Adiposidade em pacientes tratados por câncer na infância: entendendo a fisiopatologia da obesidade

As childhood cancer treatment has become more effective, survival rates have improved, and a number of complications have been described while many of these patients reach adulthood. Obesity is a well-recognized late effect, and its metabolic effects may lead to cardiovascular disease. Currently, studies concerning overweight have focused on acute lymphocytic leukemia and brain tumors, since they are at risk for hypothalamic-pituitary axis damage secondary to cancer therapies (cranial irradiation, chemotherapy, and brain surgery) or to primary tumor location. Obesity and cancer have metabolic syndrome features in common. Thus, it remains controversial if overweight is a cause or consequence of cancer, and to date additional mechanisms involving adipose tissue and hypothalamic derangements have been considered, comprising premature adiposity rebound, hyperinsulinemia, leptin regulation, and the role of peroxisome proliferator-activated receptor γ. Overall, further research is still necessary to better understand the relationship between adipogenesis and hypothalamic control deregulation following cancer therapy.Os avanços do tratamento contra o câncer infantil têm resultado no aumento da sobrevida e das complicações, à medida que os pacientes atingem a maioridade. A obesidade é um evento reconhecido, e seus efeitos metabólicos levam à doença cardiovascular. Atualmente, o estudo da obesidade tem enfocado a leucemia linfocítica aguda e os tumores cerebrais, já que ambos têm risco para lesões hipotalâmicas, secundárias às terapias (irradiação cranial, quimioterapia, e cirurgia) ou à localização do tumor. Obesidade e câncer têm em comum fatores para síndrome metabólica. Entretanto, a relação de causa e efeito entre obesidade e câncer permanece controversa, sendo que são considerados outros mecanismos envolvendo o tecido adiposo e lesões hipotalâmicas, como o rebote precoce de adiposidade, hiperinsulinemia, regulação da leptina, e o papel do receptor ativado por proliferadores de peroxissoma γ. Concluindo, mais estudos são necessários para entender a relação entre adipogênese e descontrole hipotalâmico em sobreviventes de câncer.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Universidade Federal de São Paulo (UNIFESP) Divisão de Endocrinologia Pediátrica Departamento de PediatriaUniversidade Estadual de Campinas Faculdade de Ciências Médicas Divisão de Endocrinologia PediátricaUNIFESP, Divisão de Endocrinologia Pediátrica Depto. de PediatriaSciEL

Detection of metabolic syndrome features among childhood cancer survivors: A target to prevent disease

Along with the growing epidemic of obesity, the risk of atherosclerosis, cardiovascular disease morbidity, and mortality are increasing markedly. Several risk factors for cardiovascular disease, such as visceral obesity, glucose intolerance, arterial hypertension, and dyslipidemia commonly cluster together as a condition currently known as metabolic syndrome. Thus far, insulin resistance, and endothelial dysfunction are the primary events of the metabolic syndrome. Several groups have recommended clinical criteria for the diagnosis of metabolic syndrome in adults. Nonetheless, in what concerns children and adolescents, there are no unified definitions, and modified adult criteria have been suggested by many authors, despite major problems. Some pediatric disease states are at risk for premature cardiovascular disease, with clinical coronary events occurring very early in adult life. Survivors of specific pediatric cancer groups, particularly acute lymphocytic leukemia, central nervous system tumors, sarcomas, lymphomas, testicular cancer, and following bone marrow transplantation, may develop metabolic syndrome traits due to: hormonal deficiencies (growth hormone deficiency, thyroid dysfunction, and gonadal failure), drug or radiotherapy damage, endothelial impairment, physical inactivity, adipose tissue dysfunction, and/or drug-induced magnesium deficiency. In conclusion, some primary and secondary prevention remarks are proposed in order to reduce premature cardiovascular disease risk in this particular group of patients

Adiposidade em pacientes tratados por câncer na infância: entendendo a fisiopatologia da obesidade

As childhood cancer treatment has become more effective, survival rates have improved, and a number of complications have been described while many of these patients reach adulthood. Obesity is a well-recognized late effect, and its metabolic effects may lead to cardiovascular disease. Currently, studies concerning overweight have focused on acute lymphocytic leukemia and brain tumors, since they are at risk for hypothalamic-pituitary axis damage secondary to cancer therapies (cranial irradiation, chemotherapy, and brain surgery) or to primary tumor location. Obesity and cancer have metabolic syndrome features in common. Thus, it remains controversial if overweight is a cause or consequence of cancer, and to date additional mechanisms involving adipose tissue and hypothalamic derangements have been considered, comprising premature adiposity rebound, hyperinsulinemia, leptin regulation, and the role of peroxisome proliferator-activated receptor γ. Overall, further research is still necessary to better understand the relationship between adipogenesis and hypothalamic control deregulation following cancer therapy.Os avanços do tratamento contra o câncer infantil têm resultado no aumento da sobrevida e das complicações, à medida que os pacientes atingem a maioridade. A obesidade é um evento reconhecido, e seus efeitos metabólicos levam à doença cardiovascular. Atualmente, o estudo da obesidade tem enfocado a leucemia linfocítica aguda e os tumores cerebrais, já que ambos têm risco para lesões hipotalâmicas, secundárias às terapias (irradiação cranial, quimioterapia, e cirurgia) ou à localização do tumor. Obesidade e câncer têm em comum fatores para síndrome metabólica. Entretanto, a relação de causa e efeito entre obesidade e câncer permanece controversa, sendo que são considerados outros mecanismos envolvendo o tecido adiposo e lesões hipotalâmicas, como o rebote precoce de adiposidade, hiperinsulinemia, regulação da leptina, e o papel do receptor ativado por proliferadores de peroxissoma γ. Concluindo, mais estudos são necessários para entender a relação entre adipogênese e descontrole hipotalâmico em sobreviventes de câncer.190200Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Cranial radiotherapy predisposes to abdominal adiposity in survivors of childhood acute lymphocytic leukemia

Background: Advances in treatment of acute lymphocytic leukemia increased the likelihood of developing late treatment-associated effects, such as abdominal adiposity, increasing the risk of cardiovascular disease in this population. Cranial radiotherapy is one of the factors that might be involved in this process. the aim of this study was to determine the effect of cranial radiotherapy on adiposity indexes in survivors of acute lymphocytic leukemia.Methods: A comparative cross-sectional study of 56 acute lymphocytic leukemia survivors, chronological age between 15 and 24 years, assigned into two groups according to the exposure to cranial radiotherapy (25 irradiated and 31 non-irradiated), assessed according to body fat (dual energy X-ray absorptiometry), computed tomography scan-derived abdominal adipose tissue, lipid profile, and insulin resistance.Results: Cranial radiotherapy increased body fat and abdominal adipose tissue and altered lipid panel. Yet, lipids showed no clinical relevance so far. There were significantly more obese patients among those who received cranial radiotherapy (52% irradiated versus 22.6% non-irradiated), based on dual energy X-ray absorptiometry body fat measurements. Nonetheless, no association was observed between cranial radiotherapy and body mass index, waist circumference, waist-to-height ratio or insulin resistance.Conclusions: Adolescent and young adult survivors of childhood acute lymphocytic leukemia showed an increase in body fat and an alteration of fat distribution, which were related to cranial radiotherapy. Fat compartment modifications possibly indicate a disease of adipose tissue, and cranial radiotherapy imports in this process.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Universidade Federal de São Paulo, Div Pediat Endocrinol, Dept Pediat, UNIFESP EPM, São Paulo, BrazilIOP GRAACC, Pediat Oncol Inst, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Prevent & Social Med, Div Biostat, UNIFESP EPM, São Paulo, BrazilUniv Estadual Campinas, Lab Invest Metab & Diabet LIMED, Fac Med Sci, UNICAMP, Campinas, SP, BrazilUniversidade Federal de São Paulo, Dept Diagnost Imaging, UNIFESP EPM, São Paulo, BrazilUniv Estadual Campinas, Dept Pediat, Div Pediat Endocrinol, Fac Med Sci,UNICAMP, Campinas, SP, BrazilUniversidade Federal de São Paulo, Div Pediat Endocrinol, Dept Pediat, UNIFESP EPM, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Prevent & Social Med, Div Biostat, UNIFESP EPM, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Diagnost Imaging, UNIFESP EPM, São Paulo, BrazilFAPESP: 06/06162-9Web of Scienc

Fatores precoces para síndrome metabólica em sobreviventes de câncer pediátrico: resultados em adolescentes e adultos jovens tratados por meduloblastoma na infância

OBJECTIVE: To analyze traits of metabolic syndrome (MetS) in medulloblastoma survivors. SUBJECTS AND METHODS: Sixteen childhood medulloblastoma survivors aged 18.0 (4.4) years, with history of craniospinal radiation therapy (RT) were compared with nine control subjects matched by age, gender, and body mass index, according to fat distribution, metabolic and cardiovascular variables. RESULTS: Medulloblastoma patients showed increases in waist circum-ference and its relationships (all p < 0.05), and HOMA1-IR (p = 0.006), which were modified by growth hormone (GH) secretion status. However, these increases were within normal range. CONCLUSIONS: Adolescent and young adult survivors of medulloblastoma showed centripetal fat deposition and decreased insulin sensitivity, associated with GH status. Pediatric brain tumor survivors following RT should be monitored for the diagnosis of MetS traits predisposing to cardiovascular disease.OBJETIVO: Analisar características que predispõem para síndrome metabólica (SM) em sobreviventes de meduloblastoma. SUJEITOS E MÉTODOS: Dezesseis sobreviventes de meduloblastoma pediátrico, 18,0 (4,4) anos, história de radioterapia (RT) cranioespinhal, comparados a nove controles pareados por idade, sexo e índice de massa corporal, de acordo com distribuição de gordura, variáveis metabólicas e cardiovasculares. RESULTADOS: Pacientes com meduloblastoma mostraram aumento da cintura e relações (todos p < 0,05) e HOMA1-IR (p = 0,006), modificados pela secreção do hormônio de crescimento (GH), mas dentro dos limites de normalidade. CONCLUSÕES: Sobreviventes adolescentes e adultos jovens de meduloblastoma apresentaram deposição centrípeta de gordura e diminuição da sensibilidade à insulina, associados ao estado do GH. Sobreviventes de tumor cerebral pediátrico que receberam RT devem ser monitorados para diagnosticar fatores para SM predispondo à doença cardiovascular.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Department of PediatricsUNIFESP-EPM Department of MedicineUniversidade de São Paulo Department of Food Science and Experimental Nutrition Pharmaceutical Science SchoolUNIFESP-EPM Department of PediatricsUNIFESP, EPM, Department of PediatricsUNIFESP, EPM Department of MedicineUNIFESP, EPM Department of PediatricsSciEL

O uso da hibridação in situ com fluorescência no diagnóstico de mosaicismo oculto: a propósito de três casos de anomalias de cromossomos sexuais

FISH has been used as a complement to classical cytogenetics in the detection of mosaicism in sex chromosome anomalies. The aim of this study is to describe three cases in which the final diagnosis could only be achieved by FISH. Case 1 was an 8-year-old 46,XY girl with normal female genitalia referred to our service because of short stature. FISH analysis of lymphocytes with probes for the X and Y centromeres identified a 45,X/46,X,idic(Y) constitution, and established the diagnosis of Turner syndrome. Case 2 was a 21-month-old 46,XY boy with genital ambiguity (penile hypospadias, right testis, and left streak gonad). FISH analysis of lymphocytes and buccal smear identified a 45,X/46,XY karyotype, leading to diagnosis of mixed gonadal dysgenesis. Case 3 was a 47,XYY 19-year-old boy with delayed neuromotor development, learning disabilities, psychological problems, tall stature, small testes, elevated gonadotropins, and azoospermia. FISH analysis of lymphocytes and buccal smear identified a 47,XYY/48,XXYY constitution. Cases 1 and 2 illustrate the phenotypic variability of the 45,X/46,XY mosaicism, and the importance of detection of the 45,X cell line for proper management and follow-up. In case 3, abnormal gonadal function could be explained by the 48,XXYY cell line. The use of FISH in clinical practice is particularly relevant when classical cytogenetic analysis yields normal or uncertain results in patients with features of sex chromosome aneuploidy. Arq Bras Endocrinol Metab. 2012;56(8):545-51FISH tem sido usado como um complemento para a citogenética clássica na detecção de mosaicismo em anomalias de cromossomos sexuais. O objetivo deste trabalho é descrever três casos nos quais o diagnóstico final só foi obtido por meio de FISH. O caso 1 é uma menina de 8 anos, 46,XY, com genitália feminina normal, encaminhada ao nosso setor devido à baixa estatura. A análise de linfócitos por FISH com sondas centroméricas de X e Y identificou a constituição 45,X/46,X,idic(Y) e estabeleceu o diagnóstico de síndrome de Turner. O caso 2 é um menino de 21 meses, 46,XY, com ambiguidade genital (hipospadia peniana, testículo à direita e gônada disgenética à esquerda). FISH de linfócitos e mucosa oral identificou o cariótipo 45,X/46,XY, levando ao diagnóstico de disgenesia gonadal mista. O caso 3 é um rapaz de 19 anos, 47,XYY, com atraso de desenvolvimento neuromotor, dificuldade de aprendizado, problemas psicológicos, alta estatura, testículos pequenos, gonadotrofinas elevadas e azoospermia. FISH de linfócitos e mucosa oral identificou a constituição 47,XYY/48,XXYY. Os casos 1 e 2 ilustram a variabilidade fenotípica do mosaico 45,X/46,XY e a importância da detecção da linhagem 45,X na avaliação e na condução dos casos. No caso 3, a função gonadal anormal pôde ser explicada pela linhagem 48,XXYY. O uso de FISH na prática clínica é particularmente relevante quando a análise citogenética clássica traz resultados normais ou incertos em pacientes com quadro sugestivo de uma aneuploidia de cromossomos sexuais. Arq Bras Endocrinol Metab. 2012;56(8):545-51Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Universidade Estadual de Campinas Faculdade de Ciências Médicas Departamento de Genética MédicaUnicamp FCM Grupo Interdisciplinar de Estudos da Determinação e Diferenciação do SexoUnicamp FCM Departamento de PediatriaUniversidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Departamento de PediatriaUNIFESP, EPM, Depto. de PediatriaSciEL

Subcutaneous Adipose Tissue Plays A Beneficial Effect On Subclinical Atherosclerosis In Young Survivors Of Acute Lymphocytic Leukemia.

The aim of this study was to evaluate the relationship between body composition, metabolic profile, adipokines, and carotid intima-media thickness (cIMT) in young survivors of childhood acute lymphocytic leukemia (ALL). This cross-sectional study compared 55 ALL survivors, of chronological age between 15 years and 24 years, assigned into two groups according to the exposure to cranial radiation therapy (CRT; 25 irradiated and 30 nonirradiated) with 24 leukemia-free controls, and assessed body fat mass (dual-energy X-ray absorptiometry), computed tomography scan-derived abdominal adipose tissue, lipid profile, blood pressure (BP), adipokines, and cIMT by a multiple regression analysis. Treatment with CRT had an effect on all of the variables derived from the computed tomography scan: visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) (P<0.050). In a multiple linear regression model, cIMT positively correlated with exposure to CRT (P=0.029), diastolic BP (P=0.016), and leptin-to-adiponectin ratio (P=0.048), while negatively related to SAT (P=0.007). In young survivors of childhood ALL, CRT modified the distribution of fat and played a critical role in determining cIMT. Leptin-to-adiponectin ratio, a biomarker of abdominal obesity and metabolic syndrome, and diastolic BP also influenced cIMT, a marker of subclinical atherosclerosis. Nonetheless, adiposity-associated vascular disease might be attenuated by SAT. Changes in body fat must be evaluated in this group of patients in the early course of survivorship in order to avoid premature cardiovascular disease associated with atherosclerosis. Yet, further research as regards the possible protective effect of SAT on vascular disease is warranted.11479-48

O uso da hibridação in situ com fluorescência no diagnóstico de mosaicismo oculto: a propósito de três casos de anomalias de cromossomos sexuais

FISH has been used as a complement to classical cytogenetics in the detection of mosaicism in sex chromosome anomalies. The aim of this study is to describe three cases in which the final diagnosis could only be achieved by FISH. Case 1 was an 8-year-old 46,XY girl with normal female genitalia referred to our service because of short stature. FISH analysis of lymphocytes with probes for the X and Y centromeres identified a 45,X/46,X,idic(Y) constitution, and established the diagnosis of Turner syndrome. Case 2 was a 21-month-old 46,XY boy with genital ambiguity (penile hypospadias, right testis, and left streak gonad). FISH analysis of lymphocytes and buccal smear identified a 45,X/46,XY karyotype, leading to diagnosis of mixed gonadal dysgenesis. Case 3 was a 47,XYY 19-year-old boy with delayed neuromotor development, learning disabilities, psychological problems, tall stature, small testes, elevated gonadotropins, and azoospermia. FISH analysis of lymphocytes and buccal smear identified a 47,XYY/48,XXYY constitution. Cases 1 and 2 illustrate the phenotypic variability of the 45,X/46,XY mosaicism, and the importance of detection of the 45,X cell line for proper management and follow-up. In case 3, abnormal gonadal function could be explained by the 48,XXYY cell line. The use of FISH in clinical practice is particularly relevant when classical cytogenetic analysis yields normal or uncertain results in patients with features of sex chromosome aneuploidy. Arq Bras Endocrinol Metab. 2012;56(8):545-51FISH tem sido usado como um complemento para a citogenética clássica na detecção de mosaicismo em anomalias de cromossomos sexuais. O objetivo deste trabalho é descrever três casos nos quais o diagnóstico final só foi obtido por meio de FISH. O caso 1 é uma menina de 8 anos, 46,XY, com genitália feminina normal, encaminhada ao nosso setor devido à baixa estatura. A análise de linfócitos por FISH com sondas centroméricas de X e Y identificou a constituição 45,X/46,X,idic(Y) e estabeleceu o diagnóstico de síndrome de Turner. O caso 2 é um menino de 21 meses, 46,XY, com ambiguidade genital (hipospadia peniana, testículo à direita e gônada disgenética à esquerda). FISH de linfócitos e mucosa oral identificou o cariótipo 45,X/46,XY, levando ao diagnóstico de disgenesia gonadal mista. O caso 3 é um rapaz de 19 anos, 47,XYY, com atraso de desenvolvimento neuromotor, dificuldade de aprendizado, problemas psicológicos, alta estatura, testículos pequenos, gonadotrofinas elevadas e azoospermia. FISH de linfócitos e mucosa oral identificou a constituição 47,XYY/48,XXYY. Os casos 1 e 2 ilustram a variabilidade fenotípica do mosaico 45,X/46,XY e a importância da detecção da linhagem 45,X na avaliação e na condução dos casos. No caso 3, a função gonadal anormal pôde ser explicada pela linhagem 48,XXYY. O uso de FISH na prática clínica é particularmente relevante quando a análise citogenética clássica traz resultados normais ou incertos em pacientes com quadro sugestivo de uma aneuploidia de cromossomos sexuais. Arq Bras Endocrinol Metab. 2012;56(8):545-51545551Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP