sirolimus and Angiofibroma

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.

Topics: Angiofibroma; Facial Neoplasms; Humans; Immunosuppressive Agents; MTOR Inhibitors; Ointments; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis

Potential benefits of rapamycin or rapalogs for treating people with tuberous sclerosis complex (TSC) have been shown. Currently everolimus (a rapalog) is only approved for TSC-associated renal angiomyolipoma and subependymal giant cell astrocytoma (SEGA), but not other manifestations of TSC. A systematic review needs to establish evidence for rapamycin or rapalogs for various manifestations in TSC. This is an updated review.. To determine the effectiveness of rapamycin or rapalogs in people with TSC for decreasing tumour size and other manifestations and to assess the safety of rapamycin or rapalogs in relation to their adverse effects.. We identified relevant studies from the Cochrane-Central-Register-of-Controlled-Trials (CENTRAL), Ovid MEDLINE and ongoing trials registries with no language restrictions. We searched conference proceedings and abstract books of conferences. Date of the last searches: 15 July 2022.. Randomised controlled trials (RCTs) or quasi-RCTs of rapamycin or rapalogs in people with TSC.. Two review authors independently extracted data and assessed the risk of bias of each study; a third review author verified the extracted data and risk of bias decisions. We assessed the certainty of the evidence using GRADE.. The current update added seven RCTs, bringing the total number to 10 RCTs (with 1008 participants aged 3 months to 65 years; 484 males). All TSC diagnoses were by consensus criteria as a minimum. In parallel studies, 645 participants received active interventions and 340 placebo. Evidence is low-to-high certainty and study quality is mixed; mostly a low risk of bias across domains, but one study had a high risk of performance bias (lack of blinding) and three studies had a high risk of attrition bias. Manufacturers of the investigational products supported eight studies. Systemic administration Six studies (703 participants) administered everolimus (rapalog) orally. More participants in the intervention arm reduced renal angiomyolipoma size by 50% (risk ratio (RR) 24.69, 95% confidence interval (CI) 3.51 to 173.41; P = 0.001; 2 studies, 162 participants, high-certainty evidence). In the intervention arm, more participants in the intervention arm reduced SEGA tumour size by 50% (RR 27.85, 95% CI 1.74 to 444.82; P = 0.02; 1 study; 117 participants; moderate-certainty evidence) ,and reported more skin responses (RR 5.78, 95% CI 2.30 to 14.52; P = 0.0002; 2 studies; 224 participants; high-certainty evidence). In one 18-week study (366 participants), the intervention led to 25% fewer seizures (RR 1.63, 95% CI 1.27 to 2.09; P = 0.0001) or 50% fewer seizures (RR 2.28, 95% CI 1.44 to 3.60; P = 0.0004); but there was no difference in numbers being seizure-free (RR 5.30, 95% CI 0.69 to 40.57; P = 0.11) (moderate-certainty evidence). One study (42 participants) showed no difference in neurocognitive, neuropsychiatry, behavioural, sensory and motor development (low-certainty evidence). Total adverse events (AEs) did not differ between groups (RR 1.09, 95% CI 0.97 to 1.22; P = 0.16; 5 studies; 680 participants; high-certainty evidence). However, the intervention group experienced more AEs resulting in withdrawal, interruption of treatment, or reduced dose (RR 2.61, 95% CI 1.58 to 4.33; P = 0.0002; 4 studies; 633 participants; high-certainty evidence and also reported more severe AEs (RR 2.35, 95% CI 0.99 to 5.58; P = 0.05; 2 studies; 413 participants; high-certainty evidence). Topical (skin) administration Four studies (305 participants) administered rapamycin topically. More participants in the intervention arm showed a response to skin lesions (RR 2.72, 95% CI 1.76 to 4.18; P < 0.00001; 2 studies; 187 participants; high-certainty evidence) and more participants in t. Oral everolimus reduces the size of SEGA and renal angiomyolipoma by 50%, reduces seizure frequency by 25% and 50% and implements beneficial effects on skin lesions with no difference in the total number of AEs compared to placebo; however, more participants in the treatment group required a dose reduction, interruption or withdrawal and marginally more experienced serious AEs compared to placebo. Topical rapamycin increases the response to skin lesions and facial angiofibroma, an improvement score, satisfaction and the risk of any AE, but not severe adverse events. With caution regarding the risk of severe AEs, this review supports oral everolimus for renal angiomyolipoma, SEGA, seizure, and skin lesions, and topical rapamycin for facial angiofibroma.

Topics: Adult; Angiofibroma; Angiomyolipoma; Astrocytoma; Everolimus; Humans; Kidney Neoplasms; Male; MTOR Inhibitors; Sirolimus; Tuberous Sclerosis

facial angiofibromas of tuberous sclerosis are the most prevalent cutaneous manifestation, affecting 80% of patients, which cause facial lesions with negative psychosocial consequences. Newly, topical rapamycin has been established as an effective and safe therapy for this skin condition.. to analyze the available scientific evidence about the effectiveness and safety of topical sirolimus in the treatment of facial angiofibromas in tuberous sclerosis.. a literature search was conducted in PubMed and Cochrane. Effectiveness and safety were analyzed along with the main characteristics of each formulation in all included studies.. thirty studies were included involving a total of 508 patients, developed in the last 20 years. Four randomized clinical trial, 17 case series and 9 single case reports were founded. Multiple topical rapamycin concentrations (0.003-1%) and formulations (gel, ointment, solution) were found in literature. Rapamycin demonstrated its effectiveness in all studies included, except for 5 patients in a 1 b study. Rapamycin was shown to be safe for the treatment of FA.. Topical sirolimus can be considered an effective and safety option for the treatment of facial angiofibromas in tuberous sclerosis. However, further long-term studies need to establish an evidence-based therapeutic protocol.KEY MESSAGEUpdated review to date in topical rapamycin for facial angiofibromas, allowing support in therapeutic decisions.

Topics: Angiofibroma; Facial Neoplasms; Humans; Immunosuppressive Agents; Randomized Controlled Trials as Topic; Sirolimus; Tuberous Sclerosis

Systemic mammalian target of rapamycin (mTOR) inhibitors are currently used in many dermatologic indications. Their topical use is recent and poorly codified.. To provide an overview of the topical use of mTOR inhibitors in dermatologic conditions and evaluate their efficacy and safety.. 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.. 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. High heterogeneity in most studies.. 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.

Topics: Administration, Cutaneous; Angiofibroma; Antibiotics, Antineoplastic; Humans; Port-Wine Stain; Psoriasis; Sirolimus; Skin Neoplasms; TOR Serine-Threonine Kinases; Tuberous Sclerosis

Dear Editor, Tuberous sclerosis (TS) is an autosomal dominant multisystem disease, which occurs due to genetically determined hyperplasia of ectodermal and mesodermal cells. Clinical manifestations present on the skin and in the nervous system, kidneys, heart, and other organs. Recent studies estimate the incidence of TS at 1/6000 to 1/10,000 live births, and a prevalence in the general population of approximately 1 in 20,000 (1). There are two different genetic loci responsible for TS: 9q34 (TSC1-hamartin) and 16p13.3 (TSC2-tuberin) (2). Cutaneous manifestations occur in about 96% of patients (3). Neurological disorders occur in 50% of patients in the form of seizures and motor and psychomotor symptomatology (4). A 19-year-old male patient was hospitalized for clinical and diagnostic evaluation in February 2016 year in Clinic for Nephrology, Clinical Center of Montenegro, Podgorica, Montenegro. Polycystic kidney changes were verified by ultrasound when the patient was three years old, with the presence of several calcified nodules in lateral ventricles and supraventricularly in the brain as well as the existence of several hypopigmented maculae on the skin. During the last hospitalization in February 2016, the following tests were performed: cranial magnet resonance imaging (MRI) findings showed the existence of visible changes in the signal in the form of ectopic tuber tissue in the region of the cortex and subcortical white matter of the brain, but without neurological and psychomotor abnormalities; ultrasound of the urinary tract showed that both kidneys were enlarged with multiple cysts, with dominant cysts at the lower pole of the right kidney with a size of 55 mm and at the upper pole of the left kidney, approximately 40 mm. Reduced functional capacity of kidneys was found on dynamic scintigraphy, slightly more in the left kidney (41%) compared with the right (59%). Electroencephalography, X-ray of the lungs and heart, and echocardiography were also performed, but without any pathological findings. Dermatological examination found numerous fibroma up to 0.5 cm in diameter, the largest located nasolabially, periorally, and on the chin skin (Figure 1) at the age of seven, whereas a fibroma and several white maculae were present from birth on the skin of the forehead. They were now also present on the skin of the trunk and on the upper and lower extremities (Figure 2), accompanied by surrounding minor changes in the form of confetti-like maculae. A su

Topics: Angiofibroma; Biopsy, Needle; Combined Modality Therapy; Electroencephalography; Humans; Immunohistochemistry; Laser Therapy; Magnetic Resonance Imaging; Male; Multimodal Imaging; Prognosis; Severity of Illness Index; Sirolimus; Skin Neoplasms; Tuberous Sclerosis; Tuberous Sclerosis Complex 1 Protein; Tumor Suppressor Proteins; Ultrasonography, Doppler; Young Adult

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.. 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.. A retrospective review of the English-language literature was conducted.. 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.. 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.

Topics: Administration, Cutaneous; Angiofibroma; Antibiotics, Antineoplastic; Facial Neoplasms; Gels; Humans; Ointments; Sirolimus; Skin Cream; Skin Neoplasms; Tuberous Sclerosis

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.. To assess the efficacy and safety of a novel, stabilized topical rapamycin cream formulation.. 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.. 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%).. Both rapamycin cream formulations (0.5% and 1%) were well tolerated, and either strength could lead to clinical benefit in the treatment of FA.

Topics: Angiofibroma; Double-Blind Method; Emollients; Humans; Immunoglobulin A; Immunosuppressive Agents; Sirolimus; Treatment Outcome; Tuberous Sclerosis

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.. To evaluate whether topical rapamycin-calcitriol combination is an effective and safe treatment for TSC-related FAs.. 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.. 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.. 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.

Topics: Administration, Cutaneous; Angiofibroma; Calcitriol; Facial Neoplasms; Humans; Neoplasm Recurrence, Local; Prospective Studies; Sirolimus; Treatment Outcome; Tuberous Sclerosis

Topics: Administration, Cutaneous; Adolescent; Age Factors; Angiofibroma; Child; Drug Administration Schedule; Drug Costs; Emollients; Facial Neoplasms; Female; Humans; Male; Neoplasm Recurrence, Local; Powders; Retrospective Studies; Severity of Illness Index; Sirolimus; Skin Cream; Skin Neoplasms; Tablets; Treatment Outcome; Tuberous Sclerosis

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.. To confirm the efficacy and safety of sirolimus gel, 0.2%, for treatment of patients with angiofibromas and/or skin lesions.. Multicenter, randomized clinical trial at 9 centers in Japan from December 2015 to October 2016 including 62 children and adults with TSC.. 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.. 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.". 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.. Sirolimus gel, 0.2%, demonstrated a significant clinical benefit for patients with TSC involving angiofibromas, thus providing a promising therapeutic modality.. ClinicalTrials.gov Identifier: NCT02635789.

Topics: Administration, Cutaneous; Adolescent; Adult; Angiofibroma; Child; Double-Blind Method; Facial Neoplasms; Female; Gels; Humans; Immunosuppressive Agents; Male; Middle Aged; Placebos; Sirolimus; Skin Neoplasms; Tuberous Sclerosis; Young Adult

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.. To evaluate the efficacy and safety of topical rapamycin for TSC-related facial angiofibromas.. 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.. 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.. Angiofibroma Grading Scale (AGS) change from baseline scored from photographs by independent masked dermatologists. Safety analyses included adverse events (AEs) and serum rapamycin levels.. 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.. 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.. ClinicalTrials.gov Identifier: NCT01526356.

Topics: Administration, Cutaneous; Adolescent; Adult; Angiofibroma; Child; Child, Preschool; Double-Blind Method; Facial Neoplasms; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Prospective Studies; Quality of Life; Severity of Illness Index; Sirolimus; Skin Neoplasms; Time Factors; Tuberous Sclerosis; Young Adult

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.. To evaluate the efficacy, safety, and optimal concentration of a topical sirolimus gel vs placebo for treatment of facial angiofibromas in TSC.. 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.. 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).. 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.. 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).. Topical sirolimus gel is safe and effective for facial angiofibromas in TSC. The optimal concentration of sirolimus was 0.2%.. umin.ac.jp Identifier: UMIN000012420.

Topics: Administration, Topical; Adolescent; Adult; Angiofibroma; Antibiotics, Antineoplastic; Child; Double-Blind Method; Facial Neoplasms; Female; Gels; Humans; Male; Middle Aged; Patient Satisfaction; Sirolimus; Skin Neoplasms; Treatment Outcome; Tuberous Sclerosis; Young Adult

Facial angiofibromas are disfiguring facial lesions, present in up to 80% of patients with tuberous sclerosis complex. Recent elucidation of the complex cell signaling pathways that are disrupted in tuberous sclerosis indicates that rapamycin may be successful in alleviating the appearance of these lesions. The objectives of the current study were to evaluate the safety of topically applied rapamycin in patients with tuberous sclerosis complex and to determine its potential effectiveness in treatment of facial angiofibromas.. The study was a prospective, randomized, double-blind, placebo-controlled study performed at the University of Texas Health Science Center at Houston. Study subjects were recruited from the patient populations at the University of Texas Tuberous Sclerosis Center of Excellence. All subjects were over the age of 13 years and had a diagnosis of tuberous sclerosis complex. Subjects were excluded if they were using any form of rapamycin or if they were pregnant. Study subjects applied the study product to their facial angiofibromas nightly for a duration of 6 months. The investigational product contained one of three doses of rapamycin compounded with Skincerity®: (i) no rapamycin; (ii) 1 mg of rapamycin per 30 cc (0.003%); or (iii) 5 mg of rapamycin per 30 cc (0.015%). Plasma rapamycin concentrations were measured monthly to test for systemic absorption. Complete blood counts were performed monthly to test for anemia, neutropenia, or thrombocytopenia. Upon completion of the trial, subjects were asked if the formulation had improved the appearance of their facial angiofibromas.. Twenty-three subjects completed the study. There was no detectable systemic absorption of rapamycin (all blood concentrations were <1.0 ng/mL). There were no significant changes in white blood cell, red blood cell, or platelet counts. Seventy-three percent of subjects in the treatment arms versus 38% of subjects in the placebo arm reported a subjective improvement in the appearance of their facial angiofibromas.. The application of low-dose topical rapamycin (0.003-0.015%) to the face can safely decrease the appearance of facial angiofibromas in patients with tuberous sclerosis complex.. ClinicalTrials.gov Identifier: NCT01031901.

Topics: Administration, Topical; Adolescent; Adult; Angiofibroma; Double-Blind Method; Facial Neoplasms; Female; Humans; Male; Prospective Studies; Sirolimus; Tuberous Sclerosis; Young Adult

Neurosurgical resection is the standard treatment for subependymal giant-cell astrocytomas in patients with the tuberous sclerosis complex. An alternative may be the use of everolimus, which inhibits the mammalian target of rapamycin, a protein regulated by gene products involved in the tuberous sclerosis complex.. Patients 3 years of age or older with serial growth of subependymal giant-cell astrocytomas were eligible for this open-label study. The primary efficacy end point was the change in volume of subependymal giant-cell astrocytomas between baseline and 6 months. We gave everolimus orally, at a dose of 3.0 mg per square meter of body-surface area, to achieve a trough concentration of 5 to 15 ng per milliliter.. We enrolled 28 patients. Everolimus therapy was associated with a clinically meaningful reduction in volume of the primary subependymal giant-cell astrocytoma, as assessed on independent central review (P<0.001 for baseline vs. 6 months), with a reduction of at least 30% in 21 patients (75%) and at least 50% in 9 patients (32%). Marked reductions were seen within 3 months and were sustained. There were no new lesions, worsening hydrocephalus, evidence of increased intracranial pressure, or necessity for surgical resection or other therapy for subependymal giant-cell astrocytoma. Of the 16 patients for whom 24-hour video electroencephalography data were available, seizure frequency for the 6-month study period (vs. the previous 6-month period) decreased in 9, did not change in 6, and increased in 1 (median change, -1 seizure; P=0.02). The mean (±SD) score on the validated Quality-of-Life in Childhood Epilepsy questionnaire (on which scores can range from 0 to 100, with higher scores indicating a better quality of life) was improved at 3 months (63.4±12.4) and 6 months (62.1±14.2) over the baseline score (57.8±14.0). Single cases of grade 3 treatment-related sinusitis, pneumonia, viral bronchitis, tooth infection, stomatitis, and leukopenia were reported.. Everolimus therapy was associated with marked reduction in the volume of subependymal giant-cell astrocytomas and seizure frequency and may be a potential alternative to neurosurgical resection in some cases, though long-term studies are needed. (Funded by Novartis; ClinicalTrials.gov number, NCT00411619.).

Topics: Administration, Oral; Adolescent; Adult; Angiofibroma; Anticonvulsants; Astrocytoma; Brain Neoplasms; Child; Child, Preschool; Cognition; Drug Therapy, Combination; Everolimus; Facial Neoplasms; Female; Humans; Intracellular Signaling Peptides and Proteins; Male; Prospective Studies; Protein Serine-Threonine Kinases; Quality of Life; Seizures; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis; Young Adult

Tuberous sclerosis complex is a rare autosomal dominant genetic disorder that affects multiple organ systems, primarily affecting the central nervous system. It develops with a pathogenic mutation in tumour suppressor genes i.e. Tuberous Sclerosis Complex 1 or Tuberous Sclerosis Complex 2 which codes for protein hamartin and tuberin leading to unopposed hyperactivation of the mammalian target of the rapamycin signalling pathway. It presents with a triad of facial angiofibroma, intellectual disability, and epilepsy. We present a case of a 17-month female toddler with abnormal body movement with loss of consciousness and later developing into generalised jerky movements. On magnetic resonance imaging, a diagnosis of tuberous sclerosis was made. The patient underwent symptomatic management with anti-epileptic. As seizures in these cases are subtle, they remain undiagnosed for a long time leading to delays in management and developing refractory seizures.. angiofibroma; case reports; seizures; tuberous sclerosis; tumor suppressor gene.

Topics: Angiofibroma; Female; Humans; Infant; Seizures; Sirolimus; Tuberous Sclerosis; Tumor Suppressor Proteins

Topics: Angiofibroma; Double-Blind Method; Head and Neck Neoplasms; Humans; Immunosuppressive Agents; Sirolimus; Tuberous Sclerosis

Topics: Administration, Cutaneous; Angiofibroma; Antibiotics, Antineoplastic; Emollients; Facial Neoplasms; Humans; Sirolimus

Topics: Angiofibroma; Dermoscopy; Facial Neoplasms; Humans; Sirolimus; Tuberous Sclerosis

Topics: Angiofibroma; Facial Neoplasms; Humans; Sirolimus; Skin Neoplasms; Tuberous Sclerosis

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

Topics: Angiofibroma; Antibiotics, Antineoplastic; Autophagy; Carcinogenesis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Size; Cellular Reprogramming; Estrogens; Fibroblasts; Humans; Mutation, Missense; Sirolimus; Skin; Skin Neoplasms; TOR Serine-Threonine Kinases; Tuberous Sclerosis Complex 2 Protein

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.

Topics: Angiofibroma; Animals; Drug Delivery Systems; Micelles; Sirolimus; Swine; Tissue Distribution; Tuberous Sclerosis

Topics: Adult; Angiofibroma; Astrocytoma; Biological Availability; Brain Neoplasms; Drug Administration Routes; Drug Monitoring; Everolimus; Female; Humans; Immunosuppressive Agents; Medication Therapy Management; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis

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.

Topics: Adolescent; Angiofibroma; Antibiotics, Antineoplastic; Child; Humans; Male; Nasopharyngeal Neoplasms; Sirolimus; Treatment Outcome

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.. 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.. 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.. 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.

Topics: Administration, Topical; Angiofibroma; Antibiotics, Antineoplastic; Chromatography, High Pressure Liquid; Drug Compounding; Drug Stability; Facial Neoplasms; Gels; Humans; Hydrophobic and Hydrophilic Interactions; Sirolimus; Treatment Outcome

Topics: Angiofibroma; Calcitriol; Double-Blind Method; Facial Neoplasms; Humans; Prospective Studies; Sirolimus; Tuberous Sclerosis

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.. 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.. 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.. 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.

Topics: Adolescent; Adult; Angiofibroma; Facial Neoplasms; Humans; Middle Aged; Quality of Life; Sirolimus; Tuberous Sclerosis; Young Adult

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.

Topics: Angiofibroma; Cytoreduction Surgical Procedures; Facial Neoplasms; Humans; Neoplasm Recurrence, Local; Sirolimus; Tuberous Sclerosis

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.. Absztrakt: A facialis angiofibroma a Bourneville–Pringle-kór (sclerosis tuberosa) igen karakterisztikus bőrtünete, egyben egyik major diagnosztikus kritériuma is. Az arc centrális részére lokalizálódó hamartomatosus növedékek gyermekkorban alakulnak ki, majd az életkor előrehaladtával progrediálnak, és a beteg számára jelentős kozmetológiai problémát okoznak, a kezelőorvos számára pedig terápiás kihívást jelentenek. A tradicionális, invazív kezelési eljárások mellett új, ígéretes kezelési lehetőség a lokálisan alkalmazott szirolimusz. Az új terápiás lehetőségről számos nemzetközi közlemény született az utóbbi években, azonban egységes ajánlás az optimális szirolimuszkoncentrációra és -összetételre vonatkozólag nem áll rendelkezésre. A szerzők két, Bourneville–Pringle-kór miatt gondozott gyermek esetét mutatják be, akiknél sikeresen alkalmaztak lokális szirolimuszterápiát. Orv Hetil. 2019; 160(13): 516–520.

Topics: Administration, Topical; Angiofibroma; Child; Facial Neoplasms; Humans; Sirolimus; Treatment Outcome; Tuberous Sclerosis

Topics: Angiofibroma; Humans; Immunosuppressive Agents; Sirolimus; Tuberous Sclerosis

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.. 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).. 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.. 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.

Topics: Administration, Cutaneous; Adolescent; Adult; Age Factors; Angiofibroma; Child; Child, Preschool; Erythema; Facial Neoplasms; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Ointments; Retrospective Studies; Severity of Illness Index; Sirolimus; Skin Neoplasms; Tuberous Sclerosis; Tumor Burden; Young Adult

Tuberous sclerosis is an autosomal dominant genodermatosis characterized by nonmalignant hamartomas in multiple organs. Facial angiofibromas are most commonly located on the face and have the potential to cause disfigurement. Facial disfigurement negatively affects the quality of life of patients and their families, often leading to negative psychosocial outcomes. Nowadays there are no treatment guidelines for facial angiofibromas but due to the progressive nature of facial angiofibromas a safe technique offering good results is needed.. We report the case of a 40-year-old female affected by tuberous sclerosis, whose facial angiofibromas were satisfactorily treated by rapamycin 0.05% ointment, and a combined laser therapy.

Topics: Adult; Angiofibroma; Antibiotics, Antineoplastic; Combined Modality Therapy; Facial Neoplasms; Female; Humans; Lasers, Dye; Lasers, Gas; Lasers, Solid-State; Ointments; Sirolimus; Treatment Outcome; Tuberous Sclerosis

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.. 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.. 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.. 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.

Topics: Administration, Cutaneous; Adolescent; Angiofibroma; Asian People; Child; Child, Preschool; Face; Facial Neoplasms; Female; Genetic Testing; Humans; Immunosuppressive Agents; Male; Mutation; Severity of Illness Index; Sirolimus; Treatment Outcome; Tuberous Sclerosis; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins

Topics: Administration, Topical; Angiofibroma; Antibiotics, Antineoplastic; Brain; Child; Diagnosis, Differential; Facial Neoplasms; Humans; Magnetic Resonance Imaging; Male; Sirolimus; Treatment Outcome; Tuberous Sclerosis; Tuberous Sclerosis Complex 1 Protein; Tumor Suppressor Proteins

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.

Topics: Administration, Cutaneous; Angiofibroma; Antibiotics, Antineoplastic; Chemistry, Pharmaceutical; Humans; Sirolimus; Skin Cream; Tuberous Sclerosis

Topics: Administration, Topical; Adolescent; Angiofibroma; Antibiotics, Antineoplastic; Facial Neoplasms; Humans; Hypopigmentation; Male; Neoplasms, Multiple Primary; Sirolimus; Tuberous Sclerosis

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.

Topics: Administration, Topical; Adolescent; Angiofibroma; Antibiotics, Antineoplastic; Child; Female; Follow-Up Studies; Humans; Male; Pilot Projects; Sirolimus; Tuberous Sclerosis; Young Adult

Facial angiofibromas are the most troublesome cutaneous manifestations of the tuberous sclerosis complex and are difficult to treat. Lasers are most commonly used to treat these skin lesions, but results are disappointing with frequent recurrences. Recently, treatment of facial angiofibromas with topical rapamycin has been reported to yield promising results. We observed the need of laser ablation in addition to topical rapamycin to get best results for the treatment of angiofibromas in 4 cases. The result showed that topical rapamycin ointment was enough when the papules were yet small in size, i.e. less than a few millimeters, but additional laser ablation was needed for large papules approximately larger than 4 mm. Considering the natural course of facial angiofibromas, we believe that topical rapamycin can be best used in childhood patients. In adults, topical rapamycin was useful for treating the still present small papules and for preventing recurrences after laser treatment.

Topics: Adult; Angiofibroma; Antibiotics, Antineoplastic; Child; Combined Modality Therapy; Facial Neoplasms; Female; Humans; Lasers, Gas; Maintenance Chemotherapy; Male; Neoplasm Recurrence, Local; Sirolimus; Skin Neoplasms; Tuberous Sclerosis

Facial angiofibromas are present in most of the patients with the tuberous sclerosis complex and may cause severe disfiguration of the face. The tumor growth in tuberous sclerosis complex is promoted by the disinhibition of the mammalian target of rapamycin pathway. Thus, the systemic treatment with mammalian target of rapamycin inhibitors such as sirolimus and everolimus has recently been established to treat specific tuberous sclerosis complex-associated lesions. For patients who suffer from disfiguring facial angiofibromas only, there is a need for a topical use of mammalian target of rapamycin inhibitors. Sirolimus has been shown to be beneficial in treating facial angiofibromas. But the topical use of everolimus, which has the approval to treat tuberous sclerosis complex-associated tumors, namely giant cell astrocytomas and renal angiofibromas, has not been reported.. We present a 10-year-old girl whose facial angiofibromas were successfully treated with an everolimus ointment without relevant side effects. In addition, we provide a short pharmacological overview of sirolimus and everolimus with focus on the topical use.. Topical everolimus seems to be a favorable and safe option for patients with facial angiofibromas who do not require systemic treatment.

Topics: Angiofibroma; Child; Everolimus; Face; Female; Humans; Immunosuppressive Agents; Sirolimus; Tuberous Sclerosis

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).. To validate a reproducible scale created for the assessment of clinical severity and treatment response in these patients.. 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.. 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).. 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.

Topics: Angiofibroma; Antibiotics, Antineoplastic; Facial Neoplasms; Humans; Immunosuppressive Agents; Observer Variation; Reproducibility of Results; Severity of Illness Index; Sirolimus; Tuberous Sclerosis

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.

Topics: Angiofibroma; Antibiotics, Antineoplastic; Child; Facial Neoplasms; Female; Follow-Up Studies; Humans; Male; Sirolimus; Skin Cream; Time Factors; Tuberous Sclerosis

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.. To compare the efficacy of topical rapamycin formulation with that of vehicle for angiofibromas.. 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.. 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.. 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.

Topics: Administration, Cutaneous; Adolescent; Adult; Angiofibroma; Antibiotics, Antineoplastic; Child; Child, Preschool; Facial Neoplasms; Female; Gels; Humans; Male; Neoplasm Recurrence, Local; Ointments; Sirolimus; Treatment Outcome; Tuberous Sclerosis

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.. 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).. Improvement in the number and appearance of facial angiofibromas and erythema is noted, without scarring or adverse events.. 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.

Topics: Adult; Angiofibroma; Antibiotics, Antineoplastic; Combined Modality Therapy; Electrosurgery; Facial Neoplasms; Female; Humans; Lasers, Dye; Sirolimus; Tuberous Sclerosis

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.

Topics: Angiofibroma; Antibiotics, Antineoplastic; Child, Preschool; Facial Neoplasms; Humans; Immunosuppressive Agents; Male; Ointments; Sirolimus; Treatment Outcome; Tuberous Sclerosis

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous syndrome manifesting as hamartomatous growths in multiple organs. We present two cases of patients with TSC and associated facial angiofibromata treated with topical and oral rapamycin and discuss the role for rapamycin in the treatment of these disfiguring lesions. Our patients demonstrated decreased numbers of angiofibromata and less redness with this treatment. This is the first published report on the use of topical rapamycin for the treatment of angiofibromata.

Topics: Adult; Angiofibroma; Child; Facial Neoplasms; Humans; Immunosuppressive Agents; Male; Sirolimus; Tuberous Sclerosis; Young Adult

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder characterized by the development of multisystem hamartomatous tumours. Facial angiofibroma appears in up to 80% of patients and has a considerable psychological impact. Various invasive procedures have been used, although they show limited effectiveness and potential adverse effects.. To evaluate the sustained clinical benefits and safety profile of topical sirolimus applied to treat facial angiofibromas.. This study was a non-blinded, uncontrolled case-series comprising 10 patients with TSC-associated facial angiofibroma that was treated with 0.4% sirolimus ointment 3 times a week for 9 months. Patients were clinically evaluated at baseline and at 6, 12, 24 and 36 weeks. Plasma levels of sirolimus were determined.. A sustained improvement was observed in erythema and in the size and extension of the lesions as early as the first weeks of treatment. Sirolimus plasma levels remained below detection limits (0.3 ng/mL) in all cases. The formula was well-tolerated with no local or systemic adverse effects.. Topical sirolimus seems to be an effective and safe medical alternative to surgery or laser-based treatments in patients with TSC-associated facial angiofibromas.

Topics: Administration, Topical; Adolescent; Adult; Angiofibroma; Child; Face; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Sirolimus; Tuberous Sclerosis; Young Adult

Topics: Administration, Cutaneous; Adult; Angiofibroma; Chemistry, Pharmaceutical; Erythema; Esthetics; Facial Neoplasms; Female; Humans; Neoplasm Recurrence, Local; Neoplasms, Multiple Primary; Sirolimus; Solutions; Treatment Outcome; Tuberous Sclerosis

Tuberous sclerosis (TS) is the second most common genodermatosis in our country and one of its main characteristics is the presence of facial angiofibromas. These benign tumors can be really bothersome for some patients and there is not a gold-standard treatment. Laser therapy has been used with good responses but it is a painful option and recurrence is guaranteed. TS develops as a result of a mutation of one of two genes, TSC1 or TSC2, which encode for hamartin and tuberin, respectively. TSC1 and TSC2 are tumor suppressors that inhibit mTOR, which if mutated results in mTOR activation, leading to an increase in protein translation. This eventually induces formation of hamartomatous tumors in patients with TSC. Oral rapamycin had been reported to be effective for the treatment of various tumors, apparently because of its action of inhibiting the m-TOR complex. Recently it has been suggested that the drug may be effective when applied topically. We report the 6th case of facial AF treated with topical rapamycin, 1 percent, once per day. An excellent response was achieved surprisingly rapidly. We propose this option as a safe and effective therapy.

Topics: Angiofibroma; Antibiotics, Antineoplastic; Child; Facial Neoplasms; Female; Humans; Sirolimus; Skin Neoplasms; Tuberous Sclerosis

Tuberous sclerosis complex (TSC) is an autosomal dominant genodermatosis characterised by the development of hamartomatous tumours in multiple organs including the brain, skin, kidneys, heart and lungs. Facial angiofibromas are the most visible and unsightly of the cutaneous manifestations of TSC, often resulting in stigmatisation for both the affected individuals and their families. Current treatments include vascular laser, ablative lasers and other destructive techniques such as shave excision and electrodessication. For the best outcome these treatments have to be repeated throughout childhood and teenage years, necessitating multiple general anaesthetics. We report a pilot study of topical rapamycin in four children with TSC and facial angiofibromas. Two patients were trialled on 0.1% rapamycin in petrolatum and the other two patients with 0.1% rapamycin solution (Rapamune) applied topically. Both preparations were rapidly and equally effective, however the 0.1% in petrolatum was much better tolerated. Younger patients with smaller angiofibromas had the best response with near complete clearance. Both preparations were more cost effective than pulsed dye laser under general anaesthesia. Although larger studies are needed, this treatment shows a potential to be a first-line management for facial angiofibromas in TSC and appears safe to start in early childhood.

Topics: Administration, Topical; Adolescent; Angiofibroma; Antibiotics, Antineoplastic; Child; Child, Preschool; Facial Neoplasms; Female; Follow-Up Studies; Humans; Male; Pilot Projects; Sirolimus; Treatment Outcome; Tuberous Sclerosis

Dysregulation of mTOR signalling by mutations in tuberin and/or hamartin leads to the formation of tuberous sclerosis complex (TSC). Trials to treat TSC using mTOR inhibitors, including rapamycin, have been performed. Although rapamycin improves many TSC lesions, significant side-effects appear after systemic administration. Topical administration has been recommended.. The efficacy of rapamycin-tacrolimus ointment was examined for TSC-related angiofibroma.. Left-right comparisons of the tacrolimus ointments with/without 0·2% rapamycin was conducted in symmetrical facial angiofibromas in nine patients with definitive TSC. After the 3-month treatment, a cumulative score for redness, flatness and papule size was used to evaluate the efficacy of the treatment. Blood rapamycin levels were analysed by liquid chromatography-electrospray mass spectrometry (LC-ESI/MS).. At the end of the treatment, all of the scores significantly improved for rapamycin-tacrolimus treatment compared with tacrolimus alone. No adverse reactions were noted and blood levels of rapamycin were below the detection limit in all cases.. Topical application of rapamycin-tacrolimus ointment is a safe and useful treatment for TSC-related angiofibroma.

Topics: Administration, Cutaneous; Adolescent; Adult; Aged; Aged, 80 and over; Angiofibroma; Child; Drug Combinations; Facial Neoplasms; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Ointments; Pharmaceutical Vehicles; Pilot Projects; Sirolimus; Tacrolimus; Treatment Outcome; Tuberous Sclerosis; Young Adult

Topics: Administration, Cutaneous; Adolescent; Adult; Angiofibroma; Antibiotics, Antineoplastic; Facial Neoplasms; Female; Humans; Off-Label Use; Sirolimus; Tuberous Sclerosis

Topics: Angiofibroma; Facial Neoplasms; Female; Humans; Immunosuppressive Agents; Sirolimus; Tuberous Sclerosis

Topics: Administration, Topical; Adolescent; Angiofibroma; Cheek; Diagnosis, Differential; Facial Neoplasms; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Sirolimus; Tuberous Sclerosis

Tuberous sclerosis complex (TSC) is an inherited multisystem disorder; it may involve kidney, brain, skin, lungs, and liver. We report a 37-year-old female TSC patient presenting with skin lesions (angiofibromas, molluscum pendulum). Radiologic examination revealed additional brain and renal lesions consisting of tumors, cysts, and angiomyolipomas. Treatment with rapamycin disclosed improvement in skin lesions. The number and volume of angiofibromas and molluscum pendulum reduced progressively in 6 months. During the ninth month of treatment, magnetic resonance imaging was repeated for renal and brain lesions. Imaging results showed reduction in tumor and angiomyolipoma volumes. Oral rapamycin therapy can improve renal, brain, and skin lesions in TSC disease. Therefore, it may be an alternative therapy for TSC patients.

Topics: Adult; Angiofibroma; Brain Neoplasms; Facial Neoplasms; Female; Humans; Immunosuppressive Agents; Kidney Neoplasms; Magnetic Resonance Imaging; Sirolimus; Skin Neoplasms; Tuberous Sclerosis

Herein we have reported the use of rapamycin in immunosuppressive treatment after renal transplantation as a therapy of choice in a patient with diagnosis of tuberous sclerosis complex (TSC). TSC is a genetic disorder, caused by mutations of TSC1 or TSC2 genes. Products of these genes, hamartin and tuberin, create a complex that inhibits mammalian target of rapamycin (mTOR), a key protein engaged in regulation of the cell cycle. Mutations of TSC genes lead to constitutive activation of mTOR resulting in uncontrolled proliferation, differentiation, and migration of cells. As a consequence malformations of many organs arise. We have presented a case of a 47-year-old female TSC patient with multisystem involvement (skin, brain, lungs, and kidneys), who developed end-stage renal disease ESRD due to angiomyolipomas with subsequent bilateral nephrectomy. At the age of 44 years, she started hemodialysis treatments and 10 months later underwent kidney transplantation. Immunosuppressive treatment included the mTOR inhibitor rapamycin. Since the patient was discharged from hospital, she has remained in good clinical condition with stable graft function. Clinical evaluation after 2 years treatment with rapamycin revealed significant regression of skin lesions. Brain, chest, and abdominal cavity computed tomography images remained stable. No complications of immunosuppressive treatment or TSC were observed. Experimental and clinical studies have confirmed that rapamycin exerts beneficial effects in TSC, providing a new therapeutic option. Therefore an immunosuppressive regimen with rapamycin should be considered as the treatment of choice after kidney transplantation among patients with TSC seeking to avoid development or progression of disease complications.

Topics: Adult; Angiofibroma; Facial Neoplasms; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Methylprednisolone; Mutation; Sirolimus; Tacrolimus; Tuberous Sclerosis; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder with an incidence of approximately one in 6000. It arises from a genetic abnormality involving either the TSC1 gene on chromosome 9 or the TSC2 gene on chromosome 16. The protein product of TSC1 is hamartin and that of TSC2 is tuberin. In cells, hamartin and tuberin form a complex which inhibits the mammalian target of rapamycin (mTOR), a central controller of cell growth and proliferation. Angiofibroma affects 70-80% of patients with TSC, typically on the face. We report a patient with TSC with recurrent life-threatening haemorrhage from both kidneys due to extensive angiomyolipoma formation leading to bilateral nephrectomy and renal transplantation. Immunosuppressive treatment with rapamycin, a specific mTOR inhibitor, initiated because of renal transplantation, reduced facial angiofibroma dramatically.

Topics: Adolescent; Angiofibroma; Antibiotics, Antineoplastic; Facial Neoplasms; Female; Humans; Protein Kinase Inhibitors; Protein Kinases; Sirolimus; Skin Neoplasms; TOR Serine-Threonine Kinases; Tuberous Sclerosis