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INTRODUCTION: The role of IMP3, CDK4, MDM2 and ß-catenin proteins in Enchondroma and Central Chondrosarcoma is not totally understood. The aim of this study is to evaluate the immunoexpression of these proteins, associating histological grade, clinical data and prognosis to these tumors. METHODS: This is a retrospective-analytical study of 32 Enchondroma and 70 Central Chondrosarcoma. RESULTS: IMP3, CDK4, MDM2 and ß-catenin expression was observed in 22.82 %, 13.82 %, 17.17 % and in 8.8 % of cases, respectively. All Enchondromas positive for these immunomarkers were located in short tubular bones. The positivity for these antibodies is directly proportional to Chondrosarcoma's histological grade increase. No difference was found between Enchondroma and Chondrosarcoma, Grade 1 for IMP3, CDK4 and ß-catenin positivity. Significant metastasis outcome was observed for IMP3, CDK4, MDM2 and death for MDM2 expression. CONCLUSION: IMP3, CDK4, MDM2 and ß-catenin expression in Enchondromas of short bones phenotypically characterizes these tumors. Their expression has not proven to be useful either as diagnostic markers of these neoplasms or in distinguishing between Enchondroma and Chondrosarcoma, Grade 1. The significant immunoexpression of IMP3, CDK4 and MDM2 in metastatic Chondrosarcoma and the lower survival in those with positivity for MDM2 suggest a possible association of these proteins with tumor aggressiveness.
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Biomarcadores de Tumor , Neoplasias Óseas , Condroma , Condrosarcoma , Quinasa 4 Dependiente de la Ciclina , Inmunohistoquímica , Proteínas Proto-Oncogénicas c-mdm2 , beta Catenina , Humanos , Condrosarcoma/patología , Condrosarcoma/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/análisis , Masculino , Femenino , Neoplasias Óseas/patología , Neoplasias Óseas/metabolismo , Persona de Mediana Edad , beta Catenina/análisis , beta Catenina/metabolismo , Adulto , Estudios Retrospectivos , Biomarcadores de Tumor/análisis , Pronóstico , Condroma/patología , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 4 Dependiente de la Ciclina/análisis , Anciano , Adulto Joven , Adolescente , Clasificación del Tumor , Niño , Proteínas de Unión al ARNRESUMEN
BACKGROUND: The objective of this study is to evaluate the diagnostic accuracy of plasma-based liquid biopsy for the detection of the BRAF V600E mutation in circulating cell-free DNA from patients with ameloblastoma. METHODS: This is a prospective diagnostic accuracy study conducted based on the Standards for Reporting Diagnostic Accuracy recommendations. The index test was the plasma-based liquid biopsy, whereas the reference standard was the conventional tissue biopsy. The target condition was the detection of BRAF V600E mutation. The study population consisted of individuals with ameloblastoma recruited from three tertiary hospitals from Brazil. A negative control group composed of three individuals with confirmed wild-type BRAF lesions were included. The participants underwent plasma circulating cell-free DNA and tumor tissue DNA isolation, and both were submitted to using competitive allele-specific TaqMan™ real-time polymerase chain reaction technology mutation detection assays. Sensitivity and specificity measures and positive and negative predictive values were calculated. RESULTS: Twelve patients with conventional ameloblastoma were included. BRAF V600E mutation was detected in 11/12 (91.66%) ameloblastoma tissue samples. However, the mutation was not detected in any of the plasma-based liquid biopsy circulating cell-free DNA samples in both ameloblastomas and negative control group. The sensitivity and specificity of plasma-based liquid biopsy for the detection of the BRAF V600E mutation in circulating cell-free DNA was 0.0 and 1.0, respectively. The agreement between index test and reference standard results was 26.66%. CONCLUSION: Plasma-based liquid biopsy does not seem to be an accurate method for the detection of the BRAF V600E mutation in circulating circulating cell-free DNA from patients with ameloblastoma, regardless of tumor size, anatomic location, recurrence status, and other clinicopathological features.
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Ameloblastoma , Ácidos Nucleicos Libres de Células , Humanos , Ameloblastoma/diagnóstico , Ameloblastoma/genética , Proteínas Proto-Oncogénicas B-raf/genética , Estudios Prospectivos , Mutación , Ácidos Nucleicos Libres de Células/genéticaRESUMEN
Abstract The aim of this study was to analyze the expression of mast cell markers toluidine blue, c-kit, and tryptase and presence of mononuclear inflammatory cells in oral lichen planus (OLP) and oral lichenoid lesions related to dental amalgam. Nineteen specimens of OLP, OLLC, and healthy oral mucosa were selected. Mononuclear inflammatory cells were analyzed. Histochemical and immunohistochemical analyses were performed using toluidine blue, anti-c-kit and anti-tryptase reagents, and the results were quantified in areas A and B of connective tissue. Mast cells of all OLP and OLLC samples were positive for toluidine blue, c-kit, and tryptase. The density of toluidine blue+, c-kit+ and tryptase+ mast cells was higher in tissue with OLP and OLLC compared with healthy controls (p < 0.05). No difference was noted in mast cells density between OLP and OLLC (p > 0.05). The density of tryptase+ mast cells was higher in the subepithelial region (area A) than the region below it (Area B) in OLLC (p = 0.047). The mononuclear inflammatory cell density was higher in OLLC compared to OLP, but without statistical significance (p > 0.05). A positive statistical correlation was found between mononuclear immune cells and density of c-kit+ and tryptase+ mast cells in OLP (r = 0.943 and r = 0.886, respectively). Our data demonstrate that the etiopathogenesis process of OLP and OLLC modulates the expansion and degranulation of mast cells; mast cells density, however, was similar between OLP and OLLC. The distribution of mast cells appears to vary along the lamina propria.
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Abstract Background: A lot of congenital melanocytic nevi (CMN) carry the somatic mutation in the oncogene BRAF V600E. But the detailed histopathologic characteristics and the proliferative activity of CMN with BRAF V600E gene mutation have not been systematically documented. Objective: To identify the proliferative activity and histopathological features correlating them with BRAF V600E gene mutation status in CMN. Methods: CMN were retrospectively identified from the laboratory reporting system. Mutations were determined by Sanger sequencing. The CMN were divided into a mutant group and control group according to whether there was BRAF gene mutation and were strictly matched according to gender, age, nevus size, and location. Histopathological analysis, analysis of Ki67 expression by immunohistochemistry and laser confocal fluorescence microscopy were performed. Results: The differences in Ki67 index, the depth of nevus cell involvement and the number of nevus cell nests between the mutant group and the control group was statistically significant, with p-values of 0.041, 0.002 and 0.007, respectively. Compared with BRAFV600E negative nevi, BRAF V600E positive nevi often exhibited predominantly nested intraepidermal melanocytes, and larger junctional nests, but the difference in this datasets were not statistically significant. The number of nests (p = 0.001) was positively correlated with the proportion of Ki67 positive cells. Study limitations: A small sample of patients were included and there was no follow-up. Conclusions: BRAF V600E gene mutations were associated with high proliferative activity and distinct histopathological features in congenital melanocytic nevi.
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OBJECTIVE: The objective of this systematic review with meta-analysis was to critically evaluate the available data on the association of the BRAF V600E mutation and recurrence rate of ameloblastomas. MATERIALS AND METHODS: This systematic review was registered in Prospero (CRD42020183645) and performed based on the PRISMA statement. A comprehensive search in PubMed, Web of Science, Scopus and Cochrane Library databases was performed in order to answer the question "Does BRAF V600E mutation affect recurrence rate of ameloblastomas?" Methodological quality and risk of bias of the selected studies were assessed with JBI Critical Appraise Tool. Meta-analysis of quantitative data was conducted with RevMan 5.3 and Jamovi 2.3. RESULTS: The initial search identified 302 articles, and 21 met the inclusion criteria. A total of 855 subjects with ameloblastoma were included in the analysis. The pooled measures for frequency of BRAF V600E mutation was 65.30% (95% CI: 0.56-0.75; p < .001; I2 = 90.85%; τ = 0.205; p < .001), and the pooled recurrence rate was 25.30% (95% CI: 0.19-0.31; p < .001; I2 = 79.44%; τ = 0.118; p < .001). No differences in recurrence rate were observed between the BRAF V600E and wild type BRAF ameloblastomas, with a pooled Odds Ratio of 0.93 (95% CI: 0.56-1.54; p = .78; I2 = 31%; p = .09). CONCLUSIONS: BRAF V600E mutation is a frequent event in ameloblastomas, but does not increase nor reduce its recurrence rate, and thus have a limited value in predicting its prognosis.
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Ameloblastoma , Humanos , Ameloblastoma/genética , Proteínas Proto-Oncogénicas B-raf/genética , Mutación , PronósticoRESUMEN
BACKGROUND: A lot of congenital melanocytic nevi (CMN) carry the somatic mutation in the oncogene BRAF V600E. But the detailed histopathologic characteristics and the proliferative activity of CMN with BRAF V600E gene mutation have not been systematically documented. OBJECTIVE: To identify the proliferative activity and histopathological features correlating them with BRAF V600E gene mutation status in CMN. METHODS: CMN were retrospectively identified from the laboratory reporting system. Mutations were determined by Sanger sequencing. The CMN were divided into a mutant group and control group according to whether there was BRAF gene mutation and were strictly matched according to gender, age, nevus size, and location. Histopathological analysis, analysis of Ki67 expression by immunohistochemistry and laser confocal fluorescence microscopy were performed. RESULTS: The differences in Ki67 index, the depth of nevus cell involvement and the number of nevus cell nests between the mutant group and the control group was statistically significant, with p-values of 0.041, 0.002 and 0.007, respectively. Compared with BRAF V600E negative nevi, BRAF V600E positive nevi often exhibited predominantly nested intraepidermal melanocytes, and larger junctional nests, but the difference in this data sets were not statistically significant. The number of nests (p = 0.001) was positively correlated with the proportion of Ki67 positive cells. STUDY LIMITATIONS: A small sample of patients were included and there was no follow-up. CONCLUSIONS: BRAF V600E gene mutations were associated with high proliferative activity and distinct histopathological features in congenital melanocytic nevi.
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Nevo Pigmentado , Nevo , Neoplasias Cutáneas , Humanos , Niño , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Cutáneas/patología , Estudios Retrospectivos , Antígeno Ki-67/genética , Nevo Pigmentado/genética , Nevo Pigmentado/patología , Mutación/genéticaRESUMEN
ABSTRACT Purpose: Conjunctival melanoma is a rare and aggressive tumor with a propensity for regional and distant metastases. This study aimed to analyze BRAF/NRAS markers in conjunctival melanoma and their relationship with tumor recurrences and patient prognosis. Methods: This retrospective, observational, single-center study included consecutive patients with an anatomopathological diagnosis of conjunctival melanoma, registered between January 1992 and December 2019. BRAF/NRAS mutations were analyzed using cobas®4800 kit (Roche®) in samples obtained by excisional or map biopsy. Additionally, the presence of other associated precancerous or tumor lesions was assessed. Results: A total of 12 patients with positive histological samples for conjunctival melanoma were included (7 women, 5 men), with a mean age at diagnosis of 60 years and a mean evolution time of 6.38 ± 3.4 years. BRAF V600E mutation was observed in three biopsies (25%), similar to NRAS Q61X (25%). Recurrences occurred in all patients with positive BRAF or NRAS mutation, and five of these patients developed systemic dissemination (83.33%). Moreover, four of six patients with mutated BRAF or NRAS (66.66%) had histopathological findings of tumor or precancerous lesions. Conclusions: BRAF and NRAS mutations may be risk factors for recurrence and shorter survival in conjunctival melanoma, which would make these patients candidates for targeted therapies and comprehensive and individualized follow-up. All these data warrant standardized prospective studies.
RESUMO Objetivo: O melanoma da conjuntiva é um tumor raro e agressivo, com propensão à disseminação metastática regional e distante. Este estudo tem como objetivo analisar os marcadores BRAF e NRAS no melanoma da conjuntiva e sua relação com recidivas tumorais e com o prognóstico do paciente. Métodos: Este foi um estudo retrospectivo, observacional e unicêntrico de pacientes consecutivos com diagnóstico anatomopatológico de melanoma da conjuntiva feito entre janeiro de 1992 e dezembro de 2019. As mutações BRAF e NRAS foram analisadas com o kit cobas® 4800 (Roche®) em amostras obtidas através de biópsia excisional ou por mapa. Além disso, foi avaliada a presença de lesões pré-cancerosas ou tumorais associadas. Resultados: Foram incluídos 12 pacientes com amostras histológicas positivas para melanoma da conjuntiva (7 mulheres e 5 homens), com idade média ao diagnóstico de 60 anos e tempo médio de evolução de 6,38 ± 3,4 anos. A mutação BRAF V600E foi encontrada em 3 biópsias (25%), bem como a NRAS Q61X (25%). Ocorreram recidivas em todos os pacientes positivos para mutações de BRAF ou NRAS e 5 desses pacientes desenvolveram disseminação sistêmica (83,33%). Além disso, 4 dos 6 pacientes com BRAF ou NRAS mutante (66,66%) apresentaram achados histopatológicos de lesões tumorais ou pré-cancerosas. Conclusões: As mutações BRAF e NRAS podem ser fatores de risco para recorrência e menor sobrevida no melanoma da conjuntiva, o que tornaria esses pacientes candidatos a terapias direcionadas e a um acompanhamento mais abrangente e individualizado. Todos esses dados justificam mais estudos prospectivos padronizados.
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Embora o melanoma seja representado por apenas cerca de 5% dos casos de tumores malignos de pele, é responsável pela ampla maioria de óbitos relacionados a tumores cutâneos. Seu desenvolvimento está principalmente associado à presença de mutações em oncogenes específicos, como BRAF, c-KIT e PDGFRA, os quais estão relacionados ao metabolismo celular. OBJETIVOS: Avaliar retrospectivamente a presença de mutações nos genes BRAF (éxons 15), C-KIT (éxons 9,11,13 e 17) e PDGFRA (éxons 12 ,14 e 18) e correlacionar os resultados com as características clínicas e epidemiológicas e desfecho dos pacientes. METODOLOGIA: Foi realizado um estudo retrospectivo de 94 pacientes com melanoma metastático atendidos no Hospital Amaral Carvalho entre os anos de 2015 a 2022, de acordo com as seguintes variáveis: idade ao diagnóstico, gênero, cor, local do tumor primário, local de metástase, subtipo histológico de melanoma, dosagem de LDH, positividade para marcadores de imuno-histoquímica, espessura, presença de ulceração, metástase no linfonodo ao diagnóstico do tumor primário, espessura Breslow, classificação Clark, índice mitótico e desfecho (óbito, sobrevida). RESULTADOS: A maioria dos pacientes eram do sexo masculino (52,1%), de cor branca (97,9%) e com idade acima de 60 anos (42,5%). O subtipo histológico mais encontrado foi o extensivo superficial (42,5%), sendo os membros inferiores o local mais acometido (35,1%). O nível IV de Clark (39,4%) e índice de Breslow acima de 4mm (33,0%) foram os mais prevalentes. A maior parte dos tumores não apresentou ulceração (53,2%) e mais da metade dos pacientes apresentou mais de uma mitose por mm² (47,9%). A dosagem de desidrogenase láctica (LDH) se manteve dentro da normalidade na maioria dos pacientes no momento do diagnóstico (43,6%) e no surgimento de metástases (30,9%). Todos os pacientes apresentaram ao menos uma metástase, sendo os linfonodos regionais o local de maior incidência. A maioria dos pacientes faleceu em decorrência da doença (66,0%). A análise de BRAF apresentou significância estatística para as variáveis idade ao diagnóstico (p= 0,0085), tipo histológico (p= 0,048) e nível de Clark (p= 0,0290). A mediana de sobrevivência para pacientes com mutações em BRAF foi de 62 meses e 50 meses para aqueles que não apresentaram mutações. Não foram encontradas significâncias estatísticas entre c-KIT e as variáveis analisadas. A mediana de sobrevivência para pacientes com mutações em c-KIT foi de 38 meses e 70 meses para aqueles que não apresentaram mutações. CONCLUSÕES: A presença de mutação em BRAF esteve associada à menor idade e menores índices de Clark, e relacionada à ligeira maior sobrevida. O contrário foi observado para mutações em c-KIT, apesar da ausência de significância estatística: uma ligeira menor sobrevida foi observada em pacientes mutados. O LDH não esteve bem correlacionado à presença do melanoma metastático ao se apresentar normal na maioria dos casos. Grande parte dos pacientes tiveram o tumor primário localizado nos membros inferiores, diferentemente do relatado por outros estudos, e apesar de não significante, os tumores de tronco foram em sua maioria mutados para BRAF, e o oposto observado em membros inferiores e superiores. Assim, o papel prognóstico da mutação em BRAF na progressão da doença é ainda controverso. Tais dados podem fornecer mais informações para a adequação de protocolos de prevenção e tratamento de pacientes acometidos por melanoma.
INTRODUCTION: Although melanoma is represented by only about 5% of cases of malignant skin tumors, it is responsible for the vast majority of deaths related to skin tumors. Its development is mainly associated with the presence of mutations in specific oncogenes, such as BRAF, c-KIT and PDGFRA, which are related to cell metabolism. OBJECTIVES: Retrospectively evaluate the presence of mutations in BRAF (exons 15), C-KIT (exons 9,11,13 and 17) and PDGFRA (exons 12, 14 and 18) genes and correlate the results with the clinical and epidemiological characteristics and patient outcomes. METHODS: A retrospective study of 94 patients with metastatic melanoma treated at Hospital Amaral Carvalho between the years 2015 to 2022 was carried out, according to the following variables: age at diagnosis, gender, color, site of primary tumor, site of metastasis, histological subtype of melanoma, LDH dosage, positivity for immunohistochemical markers, thickness, presence of ulceration, lymph node metastasis at diagnosis of the primary tumor, Breslow thickness, Clark classification, mitotic index and outcome (death, survival). RESULTS: Most patients were male (52.1%), white (97.9%) and aged over 60 years (42.5%). The most common histological subtype was superficial extensive (42.5%), with the lower limbs being the most affected site (35.1%). Clark's level IV (39.4%) and Breslow thickness above 4mm (33.0%) were the most prevalent. Most tumors did not show ulceration (53.2%) and more than half of the patients had more than one mitosis per mm² (47.9%). The lactate dehydrogenase (LDH) dosage remained within the normal range in most patients at the time of diagnosis (43.6%) and at the onset of metastases (30.9%). All patients had at least one metastasis, with regional lymph nodes being the site with the highest incidence. Most patients died as a result of the disease (66.0%). BRAF analysis showed statistical significance for the variables age at diagnosis (p= 0.0085), histological type (p= 0.048) and Clark's level (p= 0.0290). Median survival for patients with BRAF mutations was 62 months and 50 months for those without mutations. No statistical significance was found between c-KIT and the analyzed variables. The median survival for patients with c-KIT mutations was 38 months and 70 months for those without mutations. CONCLUSIONS: The presence of a BRAF mutation was associated with younger age and lower Clark scores, and related to slightly longer survival. The opposite was observed for mutations in c-KIT, despite the absence of statistical significance: a slightly lower survival was observed in mutated patients. LDH was not well correlated with the presence of metastatic melanoma as it was normal in most cases. Most of the patients had the primary tumor located in the lower limbs, unlike what has been reported by other studies, and although not significant, the trunk tumors were mostly mutated to BRAF, and the opposite was observed in the lower and upper limbs. Thus, the prognostic role of the BRAF mutation in disease progression is still controversial. Such data may provide more information for the adequacy of prevention and treatment protocols for patients affected by melanoma.
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Humanos , Masculino , Femenino , Proteínas Proto-Oncogénicas c-kit , Proteínas Proto-Oncogénicas B-raf , Melanoma/metabolismo , Mutación , Neoplasias Cutáneas , Instituciones Oncológicas/estadística & datos numéricos , Estudios Retrospectivos , Epidemiología Clínica , Melanoma/genéticaRESUMEN
Introducción: El cáncer de tiroides se posiciona como una de las neoplasias más prevalentes en Ecuador, manifestándose típicamente en la cuarta década de vida, con una mayor inciden-cia en mujeres. El subtipo histológico predominante es el papilar (CPT), y diversos estudios han evidenciado que hasta un 80% de los casos de CPT presentan la mutación BRAF. Esta mutación se ha asociado con factores de pronóstico desfavorable, como la presencia de me-tástasis ganglionares, estadíos tumorales avanzados, extensión extratiroidea y característi-cas histológicas agresivas. Además, se ha observado una relación con una mayor tasa de recurrencia y una respuesta reducida al tratamiento con yodo. Ante este contexto, esta inves-tigación se propone analizar la distribución de la mutación BRAF según características epide-miológicas e histopatológicas en pacientes con diagnóstico de cáncer papilar de tiroides en Ecuador. Materiales y métodos: Este estudio se llevó a cabo de manera descriptiva y retrospectiva, abarcando a pacientes con diagnóstico de cáncer papilar de tiroides a quienes se les practicó el análisis genético para la detección de la mutación BRAF. La muestra incluyó 106 historias clínicas que cumplían con los criterios de selección establecidos Resultados: La evaluación de las historias clínicas reveló la presencia de la mutación BRAF en el 75% de los casos. Este porcentaje fue más elevado en mujeres, individuos mayores de 45 años y residentes en áreas urbanas. Respecto a la ocupación, la mayoría de los pacientes se dedicaba a labores de limpieza y no presentaban antecedentes personales de exposición a radiación ionizante ni antecedentes oncológicos familiares. El 84% se encontraba en la etapa clínica I, y en su mayoría, la neoplasia estaba localizada en el lóbulo tiroideo derecho.Conclusión:Este análisis subraya la imperiosa necesidad de identificar los factores de riesgo vinculados con la aparición del carcinoma papilar de tiroides en la población ecuatoriana. Los resultados indican una prevalencia significativa de la mutación BRAF, lo que subraya su rele-vancia comomarcador pronóstico en esta enfermedad. Estos hallazgos pueden contribuir a una mejor comprensión de la epidemiología y la patogenia del cáncer de tiroides, así como a la mejora de las estrategias de prevención y tratamiento en el ámbito local.
Introduction: Thyroid cancer is positioned as one of the most prevalent neoplasms in Ecuador, typically manifesting in the fourth decade of life, with a higher incidence in women. The pre-dominant histological subtype is papillary carcinoma (PTC), and various studies presentshown that up to 80% of PTC cases present the BRAF mutation. This mutation has been as-sociated with unfavorable prognostic factors, such as the presence of lymph node metasta-ses, advanced tumor stages, extrathyroidal extension, and aggressive histologicalfeatures. Additionally, a correlationhas been observed with a higher recurrence rate and a reduced re-sponse toiodine treatment. Given this context, this research aims to analyze the distribution of the BRAF mutation according to epidemiological and histopathological characteristics in patients diagnosed with papillary thyroid cancer in Ecuador. Materials and methods: This retrospective descriptive study involved the analysis of genetic data from 106 medical records of patients diagnosed with papillary thyroid cancer who under-went BRAF mutation detection. The sample was selected based on established criteria. Results: Evaluation of medical records revealed the presence of the BRAF mutation in 75% of cases. This percentage was higher in women, individuals over 45 years of age, and residents in urban areas. Regarding occupation, most patients were dedicated to cleaning work and had no personal history of exposure to ionizing radiation orafamily history of cancer.Additionally, 84% of the patients were in clinical stage I and the neoplasmswerelocated in the right thyroid lobe.Conclusion: This analysis highlights the urgent need to identify risk factors linked to the ap-pearance of papillary thyroid carcinoma in the Ecuadorian population. The results indicate a significant prevalence of the BRAF mutation, underlining its relevance as a prognostic marker in this disease. These findings may contribute to a better understanding of the epidemiology and pathogenesis of thyroid cancerleadingtoimprovementsinprevention and treatment strategies at the local level.
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Humanos , Masculino , Femenino , Adulto , Neoplasias de las Glándulas Endocrinas , Proteínas Proto-Oncogénicas B-raf , Cáncer Papilar Tiroideo , Glándulas EndocrinasRESUMEN
OBJECTIVE: The objective of this systematic review with meta-analysis was to critically evaluate the available data on sensitivity and specificity of IHC compared with molecular tests in the detection of BRAF V600E mutation in ameloblastomas. MATERIALS AND METHODS: This systematic review was performed based on the PRISMA statement and registered in Prospero (CRD42021259117). PubMed, Web of Science, Scopus, and Cochrane Library databases were searched for observational studies to answer the question "What is the diagnostic accuracy of immunohistochemistry compared with molecular tests for the diagnosis of BRAF V600E mutation in ameloblastomas?". Methodological quality and risk of bias assessment of the selected studies were based on the QUADAS-2. Meta-analysis based on hierarchical SROC curve model and summary measures for sensitivity and specificity were computed. RESULTS: A total of 226 records were found, but only 05 articles met the inclusion criteria, with 277 FFPE specimens of ameloblastoma included in the quantitative analysis. The sensitivity of the IHC compared to molecular tests ranged from 0.71 to 1.00, while all of the included studies showed perfect specificity (1.00). Pooled measures for sensitivity and specificity were 0.95 [95% CI 0.89, 1.00] and 1.00 [95% CI 0.95, 1.00], respectively. The diagnostic odds ratio was 4.05, and the AUC for SROC curve was calculated as 0.979. CONCLUSIONS: BRAF V600E-specific IHC using VE1 antibody showed extremely high sensitivity and specificity when compared with molecular tests in the detection of the mutation in ameloblastomas.
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Ameloblastoma , Ameloblastoma/diagnóstico , Ameloblastoma/genética , Biomarcadores de Tumor/genética , Humanos , Inmunohistoquímica , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Sensibilidad y EspecificidadRESUMEN
The Erdheim-Chester's disease is extremely rare in children. We present the case of a 12-year-old girl with histological and radiological diagnosis of this disease and mutation of the BRAF gene, who developed multisystemic compromise requiring treatment with dabrafenib. We identified 22 reports of this condition among children worldwide and this is the second pediatric case in Latin America. Diagnostic imaging is critical to confirm Erdheim-Chester disease and for the surgical planning of the biopsy. Additionally, we identified the parasellar dark sign, which has previously been reported on lymphocytic hypophysitis. This report contributes to the current practice as it shows the clinical presentation and the diagnostic workout of this disease in pediatrics.
La enfermedad de Erdheim-Chester es una condición extremadamente rara en la edad pediátrica. Se presenta el caso de una niña de 12 años con diagnóstico histológico y radiológico de enfermedad de Erdheim-Chester multisistémica y mutación en el gen BRAF, que requirió tratamiento con dabrafenib. Hasta el momento, se han reportado 22 casos pediátricos en el mundo y este es el segundo en Latinoamérica. Se observó el hallazgo radiológico denominado signo oscuro paraselar, descrito hasta ahora en pacientes con hipofisitis autoinmunitaria para diferenciarlos de aquellos con adenomas hipofisarios. Este reporte contribuye a la literatura médica en dos aspectos fundamentales: las manifestaciones clínicas de la enfermedad y su diagnóstico en la población pediátrica.
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Enfermedad de Erdheim-Chester , Pediatría , Niño , Colombia , Enfermedad de Erdheim-Chester/diagnóstico , Enfermedad de Erdheim-Chester/genética , Femenino , Humanos , Mutación , Proteínas Proto-Oncogénicas B-raf/genéticaRESUMEN
Resumen | La enfermedad de Erdheim-Chester es una condición extremadamente rara en la edad pediátrica. Se presenta el caso de una niña de 12 años con diagnóstico histológico y radiológico de enfermedad de Erdheim-Chester multisistémica y mutación en el gen BRAF, que requirió tratamiento con dabrafenib. Hasta el momento, se han reportado 22 casos pediátricos en el mundo y este es el segundo en Latinoamérica. Se observó el hallazgo radiológico denominado signo oscuro paraselar, descrito hasta ahora en pacientes con hipofisitis autoinmunitaria para diferenciarlos de aquellos con adenomas hipofisarios. Este reporte contribuye a la literatura médica en dos aspectos fundamentales: las manifestaciones clínicas de la enfermedad y su diagnóstico en la población pediátrica.
Abstract | The Erdheim-Chester's disease is extremely rare in children. We present the case of a 12-year-old girl with histological and radiological diagnosis of this disease and mutation of the BRAF gene, who developed multisystemic compromise requiring treatment with dabrafenib. We identified 22 reports of this condition among children worldwide and this is the second pediatric case in Latin America. Diagnostic imaging is critical to confirm Erdheim-Chester disease and for the surgical planning of the biopsy. Additionally, we identified the parasellar dark sign, which has previously been reported on lymphocytic hypophysitis. This report contributes to the current practice as it shows the clinical presentation and the diagnostic workout of this disease in pediatrics.
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Pediatría , Enfermedad de Erdheim-Chester , Imagen por Resonancia Magnética , Histiocitosis , Proteínas Proto-Oncogénicas B-rafRESUMEN
The BRAFV600E point mutation plays a key role in the tumorigenesis of many gliomas. Inhibiting its product is part of the innovative therapies emerging in recent years. Knowing the role of these treatments is essential. The aim of this experience was to describe the clinical-radiological response of pediatric BRAFV600E mutated gliomas treated with BRAF inhibitors. To this end, a descriptive and retrospective study was performed in patients under 16 years of age with BRAFV600E gliomas, who received vemurafenib or dabrafenib at Hospital Garrahan. Thirteen patients treated in the last 7 years were included: 9 were low-grade and 4 high-grade gliomas. The median age at diagnosis was 8.6 years (0.89-14.04) and at start of targeted therapy was 11.62 years (3.64-15.42). All patients had previously a surgical procedure, and 12/13 had received another therapy prior BRAF inhibition: 11 chemotherapy (in one case, up to 4 different protocols) and 4 radiotherapy. Under targeted therapy, tumour response was obtained in 10 patients (size reduction equal to or greater than 25%), and best response was observed in the first 6 months of treatment in 7 children. Four patients progressed under treatment (all high-grade gliomas) and 2 progressed shortly after stopping the inhibitor (both low-grade gliomas). Five patients had grade 3-4 toxicity, with subsequent full recovery. A good and sustained clinical-radiological response, with acceptable tolerance, is described in patients with BRAFV600E mutated low-grade gliomas treated with BRAFV600E inhibitors. In contrast, the response in patients with high-grade gliomas was intermediate and of short duration, with early tumour progression.
La mutación puntual V600E del gen BRAF juega un papel fundamental en la tumorigénesis de muchos gliomas. La inhibición de su producto forma parte de terapias innovadoras emergentes en los últimos años. Conocer el rol de estos tratamientos resulta imprescindible. El objetivo del trabajo fue describir la respuesta clínico-radiológica en niños con gliomas BRAFV600E mutado tratados con inhibidores BRAF. Para ello se realizó un estudio descriptivo y retrospectivo en pacientes menores de 16 años con gliomas BRAFV600E mutado que recibieron vemurafenib o dabrafenib en el Hospital Garrahan. Trece pacientes tratados en los últimos 7 años fueron incluidos: 9 gliomas de bajo grado y 4 de alto grado. La mediana de edad al diagnóstico fue 8.6 años (0.89-14.04) y del comienzo del inhibidor 11.62 años (3.64-15.42). Inicialmente, todos habían realizado tratamiento quirúrgico, y 12/13 recibieron previamente otra terapia: 11 quimioterapia (eventualmente hasta 4 líneas distintas) y 4 radioterapia. Con la terapia dirigida, 10 pacientes tuvieron una disminución tumoral mayor o igual al 25%, quedando evidenciada en 7 niños la mejor respuesta dentro de los 6 meses del inicio. Hubo 4 progresados intratratamiento (todos alto grado), y 2 progresados prontamente luego de suspender el inhibidor (ambos bajo grado). Cinco presentaron efectos adversos grado 3-4, con recuperación ad-integrum. Se describe una buena y sostenida respuesta clínico-radiológica, con tolerancia aceptable, en pacientes con gliomas de bajo grado BRAFV600E mutado tratados con inhibidores BRAFV600E. En contraste, la respuesta en pacientes con gliomas de alto grado fue intermedia y de poca duración, con progresión tumoral precoz.
Asunto(s)
Glioma , Proteínas Proto-Oncogénicas B-raf , Niño , Glioma/tratamiento farmacológico , Glioma/genética , Hospitales , Humanos , Mutación , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/genética , Estudios RetrospectivosRESUMEN
Resumen La mutación puntual V600E del gen BRAF juega un papel fundamental en la tumorigénesis de muchos gliomas. La inhibición de su producto forma parte de terapias innovadoras emergentes en los últimos años. Conocer el rol de estos tratamientos resulta imprescindible. El objetivo del trabajo fue describir la respuesta clínico-radiológica en niños con gliomas BRAF V600E mutado tratados con inhibidores BRAF. Para ello se realizó un estudio descriptivo y retrospectivo en pacientes menores de 16 años con gliomas BRAF V600E mu tado que recibieron vemurafenib o dabrafenib en el Hospital Garrahan. Trece pacientes tratados en los últimos 7 años fueron incluidos: 9 gliomas de bajo grado y 4 de alto grado. La mediana de edad al diagnóstico fue 8.6 años (0.89-14.04) y del comienzo del inhibidor 11.62 años (3.64-15.42). Inicialmente, todos habían realizado tratamiento quirúrgico, y 12/13 recibieron previamente otra terapia: 11 quimioterapia (eventualmente hasta 4 líneas distintas) y 4 radioterapia. Con la terapia dirigida, 10 pacientes tuvieron una disminución tumoral mayor o igual al 25%, quedando evidenciada en 7 niños la mejor respuesta dentro de los 6 meses del inicio. Hubo 4 progresados intratratamiento (todos alto grado), y 2 progresados prontamente luego de suspender el inhibidor (ambos bajo grado). Cinco presentaron efectos adversos grado 3-4, con recuperación ad-integrum. Se describe una buena y sostenida respuesta clínico-radiológica, con tolerancia aceptable, en pacientes con gliomas de bajo grado BRAF V600E mutado tratados con inhibidores BRAF V600E . En contraste, la respuesta en pacientes con gliomas de alto grado fue intermedia y de poca duración, con progresión tumoral precoz.
Abstract The BRAF V600E point mutation plays a key role in the tumorigenesis of many gliomas. Inhibiting its product is part of the innovative therapies emerging in recent years. Knowing the role of these treatments is essential. The aim of this experience was to describe the clinical-radiological response of pediatric BRAF V600E mutated gliomas treated with BRAF inhibitors. To this end, a descriptive and retrospective study was performed in patients under 16 years of age with BRAF V600E gliomas, who received vemurafenib or dabrafenib at Hospital Garrahan. Thirteen patients treated in the last 7 years were included: 9 were low-grade and 4 high-grade gliomas. The median age at diagnosis was 8.6 years (0.89-14.04) and at start of targeted therapy was 11.62 years (3.64-15.42). All patients had previously a surgical procedure, and 12/13 had received another therapy prior BRAF inhibition: 11 chemotherapy (in one case, up to 4 different protocols) and 4 radiotherapy. Under targeted therapy, tumour response was obtained in 10 patients (size reduction equal to or greater than 25%), and best response was observed in the first 6 months of treatment in 7 children. Four patients progressed under treatment (all high-grade gliomas) and 2 progressed shortly after stopping the inhibitor (both low-grade gliomas). Five patients had grade 3-4 toxicity, with subsequent full recovery. A good and sustained clinical-radiological response, with acceptable tolerance, is described in patients with BRAF V600E mutated low-grade gliomas treated with BRAF V600E inhibitors. In contrast, the response in patients with high-grade gliomas was intermediate and of short duration, with early tumour progression.
Asunto(s)
Humanos , Niño , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/genética , Glioma/genética , Glioma/tratamiento farmacológico , Estudios Retrospectivos , Hospitales , MutaciónRESUMEN
RESUMEN La vía PI3K/AKT/mTOR participa en múltiples procesos celulares fundamentales para la célula. Algunas mutaciones genéticas de los componentes de esta vía se han asociado a diversas enfermedades humanas: las más importantes son los carcinomas de mama, tiroides y endometrio, el glioblastoma multiforme, el cáncer de próstata y los linfomas. La vía canónica PI3K/AKT/mTOR se ha estudiado ampliamente en los últimos años. Sin embargo, el conocimiento de la complejidad de sus componentes principales y su interrelación con los elementos de otras vías va en aumento. Por ello, es importantes actualizar cada cierto tiempo la información disponible para la comprensión de este mecanismo. Así mismo, se están y se han desarrollado numerosos ensayos con medicinas selectivas en búsqueda de un tratamiento más inteligente para las enfermedades asociadas a alteraciones de esta vía. Por tanto, realizamos una revisión de esta vía de transducción con el objetivo de tener una visión cercana de su funcionamiento, sus alteraciones y enumerar algunas moléculas promisorias para ser utilizadas en futuros tratamientos.
ABSTRACT The PI3K/AKT/mTOR pathway is involved in multiple cellular processes which are essential for the cells. Some genetic mutations of the components of this pathway have been associated with various human diseases, the most important of which are breast, thyroid and endometrium carcinomas; glioblastoma multiforme; prostate cancer and lymphomas. The PI3K/AKT/mTOR canonical pathway has been extensively studied in recent years. However, as the complexity of its main components and their correlation with the components of other pathways are increasing, it is important to update from time to time the available information to understand this mechanism. Furthermore, many trials have been conducted with selective medicines aimed to look for a more intelligent treatment for diseases associated with alterations in this pathway. Therefore, we review this transduction pathway to take a close look at its functioning and alterations, and to list some promising molecules for future treatments.
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Papillary thyroid carcinoma with desmoid-type fibromatosis (PTC-DTF) or nodular fasciitis-like stroma (PTC-NFS) is a rare morphological variant of PTC with a favorable prognosis. There is a paucity of molecular data regarding this entity. We present the case of a 20-year-old female who presented with a palpable mass over the anterior aspect of the neck for the past 3-4 months, which was diagnosed as PTC-NFS. Ultrasonogram of the neck revealed a bulky left lobe of thyroid that contained a well-defined heterogenous lesion measuring around 24 × 26 × 36 mm with involvement of the adjacent isthmus. She underwent a total thyroidectomy with central compartment lymph node dissection. Histological examination revealed a biphasic tumor with epithelial and stromal components resembling nodular fasciitis. Two dissected lymph nodes showed metastasis of the epithelial component only. On immunohistochemistry, BRAF mutant protein expression was evident in the epithelial component only, while ß-catenin was negative in both the components. The histopathological diagnosis of papillary thyroid carcinoma with nodular fasciitis-like stroma was offered. Sanger sequencing revealed a BRAFV600E (c.1799T>A, Val600Glu) mutation. Post-operatively, no residual tumor was detected on ultrasound and radioiodine scans. The patient was doing well at follow-up of 9 months. PTC-NFS/DTF is a histological variant of PTC with a favorable prognosis. Our index case was associated with the BRAF mutation, which was restricted to the epithelial component. Thorough sampling of the excised specimen is essential in order not to miss the epithelial component, which, in most reported cases (including ours) appears to be small.
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BACKGROUND: Viruses are being used as alternative and complementary tools for treating cancers. Oncolytic viruses exhibit tumor tropism, ability to enhance anti-tumor immunity and ability to be used in combination with conventional chemotherapy and radiotherapy. We have recently selected some rotavirus isolates which are adapted to efficiently infect and kill tumor cell lines. AIM: We tested five tumor cell-adapted rotavirus isolates for their ability to infect the human adenocarcinoma cell line MCF-7. METHODS: Cell surface membrane-associated proteins mediating virus particle attachment were characterized using ELISA, immunoprecipitation, FACS analysis, and antibody blocking. RESULTS: It was found that heat shock proteins (HSPs) such as Hsp90, Hsp70, Hsp60, and Hsp40 are expressed on the cell surface forming complexes with protein disulfide isomerase (PDI), integrin ß3, and heat shock cognate protein 70 (Hsc70) in lipid raft microdomains. Interaction of rotavirus isolates with these cellular proteins was further confirmed by a competition assay and an inhibition assay involving the HSPs tested. CONCLUSION: Our findings suggest that the tumor cell-adapted rotavirus isolates studied here offer a promising tool for killing tumor cells, thus encouraging further research into this topic, including animal models.
Asunto(s)
Adenocarcinoma , Proteínas de Choque Térmico , Virus Oncolíticos , Rotavirus , Adenocarcinoma/terapia , Proteínas del Choque Térmico HSC70 , Humanos , Células MCF-7RESUMEN
Abstract Background: Viruses are being used as alternative and complementary tools for treating cancers. Oncolytic viruses exhibit tumor tropism, ability to enhance anti-tumor immunity and ability to be used in combination with conventional chemotherapy and radiotherapy. We have recently selected some rotavirus isolates which are adapted to efficiently infect and kill tumor cell lines. Aim: We tested five tumor cell-adapted rotavirus isolates for their ability to infect the human adenocarcinoma cell line MCF-7. Methods: Cell surface membrane-associated proteins mediating virus particle attachment were characterized using ELISA, immunoprecipitation, FACS analysis, and antibody blocking. Results: It was found that heat shock proteins (HSPs) such as Hsp90, Hsp70, Hsp60, and Hsp40 are expressed on the cell surface forming complexes with protein disulfide isomerase (PDI), integrin β3, and heat shock cognate protein 70 (Hsc70) in lipid raft microdomains. Interaction of rotavirus isolates with these cellular proteins was further confirmed by a competition assay and an inhibition assay involving the HSPs tested. Conclusion: Our findings suggest that the tumor cell-adapted rotavirus isolates studied here offer a promising tool for killing tumor cells, thus encouraging further research into this topic, including animal models.
Resumen Antecedentes: Los virus se utilizan como herramientas alternativas y complementarias para el tratamiento del cáncer. Los virus oncolíticos exhiben tropismo por tumores, capacidad para intensificar la inmunidad antitumoral y la capacidad para utilizarse en combinación con quimioterapia y radioterapia convencionales. Recientemente, hemos seleccionado algunos aislamientos de rotavirus que están adaptados para infectar y eliminar de manera eficiente líneas de células tumorales. Objetivo: Se ensayaron cinco aislamientos de rotavirus adaptados a células tumorales para determinar su capacidad para infectar la línea celular de adenocarcinoma humano MCF-7. Métodos: Las proteínas asociadas a la membrana de la superficie celular que median la unión de partículas de virus se caracterizaron mediante ELISA, inmunoprecipitación, análisis FACS y bloqueo de anticuerpos. Resultados: Se encontró que las proteínas de choque térmico (HSPs) como Hsp90, Hsp70, Hsp60 y Hsp40 se expresan en la superficie celular formando complejos con la proteína disulfuro isomerasa (PDI), la integrina β3 y la proteína análoga de choque térmico 70 (Hsc70) en microdominios lipídicos (rafts). La interacción de los aislamientos de rotavirus con estas proteínas celulares se confirmó adicionalmente mediante un ensayo de competición y un ensayo de inhibición que incluía las HSP ensayadas. Conclusión: Nuestros hallazgos sugieren que los aislamientos de rotavirus adaptados a las células tumorales estudiados aquí ofrecen una herramienta prometedora para eliminar las células tumorales, lo que estimula más investigaciones sobre este tema, incluidos los modelos animales.