Highly penetrative, drug-loaded nanocarriers improve treatment of glioblastoma.

Current therapy for glioblastoma multiforme is insufficient, with nearly universal recurrence. Available drug therapies are unsuccessful because they fail to penetrate through the region of the brain containing tumor cells and they fail to kill the cells most responsible for tumor development and therapy resistance, brain cancer stem cells (BCSCs). To address these challenges, we combined two major advances in technology: (i) brain-penetrating polymeric nanoparticles that can be loaded with drugs and are optimized for intracranial convection-enhanced delivery and (ii) repurposed compounds, previously used in Food and Drug Administration-approved products, which were identified through library screening to target BCSCs. Using fluorescence imaging and positron emission tomography, we demonstrate that brain-penetrating nanoparticles can be delivered to large intracranial volumes in both rats and pigs. We identified several agents (from Food and Drug Administration-approved products) that potently inhibit proliferation and self-renewal of BCSCs. When loaded into brain-penetrating nanoparticles and administered by convection-enhanced delivery, one of these agents, dithiazanine iodide, significantly increased survival in rats bearing BCSC-derived xenografts. This unique approach to controlled delivery in the brain should have a significant impact on treatment of glioblastoma multiforme and suggests previously undescribed routes for drug and gene delivery to treat other diseases of the central nervous system.

Imaging the delivery of brain-penetrating PLGA nanoparticles in the brain using magnetic resonance.

Current therapy for glioblastoma multiforme (GBM) is largely ineffective, with nearly universal tumor recurrence. The failure of current therapy is primarily due to the lack of approaches for the efficient delivery of therapeutics to diffuse tumors in the brain. In our prior study, we developed brain-penetrating nanoparticles that are capable of penetrating brain tissue and distribute over clinically relevant volumes when administered via convection-enhanced delivery (CED). We demonstrated that these particles are capable of efficient delivery of chemotherapeutics to diffuse tumors in the brain, indicating that they may serve as a groundbreaking approach for the treatment of GBM. In the original study, nanoparticles in the brain were imaged using positron emission tomography (PET). However, clinical translation of this delivery platform can be enabled by engineering a non-invasive detection modality using magnetic resonance imaging (MRI). For this purpose, we developed chemistry to incorporate superparamagnetic iron oxide (SPIO) into the brain-penetrating nanoparticles. We demonstrated that SPIO-loaded nanoparticles, which retain the same morphology as nanoparticles without SPIO, have an excellent transverse (T(2)) relaxivity. After CED, the distribution of nanoparticles in the brain (i.e., in the vicinity of injection site) can be detected using MRI and the long-lasting signal attenuation of SPIO-loaded brain-penetrating nanoparticles lasted over a one-month timecourse. Development of these nanoparticles is significant as, in future clinical applications, co-administration of SPIO-loaded nanoparticles will allow for intraoperative monitoring of particle distribution in the brain to ensure drug-loaded nanoparticles reach tumors as well as for monitoring the therapeutic benefit with time and to evaluate tumor relapse patterns.

Biodegradable poly(amine-co-ester) terpolymers for targeted gene delivery.

Many synthetic polycationic vectors for non-viral gene delivery show high efficiency in vitro, but their usually excessive charge density makes them toxic for in vivo applications. Here we describe the synthesis of a series of high molecular weight terpolymers with low charge density, and show that they exhibit efficient gene delivery, some surpassing the efficiency of the commercial transfection reagents Polyethylenimine and Lipofectamine 2000. The terpolymers were synthesized via enzyme-catalyzed copolymerization of lactone with dialkyl diester and amino diol, and their hydrophobicity adjusted by varying the lactone content and by selecting a lactone comonomer of specific ring size. Targeted delivery of the pro-apoptotic TRAIL gene to tumour xenografts by one of the terpolymers results in significant inhibition of tumour growth, with minimal toxicity both in vitro and in vivo. Our findings suggest that the gene delivery ability of the terpolymers stems from their high molecular weight and increased hydrophobicity, which compensates for their low charge density.

Giant myofibroma of the orbit in an adult male.

A 47-year-old male with history of schizophrenia developed painful proptosis and vision loss. Computed Tomography revealed a bone-destructive mass with encroachment on the orbit and compression of the right eye. Superolateral orbitotomy and biopsy revealed a lesion composed of a mixture of spindled and epithelioid cells without significant cytologic atypia or mitotic rate. Immunohistochemical stains were positive for vimentin and multifocally for smooth muscle actin, supporting the diagnosis of orbital myofibroma. Although orbital myofibromas typically present during childhood, they may occur in older patients and act as an expanding mass causing compression of adjacent structures.

Leptomeningeal dissemination of low-grade neuroepithelial CNS tumors in adults: a 15-year experience.

BACKGROUND: Leptomeningeal dissemination (LD) in adults is an exceedingly rare complication of low-grade neuroepithelial CNS tumors (LGNs). We aimed to determine relative incidence, clinical presentation, and predictors of outcome. METHODS: We searched the quality control database of the Section of Neuro-Oncology, Yale Cancer Center, for patients with LGN (WHO grade I/II) seen between 2002 and 2017. For cases complicated by LD, we recorded demographics, clinical signs, histopathological diagnosis, and imaging findings. A comprehensive literature review was performed. RESULTS: Eleven consecutive patients with LD were identified, representing 2.3% of individuals with LGN seen at our institution between 2002 and 2017 (n = 475). Ependymoma was the predominant histological entity. Mean time interval from diagnosis of LGN to LD was 38.6 ± 10 months. Symptoms were mostly attributed to communicating hydrocephalus. Tumor deposits of LD were either nodular or linear with variable enhancement (nonenhancing lesions in 4 of 11 patients). Localized (surgery, radiosurgery, involved-field, or craniospinal radiation therapy) or systemic treatments (chemotherapy) were provided. All patients progressed radiographically. Median overall survival after LD was 102 months. Survival was prolonged when a combination of localized and systemic therapies was administered (188.5 vs 25.5 months; P = .03). Demographics and tumor spectrum reported in the literature were similar to our cohort. CONCLUSIONS: LD is a rare complication of LGNs. A high level of suspicion is required for timely diagnosis as early symptoms are nonspecific and commonly do not occur until years after initial tumor diagnosis. Repeated aggressive treatment appears to be beneficial in improving survival.

Systemic vesicular stomatitis virus selectively destroys multifocal glioma and metastatic carcinoma in brain.

Metastatic tumors and malignant gliomas make up the majority of cancers in the brain. They are invariably fatal and there is currently no cure. From in vitro comparisons of a number of viruses, we selected one that appeared the best in selectively killing glioblastoma cells. This replication-competent virus, the glioma-adapted vesicular stomatis virus strain VSVrp30a, was used for in vivo tests with the underlying view that infection of tumor cells will lead to an increase in the number of viruses subsequently released to kill additional tumor cells. Intravenous injection of VSVrp30a expressing a green fluorescent protein reporter, rapidly targeted and destroyed multiple types of human and mouse tumors implanted in the mouse brain, including glioblastoma and mammary tumors. When tumors were implanted both in the brain and peripherally, emulating systemic cancer metastasis, tumors inside and outside the brain were simultaneously infected. Intranasal inoculation, leading to olfactory nerve transport of the virus into the brain, selectively infected and killed olfactory bulb tumors. Neither control cortical wounds nor transplanted normal mouse or human cells were targeted, indicating viral tumor selectivity. Control viruses, including pseudorabies, adeno-associated, or replication-deficient VSV, did not infect the brain tumor. Confocal laser time-lapse imaging through a cranial window showed that intravenous VSV infects the tumor at multiple sites and kills migrating tumor cells. Disrupted tumor vasculature, suggested by dye leakage, may be the port of entry for intravenously delivered VSV. Quantitative PCR analysis of how VSVrp30a selectively infected tumor cells suggested multiple mechanisms, including cell surface binding and internalization.

Current concepts in the evaluation and management of WHO grade II gliomas.

Over the past two decades, the accumulated clinical and research experience has improved our understanding the biology of WHO grade II gliomas (G2G). While there have been relatively few randomized clinical trials in this population, those that exist and the experience from clinical reports have enhanced our understanding of how these tumors progressively increase in size, accumulate additional genetic mutations and ultimately transform into high-grade lesions. Our ability to reliably predict the time sequence of this transformation remains a challenge; however, recent findings have started to clarify selection criteria for adjuvant treatment. G2G remain a fatal disease for many patients. Continued investigation into the biology of these lesions will likely provide the information needed to select more appropriate therapy based on biological and genetic differences in these unique lesions. Some of this information will be derived from the study of high-grade lesions. However, experience has shown that much of the work on high-grade lesions is also applicable to low-grade lesions.

Anaplastic oligoastrocytoma in Turcot syndrome.

Turcot syndrome (TS), a rare variant of hereditary non-polyposis colorectal cancer (HNPCC), is characterized by familial clustering of cancer of the large bowel, extracolonic body sites and brain. It is caused by germline mutations in genes encoding for components of the DNA mismatch repair system. We report a 72 year old woman with anaplastic oligoastrocytoma in the setting of TS. Careful analysis of tumor DNA is required to exclude the chance occurrence of a brain tumor in HNPCC kindreds and increase our understanding of the pathogenesis of the disease. Our case adds to the handful of cases published with detailed molecular data previously.

Intracranial benign fibrous histiocytomas: a case report and review.

Fibrous histiocytomas are rare lesions, more commonly encountered in soft tissues and bones. They are uncommon as an intracranial lesion. Although there have been several reports about malignant fibrous histiocytomas, less is known about the benign variant of these intracranial tumors as they are often misclassified as other types of tumors. We describe a child who presented with seizure and was subsequently found to have a large temporal lesion. Pathology revealed benign fibrous histiocytoma. We also review other cases reported in the literature in an effort to provide further insight into the diagnosis and management of this rare tumor.

Primary, non-exophytic, optic nerve germ cell tumors.

Tumors of the optic chiasm are relatively uncommon and usually associated with phakomatoses such as neurofibromatosis. Even more rare is the presentation of a primary, non-exophytic, isolated optic chiasm germ cell tumor (GCT). These tumors have imaging characteristics nearly indistinguishable from optic chiasmatic gliomas (OCGs). Herein we describe two cases of young men who presented with similar findings of progressive, painless visual loss and hypothalamic-pituitary-adrenal axis dysfunction including diabetes insipidus. Brain imaging was non-diagnostic and suggestive of an OCG. Pathology demonstrated GCTs in each case highlighting the importance of biopsy confirmation of the diagnosis. Both patients underwent a pterional craniotomy and sub-frontal approach to the optic chiasm. The chiasm was diffusely enlarged and discolored in each case without evidence of sellar, suprasellar or perichiasmatic pathology. Pathology demonstrated a malignant mixed GCT in the first patient and a germinoma in the second. This case series highlights the importance of tissue biopsy for patients with progressive symptoms from optic chiasm tumors. Furthermore, this is the first report of a primary, non-exophytic malignant mixed GCT. As the treatment regimens differ widely between optic chiasm GCTs and chiasm gliomas, tissue diagnosis is important.

Novel tumor-specific isoforms of BEHAB/brevican identified in human malignant gliomas.

Malignant gliomas are deadly brain tumors characterized by diffuse invasion into the surrounding brain tissue. Understanding the mechanisms involved in glioma invasion could lead to new therapeutic strategies. We have previously shown that BEHAB/brevican, an extracellular matrix protein in the central nervous system, plays a role in the invasive ability of gliomas. The mechanisms that underlie BEHAB/brevican function are not yet understood, due in part to the existence of several isoforms that may have different functions. Here we describe for the first time the expression of BEHAB/brevican in human brain and characterize two novel glioma-specific isoforms, B/b(sia) and B/b(Deltag), which are generated by differential glycosylation and are absent from normal adult brain and other neuropathologies. B/b(sia) is an oversialylated isoform expressed by about half the high- and low-grade gliomas analyzed. B/b(Deltag) lacks most of the carbohydrates typically present on BEHAB/brevican and is the major up-regulated isoform of this protein in high-grade gliomas but is absent in a specific subset of low-grade, indolent oligodendrogliomas. B/b(Deltag) is detected on the extracellular surface, where it binds to the membrane by a mechanism distinct from the other BEHAB/brevican isoforms. The glioma-specific expression of B/b(Deltag), its restricted membrane localization, and its expression in all high-grade gliomas tested to date suggest that it may play a significant role in glioma progression and make it an important new potential therapeutic target. In addition, its absence from benign gliomas prompts its use as a diagnostic marker to distinguish primary brain tumors of similar histology but different pathologic course.

New methods for direct delivery of chemotherapy for treating brain tumors.

Despite advances in diagnostic imaging and drug discovery, primary malignant brain tumors remain fatal. Median survival for patients with the most severe forms is rarely past eight months. The severity of the disease and the lack of substantial improvement in patient survival demand that new approaches be explored in drug delivery to brain tumors. Recently, local delivery of chemotherapy to brain tumors has provided a way to circumvent the blood-brain barrier, allowing delivery of chemotherapy drugs directly to malignant cells in the brain. Two methods of local delivery have been developed: polymeric-controlled release and convection-enhanced delivery. Controlled release utilizes degradable or non-degradable polymers as carriers of chemotherapy; polymer implants or microparticles are implanted locally to introduce a sustained source of drug for periods of days or months. Convection-enhanced delivery employs the bulk flow of drugs dissolved in fluid, which is introduced intracranially using a catheter and pump. The convective fluid flow is capable of delivering drugs great distances within the brain, potentially treating invasive cells at a distance from the catheter infusion site. These two new delivery strategies are capable of delivering both standard chemotherapeutic drugs and new methods of anti-cancer therapy. Taken individually, or used in tandem, they represent a potential revolution in brain cancer treatment.

Increased Nanoparticle Delivery to Brain Tumors by Autocatalytic Priming for Improved Treatment and Imaging.

The blood-brain barrier (BBB) is partially disrupted in brain tumors. Despite the gaps in the BBB, there is an inadequate amount of pharmacological agents delivered into the brain. Thus, the low delivery efficiency renders many of these agents ineffective in treating brain cancer. In this report, we proposed an "autocatalytic" approach for increasing the transport of nanoparticles into the brain. In this strategy, a small number of nanoparticles enter into the brain via transcytosis or through the BBB gaps. After penetrating the BBB, the nanoparticles release BBB modulators, which enables more nanoparticles to be transported, creating a positive feedback loop for increased delivery. Specifically, we demonstrated that these autocatalytic brain tumor-targeting poly(amine-co-ester) terpolymer nanoparticles (ABTT NPs) can readily cross the BBB and preferentially accumulate in brain tumors at a concentration of 4.3- and 94.0-fold greater than that in the liver and in brain regions without tumors, respectively. We further demonstrated that ABTT NPs were capable of mediating brain cancer gene therapy and chemotherapy. Our results suggest ABTT NPs can prime the brain to increase the systemic delivery of therapeutics for treating brain malignancies.

Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas.

RNA polymerase II mediates the transcription of all protein-coding genes in eukaryotic cells, a process that is fundamental to life. Genomic mutations altering this enzyme have not previously been linked to any pathology in humans, which is a testament to its indispensable role in cell biology. On the basis of a combination of next-generation genomic analyses of 775 meningiomas, we report that recurrent somatic p.Gln403Lys or p.Leu438_His439del mutations in POLR2A, which encodes the catalytic subunit of RNA polymerase II (ref. 1), hijack this essential enzyme and drive neoplasia. POLR2A mutant tumors show dysregulation of key meningeal identity genes, including WNT6 and ZIC1/ZIC4. In addition to mutations in POLR2A, NF2, SMARCB1, TRAF7, KLF4, AKT1, PIK3CA, and SMO, we also report somatic mutations in AKT3, PIK3R1, PRKAR1A, and SUFU in meningiomas. Our results identify a role for essential transcriptional machinery in driving tumorigenesis and define mutually exclusive meningioma subgroups with distinct clinical and pathological features.

Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO.

We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1(E17K), a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ~5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive-nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics.

Neurosurgical approach.

Glioblastoma multiforme is a highly infiltrative tumor that typically has a central region of necrosis surrounded by contrast-enhancing proliferative tumor cells surrounded by diffuse isolated tumor cells that migrate into the brain. The goal of surgery is often directed toward the central necrotic region and the imaging-defined enhancing margin. To limit morbidity from removing functional brain tissue, the infiltrative tumor cells found in surrounding brain are generally not considered part of the surgical target. This is also the site where tumors recur after treatment. It is well accepted by most surgeons and neuro-oncologists that, when possible, aggressive resection of malignant gliomas is the preferred initial step in management. Although there are limited randomized prospective studies that address extent of resection and survival, the benefit of aggressive surgical resection will not be debated in this report. Tumor resection to the maximum extent that is safely possible can decrease tumor burden and thereby enhance the effects of adjuvant therapies, improve symptoms from mass effect, reduce the frequency of seizures, and provide tissue for pathological and genomic studies to better identify and test novel therapy.Surgery for glioblastoma is highly dependent on imaging. Magnetic resonance imaging can provide an anatomic definition of the lesion and functional capacity of critical cortical regions and allow for precise localization within the brain. The common use of stereotactic guidance, intraoperative imaging, functional magnetic resonance imaging, and physiologic monitoring have enhanced the surgeon's ability to achieve aggressive tumor removal while protecting the patient from neurologic impairment. This review will address the use of these techniques as an important first step in managing patients with glioblastoma.

Polymeric nanoparticles for drug delivery to the central nervous system.

The central nervous system (CNS) poses a unique challenge for drug delivery. The blood-brain barrier significantly hinders the passage of systemically delivered therapeutics and the brain extracellular matrix limits the distribution and longevity of locally delivered agents. Polymeric nanoparticles represent a promising solution to these problems. Over the past 40years, substantial research efforts have demonstrated that polymeric nanoparticles can be engineered for effective systemic and local delivery of therapeutics to the CNS. Moreover, many of the polymers used in nanoparticle fabrication are both biodegradable and biocompatible, thereby increasing the clinical utility of this strategy. Here, we review the major advances in the development of polymeric nanoparticles for drug delivery to the CNS.

Role of neurosurgery and radiation therapy in the management of brain tumors.

In the United States, approximately 65,000 people are diagnosed with primary brain tumors each year, with an incidence of 19.3 cases per 100,000 person-years. These numbers represent a wide spectrum of disease, from benign to malignant, and prognosis varies widely based on disease. Treatment of primary brain tumors most often uses a combination of surgery and radiation. However, over the past several generations, technological advancements have significantly altered the treatment paradigm. This article reviews the current role of neurosurgery and radiation therapy in the management of primary brain tumors.

Low-grade gliomas: when and how to treat.

Low-grade gliomas are uncommon tumors whose optimal management remains to be determined. Although well-designed clinical trials have been mounted to address certain aspects of postoperative radiotherapeutic management, additional studies are required to refine management based on tumor-specific and patient-specific variables. There is mounting evidence that the relative completeness of surgical resection can improve survival, and the molecular and histopathologic characterization of the glioma requires adequate samples for analysis. Current imaging and operative techniques can direct surgical resection, and the same imaging techniques can help monitor patients postoperatively and predict prognosis.