Molecular profiling of isolated histological components of wilms tumor implicates a common role for the Wnt signaling pathway in kidney and tumor development.

Wilms tumor (WT), a tumor composed of three histological components - blastema (BL), epithelia and stroma - is considered an appropriate model system to study the biological relationship between differentiation and tumorigenesis. To investigate molecular associations between nephrogenesis and WT, the gene expression pattern of individual cellular components was analyzed, using a customized platform containing 4,608 genes. WT gene expression patterns were compared to genes regulated during kidney differentiation. BL had a closer gene expression pattern to the earliest stage of normal renal development. The BL gene expression pattern was compared to that of fetal kidney (FK) and also between FK and mature kidney, identifying 25 common deregulated genes supposedly involved in the earliest events of WT onset. Quantitative RT-PCR was performed, confirming the difference in expression levels for 13 of 16 genes (81.2%) in the initial set and 8 of 13 (61.5%) in an independent set of samples. An overrepresentation of genes belonging to the Wnt signaling pathway was identified, namely PLCG2, ROCK2 and adenomatous polyposis coli (APC). Activation of the Wnt pathway was confirmed in WT, using APC at protein level and PLCG2 at mRNA and protein level. APC showed positive nuclear immunostaining for an independent set of WT samples, similarly to the FK in week 11. Lack of PLCG2 expression was confirmed in WT and in FK until week 18. Taken together, these results provided molecular evidence of the recapitulation of the embryonic kidney by WT as well as involvement of the Wnt pathway in the earliest events of WT onset.

[Severe sepsis and septic shock in children with cancer]. / Sepse grave e choque séptico em crianças com câncer: fatores preditores de óbito.

BACKGROUND: This report describes the clinical characteristics of children and adolescents bearers of oncological disease who were admitted to PICU with severe sepsis and septic shock. The predicting factors for mortality and for need of pulmonary mechanical ventilation were also determined. METHODS: Thirty-three children diagnosed with severe sepsis and septic shock were evaluated prospectively at the PICU of Hospital do Câncer between June and December of 2001. RESULTS: Thirty-three admissions were analyzed during this period; ages ranged from 1 to 23 years; 16 (48%) were boys and 17 (52%) were girls. Twenty patients had leukemia/lymphoma and 13 patients had solid tumors. Twenty-eight patients had a diagnosis of infectious diseases. In 73% of the patients, infection germs were isolated and gram negative organisms were responsible for 67% of the samples. Respiratory support was necessary for 18 patients (54%), inotropic support for 22 (67%) and dialysis for four patients. The mortality rate was of 41% for patients who needed inotropic support, of 69% for those requiring respiratory support and of 100% for those with an indication for dialysis. The overall mortality rate was of 27%. CONCLUSIONS: This research suggests that early intensive treatment for children with cancer exhibiting severe sepsis and/or septic shock could be an important factor to influence the mortality rate of these patients. Moreover, that noninvasive ventilation could be an option to reduce endotracheal intubation and invasive ventilation.

Recurrent somatic mutation in DROSHA induces microRNA profile changes in Wilms tumour.

Wilms tumour (WT) is an embryonal kidney neoplasia for which very few driver genes have been identified. Here we identify DROSHA mutations in 12% of WT samples (26/222) using whole-exome sequencing and targeted sequencing of 10 microRNA (miRNA)-processing genes. A recurrent mutation (E1147K) affecting a metal-binding residue of the RNase IIIb domain is detected in 81% of the DROSHA-mutated tumours. In addition, we identify non-recurrent mutations in other genes of this pathway (DGCR8, DICER1, XPO5 and TARBP2). By assessing the miRNA expression pattern of the DROSHA-E1147K-mutated tumours and cell lines expressing this mutation, we determine that this variant leads to a predominant downregulation of a subset of miRNAs. We confirm that the downregulation occurs exclusively in mature miRNAs and not in primary miRNA transcripts, suggesting that the DROSHA E1147K mutation affects processing of primary miRNAs. Our data underscore the pivotal role of the miRNA biogenesis pathway in WT tumorigenesis, particularly the major miRNA-processing gene DROSHA.

Gene expression analysis of blastemal component reveals genes associated with relapse mechanism in Wilms tumour.

Wilms tumour (WT) is a paediatric kidney tumour, composed of blastemal, epithelial and stromal cells, with a relapse rate of approximately 15%. Long-term survival for patients with relapse remains approximately 50%. Current clinical and molecular research is directed towards identifying prognostic factors to define the minimal and intensive therapy for successful treatment of children with low and high risk of relapse, respectively. Blastemal component presents a high level of aggressiveness and responsiveness to chemotherapy. To identify molecular prognostic markers that are predictive of chemotherapy sensitivity in tumour relapse, blastemal-enriched samples from stage III and IV WT, from patients with relapse or without relapse, were analysed for 4608 human genes immobilised on a customised cDNA platform. These analyses revealed 69 differentially expressed genes, and the top nine genes were further evaluated by qRT-PCR in the initial WT samples. TSPAN3, NCOA6, CDO1, MPP2 and MCM2 were confirmed to be down-regulated in relapse WT, and TSPAN3 and NCOA6 were also validated in an independent sample group. Protein expression of MCM2 and NCOA6 were observed in 38% (13 out of 34) and 28% (9 out of 32), respectively, of independent stage III and IV WT blastema samples, without association with relapse. However, a significant association between MCM2 positive staining and chemotherapy as first treatment suggests the involvement of MCM2 with drug metabolism in WT blastemal cells.

Tumor neuroectodérmico primitivo na infância: relato de 13 casos e revisão da literatura / Primitive neuroectodermic tumor in childwood: a report of 13 cases and literature review

Proposta: a proposta desse estudo é a análise retrospectiva dos pacientes com diagnóstico de tumor neuroectodérmico primitivo (PNET), admitidos no Departamento de Pediatria do Hospital do Câncer no periodo de 1989 a 1996. Pacientes e métodos: Ttdos os 13 pacientes portadores de PNET foram analisados retrospectivamente utilizando uma ficha para obtenção dos dados epidemiológicos clínicos, terapêuticos e seguimento de cada paciente. Resultados: a cirurgia foi a primeira abordagem terapêutica em 2 pacientes. Quimioterapia foi administrada em 12 pacientes e radioterapia em 2. Dos 13 pacientes 5 estão vivos em seguimento médio de 48 meses após o término do tratamento. Conclusão: a análise dos 13 pacientes com PNET e revisão da literatura demonstram a agressividade desse tumor. Devido a raridade dessa patologia, estudos multiinstitucionais, podem ter papel importante para análise de fatores prognósticos e consequente abordagem terapêutica.

Sepse grave e choque séptico em crianças com câncer: fatores preditores de óbito / Severe sepsis and septic shock in children with cancer

OBJETIVO: Descrever as características clínicas das crianças e adolescentes portadores de doenças oncológicas que foram admitidos na UTIP apresentando sepse grave ou choque séptico. E determinar os fatores preditores de óbito e uso de ventilação pulmonar mecânica (VPM). MÉTODOS: Foram analisadas prospectivamente 33 crianças com diagnóstico de sepse grave ou choque séptico, na UTIP do Hospital do Câncer, entre junho e dezembro de 2001. RESULTADOS: Durante o período houve 33 internações, cuja idade variou entre 1 e 23 anos; 16 (48 por cento) eram do sexo masculino e 17 (52 por cento) do sexo feminino. Vinte pacientes eram portadores de leucemia ou linfoma e 13 pacientes de tumores sólidos. Vinte e oito pacientes apresentaram quadro infeccioso documentado. Houve crescimento de patógenos em 73 por cento, sendo que as infecções por germes gram-negativos foram responsáveis por 67 por cento das amostras. Suporte respiratório foi necessário em 18 casos (54 por cento), a administração de drogas inotrópicas em 22 casos (67 por cento) e em quatro casos a diálise foi indicada. A taxa de mortalidade foi de 41 por cento para os pacientes que necessitaram de drogas inotrópicas, 69 por cento para os que utilizaram VPM e 100 por cento para aqueles submetidos à diálise. A taxa de mortalidade foi de 27 por cento. CONCLUSÕES: Nossos dados sugerem que o início precoce de tratamento intensivo para crianças com câncer apresentando sepse grave e choque séptico pode ser um fator capaz de influenciar a mortalidade desses pacientes. E a utilização da ventilação pulmonar mecânica não invasiva demonstrou ser um procedimento capaz de reduzir a necessidade de intubação orotraqueal e ventilação pulmonar mecânica invasiva.

Hemangioma hepático / Hepatic hemagioma

Objetivos: Descrever um caso de hamangioma hepático em recém-nascido tratado com cirurgia. Métodos: Relata-se o caso de recém-nascidos do sexo masculino, de 6 dias de vida, com extensa lesão hepática, e sua evolução. Resultados: A criança evoluiu com quadro de descompensação hemodinâmica devido a coagulopatia de consumo e insuficiência respiratória. Os exames de imagem foram inconclusivos, sendo indicado procedimento cirúrgico. Foi realizada ressecção total da massa hepática e confirmado o diagnóstico de hamangioma por estudo anatomopatológico. A criança evoluiu satisfatoriamente, recebeu alta após 15 dias e encontra-se assintomática. Conclusões: O hemangioma hepático deve ter tratamento conservador, estando a cirurgia reservada para os casos de insuficiência cardíaca intratável e/ou coagulopatia consumptiva refratária