RESUMEN
The cutaneous toxicity of MEK inhibitors may limit treatment adherence. The authors present a retrospective study of 41 paediatric patients with NF-1 undergoing therapy with selumetinib and propose a treatment algorithm.
Asunto(s)
Paroniquia , Enfermedades de la Piel , Humanos , Niño , Estudios Retrospectivos , Paroniquia/inducido químicamente , Inhibidores de Proteínas Quinasas/efectos adversos , Enfermedades de la Piel/inducido químicamente , Quinasas de Proteína Quinasa Activadas por Mitógenos/efectos adversosRESUMEN
Epidermolysis Bullosa (EB) is a rare group of diseases caused by genetic variants in skin structural proteins. EB is characterized by varying degrees of skin fragility, blisters and impaired wound healing, and is classified based on the ultrastructural levels of skin cleavage-simplex, junctional, dystrophic, and Kindler Syndrome. Squamous cell carcinoma (SCC) is the most severe complication and most common cause of death of patients with EB, particularly in those with recessive dystrophic Epidermolysis Bullosa (RDEB). To date, the first line of treatment of SCC in patients with RDEB is surgery, despite the high risk of recurrence. Radiotherapy and systemic therapy have been avoided due to its skin toxicity. Recently, electrochemotherapy (ECT) has been proposed as a potential treatment. We report eight sessions of ECT using bleomycin for treatment of SCC in five patients with EB. After 8 weeks all patients showed an objective response. Four patients (seven ECT sessions) had a complete response. The treatment was well tolerated, with mild adverse effects, such as local pain, erythema, and ulceration. Our results demonstrate that ECT is a potential treatment for SCC in patients with RDEB.
Asunto(s)
Carcinoma de Células Escamosas , Electroquimioterapia , Epidermólisis Ampollosa Distrófica , Epidermólisis Ampollosa , Carcinoma de Células Escamosas/tratamiento farmacológico , Epidermólisis Ampollosa Distrófica/complicaciones , Epidermólisis Ampollosa Distrófica/diagnóstico , Epidermólisis Ampollosa Distrófica/genética , Humanos , Recurrencia Local de NeoplasiaRESUMEN
BACKGROUND: Neurofibromatosis type 2 (NF2) is a rare autosomal dominant syndrome with a predisposition to the development of central nervous system tumors, ophthalmic manifestations, and dermatological lesions. The latter are present in 70-95% of patients and can precede the evolution of other tumors. However, they are not included in the diagnostic criteria and are frequently undervalued during follow-up. METHODS: An observational cross-sectional study characterizing cutaneous lesions in a cohort of NF2 patients was carried out. Dermatological examinations were performed, and lesions were classified into neural cutaneous tumors (superficial, SNCT, and deep, DNCT), hyperpigmented patches (HyperP), and hypopigmented patches (HypoP). The Dermatology Life Quality Index (DLQI) and EQ-5D questionnaires were applied to evaluate the impact on quality of life. RESULTS: Nineteen patients with a mean age of 36 years were included. Sixteen (84%) patients had cutaneous lesions, mostly developed 10 or more years before the diagnosis. SNCT, DNCT, and HyperP showed similar frequencies (58%). HypoP were observed in only one patient. HyperP developed, on average, earlier than NCT (9.6 vs. 16.5 SNCT, 17.0 DNCT; years). The excised lesions had different histological patterns, including neurofibromas, schwannomas, and a hybrid tumor. Most patients reported a low impact of cutaneous manifestations on the quality of life (DLQI 0 or 1). CONCLUSIONS: Cutaneous lesions are frequent in NF2 and may precede the diagnosis by several years. Their identification is important to establish the diagnosis earlier and potentially reduce morbidity and mortality.
RESUMEN
BACKGROUND: The treatment of advanced periocular basal cell carcinomas becomes a challenge as surgery may involve highly mutilating procedures. Vismodegib is the first selective hedgehog inhibitor approved for the treatment of locally advanced tumors or metastatic disease. OBJECTIVE: Analyze the results of treatment with vismodegib for advanced periocular basal cell carcinomas in a real-life setting of a reference center between 2014 and 2020. METHODS: Retrospective longitudinal study. The patient's demographic profile, comorbidities, tumor characteristics, and treatment outcomes were analyzed. RESULTS: A total of 13 patients were included. Median follow-up and treatment duration were 15.9 and 10.5 months, respectively. Objective clinical response rate was 76.9%: 30.8% had a complete response and 46.2% a partial response. The median duration of response was 13 months. Progressive disease was observed in 38.5% of cases, with a median of 19 months after the beginning of treatment. Eighty-four percent of the patients had at least one adverse event, and 61.54% needed to interrupt treatment temporarily or permanently to increase tolerability. STUDY LIMITATIONS: Being a retrospective study in a real-life setting, the evaluation of objective clinical response was subjective to physician appreciation. CONCLUSION: Vismodegib is a safe and effective treatment for locally advanced basal cell carcinoma. To prevent recurrences, the drug should be used continually when tolerated. The role of neoadjuvant vismodegib before surgery is being investigated and might add an important step in searching for a definitive treatment for these cases.
Asunto(s)
Carcinoma Basocelular , Neoplasias Cutáneas , Anilidas , Carcinoma Basocelular/tratamiento farmacológico , Proteínas Hedgehog , Humanos , Estudios Longitudinales , Recurrencia Local de Neoplasia/tratamiento farmacológico , Piridinas , Estudios Retrospectivos , Neoplasias Cutáneas/tratamiento farmacológicoAsunto(s)
Carcinoma de Células Escamosas/diagnóstico , Necrobiosis Lipoidea/patología , Neoplasias Cutáneas/diagnóstico , Anciano , Carcinoma de Células Escamosas/terapia , Antebrazo , Humanos , Masculino , Osteomielitis/diagnóstico , Osteomielitis/etiología , Osteomielitis/terapia , Neoplasias Cutáneas/terapiaRESUMEN
Cutaneous melanoma is one of the most aggressive human cancers due to its high invasiveness. Germline mutations in high-risk melanoma susceptibility genes have been associated with development hereditary melanoma; however, most genetic culprits remain elusive. To unravel novel susceptibility genes for hereditary melanoma, we performed whole exome sequencing (WES) on eight patients with multiple primary melanomas, high number of nevi, and negative for high and intermediate-risk germline mutations. Thirteen new potentially pathogenic variants were identified after bioinformatics analysis and validation. CDH23, ARHGEF40, and BRD9 were identified as the most promising susceptibility genes in hereditary melanoma. In silico analysis of CDH23 and ARHGEF40 variants provided clues for altered protein structure and function associated with the identified mutations. Then, we also evaluated the clinical value of CDH23, ARHGEF40, and BRD9 expression in sporadic melanoma by using the TCGA dataset (n = 461). No differences were observed in BRD9 expression between melanoma and normal skin samples, nor with melanoma stage, whereas ARHGEF40 was found overexpressed, and CDH23 was downregulated and its loss was associated with worse survival. Altogether, these results reveal three novel genes with clinical relevance in hereditary and sporadic melanoma.
Asunto(s)
Cadherinas/genética , Factores de Intercambio de Guanina Nucleótido/genética , Melanoma/genética , Factores de Transcripción/genética , Adulto , Anciano , Proteínas Relacionadas con las Cadherinas , Exoma/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Masculino , Melanoma/patología , Persona de Mediana Edad , Secuenciación del Exoma/métodosRESUMEN
BACKGROUND: Darier disease (DD) is a rare autosomal dominant condition characterized by skin lesions. Additionally, a wide range of neuropsychiatric symptoms is frequently reported in DD patients. This genodermatosis relies on mutations in the ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2 (ATP2A2) gene, which encodes an ATPase responsible for pumping Ca2+ from the cytosol to the lumen of the ER. OBJECTIVE: Herein we studied the molecular aspect of a two-generation Portuguese family with DD history with clinical variability. METHODS: All exons and intron-exon borders of genomic ATP2A2, as well as coding ATP2A2, were sequenced. Relative levels of SERCA2 mRNA and protein were quantified by qPCR and western blotting, respectively. RESULTS: The c.1287+1G > T variant was identified in all affected individuals, whereas the unaffected individual was shown to carry the wild-type ATP2A2 sequence in both alleles. This variant leads to the skipping of full exon 10, which consequently generates a frameshift originating a premature STOP codon in exon 11 (p.V395 = fs*19). Although the mutant mRNA seems to partially escape degradation, results suggest synthesis inhibition or immediate degradation of the mutant protein. Neuropsychiatric and other occurrences affecting certain patients are also reported. CONCLUSION: This is the first study of DD in Portugal, the variant identified, previously described in a single Japanese patient, may be considered a pathogenic mutation, and haploinsufficiency the mechanism underlying DD pathology in these patients. This study also highlights the co-occurrence of neuropsychiatric features in DD.
RESUMEN
Langerhans cell histiocytosis (LCH) is a multisystemic disorder that results from the clonal proliferation of immunophenotypically and functionally immature Langerhans cells (LC). The detection of the V600E mutation in the BRAF oncogene in LCH biopsy specimens supports previous evidence that LCH is a neoplastic disorder. This mutation is present in other cutaneous lesions including malignant melanoma and benign nevi. Single case reports of a correlation between LCH and the appearance of eruptive nevi limited to the inguinal folds after chemotherapy have previously been described in the literature. This suggested that LCH could be an additional cause of eruptive melanocytic nevi, with a specific distribution mimicking that of LCH cutaneous lesions. We present the case of a 6-year-old boy, previously treated with chemotherapy for Langerhans cell histiocytosis, with disseminated junctional nevi. Although this co-occurrence may be coincidental, the skin involvement is distinct from other previously reported clinical cases. It would be interesting to evaluate whether the BRAF mutation described in LCH cells might in fact support a genetic background for the development of nevi in these patients. LEARNING POINTS: Langerhans cell histiocytosis (LCH) is a clonal neoplastic proliferation of immature Langerhans cells, with the V600E mutation in the BRAF oncogene present in approximately 60% of cases.The V600E mutation in the BRAF oncogene is also documented in other cutaneous lesions, namely malignant melanoma and benign nevi.There are case reports of a correlation between LCH and the appearance of eruptive nevi after chemotherapy, but it is not known whether the BRAF mutation described in LCH cells supports a genetic background for the development of nevi in these patients.
RESUMEN
BACKGROUND: Hereditary breast and ovary cancer syndrome affects both genders but little is known about the uptake of genetic services by men. The objective of this study is to characterise the male population counselled through a multidisciplinary breast/ovarian program. METHODS: Descriptive analysis of male patients counselled from January 2000 to December 2015. Data in this analysis include new cancer diagnoses during prospective follow up. RESULTS: From 4,320 families registered, 362 male patients were identified: 236 (65.2%) from hereditary cancer families (HCF) and 126 (34.8%) from non-HCF. In HCF, 121 patients (51.3%) were mutation carriers (MC): BRCA2 - 102 (84.3%), BRCA1 - 16 (13.2%), CHEK2 - 1 (0.8%) and TP53 - 2 (1.7%). Non-HCF included 126 patients: 85 (67.5%) belonged to families without pathogenic mutations or with variants of unknown clinical significance; 22 (17.5%) refused testing after counselling and 19 (15.0%) did not meet criteria for testing. Both HCF and non-HCF included patients with previous cancer diagnoses: HCF- Breast Cancer (BC) - 18; prostate cancer (PC) - 13; melanoma - 1; others - 7) and non-HCF (BC - 77; PC - 20; gastric cancer (GC) - 1; melanoma - 8; bladder cancer - 1; others - 22). From the 121 MC identified (including the TP53 and CHEK2 carriers), 97 patients (80.2%) adhered to prospective surveillance. With a median follow-up of 36.9 months, 17 cancers were diagnosed in 14 patients, PC being the most frequently diagnosed neoplasia (5 cases). Eleven patients (78.6%) are alive and three patients died of advanced cancer (2 with GC, 1 with disseminated adenocarcinoma). CONCLUSION: We observed a high adherence to counselling, genetic testing and active surveillance by men belonging to hereditary BC families. Male carriers of pathogenic DNA variants are at risk for several cancers and should be included in prospective follow-up studies.
RESUMEN
Abstract Background: The treatment of advanced periocular basal cell carcinomas becomes a challenge as surgery may involve highly mutilating procedures. Vismodegib is the first selective hedgehog inhibitor approved for the treatment of locally advanced tumors or metastatic disease. Objective: Analyze the results of treatment with vismodegib for advanced periocular basal cell carcinomas in a real-life setting of a reference center between 2014 and 2020. Methods: Retrospective longitudinal study. The patient's demographic profile, comorbidities, tumor characteristics, and treatment outcomes were analyzed. Results: A total of 13 patients were included. Median follow-up and treatment duration were 15.9 and 10.5 months, respectively. Objective clinical response rate was 76.9%: 30.8% had a complete response and 46.2% a partial response. The median duration of response was 13 months. Progressive disease was observed in 38.5% of cases, with a median of 19 months after the beginning of treatment. Eighty-four percent of the patients had at least one adverse event, and 61.54% needed to interrupt treatment temporarily or permanently to increase tolerability. Study limitations: Being a retrospective study in a real-life setting, the evaluation of objective clinical response was subjective to physician appreciation. Conclusion: Vismodegib is a safe and effective treatment for locally advanced basal cell carcinoma. To prevent recurrences, the drug should be used continually when tolerated. The role of neoadjuvant vismodegib before surgery is being investigated and might add an important step in searching for a definitive treatment for these cases.
Asunto(s)
Humanos , Carcinoma Basocelular/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Piridinas , Estudios Retrospectivos , Estudios Longitudinales , Proteínas Hedgehog , Anilidas , Recurrencia Local de Neoplasia/tratamiento farmacológicoRESUMEN
BACKGROUND: Most available studies on the efficacy of topical photodynamic therapy focus on short-to medium-term results. Long-term data are scarce. OBJECTIVE: To evaluate the long-term efficacy of photodynamic therapy with topical methylaminolevulinate to treat Bowen's disease and basal cell carcinoma in the clinical practice setting of a dermato-oncology department. METHODS: The study included patients diagnosed with Bowen's disease or basal cell carcinoma, and who received photodynamic therapy from 2004 to 2008. Treatment protocol and clinical follow-up were standardized. The primary endpoint was clinically observed recurrence in a previous photodynamic therapy-treated area. Descriptive and survival analyses were performed. RESULTS: A total of 31 Bowen's disease lesions and 44 superficial basal cell carcinoma were treated, with a median follow-up of 43.5 months. Recurrence was observed in 14 Bowen's disease lesions (53.8%) and in 11 superficial basal cell carcinoma (33.3%). Significantly higher estimates for recurrence rates were found in patients with Bowen's disease (p=0.0036) or those aged under 58 years (p=0.039). The risk of recurrence was higher in patients with Bowen's disease than in those with superficial basal cell carcinoma and younger patients. CONCLUSIONS: Recurrence should be considered when choosing to treat non-melanoma skin cancer with photodynamic therapy. Younger age and Bowen's disease were independent predictors for long-term recurrence, suggesting the need to establish an extended period of follow-up for this subset of patients.
Asunto(s)
Ácido Aminolevulínico/análogos & derivados , Enfermedad de Bowen/tratamiento farmacológico , Carcinoma Basocelular/tratamiento farmacológico , Recurrencia Local de Neoplasia , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Administración Cutánea , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Ácido Aminolevulínico/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Medición de Riesgo , Estadísticas no Paramétricas , Factores de Tiempo , Resultado del TratamientoRESUMEN
Abstract: BACKGROUND: Most available studies on the efficacy of topical photodynamic therapy focus on short-to medium-term results. Long-term data are scarce. OBJECTIVE: To evaluate the long-term efficacy of photodynamic therapy with topical methylaminolevulinate to treat Bowen's disease and basal cell carcinoma in the clinical practice setting of a dermato-oncology department. METHODS: The study included patients diagnosed with Bowen's disease or basal cell carcinoma, and who received photodynamic therapy from 2004 to 2008. Treatment protocol and clinical follow-up were standardized. The primary endpoint was clinically observed recurrence in a previous photodynamic therapy-treated area. Descriptive and survival analyses were performed. RESULTS: A total of 31 Bowen's disease lesions and 44 superficial basal cell carcinoma were treated, with a median follow-up of 43.5 months. Recurrence was observed in 14 Bowen's disease lesions (53.8%) and in 11 superficial basal cell carcinoma (33.3%). Significantly higher estimates for recurrence rates were found in patients with Bowen's disease (p=0.0036) or those aged under 58 years (p=0.039). The risk of recurrence was higher in patients with Bowen's disease than in those with superficial basal cell carcinoma and younger patients. CONCLUSIONS: Recurrence should be considered when choosing to treat non-melanoma skin cancer with photodynamic therapy. Younger age and Bowen's disease were independent predictors for long-term recurrence, suggesting the need to establish an extended period of follow-up for this subset of patients.