Iron signature in asbestos-induced malignant pleural mesothelioma: A population-based autopsy study.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with poor prognosis. The development of MPM is frequently linked to inhalation of asbestos fibers. A genetic component of susceptibility to this disease is suggested by the observation that some individuals develop MPM following lower doses of asbestos exposure, whereas others exposed to higher quantities do not seem to be affected. This hypothesis is supported also by frequent reports of MPM familial clustering. Despite the widely recognized role of iron (Fe) in cellular asbestos-induced pulmonary toxicity, the role of the related gene polymorphisms in the etiology of MPM has apparently not been evaluated. Eighty-six single-nucleotide polymorphisms (SNPs) of 10 Fe-metabolism genes were examined by exploiting formalin-fixed paraffin-embedded postmortem samples from 77 patients who died due to MPM (designated AEM) and compared with 48 who were exposed to asbestos but from died in old age of cause other than asbestos (designated AENM). All subjects showed objective signs of asbestos exposure. Three SNPs, localized in the ferritin heavy polypeptide, transferrin, and hephaestin genes, whose frequencies were distributed differently in AEM and AENM populations, were identified. For ferritin and transferrin the C/C and the G/G genotypes, respectively, representing intronic polymorphisms, were significantly associated with protection against MPM and need to be considered as possible genetic markers of protection. Similarly, the C/C hephaestin SNP, a missense variation of this multicopper ferroxidase encoding gene, may be related, also functionally, with protection against MPM. In conclusion, it is proposed that three Fe metabolism-associated genes, significantly associated with protection against development of MPM, may serve as protective markers for this aggressive tumor.

The application of scanning near field optical imaging to the study of human sperm morphology.

BACKGROUND: The morphology of spermatozoa is a fundamental aspect to consider in fertilization, sperm pathology, assisted reproduction and contraception. Head, neck, midpiece, principal and terminal part of flagellum are the main sperm components to investigate for identifying morphological features and related anomalies. Recently, scanning near-field optical microscopy (SNOM), which belongs to the wide family of nanoscopic techniques, has opened up new routes for the investigation of biological systems. SNOM is the only technique able to provide simultaneously highly resolved topography and optical images with a resolution beyond the diffraction limit, typical of conventional optical microscopy. This offers the advantage to obtain complementary information about cell surface and cytoplasmatic structures. RESULTS: In this work human spermatozoa both healthy and with morphological anomalies are analyzed by SNOM, to demonstrate the potentiality of such approach in the visualization of sperm morphological details. The combination of SNOM topography with optical (reflection and transmission) images enables to examine typical topographic features of spermatozoa together with underlying cytoplasmic structures. Indeed the head shape and inner components as acrosome and nucleus, and the organization of mitochondria in the midpiece region are observed. Analogously for principal tract of the tail, the ridges and the columns are detected in the SNOM topography, while their internal arrangement can be observed in the corresponding SNOM optical transmission images, without requiring specific staining procedures or invasive protocols. CONCLUSIONS: Such findings demonstrate that SNOM represents a versatile and powerful tool to describe topographical and inner structural details of spermatozoa simultaneously. This analysis could be helpful for better characterizing several morphological anomalies, often related to sperm infertility, which cannot be examined by conventional techniques all together.

Bevacizumab and fotemustine for recurrent glioblastoma: a phase II study of AINO (Italian Association of Neuro-Oncology).

The optimal combination of bevacizumab with cytotoxic or cytostatic drugs in recurrent glioblastoma is unknown. We performed a phase 2 trial of combined bevacizumab and fotemustine for patients with glioblastoma at first relapse after radiotherapy and temozolomide. The primary endpoint was 6-month progression-free survival (PFS), while secondary endpoints were overall survival (OS), response rate based on RANO criteria and toxicity. Fifty-four patients with recurrent GBM were enrolled. The authors observed a 6-month PFS rate of 42.6% (95% CI 29.3-55.2) and a median PFS of 5.2 months (95% CI 3.8-6.6). The median OS was 9.1 months (95% CI 7.3-10.3). Twenty-eight patients (52%) had a radiographic response, and a significant neurological improvement with steroid reduction was observed in 25/42 symptomatic patients (60%). MGMT promoter methylation was significantly associated with improved PFS in univariate analysis. Most unifocal tumors at baseline had a focal enhancing progression (76%), while the diffuse non-enhancing progression accounted for 9.5%. Response or survival were not associated with any pattern of progression. Survival after failure of treatment was short. Twelve out of 54 patients (22%) discontinued fotemustine for grade 3/4 myelotoxicity, while 4/54 (7.4%) discontinued bevacizumab. This study failed to demonstrate a superiority of the combination of bevacizumab and fotemustine over either bevacizumab or fotemustine alone as historical controls. Future studies should explore alternative regimens of combination of the two drugs.

MGMT promoter methylation in plasma of glioma patients receiving temozolomide.

Promoter methylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene plays a role in cellular response to alkylating agents. In the present study aimed to: (i) evaluate the concordance between MGMT promoter methylation status in tumor tissue and plasma; (ii) monitor MGMT promoter methylation status in plasma taken before and during temozolomide treatment; (iii) explore the value of MGMT promoter methylation status in plasma as a prognostic/predictive biomarker in glioma patients. We enrolled 58 patients with histologically confirmed glioma at different grades of malignancy. All patients underwent surgical resection and temozolomide treatment. Paraffin-embedded tumor tissue was available for 48 patients. Blood samples were collected from all patients before temozolomide treatment (baseline) and at each MRI examination for a 12-month period. MGMT promoter methylation status was assessed in both sample types by real time PCR with a specific probe. The frequency of MGMT promoter methylation was 60.4 % in tumor tissue and 41.38 % in plasma. MGMT promoter methylation status was concordant in the two sample types (Kappa = 0.75, 95 % confidence interval (CI) 0.57-0.93; p value <0.001). Overall and progression-free survival were longer in patients with methylated MGMT promoter. Mortality was higher in patients with unmethylated MGMT promoter, whether in tumor tissue [hazard ratio (HR) 2.21; 95 % CI 0.99-4.95] or plasma (HR 2.19; 95 % CI 1.02-4.68). Progression-free survival was shorter in patients with unmethylated MGMT promoter, whether in tissue (HR 2.30; 95 % CI 1.19-4.45) or plasma (HR 1.77; 95 % CI 0.95-3.30). The cumulative incidence of unmethylated MGMT promoter in plasma at baseline was 58 %, and reached virtually 100 % at 12 months. In conclusion MGMT promoter methylation status in tumor tissue and plasma was highly concordant, and both were associated with longer survival, supporting the role of the detection of methylated MGMT promoter in predicting treatment response. However we suggest caution in using plasma as a surrogate of tumor tissue due to possible false-negative results.

Antiangiogenic therapy of brain tumors: the role of bevacizumab.

Angiogenesis is one of the hallmarks of cancer, including brain tumors. Malignant gliomas have the highest degree of vascular proliferation among solid tumors; thus, angiogenic pathways represent an attractive target to interfere with tumor growth. Up to date VEGF pathway targeting with specific drugs has yielded interesting therapeutics results. In particular bevacizumab, a monoclonal antibody against VEGF-A, has shown clinical activity in malignant gliomas, especially glioblastomas, in terms of a high response rate on MRI and a significant increase in progression-free survival.

The crocidolite fibres interaction with human mesothelial cells as investigated by combining electron microscopy, atomic force and scanning near-field optical microscopy.

In this study, we have performed a morphological analysis of crocidolite fibres interaction with mesothelial cells (MET5A) by combining conventional electron microscopy with atomic force (AFM) and scanning near-field optical microscopy (SNOM). After 6-h exposure at a crocidolite dose of 5 µg cm(-2), 90% of MET5A cells interact with fibres that under these conditions have a low cytotoxic effect. SEM images point out that fibres can be either engulfed by the cells that lose their typical morphology or they can accumulate over or partially inside the cells, which preserve their typical spread morphology. By using AFM we are able to directly visualize the entry-site of nanometric-sized fibres at the plasma membrane of the spread mesothelial cells. More importantly, the crocidolite fibres that are observed to penetrate the plasma membrane in SNOM topography can be simultaneously followed beneath the cell surface in the SNOM optical images. The analysis of SNOM data demonstrates the entrance of crocidolite fibres in proximity of nuclear compartment, as observed also in the TEM images. Our findings indicate that the combination of conventional electron microscopy with novel nanoscopic techniques can be considered a promising approach to achieve a comprehensive morphological description of the interaction between asbestos fibres and mesothelial cells that represents the early event in fibre pathogenesis.

Perioperative thromboprophylaxis in patients with craniotomy for brain tumours: a systematic review.

Venous thromboembolism (VTE) events are frequent in neurooncological patients in perioperative period thus increasing mortality and morbidity. The role of prophylaxis has not yet been established with certainty, and in various neurosurgery and intensive care units the practice is inconsistent. A better definition of the risk/cost/benefit ratio of the various methods, both mechanical (intermittent pneumatic compression-IPC, graduated compression stockings-GCS) and pharmacological (unfractionated heparin-UFH or low molecular weight heparin-LMWH), is warranted. We aim to define the optimal prophylactic treatment in the perioperative period in neurooncological patients. A systematic review of the literature was performed in Medline, Embase and Cochrane Library. Thirteen randomized controlled trials (RCTs) were identified, in which physical methods (IPC or GCS) and/or drugs (UFH or LMWHs) were evaluated in perioperative prophylaxis of neurological patients, mostly with brain cancer not treated with anticoagulants for other diseases. The analysis was conducted on a total of 1,932 randomized patients of whom 1,558 had brain tumours. Overall data show a trend of reduction of VTE in patients treated with mechanical methods (IPC or GCS) that should be initiated preoperatively and continued until discharge or longer in case of persistence of risk factors. The addition of enoxaparin starting the day after surgery, significantly reduces clinically manifest VTE, despite an increase in major bleeding events. Further studies are needed to delineate the types of patients with an increase of VTE risk and risk/benefits ratio of physical and pharmacological treatments in the perioperative period.

Targeted therapy in brain metastasis.

PURPOSE OF REVIEW: To review the state of the art and new developments in the field of targeted agents for brain metastases. RECENT FINDINGS: The huge amount of information on new molecular compounds and the advances in understanding the molecular pathways that mediate brain colonization have led to an increase of interest in preclinical and clinical investigations in the field of brain metastases. Targeted therapies can be employed either on established brain metastases or in a prevention setting. Targeting angiogenesis is an attractive approach. Up to date, large clinical trial datasets have shown that antiangiogenic agents do not increase the risk of bleeding into the brain. Bevacizumab (an anti-VEGF agent) is undergoing investigation in clinical trials on brain metastases from non-small cell lung cancer (NSCLC), breast cancer and melanoma. Sunitinib, a multitarget small molecule tyrosine kinase inhibitor (TKI), is a promising agent in brain metastases from renal cell cancer. The EGFR inhibitors gefitinib and erlotinib have a definite activity in brain metastases from NSCLC with activating EGFR mutations. Regarding HER2-positive breast cancer patients with established brain metastases, lapatinib (small molecule TKI) seems particularly active in association with capecitabine. Lapatinib alone is attractive in the prevention setting. Brain metastases from melanoma with BRAF V600E mutations respond to a specific inhibitor, such as vemurafenib. The immunomodulator ipilimumab is also active on brain metastases from melanoma. SUMMARY: The use of targeted agents in brain metastases from solid tumors is promising. The setting of prevention will be probably expanded in the next years. Well designed clinical trials with proper endpoints are needed.

Peroxidase-like activity of ferruginous bodies isolated by exploiting their magnetic property.

Ferruginous bodies (FB) are polymorphic structures whose formation is macrophage dependent, and are composed of a core, which may consist of an asbestos fiber coated with proteins, among which ferritin is the main component. Within ferritin, the ferric and ferrous ions are coordinated as ferrihydrite, which is the main iron (Fe) storage compound. However, when ferritin accumulates in some tissues following Fe overload it also contains magnetite along with ferrihydrite, which endows it with magnetic properties. Recently studies showed that magnetite exerts peroxidase-like activity, and since ferruginous bodies display magnetic properties, it was postulated that these particular structures may also contain magnetite within the ferritin coating, and thus may also exert peroxidase-like activity. Histochemical analysis for peroxidase of isolated FB smears demonstrated positive staining. Samples isolated from 4 different autopsy lung fragments were also able to oxidize 3,3',5,5'-tetramethyl-benzidine to a blue colored compound that absorbs at 655 nm. This activity was (1) azide and heat insensitive with optimal pH from 5 to 6, and (2) highly variable, changing more than 25-fold from one sample to another. These findings, together with evidence that the peroxidase-like activity of ferruginous bodies has a hydrogen peroxide and substrate requirement different from that of human myeloperoxidase, can exclude that this enzyme gives a significant contribution to the formation of FB. Standard Fe-rich asbestos fibers also express a peroxidase-like activity, but this appears negligible compared to that of ferruginous bodies. Strong acidification of standard Fe-containing asbestos fibers or magnetically isolated ferruginous bodies liberates a high amount of peroxidase-like activity, which is probably accounted for by the release of Fe ions. Further, FB also damage mesothelial cells in vitro. Data suggest that FB exert peroxidase-like activity and cytotoxic activity against mesothelial cells, and hence may be an important factor in pathogenesis of asbestos-related diseases.

Epilepsy and brain tumors.

PURPOSE OF REVIEW: To present an overview of the recent findings in pathophysiology and management of epileptic seizures in patients with brain tumors. RECENT FINDINGS: Low-grade gliomas are the most epileptogenic brain tumors. Regarding pathophysiology, the role of peritumoral changes [hypoxia and acidosis, blood-brain barrier (BBB) disruption, increase or decrease of neurotransmitters and receptors] are of increasing importance. Tumor-associated epilepsy and tumor growth could have some common molecular pathways. Total/subtotal surgical resection (with or without epilepsy surgery) allows a seizure control in a high percentage of patients. Radiotherapy and chemotherapy as well have a role. New antiepileptic drugs are promising, both in terms of efficacy and tolerability. The resistance to antiepileptic drugs is still a major problem: new insights into pathogenesis are needed to develop strategies to manipulate the pharmakoresistance. SUMMARY: Epileptic seizures in brain tumors have been definitely recognized as one of the major problems in patients with brain tumors, and need specific and multidisciplinary approaches.

Caveolin 1 expression independently predicts shorter survival in oligodendrogliomas.

Caveolin 1 (cav-1) is the basic component of the flask-shaped membrane microdomains known as caveolae that are involved in various cell functions. Caveolin 1 can be overexpressed in tumors,suggesting a proneoplastic role, or it can be downregulated. We previously reported that cav-1 expression increases with tumor grade in astrocytomas. Here, we studied cav-1 immunoreactivity in brain umors with an oligodendroglial component to determine the prognostic value of cav-1 expression and to correlate it with 1p/19q deletions. Fifty-four oligodendrogliomas, 26 mixed oligoastrocytomas,and 7 glioblastomas with an oligodendroglial component were assessed for cav-1 expression by immunohistochemistry and for 1p/19q status by fluorescence in situ hybridization. Caveolin-1 was detected in a minority of cases (22%) and was associated mostly with Grade III mixed oligoastrocytomas and glioblastomas with anoligodendroglial component; cav-1 expression was significantly correlated with the absence of a 1p/19q deletion (p = 0.0002). In the 63 cases in which survival data were available, cav-1 expression was also significantly associated with shorter survivals, whereas 1p/19q deletion was associated with longer survivals. Among high-grade tumors, cav-1 expression was the only factor that retained a statistical significance after multivariate analysis for the prediction ofa short survival (p G 0.015). These data are the first evidence that cav-1 immunohistochemistry is an independent prognostic marker in tumors with an oligodendroglial component regardless of the 1p/19q status.

Effect of methylene blue photodynamic therapy on human neutrophil functional responses.

Photodynamic therapy (PDT) has become an emerging novel therapeutic approach for treating localized microbial infections, particularly those sustained by multidrug-resistant strains. Given the irreplaceable role played by professional phagocytes in limiting infections, such as polymorphonuclear neutrophils, any newly designed antimicrobial therapeutic approach must not interfere with their function. The present investigation presents a detailed analysis of the effect of PDT on the viability and several functional responses of human polymorphonuclear neutrophils loaded with methylene blue (MB), one of the more commonly used photosensitizers in antimicrobial PDT. Taking advantage of the use of a specifically-designed optical LED array for illuminating MB-loaded human polymorphonuclear neutrophils, a number of cell functions have been assayed under miniaturized, strictly controlled and reproducible experimental conditions. The major findings of this study are the following: (1) MB-PDT increases human neutrophils adhesion and does not modify myeloperoxidase release; (2) MB-PDT markedly enhances reactive oxygen species generation that is independent of superoxide-forming phagocytic oxidase and very likely ascribable to LED-dependent excitation of accumulated methylene blue; (3) MB-PDT almost abolishes human neutrophils candidacidal activity by hindering the engulfing machinery. This in vitro study may represent a valuable reference point for future research on PDT applications for treating localized microbial infections.

Mast Cells in Peritoneal Fluid From Women With Endometriosis and Their Possible Role in Modulating Sperm Function.

Endometriosis is a local pelvic inflammatory process, frequently associated with infertility, with altered function of immune-related cells in the peritoneal environment. Mast cells are known to be key players of the immune system and have been recently involved in endometriosis and in infertility, with their mediators directly suppressing sperm motility. In this study, we evaluated the mast cell population and their mediators in the peritoneal fluid of infertile patients with endometriosis and their impact on human sperm motility. Peritoneal fluids, collected by laparoscopy from 11 infertile patients with endometriosis and 9 fertile controls were evaluated for the presence of mast cells, tryptase levels and their effect on sperm motility. Furthermore, an in vitro model of mast cells-sperm interaction in peritoneal fluid was set up, using LAD2 cell line as a mast cell model, and analyzed from a functional as well as a morphological point of view. Mast cell peritoneal fluid population and its main mediator, tryptase, is more represented in endometriosis confirming an involvement of these cells in this disease. Anyway it appears unlikely that tryptase enriched peritoneal fluid, which fails to inhibit sperm motility, could contribute to endometriosis associated infertility. Despite of this, sperm interaction with the mast cell surface (LAD2) induced a significantly mast cell-degranulation response in the peritoneal fluid from endometriosis which could directly modulate sperm function other than motility. This evidence lead us to suppose that there is, between these elements, an interrelationship which deserves further studies.

Brain metastases: current management and new developments.

PURPOSE OF REVIEW: To review the state-of-the-art and new developments in the management of patients with brain metastases. RECENT FINDINGS: Treatment decisions are based on prognostic factors to maximize neurologic function and survival, while avoiding unnecessary therapies. Whole-brain radiotherapy (WBRT) is the treatment of choice for patients with unfavorable prognostic factors. Stereotactic radiosurgery (SRS) or surgery is indicated for patients with favorable prognostic factors and limited brain disease. In single brain metastasis, the addition of either stereotactic radiosurgery or surgery to WBRT improves survival. The omission of WBRT after surgery or radiosurgery results in a worse local and distant control, though it does not affect survival. The incidence of neurocognitive deficits in long-term survivors after WBRT remains to be defined. New approaches to avoid cognitive deficits following WBRT are being investigated. The role of chemotherapy is limited. Molecularly targeted therapies are increasingly employed. Prophylaxis with WBRT is the standard in small-cell lung cancer. SUMMARY: Many questions need future trials: the usefulness of new radiosensitizers; the role of local treatments after surgery; and the impact of molecularly targeted therapies on subgroups of patients with specific molecular profiles. Quality of life and cognitive functions are recognized as major endpoints in clinical trials.

The Secretory Response of Rat Peritoneal Mast Cells on Exposure to Mineral Fibers.

BACKGROUND: Exposure to mineral fibers is of substantial relevance to human health. A key event in exposure is the interaction with inflammatory cells and the subsequent generation of pro-inflammatory factors. Mast cells (MCs) have been shown to interact with titanium oxide (TiO2) and asbestos fibers. In this study, we compared the response of rat peritoneal MCs challenged with the asbestos crocidolite and nanowires of TiO2 to that induced by wollastonite employed as a control fiber. METHODS: Rat peritoneal MCs (RPMCs), isolated from peritoneal lavage, were incubated in the presence of mineral fibers. The quantities of secreted enzymes were evaluated together with the activity of fiber-associated enzymes. The ultrastructural morphology of fiber-interacting RPMCs was analyzed with electron microscopy. RESULTS: Asbestos and TiO2 stimulate MC secretion. Secreted enzymes bind to fibers and exhibit higher activity. TiO2 and wollastonite bind and improve enzyme activity, but to a lesser degree than crocidolite. CONCLUSIONS: (1) Mineral fibers are able to stimulate the mast cell secretory process by both active (during membrane interaction) and/or passive (during membrane penetration) interaction; (2) fibers can be found to be associated with secreted enzymes-this process appears to create long-lasting pro-inflammatory environments and may represent the active contribution of MCs in maintaining the inflammatory process; (3) MCs and their enzymes should be considered as a therapeutic target in the pathogenesis of asbestos-induced lung inflammation; and (4) MCs can contribute to the inflammatory effect associated with selected engineered nanomaterials, such as TiO2 nanoparticles.

Histopathological data of iron and calcium in the mouse lung after asbestos exposure.

This data article contains data related to the research article entitled, "Synchrotron X-ray microscopy reveals early calcium and iron interaction with crocidolite fibers in the lung of exposed mice" [1]. Asbestos fibers disrupt iron homeostasis in the human and mouse lung, leading to the deposition of iron (Fe) onto longer asbestos fibers which forms asbestos bodies (AB) [2]. Similar to Fe, calcium (Ca) is also deposited in the coats of the AB. This article presents data on iron and calcium in the mouse lung after asbestos exposure detected by histochemical evaluation.

Synchrotron X-ray microscopy reveals early calcium and iron interaction with crocidolite fibers in the lung of exposed mice.

Human exposure to asbestos can cause a wide variety of lung diseases that are still a current major health concern, even if asbestos has been banned in many countries. It has been shown in many studies that asbestos fibers, ingested by alveolar macrophages, disrupt lung iron homeostasis by sequestering iron. Calcium can also be deposited on the fibers. The pathways along which iron and above all calcium interact with fibers are still unknown. Our aim was that of investigating if the iron accumulation induced by the inhaled asbestos fibers also involves calcium ions accumulation. Lung sections of asbestos-exposed mice were analyzed using an extremely sensitive procedure available at the synchrotron facilities, that provides morphological and chemical information based on X-ray fluorescence microspectroscopy (µ-XRF). In this study we show that (1) where conventional histochemical procedures revealed only weak deposits of iron and calcium, µ-XRF analysis is able to detect significant deposits of both iron and calcium on the inhaled asbestos fibers; (2) the extent of the deposition of these ions is proportionally directly related and (3) iron and calcium deposition on inhaled asbestos fibers is concomitant with the appearance of inflammatory and hyperplastic reactions.

NLRP1 and NLRP3 polymorphisms in mesothelioma patients and asbestos exposed individuals a population-based autopsy study from North East Italy.

NRLP1 (rs12150220, rs9889625, rs9900356, rs6502867, rs2670660) and NLRP3 (rs35829419, rs10754558) polymorphisms have been analyzed in 69 subjects with documented asbestos exposure and death for malignant pleural mesothelioma and 59 patients with documented asbestos exposure but death for other causes, all from a North East Italy. No association was found between NLRP1 and NLRP3 polymorphisms and susceptibility to develop mesothelioma using the general, dominant or recessive models. Also haplotype analysis did not reveal any significant association with mesothelioma. Our findings, being controversial with respect to another study on Italian patients, do suggest the need of further studies to unravel the contribution of NLRP1 and NLRP3 in susceptibility to mesothelioma.

NOD1 and NOD2 Interact with the Phagosome Cargo in Mast Cells: A Detailed Morphological Evidence.

Mast cells (MC) play a key role in triggering the inflammatory process and share some functions with professional phagocytes. It is not clear whether or not the phagocytic process in MC follows the same route and has the same meaning of that of professional phagocytes. Herein we analyze in detail the structure of the phagosome in rat peritoneal mast cells (RPMC). The ultrastructural analysis of the phagosome, containing either model particles or bacteria, reveals that these vacuoles are very tight, and in several areas, their membrane seems to have dissolved. RPMC express NOD1 and NOD2 proteins whose role is to recognize intracellular foreign components and induce the production of pro-inflammatory mediators. Following Escherichia coli ingestion, both these molecules are found on the phagosome membrane and on ingested pathogens, together with phagosome maturation markers. These findings suggest that in RPMC the ingested cargo can, through interruptions of the phagosome membrane, interact directly with NODs, which act as switches in the process of cytokine production.

Is there a Role for Bevacizumab in Non-Glial Tumors?

Angiogenesis is one of the hallmarks of cancer, including brain tumors. The vascular endothelial growth factor (VEGF) family and their receptors are of utmost importance in the complex interaction between pro- and anti-angiogenic factors, and have a crucial role in tumor angiogenesis. Up to date, targeting the VEGF pathway with specific drugs has yielded interesting results in oncology. In particular bevacizumab (Bev), a humanized monoclonal antibody against VEGF-A, has been approved by the Food and Drug Administration (FDA) for use in recurrent glioblastomas failing standard radiochemotherapy. Bevacizumab is now being extensively investigated in several non-glial brain tumors, such as vestibular schwannomas, meningiomas, ependymomas, medulloblastomas and miscellaneous histotypes. The aim of this review is to reevaluate the literature on the use of Bev in non-glial brain tumors.