Overexpression of Colligin 2 in Glioma Vasculature is Associated with Overexpression of Heat Shock Factor 2

In previous studies we found expression of the protein colligin 2 (heat shock protein 47 (HSP47), SERPINH1) in glioma neovasculature while not in normal brain tissue. Generally, the regulation of heat shock gene expression in eukaryotes is mediated by heat shock factors (HSF). In mammals, three heat shock transcription factors, HSF-1, -2, and -4, have been isolated. Here we investigated the relation between the expression of colligin 2 and these heat shock factors at the mRNA level using real-time reverse transcriptase PCR (qRT-PCR) in different grades of astrocytic tumorigenesis, viz., low-grade glioma and glioblastoma. Endometrium samples, representing physiological angiogenesis, were included as controls. Since colligin 2 is a chaperon for collagens, the gene expression of collagen I (COL1A1) was also investigated. The blood vessel density of the samples was monitored by expression of the endothelial marker CD31 (PECAM1). Because NG2-immunopositive pericytic cells are involved in glioma neovascularization, the expression of NG2 (CSPG4) was also measured

Unlocking molecular mechanisms and identifying druggable targets in matched-paired brain metastasis of breast and lung cancers

Introduction: The incidence of brain metastases in cancer patients is increasing, with lung and breast cancer being the most common sources. Despite advancements in targeted therapies, the prognosis remains poor, highlighting the importance to investigate the underlying mechanisms in brain metastases. The aim of this study was to investigate the differences in the molecular mechanisms involved in brain metastasis of breast and lung cancers. In addition, we aimed to identify cancer lineage-specific druggable targets in the brain metastasis. Methods: To that aim, a cohort of 44 FFPE tissue samples, including 22 breast cancer and 22 lung adenocarcinoma (LUAD) and their matched-paired brain metastases were collected. Targeted gene expression profiles of primary tumors were compared to their matched-paired brain metastases samples using nCounter PanCancer IO 360™ Panel of NanoString technologies. Pathway analysis was performed using gene set analysis (GSA) and gene set enrichment analysis (GSEA). The validation was performed by using Immunohistochemistry (IHC) to confirm the expression of immune checkpoint inhibitors. Results:Our results revealed the significant upregulation of cancer-related genes in primary tumors compared to their matched-paired brain metastases (adj. p ≤ 0.05). We found that upregulated differentially expressed genes in breast cancer brain metastasis (BM-BC) and brain metastasis from lung adenocarcinoma (BM-LUAD) were associated with the metabolic stress pathway, particularly related to the glycolysis. Additionally, we found that the upregulated genes in BM-BC and BM-LUAD played roles in immune response regulation, tumor growth, and proliferation. Importantly, we identified high expression of the immune checkpoint VTCN1 in BM-BC, and VISTA, IDO1, NT5E, and HDAC3 in BM-LUAD. Validation using immunohistochemistry further supported these findings. Conclusion: In conclusion, the findings highlight the significance of using matched-paired samples to identify cancer lineage-specific therapies that may improve brain metastasis patients outcomes.</p

Non-Small Cell Lung Cancer Brain Metastasis: The Link between Molecular Mechanisms and Novel Therapeutic Approaches

The prognosis of patients suffering from non-small cell lung carcinomas (NSCLC) worsens significantly when brain metastasis occurs. Seeding to the brain usually happens relatively early in the course of disease and therefore, new therapies anticipating this complication would result in considerable improvement in outcomes. In this review, we address recent molecular data of NSCLC with a focus on the risk of the formation of brain metastasis. Included is new data on the involvement of miRNAs and lncRNAs in the rise of the cerebral seeding of NSCLC. We summarize novel therapeutic approaches developed in the light of these recent molecular discoveries

Papillary meningioma with pleural metastasis: Case report and literature review

Papillary meningiomas are rare meningeal tumors which are associated with a grim prognosis. These tumors usually recur locally and in some cases they metastasize. The clinical, radiological and histopathological features of a case of a papillary meningioma with a pleural metastasis in a 13-year-old boy are presented. The literature on metastasizing papillary meningiomas is reviewed. Up to now, 131 cases of papillary meningioma have been reported in the literature. Only 8 cases gave rise to metastases outside the central nervous system. The preferential site of metastasis appeared to be the lung. This is the first report of a papillary meningioma giving rise to a metastasis in the pleura

Predictive and prognostic markers in neurooncology

Abstract Over the past few years molecular assays have been introduced to aid in typing and grading of gliomas. This is the result of improved understanding of these tumors at the molecular level. In particular, the presence or absence of combined 1p/19 loss in oligodendroglial tumors, epidermal growth factor receptor amplification, epidermal growth factor receptor vIII mutations in grade III tumors and glioblastoma multiforme, and MGMT promoter gene methylation in glioblastoma multiforme are now being used to tailor treatment decisions in patients. However, the application of these tests is far from straightforward, and certain standards are required before any test can be introduced in the daily management of patients. Some of these requirements concern inter-and intratest variability, including whether a test gives the same results if repeated in the same or in another laboratory or when different methodologies are used (e.g. loss of heterozygosity vs fluorescence in situ hybridization and a polymerase chain reaction-based test vs immunohistochemistry). The sensitivity and specificity of a test (or negative and positive predictive value) indicate the likelihood that the test results are positive if the disease is present and the likelihood that the disease is present if the test results are positive. Studies on these test characteristics usually require the presence of a gold standard to which new tests should be compared. Last but not least there is the question of what added value the test has; this criterion determines the clinical usefulness of the assay and why some recently introduced molecular assays need to be scrutinized

Diffuse infiltrating tumour with the molecular profile of an atypical teratoid rhabdoid tumour (AT/RT SHH-1B) in an adult patient

We describe a 46-year-old patient with an IDH-wildtype diffusely infiltrating atypical teratoid/rhabdoid tumour (AT/RT), SHH-1B molecular subtype. The unusual histology and subsequent diagnosis in an adult patient will be discussed.</p

A software application for comparing large numbers of high resolution MALDI-FTICR MS spectra demonstrated by searching candidate biomarkers for glioma blood vessel formation

Background: A Java™ application is presented, which compares large numbers (n > 100) of raw FTICR mass spectra from patients and controls. Two peptide profile matrices can be produced simultaneously, one with occurrences of peptide masses in samples and another with the intensity of common peak masses in all the measured samples, using the peak- and background intensities of the raw data. In latter way, more significantly differentially expressed peptides are found between groups than just using the presence or absence in samples of common peak masses. The software application is tested by searching angiogenesis related proteins in glioma by comparing laser capture micro dissected- and enzymatic by trypsin digested tissue sections. Results: By hierarchical clustering of the presence-absence matrix, it appears that proteins, such as hemoglobin alpha and delta subunit, fibrinogen beta and gamma chain precursor, tubulin specific chaperone A, epidermal fatty acid binding protein, neutrophil gelatinase-associated lipocalin prec

Medulloblastoma has a global impact on health related quality of life: Findings from an international cohort.

BackgroundUnderstanding the global impact of medulloblastoma on health related quality of life (HRQL) is critical to characterizing the broad impact of this disease and realizing the benefits of modern treatments. We evaluated HRQL in an international cohort of pediatric medulloblastoma patients.MethodsSeventy-six patients were selected from 10 sites across North America, Europe, and Asia, who participated in the Medulloblastoma Advanced Genomics International Consortium (MAGIC). The Health Utilities Index (HUI) was administered to patients and/or parents at each site. Responses were used to determine overall HRQL and attributes (ie specific subdomains). The impact of various demographic and medical variables on HRQL was considered-including molecular subgroup.ResultsThe majority of patients reported having moderate or severe overall burden of morbidity for both the HUI2 and HUI3 (HUI2&nbsp;=&nbsp;60%; HUI3&nbsp;=&nbsp;72.1%) when proxy-assessed. Self-care in the HUI2 was rated as higher (ie better outcome) for patients from Western versus Eastern sites, P&nbsp;=&nbsp;.02. Patients with nonmetastatic status had higher values (ie better outcomes) for the HUI3 hearing, HUI3 pain, and HUI2 pain, all P&nbsp;&lt;&nbsp;.05. Patients treated with a gross total resection also&nbsp;had better outcomes for the HUI3 hearing (P&nbsp;=&nbsp;.04). However, those who underwent a gross total resection reported&nbsp;having worse outcomes on the HUI3 vision (P&nbsp;=&nbsp;.02). No differences in HRQL were evident as a function of subgroup.ConclusionsBy examining an international sample of survivors, we characterized the worldwide impact of medulloblastoma. This is a critical first step in developing global standards for evaluating long-term outcomes

A method to correlate mRNA expression datasets obtained from fresh frozen and formalin-fixed, paraffin-embedded tissue samples: A matter of thresholds

Background: Gene expression profiling of tumors is a successful tool for the discovery of new cancer biomarkers and potential targets for the development of new therapeutic strategies. Reliable profiling is preferably performed on fresh frozen (FF) tissues in which the quality of nucleic acids is better preserved than in formalin-fixed paraffin-embedded (FFPE) material. However, since snap-freezing of biopsy materials is often not part of daily routine in pathology laboratories, one may have to rely on archival FFPE material. Procedures to retrieve the RNAs from FFPE materials have been developed and therefore, datasets obtained from FFPE and FF materials need to be made compatible to ensure reliable comparisons are possible. Aim: To develop an efficient method to compare gene expression profiles obtained from FFPE and FF samples using the same platform. Methods: Twenty-six FFPE-FF sample pairs of the same tumors representing various cancer types, and two FFPE-FF sample pairs of breast cancer cell lines, were included. Total RNA was extracted and gene expression profiling was carried out using Illumina's Whole-Genome cDNA-mediated Annealing, Selection, extension and Ligation (WG-DASL) V3 arrays, enabling the simultaneous detection of 24,526 mRNA transcripts. A sample exclusion criterion was created based on the expression of 11 stably expressed reference genes. Pearson correlation at the probe level was calculated for paired FFPE-FF, and three cut-off values were chosen. Spearman correlation coefficients between the matched FFPE and FF samples were calculated for three probe lists with varying levels of significance and compared to the correlation based on all measured probes. Unsupervised hierarchical cluster analysis was performed to verify performance of the included probe lists to compare matched FPPE-FF samples. Results: Twenty-seven FFPE-FF pairs passed the sample exclusion criterion. From the profiles of 27 FFPE and FF matched samp