Cerebral and tumoral blood flow in adult gliomas: a systematic review of results from magnetic resonance imaging.

OBJECTIVE: Blood flow is the rate of blood movement and relevant to numerous processes, though understudied in gliomas. The aim of this review was to pool blood flow metrics obtained from MRI modalities in adult supratentorial gliomas. METHODS: MEDLINE, EMBASE and the Cochrane database were queried 01/01/2000-31/12/2019. Studies measuring blood flow in adult Grade II-IV supratentorial gliomas using dynamic susceptibility contrast (DSC) MRI, dynamic contrast enhanced MRI (DCE-MRI) or arterial spin labelling (ASL) were included. Absolute and relative cerebral blood flow (CBF), peritumoral blood flow and tumoral blood flow (TBF) were reported. RESULTS: 34 studies were included with 1415 patients and 1460 scans. The mean age was 52.4 ± 7.3 years. Most patients had glioblastoma (n = 880, 64.6%). The most common imaging modality was ASL (n = 765, 52.4%) followed by DSC (n = 538, 36.8%). Most studies were performed pre-operatively (n = 1268, 86.8%). With increasing glioma grade (II vs IV), TBF increased (70.8 vs 145.5 ml/100 g/min, p < 0.001) and CBF decreased (85.3 vs 49.6 ml/100 g/min, p < 0.001). In Grade IV gliomas, following treatment, CBF increased in ipsilateral (24.9 ± 1.2 vs 26.1 ± 0.0 ml/100 g/min, p < 0.001) and contralateral white matter (25.6 ± 0.2 vs 26.0± 0.0 ml/100 g/min, p < 0.001). CONCLUSION: Our findings demonstrate that increased mass effect from high-grade gliomas impairs blood flow within the surrounding brain that can improve with surgery. ADVANCES IN KNOWLEDGE: This systematic review demonstrates how mass effect from brain tumours impairs blood flow in the surrounding brain parenchyma that can improve with treatment.

The LEGATOS technique: A new tissue-validated dynamic contrast-enhanced MRI method for whole-brain, high-spatial resolution parametric mapping.

PURPOSE: A DCE-MRI technique that can provide both high spatiotemporal resolution and whole-brain coverage for quantitative microvascular analysis is highly desirable but currently challenging to achieve. In this study, we sought to develop and validate a novel dual-temporal resolution (DTR) DCE-MRI-based methodology for deriving accurate, whole-brain high-spatial resolution microvascular parameters. METHODS: Dual injection DTR DCE-MRI was performed and composite high-temporal and high-spatial resolution tissue gadolinium-based-contrast agent (GBCA) concentration curves were constructed. The high-temporal but low-spatial resolution first-pass GBCA concentration curves were then reconstructed pixel-by-pixel to higher spatial resolution using a process we call LEGATOS. The accuracy of kinetic parameters (Ktrans , vp , and ve ) derived using LEGATOS was evaluated through simulations and in vivo studies in 17 patients with vestibular schwannoma (VS) and 13 patients with glioblastoma (GBM). Tissue from 15 tumors (VS) was examined with markers for microvessels (CD31) and cell density (hematoxylin and eosin [H&E]). RESULTS: LEGATOS derived parameter maps offered superior spatial resolution and improved parameter accuracy compared to the use of high-temporal resolution data alone, provided superior discrimination of plasma volume and vascular leakage effects compared to other high-spatial resolution approaches, and correlated with tissue markers of vascularity (P ≤ 0.003) and cell density (P ≤ 0.006). CONCLUSION: The LEGATOS method can be used to generate accurate, high-spatial resolution microvascular parameter estimates from DCE-MRI.

Imaging of the glioma microenvironment by TSPO PET.

Gliomas are highly dynamic and heterogeneous tumours of the central nervous system (CNS). They constitute the most common neoplasm of the CNS and the second most common cause of death from intracranial disease after stroke. The advances in detailing the genetic profile of paediatric and adult gliomas along with the progress in MRI and PET multimodal molecular imaging technologies have greatly improved prognostic stratification of patients with glioma and informed on treatment decisions. Amino acid PET has already gained broad clinical application in the study of gliomas. PET imaging targeting the translocator protein (TSPO) has recently been applied to decipher the heterogeneity and dynamics of the tumour microenvironment (TME) and its various cellular components especially in view of targeted immune therapies with the goal to delineate pro- and anti-glioma immune cell modulation. The current review provides a comprehensive overview on the historical developments of TSPO PET for gliomas and summarizes the most relevant experimental and clinical data with regard to the assessment and quantification of various cellular components with the TME of gliomas by in vivo TSPO PET imaging.

The microenvironment in sporadic and neurofibromatosis type II-related vestibular schwannoma: the same tumor or different? A comparative imaging and neuropathology study.

OBJECTIVE: Inflammation and angiogenesis may play a role in the growth of sporadic and neurofibromatosis type 2 (NF2)-related vestibular schwannoma (VS). The similarities in microvascular and inflammatory microenvironment have not been investigated. The authors sought to compare the tumor microenvironment (TME) in sporadic and NF2-related VSs using a combined imaging and tissue analysis approach. METHODS: Diffusion MRI and high-temporal-resolution dynamic contrast-enhanced (DCE) MRI data sets were prospectively acquired in 20 NF2-related and 24 size-matched sporadic VSs. Diffusion metrics (mean diffusivity, fractional anisotropy) and DCE-MRI-derived microvascular biomarkers (transfer constant [Ktrans], fractional plasma volume, tissue extravascular-extracellular space [ve], longitudinal relaxation rate, tumoral blood flow) were compared across both VS groups, and regression analysis was used to evaluate the effect of tumor size, pretreatment tumor growth rate, and tumor NF2 status (sporadic vs NF2-related) on each imaging parameter. Tissues from 17 imaged sporadic VSs and a separate cohort of 12 NF2-related VSs were examined with immunohistochemistry markers for vessels (CD31), vessel permeability (fibrinogen), and macrophage density (Iba1). The expression of vascular endothelial growth factor (VEGF) and VEGF receptor 1 was evaluated using immunohistochemistry, Western blotting, and double immunofluorescence. RESULTS: Imaging data demonstrated that DCE-MRI-derived microvascular characteristics were similar in sporadic and NF2-related VSs. Ktrans (p < 0.001), ve (p ≤ 0.004), and tumoral free water content (p ≤ 0.003) increased with increasing tumor size and pretreatment tumor growth rate. Regression analysis demonstrated that with the exception of mean diffusivity (p < 0.001), NF2 status had no statistically significant effect on any of the imaging parameters or the observed relationship between the imaging parameters and tumor size (p > 0.05). Tissue analysis confirmed the imaging metrics among resected sporadic VSs and demonstrated that across all VSs studied, there was a close association between vascularity and Iba1+ macrophage density (r = 0.55, p = 0.002). VEGF was expressed by Iba1+ macrophages. CONCLUSIONS: The authors present the first in vivo comparative study of microvascular and inflammatory characteristics in sporadic and NF2-related VSs. The imaging and tissue analysis results indicate that inflammation is a key contributor to TME and should be viewed as a therapeutic target in both VS groups.

Inflammation and vascular permeability correlate with growth in sporadic vestibular schwannoma.

BACKGROUND: Inflammation is hypothesized to be a key event in the growth of sporadic vestibular schwannoma (VS). In this study we sought to investigate the relationship between inflammation and tumor growth in vivo using the PET tracer 11C-(R)-PK11195 and dynamic contrast enhanced (DCE) MRI derived vascular biomarkers. METHODS: Nineteen patients with sporadic VS (8 static, 7 growing, and 4 shrinking tumors) underwent prospective imaging with dynamic 11C-(R)-PK11195 PET and a comprehensive MR protocol, including high temporal resolution DCE-MRI in 15 patients. An intertumor comparison of 11C-(R)-PK11195 binding potential (BPND) and DCE-MRI derived vascular biomarkers (Ktrans, vp, ve) across the 3 different tumor growth cohorts was undertaken. Tissue of 8 tumors was examined with immunohistochemistry markers for inflammation (Iba1), neoplastic cells (S-100 protein), vessels (CD31), the PK11195 target translocator protein (TSPO), fibrinogen for vascular permeability, and proliferation (Ki-67). Results were correlated with PET and DCE-MRI data. RESULTS: Compared with static tumors, growing VS displayed significantly higher mean 11C-(R)-PK11195 BPND (-0.07 vs 0.47, P = 0.020), and higher mean tumor Ktrans (0.06 vs 0.14, P = 0.004). Immunohistochemistry confirmed the imaging findings and demonstrated that TSPO is predominantly expressed in macrophages. Within growing VS, macrophages rather than tumor cells accounted for the majority of proliferating cells. CONCLUSION: We present the first in vivo imaging evidence of increased inflammation within growing sporadic VS. Our results demonstrate that 11C-(R)-PK11195 specific binding and DCE-MRI derived parameters can be used as imaging biomarkers of inflammation and vascular permeability in this tumor group.

Kinetic modelling of [11C]PBR28 for 18 kDa translocator protein PET data: A validation study of vascular modelling in the brain using XBD173 and tissue analysis.

The 18 kDa translocator protein (TSPO) is a marker of microglia activation in the central nervous system and represents the main target of radiotracers for the in vivo quantification of neuroinflammation with positron emission tomography (PET). TSPO PET is methodologically challenging given the heterogeneous distribution of TSPO in blood and brain. Our previous studies with the TSPO tracers [11C]PBR28 and [11C]PK11195 demonstrated that a model accounting for TSPO binding to the endothelium improves the quantification of PET data. Here, we performed a validation of the kinetic model with the additional endothelial compartment through a displacement study. Seven subjects with schizophrenia, all high-affinity binders, underwent two [11C]PBR28 PET scans before and after oral administration of 90 mg of the TSPO ligand XBD173. The addition of the endothelial component provided a signal compartmentalization much more consistent with the underlying biology, as only in this model, the blocking study produced the expected reduction in the tracer concentration of the specific tissue compartment, whereas the non-displaceable compartment remained unchanged. In addition, we also studied TSPO expression in vessels using 3D reconstructions of histological data of frontal lobe and cerebellum, demonstrating that TSPO positive vessels account for 30% of the vascular volume in cortical and white matter.

Cervical epidural extra-osseous Ewing sarcoma mimicking an epidural abscess.

We report a case of a 21-year-old woman presenting with quadriplegia which was initially diagnosed with an epidural abscess in view of her MR scan and raised inflammatory marker levels. Histology revealed an epidural extra-osseous Ewing's sarcoma (EES). Epidural location of EES is a very rare condition which can be very challenging to diagnose. Early diagnosis and surgical excision followed by chemotherapy represent the main stem of management.

[Ischemic heart disease and depression: an underestimated clinical association]. / Cardiopatia ischemica e depressione: una realtà sottostimata.

Patients with acute or chronic ischemic heart disease have a high incidence of depression, and a variable proportion of patients (ranging from 14% to 47%) suffer from major or subclinical depression. In addition, chronic depression has been shown to be associated with the development or progression of coronary atherosclerosis. Besides a poor quality of life, depressive symptoms in patients with ischemic heart disease result in a poor prognosis, as cardiovascular event rates are 2-2.5 times higher than in their counterparts without depressive symptoms. A variety of pathogenetic mechanisms may play a role, including pathophysiological (dysfunction of the autonomic nervous system or hypothalamic-pituitary-adrenal axis, platelet hyperaggregability, inflammation, endothelial dysfunction and genetic predisposition) and behavioral mechanisms (inadequate therapy adherence, obesity, smoking, sedentary lifestyle). However, in patients with ischemic heart disease, depression often goes undiagnosed or untreated. Several screening procedures including questionnaires for patients with heart disease, along with the help of a psychiatrist, may facilitate not only the diagnosis of depressive symptoms but also the pharmacological and/or physiotherapeutic management. The use of tricyclic antidepressant agents should be avoided in patients with heart disease, whereas selective serotonin reuptake inhibitors have been shown to be safe in this patient population. However, no evidence is available to support that use of these drugs is associated with a reduced risk of cardiovascular events at follow-up. Psychotherapy proved to be effective in reducing depressive symptoms but ineffective in improving prognosis. In this review, epidemiology and pathophysiology of depression in patients with ischemic heart disease are described, with a focus on stratification of depressive symptoms and potential therapeutic strategies.

Sex differences in biomarkers for predicting cardiovascular and coronary events.

INTRODUCTION: Primary and secondary prevention of cardiovascular Disease (CVD) are major concerns and priorities. The best tools that we actually have to prevent CVD are the biomarkers. Numerous studies have shown that the presentation of cardiac disease in women is quite different from the presentation in men. Thus, one question arises "Are there any differences in biomarkers as well?" The answer to this question could open new avenues for a tailored management of cardiac diseases. METHOD AND RESULTS: We searched the PubMed and Medline databases for articles comparing differences between the 2 genders in terms of biomarker expression. Keywords used included "Cardiovascular biomarkers sex differences". We reviewed the role of different biomarkers in the 2 genders in relation to cardiac events. CONCLUSIONS: Differences of expressions in biomarker levels were found between the 2 genders. Further investigation should be promoted.