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Flavonoids are polyphenolic plant secondary metabolites with pleiotropic biological properties, including anti-cancer activities. These natural compounds have potential utility in glioblastoma (GBM), a malignant central nervous system tumor derived from astrocytes. Conventional GBM treatment modalities such as chemotherapy, radiation therapy, and surgical tumor resection are beneficial but limited by extensive tumor invasion and drug/radiation resistance. Therefore, dietary flavonoids-with demonstrated anti-GBM properties in preclinical research-are potential alternative therapies. This review explores the synergistic enhancement of the anti-GBM effects of conventional chemotherapeutic drugs by flavonoids. Primary studies published between 2011 and 2021 on flavonoid-chemotherapeutic synergy in GBM were obtained from PubMed. These studies demonstrate that flavonoids such as chrysin, epigallocatechin-3-gallate (EGCG), formononetin, hispidulin, icariin, quercetin, rutin, and silibinin synergistically enhance the effects of canonical chemotherapeutics. These beneficial effects are mediated by the modulation of intracellular signaling mechanisms related to apoptosis, proliferation, autophagy, motility, and chemoresistance. In this light, flavonoids hold promise in improving current therapeutic strategies and ultimately overcoming GBM drug resistance. However, despite positive preclinical results, further investigations are necessary before the commencement of clinical trials. Key considerations include the bioavailability, blood-brain barrier (BBB) permeability, and safety of flavonoids; optimal dosages of flavonoids and chemotherapeutics; drug delivery platforms; and the potential for adverse interactions.

Brain metastases are the most common intracranial tumor in adults, with increasing incidence owing to prolonged survival times. Roughly half of patients diagnosed with new brain metastases have greater than 1 brain metastasis at the time of diagnosis, raising the question of how to optimize patient care with multiple brain metastases. The authors review studies relevant to the care of patients with brain metastasis, with emphasis on those relevant to the care of patients with multiple brain metastases. They discuss evolving strategies involving multiple modalities and the benefit of surgical management in patients with a large symptomatic brain metastasis., Competing Interests: Disclosure Dr Nahed BV is a consultant for Genentech-Roche, Tesaro, Angiochem, Lilly, Elevate-Bio. He received speaker’s Honoraria from Merck and Genentech-Roche. He received research funds from Lilly, Merck, and BMS., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Chemotherapy has played a minor role as adjuvant therapy in treatment of cerebral metastases from solid cancers. The blood-brain barrier and cerebral metastases' considerable machinery of self-preservation have been significant obstacles to delivery and efficacy of chemotherapy. However, several methods intended to surmount these challenges have arisen alongside advent of technology and with the development of targeted molecular therapies. Focused ultrasound and molecular Trojan horses represent two such novel means of increasing permeability of the blood-brain barrier to effector agents. Published data on efficacy of these targeted therapies remain mostly restricted to retrospective studies and phase II prospective clinical trials., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Solitary brain metastasis is defined by a single metastatic brain lesion as the only site of metastasis. The initial approach to this condition consists of radiographical evaluation to establish diagnosis, followed by assessment of functional and prognostic status. Neurologic symptom management consists of using dexamethasone and antiepileptic medications. Treatment consists of a combination of surgical and radiation therapy. Surgical treatment is indicated where there is a need for tissue diagnosis or immediate alleviation of neurologic symptoms and mass effect. Stereotactic radiosurgery has become an effective treatment modality. Whole-brain radiation therapy may have a role as an adjunctive therapy., Competing Interests: Disclosure Novocure, advisory board. BMS, scientific grant funding., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Data on frequency, clinical presentation, and outcome of primary metastatic intracranial ependymoma in children are scarce., Patients and Methods: Prospective data on patients younger than 21 years with metastatic intracranial ependymoma at first diagnosis, registered from 2001 to 2014 in the HIT-2000 trial and the HIT-2000 Interim Registry, were analyzed., Results: Of 453 registered patients with intracranial ependymoma and central neuropathology review, initial staging included spinal magnetic resonance imaging in all patients and lumbar cerebrospinal fluid (CSF) analysis in 402 patients. Ten patients (2.2%) had metastatic disease, including three with microscopic CSF positivity only (M1 metastasis stage, 0.7% of patients with CSF staging). Location of the primary tumor was supratentorial in four patients (all supratentorial RELA -fused ependymoma [ST-EPN-RELA]) and within the posterior fossa in five patients (posterior fossa ependymoma type A [PF-EPN-A], n  = 4; posterior fossa ependymoma not further classifiable, n  = 1), and multifocal in one patient.All four patients with ST-EPN-RELA were alive in first or second complete remission (CR) 7.5-12.3 years after diagnosis. All four patients with macroscopic metastases of posterior fossa or multifocal ependymoma died. Three patients with initial M1 stage (ST-EPN-RELA, n  = 1; PF-EPN-A, n  = 2) received chemotherapy and local irradiation and were alive in second or third CR 3.0-9.7 years after diagnosis. Progression-free and overall survival of the entire cohort at 5 years was 13% (±6%), and 58% (±16%), respectively., Conclusion: Primary metastatic disease is rare in children with intracranial ependymoma. Prognosis may depend on molecular subgroup and extent of dissemination, and relevance of CSF analysis for initial staging remains to be clarified., Implications for Practice: Childhood ependymoma presenting with metastasis at first diagnosis is very rare with a frequency of 2.4% in this population-based, well-characterized cohort. Detection of microscopic metastases in the cerebrospinal fluid was extremely rare, and impact on prognosis and respective treatment decision on irradiation field remains unclear. Initial metastatic presentation occurs in both supratentorial RELA -fused ependymoma and posterior fossa ependymoma. Prognosis may differ according to extent of metastasis and biological subgroup, with poor prognosis in diffusely spread metastatic posterior fossa ependymoma even after combination therapy with both intensive chemotherapy and craniospinal irradiation, which may help to guide individual therapeutic decisions for future patients., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

Purpose of Review: This review discusses the evidence base behind current and emerging strategies of management of intracranial and spinal ependymomas in children, with a particular focus on aspects of surgical techniques, challenges and complications., Recent Findings: The cornerstone of management remains maximal safe resective surgery, which has repeatedly been shown to correlate with improved survival. This is followed by focal conformal radiotherapy, although good results using proton beam therapy, with the potential for diminished side effects, are emerging. The role of chemotherapy remains largely unproven for paediatric ependymoma. Despite optimal management strategies, many children with ependymoma suffer from tumour recurrence. The standard of care for paediatric ependymoma comprises surgery and radiotherapy. Results of ongoing clinical trials will help shape its management in order to leverage our increasingly sophisticated understanding of the genetic drivers behind these tumours into survival benefit for this challenging group of patients.

Background: Assess clinical outcomes of focal radiotherapy (RT) in patients with limited brain metastasis (LBM) with whole brain RT (WBRT) avoidance., Methods: Patients diagnosed with LBM were entered into a database between January 2010 and February 2017. Patients were recommended WBRT avoidance with focal therapy and three-monthly magnetic resonance imaging. The primary endpoint was overall survival. Secondary endpoints included progression-free survival, initial-site failure (ISF), distant brain relapse (DBF), leptomeningeal disease and rate of WBRT. Analysis involved Kaplan-Meier survival estimate with log-rank tests and Cox-regression analysis., Results: One hundred and sixty-six patients were managed with median follow-up of 13 months and median overall survival of 15 months (95% confidence interval (CI) 10.8-19.2). Eighty-three patients had central nervous system (CNS) relapse with median progression-free survival of 11 months (95% CI 6.7-15.3), of which most failures were DBF (83.1%) with 27 ISF (32.5%). Of the ISFs, 12 (43%) had surgery alone, six had chemotherapy alone and nine received RT. Surgery or chemotherapy alone compared with RT had a significantly higher incidence of ISF with a hazard ratio of 4.96 (P < 0.0001, 95% CI 2.10-11.83) and 6.54 (P = 0.001, 95% CI 2.26-18.87), respectively. WBRT was utilized in only 24 patients, with 83% patients free of WBRT at 12 months. On univariate analysis, number of metastases (P = 0.04), symptomatic extracranial disease (P = 0.04) and early CNS relapse within 6 months (P < 0.01) had worse survival. No grade 3-4 toxicity events were noted in 129 patients undergoing RT., Conclusion: Focal RT has a low rate of ISF with low toxicity in patients with LBMs. CNS progression was mainly DBF with low rates of salvage WBRT., (© 2019 Royal Australasian College of Surgeons.)

The blood-brain barrier (BBB) has long limited therapeutic access to brain tumor and peritumoral tissue. In animals, MR-guided focused ultrasound (MRgFUS) with intravenously injected microbubbles can temporarily and repeatedly disrupt the BBB in a targeted fashion, without open surgery. Our objective is to demonstrate safety and feasibility of MRgFUS BBB opening with systemically administered chemotherapy in patients with glioma in a phase I, single-arm, open-label study. Five patients with previously confirmed or suspected high-grade glioma based on imaging underwent the MRgFUS in conjunction with administration of chemotherapy (n = 1 liposomal doxorubicin, n = 4 temozolomide) one day prior to their scheduled surgical resection. Samples of "sonicated" and "unsonicated" tissue were measured for the chemotherapy by liquid-chromatography-mass spectrometry. Complete follow-up was three months. The procedure was well-tolerated, with no adverse clinical or radiologic events related to the procedure. The BBB within the target volume showed radiographic evidence of opening with an immediate 15-50% increased contrast enhancement on T1-weighted MRI, and resolution approximately 20 hours after. Biochemical analysis of sonicated versus unsonicated tissue suggest chemotherapy delivery is feasible. In this study, we demonstrated transient BBB opening in tumor and peritumor tissue using non-invasive low-intensity MRgFUS with systemically administered chemotherapy was safe and feasible. The characterization of therapeutic delivery and clinical response to this treatment paradigm requires further investigation.

An estimated 20% of all patients with cancer will develop brain metastases, with the majority of brain metastases occurring in those with lung, breast and colorectal cancers, melanoma or renal cell carcinoma. Brain metastases are thought to occur via seeding of circulating tumour cells into the brain microvasculature; within this unique microenvironment, tumour growth is promoted and the penetration of systemic medical therapies is limited. Development of brain metastases remains a substantial contributor to overall cancer mortality in patients with advanced-stage cancer because prognosis remains poor despite multimodal treatments and advances in systemic therapies, which include a combination of surgery, radiotherapy, chemotherapy, immunotherapy and targeted therapies. Thus, interest abounds in understanding the mechanisms that drive brain metastases so that they can be targeted with preventive therapeutic strategies and in understanding the molecular characteristics of brain metastases relative to the primary tumour so that they can inform targeted therapy selection. Increased molecular understanding of the disease will also drive continued development of novel immunotherapies and targeted therapies that have higher bioavailability beyond the blood-tumour barrier and drive advances in radiotherapies and minimally invasive surgical techniques. As these discoveries and innovations move from the realm of basic science to preclinical and clinical applications, future outcomes for patients with brain metastases are almost certain to improve.

Glioma cells are one of the most aggressive and malignant tumors. Following initial surgery, and radio-chemotherapy they progress rapidly, so that patients' median survival remains under two years. They invade throughout the brain, which makes them difficult to treat, and are universally lethal. Though total resection is always attempted it is not curative. Standard of care in 2016 comprises surgical resection, radiotherapy and chemotherapy (temozolomide). Median survival is currently ~14-20months post-diagnosis though it can be higher in high complexity medical university centers, or during clinical trials. Why the immune system fails to recognize the growing brain tumor is not completely understood. We believe that one reason for this failure is that the brain lacks cells that perform the role that dendritic cells serve in other organs. The lack of functional dendritic cells from the brain causes the brain to be deficient in priming systemic immune responses to glioma antigens. To overcome this drawback we reconstituted the brain immune system for it to initiate and prime anti-glioma immune responses from within the brain. To achieve brain immune reconstitution adenoviral vectors are injected into the resection cavity or remaining tumor. One adenoviral vector expresses the HSV-1 derived thymidine kinase which converts ganciclovir into phospho-ganciclovir which becomes cytotoxic to dividing cells. The second adenovirus expresses the cytokine fms-like tyrosine kinase 3 ligand (Flt3L). Flt3L differentiates precursors into dendritic cells and acts as a chemokine for dendritic cells. This results in HSV-1/ganciclovir killing of tumor cells, and the release of tumor antigens, which are then taken up by dendritic cells recruited to the brain tumor microenvironment by Flt3L. Concomitant release of HMGB1, a TLR2 agonist that activates dendritic cells, stimulates dendritic cells loaded with glioma antigens to migrate to the cervical lymph nodes to prime a systemic CD8+ T cytotoxic killing of brain tumor cells. This induced immune response causes glioma-specific cytotoxicity, induces immunological memory, and does not cause brain toxicity or autoimmunity. A Phase I Clinical Trial, to test our hypothesis in human patients, was opened in December 2013 (see: NCT01811992, Combined Cytotoxic and Immune-Stimulatory Therapy for Glioma, at ClinicalTrials.gov). This trial is a first in human trial to test whether the re-engineering of the brain immune system can serve to treat malignant brain tumors. The long and winding road from the laboratory to the clinical trial follows below., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Glioblastoma is a highly aggressive brain tumor. Current standard-of-care results in a marginal therapeutic outcome, partly due to acquirement of resistance and insufficient blood-brain barrier (BBB) penetration of chemotherapeutics. To circumvent these limitations, we conjugated the chemotherapy paclitaxel (PTX) to a dendritic polyglycerol sulfate (dPGS) nanocarrier. dPGS is able to cross the BBB, bind to P/L-selectins and accumulate selectively in intracranial tumors. We show that dPGS has dual targeting properties, as we found that P-selectin is not only expressed on tumor endothelium but also on glioblastoma cells. We delivered dPGS-PTX in combination with a peptidomimetic of the anti-angiogenic protein thrombospondin-1 (TSP-1 PM). This combination resulted in a remarkable synergistic anticancer effect on intracranial human and murine glioblastoma via induction of Fas and Fas-L, with no side effects compared to free PTX or temozolomide. This study shows that our unique therapeutic approach offers a viable alternative for the treatment of glioblastoma.

Background: Lung cancer is the most common cause of cancer-related mortality in humans. There are several reasons for this high rate of mortality, including metastasis to several organs, especially the brain. In fact, lung cancer is responsible for approximately 50% of all brain metastases, which are very difficult to manage. Understanding the cellular and molecular mechanisms underlying lung cancer-associated brain metastasis brings up novel therapeutic promises with the hope to ameliorate the severity of the disease. Here, we provide an overview of the molecular mechanisms underlying the pathogenesis of lung cancer dissemination and metastasis to the brain, as well as promising horizons for impeding lung cancer brain metastasis, including the role of cancer stem cells, the blood-brain barrier, interactions of lung cancer cells with the brain microenvironment and lung cancer-driven systemic processes, as well as the role of growth factor/receptor tyrosine kinases, cell adhesion molecules and non-coding RNAs. In addition, we provide an overview of current and novel therapeutic approaches, including radiotherapy, surgery and stereotactic radiosurgery, chemotherapy, as also targeted cancer stem cell and epithelial-mesenchymal transition (EMT)-based therapies, micro-RNA-based therapies and other small molecule or antibody-based therapies. We will also discuss the daunting potential of some combined therapies., Conclusions: The identification of molecular mechanisms underlying lung cancer metastasis has opened up new avenues towards their eradication and provides interesting opportunities for future research aimed at the development of novel targeted therapies.

The clinical management/understanding of brain metastases (BM) has changed substantially in the last 5 years, with key advances and clinical trials highlighted in this review. Several of these changes stem from improvements in systemic therapy, which have led to better systemic control and longer overall patient survival, associated with increased time at risk for developing BM. Development of systemic therapies capable of preventing BM and controlling both intracranial and extracranial disease once BM are diagnosed is paramount. The increase in use of stereotactic radiosurgery alone for many patients with multiple BM is an outgrowth of the desire to employ treatments focused on local control while minimizing cognitive effects associated with whole brain radiotherapy. Complications from BM and their treatment must be considered in comprehensive patient management, especially with greater awareness that the majority of patients do not die from their BM. Being aware of significant heterogeneity in prognosis and therapeutic options for patients with BM is crucial for appropriate management, with greater attention to developing individual patient treatment plans based on predicted outcomes; in this context, recent prognostic models of survival have been extensively revised to incorporate molecular markers unique to different primary cancers., (© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Glioblastoma multiforme has a poor prognosis and is highly chemoresistant. In this study, we implanted biodegradable 1,3-bis[2-chloroethyl]-1-nitroso-urea-, irinotecan-, and cisplatin-eluting poly[(d,l)-lactide-co-glycolide] (BIC/PLGA) and virgin nanofibrous membranes on the brain surface of C6 glioma-bearing rats in concurrent and virgin groups, respectively. The concentrations of all applied drugs were significantly higher in the brain than in the blood for more than 8 weeks in all studied rats. Tumor growth was more rapid in the vehicle-treated group, and tumor volumes were significantly higher in the vehicle-treated group. Moreover, the average survival time was significantly shorter in the vehicle-treated group (P = 0.026), and the BIC/PLGA nanofibrous membranes significantly reduced the risk of mortality (P < 0.001). Furthermore, the results suggested that the BIC/PLGA nanofibers reduced the malignancy of C6 glioma. The experimental findings indicate that the multianticancer drug (i.e., BIC)-eluting PLGA nanofibers are favorable candidates for treating malignant glioma.

Auto-SCT is a common approach for metastatic neuroblastoma with the intention to rescue hematopoiesis after megadose chemotherapy. PBSC or BM is the usual stem cell source for auto-SCT. Auto-CBT for neuroblastoma has very rarely been performed. Currently, case reports are available for two patients only. We performed 13 auto-SCTs for high-risk neuroblastoma from 2007 to 2013, including four cases of metastatic neuroblastoma aged 11-64 months treated with auto-CBT. All four patients had partial or CR to upfront treatments before auto-CBT. Nucleated cell dose and CD34+ cell dose infused were 2.8-8.7 × 10(7) /kg and 0.36-3.9 × 10(5) /kg, respectively. Post-thawed viability was 57-76%. Neutrophil engraftment (>0.5 × 10(9) /L) occurred at 15-33 days, while platelet engraftment occurred at 31-43 days (>20 × 10(9) /L) and 33-65 days (>50 × 10(9) /L) post-transplant, respectively. There was no severe acute or chronic complication. Three patients survived for 1.9-7.7 yr without evidence of recurrence. One patient relapsed at 16 months post-transplant and died of progressive disease. Cord blood may be a feasible alternative stem cell source for auto-SCT in patients with stage 4 neuroblastoma, and outcomes may be improved compared to autologous PBSC or BM transplants., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We report a 67-year-old woman who was diagnosed with a gliosarcoma at a second operation after diagnosis of a fibrillary astrocytoma 5 months previously. Initially, she underwent a CT-guided stereotactic biopsy. Histological examination showed fibrillary astrocytoma (World Health Organization [WHO] grade II). Loss of heterozygosity (LOH) on 1p, 10q, and 19q was not detected. She received chemotherapy, but no radiotherapy. Five months after the biopsy, MRI revealed rapid tumor growth. Tissue obtained from partial removal of the tumor revealed gliosarcoma (WHO grade IV), and LOH on 10q and 19q was detected. The history, histopathology, and genetic alterations of this patient are discussed., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

To date, very little is known about the long-term risk of death from cerebrovascular sequelae following childhood cancer treatment. The purpose of this study was to assess the role of treatment in very long-term cerebrovascular mortality following childhood cancer. We studied 4227 5-year survivors of a childhood cancer. Information on chemotherapy was collected and the radiation dose delivered to 11 anatomical sites in the brain was estimated. The main outcome that was considered was death due to cerebrovascular disease occurring before 1 January 2008. After a median follow-up of 29 years, 23 deaths due to cerebrovascular diseases had occurred. In the brain, the radiation dose delivered to the prepontine cistern seemed to play a greater role than the average radiation dose received throughout the brain or the dose to any other specific anatomical site in the brain. The risk of death from cerebrovascular disease increased linearly with the local radiation dose to the prepontine cistern. Each unit of absorbed radiation (Gray) delivered to this area increased the risk by 22% (95% confidence interval: 1-44%). Compared with patients who had not received radiotherapy or who had received <0.1 Gray in the prepontine cistern area, those who had received >50 Gray had a 17.8-fold (4.4-73.0) higher hazard ratio of death from cerebrovascular disease. In conclusion, among 5-year survivors of childhood cancer, the radiation dose to the brain during radiotherapy was significantly associated with long-term cerebrovascular mortality.

The main objective of treating brain metastases is to improve survival and to reduce symptom burden, preserve function, and enhance quality of life. As such, concurrent local control of existing brain metastases, prevention of future metastasis elsewhere in the brain, and control of the systemic cancer are required. The treatment modalities used to achieve these aims include surgery, radiation, and medical therapy. This article is devoted to the medical management of brain metastases, namely the role of medical treatments and chemotherapy. Radiation therapy and surgery are discussed in detail elsewhere; however, a brief discussion of all of these modalities is included for the sake of thoroughness., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Drug development in neuro-oncology remains a challenge for neoplasms of the central nervous system (CNS). Drugs can be administered peripherally (i.e., oral or intravenous) or locally (into the tumor or the adjacent neuropil). Each of these routes has advantages and disadvantages. Like the treatment for non-CNS cancers, peripheral side effects are encountered (i.e., diarrhea, myelosuppression, rash); however, there also may be neural-specific side effects for patients that may be acute or delayed (i.e., seizures, somnolence, hearing loss). The nervous system is also a privileged site protected by the blood-brain barrier, so many agents developed for peripheral administration will not penetrate into the CNS due to issues of size, charge, or lack of lipid solubility. In addition, the abnormal vasculature, increased interstitial pressure, and inherent mechanisms of tumor resistance (methyl-guanine-methyl transferase [MGMT], P-glycoprotein, etc.) within brain neoplasms reduce the efficacy of many agents designed for neuro-oncologic indications. Each of these issues alone, and all of them in aggregate, are reasons for the limited success of therapeutic agents directed against CNS tumors despite promising data acquired using cell lines and animal models.

Target Population: This recommendation applies to adults with newly diagnosed brain metastases; however, the recommendation below does not apply to the exquisitely chemosensitive tumors, such as germinomas metastatic to the brain., Recommendation: Should patients with brain metastases receive chemotherapy in addition to whole brain radiotherapy (WBRT)? Level 1 Routine use of chemotherapy following WBRT for brain metastases has not been shown to increase survival and is not recommended. Four class I studies examined the role of carboplatin, chloroethylnitrosoureas, tegafur and temozolomide, and all resulted in no survival benefit. Two caveats are provided in order to allow the treating physician to individualize decision-making: First, the majority of the data are limited to non small cell lung (NSCLC) and breast cancer; therefore, in other tumor histologies, the possibility of clinical benefit cannot be absolutely ruled out. Second, the addition of chemotherapy to WBRT improved response rates in some, but not all trials; response rate was not the primary endpoint in most of these trials and end-point assessment was non-centralized, non-blinded, and post-hoc. Enrollment in chemotherapy-related clinical trials is encouraged.

Purpose: The appropriate management of low-grade gliomas is still a matter of debate. So far, there are no randomized studies that analyze the impact of surgical resection on patient outcome. The value of the data obtained from the few retrospective reports available is often limited., Patients and Methods: In the present study, we performed an analysis on data of 130 adult low-grade glioma patients. Extent of the resection was evaluated in correlation to the overall survival (OS) and progression-free survival (PFS) using Cox regression multivariate analysis., Results: Extended surgery was shown to prolong OS and PFS significantly. Re-surgery in the case of a tumor relapse has a significant impact on OS and PFS, too., Conclusions: In summary, we could retrospectively evaluate a large case series of well-defined low-grade gliomas patients with a long follow-up period showing that extended surgery would be the most effective therapy for low-grade glioma patients even in recurrent diseases.

Systemic chemotherapy has been relatively ineffective in the treatment of malignant brain tumors even though systemic chemotherapy drugs are small molecules that can readily extravasate across the porous blood-brain tumor barrier of malignant brain tumor microvasculature. Small molecule systemic chemotherapy drugs maintain peak blood concentrations for only minutes, and therefore, do not accumulate to therapeutic concentrations within individual brain tumor cells. The physiologic upper limit of pore size in the blood-brain tumor barrier of malignant brain tumor microvasculature is approximately 12 nanometers. Spherical nanoparticles ranging between 7 nm and 10 nm in diameter maintain peak blood concentrations for several hours and are sufficiently smaller than the 12 nm physiologic upper limit of pore size in the blood-brain tumor barrier to accumulate to therapeutic concentrations within individual brain tumor cells. Therefore, nanoparticles bearing chemotherapy that are within the 7 to 10 nm size range can be used to deliver therapeutic concentrations of small molecule chemotherapy drugs across the blood-brain tumor barrier into individual brain tumor cells. The initial therapeutic efficacy of the Gd-G5-doxorubicin dendrimer, an imageable nanoparticle bearing chemotherapy within the 7 to 10 nm size range, has been demonstrated in the orthotopic RG-2 rodent malignant glioma model. Herein I discuss this novel strategy to improve the effectiveness of systemic chemotherapy for the treatment of malignant brain tumors and the therapeutic implications thereof.

Brain metastases are the most common intracranial tumor in adults. The incidence of metastases is thought to be rising due to better detection and treatment of systemic malignancy. More widespread use and improved quality of MRI may lead to early detection of brain metastases. Available evidence suggests that survival is longer and quality of life improved if brain metastases are treated aggressively. This article reviews current therapeutic management used for brain metastases. To select the appropriate therapy, the physician must consider the extent of the systemic disease, primary histology, and patient age and performance status, as well as the number, size, and location of the brain metastases. Available treatment options include whole-brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), surgery, and chemotherapy. Multidisciplinary approaches such as the combination of WBRT with SRS or surgery have shown superior results in terms of survival time, neurocognitive function, and quality of life. The utility and optimal use of chemotherapy and radiosensitizing agents is less clear. It is hoped that further advances and multidisciplinary approaches currently under study will result in improved patient outcomes.

Primary central nervous system lymphoma (PCNSL) is a rare variant of extranodal non-Hodgkin lymphoma that is restricted in distribution to the brain, leptomeninges, spinal cord, and intraocular compartments. Although PCNSL shares overlapping features with systemic lymphoma, recent studies also reveal a unique pattern of gene and protein expression in PCNSL. These findings have yielded new insights into the pathophysiology of the disease, as well as the identification of novel prognostic biomarkers. Immune system compromise, such as is seen in acquired immune deficiency syndrome (AIDS), is the best established known risk factor for PCNSL. Like other lesions of the brain, meninges, and eye, the presenting symptoms associated with PCNSL typically include focal neurological deficits related to the site of disease or more global consequences of increased intracranial pressure. Diagnosis of PCNSL typically includes gadolinium-enhanced MRI and pathologic tissue analysis, as well as additional studies aimed at excluding concurrent systemic disease. PCNSL typically has a worse overall prognosis than systemic lymphoma. High-dose chemotherapy, particularly with methotrexate-based regimens, is the backbone of therapy for most patients, and chemotherapy is associated with much lower rates of treatment-related morbidity and mortality than whole-brain irradiation. Autologous stem cell transplantation is an emerging treatment modality, particularly in younger patients with relapsed disease, but high rates of treatment-related mortality are observed in older patients. Immunotherapy, including treatment with intrathecal rituximab, is another area of active research that may have promise in refractory or relapsed disease. Treatment options for intraocular lymphoma parallel those for PCNSL elsewhere in the brain: systemic chemotherapy, radiation, and local delivery of cytotoxic and immunologically active agents such as anti-CD20 antibody.

Pediatric CNS tumors are the most common solid tumors of childhood and the second most common cancer after hematological malignancies accounting for approximate 20 to 25% of all primary pediatric tumors. With over 3,000 new cases per year in the United States, childhood CNS tumors are the leading cause of death related to cancer in this population. The prognosis for these patients has improved over the last few decades, but current therapies continue to carry a high risk of significant side effects, especially for the very young. Currently a combination of surgery, radiation, and chemotherapy is often used in children greater than 3 years of age. This article will outline current and future therapeutic strategies for the most common pediatric CNS tumors, including primitive neuroectodermal tumors such as medulloblastoma, as well as astrocytomas and ependymomas.

Purpose Glioblastoma Multiforme (GBM) is the most common and lethal primary brain tumor in adults. The goal of this study was to test the predictive value of MR parameters in relation to the survival of patients with newly diagnosed GBM who were scanned prior to receiving adjuvant radiation and chemotherapy. Methods The study population comprised 68 patients who had surgical resection and were to be treated with fractionated external beam radiation therapy and chemotherapy. Imaging scans included anatomical MRI, diffusion and perfusion weighted imaging and (1)H MRSI. The MR data were acquired 3-5 weeks after surgery and approximately 1 week before treatment with radiation therapy. The diffusion, perfusion and spectroscopic parameter values were quantified and subjected to proportional hazards analysis that was adjusted for age and scanner field strength. Results The patients with larger lesion burden based upon volumes of anatomic lesions, volume of CNI2 (number of voxels within the T2 lesion having choline to NAA index >2), volume of CBV3 (number of pixels within the T2 lesion having relative cerebral blood volume >3), and volume of nADC1.5 (number of pixels within the T2 lesion having normalized apparent diffusion coefficient <1.5) had a higher risk for poor outcome. High intensities of combined measures of lactate and lipid in the T2 and CNI2 regions were also associated with poor survival. Conclusions Our study indicated that several pre-treatment anatomic, physiological and metabolic MR parameters are predictive of survival. This information may be important for stratifying patients to specific treatment protocols and for planning focal therapy.

The management of childhood brain tumors, which consist of many different histological subtypes, continues to be a challenge. Outcome, measured not only by survival rates but also by the effects of disease and therapy on quality of life, has improved over the past two decades for some tumor types, most notably medulloblastomas. For others, however, there has been little progress, and quality of life for long-term survivors remains suboptimal. Because of advances in our understanding of the biology underlying childhood brain tumors, treatments may change dramatically in the years ahead. Accordingly, survival rates may improve and long-term sequelae lessen.

Recent advances in the categorization of childhood brain tumors have improved risk-based treatment planning. In several instances, new therapeutic strategies that incorporate these advances have resulted in meaningful improvements in progression-free and overall survival. Current studies are directed at further refining therapy based on clinical, biological, and molecular data; testing the effectiveness of a number of novel therapeutic strategies for high-risk tumors; and examining approaches to reduce sequelae of treatment among more favorable-risk tumor subsets. Because multiple tumor subtypes are individually relatively uncommon, most such studies are being conducted by large co-operative groups, such as the Children's Oncology Group, or by smaller brain tumor-focused consortia, such as the Pediatric Brain Tumor Consortium.

Neurocognitive late effects are common sequelae of cancer in children, especially in those who have undergone treatment for brain tumors or in those receiving prophylactic cranial radiation therapy to treat leukemia. Neurocognitive morbidity in attention, executive functioning, processing speed, working memory, and memory frequently occurs and contributes to declines in intellectual and academic abilities. Oncologists are faced with the challenge of using the most effective, often the most intense, therapy to achieve the primary goal of medical success, balanced with the desire to prevent adverse late effects. Not all children with similar diagnoses and treatment have identical neurocognitive outcomes; some do very poorly and some do well. Attention now turns to the reliable prediction of risk for poor outcomes and then, using risk-adapted therapy, to preserve neurocognitive function. Prevention of late effects through rehabilitative strategies, continuation of school, and pharmacotherapy will be explored.

Intracranial tumors are the most common solid tumors in children. The infratentorial compartment will be the primary site for 60% to 70% of these tumors, including astrocytomas, medulloblastomas, and ependymomas. Several technological advancements have increased our knowledge of the cell biology of pediatric brain tumors, facilitated earlier diagnosis, and improved neurosurgical resections while minimizing neurological deficits. These in turn have not only improved the survival of children with brain tumors but also their quality of life. Current management strategies in most cases rely on surgery coupled with adjuvant therapies, including radiation therapy and chemotherapy. The vulnerability of the immature brain to adjuvant therapies creates many challenges for the treating physician. We review current diagnostic and therapeutic approaches and outcome for children harboring the most common pediatric brain tumors: astrocytomas (low-grade and high-grade glioma), ependymoma, medulloblastoma, and craniopharyngioma. The emphasis will be on the neurosurgical management of children with these tumors.

Complete remission can be achieved soon after irradiation in patients with intracranial germinoma. This study aimed to analyze the follow-up outcome of intracranial germinoma patients. About 39 intracranial germinoma patients (29 males and 10 females; average age, 15 years; range, 7-27 years) treated at Kyoto University Hospital from 1978 to 2004 were included in the study group. Six patients had multifocal disease at initial diagnosis, and 10 had human chorionic gonadotropin (HCG)-producing tumors. Thirteen patients were treated with craniospinal axis irradiation, 6 with whole-brain irradiation, 17 with whole-ventricle irradiation, and 3 with local field irradiation. Since 1997, 15 patients were treated with reduced-dose whole-ventricle irradiation (median, 23.4 Gy; range, 20.4-27 Gy) followed by a local boost (median, 40.8 Gy; range, 36-54 Gy) combined with chemotherapy. The median follow-up was 94 months (18 months to 25 years). The 5- and 10-year overall survival (OS) rates of the entire group were 97 and 90%, respectively. The 5- and 10-year progression-free survival (PFS) rates of the entire group were 91 and 87%, respectively. The 8-year OS and PFS in 15 patients treated by whole-ventricle irradiation combined with chemotherapy were 100% and 92%, respectively. Four patients had recurrences within a median period of 59.5 months (51-85 months). All relapses occurred outside the radiation fields. Tumor site, tumor size, HCG production, multifocal disease and radiation dose to the primary site or whole ventricle did not significantly affect PFS. All initial recurrences of intracranial germinoma occurred at the distant site out of the radiation field. Our data suggested that reduced doses to the whole ventricle, combined with chemotherapy, should be sufficiently effective in patients with intracranial germinoma.

Pediatric patients with recurrent brain tumors have a poor prognosis and limited therapeutic options. We investigated the use of high-dose chemotherapy with adoptive immunotherapy for recurrent brain tumors. Three pediatric patients with recurrent brain tumors received high-dose chemotherapy. This was followed by adoptive transfer of ex-vivo expanded T-cells. The T-cells were generated from peripheral blood after immunization with autologous cancer cells. The objectives of this study included (1) establishing the safety and feasibility of this potential treatment, (2) measuring changes in immune response after high-dose chemotherapy and adoptive immunotherapy, and (3) determining whether adoptive immunotherapy would be able to translate into a clinical response. Immune function was tested in all patients at the time of enrollment into the study. Humoral responses to recall antigens delayed-type hypersensitivity (DTH) were intact in all patients. After immunizing patients with autologous cancer cells, peripheral blood lymphocytes were harvested and activated with anti-CD3, expanded in-vitro, and infused post-autologous transplant. Patients received at least three doses of the vaccine, each consisting of an intradermal administration near a draining lymph node at biweekly intervals. Toxicity was limited and well tolerated in all patients. All three patients showed a tumor-specific immune response by serial imaging. Responses were durable at 16, 23, and 48 months, respectively.

A prospective collection of newly diagnosed cases of grade IV glioma in Lombardia, Italy, was started in 2003. In the present report, data are shown on 349 adult patients recruited up to 2005. The clinical features, pattern of care and outcome are discussed, together with the main prognostic factors. Males were affected more frequently than women; median age at onset was 60. Overall, gross total tumour resection was performed in roughly 50% of the patients, and partial resection and biopsy in 25% each; only 5 patients did not undergo histology. Adjuvant radiotherapy was delivered to 89% and chemotherapy to 82% of patients. Median survival was of 54 weeks. Most patients received protracted therapy with antiepileptic drugs, despite absence of seizures; over the course of the study, the practice pattern tended to change, shifting to the use of non-enzyme-inducing anti-epileptic drugs.

Primary rhabdomyosarcoma of the central nervous system (CNS) is rare in both adults and children (Taratuto et al. (1985) Acta Neuropathol (Berl) 66(2):98-104). The outcome in the majority of cases is poor, and many cases are associated with early mortality (Celli et al. (1998) J Neurooncol 36(3):259-267). There are very few cases reported in the literature of survival beyond 2 years after diagnosis. We report a case of primary intracranial embryonal rhabdomyosarcoma in a 5-year-old girl who was treated successfully with local radiation therapy (RT) and a combination of two different chemotherapeutic regimens. The patient is clinically well 26 months after diagnosis, with no definitive evidence of residual disease.

Purpose of Review: The purpose of this review is to provide an update on the identification of novel molecular targets in neurooncology and their translation into clinical practice., Recent Findings: Basic research is providing novel insights into the complex molecular pathways involved in the pathogenesis of malignant glioma transformation and progression. By unraveling the intricate signaling cascades responsible for sustained proliferation, angiogenesis, invasion and resistance to apoptosis in glioma, we are now confronted with an ever-expanding list of molecular targets. Clinical studies using single targeted therapies have been disappointing, therefore providing the impetus for novel combination drug trials. The potential for combination regimens brings the challenge of testing an exponentially growing number of treatments. Success will depend on an integration of novel treatment regimens and innovative trial designs combined with careful patient selection based on the results of molecular profiling of tumor tissue., Summary: Technologic advances in oncogenomics, proteomics and functional genomic screens (such as synthetic lethality) are providing mechanisms to rapidly identify the critical targets whose inactivation will lead to a substantive tumor growth arrest. Tumor tissue biomarkers that identify those tumors most likely to respond to a specific inhibitor are needed as a mechanism toward tailoring therapy to the individual patient with malignant glioma.

Purpose of Review: Knowledge of the molecular biology of gliomas may improve therapy. This review highlights several recent studies on this topic., Recent Findings: Gliomas are the most common primary brain tumors in adults, and remain refractory to therapy despite decades of work. Discoveries in the last several years have led to a better understanding of glioma biology. These include the importance of O6-methylguanine-DNA-methyltransferase (MGMT) in glioblastoma sensitivity to the DNA alkylating chemotherapy temozolomide. In addition, coexpression of phosphatase tensin homolog on chromosome ten (PTEN) and a mutant variant of the epidermal growth factor receptor (EGFRvIII) appears to predict sensitivity of recurrent glioblastomas to EGFR inhibitors. Finally, loss of heterozygosity for chromosomes 1p and 19q correlates with both response to therapy and improved prognosis for patients with oligodendrogliomas. The best way to incorporate these findings into office practice, however, remains unclear, especially in the absence of effective alternatives to currently available treatments. While subdividing gliomas molecularly may allow tailoring of therapy to individual patients based on individual tumor biology, a superior strategy may be to identify common molecular abnormalities that are targets of more universally applicable therapies., Summary: It remains unclear how best to integrate recent discoveries regarding glioma molecular biology into clinical practice.

Cerebral metastases remain a common complication among patients with cancer. Surgery and radiotherapy remain the principal therapeutic interventions. In contrast, the benefit of chemotherapy has long been viewed with skepticism. Nonetheless, as survival in cancer patients improves and the incidence of cerebral metastases increases, so does the demand for effective therapies. It is now recognized that the blood-brain barrier within metastases is permeable and thus allows entry of otherwise excluded drugs. Limited data have suggested that cerebral metastases have modest sensitivity to chemotherapy. Furthermore, novel agents and delivery strategies have been developed to facilitate central nervous system penetration. Nonetheless, data are limited by methodological flaws, including heterogeneous inclusion criteria, small sample sizes, lack of randomization, and inconsistencies in defined end points and response assessment criteria. Well-designed clinical trials are needed to address the effect of chemotherapy. Acceptable control arms must be established to measure the effect of chemotherapies. Standardized response criteria and disease-specific studies are essential.

Advances in medical and surgical treatments in the last few decades have resulted in quantum leaps in the overall survival of patients with malignant disease outside the central nervous system, whereas survival of patients with malignant gliomas (World Health Organization Grades III and IV) has remained essentially unchanged. Resection and external-beam fractionated radiotherapy remain the pillars of therapy for malignant gliomas and have shown significant beneficial effects on outcome in many clinical studies. On the other hand, numerous human trials with adjuvant agents, most of them administered systemically and causing serious complications and side effects, have not succeeded in achieving a noteworthy additional extension of survival duration, or have done so only with a considerable deterioration in the quality of life of the treated patients. The concept of local invasiveness of gliomas is not new, but only in the last one to two decades has significant attention been focused on the cell biology and molecular genetics of gliomas. Improved understanding of the fundamental features of tumor cells has resulted in the introduction and increasing clinical use of local therapies in which practitioners opt for spatially defined delivery methods and tumor-selective agents specifically designed to be used in the environment of a brain invaded by glioma. In this review, the authors summarize the key findings in some of the most important clinical studies of locally administered treatments for malignant glioma. A few such therapies have emerged in the last decade, and have shown considerable antitumor activity and a favorable profile of local and systemic side effects. These include biodegradable polymers for interstitial chemotherapy, targeted toxins administered by convection-enhanced delivery, and intra- and peritumorally injected genetically modified viruses conferring glioma-selective toxicity. In addition, areas of possible improvement of these therapies and essential further developments are outlined.

Historically, malignant gliomas are perhaps the most difficult intracranial neoplasms to treat. Surgery, radiation therapy, and traditional chemotherapy have not been able to significantly alter the course of this disease. By definition, these tumors are located in the protected space of the cranial vault, where the blood-brain barrier prevents most therapies from gaining access. Because of the difficulty in treating this disease, new, innovative treatments and alternative delivery techniques for those therapies are needed. Targeted toxins are fusion proteins that represent a novel medical treatment for these cancers that is under development. However, the efficacy of these agents is dependent on the method of delivery to the tumor. The administration of targeted toxins requires image-guided placement of catheters, either within the tumor or into the adjacent infiltrated brain, and positive pressure infusion. The term that has been applied to this microinfusion technique is convection-enhanced delivery (CED). This infusion method was first attempted via direct intratumoral infusion in nude mouse flank tumor models of human malignant glioma. After significant development of this delivery technique in animal models, the successful demonstration of in vivo efficacy of targeted toxins in Phase I and II clinical trials was reported. Currently, ongoing targeted toxin trials are being conducted at academic health centers to define the best clinical practice for CED. This work involves refining the details of delivery such as infusion rate, duration of treatment, and drug dosing. The early results of CED of targeted toxins supports their continued investigation, as few other treatment modalities have produced durable results in the fight against gliomas.

Glioblastoma multiforme (GBM) is one of the most aggressive primary brain tumors, with a grim prognosis despite maximal treatment. Advancements in the past decades have not significantly increased the overall survival of patients with this disease. The recurrence of GBM is inevitable, its management often unclear and case dependent. In this report, the authors summarize the current literature regarding the natural history, surveillance algorithms, and treatment options of recurrent GBM. Furthermore, they provide brief discussions regarding current novel efforts in basic and clinical research. They conclude that although recurrent GBM remains a fatal disease, the literature suggests that a subset of patients may benefit from maximal treatment efforts. Nevertheless, further research effort in all aspects of GBM diagnosis and treatment remains essential to improve the overall prognosis of this disease.

Despite recent advances in operative techniques, chemotherapy, and radiotherapy, the prognosis in patients with glioblastoma multiforme (GBM) remains poor; the majority die within a year of diagnosis. Although often effective at reducing mass effect and tumor burden, surgical debulking and cytotoxic therapies have never demonstrated an unequivocally significant benefit in treating patients with GBM. This shortcoming has led to the development of molecules that target specific steps in the transduction pathways of high-grade glioma cells. In this article the authors review various cellular and extracellular signaling pathways that may prove promising in the treatment of patients with malignant glioma.

Object: Convection-enhanced delivery (CED) is an increasingly used novel local/regional delivery method targeted directly to tissue. It relies on a continuous pressure gradient for distribution of therapeutic agents into the interstitial space, with administration of the infusate over a few days. Cintredekin besudotox (also known as IL13- PE38QQR) is a recombinant chimeric cytotoxin consisting of interleukin-13 and a truncated exotoxin produced by the Pseudomonas aeruginosa bacterium, which targets malignant glioma cells., Methods: Cintredekin besudotox was administered via intraparenchymal CED after resection of supratentorial recurrent malignant glioma. The safety and toxicity profile was reviewed for 53 patients in whom infusion catheters had been placed; 51 of them received CED of the study drug. Adverse events were categorized based on time of onset in relation to CED, and the causal relationship with catheter placement or delivery of cintredekin besudotox. Catheters were placed in 53 patients, although only 51 of them received cintredekin besudotox. Most adverse events related to catheter placement or the study drug originated from the central nervous system. Three symptomatic windows were defined: the first one was between surgical procedure and CED; the second was during CED and up to 1 week after its completion; and the third window was 2 to 10 weeks after treatment. Those windows generally reflected adverse events related to surgical procedures, mass effect from infusate, and drug effect on tumor-infiltrated and normal brain parenchyma, respectively., Conclusions: The symptomatic windows identified in this study apply to any CED clinical trials, particularly those in which chimeric cytotoxins are used, and will help to determine the most likely underlying pathophysiological process causing symptoms. This information, in turn, will help to prevent adverse events or minimize their severity. Those events also have implications for dose escalation and outcome measures.

Glioblastoma multiforme (GBM) tumors almost invariably recur despite initial treatments. Correct diagnosis using a variety of imaging techniques and the involvement of a multidisciplinary tumor board are critical for evaluating each stage of a patient's progression and determining optimal management. Standard therapies for recurrence generally include repeated resection, radiation therapy, chemotherapy, and supportive care; however, salvage therapy must be highly individualized, and not all patients are eligible for every type of standard therapy. Factors such as the size and location of the tumor, previous treatment, and general health of the patient must be taken into consideration. Although standard therapies can prolong a patient's duration of survival, the median survival time for patients with recurrent GBM is usually less than 1 year. Experimental targeted drug therapies have been developed to inhibit aberrant cell-signaling pathways involved in tumorigenesis, and enrolling patients in clinical trials using these therapies is another option for treatment of recurrent GBM. The use of these novel therapies is often confined to large research institutions, but the severe limitations of standard treatment options make it important to highlight the potential of experimental therapies. In this paper the authors outline standard therapies and review the emerging role of targeted drug therapy in the treatment of recurrent GBM.

Following the seminal trial conducted by the European Organisation for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC), concurrent temozolomide and radiotherapy has become the new standard of care for patients with newly diagnosed glioblastoma multiforme (GBM). Investigation of emerging therapies (which are now used as salvage therapy) such as small-molecule inhibitors (for example, epidermal growth factor receptor inhibitors) and convection-enhanced delivery (CED) of targeted toxins (for example, interleukin-13/pseudomonas exotoxin) is likely to build on the EORTC/NCIC treatment platform and will, it is hoped, improve survival rates in patients with GBM. The majority of adjuvant Phase I and II trials being conducted by the brain tumor consortia are based on the EORTC/NCIC treatment platform and have added a targeted therapy in an effort to find a promising synergistic treatment. Furthermore, researchers in the consortia are continuing to explore treatments for recurrent GBM, not otherwise eligible for local therapies, such as CED. The treatments under study include novel cytotoxic chemotherapy as well as small-molecule inhibitors; these are being assessed in a variety of Phase I or II trials.