showing 31 related works from this author
9-ING-41, a small-molecule glycogen synthase kinase-3 inhibitor, is active in neuroblastoma.
2018
Advanced stage neuroblastoma is a very aggressive pediatric cancer with limited treatment options and a high mortality rate. Glycogen Synthase Kinase-3β (GSK-3β) is a potential therapeutic target in neuroblastoma. Using immunohistochemical staining, we observed positive GSK-3β expression in 67% of human neuroblastomas (34 out of 51 cases). Chemically distinct GSK-3 inhibitors (AR-A014418, TDZD8 and 9-ING-41), suppressed the growth of neuroblastoma cells whereas 9-ING-41, a clinically relevant small molecule GSK-3β inhibitor with broad spectrum pre-clinical antitumor activity, being the most potent. Inhibition of GSK-3 resulted in a decreased expression of the antiapoptotic molecule XIAP and…
Circulating microRNA biomarkers for metastatic disease in neuroblastoma patients
2018
In this study, the circulating miRNome from diagnostic neuroblastoma serum was assessed for identification of noninvasive biomarkers with potential in monitoring metastatic disease. After determining the circulating neuroblastoma miRNome, 743 miRNAs were screened in 2 independent cohorts of 131 and 54 patients. Evaluation of serum miRNA variance in a model testing for tumor stage, MYCN status, age at diagnosis, and overall survival revealed tumor stage as the most significant factor impacting miRNA abundance in neuroblastoma serum. Differential abundance analysis between patients with metastatic and localized disease revealed 9 miRNAs strongly associated with metastatic stage 4 disease in b…
Extracellular matrix composition defines an ultra-high-risk group of neuroblastoma within the high-risk patient cohort
2016
Background: Although survival for neuroblastoma patients has dramatically improved in recent years, a substantial number of children in the high-risk subgroup still die. Methods: We aimed to define a subgroup of ultra-high-risk patients from within the high-risk cohort. We used advanced morphometric approaches to quantify and characterise blood vessels, reticulin fibre networks, collagen type I bundles, elastic fibres and glycosaminoglycans in 102 high-risk neuroblastomas specimens. The Kaplan-Meier method was used to correlate the analysed elements with survival. Results: The organisation of blood vessels and reticulin fibres in neuroblastic tumours defined an ultra-high-risk patient subgr…
Patient-Derived Xenograft Models Reveal Intratumor Heterogeneity and Temporal Stability in Neuroblastoma.
2018
Patient-derived xenografts (PDX) and the Avatar, a single PDX mirroring an individual patient, are emerging tools in preclinical cancer research. However, the consequences of intratumor heterogeneity for PDX modeling of biomarkers, target identification, and treatment decisions remain under-explored. In this study, we undertook serial passaging and comprehensive molecular analysis of neuroblastoma orthotopic PDXs, which revealed strong intrinsic genetic, transcriptional, and phenotypic stability for more than 2 years. The PDXs showed preserved neuroblastoma-associated gene signatures that correlated with poor clinical outcome in a large cohort of patients with neuroblastoma. Furthermore, we…
Gain of MYCN region in a Wilms tumor-derived xenotransplanted cell line.
2010
Wilms tumor is one of the most common pediatric malignant tumors of the kidney. Although the WT1 gene, located at 11p13, has been proven to be implicated in the development of Wilms tumor, other genes such as MYCN are also involved. The purpose of this study is to genetically characterize a Wilms tumor metastasis xenotransplanted in nude mice. Immunogenotype evolution of the xenografts material was monitored for 29 months using molecular techniques, fluorescent in situ hybridization and multiplex ligation-dependent probe amplification, in addition to immunohistochemistry in tissue microarrays. Genetic alterations present in the original tumor and retained in the xenotransplanted tumor were …
Circulating microRNA biomarkers for metastatic disease in neuroblastoma patients
2018
AbstractIn this study, the circulating miRNome from diagnostic neuroblastoma serum was assessed for identification of non-invasive biomarkers with potential in monitoring metastatic disease. After determining the circulating neuroblastoma miRNome, 743 miRNAs were screened in two independent cohorts of 131 and 54 patients. Evaluation of serum miRNA variance in a model testing for tumor stage, MYCN status, age at diagnosis and overall survival, revealed tumor stage as the most significant factor impacting miRNA abundance in neuroblastoma serum. Differential expression analysis between patients with metastatic and localized disease revealed 9 miRNAs strongly associated with metastatic stage 4 …
Comparative genetic study of intratumoral heterogenous MYCN amplified neuroblastoma versus aggressive genetic profile neuroblastic tumors.
2016
Intratumoral heterogeneous MYCN amplification (hetMNA) is an unusual event in neuroblastoma with unascertained biological and clinical implications. Diagnosis is based on the detection of MYCN amplification surrounded by non-amplified tumor cells by fluorescence in situ hybridization (FISH). To better define the genetic features of hetMNA tumors, we studied the Spanish cohort of neuroblastic tumors by FISH and single nucleotide polymorphism arrays. We compared hetMNA tumors with homogeneous MNA (homMNA) and nonMNA tumors with 11q deletion (nonMNA w11q-). Of 1091 primary tumors, 28 were hetMNA by FISH. Intratumoral heterogeneity of 1p, 2p, 11q and 17q was closely associated with hetMNA tumor…
Intra-Tumour Genetic Heterogeneity and Prognosis in High-Risk Neuroblastoma
2021
Simple Summary Neuroblastoma (NB) is the most common extra-cranial solid paediatric cancer and is responsible for 15% of childhood cancer deaths. Patients with NB are characterized by presenting a very heterogeneous clinic (inter-tumoural heterogeneity) and also both spatial and temporal intra-tumour heterogeneity (ITH) reflected in their genetic aberrations, which may be the consequence of the coexistence of different microenvironments within the tumour. Applying pangenomic techniques to detect genomic aberrations in different biopsies (solid and liquid) of high risk NB (HR-NB) we have detected spatial ITH in a surprisingly high percentage (almost 40%) of the studied cohort. Moreover, a po…
Neuroblastoma patient-derived orthotopic xenografts reflect the microenvironmental hallmarks of aggressive patient tumours.
2016
AbstractTreatment of high-risk childhood neuroblastoma is a clinical challenge which has been hampered by a lack of reliable neuroblastoma mouse models for preclinical drug testing. We have previously established invasive and metastasising patient-derived orthotopic xenografts (PDXs) from high-risk neuroblastomas that retained the genotypes and phenotypes of patient tumours. Given the important role of the tumour microenvironment in tumour progression, metastasis, and treatment responses, here we analysed the tumour microenvironment of five neuroblastoma PDXs in detail. The PDXs resembled their parent tumours and retained important stromal hallmarks of aggressive lesions including rich bloo…
Age Dependency of the Prognostic Impact of Tumor Genomics in Localized Resectable MYCN-Nonamplified Neuroblastomas. Report From the SIOPEN Biology Gr…
2020
Purpose: For localized, resectable neuroblastoma without MYCN amplification, surgery only is recommended even if incomplete. However, it is not known whether the genomic background of these tumors may influence outcome. Patients and methods: Diagnostic samples were obtained from 317 tumors, International Neuroblastoma Staging System stages 1/2A/2B, from 3 cohorts: Localized Neuroblastoma European Study Group I/II and Children's Oncology Group. Genomic data were analyzed using multi- and pangenomic techniques and fluorescence in-situ hybridization in 2 age groups (cutoff age, 18 months) and were quality controlled by the International Society of Pediatric Oncology European Neuroblastoma (SIO…
Methyl-CpG-binding domain sequencing reveals a prognostic methylation signature in neuroblastoma
2016
Accurate assessment of neuroblastoma outcome prediction remains challenging. Therefore, this study aims at establishing novel prognostic tumor DNA methylation biomarkers. In total, 396 low- and high-risk primary tumors were analyzed, of which 87 were profiled using methyl-CpG-binding domain (MBD) sequencing for differential methylation analysis between prognostic patient groups. Subsequently, methylation-specific PCR (MSP) assays were developed for 78 top-ranking differentially methylated regions and tested on two independent cohorts of 132 and 177 samples, respectively. Further, a new statistical framework was used to identify a robust set of MSP assays of which the methylation score (i.e.…
NeuPAT: an intranet database supporting translational research in neuroblastic tumors.
2013
Translational research in oncology is directed mainly towards establishing a better risk stratification and searching for appropriate therapeutic targets. This research generates a tremendous amount of complex clinical and biological data needing speedy and effective management. The authors describe the design, implementation and early experiences of a computer-aided system for the integration and management of data for neuroblastoma patients. NeuPAT facilitates clinical and translational research, minimizes the workload in consolidating the information, reduces errors and increases correlation of data through extensive coding. This design can also be applied to other tumor types.
Abstract 495: Amplification of chromosomal regions 12q13-14 and 12q15 defines a distinct subgroup of high-risk neuroblastoma patients and is associat…
2015
Abstract Neuroblastoma is a pediatric cancer of the sympathetic nervous system with wide heterogeneity regarding clinobiological subtypes, ranging from patients with tumors of spontaneous regression to patients with aggressive tumors with fatal outcome despite multimodal treatment. MYCN-amplification and 11q-deletion are important, although incomplete, markers of high-risk neuroblastoma. Thus, characterization of additional genomic alterations that can be used as prognostic and/or predictive markers is of clinical importance in order to provide best possible treatment. From genomic profiles generated through high-density SNP microarrays we identified a group of neuroblastomas (14 primary tu…
Genetic features of neuroblastic tumors associated with opsoclonus-myoclonus syndrome opens up the possibility for detection in peripheral blood
2016
Opsoclonus–myoclonus syndrome (OMS) is a rare paraneoplastic, postinfectious, or parainfectious or idiopathic acute neurological syndrome in children and adults. OMS is characterized by involuntary...
11q Deletion or ALK Activity Curbs DLG2 Expression to Maintain an Undifferentiated State in Neuroblastoma
2020
High-risk 11q deleted neuroblastomas typically display undifferentiated/poorly differentiated morphology. Neuroblastoma is thought to develop from Schwann cell precursors and undifferentiated neural crest (NC) derived cells. It is therefore vital to understand mechanisms involved in the block of differentiation. We identify an important role for oncogenic ALK-ERK1/2-SP1 signaling in maintenance of undifferentiated NC-derived progenitors via repression of DLG2, a tumor suppressor in neuroblastoma. DLG2 is expressed in the ‘bridge signature’ that represents the transcriptional transition state when neural crest cells or Schwann Cell Precursors become chromaffin cells of the adrenal gland. We …
Abstract B23: Neuroblastoma patient-derived orthotopic xenografts: Clinically relevant models for drug testing
2016
Abstract Background: We previously established neuroblastoma patient-derived orthotopic xenografts (PDXs) by implanting patient neuroblastoma fragments into immunodeficient NSG mice. SNP array analysis confirmed that PDXs maintain patient-specific chromosomal aberrations 1p del, MYCN amp and 17q gain. Immunohistochemistry showed that PDXs retain neuroblastoma markers and a highly infiltrative growth pattern. Importantly, we found spontaneous distant metastasis to lungs, liver and bone marrow. In vitro cultures established from the PDXs express neuroblastoma markers and retain their tumorigenic and metastatic ability in vivo after orthotopic injection. Methods and Results: Given the importan…
A stiff extracellular matrix is associated with malignancy in peripheral neuroblastic tumors
2017
Purpose and objective Improved prognosis for patients with peripheral neuroblastic tumors (PNB) depends on enhanced pretreatment risk stratification combined with research into new therapeutic targets. This study investigated the potential contribution of extracellular matrix (ECM) elements toward this endeavor. Methods We characterized certain elements such as reticulin fibers, collagen type I fibers, and elastic fibers by digital pathology in almost 400 untreated PNB. Results A reticular and poorly porous ECM was identified in neuroblastomas (NBs) from patients with clinical and biological features associated with poor prognosis compared with a loose and permeable matrix found in NBs of t…
Neuroblastoma after Childhood: Prognostic Relevance of Segmental Chromosome Aberrations, ATRX Protein Status, and Immune Cell Infiltration
2014
AbstractNeuroblastoma (NB) is a common malignancy in children but rarely occurs during adolescence or adulthood. This subgroup is characterized by an indolent disease course, almost uniformly fatal, yet little is known about the biologic characteristics. The aim of this study was to identify differential features regarding DNA copy number alterations, α-thalassemia/mental retardation syndrome X-linked (ATRX) protein expression, and the presence of tumor-associated inflammatory cells. Thirty-one NB patients older than 10 years who were included in the Spanish NB Registry were considered for the current study; seven young and middle-aged adult patients (range 18-60 years) formed part of the c…
Vascular patterns provide therapeutic targets in aggressive neuroblastic tumors
2016
// Irene Tadeo 1 , Gloria Bueno 2 , Ana P. Berbegall 1 , M. Milagro Fernandez-Carrobles 2 , Victoria Castel 3 , Marcial Garcia-Rojo 4 , Samuel Navarro 1 , Rosa Noguera 1 1 Pathology Department, Medical School, University of Valencia, INCLIVA, 46010 Valencia, Spain 2 VISILAB, E.T.S. Ingenieros Industriales, University of Castilla-La Mancha, 13071 Ciudad Real, Spain 3 Pediatric Oncology Unit, University and Polytechnic Hospital La Fe, 46026 Valencia, Spain 4 Department of Pathology, Hospital de Jerez de la Frontera, 11407 Jerez de la Frontera, Cadiz, Spain Correspondence to: Rosa Noguera Salva, e-mail: rnoguera@uv.es Keywords: extracellular matrix, blood vessels, capillaries, sinusoids, neuro…
Genetic Instability and Intratumoral Heterogeneity in Neuroblastoma with MYCN Amplification Plus 11q Deletion
2013
Background/Aim Genetic analysis in neuroblastoma has identified the profound influence of MYCN amplification and 11q deletion in patients’ prognosis. These two features of high-risk neuroblastoma usually occur as mutually exclusive genetic markers, although in rare cases both are present in the same tumor. The purpose of this study was to characterize the genetic profile of these uncommon neuroblastomas harboring both these high-risk features. Methods We selected 18 neuroblastomas with MNA plus 11q loss detected by FISH. Chromosomal aberrations were analyzed using Multiplex Ligation-dependent Probe Amplification and Single Nucleotide Polymorphism array techniques. Results and Conclusion Thi…
Diagnostic implications of intrapatient genetic tumor heterogeneity
2015
The complex genetic composition of neuroblastoma emphasizes the importance of conscientious and meticulous diagnosis. Clones with amplification or segmental chromosomal aberrations sometimes remain hidden. Several determinations should be performed when sufficient tumor material is available to establish the final diagnosis by combining the results of different techniques on tumor fragments or liquid biopsies.
Anaplastic lymphoma kinase expression in neuroblastomas and its relationship with genetic, prognostic, and predictive factors
2011
Tumor de Wilms: estudio morfológico, inmunohistoquímico y genético de un caso de nefroblastoma con diferenciación rabdomioblástica
2016
Resumen El tumor de Wilms es el tumor renal primario mas frecuente en la infancia, y afecta a uno de cada 10.000 ninos en Estados Unidos. Tipicamente se muestra como un tumor trifasico con componente epitelial, blastemal y estromal, pudiendo presentar areas de anaplasia y diferenciaciones hacia otros tejidos. En cuanto a su genetica, se han descrito varios genes relacionados en su desarrollo. En el presente trabajo se realizo un estudio anatomopatologico, ademas de uno pangenomico mediante el chip de single nucleotide polymorphism (SNP) HumanCytoSNP-12. En el caso que se presenta se observo un tumor trifasico con diferenciacion rabdomioblastica solo visible mediante tinciones inmunohistoqui…
Abstract 2435: Amplification of CDK4 and MDM2 is associated with atypical clinical features in high risk neuroblastoma patients
2016
Abstract MYCN-amplification and 11q-deletion are important, although incomplete, markers of high-risk neuroblastoma. Thus, characterization of additional genomic alterations that can be used as prognostic and/or predictive markers is of clinical importance in order to provide best treatment possible. By using SNP-microarrays we identified a small group of neuroblastomas with high grade amplification of one or multiple loci on 12q, commonly involving the potential oncogenic target genes CKD4 (12q13-14) and/or MDM2 (12q15). The CDK4 and MDM2 regions were co-amplified in 13/16 samples, two tumors had CDK4-amplification in absence of MDM2-amplification while one tumor had MDM2-amplification wit…
Extra-Adrenal Adult Neuroblastoma With Aberrant Germ Cell Marker Expression: Maturation After Chemotherapy as an Important Clue to a Challenging Diag…
2019
Adult neuroblastoma is an extremely infrequent neoplasm, usually occurring in the adrenal medulla or in the paraspinal sympathetic ganglia, as its childhood counterpart. We report a very unusual case of a Schwannian stroma-poor adult neuroblastoma of inguinal location, showing aberrant expression of germ cell markers: SALL4 and OCT4. This aberrant marker expression, the unusual positivity for NKX2.2 and the very scattered (instead of diffuse strong) PHOX2B expression, complicated the initial diagnosis. In this case, the posttreatment histological evaluation revealed the neuroblastic nature of the lesion. Neuroblastoma maturation after treatment is an unusual finding in adults, and in this …
Multiplex Ligation-dependent Probe Amplification (MLPA)
2011
The Multiplex Ligation-dependent Probe Amplification (MLPA) is a PCR-based method. The procedure relies on sequence-specific probe hybridization of genomic DNA, followed by multiplex-PCR amplification of the hybridized probe and a semiquantitative analysis of the resulting PCR products. MLPA allows the analysis of around 40 loci in the same reaction, and is a sensitive and relatively fast technique. Only a small amount of DNA is required and results are available within 2 days.The critical factors when performing MLPA analyses from formalin-fixed paraffin-embedded (FFPE) tissues are DNA integrity and purity; for this reason, a suitable DNA extraction method must be chosen.The MLPA protocol …
Imbalance between genomic gain and loss identifies high-risk neuroblastoma patients with worse outcomes
2021
Survival in high-risk neuroblastoma (HR-NB) patients remains poor despite multimodal treatment. We aimed to identify HR-NB patients with worse outcomes by analyzing the genomic instability derived from segmental chromosomal aberrations. We calculated 3 genomic instability indexes for primary tumor SNP array profiles from 127 HR-NB patients: (1) Copy number aberration burden (%gainslength+%losseslength), (2) copy number load (CNL) (%gainslength-%losseslength) and (3) net genomic load (NGL) (%gainsamount-%lossesamount). Tumors were classified according to positive or negative CNL and NGL genomic subtypes. The impact of the genomic instability indexes on overall survival (OS) was assessed with…
Abstract 4107: Targeted re-sequencing of neuroblastoma tumors reveals chromosomal rearrangements that involve the Anaplastic Lymphoma Kinase (ALK) ge…
2013
Abstract Neuroblastoma (NBL) is a cancer of early childhood arising from the developing sympathetic nervous system. NBL tumors display a broad clinical and biological heterogeneity, ranging from highly aggressive tumors with fatal outcome to tumors with spontaneous regression. Recurrent mutations are mainly only observed in Anaplastic Lymphoma Kinase (ALK), which is involved in the pathogenesis of both familiar and sporadic NBL. ALK encodes a tyrosine kinase receptor with importance in neuronal development and was initially characterized in anaplastic large cell lymphoma from a translocation leading to the NPM-ALK fusion protein. Subsequent studies show that additional ALK chimeras have bee…
Intragenic anaplastic lymphoma kinase (ALK) rearrangements: Translocations as a novel mechanism ofALKactivation in neuroblastoma tumors
2014
Anaplastic lymphoma kinase (ALK) has been demonstrated to be deregulated in sporadic as well as in familiar cases of neuroblastoma (NB). Whereas ALK-fusion proteins are common in lymphoma and lung cancer, there are few reports of ALK rearrangements in NB indicating that ALK mainly exerts its oncogenic capacity via activating mutations and/or overexpression in this tumor type. In this study, 332 NB tumors and 13 cell lines were screened by high resolution single nucleotide polymorphism microarray. Gain of 2p was detected in 23% (60/332) of primary tumors and 46% (6/13) of cell lines, while breakpoints at the ALK locus were detected in four primary tumors and two cell lines. These were furthe…
Influence of segmental chromosome abnormalities on survival in children over the age of 12 months with unresectable localised peripheral neuroblastic…
2014
Background: The prognostic impact of segmental chromosome alterations (SCAs) in children older than 1 year, diagnosed with localised unresectable neuroblastoma (NB) without MYCN amplification enrolled in the European Unresectable Neuroblastoma (EUNB) protocol is still to be clarified, while, for other group of patients, the presence of SCAs is associated with poor prognosis. Methods: To understand the role of SCAs we performed multilocus/pangenomic analysis of 98 tumour samples from patients enrolled in the EUNB protocol. Results: Age at diagnosis was categorised into two groups using 18 months as the age cutoff. Significant difference in the presence of SCAs was seen in tumours of patients…
Quantitative modeling of clinical, cellular, and extracellular matrix variables suggest prognostic indicators in cancer: a model in neuroblastoma
2014
BACKGROUND: Risk classification and treatment stratification for cancer patients is restricted by our incomplete picture of the complex and unknown interactions between the patient's organism and tumor tissues (transformed cells supported by tumor stroma). Moreover, all clinical factors and laboratory studies used to indicate treatment effectiveness and outcomes are by their nature a simplification of the biological system of cancer, and cannot yet incorporate all possible prognostic indicators. METHODS: A multiparametric analysis on 184 tumor cylinders was performed. To highlight the benefit of integrating digitized medical imaging into this field, we present the results of computational s…