Glioblastomas (GBMs), the most common primary brain tumor in adults, are characterized by resistance to chemotherapy and radiotherapy. One of the defining characteristics of GBM is an abundant and ...aberrant vasculature. The processes of vascular co-option, angiogenesis, and vasculogenesis in gliomas have been extensively described. Recently, however, it has become clear that these three processes are not the only mechanisms by which neovascularization occurs in gliomas. Furthermore, it seems that these processes interact extensively, with potential overlap among them. At least five mechanisms by which gliomas achieve neovascularization have been described: vascular co-option, angiogenesis, vasculogenesis, vascular mimicry, and (the most recently described) glioblastoma-endothelial cell transdifferentiation. We review these mechanisms in glioma neovascularization, with a particular emphasis on the roles of hypoxia and glioma stem cells in each process. Although some of these processes are well established, others have been identified only recently and will need to be further investigated for complete validation. We also review strategies to target glioma neovascularization and the development of resistance to these therapeutic strategies. Finally, we describe how these complex processes interlink and overlap. A thorough understanding of the contributing molecular processes that control the five modalities reviewed here should help resolve the treatment resistance that characterizes GBMs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Patients with the Coronavirus Disease of 2019 (COVID-19) are at increased risk for thrombotic events and mortality. Various anticoagulation regimens are now being considered for these patients. ...Anticoagulation is known to increase the risk for adverse bleeding events, of which intracranial hemorrhage (ICH) is one of the most feared. We present a retrospective study of 33 patients positive for COVID-19 with neuroimaging-documented ICH and examine anticoagulation use in this population.
Patients over the age of 18 with confirmed COVID-19 and radiographic evidence of ICH were included in this study. Evidence of hemorrhage was confirmed and categorized by a fellowship trained neuroradiologist. Electronic health records were analyzed for patient information including demographic data, medical history, hospital course, laboratory values, and medications.
We identified 33 COVID-19 positive patients with ICH, mean age 61.6 years (range 37–83 years), 21.2% of whom were female. Parenchymal hemorrhages with mass effect and herniation occurred in 5 (15.2%) patients, with a 100% mortality rate. Of the remaining 28 patients with ICH, 7 (25%) had punctate hemorrhages, 17 (60.7%) had small- moderate size hemorrhages, and 4 (14.3%) had a large single site of hemorrhage without evidence of herniation. Almost all patients received either therapeutic dose anticoagulation (in 22 66.7% patients) or prophylactic dose (in 3 9.1 patients) prior to ICH discovery.
Anticoagulation therapy may be considered in patients with COVID-19 though the risk of ICH should be taken into account when developing a treatment regimen.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A critical event in the pathogenesis of invasive and metastatic cancer is E-cadherin loss of function. Renal clear cell carcinoma (RCC) is characterized by loss of function of the von Hippel-Lindau ...tumor suppressor (VHL), which negatively regulates hypoxia-inducible factor-1 (HIF-1). Loss of E-cadherin expression and decreased cell-cell adhesion in VHL-null RCC4 cells were corrected by enforced expression of VHL, a dominant-negative HIF-1alpha mutant, or a short hairpin RNA directed against HIF-1alpha. In human RCC biopsies, expression of E-cadherin and HIF-1alpha was mutually exclusive. The expression of mRNAs encoding TCF3, ZFHX1A, and ZFHX1B, which repress E-cadherin gene transcription, was increased in VHL-null RCC4 cells in a HIF-1-dependent manner. Thus, HIF-1 contributes to the epithelial-mesenchymal transition in VHL-null RCC by indirect repression of E-cadherin.
Isocitrate dehydrogenase (
)-mutant glioma is a distinct glioma molecular subtype for which no effective molecularly directed therapy exists. Low-grade gliomas, which are 80%-90%
-mutant, have high ...RNA levels of the cell surface Notch ligand DLL3. We sought to determine DLL3 expression by IHC in glioma molecular subtypes and the potential efficacy of an anti-DLL3 antibody-drug conjugate (ADC), rovalpituzumab tesirine (Rova-T), in
-mutant glioma.
We evaluated
expression by RNA using TCGA data and by IHC in a discovery set of 63 gliomas and 20 nontumor brain tissues and a validation set of 62 known
wild-type and mutant gliomas using a monoclonal anti-DLL3 antibody. Genotype was determined using a DNA methylation array classifier or by sequencing. The effect of Rova-T on patient-derived endogenous
-mutant glioma tumorspheres was determined by cell viability assay.
Compared to
wild-type glioblastoma,
-mutant gliomas have significantly higher
RNA (
< 1 × 10
) and protein by IHC (
= 0.0014 and
< 4.3 × 10
in the discovery and validation set, respectively). DLL3 immunostaining was intense and homogeneous in
-mutant gliomas, retained in all recurrent tumors, and detected in only 1 of 20 nontumor brains. Patient-derived
-mutant glioma tumorspheres overexpressed DLL3 and were potently sensitive to Rova-T in an antigen-dependent manner.
DLL3 is selectively and homogeneously expressed in
-mutant gliomas and can be targeted with Rova-T in patient-derived
-mutant glioma tumorspheres. Our findings are potentially immediately translatable and have implications for therapeutic strategies that exploit cell surface tumor-associated antigens.
Summary
Objective
Genetic loss of Tsc1/Tsc2 function in tuberous sclerosis complex (TSC) results in altered mammalian target of rapamycin (mTOR) signaling and abnormal brain development. Although ...earlier studies have focused on characterization of cortical tubers, in this study we sought to examine the unique cellular and molecular features of the perituberal cortex in order to better understand its contribution to epileptogenesis, cognitive dysfunction, and autism.
Methods
Standard histologic and immunohistochemical labeling was used to assess structural abnormalities and cell‐specific pattern of mTORC1 activation in surgically resected cortical tubers and perituberal cortex. Western blotting was performed to quantify the expression of the mTORC1 and mTORC2 biomarkers phospho‐S6 (Ser235/236), phospho‐S6 (Ser240/244), and phospho‐Akt (Ser473), in addition to evaluating the differential expression levels of several neuronal and glial‐specific proteins in tubers and peritubers, as compared to non‐TSC epilepsy specimens.
Results
Tubers demonstrated mild to severe disruption of cortical lamination, the presence of pS6‐positive dysplastic neurons and giant cells, an overall increase in mTORC1 and a decrease in mTORC2 activity, increased axonal connectivity and growth, and hypomyelination. Perituberal cortex presented similar histologic, immunohistochemical, and molecular features; however, they were overall milder. Axonal growth was specific for TSC and was negatively correlated with deficient myelination.
Significance
Our results show an extension of cellular dysplasia and dysregulated mTOR signaling in the perituberal tissue, and demonstrate for the first time aberrant connectivity in human TSC brain. This study provides new insights into the pathophysiology of neurologic dysfunction associated with TSC and supports the intrinsic epileptogenicity of normal‐appearing perituberal cortex.
A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
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The carotid web (CW) is an underrecognized source of cryptogenic, embolic stroke in patients younger than 55 years of age, with up to 37% of these patients found to have CW on angiography. Currently, ...there are little data detailing the best treatment practices to reduce the risk of recurrent stroke in these patients. The authors describe their institutional surgical experience with patients treated via carotid endarterectomy (CEA) for a symptomatic internal carotid artery web.
A retrospective, observational cohort study was performed including all patients presenting to the authors' institution with CW. All patients who were screened underwent either carotid artery stenting (CAS) or CEA after presentation with ischemic stroke from January 2019 to February 2020. From this sample, patients with suggestive radiological features and pathologically confirmed CW who underwent CEA were identified. Patient demographics, medical histories, radiological images, surgical results, and clinical outcomes were collected and described using descriptive statistics.
A total of 45 patients with symptomatic carotid lesions were treated at the authors' institution during the time period. Twenty patients underwent CAS, 1 of them for a CW. Twenty-five patients were treated via CEA, and of these, 6 presented with ischemic strokes ipsilateral to CWs, including 3 patients who presented with recurrent strokes. The mean patient age was 55 ± 12.6 years and 5 of 6 were women. CT angiography or digital subtraction angiography demonstrated the presence of CWs ipsilateral to the stroke in all patients. All patients underwent resection of CWs using CEA. There were no permanent procedural complications and no patients had stroke recurrence following intervention at the latest follow-up (mean 6.1 ± 4 months). One patient developed mild tongue deviation most likely related to retraction, with complete recovery at follow-up.
CEA is a safe and feasible treatment for symptomatic carotid webs and should be considered a viable alternative to CAS in this patient population.
Antiangiogenic agents have recently shown impressive radiological responses in high-grade glioma. However, it is not clear if the responses are related to vascular changes or due to antitumoral ...effects. The authors report the mature results of a clinical study of bevacizumab-based treatment of recurrent high-grade gliomas.
Sixty-one patients with recurrent high-grade gliomas received treatment with bevacizumab at 10 mg/ kg every 2 weeks for 4 doses in an 8-week cycle along with either irinotecan or carboplatin. The choice of concomitant chemotherapeutic agent was based on the number of recurrences and prior chemotherapy.
At a median follow-up of 7.5 months (range 1-19 months), 50 (82%) of 61 patients relapsed and 42 patients (70%) died of the disease. The median number of administered bevacizumab cycles was 2 (range 1-7 cycles). The median progression-free survival (PFS) and overall survival (OS) were 5 (95% confidence interval CI 2.3-7.7) and 9 (95% CI 7.6-10.4) months, respectively, as calculated from the initiation of the bevacizumab-based therapy. Radiologically demonstrated responses following therapy were noted in 73.6% of cases. Neither the choice of chemotherapeutic agent nor the performance of a resection prior to therapy had an impact on patient survival. Although the predominant pattern of relapse was local, 15 patients (30%) had diffuse disease.
Antiangiogenic therapy using bevacizumab appears to improve survival in patients with recurrent high-grade glioma. A possible change in the invasiveness of the tumor following therapy is worrisome and must be closely monitored.
To simulate and study the hypoxic microenvironment associated with intracerebral glioma in vivo, simple and reproducible methods are described and discussed for inducing hypoxia or chemical ...pseudohypoxia in glioma cell cultures and assessing their effects on the expression and nuclear translocation of hypoxia-inducible factor (HIF)-1α, a key transcriptional factor of oxygen homeostasis, by Western blot analysis and immunocytochemistry.
The presence of angiogenesis is a hallmark of glioblastoma (GBM). Vascular endothelial growth factor (VEGF), which drives angiogenesis, provides an additional target for conventional therapy. The ...authors conducted a prospective clinical trial to test the effectiveness of bevacizumab, an inhibitor of VEGF, in newly diagnosed GBM.
From 2006 through 2010, 51 eligible patients with newly diagnosed GBM were treated with involved-field radiation therapy and concomitant temozolomide (75 mg/m(2) daily for 42 days) along with bevacizumab (10 mg/kg every 2 weeks), starting 29 days after surgery. This was followed by 6 cycles of adjuvant temozolomide therapy (150 mg/m(2) on Days 1-7 of a 28-day cycle) with bevacizumab administered at 10 mg/kg on Days 8 and 22 of each 28-day cycle.
The 6- and 12-month progression-free survival (PFS) rates were 85.1% and 51%, respectively. The 12- and 24-month overall survival (OS) rates were 85.1% and 42.5%, respectively. Grade III/IV toxicities were noted in 10 patients (19.6%). No treatment-related deaths were observed. Asymptomatic intracranial bleeding was noted in 5 patients.
The addition of bevacizumab to conventional therapy in newly diagnosed GBM appears to improve both PFS and OS in patients with newly diagnosed GBM, with acceptable morbidity. A shift toward diffuse relapse was noted in a significant number of patients. Ongoing Phase III clinical trials will show the true benefit of this antiangiogenic approach.
Glioblastoma multiforme (GBM) is characterized by exuberant angiogenesis, a key event in tumor growth and progression. The pathologic mechanisms driving this change and the biological behavior of ...gliomas remain unclear. One mechanism may involve cooption of native blood vessels by glioma cells inducing expression of angio‐poietin‐2 by endothelial cells. Subsequently, vascular apoptosis and involution leads to necrosis and hypoxia. This in turn induces angiogenesis that is associated with expression of hypoxia‐inducible factor (HIF)‐1 a and vascular endothelial growth factor (VEGF) in perinecrotic pseudopalisading glioma cells. Here we review the molecular and cellular mechanisms implicated in HIF‐1 ‐dependent and HIF‐1 ‐independent glioma‐associated angiogenesis. In GBMs, both tumor hypoxia and genetic alterations commonly occur and act together to induce the expression of HIF‐1. The angiogenic response of the tumor to HIF‐1 is mediated by HIF‐1‐regulated target genes leading to the upregulation of several proangiogenic factors such as VEGF and other adaptive response molecules. Understanding the roles of these regulatory processes in tumor neovascularization, tumor growth and progression, and resistance to therapy will ultimately lead to the development of improved antiangiogenic therapies for GBMs.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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