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Androgens have been reported to elongate telomeres in retrospective and prospective trials with patients with telomeropathies, mainly with bone marrow failure. In our single-arm prospective clinical trial (clinicaltrials gov. Identifier: NCT02055456), 17 patients with short telomeres and/or germline pathogenic variants in telomere biology genes associated with at least one cytopenia and/or radiologic diagnosis of interstitial lung disease were treated with 5 mg/kg of intramuscular nandrolone decanoate every 15 days for 2 years. Ten of 13 evaluable patients (77%) showed telomere elongation at 12 months by flow-fluorescence in situ hybridization (average increase, 0.87 kb; 95% confidence interval: 0.20-1.55 kb; P=0.01). At 24 months, all ten evaluable patients showed telomere elongation (average increase, 0.49 kb; 95% confidence interval: 0.24-1.23 kb; P=0.18). Hematologic response was achieved in eight of 16 patients (50%) with marrow failure at 12 months, and in ten of 16 patients (63%) at 24 months. Seven patients had interstitial lung disease at baseline, and two and three had pulmonary response at 12 and 24 months, respectively. Two patients died due to pulmonary failure during treatment. In the remaining evaluable patients, the pulmonary function remained stable or improved, but showed consistent decline after cessation of treatment. Somatic mutations in myeloid neoplasm-related genes were present in a minority of patients and were mostly stable during drug treatment. The most common adverse events were elevations in liver function test levels in 88%, acne in 59%, and virilization in 59%. No adverse events grade ≥4 was observed. Our findings indicate that nandrolone decanoate elongates telomeres in patients with telomeropathies, which correlated with clinical improvement in some cases and tolerable adverse events.
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Enfermedades Pulmonares Intersticiales , Humanos , Hibridación Fluorescente in Situ , Nandrolona Decanoato , Estudios Prospectivos , Estudios Retrospectivos , TelómeroAsunto(s)
Adenosina Desaminasa/genética , Agammaglobulinemia/genética , Anemia Hemolítica Autoinmune/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Inmunodeficiencia Combinada Grave/genética , Trombocitopenia/genética , Agammaglobulinemia/complicaciones , Agammaglobulinemia/tratamiento farmacológico , Anemia Hemolítica Autoinmune/complicaciones , Anemia Hemolítica Autoinmune/tratamiento farmacológico , Antirreumáticos/uso terapéutico , Niño , Etanercept/uso terapéutico , Femenino , Glucocorticoides/uso terapéutico , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Factores Inmunológicos/uso terapéutico , Mutación Missense , Linaje , Eliminación de Secuencia , Inmunodeficiencia Combinada Grave/complicaciones , Inmunodeficiencia Combinada Grave/tratamiento farmacológico , Trombocitopenia/complicaciones , Trombocitopenia/tratamiento farmacológicoRESUMEN
Members of the HDAC family are predictive biomarkers and regulate the tumorigenesis in several cancers. However, the role of these genes in the biology of intracranial ependymomas (EPNs) remains unexplored. Here, an analysis of eighteen HDACs genes in an EPN transcriptomic dataset, revealed significantly higher levels of HDAC4 in supratentorial ZFTA fusion (ST-ZFTA) compared with ST-YAP1 fusion and posterior fossa EPNs, while HDAC7 and SIRT2 were downregulated in ST-ZFTA. HDAC4 was also overexpressed in ST-ZFTA as measured by single-cell RNA-Seq, quantitative real time-polymerase chain reaction, and immunohistochemistry. Survival analyses showed a significantly worse outcome for EPNs with higher HDAC4 and SIRT1 mRNA levels. Ontology enrichment analysis showed an HDAC4-high signature consistent with viral processes while collagen-containing extracellular matrix and cell-cell junction were enriched in those with an HDAC4-low signature. Immune gene analysis demonstrated a correlation between HDAC4 expression and low levels of NK resting cells. Several small molecules compounds targeting HDAC4 and ABCG2, were predicted by in silico analysis to be effective against HDAC4-high ZFTA. Our results provide novel insights into the biology of the HDAC family in intracranial ependymomas and reveal HDAC4 as a prognostic marker and potential therapeutic target in ST-ZFTA.
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Neoplasias Encefálicas , Ependimoma , Humanos , Pronóstico , Factores de Transcripción/genética , Ependimoma/genética , Ependimoma/metabolismo , Neoplasias Encefálicas/genética , Perfilación de la Expresión Génica , Histona Desacetilasas/genética , Proteínas Represoras/genéticaRESUMEN
CONTEXT: Skull base tumors are varied in children and are particularly challenging to pediatric neurosurgeons, with few papers in the literature describing the evolution, complications, and outcome. The authors evaluated long-term outcomes in children submitted to skull base tumor surgery and performed a literature review. AIMS: The aim of this study was to analyze surgical results, complications, and outcomes, on comparison with previous publications. MATERIALS AND METHODS: A retrospective analysis of children undergoing surgery at a single institution between 2000 and 2018 for lesions of the cranial base was carried out. In addition, a literature review was carried out describing a total of 115 children operated on for skull base tumors. STATISTICAL ANALYSIS: Chi-squared and Fisher's exact tests were performed to compare the distribution of categorical variables and a nonparametric Mann-Whitney U test was used to perform intergroup comparisons of continuous variables. RESULTS: Seventeen children ranging in age from 8 months to 17 years (mean, 10.9 years) underwent skull base approaches. Tumor types included schwannoma, meningioma, chondroid chordoma, mature teratoma, epidermoid cyst, hemangiopericytoma, rhabdomyosarcoma, myofibroblastic inflammatory tumor, fibromyxoid sarcoma, Crooke's cell adenoma, ossifying fibroma, osteoblastoma, nasopharyngeal angiofibroma and Ewing's sarcoma. Gross total resection was achieved in 6 patients (35.3%), 12 patients (70.6%) had benign histology, and 5 patients (29.4%) had a malignant tumor. Transient postoperative cerebrospinal fluid leak affected only one patient. Thirteen children (76.4%) had a residual neurological deficit at last follow-up evaluation. Three (17.6%) surviving patients received adjuvant therapy. The rate of recurrence or lesion progression was 17.6%. CONCLUSIONS: Skull base tumors in children present a therapeutic challenge because of their unique pathological composition and can lead to considerable morbidity and mortality in pediatric age.
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Myelodysplastic syndrome (MDS) is a rare hematological malignancy in children. It was performed FISH analysis in 19 pediatric MDS patients to investigate deletions involving the PPARgamma and TP53 genes. Significant losses in the PPARgamma gene and deletions in the tumor suppressor gene TP53 were observed in 17 and 18 cases, respectively. Using quantitative RT-PCR, it was detected PPARgamma transcript downexpression in a subset of these cases. G-banding analysis revealed 17p deletions in a small number of these cases. One MDS therapy-related patient had neither a loss of PPARgamma nor TP53. These data suggest that the PPARgamma and TP53 genes may be candidates for molecular markers in pediatric MDS, and that these potentially recurrent deletions could contribute to the identification of therapeutic approaches in primary pediatric MDS.
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Eliminación de Gen , Síndromes Mielodisplásicos/genética , PPAR gamma/genética , Proteína p53 Supresora de Tumor/genética , Adolescente , Niño , Preescolar , Bandeo Cromosómico , Femenino , Humanos , Hibridación Fluorescente in Situ , Lactante , Cariotipificación , Masculino , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
BACKGROUND: Increased activity of multidrug resistance (MDR) genes has been associated with treatment failure in acute leukemias, although with controversial reports. The objective of the present study was to assess the expression profile of the genes related to MDR: ABCB1, ABCC1, ABCC3, ABCG2, and LRP/MVP in terms of the clinical and biological variable and the survival of children with acute lymphoblastic leukemia (ALL). PROCEDURE: The levels of mRNA expression of the drug resistance genes ABCB1, ABCC1, ABCC3, ABCG2, and LRP/MVP were analyzed by quantitative real-time PCR using the median values as cut-off points, in consecutive samples from 140 children with ALL at diagnosis. RESULTS: Expression levels of the ABCG2 gene in the patient group as a whole (P = 0.05) and of the ABCG2 and ABCC1 genes in patients classified as being at high risk were associated with higher rates of 5-year event-free survival (EFS) (P = 0.04 and P = 0.01). Expression levels of the ABCG2 gene below the median were associated with a greater chance of death related to treatment toxicity for the patient group as a whole (P = 0.009) and expression levels below the median of the ABCG2 and ABCC1 genes were associated with a greater chance of death due to treatment toxicity for the high-risk group (P = 0.02 and P = 0.03, respectively). CONCLUSION: The present data suggest a low participation of the drug efflux genes in treatment failure in patients with childhood ALL. However, the low expression of some of these genes may be associated with a higher death risk related to treatment toxicity.
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Transportadoras de Casetes de Unión a ATP/genética , Genes MDR/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Proteínas de Neoplasias/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Niño , Preescolar , Perfilación de la Expresión Génica , Humanos , Lactante , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , ARN Mensajero/análisis , Medición de Riesgo , Análisis de Supervivencia , Tasa de Supervivencia , Insuficiencia del TratamientoRESUMEN
In the version of this article originally published, the main-text sentence "In three patients of European ancestry, we identified the germline variant encoding p.Ile97Met in TIM-3, which was homozygous in two (P12 and P13) and heterozygous in one (P15) in the germline but with no TIM-3 plasma membrane expression in the tumor" misstated the identifiers of the two homozygous individuals, which should have been P13 and P14. The error has been corrected in the HTML, PDF and print versions of the paper.
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BACKGROUND: Glioblastoma is the most lethal primary malignant brain tumor. Although considerable progress has been made in the treatment of this aggressive tumor, the clinical outcome for patients remains poor. Histone deacetylases (HDACs) are recognized as promising targets for cancer treatment. In the past several years, HDAC inhibitors (HDACis) have been used as radiosensitizers in glioblastoma treatment. However, no study has demonstrated the status of global HDAC expression in gliomas and its possible correlation to the use of HDACis. The purpose of this study was to evaluate and compare mRNA and protein levels of class I, II and IV of HDACs in low grade and high grade astrocytomas and normal brain tissue and to correlate the findings with the malignancy in astrocytomas. METHODS: Forty-three microdissected patient tumor samples were evaluated. The histopathologic diagnoses were 20 low-grade gliomas (13 grade I and 7 grade II) and 23 high-grade gliomas (5 grade III and 18 glioblastomas). Eleven normal cerebral tissue samples were also analyzed (54 total samples analyzed). mRNA expression of class I, II, and IV HDACs was studied by quantitative real-time polymerase chain reaction and normalized to the housekeeping gene beta-glucuronidase. Protein levels were evaluated by western blotting. RESULTS: We found that mRNA levels of class II and IV HDACs were downregulated in glioblastomas compared to low-grade astrocytomas and normal brain tissue (7 in 8 genes, p < 0.05). The protein levels of class II HDAC9 were also lower in high-grade astrocytomas than in low-grade astrocytomas and normal brain tissue. Additionally, we found that histone H3 (but not histone H4) was more acetylated in glioblastomas than normal brain tissue. CONCLUSION: Our study establishes a negative correlation between HDAC gene expression and the glioma grade suggesting that class II and IV HDACs might play an important role in glioma malignancy. Evaluation of histone acetylation levels showed that histone H3 is more acetylated in glioblastomas than normal brain tissue confirming the downregulation of HDAC mRNA in glioblastomas.
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Astrocitoma/enzimología , Neoplasias Encefálicas/enzimología , Encéfalo/enzimología , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Glioblastoma/enzimología , Histona Desacetilasas/biosíntesis , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Fármacos Sensibilizantes a Radiaciones/farmacologíaRESUMEN
Subcutaneous panniculitis-like T cell lymphoma (SPTCL), a non-Hodgkin lymphoma, can be associated with hemophagocytic lymphohistiocytosis (HLH), a life-threatening immune activation that adversely affects survival1,2. T cell immunoglobulin mucin 3 (TIM-3) is a modulator of immune responses expressed on subgroups of T and innate immune cells. We identify in ~60% of SPTCL cases germline, loss-of-function, missense variants altering highly conserved residues of TIM-3, c.245A>G (p.Tyr82Cys) and c.291A>G (p.Ile97Met), each with specific geographic distribution. The variant encoding p.Tyr82Cys TIM-3 occurs on a potential founder chromosome in patients with East Asian and Polynesian ancestry, while p.Ile97Met TIM-3 occurs in patients with European ancestry. Both variants induce protein misfolding and abrogate TIM-3's plasma membrane expression, leading to persistent immune activation and increased production of inflammatory cytokines, including tumor necrosis factor-α and interleukin-1ß, promoting HLH and SPTCL. Our findings highlight HLH-SPTCL as a new genetic entity and identify mutations causing TIM-3 alterations as a causative genetic defect in SPTCL. While HLH-SPTCL patients with mutant TIM-3 benefit from immunomodulation, therapeutic repression of the TIM-3 checkpoint may have adverse consequences.
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Mutación de Línea Germinal , Receptor 2 Celular del Virus de la Hepatitis A/genética , Linfohistiocitosis Hemofagocítica/genética , Linfoma de Células T/genética , Paniculitis/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Diagnóstico Diferencial , Femenino , Predisposición Genética a la Enfermedad , Humanos , Lactante , Linfohistiocitosis Hemofagocítica/clasificación , Linfohistiocitosis Hemofagocítica/diagnóstico , Linfoma de Células T/clasificación , Linfoma de Células T/diagnóstico , Masculino , Persona de Mediana Edad , Paniculitis/clasificación , Paniculitis/diagnóstico , Linaje , Secuenciación del Exoma , Adulto JovenRESUMEN
Medulloblastoma (MB) treatment is continuously evolving. Better treatment approaches, focused on particular molecular pathways involved in MB development and progression support new treatment strategies. This article explores the antiproliferative, proapoptotic and radiosensitizing effects of Methoxyamine (MX), a base excision repair (BER) inhibitor that has shown anticancer potential by sensitizing tumor cells to ionizing radiation and chemotherapy. The DAOY (a desmoplastic cerebellar-derived MB) and ONS-76 (classical MB) cell lines were treated with MX at different concentrations, either alone or combined with various chemotherapeutic compounds: cisplatin (CDDP), temozolomide (TMZ) and thiotepa (THIO). Additionally, cell lines were exposed to MX and treated at different ionizing radiation fractions. Measurement of cell growth by XTT assay, clonogenic assay and detection of apoptotic cell death through caspase activity was obtained. Exposure to MX significantly decreased cell proliferation (p<0.05) while increasing cell apoptosis (p<0.05). Growth reduction was concentration-dependent for both DAOY and ONS-76 cells lines. Conversely, MX failed to enhance the cytotoxicity of CDDP, TMZ, and THIO. Moreover, MX treatment radiosensitized both cell lines, with ONS-76 cells being more prone to radiation effects at higher doses of exposure. These data support the role of MX as a direct cytotoxic compound for pediatric MB cells by inhibiting the BER pathway. Nevertheless, an antagonism, rather than a synergic or additive effect of MX with different concentrations of CDDP, TMZ and THIO was observed. Likewise, the radiosensitizing effect on MB cell lines seems to depend on radiation doses and MB subtype. This information may be relevant for clinical study designs employing BER inhibitors for MB.
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Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Neoplasias Cerebelosas/tratamiento farmacológico , Hidroxilaminas/farmacología , Meduloblastoma/tratamiento farmacológico , Antineoplásicos Alquilantes/farmacología , Caspasas/análisis , Caspasas/metabolismo , Línea Celular Tumoral , Neoplasias Cerebelosas/patología , Niño , Cisplatino/farmacología , Reparación del ADN/efectos de los fármacos , Dacarbazina/análogos & derivados , Dacarbazina/farmacología , Humanos , Meduloblastoma/patología , Radiación Ionizante , Fármacos Sensibilizantes a Radiaciones/farmacología , Temozolomida , Tiotepa/farmacología , Ensayo de Tumor de Célula MadreRESUMEN
OBJECTIVE: To report the experience with OK-432 therapy for lymphangioma in children. METHODS: Retrospective study of 19 children with lymphangioma treated with OK-432 in Ribeirão Preto, state of São Paulo, Brazil, between 1999 and 2003. RESULTS: All patients presented response to OK-432, 12 had total shrinkage and seven had partial shrinkage varying from 50 to 80%. Patients had fever after injections of OK-432 for 2 to 10 days, no damage to the overlying skin was observed. CONCLUSION: OK- 432 is safe, effective and can be used as primary choice of treatment of patients with lymphangiomas because of the excellent response. In these cases surgery should not be necessary. In patients with partial regression new injections of OK-432 must be used to shrink the lesion. Thereby safely surgery could be made.
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Antineoplásicos/uso terapéutico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Linfangioma/tratamiento farmacológico , Picibanil/uso terapéutico , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Estudios RetrospectivosRESUMEN
Pediatric brain tumors (BT) represent a broad group of malignancies that affect children, displaying different degrees of aggressiveness and prognosis. Current studies demonstrate a crosslink between genetic and epigenetic changes within these tumors. Histone modifications are key elements in the pathogenesis of cancer in general and in brain tumors in particular. It is well documented that at least two classes of enzymes control acetylation of histones: histone acetyltransferases (HATs) and histone deacetylase (HDACs). Transformed HAT or HDAC action was identified in a number of human tumors. It has been hypothesized that HDACs regulate gene expression by deacetylating important genes for cell maintenance. Several HDACs inhibitors have been characterized in the last years and have been shown to promote growth blockage, differentiation and apoptosis in various types of tumors, including glioblastomas, medulloblastomas, neuroblastomas, melanomas, and leukemias. Some of these inhibitors are currently under clinical investigation for different cancer treatments. This review summarizes important mechanisms of histone modifications and discusses recent discoveries with impact on the pre-clinical and clinical field of pediatric brain tumor treatment.
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Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/enzimología , Inhibidores de Histona Desacetilasas/uso terapéutico , Animales , Neoplasias Encefálicas/diagnóstico , Niño , Ensayos Clínicos como Asunto/tendencias , Humanos , Resultado del TratamientoRESUMEN
Cavernous hemangioma (CH) is a sporadic vascular malformation occurring either as an autosomal dominant condition or as a well-known complication of radiation exposure. Medulloblastoma is a primitive neuroectodermal tumor common in children and currently treated with surgical resection, chemotherapy, and radiotherapy. Neurofibromatosis is the most common single-gene disorder of the central nervous system. Posterior fossa malignant tumors in the context of neurofibromatosis type I (NF1) are very infrequent. This is the first documented case of an unusual metachronous occurrence of non-radiation-induced CH and medulloblastoma in a child with NF1 phenotype. We report the case of a 13-month-old boy with café-au-lait skin lesions associated with NF1-like phenotype who underwent surgical resection of a single CH in the temporal lobe due to recurrent seizures. Four years later he presented with signs of raised intracranial pressure associated with a posterior fossa tumor and hydrocephalus, thus requiring gross total resection of the lesion. Histological analysis revealed a medulloblastoma. After being treated with radiotherapy and chemotherapy, he achieved total remission. Six years later a massive recurrence of the tumor was observed and the child eventually died. The interest in this case lies in the rarity of NF1-like phenotype associated with a non-radiation-induced brain CH and medulloblastoma in a child.
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Bladder cancer is a common malignancy worldwide. Despite the increased use of cisplatin-based combination therapy, the outcomes for patients with advanced disease remain poor. Recently, altered activation of the PI3K/ Akt/mTOR pathway has been associated with reduced patient survival and advanced stage of bladder cancer, making its upstream or downstream components attractive targets for therapeutic intervention. In the present study, we showed that treatment with DTCM-glutaramide, a piperidine that targets PDK1, results in reduced proliferation, diminished cell migration and G1 arrest in 5637 and T24 bladder carcinoma cells. Conversely, no apoptosis, necrosis or autophagy were detected after treatment, suggesting that reduced cell numbers in vitro are a result of diminished proliferation rather than cell death. Furthermore previous exposure to 10 µg/ml DTCM- glutarimide sensitized both cell lines to ionizing radiation. Although more studies are needed to corroborate our findings, our results indicate that PDK1 may be useful as a therapeutic target to prevent progression and abnormal tissue dissemination of urothelial carcinomas.
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Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Citostáticos/farmacología , Piperidonas/farmacología , Tolerancia a Radiación/efectos de los fármacos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Apoptosis/efectos de la radiación , Autofagia/efectos de los fármacos , Autofagia/efectos de la radiación , Western Blotting , Caspasas/metabolismo , Adhesión Celular/efectos de los fármacos , Adhesión Celular/efectos de la radiación , Ciclo Celular/efectos de los fármacos , Ciclo Celular/efectos de la radiación , Movimiento Celular/efectos de los fármacos , Movimiento Celular/efectos de la radiación , Proliferación Celular/efectos de la radiación , Ensayo de Unidades Formadoras de Colonias , Rayos gamma , Humanos , Necrosis , Células Tumorales Cultivadas , Neoplasias de la Vejiga Urinaria/metabolismoRESUMEN
OBJECTIVE: To evaluate treatment outcomes in Wilms' tumor (WT). MATERIALS AND METHODS: We studied 53 children with median age of 2 years with WT, stages I-19, II-14, III-12, IV-6 and V-2. Treatment consisted of surgical excision plus adjuvant (40 children) or neoadjuvant and adjuvant chemotherapy (unresectable tumor, n=8, or caval tumor extension, n=5). Chemotherapy and radiotherapy followed protocols of Brazilian Wilms' Tumor Study Group excepting 16 cases with stage I disease that received a short duration postoperative treatment with vincristine (VCR - 11 doses) and dactinomycin (AMD - 4 doses). Relapsed WT was treated with multiagent regimens including cisplatin/carboplatin, cyclophosphamide, ifosfamide and etoposide. One patient with resistant relapsed WT was treated by high-dose conditioning chemotherapy with stem cell rescue. RESULTS: Overall and disease-free survival rates at 5 years were respectively 88.2 +/- 5.0% and 76.7 +/- 6.6%. Short duration therapy for stage I tumor showed a disease-free survival rate of 100% in a median time of 101 months (range 14 to 248 months). Overall and disease-free survival of 10 patients with recurrent WT at 5 years was 42.8%. The child treated with high-dose chemotherapy plus stem cell transplant is alive without evidence of disease 84 months from relapse. CONCLUSION: The postoperative chemotherapy in stage I disease can be reduced without compromising the cure rate. The treatment of unfavorable stage III and IV disease or relapsed tumor remains a challenge.
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Neoplasias Renales/cirugía , Tumor de Wilms/cirugía , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Niño , Preescolar , Terapia Combinada/métodos , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Lactante , Neoplasias Renales/tratamiento farmacológico , Masculino , Estadificación de Neoplasias , Nefrectomía , Recurrencia , Tumor de Wilms/tratamiento farmacológicoRESUMEN
PURPOSE: Pediatric glioblastoma (pGBM) is a rare, but devastating brain tumor. In contrast to GBM in adults (aGBM), little is known about the mechanisms underlying its development. Our aim is to gain insight into the molecular pathways of pGBM. MATERIALS AND METHODS: Thirty-two pGBM and seven aGBM samples were investigated using biochemical and transcriptional profiling. Ras and Akt pathway activation was assessed through the phosphorylation of downstream effectors, and gene expression profiles were generated using the University Health Network Human 19K cDNA arrays. Results were validated using real-time polymerase chain reaction and immunohistochemistry and compared with existing data sets on aGBM. RESULTS: There are at least two subsets of pGBM. One subset, associated with Ras and Akt pathway activation, has very poor prognosis and exhibits increased expression of genes related to proliferation and to a neural stem-cell phenotype, similar to findings in aggressive aGBM. This subset was still molecularly distinguishable from aGBM after unsupervised and supervised analysis of expression profiles. A second subset, with better prognosis, is not associated with activation of Akt and Ras pathways, may originate from astroglial progenitors, and does not express gene signatures and markers shown to be associated with long-term survival in aGBM. Both subsets of pGBM show overexpression of Y-box-protein-1 that may help drive oncogenesis in this tumor. CONCLUSION: Our work, the first study of gene expression profiles in pGBM, provides valuable insight into active pathways and targets in a cancer with minimal survival, and suggests that these tumors cannot be understood exclusively through studies of aGBM.
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Neoplasias Encefálicas/genética , Proteínas de Unión al ADN/genética , Perfilación de la Expresión Génica , Glioblastoma/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis , Neoplasias Encefálicas/etiología , Neoplasias Encefálicas/mortalidad , Niño , Preescolar , Receptores ErbB/genética , Femenino , Glioblastoma/etiología , Glioblastoma/mortalidad , Humanos , Lactante , Masculino , Persona de Mediana Edad , Proteínas Nucleares , Fosforilación , Pronóstico , Proteínas Proto-Oncogénicas c-akt/fisiología , Proteínas Proto-Oncogénicas p21(ras)/fisiología , Transducción de Señal , Proteína 1 de Unión a la Caja YRESUMEN
Infantile myofibromatosis is a rare disorder of infancy that can provoke osteolytic lesions. A 15-day-old infant presented with three round, firm lesions located on the forehead, shoulder, and back. Excisional biopsy of the forehead lesion revealed that the tumor was composed of spindle cells resembling normal smooth muscle arranged in short fascicles. Immunohistochemical staining was positive for vimentin and actin. Five months later, the child presented with three new lesions, including one in the superolateral aspect of the left orbit. It is important to recognize the multicentric form of infantile myofibromatosis because, despite its aggressive clinical presentation, the disease is benign and usually does not require extensive surgery or chemotherapy.
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Miofibromatosis/diagnóstico por imagen , Miofibromatosis/patología , Órbita/diagnóstico por imagen , Órbita/patología , Neoplasias Orbitales/diagnóstico por imagen , Neoplasias Orbitales/patología , Actinas/metabolismo , Biopsia , Humanos , Inmunohistoquímica/métodos , Recién Nacido , Miofibromatosis/metabolismo , Miofibromatosis/cirugía , Órbita/metabolismo , Órbita/cirugía , Neoplasias Orbitales/metabolismo , Neoplasias Orbitales/cirugía , Coloración y Etiquetado , Tomografía Computarizada por Rayos X , Vimentina/metabolismoRESUMEN
OBJECTIVE: To evaluate treatment outcomes in Wilms' tumor (WT). MATERIALS AND METHODS: We studied 53 children with median age of 2 years with WT, stages I-19, II-14, III-12, IV-6 and V-2. Treatment consisted of surgical excision plus adjuvant (40 children) or neoadjuvant and adjuvant chemotherapy (unresectable tumor, n = 8, or caval tumor extension, n = 5). Chemotherapy and radiotherapy followed protocols of Brazilian Wilms' Tumor Study Group excepting 16 cases with stage I disease that received a short duration postoperative treatment with vincristine (VCR - 11 doses) and dactinomycin (AMD - 4 doses). Relapsed WT was treated with multiagent regimens including cisplatin/carboplatin, cyclophosphamide, ifosfamide and etoposide. One patient with resistant relapsed WT was treated by high-dose conditioning chemotherapy with stem cell rescue. RESULTS: Overall and disease-free survival rates at 5 years were respectively 88.2 ± 5.0 percent and 76.7 ± 6.6 percent. Short duration therapy for stage I tumor showed a disease-free survival rate of 100 percent in a median time of 101 months (range 14 to 248 months). Overall and disease-free survival of 10 patients with recurrent WT at 5 years was 42.8 percent. The child treated with high-dose chemotherapy plus stem cell transplant is alive without evidence of disease 84 months from relapse. CONCLUSION: The postoperative chemotherapy in stage I disease can be reduced without compromising the cure rate. The treatment of unfavorable stage III and IV disease or relapsed tumor remains a challenge.
Asunto(s)
Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Neoplasias Renales/cirugía , Tumor de Wilms/cirugía , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Combinada/métodos , Supervivencia sin Enfermedad , Estudios de Seguimiento , Neoplasias Renales/tratamiento farmacológico , Estadificación de Neoplasias , Nefrectomía , Recurrencia , Tumor de Wilms/tratamiento farmacológicoRESUMEN
OBJETIVO: Relatar a experiência no uso do OK-432 para tratamento de linfangiomas em crianças. MÉTODOS: Estudo retrospectivo de 19 crianças com linfangioma tratadas com OK-432 no Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP, durante o período de 1999 a 2003. RESULTADOS: Todos os pacientes apresentaram alguma resposta ao OK-432, 12 pacientes apresentaram regressão total, sete apresentaram regressão parcial variando de 50 por cento a 80 por cento. Os pacientes apresentaram febre após a aplicação da droga com duração de 2 a 10 dias. Não se observaram cicatrizes após a aplicação do OK-432. CONCLUSÕES: A droga OK-432 é segura, eficaz e pode ser utilizada como primeira escolha no tratamento de pacientes com linfangiomas devido à excelente resposta, podendo tornar desnecessária a realização de cirurgia. Em pacientes com resposta parcial, podem ser realizadas novas aplicações de OK-432 ou cirurgia menos mutilante, devido à redução das dimensões da lesão.