Fast and safe clinical response to sonidegib in a 98-year old woman affected by locally advanced basal cell carcinoma.

A 98-year-old woman presented with histologically confirmed locally advanced basal cell carcinoma of the face. A multidisciplinary approach excluded surgery because of the site near sensitive organs, extension, age, and comorbidities. Patient and caregivers declined radiotherapy considering the necessity of multiple hospital appointments. The patient was then placed on therapy with sonidegib, an oral inhibitor of the Hedgehog signaling pathway. There was a very rapid clinical response after only 28 days of treatment. The basal cell carcinoma improved progressively, with no adverse events reported. This case illustrates the efficacy and safety of this treatment in an advanced age patient. This treatment had a remarkably positive impact on quality of life, including that of the caregivers.

Validation of the Index for Facial Angiofibromas: Data analysis from a randomized controlled trial of sirolimus gel treatment in patients with tuberous sclerosis complex.

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.

Long-term follow-up of patients with high-risk facial basal cell carcinoma treated with interferon.

BACKGROUND: Surgery is the treatment of choice for patients with basal cell carcinoma (BCC). When surgery is not a choice, only radiotherapy is recommended for patients with high-risk facial BCC. Interferon could be an acceptable therapeutic option for these patients. OBJECTIVE: To evaluate the long-term clinical response to interferon therapy in patients with high-risk facial BCC. METHODS: Patients with high-risk facial BCC were treated with perilesional injections of alpha-2b+ gamma interferons. Those with incomplete clinical response were reevaluated, their residual tumors excised, and declared cured. Patients treated with interferon and those treated with interferon plus surgery were followed for five years. Time to recurrence and the emergence of a new facial BCC were estimated by Kaplan-Meier survival analysis. Adverse events were documented. RESULTS: This study included 195 participants; 143 (73.3%) showed a complete response (95% CI 67.2‒80.1). Patients developed recurrence after a mean of 55 months (95% CI 53.8‒57.4). The estimated rate of recurrence was 12.3% (95% CI 7.4‒17.1). Patients developed a new BCC after a mean of 52.7 months (95% CI 50.4‒54.9). The estimated rate for development of a new BCC was 20.0% (95% CI 14.4‒25.9). Fifteen (7.7%) patients abandoned the study during follow-up. Adverse events were frequent but moderate or mild; fever and local pain were the most frequent. STUDY LIMITATIONS: Observational cohort design without a control group for comparison. CONCLUSIONS: Perilesional injections of alpha-2b+ gamma interferons in patients with facial high-risk BCC offer a satisfactory cure rate after five years of follow-up with an acceptable safety profile.

A survey of patients with facial angiofibromas associated with tuberous sclerosis complex: Short-, medium- and long-term efficacy and safety of topical rapamycin.

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.

Hemangioma segmentario de la barba / Segmental Beard Hemangioma

Los hemangiomas infantiles son el resultado de la proliferación de células del endotelio vascular y representan los tumores benignos más frecuentes en la infancia, con una incidencia estimada del 4-10% en bebés caucásicos. Se clasifican según el número, la profundidad y la distribución. Dentro de esta última clasificación se encuentran aquellos denominados segmentarios, que se caracterizan por su distribución extensa en áreas de prolongaciones mesodérmicas embrionarias. Se comunica el caso de una paciente evaluada al mes y medio de vida, con un hemangioma extenso del área mandibular y cuello anterior (hemangioma segmentario de la barba). Se describe la importancia de los estudios complementarios para evaluar el compromiso de órganos subyacentes, para detectar síndromes asociados y definir el tratamiento sobre la base de estos resultados. (AU)

Infantile hemangiomas arise from the proliferation of vascular endothelial cells and represent the most common benign tumors in infancy, with an estimated incidence of 4-10% in Caucasian infants. They vary according to their number, depth, and distribution. Within the latter classification are the so-called segmental ones, which feature an extensive distribution in areas of embryonic mesodermal extensions. We report the case of a patient evaluated at one and a half months of life with an extensive hemangioma of the mandibular area and anterior neck (segmental hemangioma of the beard). We describe the importance of complementary studies for evaluating the involvement of underlying organs, detecting associated syndromes, and defining the treatment based on these findings. (AU)

Analysis of current data on the use of topical mTOR inhibitors in the treatment of facial angiofibromas in tuberous sclerosis complex-An update.

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.

Asociación de hemangioma en zona cérvico facial y hemangioma subglótico en un neonato / Association of cervical-facial and subglottic hemangioma in neonates / Associação de hemangioma cervicofacial e subglótico em neonatos

Se presenta un neonato con hemangioma cérvico facial y posterior diagnóstico de hemangioma subglótico. Los hemangiomas en el período neonatal y los primeros meses de vida requieren una atención cuidadosa. Debido a su patrón de crecimiento y la futura aparición de nuevas lesiones, son considerados imprevisibles en esta etapa. Se encontró una fuerte asociación entre los hemangiomas difusos de localización cérvico facial y los hemangiomas sintomáticos de la vía aérea alta. El riesgo está relacionado con el grado de extensión de la afectación cutánea en un área que incluye la piel de la región mandibular, el mentón, el labio inferior y la parte anterior del cuello. Los hemangiomas infantiles requieren tratamiento cuando presentan riesgo vital y alteraciones funcionales, como compromiso de la vía aérea.

This is the case of a newborn with cervical hemangioma and a subsequent diagnosis of subglottic hemangioma. Hemangiomas in neonates and infants require careful attention. Due to their growth pattern and the potential appearance of new lesions, they are considered unpredictable at this stage. A strong link was found between diffuse cervical-facial and symptomatic upper airway hemangiomas. The risk is related to the extent of skin involvement in a given area, which might include the jaw, chin, lower lip, and front of the neck skin. Infant hemangiomas require treatment when they present life-threatening and functional alterations, such as airway compromise.

Relatamos o caso de um recém-nascido com hemangioma cervical com diagnóstico posterior de hemangioma subglótico. Hemangiomas em recém-nascidos e lactentes requerem atenção cuidadosa. Devido ao seu padrão de crescimento e ao potencial aparecimento de novas lesões, são considerados imprevisíveis nessa fase. Uma forte associação foi encontrada entre hemangiomas cervicofaciais difusos e hemangiomas sintomáticos das vias aéreas superiores. O risco está relacionado à extensão do envolvimento da pele da mandíbula, o queixo, o lábio inferior e a pele da frente do pescoço. Os hemangiomas infantis necessitam de tratamento quando apresentam alterações funcionais ou risco de vida, como comprometimento das vias aéreas.

The combination of photodynamic therapy and ultrapulse carbon dioxide laser for facial angiofibromas in tuberous sclerosis complex: A case report.

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.

The Efficacy of Everolimus for Facial Angiofibromas in Tuberous Sclerosis Complex Patients Treated for Renal Angiomyolipoma/Subependymal Giant Cell Astrocytoma.

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.

Evaluation of Clinical Properties and Treatment Responses of Infantile Hemangioma.

BACKGROUND: Infantile hemangiomas are the most common vascular tumors in childhood. Although spontaneous regression is common; several infantile hemangioma patients need treatment due to possible morbidities. The aim of this study was to investigate the medical methods used in the treatment of infantile hemangiomas and to evaluate the factors affecting treatment response. METHODS: Clinical and demographic characteristics, risk factors, treatment indications, modalities, duration, and responses of 100 patients between January 2007 and January 2017 were evaluated. RESULTS: The most common form of hemangiomas was superficial lesions. Sixty three per cent of the patients were female. Ulceration and hemorrhage were found in 26% of the cases and ocular problems were detected in 3% of the cases. Among the indications for treatment were cosmetic reasons with 56%, ulcer and bleeding with 25% and risk of vision problems with 13%. Propranolol with/without steroid was used as first line treatment and response rates were: 84 patients with more than 50% response, 9 patients with less than 50% response and 7 patients with treatment refractory. The most important factor affecting the treatment response was age at the beginning of the treatment. Duration of treatment, presence of ulceration, location, and size of hemangioma were also found to have significant effects on responses. CONCLUSIONS: This study demonstrated the importance of the kind and initiation time of infantile hemangioma treatment. A strong positive effect can be reached by starting treatment before the end of the proliferation phase. J Drugs Dermatol. 2020;19(12): doi:10.36849/JDD.2020.5009.

Improved health-related quality of life in patients treated with topical sirolimus for facial angiofibroma associated with tuberous sclerosis complex.

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.

Long-term stability of 0.1% rapamycin hydrophilic gel in the treatment of facial angiofibromas.

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.