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Testicular Germ Cell Tumors (TGCTs) are a rare group of neoplasms and the most common solid malignancy arising in young male adults. Despite the good response of these tumors to platinum-based chemotherapy, some patients are refractory to treatment and present poor clinical outcomes. During carcinogenesis and tumor development, cancer cells reprogram energy metabolism toward a hyper-glycolytic phenotype, an emerging hallmark of cancer. This phenomenon, known as the Warburg effect or aerobic glycolysis, involves overexpression of metabolism-related proteins, like glucose and monocarboxylate transporters, pH regulators and intracellular glycolytic enzymes. The metabolic profile of TGCTs is very little explored and, recently, this metabolic rewiring of cancer cells has been associated with aggressive clinicopathological characteristics of these tumors. The overexpression of monocarboxylate transporter 4 (MCT4) in TGCTs has been pointed out as a poor prognostic factor, as well as a promising therapeutic target. As a result, the main aim of the present study was to evaluate the prognostic value of key metabolism-related proteins in TGCTs. The immunohistochemical expressions of CD44 (as a monocarboxylate transporter chaperone), glucose transporter 1 (GLUT1), carbonic anhydrase IX (CAIX), hexokinase II (HKII) and lactate dehydrogenase V (LDHV) were evaluated in a series of 148 adult male patients with TGCTs and associated with clinicopathological parameters. In addition, paired normal tissues were also evaluated. The sample included 75 seminoma and 73 non-seminoma tumors. GLUT1 and CD44 expression was significantly increased in malignant samples when compared to paired normal samples. Conversely, HKII and LDHV expressions were significantly decreased in malignant samples. Concerning the clinicopathological values, CAIX expression was significantly associated with disease recurrence, while HKII expression was significantly associated with aggressive characteristics of TGCTs, including higher staging and non-seminoma histology. In conclusion, this study brings new insights on the metabolic characteristics of TGCTs, showing alterations in the expression of proteins related with the Warburg effect, as well as associations of the hyper-glycolytic and acid-resistant phenotype with aggressive clinicopathological parameters.
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BACKGROUND: Metabolic reprogramming is one of the hallmarks of cancer. The hyperglycolytic phenotype is often associated with the overexpression of metabolism-associated proteins, such as monocarboxylate transporters (MCTs). MCTs are little explored in germ cell tumors (GCTs), thus, the opportunity to understand the relevance of these metabolic markers and their chaperone CD147 in this type of tumor arises. The main aim of this study was to evaluate the expression of MCT1, MCT2, MCT4 and CD147 in testicular GCT samples and the clinicopathological significance of these metabolism related proteins. RESULTS: MCT1, MCT4 and CD147 were associated with higher stages, higher M and N stages and histological type, while MCT4 was also associated with higher risk stratification, presence of vascular invasion, and lower overall and event free survival. MCT4 silencing in JEG-3 had no significant effect in cell viability, proliferation and death, as well as extracellular levels of glucose and lactate. However, MCT4-silenced cells showed an increase in migration and invasion. CONCLUSION: The proteins herein studied, with the exception of MCT2, were associated with characteristics of worse prognosis, lower global and event free survival of patients with GCTs. Also, in vitro MCT4 silencing stimulated cell migration and invasion. MATERIALS AND METHODS: Immunohistochemical expression was evaluated on samples from 149 adult patients with testicular GCT, arranged in Tissue Microarrays (TMAs), and associated with the clinicopathological data. Also, MCT4 silencing studies using siRNA were performed in JEG-3 cells.
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BACKGROUND: Immunophenotyping of bone marrow (BM) hemopoietic precursors is useful for diagnosis of adult myelodysplastic syndrome (MDS), but data concerning pediatric patients are limited. We analyzed immunophenotypic features of BM cells at diagnosis of children who were referred to the Brazilian Pediatric Cooperative Group of Myelodysplastic Syndromes. METHODS: Diagnosis was based on clinical information, peripheral blood counts, BM cytology and cytogenetics. Patients with Down syndrome were excluded. Children with deficiency anemias or transitory neutropenias were used as controls (CTRLs). Immunophenotyping was performed on an eight-color antibody platform evaluating myelomonocytic maturation and progenitor cells. RESULTS: A total of 32 patients were examined: 6 refractory cytopenia of childhood [RCC]; 5 refractory anemia with excess of blasts [RAEB]; 8 refractory anemia with excess of blasts in transformation [RAEB-t]; 13 juvenile myelomonocytic leukemia [JMML] and 10 CTRLs. Median age was 66 months (RCC), 68 months (RAEB/RAEB-t), 29 months (JMML) and 70 months (CTRLs). Median number of phenotypic alterations was 4 (range 1-6) in RCC; 6 (range 2-11) in RAEB/RAEB-t and 6 (range 2-11) in JMML (P = 0.004). The percentage of CD34+ /CD117+ /CD13+ cells was 0.5% (range 0.1-2.8) in RCC; 4.2% (range 0.3-10.1) in RAEB/RAEB-t and 3.7 % (range 0.5-8.6) in JMML cases, compared with 0.7% (0.5-1.2) in CTRLs (P < 0.0005). Aberrancies in antigen expression of myeloid progenitors were seen in 63% of JMML and in 45% of RAEB/RAEB-t. CD34+ /CD19+ /CD10+ cells were decreased or absent in patients compared with age-matched controls. T lymphocytes were decreased in JMML. CONCLUSIONS: Phenotypic abnormalities were similar to those found in adult MDS. A decrease in B-cell precursors was observed especially in RAEB/RAEB-t. JMML and RAEB showed a similar pattern.
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Médula Ósea/patología , Leucemia Mielomonocítica Juvenil/patología , Síndromes Mielodisplásicos/patología , Adolescente , Adulto , Médula Ósea/inmunología , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Citometría de Flujo , Estudios de Seguimiento , Humanos , Inmunofenotipificación , Lactante , Leucemia Mielomonocítica Juvenil/inmunología , Masculino , Síndromes Mielodisplásicos/inmunología , Fenotipo , Pronóstico , Estudios Retrospectivos , Adulto JovenRESUMEN
AIM: Maintenance therapy is an important phase of the childhood ALL treatment, requiring 2-year long therapy adherence of the patients and families. Weekly methotrexate with daily 6-mercaptopurine (6MP) constitutes the backbone of maintenance therapy. Reduction in the maintenance therapy could overweight problems related with poverty of children with ALL living in limited-income countries (LIC). OBJECTIVE: To compare, prospectively, the EFS rates of children with ALL treated according to two maintenance regimens: 18 vs. 24 months duration. MATERIALS AND METHODS: From October 1993 to September 1999, 867 consecutive untreated ALL patients <18 years of age were treated according to the Brazilian Cooperative Group for Childhood ALL Treatment (GBTLI) ALL-93 protocol. Risk classification was based exclusively on patient's age and leukocyte count (NCI risk group) and clinical extra medullary involvement of the disease. Data were analyzed by the intention-to-treat approach. RESULTS: Fourteen patients (1.6%) were excluded: wrong diagnosis (n = 7) and previous corticosteroid (n = 7). Of the 853 eligible patients, 421 were randomly allocated, at study enrollment, to receive 18-month (group 1) and 432 to receive 24-month (group 2) maintenance therapy. Complete remission rate was achieved in 96% of the patients (817/853). Twenty-eight patients (3.4%) died during the induction phase. Thirty-four patients (4.0%) were lost to follow-up. The overall EFS was 66.1 ± 1.7% at 15 years. No difference was seen according to maintenance: EFS15y was 65.8 ± 2.3% (group 1) and 66.3 ± 2.3% (group 2; p = 0.79). No difference between regimens was detected after stratifying the analyses according to factors associated with adverse prognosis in this study (age group <1 year or >10 years and high WBC at diagnosis). Overall death in remission rate was 6.85% (56 patients). Deaths during maintenance were 13 in group 1 and 12 in group 2, all due to infection. Over 15 years of follow-up, two patients both from group 2 presented a second malignancy (Hodgkin's disease and thyroid carcinoma) after 8.3 and 11 years off therapy, respectively. CONCLUSION: Six-month reduction of maintenance therapy in ALL children treated according to the GBTLI ALL-93 protocol provided the same overall outcome as 2-year duration regimen.
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Citocromo P-450 CYP1A1/genética , NAD(P)H Deshidrogenasa (Quinona)/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Brasil , Estudios de Casos y Controles , Preescolar , Contaminantes Ambientales/metabolismo , Contaminantes Ambientales/toxicidad , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Variación Genética , Genotipo , Humanos , Inactivación Metabólica/genética , Inactivación Metabólica/fisiología , Lactante , Masculino , Persona de Mediana Edad , Hidrocarburos Policíclicos Aromáticos/metabolismo , Hidrocarburos Policíclicos Aromáticos/toxicidad , Polimorfismo de Nucleótido Simple , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiología , Factores de RiesgoRESUMEN
PURPOSE To describe event-free survival (EFS) and toxicities in children with low-risk acute lymphoblastic leukemia (ALL) assigned to receive either continuous 6-mercaptopurine (6-MP) and weekly methotrexate (MTX) or intermittent 6-MP with intermediate-dose MTX, as maintenance treatment. PATIENTS AND METHODS Between October 1, 2000, and December 31, 2007, 635 patients with low-risk ALL were enrolled onto Brazilian Childhood Cooperative Group for ALL Treatment (GBTLI) ALL-99 protocol. Eligible children (n = 544) were randomly allocated to receive either continuous 6-MP/MTX (group 1, n = 272) or intermittent 6-MP (100 mg/m(2)/d for 10 days, with 11 days resting) and MTX (200 mg/m(2) every 3 weeks; group 2, n = 272). RESULTS The 5-year overall survival (OS) and EFS were 92.5% +/- 1.5% SE and 83.6% +/- 2.1% SE, respectively. According to maintenance regimen, the OS was 91.4% +/- 2.2% SE (group 1) and 93.6% +/- 2.1% SE (group 2; P = .28) and EFS 80.9% +/- 3.2% SE (group 1) and 86.5% +/- 2.8% SE (group 2; P = .089). Remarkably, the intermittent regimen led to significantly higher EFS among boys (85.7% v 74.9% SE; P = .027), while no difference was seen for girls (87.0% v 88.8% SE; P = .78). Toxic episodes were recorded in 226 and 237 children, respectively. Grade 3 to 4 toxic events for groups 1 and 2 were, respectively, 273 and 166 for hepatic dysfunction (P = .002), and 772 and 636 for hematologic episodes (P = .005). Deaths on maintenance were: seven (group 1) and one (group 2). CONCLUSION The intermittent use of 6-MP and MTX in maintenance is a less toxic regimen, with a trend toward better long-term EFS. Boys treated with the intermittent schedule had significantly better EFS.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adolescente , Brasil , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Mercaptopurina/administración & dosificación , Metotrexato/administración & dosificación , Estadificación de Neoplasias , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Estudios Prospectivos , Factores de Riesgo , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Mortality from childhood leukemia has declined substantially in developed countries but less markedly in the developing world. This study was designed to describe mortality trends in childhood leukemia and the impact of social inequalities on these trends in Brazil from 1980 to 2002. METHODS: Cancer mortality data by cause and estimates of resident population stratified by age and sex were obtained from the Brazilian Mortality Information System (SIM) for the years 1980 to 2002. Age-standardized (ages 0-19 years) mortality rates were calculated by the direct method using the 1960 world standard population. Trends were modeled using linear regression with 3-year moving average rates as the dependent variable and with the midpoint of the calendar year interval (1991) as the independent variable. The Index of Social Exclusion was used to classify the 27 Brazilian states. Pearson correlation was used to describe the correlation between social exclusion and variations in mortality in each state. RESULTS: Age-standardized mortality rates for boys decreased from 2.05 per 100,000 habitants in 1984 to 1.44 100,000 habitants in 1995, whereas the observed corresponding decline among girls was from 1.60 per 100,000 habitants in 1986 to 1.14 per 100,000 habitants in 1995. Statistically significant declining trends in mortality rates were observed for boys (adjusted correlation coefficient [r(2)] = 0.68; P < .001) and girls (adjusted r(2) = 0.62; P < .001). Significant negative correlations between social inequality and changes in mortality were noted for boys (r = -0.66; P = .001) and for girls (r = -0.78; P < .001). CONCLUSIONS: A consistent decrease in mortality rates from childhood leukemia was noted in Brazil. Higher decreases in mortality were observed in more developed states, possibly reflecting better health care.
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Leucemia/mortalidad , Mortalidad/tendencias , Clase Social , Adolescente , Adulto , Distribución por Edad , Brasil/epidemiología , Niño , Preescolar , Manejo de la Enfermedad , Femenino , Humanos , Lactante , Recién Nacido , Leucemia/epidemiología , Leucemia/terapia , Masculino , PrejuicioRESUMEN
O Grupo Cooperativo Brasileiro de Síndrome Mielodisplásica em Pediatria (GCB-SMD-PED) foi formado em janeiro de 1997 com o objetivo de estudar crianças (menores de 18 anos) com diagnóstico confirmado ou suspeita de mielodisplasia de todo o país. As SMD entretanto, por fazerem interfaces com as leucemias mielóides agudas - LMA), bem como com as doenças mieloproliferativas crônicas - DMPC), podem apresentar-se morfologicamente de várias formas, passíveis de confusão diagnóstica. Assim também, outras doenças com alteração hematológica podem trazer confusão e erros diagnósticos. Daí a necessidade da criação do GCB-SMD-PED para oferecer revisão e suporte no diagnóstico e nos exames complementares dos casos suspeitos de SMD na faixa pediátrica. Embora ainda se use a classificação FAB, duas novas classificações em pediatria foram recentemente propostas: a do Hospital for Sick Children, University of Toronto, Canadá, que propõe a "Classificação CCC" (categoria, citologia e citogenética), na qual foram utilizadas três características principais: categorias de origem "de novo", secundárias e/ou associadas a anormalidades constitucionais, critérios citológicos, com evidências ou não de displasia, e critérios citogenéticos, e a classificação proposta por Hasle e colaboradores, chamada de WHO pediátrica. Neste artigo serão apresentados os dados de 173 pacientes cadastrados no GCB-SMD-PED provenientes de 15 estados brasileiros (41 centros de tratamento em oncologia e hematologia pediátrica). De 1983 a 1997, 51 pacientes foram registrados de forma retrospectiva, e de janeiro de 1998 a fevereiro de 2003, 122 pacientes foram encaminhados ao grupo brasileiro e os seus dados coletados de forma prospectiva. Dos casos registrados e analisados, 93 tiveram confirmação de SMD. Em 36,5 por cento, houve transformação para leucose aguda, sendo que a maioria sofreu transformação para LMA (82,3 por cento) e menor porcentagem para LLA (17,7 por cento). Quanto à evolução...
The Brazilian Cooperative Study Group on Pediatric Myelodysplastic Syndromes (GCB-SMD-PED) started in January 1997 with the goal of studying under 18-year-old patients with MDS or suspected MDS from all over the country. Some primary or secondary disorders are incorrectly called MDS. Because of this the GCB-SMD-PED is a referral group in the country to review and also to give diagnostic support (morphology, genetics, etc.). Some groups still use the FAB classification but two new classifications for pediatric cases have been published: one from the Sick Children's Hospital, University of Toronto, Canada the "CCC Classification" (category, cytology and cytogenetic), and the WHO pediatric classification by Hasle et al. Our proposal here is to present data from the 173 pediatric cases which were referred to the GCB-SMD-PED from 15 states (41 centers). From 1983 to 1997, 51 pediatric cases were registered as retrospective cases and from January 1998 to February 2003, 122 prospective cases were registered. From these 173 cases, 93 where confirmed as MDS. In 36.5 percent of them there was a transformation into acute leukemia with 82.3 percent as AML and 17.7 percent as ALL. The follow up showed that 54.8 percent died, 5.4 percent had spontaneous remission and 16.1 percent were in treatment with no chemotherapy (just transfusion or conservative approach). Infections were the primary cause of death (58.8 percent). Additionally, in this article the diagnostic approach according to classical or molecular genetics is shown with a review of literature for bone marrow transplantation in pediatric cases and other aspects which are different from the approach offered to adult patients with MDS.
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Humanos , Trasplante de Médula Ósea , Síndromes Mielodisplásicos , Defectos del Tubo Neural , PediatríaRESUMEN
We studied bone marrow stromal cell cultures from patients with childhood myelodysplastic syndromes (MDS, refractory anemia with excess of blasts, RAEB) and from matched normal donors. Stromal cell monolayers were characterized as myofibroblasts by the expression of smooth muscle alpha-actin, collagen IV, laminin and fibronectin. When normal cord blood cells were plated onto myelodysplastic stromas, a pathologic cell differentiation was observed, indicating altered myelosupportive properties. cDNA array analysis showed that patient stromas expressed increased levels of thrombospondin-1, collagen-I alpha2-chain, osteoblast-specific factor-2 and osteonectin, indicating the presence of increased osteoblast content, as confirmed by enhanced alkaline phosphatase synthesis. Alterations in the myelodysplastic stroma environment might contribute to abnormal hematopoiesis in this pathology.
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Médula Ósea/patología , Regulación Neoplásica de la Expresión Génica , Hematopoyesis , Músculo Liso/patología , Síndromes Mielodisplásicos/patología , Células del Estroma/patología , Actinas/metabolismo , Fosfatasa Alcalina/metabolismo , Anemia Refractaria con Exceso de Blastos , Médula Ósea/metabolismo , Estudios de Casos y Controles , Diferenciación Celular , Niño , Preescolar , Colágeno Tipo IV/metabolismo , Femenino , Sangre Fetal/química , Sangre Fetal/metabolismo , Fibroblastos/patología , Fibronectinas/metabolismo , Perfilación de la Expresión Génica , Humanos , Técnicas In Vitro , Lactante , Laminina/metabolismo , Masculino , Músculo Liso/metabolismo , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Osteoblastos/metabolismo , Preleucemia , Células del Estroma/metabolismoRESUMEN
O tratamento da Síndrome Mielodisplásica (SMD) na criança ainda é assunto de debate e controvérsias. O atrelamento histórico da doença na infância com a SMD do adulto levou a um retrocesso em diversas áreas do conhecimento desta patologia, sendo talvez as questões relativas ao tratamento as mais afetadas. Dado a origem clonal da doença, postula-se que ela seja virtualmente incurável com as terapias convencionais. Muito se tem estudado a respeito do transplante de células-tronco hematopoéticas, nas suas mais diversas fontes e possibilidades, com alguns resultados promissores. O Grupo Cooperativo Brasileiro de Síndrome Mielodisplásica em Pediatria (GCB-SMD-PED) foi criado em 1997, com o objetivo de estudar esta doença na população brasileira, em seus mais diversos aspectos, quer sejam clínicos, epidemiológicos, citológicos, patológicos, citogenéticos ou moleculares. Após cinco anos de atividades, o Grupo Cooperativo iniciou discussões afim de propor protocolo terapêutico para suas crianças. Para tanto, como passo inicial, fez-se ampla revisão de literatura sobre o assunto, a qual é aqui discutida. Ainda com este fim, o grupo analisou a sobrevida dos pacientes matriculados no GCB-SMD-PED, os diagnósticos realizados na instituição de origem e as mais diversas abordagens terapêuticas seguidas, as quais variaram desde tratamento conservador, medidas de suporte, transfusões sangüíneas à transplante de medula óssea. Os autores descrevem as mais diferentes abordagens utilizadas para o tratamento da SMD em crianças, bem como o racional do emprego de cada modalidade terapêutica e os estudos pertinentes na área.
The management of Myelodysplastic Syndrome (MDS) in childhood is still a matter of debate and controversy. The historic relationship of this illness in children with MDS in adulthood delayed development in different areas, where perhaps knowledge related to treatment was the most affected. Due to the clonal origin of this illness, it is thought that it is virtually incurable with conventional therapies. There have been plenty of studies related to hematopoetic stem-cell transplantation with some promising results.The Brazilian Pediatric Myelodysplastic Cooperative Group (GCB-SMD-PED) was created in 1997, with the aim of studying this disease in the Brazilian population and its different aspects, whether clinical, epidemiological, cytological, pathological, cytogenetical or molecular. After five years of activities, the Co-operative Group has initiated discussions to propose therapeutic protocols for children. For this, as an initial step, a review of publications was performed about this subject, which is discussed in this article. The group also analysed the overall survival of patients referred to the Bra-PMD-CG and the different diagnostic and treatment schedules employed in each institution, varying from simply conservative treatment, palliative measures, blood transfusions to bone marrow transplantation.The authors describe the different ways used for MDS treatment in childhood, as well as the rationale employed of each therapeutic modality and the studies related to this area.
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Humanos , Niño , Síndromes Mielodisplásicos , Trasplante de Células Madre , Síndromes Mielodisplásicos/prevención & control , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/terapiaRESUMEN
Neste relato são apresentados os marcadores moleculares mais frequentes das leucemias linfocíticas agudas, tipo de entidade mais frequente na infância e que em 90 por cento dos casos apresenta algum tipo de anormalidade citogenética.
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Aberraciones Cromosómicas , Citogenética , Marcadores Genéticos , Leucemia-Linfoma Linfoblástico de Células PrecursorasRESUMEN
Neste relato são apresentados o histórico e a evolução do conhecimento sobre as mielodisplasias, aspectos da epidemiologia e o tratamento utilizado atualmente nestas entidades.
The history and evolution of knowledge relating to myelodysplasias, including the epidemiological aspects, are related in this work together with the treatment as used currently in these cases.