RESUMO
The treatment of choice for non-metastatic pheochromocytoma is surgical resection. Its goals are to abolish catecholamine hypersecretion, normalize blood pressure, and prevent further tumor growth or progression to metastatic disease. Data on long-term mortality and morbidity after pheochromocytoma surgery are limited. We here report a retrospective study on the long-term outcome after surgery for apparently benign pheochromocytoma at the Radboud University Nijmegen Medical Centre. Data on clinical presentation, treatment, post-surgical blood pressure and recurrence, metastasis and death were collected of 69 consecutive patients (January 1966-December 2000; follow-up: until death or January 2006). Survival was compared with survival of a matched reference population. Two patients died of surgical complications. All ten patients with metastatic disease (including three diagnosed at first surgery) died. At follow-up, 40 patients were alive and recurrence free and three patients were lost to follow up. Two patients experienced a benign recurrence. Mean+/-s.d. follow-up was 10.2+/-7.5 (median 9, range 1-38) years. Kaplan-Meier estimates for 5- and 10-year survival since surgery were 85.8% (95% CI: 77.2-94.4%) and 74.2% (95% CI: 62.0-86.4%) for patients versus 95.5 and 89.4% in the reference population (P<0.05). Sixty-four percent of all patients with hypertension prior to surgery showed a significant decrease in blood pressure, but remained hypertensive after surgery. In conclusion, compared with the general population patients have a reduced life expectancy following pheochromocytoma surgery, due to their risk of developing metastatic disease. Only one-third becomes normotensive without antihypertensive medication. Therefore, lifelong follow-up is warranted.
Assuntos
Neoplasias das Glândulas Suprarrenais/patologia , Neoplasias das Glândulas Suprarrenais/cirurgia , Doenças Cardiovasculares/mortalidade , Expectativa de Vida , Feocromocitoma/secundário , Feocromocitoma/cirurgia , Neoplasias das Glândulas Suprarrenais/mortalidade , Adulto , Idoso , Pressão Sanguínea , Doenças Cardiovasculares/epidemiologia , Catecolaminas/sangue , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/cirurgia , Feocromocitoma/mortalidade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
Mitochondrial research has influenced our understanding of human evolution, physiology and pathophysiology. Mitochondria, intracellular organelles widely known as 'energy factories' of the cell, also play fundamental roles in intermediary metabolism, steroid hormone and heme biosyntheses, calcium signaling, generation of radical oxygen species, and apoptosis. Mitochondria possess a distinct DNA (mitochondrial DNA); yet, the vast majority of mitochondrial proteins are encoded by the nuclear DNA. Mitochondria-related genetic defects have been described in a variety of mostly rare, often fatal, primary mitochondrial disorders; furthermore, they are increasingly reported in association with many common morbid conditions, such as cancer, obesity, diabetes and neurodegenerative disorders, although their role remains unclear. This study describes the creation of a human mitochondria-focused cDNA microarray (hMitChip) and its validation in human skeletal muscle cells treated with glucocorticoids. We suggest that hMitChip is a reliable and novel tool that will prove useful for systematically studying the contribution of mitochondrial genomics to human health and disease.
Assuntos
Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Proteínas Mitocondriais/metabolismo , Músculo Esquelético/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Adolescente , Adulto , Células Cultivadas , Bases de Dados Genéticas , Dexametasona/farmacologia , Glucocorticoides/farmacologia , Humanos , Masculino , Proteínas Mitocondriais/genética , Músculo Esquelético/efeitos dos fármacos , Farmacogenética , Reação em Cadeia da Polimerase , RNA Mensageiro/metabolismo , Reprodutibilidade dos TestesRESUMO
Metastatic lesions occur in up to 36% of patients with pheochromocytoma. Currently there is no way to reliably detect or predict which patients are at risk for metastatic pheochromocytoma. Thus, the discovery of biomarkers that could distinguish patients with benign disease from those with metastatic disease would be of great clinical value. Using surface-enhanced laser desorption ionization protein chips combined with high-resolution mass spectrometry, we tested the hypothesis that pheochromocytoma pathologic states can be reflected as biomarker information within the low molecular weight (LMW) region of the serum proteome. LMW protein profiles were generated from the serum of 67 pheochromocytoma patients from four institutions and analyzed by two different bioinformatics approaches employing pattern recognition algorithms to determine if the LMW component of the circulatory proteome contains potentially useful discriminatory information. Both approaches were able to identify combinations of LMW molecules which could distinguish all metastatic from all benign pheochromocytomas in a separate blinded validation set. In conclusion, for this study set low molecular mass biomarker information correlated with pheochromocytoma pathologic state using blinded validation. If confirmed in larger validation studies, efforts to identify the underlying diagnostic molecules by sequencing would be warranted. In the future, measurement of these biomarkers could be potentially used to improve the ability to identify patients with metastatic disease.
Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico , Biomarcadores Tumorais/sangue , Proteínas de Neoplasias/sangue , Feocromocitoma/diagnóstico , Proteoma/análise , Adolescente , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Idoso , Criança , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Peso Molecular , Metástase Neoplásica , Feocromocitoma/patologia , ProteômicaRESUMO
Pheochromocytomas in von Hippel-Lindau (VHL) syndrome produce exclusively norepinephrine, whereas those in multiple endocrine neoplasia type 2 (MEN 2) produce epinephrine. This study examined the pathways activated in VHL-associated pheochromocytomas by comparing gene expression profiles in VHL and MEN 2 tumors in relationship to profiles in sporadic norepinephrine- and epinephrine-producing tumors. Larger and more distinct differences in gene expression among hereditary than sporadic tumors indicated the importance of the underlying mutation to gene expression profiles. Many of the genes over-expressed in VHL compared with MEN 2 tumors were clearly linked to the hypoxia-driven angiogenic pathways that are activated in VHL-associated tumorigenesis. Such genes included those for the glucose transporter, vascular endothelial growth factor (VEGF), placental growth factor, angiopoietin 2, tie-1, VEGF receptor 2 and its coreceptor, neuropilin-1. Other up-regulated genes, such as connective tissue growth factor, cysteine-rich 61, matrix metalloproteinase 1, vascular endothelial cadherin, tenascin C, stanniocalcin 1, and cyclooxygenases 1 and 2 are known to be involved in VEGF-regulated angiogenesis. Shared differences in expression of subsets of genes in norepinephrine- versus epinephrine-producing hereditary and sporadic pheochromocytomas indicated other differences in gene expression that may underlie the biochemical phenotype. Over-expression of the hypoxia-inducible transcription factor, HIF-2alpha, in norepinephrine-predominant sporadic and VHL tumors compared with epinephrine-producing tumors indicates that expression of this gene depends on the noradrenergic biochemical phenotype. The findings fit with the known expression of HIF-2alpha in norepinephrine-producing cells of the sympathetic nervous system and might explain both the development and noradrenergic biochemical phenotype of pheochromocytomas in VHL syndrome.
Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Feocromocitoma/genética , Doença de von Hippel-Lindau/genética , Adolescente , Neoplasias das Glândulas Suprarrenais/complicações , Adulto , Fatores de Transcrição Hélice-Alça-Hélice Básicos/biossíntese , Criança , Epinefrina , Feminino , Perfilação da Expressão Gênica , Humanos , Hipóxia , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 2a/complicações , Neoplasia Endócrina Múltipla Tipo 2a/genética , Norepinefrina , Análise de Sequência com Séries de Oligonucleotídeos , Feocromocitoma/complicações , Doença de von Hippel-Lindau/complicaçõesRESUMO
Ganglioneuromas (GNs) are neural crest cell-derived tumors and rarely occur in the adrenal gland. There are presently no markers that can reliably distinguish benign and malignant neuroendocrine tumors. Here we describe a 63-year-old woman who developed sudden chest pain and hypertension combined with increased stool frequency. An incidental adrenal mass 5 cm in size with a bright signal on T2-weighted magnetic resonance imaging was discovered. Biochemical evaluation and (131)I-metaiodobenzylguanidine (MIBG) scintigraphy were negative. Histopathological examination revealed a mature adrenal GN. Neuroblastoma, the immature form of a GN, is known for deletions on chromosomal locus 1p36, and adrenal tumors frequently show allele loss on 17p. To further elucidate the histo- and pathogenesis of adrenal GN, we performed loss of heterozygosity studies on chromosomal loci 1p34-36 and 17p13 (the p53 gene locus) after careful microdissection of tumor and normal tissue. We did not detect allelic losses at these loci with the informative polymorphic markers used, suggesting that these loci are not involved in tumorigenesis. In addition, immunohistochemical investigation of the GN was positive for vasoactive intestinal peptide, a hormone commonly expressed in ganglion cells. We suggest that in our patient with an adrenal GN, the combination of biochemical, scintigraphic, molecular, immunohistochemical, and histopathological findings are all consistent with the benign morphology of this tumor.
Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico , Diarreia/diagnóstico , Ganglioneuroma/diagnóstico , Hipertensão/diagnóstico , Neoplasias das Glândulas Suprarrenais/genética , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 17/genética , Feminino , Ganglioneuroma/genética , Humanos , Técnicas Imunoenzimáticas , Perda de Heterozigosidade , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Peptídeo Intestinal Vasoativo/metabolismoRESUMO
BACKGROUND: The efficacy of dietary supplements in chronic fatigue syndrome (CFS) is uncertain, with conflicting evidence. AIM: To assess the effect of a polynutrient supplement on fatigue and physical activity of patients with CFS. DESIGN: Prospective randomized placebo-controlled, double-blind trial. METHODS: Fifty-three patients (16 males, 37 females) fulfilling the CDC criteria of CFS. The entry criteria were a score on the Checklist Individual Strength subscale fatigue severity (CIS fatigue) >or=40 and a weighted sum score of >or=750 for the eight subscales of the Sickness Impact Profile (SIP8) and no use of nutritional supplements in the 4 weeks prior to entry. The exclusion criteria were pregnancy and lactose intolerance. The intervention-a polynutrient supplement containing several vitamins, minerals and (co)enzymes, or placebo, twice daily for 10 weeks-was preceded by 2 weeks of baseline measurements. Outcome measurements took place in week 9 and 10 of the intervention. Five participants dropped out (4 supplement, 1 placebo). The main outcome measures were CIS fatigue score, number of CDC symptoms and SIP8 score. Efficacy analyses were performed on an intention-to-treat basis. RESULTS: No significant differences were found between the placebo and the treated group on any of the outcome measures: CIS fatigue +2.16 (95%CI -4.3 to +4.39, p=0.984); CDC symptoms +0.42 (95%CI -0.61 to +1.46, p=0.417); SIP8 +182 (95%CI -165 to +529, p=0.297). No patient reported full recovery. DISCUSSION: The findings do not support the use of a broad-spectrum nutritional supplement in treating CFS-related symptoms.