RESUMEN
BACKGROUND: Epithelioid haemangioma (EH) arising from the skin is a benign vascular tumour with marked inflammatory cell infiltration, which exhibits a high tendency to persist and frequently recurs after resection. So far, the underlying pathogenesis is largely elusive. OBJECTIVES: To identify genetic alterations by next-generation sequencing and/or droplet digital polymerase chain reaction (ddPCR) in cutaneous EH. METHODS: DNA and RNA from an EH lesion of an index patient were subjected to whole-genome and RNA sequencing. Multiplex PCR-based panel sequencing of genomic DNA isolated from archival formalin-fixed paraffin-embedded tissue of 18 patients with cutaneous EH was performed. ddPCR was used to confirm mutations. RESULTS: We identified somatic mutations in genes of the mitogen-activated protein kinase (MAPK) pathway (MAP2K1 and KRAS) in cutaneous EH biopsies. By ddPCR we could confirm the recurrent presence of activating, low-frequency mutations affecting MAP2K1. In total, nine out of 18 patients analysed showed activating MAPK pathway mutations, which were mutually exclusive. Comparative analysis of tissue areas enriched for lymphatic infiltrate or aberrant endothelial cells, respectively, revealed an association of these mutations with the presence of endothelial cells. CONCLUSIONS: Taken together, our data suggest that EH shows somatic mutations in genes of the MAPK pathway which might contribute to the formation of this benign tumour.
Asunto(s)
Hemangioma , Neoplasias Cutáneas , ADN , Células Endoteliales , Hemangioma/genética , Humanos , Proteínas Quinasas Activadas por Mitógenos/genética , Reacción en Cadena de la Polimerasa Multiplex , Mutación/genética , Recurrencia Local de Neoplasia , Neoplasias Cutáneas/genéticaRESUMEN
The introduction of new therapeutic agents has revolutionized the treatment of metastatic melanoma. The approval of adjuvant anti-programmed death-1 monotherapy with nivolumab or pembrolizumab, and dabrafenib plus trametinib has recently set a new landmark in the treatment of stage III melanoma. Now, clinical trials have shown that immune checkpoint blockade can be performed in a neoadjuvant setting, an approach established as a standard therapeutic approach for other tumour entities such as breast cancer. Recent studies suggest that a pathological response achieved by neoadjuvant immunotherapy is associated with long-term tumour control and that short neoadjuvant application of checkpoint inhibitors may be superior to adjuvant therapy. Most recently, neoadjuvant ipilimumab plus nivolumab in stage III melanoma was reported. With two courses of dose-optimized ipilimumab (1 mg kg-1 ) combined with nivolumab (3 mg kg-1 ), pathological responses were observed in 77% of patients, while only 20% of patients experienced grade 3 or 4 adverse events. However, the neoadjuvant trials employing combined immune checkpoint blockade conducted so far have excluded patients with in transit metastases, a common finding in stage III melanoma. Here we report four patients with in transit metastases or an advanced primary tumour who have been treated with neoadjuvant ipilimumab plus nivolumab according to the OpACIN-neo trial scheme (arm B). All patients achieved radiological disease control and a pathological response. None of the patients has relapsed so far. Linked Comment: Blankenstein and van Akkooi. Br J Dermatol 2020; 183:421-422.
Asunto(s)
Melanoma , Nivolumab , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Humanos , Inmunoterapia , Ipilimumab/uso terapéutico , Melanoma/tratamiento farmacológico , Terapia Neoadyuvante , Nivolumab/uso terapéuticoRESUMEN
Sarcoidosis is a rare multisystem inflammatory disease of largely unknown etiology. While pulmonary sarcoidosis is the most abundant organ manifestation, involvement of the skin that occurs in up to 30% of patients is the most common extrapulmonary presentation of the disease. Dermatologists therefore play an important role not only for establishing the diagnosis and delineating it from potential differential diagnoses but also for the interdisciplinary care of the patient. The clinical presentation of skin sarcoidosis is manifold, which occasionally aggravates making the final diagnosis. Specific skin lesions (with granulomas) and nonspecific skin manifestations (without granulomas) can be differentiated. Since a variety of organ systems can be affected, multidisciplinary cooperation is mandatory. Therapy of sarcoidosis is difficult; evidence-based studies and therapy guidelines are widely lacking. Our review intends to outline the characteristic clinical presentations of cutaneous sarcoidosis, describe the diagnostic approach and how to assure or exclude extracutaneous manifestations of sarcoidosis, and suggest a therapy algorithm for the treatment of skin sarcoidosis.
Asunto(s)
Sarcoidosis/diagnóstico , Enfermedades de la Piel/diagnóstico , Dermoscopía , Diagnóstico Diferencial , Dermatosis Facial/diagnóstico , Dermatosis Facial/patología , Dermatosis Facial/terapia , Histiocitos/patología , Humanos , Factores Inmunológicos/uso terapéutico , Inmunosupresores/uso terapéutico , Comunicación Interdisciplinaria , Colaboración Intersectorial , Pulmón/patología , Linfocitos/patología , Factores de Riesgo , Sarcoidosis/patología , Sarcoidosis/terapia , Piel/patología , Enfermedades de la Piel/patología , Enfermedades de la Piel/terapiaAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células de Merkel/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Cutáneas/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Carcinoma de Células de Merkel/patología , Humanos , Ipilimumab/administración & dosificación , Masculino , Persona de Mediana Edad , Nivolumab/administración & dosificación , Pronóstico , Neoplasias Cutáneas/secundarioRESUMEN
A woman presented in the emergency room with the diagnosis of angioedema refractory to treatment. She had soft, compressible periorbital edema, as well as edema of her hands and lower arms. She also complained of severe pain in her hands including sensations of numbness and tingling. The history, course and examination results eliminated several possible differential diagnostic considerations like an acute histamine- or bradykinin-mediated angioedema or superior vena cava syndrome. Histological examination confirmed the diagnosis of scleromyxedema.
Asunto(s)
Angioedema/patología , Dermatosis de la Mano/patología , Escleromixedema/patología , Anciano , Diagnóstico Diferencial , Femenino , HumanosAsunto(s)
Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Carcinoma de Células de Merkel/tratamiento farmacológico , Penfigoide Benigno de la Membrana Mucosa/inducido químicamente , Neoplasias Cutáneas/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Mucosa Bucal/efectos de los fármacos , Mucosa Bucal/inmunología , Mucosa Bucal/patología , Penfigoide Benigno de la Membrana Mucosa/inmunología , Penfigoide Benigno de la Membrana Mucosa/patología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunologíaRESUMEN
A small hyperpigmented nodule 4 mm in diameter with a smaller satellite lesion was noted on the left hip 5 weeks after spontaneous birth of an otherwise unharmed 490 g female infant at 23 + 5 weeks of gestation. The mother had been treated with antibiotics for a clinically suspected amniotic infection syndrome. Aspergillus fumigatus was identified in both repeated swabs of the lesions and culture of the resected tissue. The infant received liposomal amphotericin B (3 mg/kg/day) for 8 days. No new lesions were noted thereafter. There was no evidence for a primary immunodeficiency.
Asunto(s)
Anfotericina B/uso terapéutico , Aspergilosis/diagnóstico , Aspergilosis/tratamiento farmacológico , Aspergillus fumigatus/aislamiento & purificación , Recien Nacido con Peso al Nacer Extremadamente Bajo , Dermatosis de la Pierna/diagnóstico , Dermatosis de la Pierna/tratamiento farmacológico , Antifúngicos/uso terapéutico , Aspergilosis/microbiología , Femenino , Humanos , Recién Nacido , Dermatosis de la Pierna/microbiología , Resultado del TratamientoRESUMEN
Muir-Torre syndrome (MTS) is a rare autosomal dominant tumor syndrome characterized by the occurrence of tumors of the sebaceous glands and/or multiple keratoacanthomas in addition to internal neoplasia. Skin tumors include not only sebaceous adenomas and sebaceomas but also sebaceous carcinomas which are associated with colorectal carcinomas in over 50%, less commonly with carcinomas of the remaining gastrointestinal, urinary or genital tract. The underlying pathogenesis is a defect of the DNA mismatch repair system introducing microsatellite instability in tumor tissue.
Asunto(s)
Aberraciones Cromosómicas , Conducta Cooperativa , Genes Dominantes/genética , Comunicación Interdisciplinaria , Síndrome de Muir-Torre/genética , Biopsia , Reparación de la Incompatibilidad de ADN/genética , Diagnóstico Diferencial , Humanos , Masculino , Inestabilidad de Microsatélites , Persona de Mediana Edad , Síndrome de Muir-Torre/diagnóstico , Síndrome de Muir-Torre/patología , Neoplasias Primarias Múltiples/diagnóstico , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/patología , Piel/patologíaRESUMEN
Chelation therapy with (RS)-2,3-Bis(sulfonyl)propane-1-sulfonic acid (DMPS) after an occupational lead exposure led to the development of a severe bullous drug eruption. Skin tests and histology/immunohistology of the test reactions indicated a T-cell-mediated immune response against DMPS. Metal-binding thiol groups as in DMPS are chemically highly reactive and therefore effectively mediate the development of immunogenic hapten (DMPS)-protein complexes. Therefore, the pharmacological effects and sensitization potential of dithiols are tightly connected. Cross-reactivity of DMPS to other chelators like D-penicillamine is possible; the indications for chelation therapy should be weighed carefully.
Asunto(s)
Contaminantes Ocupacionales del Aire/toxicidad , Quelantes/toxicidad , Erupciones por Medicamentos/diagnóstico , Intoxicación por Plomo/tratamiento farmacológico , Enfermedades Profesionales/tratamiento farmacológico , Enfermedades Cutáneas Vesiculoampollosas/inducido químicamente , Unitiol/toxicidad , Adulto , Apoptosis/efectos de los fármacos , Quelantes/uso terapéutico , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Erupciones por Medicamentos/patología , Humanos , Queratinocitos/efectos de los fármacos , Masculino , Microscopía Fluorescente , Pruebas del Parche , Piel/efectos de los fármacos , Piel/patología , Enfermedades Cutáneas Vesiculoampollosas/diagnóstico , Enfermedades Cutáneas Vesiculoampollosas/patología , Unitiol/uso terapéuticoAsunto(s)
Infecciones Cutáneas Estafilocócicas/diagnóstico , Infecciones Cutáneas Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus , Antibacterianos/uso terapéutico , Nalgas , Enfermedad Crónica , Diagnóstico Diferencial , Femenino , Humanos , Dermatosis de la Pierna , Persona de Mediana Edad , Infecciones Cutáneas Estafilocócicas/microbiología , Muslo , Insuficiencia del Tratamiento , Resultado del TratamientoAsunto(s)
Carcinoma de Células de Merkel , Neoplasias Cutáneas , Humanos , Carcinoma de Células de Merkel/diagnóstico , Carcinoma de Células de Merkel/terapia , Neoplasias Cutáneas/terapia , Neoplasias Cutáneas/diagnóstico , Estadificación de Neoplasias , Europa (Continente)/epidemiología , Estudios de SeguimientoAsunto(s)
Amiloidosis/complicaciones , Amiloidosis/diagnóstico , Macroglosia/complicaciones , Macroglosia/diagnóstico , Enfermedades Musculares/complicaciones , Enfermedades Musculares/diagnóstico , Amiloidosis/terapia , Diagnóstico Diferencial , Humanos , Macroglosia/terapia , Masculino , Persona de Mediana Edad , Enfermedades Musculares/terapiaAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de Cabeza y Cuello , Hemangiosarcoma , Cuero Cabelludo , Terapia Combinada/métodos , Doxorrubicina/administración & dosificación , Neoplasias Faciales/tratamiento farmacológico , Neoplasias Faciales/radioterapia , Frente , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapia , Hemangiosarcoma/tratamiento farmacológico , Hemangiosarcoma/radioterapia , Humanos , Masculino , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Resultado del TratamientoRESUMEN
Promoter methylation represents an important mechanism for silencing gene expression in higher eukaryotes. To study methylation of the promoter of the tumor suppressor p16INK4a, a fast and simple method was developed that, in contrast to previous studies, relies on the positive display of methylated sites (PDM). The method is based on bisulfite treatment of DNA, polymerase chain reaction (PCR)-amplification of the modified DNA and restriction digest of de novo created restriction sites to positively display DNA methylation in a background of unmethylated DNA. Since methylated as well as unmethylated DNA is amplified, information on the proportion of both is provided. Using this approach, 33 ductal invasive carcinomas, 4 normal mammary tissues, and 4 cell lines were analyzed for methylation. Methylation in the p16INK4a promoter was detected in 1 of 33 carcinomas (3%) and in 0 of 4 normal tissues. The conclusion is that PDM provides a useful tool in determining the degree and pattern of promoter methylation and is suitable to screen large series of tissue samples.
Asunto(s)
Metilación de ADN , ADN/genética , Genes p16 , Reacción en Cadena de la Polimerasa/métodos , Polimorfismo de Longitud del Fragmento de Restricción , Regiones Promotoras Genéticas , Mapeo Restrictivo/métodos , Emparejamiento Base/efectos de los fármacos , Secuencia de Bases , Mama/química , Neoplasias de la Mama/química , Neoplasias de la Mama/genética , Linfoma de Burkitt/patología , Carcinoma Ductal de Mama/química , Carcinoma Ductal de Mama/genética , Islas de CpG , ADN/efectos de los fármacos , ADN de Neoplasias/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Células HeLa/química , Humanos , Datos de Secuencia Molecular , Sensibilidad y Especificidad , Sulfitos/farmacología , Células Tumorales Cultivadas/químicaRESUMEN
The application of Southern blotting to determine the methylation status of a particular gene has already been alluded to in Chapter 17 by Tennant et al., and methodology for Southern blotting described. This chapter examines methylation analysis of CpG islands in more depth and describes a technique by which quantitative changes may be monitored with greater sensitivity than that achieved by Southern blotting, and by which multiple CpG sites can be monitored simultaneously.In higher order eukaryotes, DNA is methylated primarily at cytosines that are located 5' to guanosines in a CpG dinucleotide. In mammalian species, 3'5% of the cytosine residues are modified to 5-methylcytosine (Fig. 1A) and there is now considerable evidence to show that this post-transcriptional modification plays an important role in gene function (1,2). Some CpG dinucleotides are clustered together in 1-2-kb long stretches of DNA called "CpG islands" which account for approx 2% of the genome and have distinct properties when compared to the rest of the genome. CpG islands are often located in the promoter region or the first exon of expressed genes and show a high G + C content (60/270%), the remainder of the genomic DNA has a G + C content of 40% (3 and references therein). Furthermore, bulk genomic DNA has only 25% of the CpG dinucleotides one would expect from random base composition, whereas CpG islands show the expected number. The "depletion" of CpG dinucleotides may be a result of spontaneous deamination of 5-methylcytosine to thymidine, leading to the mutation of CpG to TpG and CpA on the sense and the antisense strands, respectively. Fig. 1. (A) Cytosine is methylated at its 5-position to form 5-methylcytosine. (B) The chemical conversion of cytosine to uracil is achieved under the influence of high concentrations of bisulfite at low pH. Sulfonation of cytosine at its 6-position destabilizes the amino group in position 4, which is hydrolytically deaminated to form uracilsulfonate. Under alkaline conditions, the SO(3) - group is split off again, resulting in a PCR-amplifiable uracil. Methylation of position 5, however, prevents sulfonation of cytosine and its conversion to uracil.
RESUMEN
AIMS: To investigate the correlation between centrally assessed human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH) results and response to treatment of patients with metastatic breast cancer enrolled in a first-line, phase II, open-label, 3-weekly trastuzumab (Herceptin) monotherapy trial (WO16229). METHODS: Samples from participants in the WO16229 trial were collected and tumour HER2 status determined by IHC and FISH. HER2 test results were interpreted according to manufacturers' test kit protocols. Responders were defined as patients showing either partial or complete responses. RESULTS: Response data were available for 103/105 patients; centrally confirmed HER2 status was available for 95 patients. Intra-laboratory concordance for central IHC and FISH results was 93%. Complete responses were seen in two patients; their samples were IHC 3+ and FISH positive. Partial responses were seen in 17 patients; all were IHC 3+ and 14 were FISH positive. IHC and FISH showed 100% and 84.2% sensitivity, respectively, in determining response to trastuzumab. Polysomy was observed in 27% of patients; six responded to trastuzumab treatment. All six responders showed HER2 overexpression (IHC 3+) and HER2 gene amplification; two were FISH negative due to chromosome 17 polysomy. CONCLUSIONS: HER2 determination by IHC and FISH correlates with clinical response data in the WO16229 trial with high concordance of IHC and FISH results. Polysomy is the major cause of response in FISH-negative cases; polysomic cases should be retested by strictly standardised IHC.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Receptor ErbB-2/metabolismo , Anticuerpos Monoclonales Humanizados , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Cromosomas Humanos Par 17/genética , Femenino , Humanos , Hibridación Fluorescente in Situ/métodos , Poliploidía , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Trastuzumab , Resultado del TratamientoRESUMEN
The highly proliferating phenotype of mammary carcinoma is known to be associated with a particularly aggressive clinical course. We have been interested in the underlying molecular causes that give rise to the increased proliferative activity Proliferative activity was determined immunohistochemically by the detection of topoisomerase II-alpha (Ki-S1). The subgroup of highly proliferating tumors with a Ki-S1 index exceeding 30% was characterized by a high frequency of c-myc amplification and aberrant p53 expression, whereas tumors, with a low mitotic activity rarely exhibited gene amplification or an altered p53 expression. We conclude, that the highly proliferating phenotype is not capable of regular replication and tends to develop gene amplifications. One of the causes might be a defective cell cycle control by p53.