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The relationship of a CD105- and b CD34-staining in GBM with hemorrhage (N = 17), without hemorrhage (N = 22), and controls (N = 4)
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There is little data on why glioblastomas (GBM) hemorrhage and how it may affect patient outcomes. The aim of this study was to investigate the mechanisms of hemorrhage in glioblastoma by examining molecular and genetic features by immunohistochemistry (IHC) and mRNA expression profiles in association with imaging and clinical outcomes. An observat...
Citations
... Similar to our study, Mikkelsen et al. demonstrated that CD105-MVD did not significantly correlate with endothelial cell density, with a mean value of 16.5% [40]. McGahan et al., in their immunohistochemical study evaluating microvascular density, described a positive correlation between CD105, CD34 expression, and tumorassociated hemorrhage [41]. Tamma et al., in their study, showed that p53-negative tumor cells are positively correlated with CD34-positive endothelial cells. ...
Glioblastoma is the most aggressive tumor in the central nervous system, with a survival rate of less than 15 months despite multimodal therapy. Tumor recurrence frequently occurs after removal. Tumoral angiogenesis, the formation of neovessels, has a positive impact on tumor progression and invasion, although there are controversial results in the specialized literature regarding its impact on survival. This study aims to correlate the immunoexpression of angiogenesis markers (CD34, CD105) with the proliferation index Ki67 and p53 in primary and secondary glioblastomas. This retrospective study included 54 patients diagnosed with glioblastoma at the Pathology Department of County Emergency Clinical Hospital Târgu Mureș. Microvascular density was determined using CD34 and CD105 antibodies, and the results were correlated with the immunoexpression of p53, IDH1, ATRX and Ki67. The number of neoformed blood vessels varied among cases, characterized by different shapes and calibers, with endothelial cells showing modified morphology and moderate to marked pleomorphism. Neovessels with a glomeruloid aspect, associated with intense positivity for CD34 or CD105 in endothelial cells, were observed, characteristic of glioblastomas. Mean microvascular density values were higher for the CD34 marker in all cases, though there were no statistically significant differences compared to CD105. Mutant IDH1 and ATRX glioblastomas, wild-type p53 glioblastomas, and those with a Ki67 index above 20% showed a more abundant microvascular density, with statistical correlations not reaching significance. This study highlighted a variety of percentage intervals of microvascular density in primary and secondary glioblastomas using immunohistochemical markers CD34 and CD105, respectively, with no statistically significant correlation between evaluated microvascular density and p53 or Ki67.
... Hemorrhage and epileptogenicity have been assessed as the main symptomatology of GBM that derives from HIF-1 and VEGF [80]. Hemorrhage, which is present in many GBM cases, has been linked to increased expression of angiogenic markers (CD34 and CD105), of some angiogenic genes-(HIF-1α and MDK) which share similar mechanisms of induction [81], and decreased expression of the Coagulation factor III (F3), enhancing susceptibility to hemorrhage. ...
... Hemorrhage, which is present in many GBM cases, has been linked to increased expression of angiogenic markers (CD34 and CD105), of some angiogenic genes-(HIF-1α and MDK) which share similar mechanisms of induction [81], and decreased expression of the Coagulation factor III (F3), enhancing susceptibility to hemorrhage. However, hemorrhage has not been associated with prognosis [80]. On the other hand, epileptogenicity appears to favor the survival of GBM patients [82]. ...
... HIF-1α/VEGF immunophenotypes have also been associated with clinical and Imaging manifestations of GBM (Fig. 2). These may include hemorrhage and epileptogenicity [80]. Hemorrhage has not been associated with prognosis [80]. ...
... The robust angiogenesis and abnormal vasculature in glioblastoma IDH-wildtype (GBM) are defining features of these highly aggressive gliomas [1][2][3][4][5][6]. GBMs represent the most lethal central nervous system (CNS) tumors in adults [7,8]. ...
Simple Summary
This study seeks to assess the efficacy of bevacizumab (BVZ) in the context of glioblastoma treatment, with a particular focus on the identification of a predictive biomarker, rCBVmax. The findings indicate that BVZ demonstrates marked benefits for patients with moderately vascularized tumors, resulting in a substantially extended median survival after tumor progression compared to those who do not receive second-line treatment. The proposed utilization of rCBVmax as a biomarker has the potential to enable personalized treatment decisions, enhancing patient outcomes by guiding the selection of optimal therapy. Additionally, the establishment of a threshold at 7.5 for categorizing patients based on tumor vascularity presents a more refined approach to the selection of second-line treatments. This research holds promise for improving the management of glioblastoma and optimizing treatment strategies for individual patients.
Abstract
Background: Aberrant vascular architecture and angiogenesis are hallmarks of glioblastoma IDH-wildtype, suggesting that these tumors are suitable for antiangiogenic therapy. Bevacizumab was FDA-approved in 2009 following promising results in two clinical trials. However, its use for recurrent glioblastomas remains a subject of debate, as it does not universally improve patient survival. Purposes: In this study, we aimed to analyze the influence of tumor vascularity on the benefit provided by BVZ and propose preoperative rCBVmax at the high angiogenic tumor habitat as a predictive biomarker to select patients who can benefit the most. Methods: Clinical and MRI data from 106 patients with glioblastoma IDH-wildtype have been analyzed. Thirty-nine of them received BVZ, and the remaining sixty-seven did not receive a second-line treatment. The ONCOhabitats method was used to automatically calculate rCBV. Results: We found a median survival from progression of 305 days longer for patients with moderate vascular tumors who received BVZ than those who did not receive any second-line treatment. This contrasts with patients with high-vascular tumors who only presented a median survival of 173 days longer when receiving BVZ. Furthermore, better responses to BVZ were found for the moderate-vascular group with a higher proportion of patients alive at 6, 12, 18, and 24 months after progression. Conclusions: We propose rCBVmax as a potential biomarker to select patients who can benefit more from BVZ after tumor progression. In addition, we propose a threshold of 7.5 to stratify patients into moderate- and high-vascular groups to select the optimal second-line treatment.
... The patient backgrounds were similar in the groups with and without EVF, but w found laterality in the presence of EVF. Regarding the laterality in clinical manifestatio of GBMs, bleeding is more frequent on the right side than on the left side [20]. Moreove symptoms are milder on the right side, resulting in delayed diagnosis and reduced quali of life [21]. ...
... The patient backgrounds were similar in the groups with and without EVF, but we found laterality in the presence of EVF. Regarding the laterality in clinical manifestations of GBMs, bleeding is more frequent on the right side than on the left side [20]. Moreover, symptoms are milder on the right side, resulting in delayed diagnosis and reduced quality of life [21]. ...
Simple Summary
Our study examined early venous filling (EVF) on angiography, a potential sign of aggressiveness in a type of brain cancer known as glioblastoma (GBM). The study aimed to determine if there were differences in survival rates between GBM patients with and without EVF, and if EVF was associated with a neovascularization process called vascular mimicry. Vascular mimicry occurs when cancer cells form blood vessel-like structures, making the cancer more aggressive and difficult to treat. The study found that GBM patients with EVF generally had shorter survival and were more likely to show signs of vascular mimicry. Simply put, the presence of EVF in GBM patients may indicate a more aggressive form of the disease, which could lead to a worse prognosis. This finding could potentially help physicians predict disease progression and tailor treatment plans. However, more research is needed to confirm these findings and to understand whether they could be used to develop new treatments.
Abstract
Preoperative angiography in glioblastoma (GBM) often shows arteriovenous shunts and early venous filling (EVF). Here, we investigated the clinical implications of EVF in GBM as a prognostic and vascular mimicry biomarker. In this retrospective multicenter study, we consecutively enrolled patients who underwent angiography with a GBM diagnosis between 1 April 2013 and 31 March 2021. The primary and secondary endpoints were the differences in overall survival (OS) and progression-free survival (PFS), respectively, between cases with and without EVF. Of the 133 initially enrolled patients, 91 newly diagnosed with GBM underwent preoperative angiography and became the study population. The 6-year OS and PFS were significantly worse in the EVF than in the non-EVF group. Moreover, 20 GBM cases (10 with EVF and 10 without EVF) were randomly selected and evaluated for histological vascular mimicry. Except for two cases that were difficult to evaluate, the EVF group had a significantly higher frequency of vascular mimicry than the non-EVF group (0/8 vs. 5/10, p = 0.04). EVF on preoperative angiography is a robust prognostic biomarker for GBM and may help detect cases with a high frequency of histological vascular mimicry.
... Apixaban appears to be safest DOAC overall for AF 13 but notably patients with brain cancers were excluded from the CARAVAGGIO trial. 2 Dabigatran is associated with the best risk reduction of ICH compared to warfarin (60%, apixaban: 57%, edoxaban: 56%, rivaroxaban 41%) 14 but importantly, the pathological mechanisms of ICH in patients with brain cancer are different to spontaneous ICH. 15 A drawback to dabigatran is its heavy reliance on renal excretion (~80% 16 ) making it unsuitable for more patients than other DOACs and LMWH. Licensed dose reductions according to renal function are available for dabigatran, edoxaban, and rivaroxaban (the apixaban 2.5mg twice daily dose is for AF only) but only edoxaban's dose reduction is supported by prospective clinical data in VTE. ...
... GBM vessels create a tumor microenvironment that, in an intra-and intertumoral heterogeneous manner, include severe hypoxia, acidosis, necrosis and high interstitial pressure and promote tumor progress [31]. CD105 expression is identified as a diagnostic hallmark of GBM vascular structures [32,33], and a higher expression level of CD105 correlates with a shorter overall survival time [34]. Our own result proved that CD105 + Nestin + cells exist outside of the GBM margin and might be related with tumor recurrence. ...
Glioblastoma (GBM) is the most common and most aggressive primary brain tumor in adults. Glioma stem like cells (GSC) represent the highest cellular hierarchy in GBM and have a determining role in tumor growth, recurrence and patient prognosis. However, a better definition of GSC subpopulations, especially at the surgical resection margin, is warranted for improved oncological treatment options. The present study interrogated cells expressing CD105 (CD105 ⁺ ) specifically within the tumor front and the pre-invasive niche as a potential GSC subpopulation. GBM primary cell lines were generated from patients (n = 18) and CD105 ⁺ cells were isolated and assessed for stem-like characteristics. In vitro, CD105 ⁺ cells proliferated and enriched in serum-containing medium but not in serum-free conditions. CD105 ⁺ cells were characterized by Nestin ⁺ , Vimentin ⁺ and SOX2 ⁻ , clearly distinguishing them from SOX2 ⁺ GCS. GBM CD105 ⁺ cells differentiated into osteocytes and adipocytes but not chondrocytes. Exome sequencing revealed that GBM CD105 ⁺ cells matched 83% of somatic mutations in the Cancer cell line encyclopedia, indicating a malignant phenotype and in vivo xenotransplantation assays verified their tumorigenic potential. Cytokine assays showed that immunosuppressive and protumorigenic cytokines such as IL6, IL8, CCL2, CXCL-1 were produced by CD105 ⁺ cells. Finally, screening for 88 clinical drugs revealed that GBM CD105 ⁺ cells are resistant to most chemotherapeutics except Doxorubicin, Idarubicin, Fludarabine and ABT-751. Our study provides a rationale for targeting tumoral CD105 ⁺ cells in order to reshape the tumor microenvironment and block GBM progression.
... It was well documented that tumor growth and progression depended on the formation of new blood vessels, which may further lead to GBM hemorrhage and poor prognosis. 33,34 Therefore, future studies should investigate whether anti-angiogenesis therapy, such as bevacizumab treatment, has a different effect in male and female patients. ...
Glioblastoma (GBM) is the most lethal primary tumor in the human brain and lacks favorable treatment options. Sex differences in the outcome of GBM are broadly acknowledged, but the underlying molecular mechanisms remain largely unknown. To identify the sex‐dependent critical genes in the progression of GBM, raw data from several microarray datasets with the same array platform were downloaded from the Gene Expression Omnibus (GEO) database. These datasets included tumorous and normal tissue from patients with GBM and crucial sex features. Then, the differentially expressed genes (DEGs) in female and male tumors were identified via bioinformatics analysis, respectively. Functional signatures of the identified DEGs were further annotated by Gene Ontology (GO) and pathway enrichment analyses. Venn diagram and functional protein–protein interaction (PPI) network analyses were performed to screen out the sex‐specific DEGs. Survival analysis of patients with differences in the expression level of selected genes was then carried out using the data from The Cancer Genome Atlas (TCGA). Here, we showed that ECT2, AURKA, TYMS, CDK1, NCAPH, CENPU, OIP5, KIF14, ASPM, FBXO5, SGOL2, CASC5, SHCBP1, FN1, LOX, IGFBP3, CSPG4, and CD44 were enriched in female tumor samples, whereas TNFSF13B, CXCL10, CXCL8, CXCR4, TLR2, CCL2, and FCGR2A were enriched in male tumor samples. Among these key genes, interestingly, ECT2 was associated with increased an survival rate for female patients, whileTNFSF13B could be regarded as a potential marker of poor prognosis in male patients. These results suggested that sex differences in patients may be attributed to the heterogeneous gene activity, which might influence the oncogenesis and the outcomes of GBM.
... [2][3][4][5] Key words -Fractal dimension -Glioblastoma -Lacunarity -Microvascularity -Tumor hemorrhage Previously, we investigated the link between intracranial hemorrhage in patients with GBM, clinical outcomes, and messenger RNA (mRNA) expression profiles. 6 We found that there was no significant difference in progression-free survival (PFS) or overall survival (OS) in the presence or absence of tumor hemorrhage. However, our genetic analysis revealed that HIF1a and MDK mRNA expression were increased in GBM compared with normal brain controls, and expression was higher for both genes in tumors that hemorrhaged. ...
... Our hypothesis was that FD would associate with the vascularity profiles and clinical outcomes of our previously analyzed GBM cohort. 6 ...
... The FFPE specimens from 43 GBM patients and 4 normal brain controls were previously analyzed as part of our prior work, undergoing microarray assay using the Affymetrix QuantiGene Plex 2.0 Assay (Thermo Fisher Scientific, Waltham, Massachusetts, USA). 6 A total of 92 genes related to angiogenesis and vascularity were chosen, and custom plexes were created to run each sample in duplicate. ...
Introduction:
Growing evidence indicates fractal analysis (FA) has potential as a computational tool to assess tumor microvasculature in glioblastoma (GBM). As fractal parameters of microvasculature have shown to be reliable quantitative biomarkers in brain tumors, there has been similar success in measuring the architecture of tumor tissue using fractal analysis in other tumor types. However, evaluating the fractal parameters of tissue structure in relation to the microvasculature has not yet been implemented in GBM. We aimed to assess the utility of this methodology in quantifying structural characteritics of GBM cytoarchitecture and vascularity by correlating fractal parameters with gene expression.
Methods:
Formalin fixed paraffin embedded (FFPE) specimens were retrospsecitvely collected from 43 patients following resection of a newly diagnosed GBM and 4 control normal brain epilepsy cases. Tumor samples were processed using FA using a software-based box-counting method algorithm and custom mRNA expression assays. Fractal parameters were the correlated with clinical features, outcomes, and a panel of 92 genes associated with vascularity and angiogenesis.
Results:
Statistical analysis demonstrated that fractal-based indices were not adequate parameters for distinction of GBM cytoarchitecture when compared to normal brain. Correlation analysis of our gene expression findings suggests that H&E-based fractal analysis may have adequate sensitivity to detect associations with vascular gene expression.
Conclusion:
The combination of neuropathological assessment and histology does not provide optimized data for FA in GBM. However, we report association between FA and gene expression in GBM of genes pertaining to cytoarchitecture and angiogenesis that warrant futher investigation.
... Hypertension, anticoagulation, surgical intervention, angiogenesis and invasion of blood vessels by malignant cells may cause hemorrhage [43]. Mc-Gahan et al. [44] showed that the presence of hemorrhage in glioblastomas had no effect on prognosis. Contrary to this result, we found that the mean Ki-67 values of hemorrhagic tumors is higher than the nonhemorrhagic (p = 0.002). ...
Objectives: Glioblastoma is the most common primary neoplasm of the central nervous system (CNS) and has a very poor prognosis. Ki-67 proliferative index is a value that reflects the mitotic index of the tumor and is associated with poor prognosis. The radiological features of the tumors can predict the course of the disease. The aim of this study is to evaluate the relationship between the morphology and the apparent diffusion coefficient (ADC) values of the tumor with the Ki-67 index on preoperative magnetic resonance imaging (MRI). Methods: Preoperative MRI images of 52 patients with pathological diagnosis of glioblastoma were evaluated retrospectively. A score ranging from 1 to 3 was assigned to each of the morphological features of the tumors (peritumoral edema, necrosis, contrasting pattern, heterogeneity, hemorrhage, mass effect, tumor contour irregularity), and was added up to obtain the total score. In addition, the ADC values of each tumor were measured at the workstation. ADC value and total score of each tumor, and Ki-67 values obtained histopathologically were compared. Results: There was a negative correlation between Ki-67 index of tumors and ADC values (r =-0.895, p = 0.0001). A significant positive correlation was found between the morphological features of the tumors and their total scores (r = 0.772, p = 0.0001). A statistically significant negative correlation was found between total score and ADC values (r =-0.780, p = 0.0001). Heterogeneity and necrosis were the features most closely associated with Ki-67. These were followed by mass effect, hemorrhage and contour irregularity, respectively. Conclusions: The morphological findings and ADC values obtained from preoperative MRI are related to the Ki-67 value, and thus can be used to predict prognosis and guide treatment in the early period.
... Glioblastomas are highly vascular with increased angiogenic activity associated with the presence of hemorrhaging [45] and increased presence of T cells [17]. Indeed, perivascular T cells were common in both primary and recurrent tumours in our cohort and Mu et al (2017) [46] found that the majority of T cells in both primary and recurrent glioblastoma were present in this location. ...
Immunotherapies targeting tumour-infiltrating lymphocytes (TILs) that express the immune checkpoint molecule programmed cell death-1 (PD-1) have shown promise in preclinical glioblastoma models but have had limited success in clinical trials. To assess when glioblastoma is most likely to benefit from immune checkpoint inhibitors we determined the density of TILs in primary and recurrent glioblastoma. Thirteen cases of matched primary and recurrent glioblastoma tissue were immunohistochemically labelled for CD3, CD8, CD4 and PD-1, and TIL density assessed. CD3+ TILs were observed in all cases, with the majority of both primary (69.2%) and recurrent (61.5%) tumours having low density of TILs present. CD8+ TILs were observed at higher densities than CD4+ TILs in both tumour groups. PD-1+ TILs were sparse and present in only 25% of primary and 50% of recurrent tumours. Quantitative analysis of TILs demonstrated significantly higher CD8+ TIL density at recurrence (p = 0.040). No difference was observed in CD3+ (p = 0.191), CD4+ (p = 0.607) and PD-1+ (p = 0.070) TIL density between primary and recurrent groups. This study shows that TILs are present at low densities in both primary and recurrent glioblastoma. Furthermore, PD-1+ TILs were frequently absent, which may provide evidence as to why anti-PD-1 immunotherapy trials have been largely unsuccessful in glioblastoma.
