sirolimus (mean [SD], 1.94 [0.68]; P < .001) and not in the adult subgroups receiving 0.1% (mean [SD], 0.88 [0.85]; P = .31) and 0.05% (mean [SD], 1.63 [1.11]; P = .09) concentrations of sirolimus. No significant adverse effects were observed. Mild skin dryness (13 patients [36%]) and irritation (11 patients [31%]) were observed. Low blood levels of sirolimus (<0.25 ng/mL) were detected in adults (1 patient [25%] in the 0.1% adult subgroup and 2 patients [50%] in the 0.2% adult subgroup) and particularly in children (1 patient [25%] in the 0.05% child subgroup, 2 patients [50%] in the 0.1% child subgroup, and 4 patients [100%] in the 0.2% child subgroup)., Conclusions and Relevance: Topical sirolimus gel is safe and effective for facial angiofibromas in TSC. The optimal concentration of sirolimus was 0.2%., Trial Registration: umin.ac.jp Identifier: UMIN000012420.

Background: The skin is one of the most affected organs in tuberous sclerosis complex and angiofibromas are seen in almost 80% of such patients. These benign tumors impose a great psycho-social burden on patients., Objective: The aim of the study was to evaluate the effectiveness and tolerability of topical sirolimus for facial angiofibromas in patients with tuberous sclerosis complex., Methods: This was a prospective, single-blinded, cross-over study which involved twelve patients. We investigated the effect and safety of topical 0.1% sirolimus, which was obtained by crushing sirolimus tablets and mixing it with petrolatum. The patients were asked to apply the cream to one side of their face, and vaseline to the other side. The effect of topical sirolimus was evaluated using the "facial angiofibroma severity index.", Results: There was a significant improvement in the redness and extension of the tumors on the sides to which the active ingredient was applied. Some side effects such as itching and irritation occurred in three patients, which were treated with topical hydrocortisone cream., Conclusion: Topical sirolimus appears to be a promising, fairly well tolerated treatment for facial angiofibromas in patients with tuberous sclerosis complex. Although its efficacy diminishes with time, repetitive usage is effective.

Medicines for the treatment of rare diseases frequently do not attract the interest of the pharmaceutical industry, and hospital pharmacists are thus often requested by physicians to prepare personalized medicines. Tuberous Sclerosis Complex (TSC) is a rare disease that causes disfiguring lesions named facial angiofibromas. Various topical formulations of rapamycin (=sirolimus) have been proved effective in treating these changes in small case series. The present study provides for the first time characterization of a 0.1% rapamycin cream formulation presenting good rapamycin solubilisation. The first step of the formulation is solubilisation of rapamycin in Transcutol(®), and the second step is the incorporation of the mixture in an oil-in-water cream. A HPLC stability-indicating method was developed. Rapamycin concentration in the cream was tested by HPLC and confirmed that it remained above 95% of the initial concentration for at least 85days, without characteristic degradation peaks. The preparation met European Pharmacopoeia microbial specifications throughout storage in aluminum tubes, including when patient use was simulated. Odour, appearance and colour of the preparation were assessed and no change was evidenced during storage. The rheological properties of the cream also remained stable throughout storage. To conclude, we report preparation of a novel cream formulation presenting satisfactory rapamycin solubilisation for the treatment of TSC cutaneous manifestations, with stability data. The cream is currently being used by our patients. Efficacy and tolerance will be reported later., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Angiofibromas are the most recognized cutaneous manifestations of tuberous sclerosis complex. Angiofibromas can be associated with disfigurement, bleeding, pruritus, and erythema and may lead to significant psychosocial consequences for affected patients. Histopathologically, angiofibromas consist of a mixture of vascular and interstitial cells. Traditional treatment options include cryotherapy, electrocoagulation, radiofrequency ablation, dermabrasion, laser treatment, and topical agents such as podophyllotoxin. However, complications such as pain, postinflammatory hyperpigmentation, scarring, and the frequent recurrence rate reduce the utility of these treatment options. The introduction of topical rapamycin marked a turning point for treatment of facial angiofibromas; however, the lack of a standardized formulation, limited insurance coverage, and significant financial cost restrict universal access for patients and their caregivers. Both oral and topical β-blockers have proven extremely effective treatments for superficial vascular tumors such as hemangiomas and pyogenic granulomas. Topical β-blockers may potentially be useful for treatment of angiofibromas considering these lesions also contain a vascular component. Here we present an exploratory case report of a patient with tuberous sclerosis complex who had significant clinical improvement of her facial angiofibromas utilizing a "split-face" comparison protocol of topical timolol 0.5% gel after full-field treatment with ablative fractional laser resurfacing and pulsed-dye laser.

Topical sirolimus, or rapamycin, is known to inhibit tumorigenesis in tuberous sclerosis. We report two cases of successful treatment of children with facial angiofibromata and summarize the encouraging evidence of the effectiveness of this therapy in the literature., (© 2015 Wiley Periodicals, Inc.)

Background: Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous syndrome causing hamartomatous growths in multiple organs. Facial angiofibromas occur in up to 80% of patients and can be highly disfiguring. Treatment for these lesions has historically been challenging. Recently, topical rapamycin has been proposed as an effective option to treat angiofibromas but a commercially available compound has not yet been developed., Objectives: The aim of this review is to analyse the current data on the use of topical rapamycin in the treatment of angiofibromas in TSC, focusing on the risk-benefit profile., Methods: A retrospective review of the English-language literature was conducted., Results: Sixteen reports describing the use of topical rapamycin in the treatment of angiofibromas in TSC were considered, involving a total of 84 patients. An improvement of the lesions has been shown in 94% of subjects, particularly if the treatment was started at early stages. Several different formulations (ointment, gel, solution and cream) with a wide range of concentrations (0.003%-1%) were proposed. Only 4 local adverse side-effects were reported after the use of rapamycin solution., Conclusion: Topical rapamycin can be considered a safe option for the treatment and the prevention of facial angiofibromas in younger patients, but the best formulation has not been established. Our review demonstrates that ointment and gel should be preferred, but it is not clear which concentration is optimal. Long-term and comparative studies between topical rapamycin and ablative techniques are required to establish which treatment has a better outcome and lower recurrence rate., (© 2014 European Academy of Dermatology and Venereology.)

Background: Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder characterized by the development of multisystem hamartomatous tumours. Topical sirolimus has recently been suggested as a potential treatment for TSC-associated facial angiofibroma (FA)., Aim: To validate a reproducible scale created for the assessment of clinical severity and treatment response in these patients., Methods: We developed a new tool, the Facial Angiofibroma Severity Index (FASI) to evaluate the grade of erythema and the size and extent of FAs. In total, 30 different photographs of patients with TSC were shown to 56 dermatologists at each evaluation. Three evaluations using the same photographs but in a different random order were performed 1 week apart. Test and retest reliability and interobserver reproducibility were determined., Results: There was good agreement between the investigators. Inter-rater reliability showed strong correlations (> 0.98; range 0.97-0.99) with inter-rater correlation coefficients (ICCs) for the FASI. The global estimated kappa coefficient for the degree of intra-rater agreement (test-retest) was 0.94 (range 0.91-0.97)., Conclusions: The FASI is a valid and reliable tool for measuring the clinical severity of TSC-associated FAs, which can be applied in clinical practice to evaluate the response to treatment in these patients., (© 2014 British Association of Dermatologists.)

Sirolimus, also known as rapamycin (SRL, Rapamune®), was approved in 1999 by the US Food and Drug Administration to prevent graft rejection in renal transplantation. As a member of the mammalian target of rapamycin (mTOR) inhibitor class, its potent immunosuppressant, anti-angiogenic and anti-proliferative properties are well recognized. When compared to other immunosuppressants, SRL has a lower risk of renal, neurologic and lymphoproliferative complications. It has become a promising treatment modality for angiofibromas, Kaposi's sarcoma and other inflammatory and malignant disorders of the skin. With the recent discovery that mTOR inhibitors extend the lifespan of mice, sirolimus and other rapamycin analogs (rapalogs) are emerging as therapeutic targets for the treatment and prevention of age-related diseases.

Purpose: To present the clinical, imaging, pathological and immunohistochemical features of giant cell angiofibroma (GCA)., Case Presentation: In this paper we report an atypical case of a GCA extending from the parotid to the parapharyngeal space. The lesion was being treated as a vascular malformation for one year prior to surgical removal. We summarize the clinical manifestations, imaging, pathological and molecular features of this rare disease.After complete surgical removal of the tumor, immunohistochemical analysis revealed strong positivity for the mesenchymal markers vimentin, CD34, CD31 and CD99 in neoplastic cells. Tumor proliferation antigen marker Ki67 was partly positive (<5% of cells). Tumor cells were negative for muscle-specific actin, epithelial membrane antigen, smooth muscle actin, cytokeratin pan, S100, desmin, glial fibrillary acidic protein, myogenin, MyoD1 and F8. The morphological and immunohistochemical profile was consistent with the diagnosis of GCA., Conclusion: GCA is a rare soft tissue tumor that can easily be misdiagnosed in the clinical preoperative setting. In view of the clinical, pathological and molecular features of the tumor, complete surgical removal is the current optimal treatment option, providing accurate diagnosis and low to minimal recurrence rate.

One of the most visible and potentially disfiguring cutaneous manifestations of tuberous sclerosis complex is the development of multiple facial angiofibromas, present in over 80% of patients. Topical rapamycin has been shown in many reports to be a safe and effective treatment for facial angiofibromas. In February 2012 we reported the results of a pilot study of four patients undertaken at a paediatric tertiary hospital in Australia. Since then, we have continued to refine the optimal formulation and concentration of topical rapamycin and expanded our selection of patients. We present an update on our current cohort of treated patients, discuss the optimal formulation of topical rapamycin and include a literature review on all published cases to date. Although topical rapamycin is not a curative treatment, we have demonstrated that its early institution significantly reduces both the vascularity and palpability of angiofibromas and prevents their progression with age. It is well tolerated and now a cost effective option., (© 2013 The Australasian College of Dermatologists.)

Background: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder causing multiple hamartomas. Treatment of TSC lesions with mammalian target of rapamycin inhibitors is effective. Recently, several reports have shown the efficacy of topical rapamycin (sirolimus) for angiofibromas. However, almost all studies have been case studies and the 0·1% solution caused skin irritation. A comparative study of topical rapamycin and a vehicle has not yet been reported., Objectives: To compare the efficacy of topical rapamycin formulation with that of vehicle for angiofibromas., Methods: A left-right comparative study between rapamycin 0·2% topical formulation and vehicle was conducted in 11 patients with TSC. Two formulations, an ointment and a gel, were prepared and in vitro percutaneous absorption of rapamycin was determined., Results: In vitro percutaneous absorption of rapamycin was significantly greater with the gel compared with the ointment. In the clinical study, the rapamycin-treated cheek showed significant improvements relative to the vehicle-treated cheek in all outcome measures after 12 weeks of treatment. The improvement was particularly remarkable in children aged ≤ 10 years. No side-effects were noted, and rapamycin was not detected in the blood of the patients., Conclusions: Topical rapamycin was significantly effective against angiofibromas. Both formulations used were effective and safe. The 0·2% gel is especially useful because of its better skin penetration and low irritancy. Initiation of topical rapamycin therapy in early childhood would be beneficial for patients with TSC., (© 2013 British Association of Dermatologists.)

Background and Objective: The angiofibromas of Tuberous sclerosis (TS) is well described manifestation. Due to the progressive nature of the skin lesion, a safe and effective technique for treating these disfiguring skin lesions is needed., Study Design/patients and Methods: We report a targeted topical and combination laser technique for treating the angiofibromas of TS in one patient. This includes treatment with topical sirolimus, pinpoint electrosurgery, pulsed-dye laser treatment, and ablative fractional resurfacing (AFR)., Results: Improvement in the number and appearance of facial angiofibromas and erythema is noted, without scarring or adverse events., Conclusion: The technique of targeted therapy with sirolimus with electrosurgery, pulsed dye laser treatment, and AFR represents an innovative, safe therapeutic option for treating facial angiofibromas associated with TS., (© 2013 Wiley Periodicals, Inc.)

We present a five-year-old boy with facial angiofibromas associated to tuberous sclerosis successfully treated with topical sirolimus 0.4% applied three times a week for six months. After six months we observed a nearly complete resolution of facial angiofibromas. The blood levels of sirolimus remained under a detectable limit and no side-effects were observed. Topically applied sirolimus seems to be a safe and effective alternative to surgery or laser therapy.

Facial angiofibromas are dermatological manifestations of tuberous sclerosis complex, a neurocutaneous disorder characterized by excess cell growth and proliferation. Oral rapamycin has been used to treat visceral tuberous sclerosis-related tumors; however, the side effect profile of this medicine precludes its routine use in patients lacking significant internal involvement. The authors formulated a novel rapamycin cream that is easy to compound and apply, does not cause local or systemic side effects, and results in a dramatic improvement of facial angiofibromas.

Background: Glucocorticoids (GCs) not only regulate metabolic and inflammatory mechanisms, but also are known to suppress tumor growth. Despite previous detection of glucocorticoid receptors (GRs) in juvenile angiofibromas, their distribution and function have not further been studied., Methods: Juvenile angiofibroma tissue (n = 30), nasal mucosa specimens (n = 10), subepithelial stroma of nasal mucosa (n = 20), and primary fibroblasts from juvenile angiofibroma (n = 6) and nasal mucosa samples (n = 6) were analyzed by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and immunofluorescence staining. The antiproliferative effect of GCs (dexamethasone, prednisolone, and hydrocortisone) in vitro was assessed using a bromdeoxyuridine (BrdU) assay., Results: An upregulation of GR transcripts and protein was shown in juvenile angiofibroma tissue and primary mesenchymal cells compared to nasal mucosa. Application of GCs resulted in a significantly higher antiproliferative effect on juvenile angiofibroma versus nasal mucosa fibroblasts in vitro., Conclusion: Expression of GRs and antiproliferative effects of GCs on juvenile angiofibroma fibroblasts offer novel options for the treatment of this unique fibrovascular tumor., (Copyright © 2012 Wiley Periodicals, Inc.)