RESUMEN
PURPOSE: Cardiac myxomas (CMs) are the second most common benign primary cardiac tumors, mainly originating within the left atrium. Approximately 5% of CM cases are associated with Carney Complex (CNC), an autosomal dominant multiple neoplasia syndrome often caused by germline mutations in the protein kinase A regulatory subunit 1A (PRKAR1A). Data concerning PRKAR1A alterations in sporadic myxomas are variable and sparse, with PRKAR1A mutations reported to range from 0% to 87%. Therefore, we investigated the frequency of PRKAR1A mutations in sporadic CM using next-generation sequencing (NGS). Additionally, we explored mutations in the catalytic domain of the Protein Kinase A complex (PRKACA) and examined the presence of GNAS mutations as another potential driver. METHODS AND RESULTS: This study retrospectively collected histological and clinical data from 27 patients with CM. First, we ruled out the possibility of underlying CNC through clinical evaluations and standardized interviews for each patient. Second, we performed PRKAR1A immunohistochemistry (IHC) analysis and graded the reactivity of myxoma cells semi-quantitatively. NGS was then applied to analyze the coding regions of PRKAR1A, PRKACA, and GNAS in all 27 cases. Of the 27 sporadic CM cases, 13 (48%) harbored mutations in PRKAR1A. Among these 13 mutant cases, six displayed more than one mutation in PRKAR1A. Most of the identified mutations resulted in premature stop codons or affected splicing. In PRKAR1A mutant CM cases, the loss of PRKAR1A protein expression was significantly more common. In two cases with missense mutations, protein expression remained preserved. Furthermore, a single mutation was detected in the catalytic domain of the protein kinase A complex, while no GNAS mutations were found. CONCLUSION: We identified a relatively high frequency of PRKAR1A mutations in sporadic CM. These PRKAR1A mutations may also represent an important oncogenic mechanism in sporadic myxomas, as already known in CM cases associated with CNC.
Asunto(s)
Cromograninas , Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico , Subunidades alfa de la Proteína de Unión al GTP Gs , Neoplasias Cardíacas , Mixoma , Humanos , Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico/genética , Subunidades alfa de la Proteína de Unión al GTP Gs/genética , Cromograninas/genética , Neoplasias Cardíacas/genética , Neoplasias Cardíacas/patología , Neoplasias Cardíacas/enzimología , Persona de Mediana Edad , Femenino , Masculino , Mixoma/genética , Mixoma/patología , Mixoma/enzimología , Adulto , Anciano , Estudios Retrospectivos , Análisis Mutacional de ADN , Predisposición Genética a la Enfermedad , Mutación , Adulto Joven , Fenotipo , Secuenciación de Nucleótidos de Alto Rendimiento , Adolescente , Complejo de Carney/genética , Complejo de Carney/enzimología , Complejo de Carney/patología , Biomarcadores de Tumor/genética , Subunidades Catalíticas de Proteína Quinasa Dependientes de AMP CíclicoRESUMEN
Intimal sarcoma is a rare malignant mesenchymal tumor arising from the intima of the great vessels and the heart, and is associated with poor outcomes. As clinico-radiological findings and pathological features are often non-specific, the diagnosis of intimal sarcoma is challenging. Recently, MDM2 amplification was reported to be a characteristic genetic event in this tumor. In the present study, we examined MDM2 status by immunohistochemistry, and by fluorescence and dual-color in situ hybridization (FISH and DISH) using intimal sarcoma (10 tumors), angiosarcoma (5), pulmonary sarcomatoid carcinoma (p-SC) (14) and chronic pulmonary thrombosis (CPT) (3) to investigate MDM2 amplification for the diagnosis of intimal sarcoma. MDM2 and CDK4 were immunopositive in all 10 intimal sarcoma tumors, and high-level amplification of MDM2 was detected in eight tumors by both FISH and DISH. The other two tumors had polysomy of chromosome 12 and overexpression of p53 protein. Although MDM2 aberrations were observed in three p-SCs (two with amplification and one with polysomy), angiosarcomas and CPTs lacked MDM2 amplification. Furthermore, there was high concordance between FISH and DISH. In conclusion, we found that MDM2 amplification strongly supports the diagnosis of intimal sarcoma, and MDM2 DISH was a concordant method and an acceptable alternative to FISH. As MDM2 amplification and p53 overexpression were mutually exclusive, disruption of the MDM2-p53 pathway may be an essential genetic event for this malignant tumor.
Asunto(s)
Biomarcadores de Tumor/genética , Amplificación de Genes , Neoplasias Cardíacas/genética , Hibridación in Situ/métodos , Proteínas Proto-Oncogénicas c-mdm2/genética , Sarcoma/genética , Túnica Íntima/enzimología , Neoplasias Vasculares/genética , Adulto , Anciano , Femenino , Neoplasias Cardíacas/enzimología , Neoplasias Cardíacas/patología , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Sarcoma/enzimología , Sarcoma/patología , Túnica Íntima/patología , Neoplasias Vasculares/enzimología , Neoplasias Vasculares/patologíaRESUMEN
Cardiac myxoma is the most common cardiac tumour. Most lesions occur sporadically, but occasional lesions develop in patients with Carney complex, a syndrome characterized by cardiac myxoma, spotty pigmentation, and endocrine overactivity. Two-thirds of patients with Carney complex harbour germline mutations in PRKAR1A, which encodes the type I regulatory subunit of protein kinase A (PKA). Most studies have not found a mutation in PRKAR1A in sporadic cardiac myxoma cases. Recent studies identified frequent mutations in PRKACA, which encodes the catalytic subunit of PKA, in cortisol-secreting adrenocortical adenoma cases. To determine whether the PRKACA mutation is involved in the tumourigenesis of cardiac myxoma, we performed Sanger sequencing of 41 specimens of sporadic cardiac myxoma to test for the presence of mutations in the coding regions and intron-exon boundaries of PRKACA. Mutations were identified in four cases (9.7%). In contrast to the point mutations identified in adrenocortical adenoma, all mutations were in-frame microinsertions of 18-33 bp clustered in exons 7 and 8. The mutated PRKACA proteins lost their ability to bind to PRKAR1A, and thereby lead to constitutive activation of the PKA pathway. Together with previous reports of PRKAR1A mutations in syndromic cardiac myxoma, our study demonstrates the importance of the PKA pathway in the tumourigenesis of cardiac myxoma. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Asunto(s)
Carcinogénesis/genética , Subunidades Catalíticas de Proteína Quinasa Dependientes de AMP Cíclico/genética , Neoplasias Cardíacas/genética , Mixoma/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Subunidades Catalíticas de Proteína Quinasa Dependientes de AMP Cíclico/metabolismo , Análisis Mutacional de ADN , Exones/genética , Femenino , Células HEK293 , Neoplasias Cardíacas/enzimología , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Modelos Moleculares , Mutación , Mixoma/enzimología , Análisis de Secuencia de ADN , Adulto JovenRESUMEN
We present the case of a patient with left atrial myxoma that presented with pulmonary embolism. The patient did not have any intracardiac communication between right and left sides of the heart. Using thrombelastography, the patient was determined to have an abnormally large velocity of plasma thrombus growth and strength with reduced vulnerability to lysis. Critically, increased carboxyhemoglobin concentrations were present, likely secondary to hemolysis from the tumor and engagement of systemic heme oxygenase-1. It was determined that the patient's plasmatic hypercoagulability was in part due to carboxyhemefibrinogen formation via a thrombelastographic method. In addition to circulating hypercoagulability, the patient also had an area of chronic venous stasis in his left ankle that had not changed for over a decade prior to this thrombophilic episode. In conclusion, we present the first case of paradoxical pulmonary embolism in the presence of a left atrial myxoma, potentially secondary to a combination of hemolysis, heme oxygenase-1 up-regulation, systemic hypercoagulability/hypofibrinolysis, and regional venous stasis.
Asunto(s)
Neoplasias Cardíacas/enzimología , Hemo-Oxigenasa 1/sangre , Mixoma/enzimología , Embolia Pulmonar/enzimología , Trombofilia/enzimología , Anciano , Carboxihemoglobina/metabolismo , Atrios Cardíacos/enzimología , Atrios Cardíacos/patología , Neoplasias Cardíacas/complicaciones , Neoplasias Cardíacas/diagnóstico , Neoplasias Cardíacas/patología , Hemo-Oxigenasa 1/genética , Humanos , Masculino , Mixoma/complicaciones , Mixoma/diagnóstico , Mixoma/patología , Embolia Pulmonar/complicaciones , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/patología , Tromboelastografía , Trombofilia/complicaciones , Trombofilia/diagnóstico , Trombofilia/patología , Regulación hacia ArribaRESUMEN
OBJECTIVE: To study the clinical and pathologic features of primary cardiac inflammatory myofibroblastic tumor. METHODS: A total of 4 patients with primary cardiac inflammatory myofibroblastic tumor were encountered during the period from 1993 to 2013 in National Center for Cardiovascular Disease. The clinical features, imaging findings and outcomes of the 4 patients were evaluated. ALK protein expression and ALK gene status were studied using the archival tumor tissues. RESULTS: There were 1 female and 3 male patients. The age of patients ranged from 5 months to 30 years (mean = 16 years). The tumor was located in right ventricle (n = 2), right atrium (n = 1) or pericardium (n = 1). Histologic patterns included 2 cases of fibrous histiocytoma type, 1 case of granulomatous type and 1 case of sclerosing type. Immunohistochemical study showed that 2 cases expressed ALK protein. Fluorescence in-situ hybridization however did not reveal any ALK gene rearrangement. CONCLUSIONS: Inflammatory myofibroblastic tumor of the heart is rarely encountered and easily misdiagnosed. It carries distinctive clinical and pathologic features. ALK protein expression is helpful in arriving at the correct diagnosis.
Asunto(s)
Granuloma de Células Plasmáticas/patología , Neoplasias Cardíacas/patología , Histiocitoma Fibroso Benigno/patología , Adolescente , Adulto , Quinasa de Linfoma Anaplásico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Niño , Diagnóstico Diferencial , Femenino , Granuloma de Células Plasmáticas/enzimología , Neoplasias Cardíacas/enzimología , Histiocitoma Fibroso Benigno/enzimología , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Lactante , Masculino , Proteínas Tirosina Quinasas Receptoras/genética , Proteínas Tirosina Quinasas Receptoras/metabolismoRESUMEN
Insulin-like growth factor 1 (IGF-1) is a molecule with strong proliferative effects, and statins have been reported to exhibit antitumor effects based on clinical and experimental studies. However, their effects on cardiac myxoma (CM) cells and the underlying signaling mechanism(s) are largely unknown. Therefore, we investigated whether the protein/lipid phosphatases and tensin homolog deleted on chromosome ten (PTEN) and pleckstrin homology domain leucine-rich repeat phosphatase 1 and 2 (PHLPP1 and 2) are involved in the proliferative effect of IGF-1 on CM cells and the pharmacological impact of atorvastatin. The activity of PTEN and PHLPPs was determined using specific substrate diC16PIP3 and pNPP. We found that IGF-1 enhanced CM cell proliferation and inhibited both PTEN and PHLPP2 activity in a concentration- and time-dependent manner. Atorvastatin acted counter to IGF-1 and reversed the above effects mediated by IGF-1. Both IGF-1 and atorvastatin did not affect the activity of PHLPP1 and the protein expression of the three phosphatases. The results suggest that IGF-1 may exert its proliferative effects by negatively regulating the PTEN/PHLPP2 signaling pathway in CM cells, and atorvastatin may be a potential drug for the treatment of CM by enhancing the activity of PTEN and PHLPP2.
Asunto(s)
Neoplasias Cardíacas/tratamiento farmacológico , Ácidos Heptanoicos/farmacología , Mixoma/tratamiento farmacológico , Fosfohidrolasa PTEN/metabolismo , Fosfoproteínas Fosfatasas/metabolismo , Pirroles/farmacología , Atorvastatina , Proliferación Celular/efectos de los fármacos , Neoplasias Cardíacas/enzimología , Neoplasias Cardíacas/genética , Neoplasias Cardíacas/metabolismo , Humanos , Factor I del Crecimiento Similar a la Insulina/farmacología , Persona de Mediana Edad , Mixoma/enzimología , Mixoma/genética , Mixoma/metabolismo , Fosfohidrolasa PTEN/genética , Fosfoproteínas Fosfatasas/genética , Transducción de Señal/efectos de los fármacosRESUMEN
Primary cardiac tumors do not occur frequently, and only one quarter of them, chiefly sarcomas, are malignant. Patients with angiosarcoma typically have a shorter survival time than do patients with other sarcomas, and the prognosis for survival depends strictly on the stage of the disease at the time of diagnosis and the possibility of complete surgical excision. Chemotherapy and radiotherapy have well-established postoperative roles because of the high probability of metastasis. We report the case of a 25-year-old man who presented with pericardial effusion and echocardiographic evidence of an intracavitary right atrial mass but without the bulky, infiltrative growth typical of this location of the disease. Malignancy was suggested by the clinical presentation, the location of the mass in the right side of the heart, and the absence of conditions favoring thrombus formation. After complete surgical excision, the mass was confirmed to be an angiosarcoma. Conventional adjuvant chemotherapy and maintenance therapy with inhibitors of CD117 (c-kit) and vascular endothelial growth factor relieved the patient's clinical symptoms and enabled his long-term, disease-free survival. In addition to reporting this case, we discuss aspects of the diagnosis and treatment of angiosarcoma.
Asunto(s)
Benzamidas/uso terapéutico , Procedimientos Quirúrgicos Cardíacos , Neoplasias Cardíacas/terapia , Hemangiosarcoma/terapia , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Adulto , Antineoplásicos/uso terapéutico , Biopsia , Quimioterapia Adyuvante , Ecocardiografía Transesofágica , Neoplasias Cardíacas/enzimología , Neoplasias Cardíacas/patología , Hemangiosarcoma/enzimología , Hemangiosarcoma/patología , Humanos , Mesilato de Imatinib , Masculino , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-kit/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-kit/metabolismo , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND: Malignancy is the most common cause of effusive pericarditis with a haemodynamically significant amount of pericardial fluid. Early diagnosis and management of malignant pericarditis may significantly improve outcomes. AIM: To evaluate retrospectively the rate and clinical presentation of malignant pericarditis among patients undergoing invasive treatment, with a view to identification of optimal diagnostic modalities to distinguish this group among other patients. METHODS: We studied 191 patients (100 men and 91 women, median age 57 years, range 19-88 years) with effusive pericarditis who underwent invasive treatment in the National Institute of Tuberculosis and Lung Diseases in Warsaw in 1982- -2008 due to a significant amount of pericardial fluid and/or echocardiographic evidence of cardiac tamponade. Pericardiocentesis was performed in 93 cases, pericardioscopy in 61 cases, and substernal pericardiotomy in 37 cases. Pericardial fluid was sent for examination in all patients, and a pericardial specimen was obtained in 96 patients. The patients were divided into 3 groups: Group 1 included patients with malignant pericarditis (malignant cells found in the cytological examination of the pericardial fluid and/or neoplastic infiltration in the histological examination of the pericardial specimen), Group 2 included patients with probable malignant pericarditis (pericardial fluid without malignant cells with histologically confirmed malignancy at some other location), and Group 3 included patients with non-malignant pericarditis (negative cytological examination of pericardial fluid and histological examination of the pericardial specimen, with no evidence of malignancy during hospitalization and one-year follow-up). RESULTS: Malignancy was found in 111 (58%) of 191 patients, including 66 (35%) patients with definite malignant pericarditis and 45 (23%) patients with probable malignant pericarditis. Lung cancer, including adenocarcinoma, was the most common type of malignancy, present in 44 (67%) patients. Non-malignant pericarditis was found in 80 (42%) patients. Among patients with the diagnosis of malignancy (Groups 1 and 2), a positive result of the cytological examination of the pericardial fluid was obtained in 52 cases (sensitivity of 46%). Among patients without malignancy, a negative result of the cytological examination of the pericardial fluid was obtained in all 80 cases (specificity of 100%). Malignant infiltration was found in 20 of 44 patients with the diagnosis of malignancy (sensitivity of 46%) and in none among 52 patients without malignancy (specificity of 100%). Compared to patients with non-malignant pericarditis, patients with malignant pericarditis significantly more commonly presented with tachycardia of >100 bpm in a resting electrocardiogram (ECG) (in 77% of patients with malignant pericarditis vs. 43% of patients with non-malignant pericarditis, p = 0.01), low QRS amplitude (52% vs. 34%, respectively, p = 0.03), electrical alternans (19% vs. 3%, respectively, p = 0.001), echocardiographic evidence of cardiac tamponade (67% vs. 34%, respectively, p = 0.0001), enlarged mediastinal lymph nodes by chest computed tomography (CT) (90% vs. 29%, respectively, p <0.00001), pericardial thickness >8 mm by chest CT (62% vs. 16%, respectively, p <0.0001), and bloody pericardial effusion (94% vs. 43%, respectively, p <0.0001). Levels of carcinoembryonic antigen (CEA) and cytokeratin fragment-19 (CYFRA 21-1) in the pericardial fluid were higher in patients with malignant pericarditis compared to patients with non-malignant pericarditis, with median values of 40.8 ng/mL vs. 0.9 ng/mL, p <0.0001, and 162.85 ng/mL vs. 13.35 ng/mL, p <0.0001, respectively. CONCLUSIONS: 1. Malignancy was found in 58% of patients undergoing invasive treatment due to large pericardial effusion. 2. Cytological examination of the pericardial fluid and histological examination of a pericardial specimen showed high specificity (100%) but low sensitivity (46%) in the diagnosis of malignant pericarditis. 3. The most important predictors of malignant pericarditis included tachycardia of >100 bpm as revealed by the physical examination and ECG, echocardiographic evidence of cardiac tamponade, presence of enlarged mediastinal lymph nodes (>1 cm) and thickened pericardium (>8 mm) by chest CT, bloody pericardial effusion, and elevated levels of CEA (>5 ng/mL) and CYFRA 21-1 (>50 ng/mL) in the pericardial fluid.
Asunto(s)
Neoplasias Cardíacas/epidemiología , Neoplasias Cardíacas/patología , Derrame Pericárdico/epidemiología , Derrame Pericárdico/patología , Pericarditis/diagnóstico , Pericarditis/epidemiología , Fosfopiruvato Hidratasa/análisis , Adenocarcinoma/epidemiología , Adenocarcinoma/patología , Adenocarcinoma/secundario , Adulto , Anciano , Anciano de 80 o más Años , Antígenos de Neoplasias/análisis , Biomarcadores de Tumor/análisis , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/patología , Antígeno Carcinoembrionario/análisis , Causalidad , Comorbilidad , Neoplasias del Sistema Digestivo/epidemiología , Neoplasias del Sistema Digestivo/patología , Ecocardiografía , Electrocardiografía , Femenino , Neoplasias Cardíacas/enzimología , Humanos , Incidencia , Queratina-19/análisis , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/patología , Linfoma/epidemiología , Linfoma/patología , Masculino , Mesotelioma/epidemiología , Mesotelioma/patología , Mesotelioma/secundario , Persona de Mediana Edad , Neoplasias Ováricas/epidemiología , Neoplasias Ováricas/patología , Derrame Pericárdico/química , Pericardiocentesis , Pericarditis/enzimología , Neoplasias Pleurales/epidemiología , Neoplasias Pleurales/patología , Valor Predictivo de las Pruebas , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
Effects of phosphatidylcholine, oxidized phosphatidylcholine, sphyngomyelin, cholesterol, and cholesterol esters incorporated in LDL on activity of group IIA secretory phospholipase A2 from human cardiac myxoma were studied. Liposomes containing radioisotope-labeled phosphatidylethanolamine served as the substrate for group IIA secretory phospholipase A2. Oxidized phosphatidylcholine significantly stimulated activity of group IIA secretory phospholipase A2, while phosphatidylcholine in the same concentrations did not modify enzyme activity. Sphyngomyelin incorporated in LDL inhibited group IIA secretory phospholipase A2 activity. Cholesterol and cholesterol esters virtually did not modify enzyme activity. The results indicate that LDL phospholipids and their oxidized forms can be involved in regulation of group IIA secretory phospholipase A2. Study of the mechanisms regulating the proinflammatory group IIA secretory phospholipase A2 can promote the development of new approaches to the diagnosis and treatment of inflammatory processes.
Asunto(s)
Ésteres del Colesterol/metabolismo , Colesterol/metabolismo , Fosfolipasas A2 Grupo II/metabolismo , Fosfatidilcolinas/metabolismo , Esfingomielinas/metabolismo , Colesterol/química , Ésteres del Colesterol/química , Neoplasias Cardíacas/enzimología , Neoplasias Cardíacas/metabolismo , Humanos , Liposomas/química , Liposomas/metabolismo , Mixoma/enzimología , Mixoma/metabolismo , Fosfatidilcolinas/química , Esfingomielinas/químicaRESUMEN
Elevated circulating level and activity of secretory phospholipase A(2) group IIA (sPLA(2)(IIA)) are associated with the development of adverse cardiovascular events. The mechanisms of sPLA(2)(IIA) activity regulation in human blood serum so far remain obscure. We have suggested that the enzyme activity is influenced by circulating lipoproteins. The activity of sPLA(2)(IIA) was examined in whole serum of healthy individuals and after removal of lipoproteins from it. The effects of different classes of native and oxidized lipoproteins on sPLA(2)(IIA) in blood serum were compared with their effects on purified sPLA(2)(IIA). Activity of sPLA(2)(IIA) was not detected in whole serum despite the high concentration of the enzyme. However after lipoproteins had been removed from the serum, the lipoprotein-depleted serum displayed sPLA(2)(IIA) activity which was proportional to the amount of sPLA(2)(IIA) in it. Native LDL, HDL and VLDL+IDL inhibited the activity of both purified sPLA(2)(IIA) and the enzyme activity in lipoprotein-depleted serum. By contrast, oxidized LDL, HDL and VLDL+IDL significantly stimulated the activity of purified and serum sPLA(2)(IIA) and enhanced the release of fatty acids from the substrate. The data indicate that native and oxidized lipoproteins regulate catalytic activity of sPLA(2)(IIA). Activation of sPLA(2)(IIA) by oxidized lipoproteins may be regarded as one of the mechanisms of atherosclerosis development.
Asunto(s)
Fosfolipasas A2 Grupo II/metabolismo , Lipoproteínas/metabolismo , Lipoproteínas/farmacología , Fosfolipasas A2 Grupo II/antagonistas & inhibidores , Neoplasias Cardíacas/enzimología , Humanos , Inflamación/enzimología , Inflamación/metabolismo , Lipoproteínas/sangre , Mixoma/enzimología , Oxidación-ReducciónRESUMEN
Cardiac myxomas are the most common primary tumors of the heart, although little is known about their etiology. Mutations of the protein kinase A regulatory subunit gene PRKAR1A cause inherited myxomas in the setting of the Carney complex tumor syndrome, providing a possible window for understanding their pathogenesis. We recently reported that cardiac-specific knockout of this gene causes myxomatous changes in the heart, although the mice die during gestation from cardiac failure. In this review, we discuss these findings and place them in the larger understanding of how protein kinase A dysregulation might affect cardiac function and cause myxomagenesis.
Asunto(s)
Transformación Celular Neoplásica/metabolismo , Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico/metabolismo , Neoplasias Cardíacas/enzimología , Corazón/crecimiento & desarrollo , Miocardio/enzimología , Mixoma/enzimología , Animales , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , AMP Cíclico/metabolismo , Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico/deficiencia , Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico/genética , Regulación Neoplásica de la Expresión Génica , Predisposición Genética a la Enfermedad , Insuficiencia Cardíaca/enzimología , Insuficiencia Cardíaca/genética , Neoplasias Cardíacas/genética , Neoplasias Cardíacas/patología , Humanos , Ratones , Ratones Noqueados , Mutación , Miocardio/patología , Mixoma/genética , Mixoma/patología , Transducción de SeñalRESUMEN
Phospholipase A2 group IIA which is secreted in inflammation [secPLA2(IIA)] does not always exhibit catalytic activity, although being present in patients' serum. The mechanisms regulating the enzyme activity in peripheral blood have not been studied in sufficient detail. In this study we examined the effects of native and oxidized LDL with varied degree of oxidation on secPLA2(IIA) from human heart myxoma. The degree of LDL oxidation was evaluated from the amount of conjugated dienes and lysophosphatidylcholine. Liposomes containing radio-labelled phosphatidylcholine were used as a substrate in the secPLA2(IIA) activity assay. Native LDL isolated from serum of healthy subjects inhibited secPLA2(IIA) in a dose-dependent manner. Minimally and moderately oxidized LDL in which < 40 % phosphatidylcholine was hydrolysed to lysophosphatidylcholine activated secPL2(IIA). Strongly oxidized LDL in which > 40 % phosphatidylcholine was hydrolysed to lysophosphatidylcholine inhibited the enzyme. Thus, our findings indicate that the characteristics of circulating lipoproteins are changed by their oxidation. Minimal and moderate oxidation of LDL results in activation of secPLA2(IIA), while strong oxidation causes inhibition of the enzyme. Since inflammation leads to an increase in secPLA2(IIA) secretion and LDL oxidation, the results obtained can be used for the diagnostics of inflammatory processes and provide more insight into molecular mechanisms underlying the development of atherosclerosis.
Asunto(s)
Fosfolipasas A2 Grupo II/antagonistas & inhibidores , Lipoproteínas LDL/farmacología , Radioisótopos de Carbono , Catálisis , Relación Dosis-Respuesta a Droga , Fosfolipasas A2 Grupo II/química , Fosfolipasas A2 Grupo II/metabolismo , Neoplasias Cardíacas/enzimología , Humanos , Lipoproteínas LDL/sangre , Lipoproteínas LDL/aislamiento & purificación , Liposomas , Mixoma/enzimología , Oxidación-ReducciónRESUMEN
Cardiac myxomas are rare tumors that usually occur as sporadic lesions or,more rarely, in the familial form,mostly in the context of Carney complex (CNC). The molecular basis for the development of cardiac myxomas is unclear. However, somatic activating mutations in the GNAS1 gene (the gsp oncogene) are detected in the myocardium ofMcCune-Albright syndrome patients while germ-line mutations in the PRKAR1A gene are associated with CNC and familial myxomas. We investigated the presence of activating missense mutations in the GNAS1 gene as well as of inactivating mutations in PRKAR1A in 29 sporadically occurring cardiac myxomas. No gsp and no PRKAR1A mutations were found by direct sequencing of PCR products amplified from tumoral DNA. This is the first study including a large series of sporadic, isolated cardiac myxomas and showing that these cardiac neoplasms do not share the same mutations found in familial forms.
Asunto(s)
Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico/genética , Subunidades alfa de la Proteína de Unión al GTP Gs/genética , Neoplasias Cardíacas/genética , Mutación Missense , Mixoma/genética , Adulto , Anciano , Western Blotting , Cromograninas , ADN de Neoplasias/química , ADN de Neoplasias/genética , Femenino , Variación Genética , Neoplasias Cardíacas/enzimología , Neoplasias Cardíacas/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Mixoma/enzimología , Mixoma/metabolismo , Reacción en Cadena de la Polimerasa , Análisis de Secuencia de ADNRESUMEN
Tuberous sclerosis (TS) is a neurological disorder associated with the formation of tumors in several organs. Cardiac rhabdomyomas are possibly the earliest symptom of TS. Although rhabdomyomas are present in about half of TS patients, little is known of their molecular background since these tumors are rarely resected. Here we present a patient diagnosed with TS, in whom rhabdomyoma has been excised due to deterioration of hemodynamics. We found, that the tumor remained heterozygous for the affected TSC2 gene. To analyze molecular mechanisms implicated in rhabdomyoma growth, we determined the status of mTOR, Akt and Erk pathways. We found that Akt was not upregulated, while mTOR, Erk and its substrates were hyperactive. Classic activator of Erk, MEK, was only modestly active. We hypothesize that rhabdomyoma arising in TS may progress due to Erk potentiation.
Asunto(s)
Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Neoplasias Cardíacas/etiología , Rabdomioma/etiología , Transducción de Señal , Esclerosis Tuberosa/complicaciones , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Reguladoras de la Apoptosis/genética , Preescolar , Quinasas MAP Reguladas por Señal Extracelular/genética , Femenino , Neoplasias Cardíacas/enzimología , Neoplasias Cardíacas/genética , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Rabdomioma/enzimología , Rabdomioma/genética , Serina-Treonina Quinasas TOR , Esclerosis Tuberosa/genética , Proteína 2 del Complejo de la Esclerosis Tuberosa , Proteínas Supresoras de Tumor/genéticaRESUMEN
Phospholipase A2, group IIA, gene expression has been analyzed in primary heart tumors. High expression has been demonstrated through several ways: reverse-transcriptase chain polymerase chain, Northern blotting hybridization at the RNA level and immunoblotting, immunohistochemical assay at the protein level. Human cardiac myxoma exhibits highly positive phospholipase A2, group IIA, immunophenotype (100% positive cases). The immunophenotype is unique among human primary cardiac tumors. Phospholipase A2, group IIA, can be proposed as a tissue marker for pathological examination after heart tumor resection.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Fosfolipasas A2 Grupo II/metabolismo , Neoplasias Cardíacas/enzimología , Neoplasias Cardíacas/patología , Mixoma/enzimología , Mixoma/patología , Adolescente , Adulto , Anciano , Biomarcadores de Tumor/inmunología , Niño , Femenino , Fosfolipasas A2 Grupo II/inmunología , Neoplasias Cardíacas/inmunología , Humanos , Masculino , Persona de Mediana Edad , Mixoma/inmunologíaRESUMEN
The objective of this study was to evaluate the adenosine deaminase (ADA) activity usefulness in the diagnosis of tuberculous pericarditis (TP), comparing its value with pericardial effusions (PE) caused by other pericardial diseases. A retrospective case-control study was conducted with nine cases of TP and 39 other than TP diseases (12 neoplastic, 11 septic and 16 unknown origin). Every patient included in this study had PE samples submitted to ADA activity measures and microbiological analysis, and then had pericardial tissue samples submitted to microbiological and histopathological examination. Considering the value of 40 U/L as the cut-off for the diagnosis of TP, the specificity and sensitivity were respectively of 72% and 89%. The specificity of ADA activity for the TP was best applied in the differential diagnosis from PE of unknown origin. The present study demonstrates the clinical value of the measurement of ADA activity in PE in the diagnosis of TP.
Asunto(s)
Adenosina Desaminasa/análisis , Derrame Pericárdico/enzimología , Pericarditis Tuberculosa/diagnóstico , Adulto , Anciano , Biomarcadores/análisis , Estudios de Casos y Controles , Femenino , Neoplasias Cardíacas/diagnóstico , Neoplasias Cardíacas/enzimología , Humanos , Masculino , Persona de Mediana Edad , Pericarditis/diagnóstico , Pericarditis/enzimología , Pericarditis Tuberculosa/enzimología , Reproducibilidad de los Resultados , Estudios Retrospectivos , Sensibilidad y EspecificidadRESUMEN
The objective of this study was to evaluate the adenosine deaminase (ADA) activity usefulness in the diagnosis of tuberculous pericarditis (TP), comparing its value with pericardial effusions (PE) caused by other pericardial diseases. A retrospective case-control study was conducted with nine cases of TP and 39 other than TP diseases (12 neoplastic, 11 septic and 16 unknown origin). Every patient included in this study had PE samples submitted to ADA activity measures and microbiological analysis, and then had pericardial tissue samples submitted to microbiological and histopathological examination. Considering the value of 40 U/L as the cut-off for the diagnosis of TP, the specificity and sensitivity were respectively of 72 percent and 89 percent. The specificity of ADA activity for the TP was best applied in the differential diagnosis from PE of unknown origin. The present study demonstrates the clinical value of the measurement of ADA activity in PE in the diagnosis of TP.
O objetivo deste estudo foi avaliar a atividade da adenosina deaminase (ADA) como auxiliar no diagnóstico da tuberculose pericárdica (TP), comparando o seu valor no derrame pericárdico com outras doenças pericárdicas. Um estudo retrospectivo tipo caso-controle foi conduzido com nove casos de TP e 39 pacientes com outras doenças pericárdicas (12 neoplasias, 11 pericardites bacterianas e 16 pericardites de etiologia indeterminada). Cada paciente incluído no estudo teve sua amostra de tecido pericárdico encaminhada para estudo microbiológico e histopatológico. Considerando o valor de 40 U/L como corte para o diagnóstico de TP, a especificidade e sensibilidade foram respectivamente 72 e 89 por cento. A especificidade da atividade de ADA para a TP foi melhor aplicada no diagnóstico diferencial entre derrame pericárdico de origem indeterminada. O presente estudo demonstrou o valor clínico da mensuração da atividade de ADA no diagnóstico de TP.
Asunto(s)
Humanos , Masculino , Femenino , Niño , Adolescente , Adulto , Persona de Mediana Edad , Adenosina Desaminasa/análisis , Derrame Pericárdico/enzimología , Pericarditis Tuberculosa/diagnóstico , Biomarcadores/análisis , Estudios de Casos y Controles , Neoplasias Cardíacas/diagnóstico , Neoplasias Cardíacas/enzimología , Pericarditis Tuberculosa/enzimología , Pericarditis/diagnóstico , Pericarditis/enzimología , Reproducibilidad de los Resultados , Estudios Retrospectivos , Sensibilidad y EspecificidadRESUMEN
Primary sarcomas of the great vessels are very rare neoplasms and only a few cases have been reported. They are divided into the two broad categories of intimal or luminal and mural sarcomas. We analysed eight advanced high-grade sarcomas originating from major vessels (seven intimal and one mural sarcoma) by means of immunohistochemistry and FISH analysis for PDGFRA, PDGFRB, EGFR and KIT receptor tyrosine kinases (RTKs), together with immunoprecipitation/western blotting, sequencing of the corresponding genes, and the search for cognate ligands. The intimal sarcomas showed a wide spectrum of morphologies and immunophenotypes, whereas the mural sarcoma had common leiomyosarcomatous features. Regardless of their category, all of the cases had a PDGFRA-deregulated cytogenetic profile mainly consisting of an amplification cluster; five were also polysomic for PDGFRB, whereas three showed disomy. Six cases had a deregulated EGFR gene, and c-Kit gene status was similar to that of PDGFRA. In one case, biochemical analysis revealed the presence of activated and highly expressed PDGFRA, PDGFRB and EGFR, whereas KIT was expressed at reference level. Sequencing of the corresponding genes revealed no activating mutations in any of the analysed receptors. The cognate ligands were detected in all cases. In predictive terms, the evidence of gene amplification/high polysomy of several RTKs, together with PDGFRA, PDGFRB and EGFR expression and phosphorylation, suggests that these tumours may be sensitive to RTK-inhibiting treatments.
Asunto(s)
Vasos Coronarios/enzimología , Neoplasias Cardíacas/enzimología , Proteínas Tirosina Quinasas Receptoras/análisis , Sarcoma/enzimología , Adulto , Western Blotting/métodos , Receptores ErbB/análisis , Receptores ErbB/genética , Femenino , Amplificación de Genes/genética , Neoplasias Cardíacas/genética , Humanos , Inmunohistoquímica/métodos , Inmunofenotipificación , Inmunoprecipitación , Hibridación Fluorescente in Situ/métodos , Ligandos , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-kit/análisis , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Tirosina Quinasas Receptoras/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/análisis , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/análisis , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Sarcoma/genéticaRESUMEN
AIM: To improve the understanding of factors that influence adenosine deaminase ( ADA) activity in large pericardial effusions. METHODS: A prospective study was carried out at Tygerberg Academic Hospital, South Africa. Patients underwent echocardiographically guided pericardiocentesis. ADA activity, as well as biochemistry, haematology, cytology, and in some cases, histology, were determined. Human immunodeficiency virus (HIV) status was assessed in all patients. RESULTS: Two hundred and thirty-three patients presented to Tygerberg Hospital with large pericardial effusions requiring pericardiocentesis. Tuberculous pericarditis accounted for 162 effusions (69.5%). An ADA cut-off level of 40 U/l resulted in a test sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and diagnostic efficiency of 84.0%, 80.0%, 91.0%, 66.0% and 83.0%, respectively. Pericardial exudates with an ADA activity > or = 40 U/l were associated with increased total leukocyte and neutrophil counts. Patients with tuberculous pericarditis and ADA > or = 40 U/l also had increased lymphocyte counts. Pericardial ADA activity < 30 U/l was associated with severe depletion of CD4 cell counts in HIV-positive patients. ADA levels were higher in cases with histological evidence of granulomatous inflammation than in cases with serofibrinous pericarditis. CONCLUSIONS: An ADA cut-off level of 40 U/l results in best diagnostic test results. ADA production appears to be influenced by factors associated with the antituberculous immune response.
Asunto(s)
Adenosina Desaminasa/metabolismo , Pericarditis Tuberculosa/diagnóstico , Pericarditis Tuberculosa/enzimología , Adenocarcinoma/diagnóstico , Adenocarcinoma/enzimología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/metabolismo , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/enzimología , Reacciones Falso Positivas , Femenino , Neoplasias Cardíacas/diagnóstico , Neoplasias Cardíacas/enzimología , Humanos , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Derrame Pericárdico/diagnóstico , Derrame Pericárdico/enzimología , Pericarditis Tuberculosa/epidemiología , Valor Predictivo de las Pruebas , Estudios Prospectivos , Sensibilidad y Especificidad , Sudáfrica/epidemiologíaRESUMEN
AIM: To investigate the association between single nucleotide polymorphism (SNP) in promoter of the DNA methyltransferase 3B (DNMT3B) gene and risk for development and lymphatic metastasis of gastric cardiac adenocarcinoma (GCA). METHODS: The hospital based case-control study included 212 GCA patients and 294 control subjects without overt cancer. The DNMT3B SNP was genotyped by PCR and restriction fragment length polymorphism (RFLP) analysis. RESULTS: The C/C genotype was not detected in both GCA patients and controls. In control subjects, the frequency of T/T and C/T genotypes was 94.9% and 5.1% respectively, and that of T and C alleles was 97.4% and 2.6%, respectively. The genotype and allelotype distribution in the GCA patients was not significantly different from that in controls (P=0.34 and 0.33, respectively). When stratified by smoking status and family history of upper gastrointestinal cancer, significant difference in the genotype distribution was not observed between GCA patients and controls. The distribution of DNMT3B genotypes in GCA patients with or without lymphatic metastasis did not show significant difference (P=0.42). CONCLUSION: The distribution of DNMT3B SNP in North China is distinct from that in Caucasians. Although this SNP has been associated with susceptibility to lung, head, neck and breast cancer, it may not be used as a stratification marker to predict susceptibility and lymphatic metastasis of GCA, at least in the population of North China.