Potential use of prostate specific membrane antigen (PSMA) for detecting the tumor neovasculature of brain tumors by PET imaging with <Superscript>89</Superscript>Zr-Df-IAB2M anti-PSMA minibody

Tumor angiogenesis has attracted increasing attention because of its potential as a valuable marker in the differential diagnosis of brain tumors as well as a novel therapeutic target. Prostate-specific membrane antigen (PSMA) is expressed by the neovasculature endothelium of some tumors, with little to no expression by the tumor cells or normal vasculature endothelium. The aim of this study was to investigate the potential of PSMA for the evaluation of the tumor neovasculature of various brain tumors and the possibility of detecting PSMA expression in brain tumors using PET imaging with ⁸⁹Zr-Df-IAB2M (anti-PSMA minibody). Eighty-three tissue specimens including gliomas, metastatic brain tumors, primary central nervous system lymphomas (PCNSL), or radiation necroses were analyzed by immunohistochemical staining with PSMA antibody. ⁸⁹Zr-Df-IAB2M PET scans were performed in three patients with recurrent high-grade gliomas or metastatic brain tumor. PSMA was highly expressed in the vascular endothelium of high-grade glioma and metastatic brain tumor, whereas PSMA was poorly expressed in the vascular endothelium of PCNSL and radiation necrosis. PSMA expression in high-grade gliomas and a metastatic brain tumor was clearly visualized by PET imaging with ⁸⁹Zr-Df-IAB2M. Furthermore, a trend toward a positive correlation between the degree of ⁸⁹Zr-Df-IAB2M uptake and PSMA expression levels in tumor specimens was observed. PET imaging of PSMA using ⁸⁹Zr-Df-IAB2M may have potential value in the differential diagnosis of high-grade glioma from PCNSL or radiation necrosis as well as in the prediction of treatment efficacy and assessment of treatment response to bevacizumab therapy for high-grade glioma.     

Improving outcomes for neurofibromatosis 1–associated brain tumors

Children and adults with neurofibromatosis type 1 (NF1) are predisposed to developing CNS tumors, including optic pathway gliomas (OPGs), brainstem gliomas (BSGs) and high-grade gliomas. Although current first-line treatments for low-grade gliomas (OPGs and BSGs) may prevent further tumor growth, they rarely result in restoration of the associated visual or neurological deficits. The availability of accurate small-animal models of NF1-associated brain tumors has established tractable experimental platforms for the discovery and evaluation of promising therapeutic agents. On the basis of these preclinical studies, biologically targeted agents are now being evaluated in children with NF1-associated low-grade brain tumors. Collectively, these models have also begun to reveal potential neuroprotective and risk assessment strategies for this brain tumor-prone population.     

The 150 most important questions in cancer research and clinical oncology series:questions 6–14

To accelerate our endeavors to overcome cancer, Chinese Journal of Cancer has launched a program of publishing 150 most important questions in cancer research and clinical oncology. In this article, nine more questions are presented as followed. Question 6. Why do nasopharyngeal carcinomas rarely metastasize to the brain? Question 7. Can distant spread of cancer cells be blocked by inhibiting the remodeling of high endothelial venules in the sentinel lymph node? Question 8. What sort of live-imaging techniques can be developed to directly observe the dynamic processes of metastasis? Question 9. How does chronic hepatitis prevent liver metastasis from colorectal cancer? Question 10.How many types of host cells contribute to forming the pre-metastatic niche in the lung favorable for metastasis?Question 11. Why do cancers rarely metastasize to the small bowel? Question 12. Why do glioblastomas rarely metastasize outside the central nervous system? Question 13. Despite increased understanding of the molecular genetic events leading to the development and progression of high-grade gliomas, these tumors are the most therapeutically refractory among all human cancers. What then would be the most effective therapeutic approaches to treat what in essence can be regarded as a whole brain malignancy, since even a surgical resection of greater than 99% of tumor tissues is invariably associated with recurrence? Question 14. The blood–brain barrier (BBB) effectively limits a wide variety of potential therapeutic agents from reaching glioma cells widely dispersed in the brain. What therapeutic approaches can be used to breach the BBB and allow therapeutic agents to seek out and kill these tumor cells?     

DTI在高级别胶质瘤及转移瘤鉴别诊断中价值初探

 目的　初步研究DTI在高级别胶质瘤和转移瘤鉴别诊断中的作用。方法　对 8例高级别胶质瘤、6例转移瘤患者进行常规MRI及DTI检查 ,测量患侧感兴趣区ADC、FA值 ,部分求出与对侧相应部位兴趣区比值 ,行组间统计学分析。结果　两组间肿瘤实性部分、肿瘤囊性部分ADC值及瘤周水肿ADC比值、FA比值差异无显著性 ,水肿周围正常白质ADC及FA比值两组间差异有显著性。结论　水肿周围正常白质ADC、FA比值的测定有利于高级别胶质瘤与转移瘤的鉴别诊断 ,DTI较常规MRI可更好地观察肿瘤与脑白质的关系。     

Unsanctifying the sanctuary: challenges and opportunities with brain metastases

While the use of targeted therapies, particularly radiosurgery, has broadened therapeutic options for CNS metastases, patients respond minimally and prognosis remains poor. The inability of many systemic chemotherapeutic agents to penetrate the blood-brain barrier (BBB) has limited their use and allowed brain metastases to become a burgeoning clinical challenge. Adequate preclinical models that appropriately mimic the metastatic process, the BBB, and blood-tumor barriers (BTB) are needed to better evaluate therapies that have the ability to enhance delivery through or penetrate into these barriers and to understand the mechanisms of resistance to therapy. The heterogeneity among and within different solid tumors and subtypes of solid tumors further adds to the difficulties in determining the most appropriate treatment approaches and methods of laboratory and clinical studies. This review article discusses therapies focused on prevention and treatment of CNS metastases, particularly regarding the BBB, and the challenges and opportunities these therapies present.     

New therapeutic approaches for brainstem tumors: a comparison of delivery routes using nanoliposomal irinotecan in an animal model

Despite the advances in imaging, surgery and radiotherapy, the majority of patients with brainstem gliomas die within 2 years after initial diagnosis. Factors that contribute to the dismal prognosis of these patients include the infiltrative nature and anatomic location in an eloquent area of the brain, which prevents total surgical resection and the presence of the blood–brain barrier (BBB), which reduces the distribution of systemically administered agents. The development of new therapeutic approaches which can circumvent the BBB is a potential path to improve outcomes for these children. Convection-enhanced delivery (CED) and intranasal delivery (IND) are strategies that permit direct drug delivery into the central nervous system and are an alternative to intravenous injection (IV). We treated rats bearing human brainstem tumor xenografts with nanoliposomal irinotecan (CPT-11) using CED, IND, and IV. A single treatment of CED irinotecan had a similar effect on overall survival as multiple treatments by IV route. IND CPT-11 showed significantly increased survival of animals with brainstem tumors, and demonstrated the promise of this non-invasive approach of drug delivery bypassing the BBB when combined with nanoliposomal chemotherapy. Our results indicated that using CED and IND of nanoliposomal therapy increase likelihood of practical therapeutic approach for the treatment of brainstem gliomas.     

Growth inhibition of the 9L glioma using polymers to release heparin and cortisone acetate

Summary Malignant gliomas are difficult to treat systemically because of exclusion of many chemotherapeutic agents by the blood brain barrier. Furthermore, as opposed to other neoplasms, malignant gliomas recur locally, at the site of original presentation. These tumors are remarkably vascular and hence may be more dependent on angiogenesis for continued growth than other tumors. The inhibition of tumor angiogenesis can control tumor growth by preventing the exponential vascular growth phase. We report the inhibition of the growth of the 9L glioma by the localized, controlled release of known angiogenesis inhibitors administered in a biodegradable polyanhydride polymer matrix. In the presence of heparin and cortisone and of cortisone alone there was a 4.5- and 2.3-fold reduction, respectively, in the growth of the 9L glioma. We compared these results to the inhibition of tumor neovascularization in the rabbit cornea by the localized delivery of the same agents. In the rabbit cornea model, the local release of heparin and cortisone and of cortisone alone resulted in a 2.5- and 2.0-fold reduction, respectively, in the angiogenesis response evoked by the VX2 carcinoma. This study introduces two new potential therapeutic modalities for the treatment of malignant gliomas: the use of the combination of heparin and cortisone as antineoplastic agents and the use of polymeric carriers for the local delivery of such agents in the central nervous system.     

Clinical trial of MCNU for malignant brain tumors

A total of 71 cases with primary brain tumors (44 cases) and metastatic brain tumors (30 cases) were entered into our clinical studies with MCNU and radiation therapy or MCNU alone. With regard to tumor reduction on CT scan, the response rates obtained for MCNU and radiation were 21.7% for malignant gliomas and 50.0% for metastatic brain tumors. With regard to improvement of neurological signs, the response rates obtained for MCNU and radiation were 62.9% for malignant gliomas and 71.4% for metastatic brain tumors. The response rates for MCNU were 5.8% for malignant gliomas and 46.1% for metastatic brain tumors. In the improvement of performance status, the response rates for MCNU and radiation were 51.8% for malignant gliomas and 64.2% for metastatic brain tumors. The response rates for MCNU were 46.1% for malignant gliomas and 30.7% for metastatic brain tumors. A minimal degree of hematological toxicity occurred but this gradually disappeared. These results suggested that MCNU has relatively effective antitumor activity against metastatic brain tumors and an enhanced effect with radiation against malignant gliomas.     

Nestin expression in brain tumors: its utility for pathological diagnosis and correlation with the prognosis of high-grade gliomas

One of the type VI intermediate filament proteins, nestin, is expressed in neuroepithelial stem cells during neural embryogenesis. Nestin is also expressed in a variety of neoplasms. Its expression in brain tumors has not been thoroughly studied. The objectives of this study were to survey nestin expression in different types of brain tumor, and to evaluate nestin as a marker for diagnosis and prognosis. We used tissue microarrays of 257 brain tumors for an immunohistochemical overview of nestin expression: nestin was frequently expressed in gliomas and schwannomas. Most of the gliomas that expressed high levels of nestin were high-grade gliomas (anaplastic astrocytomas, anaplastic oligodendrogliomas, anaplastic oligoastrocytomas, and glioblastomas). We then focused on high-grade gliomas and performed immunohistochemistry again, using whole-mount slides. As a result, we found (1) significantly different nestin expression between glioblastomas and other high-grade gliomas, and (2) worse overall survival for high-grade gliomas with high nestin expression. Our results suggest that: (1) nestin is a useful marker for diagnosis of high-grade gliomas, (2) nestin is helpful in diagnosis of schwannomas, and (3) nestin expression is related to poor prognosis in high-grade gliomas.     

Increased delivery of erucylphosphocholine to C6 gliomas by chemical opening of the blood-brain barrier using intracarotid pentylglycerol in rats

BACKGROUND: Erucylphosphocholine (ErPC) has been shown to exert strong antineoplastic effects against various brain tumor cell lines in vitro. Since ErPC only enters the brain after long-term treatment, ineffective drug delivery to the tumor is considered to be the reason for the moderate responses to chemotherapy with ErPC observed in animal brain tumor models. We investigated a recently described method for chemically opening the blood-brain barrier (BBB) using intraarterial administration of alkylglycerols to increase the transfer of ErPC into the brain. METHODS: ErPC (40 mg/kg) was given to C6 glioma-bearing rats either as a single intracarotid bolus injection in the presence or absence of 1- O-pentylglycerol (300 m M) or as an intracarotid infusion in conjunction with bradykinin. Brain tissue concentrations were analyzed and compared to values obtained after intravenous ErPC treatment over 14 and 30 days (cumulative ErPC doses of 210 and 350 mg/kg, respectively). RESULTS: Pentylglycerol-induced BBB opening resulted in a significant increase in ErPC delivery to the tumor (17-fold) and, to a lesser extent, to the surrounding ipsilateral brain (7-fold) compared to intraarterial ErPC administration without alkylglycerol ( P<0.05). Furthermore, the resulting ErPC concentrations in the brain tumor exceeded those obtained in tumor and tumor-free brain after long-term intravenous ErPC administration. In contrast to this, intracarotid bradykinin did not increase the transfer of ErPC to the tumor or tumor-free brain. CONCLUSIONS: The intracarotid administration of pentylglycerol represents a novel and nontoxic method of overcoming the limited access of ErPC to both brain tumors and brain tissue adjacent to tumors. The present results provide further evidence that chemical opening of the BBB by intraarterial alkylglycerols is a promising new concept for improving delivery of chemotherapeutic agents to brain tumors.     

Proteomic-based prognosis of brain tumor patients using direct-tissue matrix-assisted laser desorption ionization mass spectrometry

Clinical diagnosis and treatment decisions for a subset of primary human brain tumors, gliomas, are based almost exclusively on tissue histology. Approaches for glioma diagnosis can be highly subjective due to the heterogeneity and infiltrative nature of these tumors and depend on the skill of the neuropathologist. There is therefore a critical need to develop more precise, non-subjective, and systematic methods to classify human gliomas. To this end, mass spectrometric analysis has been applied to these tumors to determine glioma-specific protein patterns. Protein profiles have been obtained from human gliomas of various grades through direct analysis of tissue samples using matrix-assisted laser desorption ionization mass spectrometry (MS). Statistical algorithms applied to the MS profiles from tissue sections identified protein patterns that correlated with tumor histology and patient survival. Using a data set of 108 glioma patients, two patient populations, a short-term and a long-term survival group, were identified based on the tissue protein profiles. In addition, a subset of 57 patients diagnosed with high-grade, grade IV, malignant gliomas were analyzed and a novel classification scheme that segregated short-term and long-term survival patients based on the proteomic profiles was developed. The protein patterns described served as an independent indicator of patient survival. These results show that this new molecular approach to monitoring gliomas can provide clinically relevant information on tumor malignancy and is suitable for high-throughput clinical screening.     

The Role of Surgery in Pediatric Gliomas

Pediatric glial tumors differ from adult gliomas in several ways that are of major therapeutic importance. First, the value of extensive tumor resection, which is controversial for malignant intrinsic brain tumors in adults, has been confirmed for a variety of childhood brain tumors, such as supratentorial high-grade and low-grade gliomas and infratentorial low-grade gliomas, ependymomas, and some medulloblastomas. Second, chemotherapy has been found to be effective in improving overall outcome in several childhood brain tumors, such as medulloblastoma and supratentorial high-grade glioma, but has yet to be proven to have a major benefit for adult tumors. In addition, chemotherapy is increasingly used to delay or avoid radiotherapy in young children with high-grade and incompletely resected low-grade tumors to avoid the morbidity of irradiation on the developing nervous system. Third, the prognosis for histologically similar tumors is often more favorable in children than adults. The present chapter will highlight the unique features of childhood glial tumors, discuss general principles in the clinical presentation, diagnostic evaluation, and treatment of these tumors, and then focus on the surgical management and outcome of the more common types of tumors.     

A critical assessment of boron neutron capture therapy: an overview

Summary Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when boron-10 is irradiated with neutrons of the appropriate energy to produce high-energy alpha particles and recoiling lithium-7 nuclei. BNCT has been used clinically to treat patients with high-grade gliomas, and a much smaller number with primary and metastatic melanoma. The purpose of this special issue of the Journal of Neuro-Oncology is to provide a critical and realistic assessment of various aspects of basic and clinical BNCT research in order to better understand its present status and future potential. Topics that are covered include neutron sources, tumor-targeted boron delivery agents, brain tumor models to assess therapeutic efficacy, computational dosimetry and treatment planning, results of clinical trails in the United States, Japan and Europe, pharmacokinetic studies of sodium borocaptate and boronopheylalanine (BPA), positron emission tomography imaging of BPA for treatment planning, and finally an overview of the challenges and problems that must be faced if BNCT is to become a useful treatment modality for brain tumors. Clinical studies have demonstrated the safety of BNCT. The next challenge is an unequivocal demonstration of therapeutic efficacy in one or more of the clinical trails that either are in progress or are planned over the next few years.     

多层螺旋CT灌注成像诊断中老年脑胶质瘤

目的:探讨多层螺旋CT灌注成像对中老年脑胶质瘤的诊断作用,以期为临床中老年脑胶质瘤的诊疗提供借鉴。方法:以自2012年6月份以来入我院治疗的确诊为中老年脑胶质瘤的患者为研究对象,先后对患者行多层螺旋CT灌注成像扫描,获得并分析扫描图像中脑组织的多维多层螺旋灌注图像、CT血管成像,计算并分析多层螺旋CT灌注成像图像的病变实质部分和正常脑组织的达峰时间（TTP）、平均通过时间（MTT）、脑血流量（CBF）、脑血容量（CBV）参数、毛细血管表面通透性(ＰＳ)等灌注参数,通过灌注分析软件获得并分析时间-密度曲线(ＴＤＣ)。结果:共纳入患者43例患者,在所有病例中,多维多层螺旋灌注图像平均视觉评价分数明显高于单纯轴向灌注图(P=0.000),且对病变定位更为精确。CT血管造影（CT angiography,CTA）图中43 例患者中,有36例肿瘤发现供血大动脉,23 例肿瘤有引流静脉,29例大动脉受压,15例大动脉被肿瘤包裹,17例静脉窦受压。统计分析示,多层螺旋CT灌注成像图像的病变实质部分和正常脑组织的脑血流量（CBF）、毛细血管表面通透性(ＰＳ)、脑血容量（CBV）参数等灌注参数,两者之间差异具有统计学意义（P<0.05）。多层螺旋CT灌注成像图像的病变实质部分和正常脑组织的达峰时间（TTP）、平均通过时间（MTT）等灌注参数,两者之间差异无统计学意义（P>0.05）;低、高级别胶质瘤的病灶关键测试参数（critical test parameter,CTP）比较,ＣＢＦ、ＴＴＰ等灌注参数,两者之间差异具有统计学意义（P<0.05）。不同种类颅内肿瘤ＴＤＣ比较,高级别胶质瘤速升速降,低级别胶质瘤速升缓降型。结论:多层螺旋CT灌注成像图像不仅可以实现对邻近大血管颅内肿瘤的全面评价,有利于颅内肿瘤的术前整体评估和精确定位;且对颅内肿瘤的诊断及评价肿瘤与周围大血管的关系、对中老年脑胶质瘤的级别诊断也有一定的临床应用价值。     

BR96–DOX Immunoconjugate Targeting of Chemotherapy in Brain Tumor Models

An immunoconjugate of doxorubicin (adriamycin) and a tumor-specific monoclonal antibody, BR96–DOX (now SGN-15) targets chemotherapy to cells that express the Lewis^Y antigen. This immunoconjugate is internalized into lysosomes in antigen-expressing cells, with release of free doxorubicin after hydrolysis of the acid-labile linker. We review our studies using BR96–DOX in a human small-cell lung carcinoma intracerebral xenograft model in nude rats. We have found that the immunoconjugate is effective against intracerebral tumors when delivery is enhanced with osmotic disruption of the blood–brain barrier (BBB). Enhanced delivery of BR96–DOX with BBB opening can work together with radiotherapy to increase antitumor efficacy, which is maximally effective if immunoconjugate is administered prior to radiotherapy. In heterogeneous brain tumors, enhanced delivery of BR96–DOX significantly reduced tumor volumes, but local release of doxorubicin by targeting antigen expressing cells shows modest cytotoxicity against adjacent non-expressor cells. Although BR96–DOX is not effective against glioma cells tested, it does provide a model for drug-immunoconjugate therapy of gliomas. Our studies in a rat brain tumor model point out the importance of optimized delivery, antigenic heterogeneity, and bystander effect for brain tumor therapy. We review additional studies of drug–mAb immunoconjugates pertinent to the treatment of gliomas.     

Gene therapy as an adjuvant treatment for malignant gliomas: from bench to bedside

Malignant brain tumors, including high-grade gliomas, are among the most lethal of all cancers. Despite considerable advances, including multi-modality treatments with surgery, radiotherapy, and chemotherapy, the overall prognosis for patients with this disease remains dismal. Currently available treatments necessitate the development of more effective tumor-selective therapies. The use of gene therapy for brain tumor therapy is promising as it can be delivered in situ and selectively targets brain tumor cells while sparing the adjacent normal brain tissue. In this article, we summarize the laboratory and clinical work using viral, cell-based, and synthetic vectors, as well as other strategies focused on potentiate gene delivery. Although tangible results on patients’ survival remains to be further documented, significant advances in therapeutic gene transfer strategies have been made. The enthusiasm of this progress needs to be tempered by the realistic assessment of the challenges needed to be overcome. Finally, as the field of gene delivery progresses, advances must be made in identifying genes and proteins key to the treatment of malignant gliomas. Due to the great heterogeneity of malignant glioma cells, only approaches combining different strategies may be ultimately successful in defeating this disease.     

Do anticancer agents reach the tumor target in the human brain?

Summary The development of effective chemotherapy for tumors of the central nervous system (CNS) is complicated in that the blood-brain barrier (BBB) hampers the penetration of most drugs into the brain and cerebrospinal fluid (CSF). This review summarizes the main reports on the distribution to CNS tumors and peritumoral normal brain of antitumor agents such as epipodophyllotoxins,cis-diamminedichloroplatinum(II), some nitrosoureas, bleomycin, vinblastine, and other clinically used antitumor agents as well as that of some experimental compounds with specific physicochemical properties. Drug levels were measured at surgical resection or in autopsy samples taken from patients who presented with different primary brain tumors or with brain metastases from extracerebral tumors. The observations made in each study were summarized in some detail, and the main points were then evaluated comparatively so as to highlight common aspects in the pharmacokinetic patterns of antitumor agents in human CNS tumors. Independently of their physicochemical properties, most antitumor agents appear to accumulate to a greater extent and to persist longer in intracerebral tumors than in the normal peritumoral brain. From in vitro cytotoxicity assays, it appears that epipodophyllotoxins, platinum compounds, bleomycin, and nitrosoureas reach potentially active therapeutic concentrations at the tumor target. However, all drugs have difficulty in reaching brain tissue adjacent to the tumor, as the intact BBB hampers their penetration. Plasma and CSF drug concentrations usually give little useful indication of the absolute quantity of drugs in brain tumors. To obtain a clear understanding of the CNS distribution of antitumor agents, one must determine whether the compound being measured is actually responsible for the observed activity and must consider the role of metabolites in the effect of the parent drug.Abbreviations AZQ aziridinylbenzoquinone - BBB blood-brain barrier - CNS central nervous system - CSF cerebrospinal fluid - BCNU carmustine - BLEO bleomycin - CDDP cisplatin - DAU 3-deazauridine - DBD dibromodulcitol - DTIC dimethyl triazene imidazole carboxamide - MGBG methylglyoxal bis(guanylhydrazone) - MITXR mitoxantrone - PALA N-phosphonacetyl-l-aspartate - PMM pentamethylmelamine - TCNU tauromustine - VLB vinblastine - VM-26 teniposide - VP-16 etoposide This work was supported by the Italian Association for Cancer Research, by the Tettamenti Foundation, and by M.U.R.S.T. (60%) and was conducted under the auspices of the PAMM group of the EORTC     

Safety,feasibility, and optimization of intra-arterial mitoxantrone delivery to gliomas

Mitoxantrone is a highly cytotoxic antineoplastic drug, however, its poor penetration of the blood–brain barrier has limited its role in the treatment of brain cancers. We hypothesize that intra-arterial (IA) delivery of mitoxantrone may enhance its capacity for regional brain deposition thus expanding its potential as a brain tumor therapy agent. In this study we assessed the dose-response characteristics as well as the feasibility and safety of mitoxantrone delivery to the brain and specifically to gliomas in a rodent model. We show that delivery optimization utilizing the technique of intra-arterial transient cerebral hypoperfusion (IA-TCH) facilitates achieving the highest peak- and end- brain drug concentrations as compared to intravenous and IA delivery without hypoperfusion. Additionally, we observed significant tumor-specific uptake of mitoxantrone when delivered by the IA-TCH method. No untoward effects of IA-TCH delivery of mitoxantrone were observed. The IA-TCH method is shown to be a safely tolerated and feasible strategy for delivering mitoxantrone to tumors in the glioma model tested. Additional investigation is warranted to determine if IA-TCH delivery of mitoxantrone produces clinically relevant benefit.     

Advances in genetic and epigenetic analyses of gliomas: a neuropathological perspective

Gliomas, the most common malignant primary brain tumors, are universally fatal once they progress from low-grade into high-grade neoplasms. In recent years, we have accumulated unprecedented data about the genetic and epigenetic abnormalities in gliomas; yet, our appreciation of how these deadly tumors arise is still rudimentary. One of the major deterrents in understanding gliomagenesis is the remarkably complex and heterogeneous molecular composition of gliomas, as well as their ability to change phenotypically as they progress and recur. In the past decade, several monumental studies have begun to define better glioma heterogeneity. Four distinct molecular subgroups have emerged: proneural, classical, mesenchymal, and neural; which have unique gene expression signatures and prognostic significance. Of these, gliomas of the proneural subtype, which encompass most grade II/III diffuse gliomas and secondary glioblastomas and often carry isocitrate dehydrogenase (IDH) mutations, have emerged as a distinct tumor subclass with a notably superior prognosis. Important molecular markers with prognostic relevance, such as mutant IDH1/2, have already been incorporated into clinical neuropathological practice. The recent molecular discoveries in gliomas have also emphasized the intimate link between epigenetics and genetics in gliomagenesis. Several of the novel genetic mutations described are responsible for distinct epigenetic remodeling in gliomas, the mechanisms of which are currently being elucidated. Importantly, these epigenetic and genomic alterations represent new and exciting drug targets for future therapeutic interventions in our continuous fight with this fatal malignancy.     

Therapeutic anti-angiogenesis for malignant brain tumors.

Malignant brain tumors, especially malignant gliomas, have a poor prognosis, a fact which has remained unchanged over the last decades despite the employment of multimodal therapeutic approaches. Malignant gliomas are among the most vascularized tumors known and the amount of vascularization has been correlated to their prognosis. Since tumor growth is dependent on concomitant vascularization, recent experimental studies have focused on the use of anti-angiogenic molecules as a novel strategy in brain tumor therapy. Angiogenesis inhibitors target at proliferating endothelial cells and suppress the formation of a sufficient vascular bed. Inhibitors such as TNP-470, suramin and angiostatin have shown their therapeutic potential in experimental studies. In a clinical setting, they could be applied for the treatment of multiple tumors or postsurgically as an adjuvant therapy to prevent recurrence. This article discusses presently available anti-angiogenic agents, emphasizing on substances already in clinical trials.