RESUMO
Xeroderma pigmentosum (XP) is a rare autosomal recessive disease; relatively mild XP patients are sometimes designated as having pigmented xerodermoid or xerodermoid pigmentosum (XP-V), a variant of XP. It is commonly associated with many long-standing skin conditions and tumors, including malignancies, management of which is necessary to prevent the progress of the disease. The objective of the study was to report the use of a number of innovative therapeutic and prophylactic treatments, beyond surgery, such as topical 5-fluorouracil, topical imiquimod, other topical immunomodulators, or photodynamic therapy, in treating skin eruptions and their complications in XP patients. This was a prospective therapeutic interventional study in which 50 patients with XP-V were evaluated. Age of subjects ranged from 2 to 50 years with a mean age of 18 years. This study was divided into two parts. In part one, patients were treated by applying topical zinc sulfate 25% twice daily on entire face for 2 months, then once daily for several months or years. In another instance, two women were treated with heat dermabrasion with needle diathermy on the entire face under local anesthesia, followed by application of trichloroacetic acid 35% peeling in a single session. In part two, topical podophyllin 25% was used as therapy for 18 patients, all of whom had XP complications, such as keratoacanthoma, basal cell carcinomas and squamous cell cancers.1 Podophyllin was applied to the lesions until complete resolution was documented. All patients treated with topical zinc sulfate 25% responded well as determined by clearance of actinic keratoses (ActK) and small malignant lesions, minimization of pigmented freckles, prevention of new lesions, and ceased progress of eruptions. Heat dermabrasion administered in a single session resulted in the clearance of pigmented freckles, ActK, and small tumors, and cessation of new eruptions during follow-up that continued for up to 6 years.
Assuntos
Ceratose Actínica , Melanose , Neoplasias Cutâneas , Xeroderma Pigmentoso , Humanos , Feminino , Adolescente , Pré-Escolar , Criança , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Xeroderma Pigmentoso/complicações , Xeroderma Pigmentoso/tratamento farmacológico , Xeroderma Pigmentoso/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/prevenção & controle , Ácido Tricloroacético/uso terapêutico , Sulfato de Zinco/uso terapêutico , Dermabrasão , Temperatura Alta , Podofilina/uso terapêuticoRESUMO
Xeroderma pigmentosum(XP) is a rare autosomal recessive genodermatosis. Individuals with XP are characterized by severe skin sensitivity to sunlight, and more susceptible to the development of skin malignancies in sun-exposed regions. We report the experience of modified 5-aminolaevulinic acid photodynamic therapy (M-PDT) in the treatment of three children with XP. They all developed multiple freckle-like hyperpigmented papules and plaques on the face from an early age. Multiple cutaneous squamous cell carcinoma (cSCC) and actinic keratosis (AK) were developed in case 1 and case 2, and basal cell carcinoma (BCC) was observed in case 3. Sanger sequencing of targeted gene identified that case 1 and case 3 carried compound heterozygous mutations, and case 2 carried a homozygous mutation in the XPC gene. After multiple courses of M-PDT, the lesions were removed with mild adverse reactions, nearly painless and satisfactory safety.
Assuntos
Carcinoma de Células Escamosas , Fotoquimioterapia , Neoplasias Cutâneas , Xeroderma Pigmentoso , Criança , Humanos , Xeroderma Pigmentoso/complicações , Xeroderma Pigmentoso/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Fotoquimioterapia/métodosAssuntos
Neoplasias Cutâneas , Xeroderma Pigmentoso , Humanos , Imiquimode/uso terapêutico , Xeroderma Pigmentoso/complicações , Xeroderma Pigmentoso/tratamento farmacológico , Estudos Prospectivos , Neoplasias Cutâneas/prevenção & controle , Neoplasias Cutâneas/tratamento farmacológico , QuimioprevençãoRESUMO
This case report describes treatment regimens with topical calcipotriol plus fluorouracil for 2 patients with xeroderma pigmentosum.
Assuntos
Neoplasias Cutâneas , Xeroderma Pigmentoso , Humanos , Xeroderma Pigmentoso/complicações , Xeroderma Pigmentoso/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/prevenção & controle , Fluoruracila , CalcitriolAssuntos
Carcinoma de Células Escamosas , Neoplasias Cutâneas , Xeroderma Pigmentoso , Humanos , Xeroderma Pigmentoso/complicações , Xeroderma Pigmentoso/tratamento farmacológico , Xeroderma Pigmentoso/genética , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Carcinoma de Células Escamosas/complicações , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Anticorpos Monoclonais Humanizados/uso terapêuticoRESUMO
Xeroderma Pigmentosum protein C (XPC) is involved in recognition and repair of bulky DNA damage such as lesions induced by Ultra Violet (UV) radiation. XPC-mutated cells are, therefore, photosensitive and accumulate UVB-induced pyrimidine dimers leading to increased cancer incidence. Here, we performed a high-throughput screen to identify chemicals capable of normalizing the XP-C phenotype (hyper-photosensitivity and accumulation of photoproducts). Fibroblasts from XP-C patients were treated with a library of approved chemical drugs. Out of 1280 tested chemicals, 16 showed ≥25% photo-resistance with RZscore above 2.6 and two drugs were able to favor repair of 6-4 pyrimidine pyrimidone photoproducts (6-4PP). Among these two compounds, Isoconazole could partially inhibit apoptosis of the irradiated cells especially when cells were post-treated directly after UV irradiation while Clemizole Hydrochloride-mediated increase in viability was dependent on both pre and post treatment. No synergistic effect was recorded following combined drug treatment and the compounds exerted no effect on the proliferative capacity of the cells post UV exposure. Amelioration of XP-C phenotype is a pave way towards understanding the accelerated skin cancer initiation in XP-C patients. Further examination is required to decipher the molecular mechanisms targeted by these two chemicals.
Assuntos
Benzimidazóis/farmacologia , Miconazol/análogos & derivados , Dermatopatias/tratamento farmacológico , Raios Ultravioleta/efeitos adversos , Xeroderma Pigmentoso/tratamento farmacológico , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Reposicionamento de Medicamentos , Humanos , Miconazol/farmacologiaAssuntos
Anilidas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Basocelular/tratamento farmacológico , Hemangiossarcoma/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Recidiva Local de Neoplasia , Nivolumabe/uso terapêutico , Piridinas/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Xeroderma Pigmentoso/tratamento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Basocelular/diagnóstico por imagem , Carcinoma Basocelular/patologia , Ensaios de Uso Compassivo , Hemangiossarcoma/diagnóstico por imagem , Hemangiossarcoma/patologia , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Masculino , Terapia de Alvo Molecular , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/patologia , Resultado do Tratamento , Xeroderma Pigmentoso/diagnóstico por imagem , Xeroderma Pigmentoso/patologiaRESUMO
Xeroderma pigmentosum (XP) is a rare autosomal recessive dermatosis that is often complicated by multiple skin tumours at exposed locations, which are difficult to treat. We report a case of a 12-year-old girl with XP treated with oral retinoic acid and photodynamic therapy (PDT) with good clinical results. She had an 8-year history of multiple skin lesions that first appeared on her nasal dorsum, but gradually increased in size and spread to her entire face, neck, and upper limbs. Notably, the lesions became evidently aggravated after sun exposure. When she was 6 years old, sesame-seed-sized papules and plaques appeared, which were fragile and irregular in shape and would self-rupture, accompanied with slight itchiness and bloody exudate. Examination revealed multiple basal cell carcinomas. The tumours were treated with local carbon dioxide laser therapy combined with PDT. On the follow-up visit 2 months after the surgery, most of the skin lesions on her face had subsided. In cases of multiple tumours, PDT can be the treatment method of choice because it is less invasive, has less side effects, and does not damage the surrounding normal tissues.
Assuntos
Carcinoma Basocelular/tratamento farmacológico , Lasers de Gás/uso terapêutico , Fotoquimioterapia/métodos , Neoplasias Cutâneas/tratamento farmacológico , Tretinoína/uso terapêutico , Xeroderma Pigmentoso/tratamento farmacológico , Carcinoma Basocelular/complicações , Criança , Quimioterapia Combinada , Face , Feminino , Hematoporfirinas/uso terapêutico , Humanos , Fármacos Fotossensibilizantes/uso terapêutico , Neoplasias Cutâneas/complicações , Xeroderma Pigmentoso/complicações , Xeroderma Pigmentoso/patologiaRESUMO
BACKGROUND: Xeroderma pigmentosum (XP) is a very rare and severe genetic disorder with a DNA repair defect of ultraviolet (UV)-induced damage. Photodynamic therapy (PDT) has been successfully used in XP patients to treat actinic keratosis (AK) and daylight PDT (DL-PDT) has demonstrated similar efficacy to conventional PDT (C-PDT) for AK. OBJECTIVES: To assess DL-PDT for the treatment of AK in patients with XP. METHODS: Patients with XP were evaluated by a group of Spanish and African dermatologists. Clinical characteristics of the patients were assessed and divided in mild, severe or moderate affectation of AK in the face. A topical photosensitizer was extended on the patients' faces and after two hours of indoor light exposure, fluorescence was assessed and the cream was removed. Patients were examined two and seven days later to assess the reaction to PDT and followed up three months later. RESULTS: A total of 13 patients were treated on the whole face. Three were classified as severe AK, six as moderate AK and four as mild AK. Fluorescence assessment showed a soft yellow-green colour and a pink-color delineating the AK. Two days after treatment patients presented a scaly reaction. After one week the reaction healed, there was improvement and after three months no adverse events were noticed. CONCLUSIONS: PDT is an option for treatment of AK in patients with XP.
Assuntos
Ácido Aminolevulínico/uso terapêutico , Ceratose Actínica/tratamento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/uso terapêutico , Xeroderma Pigmentoso/tratamento farmacológico , Adolescente , Adulto , África , Criança , Pré-Escolar , Feminino , Humanos , Lactente , MasculinoRESUMO
"Mutational signatures" are patterns of mutations that report DNA damage and subsequent repair processes that have occurred. Whole-genome sequencing (WGS) can provide additional information to standard diagnostic techniques and can identify therapeutic targets. A 32-yr-old male with xeroderma pigmentosum developed metastatic angiosarcoma that was unresponsive to three lines of conventional sarcoma therapies. WGS was performed on his primary cancer revealing a hypermutated tumor, including clonal ultraviolet radiation-induced mutational patterns (Signature 7) and subclonal signatures of mutated DNA polymerase epsilon (POLE) (Signature 10). These signatures are associated with response to immune checkpoint blockade. Immunohistochemistry confirmed high PD-L1 expression in metastatic deposits. The anti-PD-1 monoclonal antibody pembrolizumab was commenced off-label given the POLE mutation and high mutational load. After four cycles, there was a significant reduction in his disease with almost complete resolution of the metastatic deposits. This case highlights the importance of WGS in the analysis, interpretation, and treatment of cancers. We anticipate that as WGS becomes integral to the cancer diagnostic pathway, treatments will be stratified to the individual based on their unique genomic and/or transcriptomic profile, enhancing classical approaches of histologically driven treatment decisions.
Assuntos
Hemangiossarcoma/genética , Xeroderma Pigmentoso/tratamento farmacológico , Xeroderma Pigmentoso/genética , Adulto , Anticorpos Monoclonais/genética , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Análise Mutacional de DNA/métodos , DNA Polimerase II/genética , Humanos , Masculino , Instabilidade de Microssatélites , Mutação/genética , Proteínas de Ligação a Poli-ADP-Ribose/genética , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Sequenciamento Completo do Genoma/métodosAssuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Escamosas/prevenção & controle , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Cutâneas/prevenção & controle , Xeroderma Pigmentoso/tratamento farmacológico , Adolescente , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Ipilimumab/uso terapêutico , Masculino , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/patologia , Resultado do Tratamento , Xeroderma Pigmentoso/complicações , Adulto JovemRESUMO
Xeroderma pigmentosum (XP) encompasses a group of rare diseases characterized in most cases by malfunction of nucleotide excision repair (NER), which results in an increased sensitivity to UV radiation in affected individuals. Approximately 25-30% of XP patients present with neurological symptoms, such as sensorineural deafness, mental deterioration and ataxia. Although it is known that dysfunctional DNA repair is the primary pathogenesis in XP, growing evidence suggests that mitochondrial pathophysiology may also occur. This appears to be secondary to dysfunctional NER but may contribute to the neurodegenerative process in these patients. The available pharmacological treatments in XP mostly target the dermal manifestations of the disease. In the present review, we outline how current understanding of the pathophysiology of XP could be used to develop novel therapies to counteract the neurological symptoms. Moreover, the coexistence of cancer and neurodegeneration present in XP led us to focus on possible new avenues targeting mitochondrial pathophysiology. LINKED ARTICLES: This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc.
Assuntos
Doenças Neurodegenerativas/tratamento farmacológico , Xeroderma Pigmentoso/tratamento farmacológico , Humanos , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Xeroderma Pigmentoso/complicações , Xeroderma Pigmentoso/genética , Xeroderma Pigmentoso/metabolismoAssuntos
Antineoplásicos/uso terapêutico , Carcinoma Basocelular/tratamento farmacológico , Neoplasias Palpebrais/tratamento farmacológico , Imiquimode/uso terapêutico , Neoplasias Nasais/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Xeroderma Pigmentoso/tratamento farmacológico , Administração Cutânea , Antineoplásicos/administração & dosagem , Pré-Escolar , Humanos , Imiquimode/administração & dosagem , MasculinoRESUMO
We report the case of a 6-year-old female with xeroderma pigmentosum (XP) who developed a nonoperable scalp tumor, treated with anti-programmed cell death protein 1 (anti-PD-1) therapy (nivolumab). She presented with a sarcomatoid carcinoma of the scalp with bone lysis as well as vascular and meningeal contact. Nivolumab was initiated because it has emerged as a promising immunotherapy. We observed a dramatic tumor response with excellent tolerance. However, while on nivolumab therapy she developed two large skin melanomas and several squamous cell carcinomas, which have been resected. These results demonstrate that cancer immunotherapy in patients with XP can be impressive but complex and warrants further investigation.
Assuntos
Anticorpos Monoclonais , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Xeroderma Pigmentoso/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Carcinoma de Células Escamosas/induzido quimicamente , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Criança , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Melanoma/induzido quimicamente , Melanoma/patologia , Melanoma/cirurgia , Segunda Neoplasia Primária/induzido quimicamente , Segunda Neoplasia Primária/patologia , Segunda Neoplasia Primária/cirurgia , Nivolumabe , Neoplasias Cutâneas/patologia , Xeroderma Pigmentoso/patologiaAssuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Xeroderma Pigmentoso/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Indução de Remissão , Neoplasias Cutâneas/patologia , Fatores de Tempo , Xeroderma Pigmentoso/patologiaAssuntos
Antineoplásicos/uso terapêutico , Eletroquimioterapia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Xeroderma Pigmentoso/tratamento farmacológico , Criança , Códon sem Sentido , Proteínas de Ligação a DNA/genética , Feminino , Predisposição Genética para Doença , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Fenótipo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Resultado do Tratamento , Xeroderma Pigmentoso/genética , Xeroderma Pigmentoso/patologiaAssuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Primárias Múltiplas/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Carga Tumoral/efeitos dos fármacos , Xeroderma Pigmentoso/tratamento farmacológico , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Primárias Múltiplas/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Indução de Remissão , Neoplasias Cutâneas/patologia , Resultado do Tratamento , Xeroderma Pigmentoso/complicações , Xeroderma Pigmentoso/patologiaRESUMO
Transcription factor IIH (TFIIH) is a multiprotein complex involved in both transcription and DNA repair, revealing a striking functional link between these two processes. Some of its subunits also belong to complexes involved in other cellular processes, such as chromosome segregation and cell cycle regulation, emphasizing the multitasking capabilities of this factor. This review aims to depict the structure of TFIIH and to dissect the roles of its subunits in different cellular mechanisms. Our understanding of the biochemistry of TFIIH has greatly benefited from studies focused on diseases related to TFIIH mutations. We address the etiology of these disorders and underline the fact that TFIIH can be considered a promising target for therapeutic strategies.