Assuntos
Síndrome do Nevo Basocelular , Consenso , Proteínas Hedgehog , Neoplasias Cutâneas , Humanos , Proteínas Hedgehog/antagonistas & inibidores , Proteínas Hedgehog/metabolismo , Síndrome do Nevo Basocelular/tratamento farmacológico , Síndrome do Nevo Basocelular/diagnóstico , Síndrome do Nevo Basocelular/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Anilidas/uso terapêutico , Piridinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacosAssuntos
Anilidas , Síndrome do Nevo Basocelular , Piridinas , Qualidade de Vida , Humanos , Síndrome do Nevo Basocelular/tratamento farmacológico , Estudos Retrospectivos , Masculino , Feminino , Piridinas/uso terapêutico , Piridinas/efeitos adversos , Anilidas/uso terapêutico , Anilidas/efeitos adversos , Pessoa de Meia-Idade , Adulto , Resultado do Tratamento , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológicoRESUMO
ABSTRACT: Targeting the mammalian target of rapamycin (mTOR) pathway represents a potentially novel approach to treat basal cell carcinoma (BCC), but activation of this pathway has not been well described in human BCCs. The purpose of this study was to assess whether mTOR pathway activation occurs in BCCs (both sporadic and syndromic) and report a case of a patient with Gorlin syndrome (GS) whose clinically suspicious BCCs responded to mTOR inhibition through topical sirolimus treatment. After Stanford Institutional Review Board Approval, archived BCCs from patients with GS (n = 25), sporadic BCCs (n = 35), and control tissues were subjected to immunohistochemical analysis for the activation of mTOR pathway, and immunohistochemical staining intensity was evaluated by a dermatopathologist. BCCs (compared with normal skin) had elevated levels of eIF4EBP1 ( Padjusted = 0.0336), which is downstream of mTOR. a serine/threonine kinase Phospho-(AKT), which interacts with mTOR, was also significantly elevated (perinuclear: Padjusted < 0.0001; cytoplasmic: Padjusted = 0.0021). When off-label topical 1% sirolimus was used on a pediatric patient with GS, we noted reduction of new BCC development and decreased size of existing neoplasms clinically suspicious for BCCs. This treatment was well tolerated after 2 years of continuous use, with no other treatments needed during this period. Topical sirolimus is a promising therapeutic candidate against both sporadic and GS-associated BCC. Multicenter, prospective studies are needed to understand the efficacy and safety of topical mTOR inhibitors in BCC treatment, and ascertain whether the immunohistochemical markers downstream of mTOR could have predictive value in identifying BCCs most likely to respond to topical mTOR inhibitors, such as sirolimus.
Assuntos
Carcinoma Basocelular , Inibidores de MTOR , Transdução de Sinais , Sirolimo , Neoplasias Cutâneas , Serina-Treonina Quinases TOR , Humanos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/metabolismo , Carcinoma Basocelular/tratamento farmacológico , Carcinoma Basocelular/patologia , Carcinoma Basocelular/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Masculino , Feminino , Transdução de Sinais/efeitos dos fármacos , Pessoa de Meia-Idade , Inibidores de MTOR/farmacologia , Inibidores de MTOR/uso terapêutico , Adulto , Idoso , Síndrome do Nevo Basocelular/tratamento farmacológico , Síndrome do Nevo Basocelular/patologia , Síndrome do Nevo Basocelular/metabolismo , Imuno-Histoquímica , Antibióticos Antineoplásicos , Criança , Adolescente , Adulto Jovem , Idoso de 80 Anos ou mais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Uso Off-Label , Resultado do Tratamento , Proteínas de Ciclo Celular , Proteínas Adaptadoras de Transdução de SinalAssuntos
Anilidas , Síndrome do Nevo Basocelular , Carcinoma Basocelular , Piridinas , Neoplasias Cutâneas , Humanos , Síndrome do Nevo Basocelular/tratamento farmacológico , Estudos Retrospectivos , Carcinoma Basocelular/tratamento farmacológico , Carcinoma Basocelular/patologia , Neoplasias Cutâneas/tratamento farmacológicoRESUMO
Although basal cell carcinomas arise from ectopic Hedgehog pathway activation and can be treated with pathway inhibitors, sporadic basal cell carcinomas display high resistance rates, whereas tumors arising in patients with Gorlin syndrome with germline Patched (PTCH1) alterations are uniformly suppressed by inhibitor therapy. In rare cases, patients with Gorlin syndrome on long-term inhibitor therapy will develop individual resistant tumor clones that rapidly progress, but the basis of this resistance remains unstudied. In this study, we report a case of an SMO inhibitor-resistant tumor arising in a patient with Gorlin syndrome on suppressive SMO inhibitor for nearly a decade. Using a combination of multiomics and spatial transcriptomics, we define the tumor populations at the cellular and tissue level to conclude that Gorlin tumors can develop resistance to SMO inhibitors through the previously described basal to squamous cell carcinoma transition. Intriguingly, through spatial whole-exome genomic analysis, we nominate PCYT2, ETNK1, and the phosphatidylethanolamine biosynthetic pathway as genetic suppressors of basal to squamous cell carcinoma transition resistance. These observations provide a general framework for studying tumor evolution and provide important clinical insight into mechanisms of resistance to SMO inhibitors for not only Gorlin syndrome but also sporadic basal cell carcinomas.
Assuntos
Síndrome do Nevo Basocelular , Carcinoma Basocelular , Carcinoma de Células Escamosas , Resistencia a Medicamentos Antineoplásicos , Neoplasias Cutâneas , Receptor Smoothened , Humanos , Síndrome do Nevo Basocelular/genética , Síndrome do Nevo Basocelular/patologia , Síndrome do Nevo Basocelular/tratamento farmacológico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Receptor Smoothened/genética , Receptor Smoothened/antagonistas & inibidores , Receptor Smoothened/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma Basocelular/genética , Carcinoma Basocelular/tratamento farmacológico , Carcinoma Basocelular/patologia , Masculino , Anilidas/uso terapêutico , Feminino , Transdução de Sinais/efeitos dos fármacos , Piridinas/uso terapêuticoRESUMO
Nevoid basal-cell carcinoma syndrome (Gorlin syndrome) is characterized by numerous cutaneous basal cell carcinomas mediated by mutations in the hedgehog pathway. Vismodegib or sonidegib represent promising treatment options. We identified 10 Gorlin patients who were treated with sonidegib (n = 6) or vismodegib (n = 4) between March 2012 and March 2022. We analyzed the activity, toxicity, and duration of the response to oral hedgehog inhibitors. The number of new tumors that developed prior to treatment or after treatment as well as the time of response and durability of responses were assessed. All patients achieved a complete remission. With a 30.7 ± 48.4-month median follow-up, the drug treatment significantly reduced the number of new basal cell cancers from a mean of 28.3 ± 24.6 prior to treatment to a mean of 1.4 ± 2.0 during treatment (p = 0.0048). The median time to develop a new basal cell cancer was 47.3 months. Three patients eventually developed localized recurrences. After resection, ongoing treatment suppressed the development of additional lesions. One patient developed numerous new drug-resistant basal cell cancers and died of acute leukemia. Six patients required treatment modifications for toxicity. Sustained hedgehog inhibitor treatment can suppress the progression of both new and existing basal cell carcinomas for an extended period. Drug administration schedule adjustments improved tolerance without altering efficacy, potentially contributing to a prolonged response duration.
Assuntos
Síndrome do Nevo Basocelular , Carcinoma Basocelular , Neoplasias Cutâneas , Humanos , Síndrome do Nevo Basocelular/tratamento farmacológico , Síndrome do Nevo Basocelular/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Proteínas Hedgehog/metabolismo , Proteínas Hedgehog/uso terapêutico , Carcinoma Basocelular/tratamento farmacológico , Carcinoma Basocelular/patologiaRESUMO
INTRODUCTION: Non-melanoma skin cancer within previously irradiated areas presents a common challenge, requiring innovative therapies. Complex scenarios, like XRT-induced basal cell carcinoma (BCC) or Gorlin's syndrome, often involve multiple synchronous tumor lesions where photodynamic therapy (PDT) offers a viable therapeutic alternative. CLINICAL CASE: We present the case of a 49-year-old male with a history of XRT for brain tumors. The patient was undergoing treatment for recurrent basal cell carcinomas (BCCs) in the right temporal irradiated area, unresponsive to conventional treatments. In the latest evaluation, the patient presented a nodular tumor and several peripheral superficial foci. Photodynamic therapy (PDT) was administered using methyl aminolevulinate 160 mg/g in cream (Metvix®) in two sessions spaced 7 days apart before surgery. The photosensitizer was applied 3 h before initiating PDT, and red light exposure was performed with the Aktilite© lamp (wavelength 630 nm, 100 mm distance, voltage 100 to 240 V, frequency 50 Hz, power 180 W) for 7 min. CONCLUSIóN: PDT with methyl aminolevulinate demonstrated efficacy as a neoadjuvant treatment in a case of multiple XRT-induced BCCs before surgery. PDT emerges as a valuable therapeutic alternative for multiple BCCs, particularly in non-responsive cases.
Assuntos
Síndrome do Nevo Basocelular , Carcinoma Basocelular , Fotoquimioterapia , Neoplasias Cutâneas , Masculino , Humanos , Pessoa de Meia-Idade , Fármacos Fotossensibilizantes/uso terapêutico , Terapia Neoadjuvante , Neoplasias Cutâneas/patologia , Fotoquimioterapia/métodos , Carcinoma Basocelular/tratamento farmacológico , Carcinoma Basocelular/radioterapia , Carcinoma Basocelular/patologia , Ácido Aminolevulínico/uso terapêutico , Síndrome do Nevo Basocelular/tratamento farmacológico , Resultado do TratamentoAssuntos
Síndrome do Nevo Basocelular , Carcinoma Basocelular , Neoplasias Cutâneas , Humanos , Síndrome do Nevo Basocelular/tratamento farmacológico , Síndrome do Nevo Basocelular/patologia , Fluoruracila , Ácido Salicílico , Carcinoma Basocelular/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológicoAssuntos
Síndrome do Nevo Basocelular , Carcinoma Basocelular , Fotoquimioterapia , Neoplasias Cutâneas , Humanos , Síndrome do Nevo Basocelular/tratamento farmacológico , Seguimentos , Carcinoma Basocelular/tratamento farmacológico , Ácido Aminolevulínico/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/prevenção & controle , Fármacos Fotossensibilizantes/uso terapêuticoAssuntos
Síndrome do Nevo Basocelular , Carcinoma Basocelular , Idoso de 80 Anos ou mais , Anilidas , Síndrome do Nevo Basocelular/diagnóstico , Síndrome do Nevo Basocelular/tratamento farmacológico , Compostos de Bifenilo , Carcinoma Basocelular/tratamento farmacológico , Feminino , Síndrome do Hamartoma Múltiplo , Humanos , PiridinasRESUMO
INTRODUCTION: Conventional methods of basal cell carcinomas (BCC) treatment bring many severe side effects, especially, if they are repeated many times. The aim of this study is to present the clinical effectiveness of photodynamic method in the treatment and prevention of BCC relapses on the face and to propose a management algorithm. METHODS: In a patient with Gorlin-Goltz syndrome (NBCCS) lesions on the face were assessed clinically and with photodynamic diagnostics (PDD), initially and in follow-up every 3 months, for a total of 12 months. Detected BCCs were treated with photodynamic therapy three times every week. RESULTS: In whole follow-up period no clinical relapses were shown. However, in PDD after 6 month in one irradiated and in one initially clinically clear area red fluorescence indicating atypical foci was observed and irradiated additional one time. DISCUSSION: Photodynamic therapy is not limited by previous treatments, can be repeated without adverse events, heals multiple lesions at once and prevents new ones. Because BCC in NBCCS will occur constantly, the implementation of PDD to control the condition of the skin in long-term care should be obligatory. We indicate the validity of using the photodynamic diagnostic and therapy, as a medical procedures of choice.
Assuntos
Síndrome do Nevo Basocelular , Carcinoma Basocelular , Fotoquimioterapia , Neoplasias Cutâneas , Algoritmos , Síndrome do Nevo Basocelular/diagnóstico , Síndrome do Nevo Basocelular/tratamento farmacológico , Carcinoma Basocelular/tratamento farmacológico , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológicoRESUMO
This report describes a PTCH1 c.1804C > T (p.Arg602*) mutation causing a Chinese nevoid basal cell carcinoma syndrome (NBCCS) with multiple basal cell carcinoma (BCC) phenotype. Multiple modalities including microwave ablation, photodynamic therapy, and excision surgery have a good respond to the NBCCS. The current results broaden the spectrum of PTCH1 mutations responsible for NBCCS.
Assuntos
Síndrome do Nevo Basocelular , Carcinoma Basocelular , Fotoquimioterapia , Ácido Aminolevulínico/uso terapêutico , Síndrome do Nevo Basocelular/tratamento farmacológico , Síndrome do Nevo Basocelular/genética , Síndrome do Hamartoma Múltiplo , Humanos , Mutação , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/uso terapêuticoRESUMO
Sonic hedgehog pathway inhibitor Vismodegib is the first systemic treatment to be approved for metastatic or locally advanced basal cell carcinoma non-subsidiary of surgical treatment, and appears to be a promising treatment option for patients with nevoid basal cell carcinoma syndrome. In these patients, where repeated or prolonged treatment may be necessary, the psychological exhaustion caused by the chronicity of less severe adverse effects appears as the main limiting factor in the persistence of the drug in the long term and in the willingness of patients to take the drug again after its suspension. We report our experience with three cases where a drug holiday approach was effective in decreasing the intensity of adverse effects or improving the patient's subjective tolerance to the drug while maintaining clinical response.