Unsupervised machine learning models reveal predictive clinical markers of glioblastoma patient survival using white blood cell counts prior to initiating chemoradiation.

Background: Glioblastoma is a malignant brain tumor requiring careful clinical monitoring even after primary management. Personalized medicine has suggested the use of various molecular biomarkers as predictors of patient prognosis or factors utilized for clinical decision-making. However, the accessibility of such molecular testing poses a constraint for various institutes requiring identification of low-cost predictive biomarkers to ensure equitable care. Methods: We collected retrospective data from patients seen at Ohio State University, University of Mississippi, Barretos Cancer Hospital (Brazil), and FLENI (Argentina) who were managed for glioblastoma-amounting to 581 patient records documented using REDCap. Patients were evaluated using an unsupervised machine learning approach comprised of dimensionality reduction and eigenvector analysis to visualize the inter-relationship of collected clinical features. Results: We discovered that the serum white blood cell (WBC) count of a patient during baseline planning for treatment was predictive of overall survival with an over 6-month median survival difference between the upper and lower quartiles of WBC count. By utilizing an objective PD-L1 immunohistochemistry quantification algorithm, we were further able to identify an increase in PD-L1 expression in glioblastoma patients with high serum WBC counts. Conclusions: These findings suggest that in a subset of glioblastoma patients the incorporation of WBC count and PD-L1 expression in the brain tumor biopsy as simple biomarkers predicting glioblastoma patient survival. Moreover, machine learning models allow the distillation of complex clinical data sets to uncover novel and meaningful clinical relationships.

Unsupervised machine learning models reveal predictive markers of glioblastoma patient survival using white blood cell counts prior to initiating chemoradiation.

Purpose: Glioblastoma is a malignant brain tumor requiring careful clinical monitoring even after primary management. Personalized medicine has suggested use of various molecular biomarkers as predictors of patient prognosis or factors utilized for clinical decision making. However, the accessibility of such molecular testing poses a constraint for various institutes requiring identification of low-cost predictive biomarkers to ensure equitable care. Methods: We collected retrospective data from patients seen at Ohio State University, University of Mississippi, Barretos Cancer Hospital (Brazil), and FLENI (Argentina) who were managed for glioblastoma-amounting to nearly 600 patient records documented using REDCap. Patients were evaluated using an unsupervised machine learning approach comprised of dimensionality reduction and eigenvector analysis to visualize the inter-relationship of collected clinical features. Results: We discovered that white blood cell count of a patient during baseline planning for treatment was predictive of overall survival with an over 6-month median survival difference between the upper and lower quartiles of white blood cell count. By utilizing an objective PDL-1 immunohistochemistry quantification algorithm, we were further able to identify an increase in PDL-1 expression in glioblastoma patients with high white blood cell counts. Conclusion: These findings suggest that in a subset of glioblastoma patients the incorporation of white blood cell count and PDL-1 expression in the brain tumor biopsy as simple biomarkers predicting glioblastoma patient survival. Moreover, use of machine learning models allows us to visualize complex clinical datasets to uncover novel clinical relationships.

Information theory approaches to improve glioma diagnostic workflows in surgical neuropathology.

AIMS: Resource-strained healthcare ecosystems often struggle with the adoption of the World Health Organization (WHO) recommendations for the classification of central nervous system (CNS) tumors. The generation of robust clinical diagnostic aids and the advancement of simple solutions to inform investment strategies in surgical neuropathology would improve patient care in these settings. METHODS: We used simple information theory calculations on a brain cancer simulation model and real-world data sets to compare contributions of clinical, histologic, immunohistochemical, and molecular information. An image noise assay was generated to compare the efficiencies of different image segmentation methods in H&E and Olig2 stained images obtained from digital slides. An auto-adjustable image analysis workflow was generated and compared with neuropathologists for p53 positivity quantification. Finally, the density of extracted features of the nuclei, p53 positivity quantification, and combined ATRX/age feature was used to generate a predictive model for 1p/19q codeletion in IDH-mutant tumors. RESULTS: Information theory calculations can be performed on open access platforms and provide significant insight into linear and nonlinear associations between diagnostic biomarkers. Age, p53, and ATRX status have significant information for the diagnosis of IDH-mutant tumors. The predictive models may facilitate the reduction of false-positive 1p/19q codeletion by fluorescence in situ hybridization (FISH) testing. CONCLUSIONS: We posit that this approach provides an improvement on the cIMPACT-NOW workflow recommendations for IDH-mutant tumors and a framework for future resource and testing allocation.

Generation of a human induced pluripotent stem cell line from a familial Alzheimer's disease PSEN1 T119I patient.

Human induced pluripotent stem cells (hiPSC) line FLENIi001-A was reprogrammed from dermal fibroblasts using the lentiviral-hSTEMCCA-loxP vector. Fibroblasts were obtained from a skin biopsy of a 72-year-old Caucasian male familial Alzheimer's disease patient carrying the T119I mutation in the PSEN1 gene. PSEN1 genotype was maintained and stemness and pluripotency confirmed in the FLENIi001-A hiPSC line.

Biomarcadores radiológicos en RM para una aproximación al diagnóstico molecular en gliomas IDH-mutados (grado II y III) / MR Imaging Biomarkers for a Diagnostic Approach of IDH-mutated Gliomas (Grades II/III)

Resumen Objetivo: Analizar características por resonancia magnética (RM) de gliomas IDH-mutados (grado II y III) en base a parámetros cualitativos, a fin de valorar el rendimiento del signo del mismatch T2-FLAIR y otras características morfológicas de los tumores, en predecir el estado del 1p/19q y su reproducibilidad interobservador. Métodos Estudio retrospectivo, descriptivo y analítico sobre una cohorte de 53 gliomas IDH-mutados (grado II y III) y molecularmente definidos respecto al 1p/19q, seleccionados a partir de la base de datos de la institución, durante el periodo 2014- 2019. Dos neuroradiólogos evaluaron características imagenológicas de forma independiente y enmascarada al diagnóstico: mismatch T2-FLAIR, localización tumoral, bordes, señal, infiltración cortical e inhomogeneidad en T2. Los casos discordantes fueron evaluados por un tercer neuroradiólogo de mayor experiencia. Resultados: Treinta de 53 (56,6%) gliomas fueron no codelecionados, y 23/53 (43,4%) codelecionados. El signo del mismatch T2-FLAIR fue positivo en 16/53 (30,18%) pacientes, 15/16 (93,75%) no codelecionados y 1/16 (6,25%) codelecionado (Exacto de Fisher p = <,0001). Los dos evaluadores demostraron una concordancia interobservador casi perfecta para ese signo, κ =,907 (95% CI, 0,781 a 1,0). La especificidad y el valor predictivo positivo del signo para predecir la ausencia de la codeleción fue de un 95,7% y un 93,8% respectivamente. Discusión: La reciente actualización en la clasificación de los gliomas los clasifica acorde a su perfil molecular. En los últimos años, varios investigadores han estudiado características morfológicas por RM de los tumores con la intención de predecir las características moleculares de los mismos. Conclusión: En nuestra población, el signo del mismatch T2-FLAIR es el único biomarcador radiológico que muestra asociación estadísticamente significativa en predecir la ausencia de codeleción en los gliomas IDH-mutados (grado II y III), con una alta especificidad y un alto valor predictivo positivo.

Abstract Objective: To analyze magnetic resonance (MR) characteristics of IDH-mutated gliomas (grades II/III) utilizing qualitative parameters with the goal of assessing the performance of the T2-FLAIR mismatch sign and other morphological characteristics of tumors in predicting the 1p/19q co-deletion status as well as inter-observer reproducibility. Methods: Retrospective and descriptive study analyzing a cohort of 53 IDH-mutated lower-grade (grades II/III) gliomas with known 1p/19q co-deletion status. Patients meeting selection criteria for this study were taken from our institutional data from 2014-2019. Two neuroradiologists assessed the following imaging characteristics independently, and blinded from the diagnosis: T2-FLAIR mismatch, tumor location, borders, signal characteristics, cortical infiltration and T2* inhomogeneity. In the event of discordant interpretations, a third senior neuroradiologist also evaluated the case. Results: 23 of the 53 (43.4%) gliomas demonstrated 1p/19q co-deletion and 30 of 53 (56.6%) did not. T2-FLAIR mismatch was positive in 16 of 53 cases (30.2%) with 15 of 16 (93.8%) demonstrating no co-deletion and 1/16 (6.25%) with co-deletion (Fisher's exact p = < .0001). The two readers showed an almost perfect interreader agreement for this sign κ = 0.907 (95% CI, 0.781 to 1.0). Specificity and positive predictive value of the sign to predict the absence of co-deletion was 95.7% and 93.8% respectively. Discussion: The recent update in classification of lower-grade gliomas segregates gliomas according to molecular profile. In the recent past, many researchers have studied MR morphologic characteristics of these tumors with the intention of predicting molecular features of said tumors Conclusion: In our patient population, T2-FLAIR mismatch sign is the only radiologic biomarker that shows statistically significant association with the absence of 1p/19q co-deletion in lower-grade gliomas, with high specificity and positive predictive value.

A novel mutation in PSEN1 (p.T119I) in an Argentine family with early- and late-onset Alzheimer's disease.

Mutations in PSEN1 are the most common cause of early-onset Alzheimer's disease (AD). In this article, we present an Argentine family with autosomal dominant early- and late-onset AD. The proband and 6 family members were available for genetic testing and clinical and neuropsychological assessments. Cerebrospinal fluid biomarkers were analyzed in the proband and a cousin (mutation carrier), who also underwent positron emission tomography using F-18-2-fluoro-2-deoxy-D-glucose and Pittsburgh compound B. Exon sequencing of PSEN1, PSEN2, and APP revealed a novel heterozygous variant in PSEN1 (c.356C>T; p.T119I). Median age of onset in the family was 56 years. However, the proband's uncle showed initial symptoms at age 71. Although no DNA was available, he was an obligate carrier because his daughter (proband's cousin) carried the mutation. Both the proband and his cousin exhibited biomarker evidence (cerebrospinal fluid or imaging) of underlying Alzheimer's pathology. Overall, our results support that the PSEN1 p.T119I variant is likely pathogenic.

Evaluation of Cerebrospinal Fluid Neurofilament Light Chain as a Routine Biomarker in a Memory Clinic.

Systematic evaluation of biomarkers in representative populations is needed to validate their clinical utility. In this work, we assessed the diagnostic performance of cerebrospinal fluid (CSF) neurofilament light chain (NfL) in a neurocognitive clinical setting. A total of 51 patients with different cognitive clinical syndromes and 11 cognitively normal individuals were evaluated in a memory clinic in Argentina. Clinical conditions included mild cognitive impairment (MCI, n = 12), dementia of Alzheimer's type (DAT, n = 14), behavioral variant frontotemporal dementia (bvFTD, n = 13), and primary progressive aphasia (logopenic [n = 6], semantic [n = 2], and nonfluent [n = 4]). We quantified CSF NfL and core Alzheimer's disease biomarkers using commercially available ELISA kits. Cortical thickness was analyzed on brain magnetic resonance imaging scans from 10 controls and 10 patients. CSF NfL was significantly increased in MCI, FTD, and DAT patients compared with controls (Kruskal-Wallis, p < .0001). Interestingly, receiver operating characteristic curve analysis showed the highest area under the curve (AUC) value when analyzing control versus bvFTD patients (AUC = 0.9441). Also, we observed a marginally significant correlation between NfL levels and left orbitofrontal cortex thickness in a small group of patients with FTD. Overall, our results further support CSF NfL as a promising biomarker in the diagnostic workup of bvFTD.

Argentina-Alzheimer's disease neuroimaging initiative (Arg-ADNI): neuropsychological evolution profile after one-year follow up.

The Argentina-Alzheimer's disease neuroimaging initiative (Arg-ADNI) study is a longitudinal prospective cohort of 50 participants at a single institution in Buenos Aires, Argentina. Longitudinal assessments on a neuropsychological test battery were performed on 15 controls, 24 mild cognitive impairment (MCI) patients and 12 Alzheimer's disease (AD) dementia patients. In our study population, there was a high prevalence of positive AD biomarkers in the AD group, 92.3% (12/13); and a low prevalence in the normal controls, 20%; almost half (48%) of the patients diagnosed with MCI had positive amyloid detection. After a one year, the significant differences found at baseline on neuropsychological testing were similar at the follow-up assessment even though the AD group had significantly altered its functional performance (FAQ and CDR). The exception was semantic fluency, which showed greater impairment between the AD group and MCI and normal controls respectively. For these tests, the addition of AD biomarkers as a variable did not significantly alter the variations previously found for the established clinical group's model. Finally, the one-year conversion rate to dementia was 20% in the MCI cohort.

Argentina-Alzheimer's disease neuroimaging initiative (Arg-ADNI): neuropsychological evolution profile after one-year follow up / Argentina-Alzheimer's disease neuroimaging initiative (Arg-ADNI): evolução do perfil neuropsicológico depois de um ano de seguimento

ABSTRACT The Argentina-Alzheimer's disease neuroimaging initiative (Arg-ADNI) study is a longitudinal prospective cohort of 50 participants at a single institution in Buenos Aires, Argentina. Longitudinal assessments on a neuropsychological test battery were performed on 15 controls, 24 mild cognitive impairment (MCI) patients and 12 Alzheimer's disease (AD) dementia patients. In our study population, there was a high prevalence of positive AD biomarkers in the AD group, 92.3% (12/13); and a low prevalence in the normal controls, 20%; almost half (48%) of the patients diagnosed with MCI had positive amyloid detection. After a one year, the significant differences found at baseline on neuropsychological testing were similar at the follow-up assessment even though the AD group had significantly altered its functional performance (FAQ and CDR). The exception was semantic fluency, which showed greater impairment between the AD group and MCI and normal controls respectively. For these tests, the addition of AD biomarkers as a variable did not significantly alter the variations previously found for the established clinical group's model. Finally, the one-year conversion rate to dementia was 20% in the MCI cohort.

RESUMO El estudio de Argentina-Alzheimer's Disease Neuroimaging Initiative (Arg-ADNI) es una cohorte prospectiva de 50 pacientes seguidos en una misma institución. Fueron evaluados cognitivamente 15 controles normales (CN), 24 sujetos con deterioro cognitivo leve (DCL) y 12 con demencia tipo Alzheimer (DTA) leve. En los DTA, 92,3% tuvieron biomarcadores positivos para Alzheimer y 20% en los CN. Casi la mitad de los DCL presentaron biomarcadores positivos. Después de un año de seguimiento, la diferencias significativas halladas en la visita de inicio en las pruebas cognitivas fueron similares al año aunque los DTA tuvieron empeoramiento funcional medido en el FAQ y CDR. La excepción fue la fluencia semántica, la cual mostró mayor declinación entre DTA y los demás grupos. La incorporación de los biomarcadores como variable no alteró significativamente los hallazgos de grupo. La tasa de conversión a demencia anual fue del 20%.

The NSL Chromatin-Modifying Complex Subunit KANSL2 Regulates Cancer Stem-like Properties in Glioblastoma That Contribute to Tumorigenesis.

KANSL2 is an integral subunit of the nonspecific lethal (NSL) chromatin-modifying complex that contributes to epigenetic programs in embryonic stem cells. In this study, we report a role for KANSL2 in regulation of stemness in glioblastoma (GBM), which is characterized by heterogeneous tumor stem-like cells associated with therapy resistance and disease relapse. KANSL2 expression is upregulated in cancer cells, mainly at perivascular regions of tumors. RNAi-mediated silencing of KANSL2 in GBM cells impairs their tumorigenic capacity in mouse xenograft models. In clinical specimens, we found that expression levels of KANSL2 correlate with stemness markers in GBM stem-like cell populations. Mechanistic investigations showed that KANSL2 regulates cell self-renewal, which correlates with effects on expression of the stemness transcription factor POU5F1. RNAi-mediated silencing of POU5F1 reduced KANSL2 levels, linking these two genes to stemness control in GBM cells. Together, our findings indicate that KANSL2 acts to regulate the stem cell population in GBM, defining it as a candidate GBM biomarker for clinical use. Cancer Res; 76(18); 5383-94. ©2016 AACR.

Analysis of C9orf72 in patients with frontotemporal dementia and amyotrophic lateral sclerosis from Argentina.

Pathologic expansion of the G4C2 repeat in C9orf72 is the main genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). To evaluate the frequency of the G4C2 expansion in a Latin American cohort of FTD and ALS patients, we used a 2-step genotyping strategy. For FTD, we observed an overall expansion frequency of 18.2% (6 of 33 unrelated cases). Moreover, the C9orf72 expansion accounted for 37.5% of all familial FTD cases (6 of 16 families). The expansion frequency in sporadic ALS cases was 2% (1 of 47 unrelated patients), whereas we observed the expansion in 1 of 3 families with a positive history for ALS. Overall, the expansion frequency in our FTD group was similar to that reported for patients in Europe and North America, whereas the frequency in our sporadic ALS group was significantly lower. To our knowledge, this is the first report on the frequency of the C9orf72 expansion in a Latin American population.

Specific Preferences in Lineage Choice and Phenotypic Plasticity of Glioma Stem Cells Under BMP4 and Noggin Influence.

Although BMP4-induced differentiation of glioma stem cells (GSCs) is well recognized, details of the cellular responses triggered by this morphogen are still poorly defined. In this study, we established several GSC-enriched cell lines (GSC-ECLs) from high-grade gliomas. The expansion of these cells as adherent monolayers, and not as floating neurospheres, enabled a thorough study of the phenotypic changes that occurred during their differentiation. Herein, we evaluated GSC-ECLs' behavior toward differentiating conditions by depriving them of growth factors and/or by adding BMP4 at different concentrations. After analyzing cellular morphology, proliferation and lineage marker expression, we determined that GSC-ECLs have distinct preferences in lineage choice, where some of them showed an astrocyte fate commitment and others a neuronal one. We found that this election seems to be dictated by the expression pattern of BMP signaling components present in each GSC-ECL. Additionally, treatment of GSC-ECLs with the BMP antagonist, Noggin, also led to evident phenotypic changes. Interestingly, under certain conditions, some GSC-ECLs adopted an unexpected smooth muscle-like phenotype. As a whole, our findings illustrate the wide differentiation potential of GSCs, highlighting their molecular complexity and paving a way to facilitate personalized differentiating therapies.

Correlation between EGFR amplification and the expression of microRNA-200c in primary glioblastoma multiforme.

Extensive infiltration of the surrounding healthy brain tissue is a critical feature in glioblastoma. Several miRNAs have been related to gliomagenesis, some of them related with the EGFR pathway. We have evaluated whole-genome miRNA expression profiling associated with different EGFR amplification patterns, studied by fluorescence in situ hybridization in tissue microarrays, of 30 cases of primary glioblastoma multiforme, whose clinicopathological and immunohistochemical features have also been analyzed. MicroRNA-200c showed a very significant difference between tumors having or not EGFR amplification. This microRNA plays an important role in epithelial-mesenchymal transition, but its implication in the behavior of glioblastoma is largely unknown. With respect to EGFR status our cases were categorized into three groups: high level EGFR amplification, low level EGFR amplification, and no EGFR amplification. Our results showed that microRNA-200c and E-cadherin expression are down-regulated, while ZEB1 is up-regulated, when tumors showed a high level of EGFR amplification. Conversely, ZEB1 mRNA expression levels were significantly lower in the group of tumors without EGFR amplification. Tumors with a low level of EGFR amplification showed ZEB1 expression levels comparable to those detected in the group with a high level of amplification. In this study we provide what is to our knowledge the first report of association between microRNA-200c and EGFR amplification in glioblastomas.

Gerstmann-Sträussler-Scheinker syndrome with variable phenotype in a new kindred with PRNP-P102L mutation.

Gerstmann-Sträussler-Scheinker syndrome (GSS) is a dominantly inherited disorder belonging to the group of transmissible human spongiform encephalopathies or prion diseases. Several families affected by GSS with patients carrying mutations in the prion protein gene have been described worldwide. We report clinical, genealogical, neuropathology and molecular study results from two members of the first Argentine kindred affected by GSS. Both family members presented a frontotemporal-like syndrome, one with and the other without ataxia, with different lesions on neuropathology. A Pro to Leu point mutation at codon 102 (P102L) of the prion protein gene was detected in one of the subjects studied. The pathogenic basis of phenotypic variability observed in this family remains unclear, but resembles that observed in other P102L GSS patients from the same family.

Creutzfeldt-Jakob disease surveillance in Argentina, 1997-2008.

BACKGROUND: Epidemiological data on Creutzfeldt-Jakob disease (CJD) from Latin America are limited. We present a comprehensive epidemiological survey on CJD patients in Argentina based on systematic surveillance between 1997 and 2008. METHODS: A CJD Surveillance Referral Center (SRC) was established in Argentina in 1997; previously a Neuropathology Referral Center was used from 1983 to 1996. All suspected cases referred to the SRC were classified using established criteria on the basis of information derived from the following: clinical data form, EEG, MRI (both for central review), cerebrospinal fluid (CSF) for protein 14-3-3 Western blot (WB), autopsy or biopsy material for neuropathology, prion protein (PrP) immunohistochemistry and PrP WB, as well as blood for DNA studies (when brain tissue was not available). RESULTS: Of the 517 patients referred to the SRC between 1997 and 2008, 211 (40.8%) had CJD or other transmissible spongiform encephalopathies (TSEs) (definite or probable). Possible cases totaled 14.5%, while cases with no WHO criteria accounted for 16.4%. Non-CJD cases excluded by biopsy/autopsy or during follow-up corresponded to 28.2% of the 517 referrals. Main differential diagnoses included neurodegenerative diseases such as Alzheimer's disease, frontotemporal dementia, vascular, metabolic or viral encephalopathy, and Hashimoto's disease. Five percent of referred patients ultimately recovered. Eighty-three percent of TSE cases were sporadic CJD; 17% were genetic, mainly E200K (15.6%); the remaining 1.4% included an octarepeat insertion and two Gerstmann-Sträussler-Scheinker cases (P102L). Seventy-four of 100 definite cases had frozen tissue available for molecular subtyping (PrP(Sc)/codon 129). CSF protein 14-3-3 WB sensitivity was 72.3% and specificity was 92.1%. Clinical diagnostic criteria for probable CJD when compared to definite diagnosis by neuropathology showed 71.3% sensitivity, 86.2% specificity, 94.4% positive predictive value and 48% negative predictive value. Country incidence increased over time and reached 0.85 cases per million in 2008, with the highest rate detected in the city of Buenos Aires (1.8). Districts with 6% of the total population have never reported suspected cases. CONCLUSION: In spite of an increase in incidence observed over time, the difference between Buenos Aires city, where the incidence is comparable to that of smaller European countries with higher population density, and the incidence observed in the rest of the country suggests underreporting in nonmetropolitan areas, probably due to a lack of access to specialized medical facilities. CSF WB sensitivity results for protein 14-3-3 were probably linked to the fact that testing was not routinely repeated during the course of the disease, when earlier test results had been negative. The spectrum of molecular CJD subtypes observed did not differ from other countries in Europe. No iatrogenic or variant CJD cases were identified. The sensitivity and negative predictive value of clinical diagnostic criteria for probable CJD (which includes EEG and/or CSF protein 14-3-3 levels) may have been resulted from confirmed cases not meeting probable criteria before autopsy, due to a lack of ancillary tests such as EEG and/or CSF 14-3-3 WB, or because negative tests were not repeated during follow-up.

Tumores oligodendrogliales: correlación entre el genotipo tumoral e imágenes de perfusión por RM / Oligodendroglial tumors: correlation between tumor genotype and perfusion magnetic resonance imaging

Objetivo: realizar una evaluación retrospectiva respecto de la correlación entre la técnica de perfusión (PWI) por resonancia magnética (RM), el volumen sanguíneo cerebral relativo (VSCr) y el genotipo tumoral, en pacientes con neoplasias oligodendrogliales grado II. Materiales y métodos: once pacientes (7 hombres y 4 mujeres), con un rango de edad entre los 28 y 64 años, con tumores oligodendrogliales (OD) grado II, fueron estudiados con RM convencional y PWI, con la finalidad de obtener un valor de VSCr. Se realizó el análisis genético en todos los pacientes para evaluar el estado de los cromosomas 1p/19q. Resultados: cinco pacientes con tumores ODs grado II (45%) presentaron un VSCr < 1,75 y ausencia de alteraciones en 1p/19q. Tres pacientes tenían oligoastrocitomas (OA), 2 de ellos con alteraciones en 1p/19q y el restante con 1p/19q intacto. Dos de los pacientes con gliomas mixtos, uno con alteración en 1p/19q y el otro con 1p/19q intacto, presentaron un VSCr> 1,75, mientras que en el paciente restante con glioma mixto y deleción en 1p/19q, el VSCr fue de < 1,75. Dos pacientes con ODs grado II presentaron un VSCr> 1,75, uno con 1p/19q intacto y el restante con deleción en 1p/19q. El último paciente presentó un OD grado II con un VSCr< 1,75 y pérdida de 1p/19q. Conclusiones: aproximadamente el 45% de los pacientes con los cromosomas 1p/19q intactos mostró un VSCr< 1,75, lo que sugiere una neoangiogénesis tumoral limitada. Estos hallazgos podrían ser de utilidad para monitorear respuesta a agentes antiangiogénicos. Los estudios realizados en series mayores podrían proporcionar información valiosa antes de la cirugía y contribuir a un mejor manejo de estos pacientes.

Objective: To perform a retrospective assessment of the correlation between perfusion MR imaging, relative cerebral blood volume (rCBV) and genotype in patients with grade II oligodendroglial neoplasms. Materials and methods: Eleven patients (7 men and 4 women), age range: 28-64 years, with grade II oligodendroglial tumors (OD) were studied using conventional MR and perfusion MR imaging (rCBV). Genetic analysis was carried out in all patients to assess -1p/-19q genotype status. Results: Five patients with grade II oligodendroglial tumors (45%) presented rCBV < 1.75 and intact 1p/19q. Three patients had mixed gliomas, two of them had deletion in 1p/19q, and the other presented intact 1p/19 q. rCBV was > 1.75 in two patients and < 1.75 in the other patient. Two patients with grade II oligodendroglioma had an rCBV > 1.75, one with intact 1p/19q, and the other with deletion. The last patient presented a grade II oligodendroglial tumor with rCBV < 1.75 and 1p/19q loss. Conclusions: Approximately 45% of patients with intact 1p/19q showed rCBV < 1.75, suggesting limited tumor neoangiogenesis. These findings could be important for the antiangiogenic therapy follow-up. Studies in larger series could provide valuable information prior to surgery and contribute to a better management of these patients.

Whole-genomic survey of oligodendroglial tumors: correlation between allelic imbalances and gene expression profiles.

Malignant gliomas are the most common subtype of primary central nervous system (CNS) tumors. Their pathological classification, however, remains subjective, stimulating researchers to actively seek objective molecular markers to discover alternative and more reproducible tools for improved subtypification. Herein, we present a global survey of genomic alterations in oligodendroglial tumors (OT). Genetic and epigenetic alterations identified in this study are correlated with OT molecular groups we have recently reported: a neurogenic group composed of tumors with loss of heterozygosity (LOH) at 1p-19q, IDH1 mutations, and MGMT promoter methylation, showing good prognosis; an intermediate group, presenting TP53 mutations or LOH at 17p, IDH1 mutations, and GSTP1 promoter methylation; and a proliferative group, presenting major genetic alterations (LOH at 10q, EGFR amplification, and CDKN2A/ARF deletion) and poor prognosis. These results allowed us to refine our molecular characterization associated with prognosis, referring exclusively to oligodendroglial tumors.

Loss of heterozygosity at 1p-19q induces a global change in oligodendroglial tumor gene expression.

Oligodendroglial tumors presenting loss of heterozygosity (LOH) at 1p and 19q have been shown to be sensitive to chemotherapy, thus making 1p-19q status testing a key aspect in oligodendroglioma diagnosis and prognosis. Twenty-nine tumor samples (19 oligodendrogliomas, 10 oligoastrocytomas) were analyzed in order to obtain a molecular profile identifying those bearing 1p-19q LOH. Other genomic anomalies usually present in gliomas, such as EGFR amplification, CDKN2A/ARF deletion, 10q LOH and TP53 mutation, were also studied. Tumors with 1p-19q LOH overexpressed genes related to neurogenesis. Genes linked to immune response, proliferation and inflammation were overexpressed in the group with intact 1p-19q; this group could in turn be further divided in two subgroups: one overexpressing genes involved in immune response and inflammation that did not show major genetic aberrations other than the TP53 mutation and EGFR trisomy in a few cases, and another overexpressing genes related to immune response and proliferation that had a predominance of samples carrying several anomalies and presenting worse outcomes. This molecular signature was validated by analyzing a set of ten tumor samples (three oligodendrogliomas, seven oligoastrocytomas); all ten samples were correctly assigned. LOH at 1p-19q results in haploinsufficiency and copy number reduction of several genes, including NOTCH 2; this phenomenon produces a global change in gene expression inducing a pro-neural status that results in restrictions to cell migration and proliferation. Tumors without LOH at 1p-19q exhibit the opposite characteristics, explaining their more aggressive behavior.