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1.  N-Cadherin in Neuroblastoma Disease: Expression and Clinical Significance 
PLoS ONE  2012;7(2):e31206.
One of the first and most important steps in the metastatic cascade is the loss of cell-cell and cell-matrix interactions. N-cadherin, a crucial mediator of homotypic and heterotypic cell-cell interactions, might play a central role in the metastasis of neuroblastoma (NB), a solid tumor of neuroectodermal origin. Using Reverse Transcription Quantitative PCR (RT-qPCR), Western blot, immunocytochemistry and Tissue MicroArrays (TMA) we demonstrate the expression of N-cadherin in neuroblastoma tumors and cell lines. All neuroblastic tumors (n = 356) and cell lines (n = 10) expressed various levels of the adhesion protein. The N-cadherin mRNA expression was significantly lower in tumor samples from patients suffering metastatic disease. Treatment of NB cell lines with the N-cadherin blocking peptide ADH-1 (Exherin, Adherex Technologies Inc.), strongly inhibited tumor cell proliferation in vitro by inducing apoptosis. Our results suggest that N-cadherin signaling may play a role in neuroblastoma disease, marking involvement of metastasis and determining neuroblastoma cell viability.
PMCID: PMC3280274  PMID: 22355346
2.  Outcome Prediction of Children with Neuroblastoma using a Multigene Expression Signature, a Retrospective SIOPEN/COG/GPOH Study 
The lancet oncology  2009;10(7):663-671.
More accurate prognostic assessment of patients with neuroblastoma is required to improve the choice of risk-related therapy. The aim of this study is to develop and validate a gene expression signature for improved outcome prediction.
Fifty-nine genes were carefully selected based on an innovative data-mining strategy and profiled in the largest neuroblastoma patient series (n=579) to date using RT-qPCR starting from only 20 ng of RNA. A multigene expression signature was built using 30 training samples, tested on 313 test samples and subsequently validated in a blind study on an independent set of 236 additional tumours.
The signature accurately classifies patients with respect to overall and progression-free survival (p<0·0001). The signature has a performance, sensitivity, and specificity of 85·4% (95%CI: 77·7–93·2), 84·4% (95%CI: 66·5–94·1), and 86·5% (95%CI: 81·1–90·6), respectively to predict patient outcome. Multivariate analysis indicates that the signature is a significant independent predictor after controlling for currently used riskfactors. Patients with high molecular risk have a higher risk to die from disease and for relapse/progression than patients with low molecular risk (odds ratio of 19·32 (95%CI: 6·50–57·43) and 3·96 (95%CI: 1·97–7·97) for OS and PFS, respectively). Patients with increased risk for adverse outcome can also be identified within the current treatment groups demonstrating the potential of this signature for improved clinical management. These results were confirmed in the validation study in which the signature was also independently statistically significant in a model adjusted for MYCN status, age, INSS stage, ploidy, INPC grade of differentiation, and MKI. The high patient/gene ratio (579/59) underlies the observed statistical power and robustness.
A 59-gene expression signature predicts outcome of neuroblastoma patients with high accuracy. The signature is an independent risk predictor, identifying patients with increased risk in the current clinical risk groups. The applied method and signature is suitable for routine lab testing and ready for evaluation in prospective studies.
The Belgian Foundation Against Cancer, found of public interest (project SCIE2006-25), the Children Cancer Fund Ghent, the Belgian Society of Paediatric Haematology and Oncology, the Belgian Kid’s Fund and the Fondation Nuovo-Soldati (JV), the Fund for Scientific Research Flanders (KDP, JH), the Fund for Scientific Research Flanders (grant number: G•0198•08), the Institute for the Promotion of Innovation by Science and Technology in Flanders, Strategisch basisonderzoek (IWT-SBO 60848), the Fondation Fournier Majoie pour l’Innovation, the Instituto Carlos III,RD 06/0020/0102 Spain, the Italian Neuroblastoma Foundation, the European Community under the FP6 (project: STREP: EET-pipeline, number: 037260), and the Belgian program of Interuniversity Poles of Attraction, initiated by the Belgian State, Prime Minister's Office, Science Policy Programming.
PMCID: PMC3045079  PMID: 19515614
3.  Influence of Neuroblastoma Stage on Serum-Based Detection of MYCN Amplification 
Pediatric blood & cancer  2009;53(3):329-331.
MYCN oncogene amplification has been defined as the most important prognostic factor for neuroblastoma, the most common solid extracranial neoplasm in children. High copy numbers are strongly associated with rapid tumor progression and poor outcome, independently of tumor stage or patient age, and this has become an important factor in treatment stratification.
By Real Time Quantitative PCR analysis, we evaluated the clinical relevance of circulating MYCN DNA of 267 patients with locoregional or metastatic neuroblastoma in children less than 18 months of age.
For patients in this age group with INSS stage 4 or 4S NB and stage 3 patients, serum-based determination of MYCN DNA sequences had good sensitivity (85%, 83% and 75% respectively) and high specificity (100%) when compared to direct tumor gene determination. In contrast, the approach showed low sensitivity patients with stage 1 and 2 disease.
Our results show that the sensitivity of the serum-based MYCN DNA sequence determination depends on the stage of the disease. However, this simple, reproducible assay may represent a reasonably sensitive and very specific tool to assess tumor MYCN status in cases with stage 3 and metastatic disease for whom a wait and see strategy is often recommended.
PMCID: PMC2857568  PMID: 19301388
Circulating DNA; MYCN amplification; neuroblastoma
4.  Array comparative genomic hybridization and flow cytometry analysis of spontaneous abortions and mors in utero samples 
BMC Medical Genetics  2009;10:89.
It is estimated that 10-15% of all clinically recognised pregnancies result in a spontaneous abortion or miscarriage. Previous studies have indicated that in up to 50% of first trimester miscarriages, chromosomal abnormalities can be identified. For several decades chromosome analysis has been the golden standard to detect these genomic imbalances. A major drawback of this method is the requirement of short term cultures of fetal cells. In this study we evaluated the combined use of array CGH and flow cytometry (FCM), for detection of chromosomal abnormalities, as an alternative for karyotyping.
In total 100 spontaneous abortions and mors in utero samples were investigated by karyotyping and array CGH in combination with FCM in order to compare the results for both methods.
Chromosome analysis revealed 17 abnormal karyotypes whereas array CGH in combination with FCM identified 26 aberrations due to the increased test success rate. Karyotyping was unsuccessful in 28% of cases as compared to only two out of hundred samples with inconclusive results for combined array CGH and FCM analysis.
This study convincingly shows that array CGH analysis for detection of numerical and segmental imbalances in combination with flow cytometry for detection of ploidy status has a significant higher detection rate for chromosomal abnormalities as compared to karyotyping of miscarriages samples.
PMCID: PMC2753309  PMID: 19751515

Results 1-4 (4)