Elvis Terci Valera

Molecular Profiling Identifies Prognostic Subgroups of Pediatric Glioblastoma and Shows Increased YB-1 Expression in Tumors

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.

Differential expression of HDAC3, HDAC7 and HDAC9 is associated with prognosis and survival in childhood acute lymphoblastic leukaemia

Altered expression of histone deacetylases (HDACs) is a common feature in several human malignancies and may represent an interesting target for cancer treatment, including haematological malignancies. We evaluated the mRNA gene expression profile of 12 HDAC genes by quantitative real‐time polymerase chain reaction in 94 consecutive childhood acute lymphoblastic leukaemia (ALL) samples and its association with clinical/biological features and survival. ALL samples showed higher expression levels of HDAC2, HDAC3, HDAC8, HDAC6 and HDAC7 when compared to normal bone marrow samples. HDAC1 and HDAC4 showed high expression in T‐ALL and HDAC5 was highly expressed in B‐lineage ALL. Higher than median expression levels of HDAC3 were associated with a significantly lower 5‐year event‐free survival (EFS) in the overall group of patients (P = 0·03) and in T‐ALL patients (P = 0·01). HDAC7 and HADC9 expression levels higher than median were associated with a lower 5‐year EFS in the overall group (P = 0·04 and P = 0·003, respectively) and in B‐lineage CD10‐positive patients (P = 0·009 and P = 0·005, respectively). Our data suggest that higher expression of HDAC7 and HDAC9 is associated with poor prognosis in childhood ALL and could be promising therapeutic targets for the treatment of refractory childhood ALL.

research paper: Differential expression of HDAC3, HDAC7 and HDAC9 is associated with prognosis and survival in childhood acute lymphoblastic leukaemia

Altered expression of histone deacetylases (HDACs) is a common feature in several human malignancies and may represent an interesting target for cancer treatment, including haematological malignancies. We evaluated the mRNA gene expression profile of 12 HDAC genes by quantitative real‐time polymerase chain reaction in 94 consecutive childhood acute lymphoblastic leukaemia (ALL) samples and its association with clinical/biological features and survival. ALL samples showed higher expression levels of HDAC2, HDAC3, HDAC8, HDAC6 and HDAC7 when compared to normal bone marrow samples. HDAC1 and HDAC4 showed high expression in T‐ALL and HDAC5 was highly expressed in B‐lineage ALL. Higher than median expression levels of HDAC3 were associated with a significantly lower 5‐year event‐free survival (EFS) in the overall group of patients (P = 0·03) and in T‐ALL patients (P = 0·01). HDAC7 and HADC9 expression levels higher than median were associated with a lower 5‐year EFS in the overall group (P = 0·04 and P = 0·003, respectively) and in B‐lineage CD10‐positive patients (P = 0·009 and P = 0·005, respectively). Our data suggest that higher expression of HDAC7 and HDAC9 is associated with poor prognosis in childhood ALL and could be promising therapeutic targets for the treatment of refractory childhood ALL.

Multiple drug resistance protein (MDR-1), multidrug resistance-related protein (MRP) and lung resistance protein (LRP) gene expression in childhood acute lymphoblastic leukemia

CONTEXT Despite the advances in the cure rate for acute lymphoblastic leukemia, approximately 25% of affected children suffer relapses. Expression of genes for the multiple drug resistance protein (MDR-1), multidrug resistance-related protein (MRP), and lung resistance protein (LRP) may confer the phenotype of resistance to the treatment of neoplasias. OBJECTIVE To analyze the expression of the MDR-1, MRP and LRP genes in children with a diagnosis of acute lymphoblastic leukemia via the semiquantitative reverse transcription polymerase chain reaction (RT-PCR), and to determine the correlation between expression and event-free survival and clinical and laboratory variables. DESIGN A retrospective clinical study. SETTING Laboratory of Pediatric Oncology, Department of Pediatrics, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Brazil. METHODS Bone marrow aspirates from 30 children with a diagnosis of acute lymphoblastic leukemia were assessed for the expression of messenger RNA for the MDR-1, MRP and LRP genes by semi-quantitative RT-PCR. RESULTS In the three groups studied, only the increased expression of LRP was related to worsened event-free survival (p = 0.005). The presence of the common acute lymphoblastic leukemia antigen (CALLA) was correlated with increased LRP expression (p = 0.009) and increased risk of relapse or death (p = 0.05). The relative risk of relapse or death was six times higher among children with high LRP expression upon diagnosis (p = 0.05), as confirmed by multivariate analysis of the three genes studied (p = 0.035). DISCUSSION Cell resistance to drugs is a determinant of the response to chemotherapy and its detection via RT-PCR may be of clinical importance. CONCLUSIONS Evaluation of the expression of genes for resistance to antineoplastic drugs in childhood acute lymphoblastic leukemia upon diagnosis, and particularly the expression of the LRP gene, may be of clinical relevance, and should be the object of prospective studies.

Polymorphisms of xenobiotic metabolizing enzymes and DNA repair genes and outcome in childhood acute lymphoblastic leukemia

The interindividual variation in the activity of xenobiotic metabolizing enzymes and DNA repair genes could modify an individuals risk of recurrent malignancy and response to therapy. We investigated whether ALL outcome was related to polymorphisms in genes CYP2D6, MPO, EPHX1, NQO1, TS, XPD and XRCC1 in 95 consecutive ALL children by PCR or PCR-FRLP techniques. Polymorphisms in genes NQO1 and TS were associated with a significantly slow response to induction chemotherapy and NQO1 was also associated with a lower five-year event-free survival. This study suggests that polymorphisms of NQO1 and TS could be important for patient response to induction therapy and for treatment outcome.

mRNA expression profile of multidrug resistance genes in childhood acute lymphoblastic leukemia. Low expression levels associated with a higher risk of toxic death

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).

Polyploidy in atypical grade II choroid plexus papilloma of the posterior fossa.

Cytogenetic studies of choroid plexus tumors, particularly for atypical choroid plexus papillomas, have been rarely described. In the present report, the cytogenetic investigation of an atypical choroid plexus papilloma occurring at the posterior fossa of a 16‐year‐old male is described. Comparative genome hybridization analysis demonstrated gains of genetic material from almost all chromosomes. Chromosome losses involved 19p, regional losses at chromosome X and loss of chromosome Y. The presence of polyploid cells was confirmed by fluorescence in situ hybridization analysis with probes directed to centromeric regions. Furthermore, the microscopic analysis of cultures showed nuclear buds, nucleoplasmic bridges, and micronuclei in 23% of tumor cells suggesting the presence of complex chromosomal abnormalities. Previous cytogenetic studies on choroid plexus papillomas showed either normal, hypodiploid or hyperdiploid karyotypes. To the best of our knowledge, this is the first report of polyploidy in choroid plexus papilloma of intermediate malignancy grade. Although the mechanisms beneath such genome duplication remain to be elucidated, the observed abnormal nuclear shapes indicate constant restructuring of the tumors genome and deserves further investigation.

mRNA expression of matrix metalloproteinases (MMPs) 2 and 9 and tissue inhibitor of matrix metalloproteinases (TIMPs) 1 and 2 in childhood acute lymphoblastic leukemia: potential role of TIMP1 as an adverse prognostic factor.

This study evaluates the mRNA expression profile of genes TIMP1, TIMP2, MMP2 and MMP9 in diagnostic bone marrow samples from 134 consecutive ALL children by real-time quantitative PCR. A significant association was observed between higher expression levels of MMP9 and low risk group and absence of extramedullary infiltration and higher expression levels of TIMP2 and MMP2 with T-ALL. TIMP1 gene expression values higher than the median were associated with a significantly lower 5-year event free-survival in univariable (P=0.04) and multivariable analysis (P=0.01). Our data address new information in the complex interaction of the migration/adhesion genes and childhood ALL.

Fungal infection by Paracoccidioides brasiliensis mimicking bone tumor

Paracoccidioides brasiliensis infection causes a systemic mycosis originally described in Latin America but with current reports of worldwide distribution. The clinical presentation of paracoccidiodomycosis as an isolated long‐bone lesion in children is quite unusual. This article describes a 10‐year‐old male with a lytic femoral bone lesion caused by P. brasiliensis infection that was first suspected of being of neoplasic etiology. The text also emphasizes the importance of including endemic fungal infections in the differential diagnosis of bone lesions. Pediatr Blood Cancer 2008;50:1284–1286.

OK-432 therapy for lymphangioma in children

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.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 Ribeirao Preto, state of Sao 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.