A common tumour in a rare location: a single centre case series of cerebellar glioblastoma.

Although glioblastoma is the commonest primary brain tumour in adults, its location in the cerebellum is extremely rare. We present thirteen cases (3 female, 10 male; median age at presentation 56 [age range 21-77]) of surgically managed, histologically confirmed, primary cerebellar glioblastoma (cGB) over a 17 year period (2005-2022). Pre-operative radiological diagnosis was challenging given cGB rarity, although MRI demonstrated ring enhancement in all cases. Surgical management included posterior fossa craniectomy and debulking in 11 cases and burr hole biopsy in two. CSF diversion was necessary in four cases. No evidence of IDH or ATRX gene mutations was found when tested. Survival ranged from 1 to 22 months after diagnosis (mean 10.9 months). We also seek to understand why glioblastoma is rare in this location and discuss potential reasons for this. We hypothesise that increasing anatomical distance from germinal regions and decreased local endogenous neural stem cell activity (which has been associated with glioblastoma) may explain why glioblastoma is rare in the cerebellum. We hereby seek to add to the limited literature on cGB as this is the largest UK cGB series to date.

Craniectomy with soft tissue reconstruction for locally advanced non-melanoma skin cancer of scalp with calvarial invasion: The Nottingham experience.

INTRODUCTION: Locally advanced non-melanoma skin cancer (NMSC) involving the periosteum or calvarium poses a clinical challenge for patients who are unfit for immunotherapy due to medical comorbidities and/or frailty. This case series aims to investigate outcomes for patients undergoing craniectomy and soft tissue reconstruction. METHOD: Patients who underwent craniectomy and soft tissue reconstruction for invasive NMSC with calvarium or periosteal invasion between 2016 and 2022 were included. Data, including demographics, operative details, and clinical outcomes, were gathered from Nottingham University Hospitals' digital health record and the histopathology electronic database. RESULT: Eight patients (average age: 78.4 years, 3 females 5 males) with significant comorbidities and varying degrees of periosteal or bone invasion fulfilled the inclusion criteria. Diagnoses included four squamous cell carcinomas, two basal cell carcinomas, and two pleomorphic dermal sarcomas. Five patients had a history of prior incomplete deep margin excision. The median sizes for soft tissue defect, tumor and bone defect size were 51.83 cm2, 34.63 cm2 and 42.25 cm2, respectively. Intraoperative complications included one dural tear. Four patients underwent local flap reconstruction and with split-thickness skin grafting, four patients underwent free flap reconstruction. Adjuvant radiotherapy was administered to three patients. Complications comprised partial graft loss in two and complete graft loss in one. There was partial flap loss in one case. One patient required subsequent parotidectomy due to regional progression before achieving disease control. All patients achieved lasting locoregional disease control (average follow-up 29.7 months). CONCLUSION: Craniectomy with soft tissue reconstruction proves to be a safe and effective treatment option in advanced NMSC of the scalp in patients unsuitable for immunotherapy due to frailty or medical co-morbidity.

Total intravenous anaesthesia with propofol and remifentanil is associated with reduction in operative time in surgery for glioblastoma when compared with inhalational anaesthesia with sevoflurane.

BACKGROUND: Total intravenous anaesthesia (TIVA) is emerging as a preferred neuroanaesthetic agent compared with inhalational anaesthetic (IA) agents. We asked if TIVA with propofol and remifentanil was associated with shorter operative times compared to IA using sevoflurane in brain tumour surgery under GA. METHODS: We performed a retrospective analysis of all patients undergoing surgery for glioblastoma (GBM). We assessed choice of GA agent (TIVA or IA) with total time patient was under GA (anaesthetic time), operative time and time taken to recover fully from GA (recovery time). RESULTS: Over a two year period 263 patients underwent surgery under GA for their GBM including 188 craniotomy operations, 63 burr hole biopsy procedures and 12 open biopsy procedures. Of these, 79 operations took place under TIVA and 184 operations under IA. TIVA was associated with significantly reduced mean operative time including time taken to wake up in theatre (104 min with TIVA, 129 min with IA; p = 0.02). TIVA was also associated with trends toward shorter mean recovery time (118 min, versus 135 min with IA; p = 0.08) and shorter mean anaesthetic time (163 min, versus 181 min with IA; p = 0.07). There was no difference between TIVA and IA groups as regards duration of inpatient stay, readmission rates, complications or survival. CONCLUSIONS: TIVA with propofol and remifentanil may reduce anaesthetic, operative and recovery times in patients undergoing surgery for their GBM. These findings may be attributable to favourable effects on intracranial pressure and cerebral perfusion, as well as rapid recovery from GA. In addition to clinical advantages, there may be financial and logistical benefits.

Wireless electrical-molecular quantum signalling for cancer cell apoptosis.

Quantum biological tunnelling for electron transfer is involved in controlling essential functions for life such as cellular respiration and homoeostasis. Understanding and controlling the quantum effects in biology has the potential to modulate biological functions. Here we merge wireless nano-electrochemical tools with cancer cells for control over electron transfer to trigger cancer cell death. Gold bipolar nanoelectrodes functionalized with redox-active cytochrome c and a redox mediator zinc porphyrin are developed as electric-field-stimulating bio-actuators, termed bio-nanoantennae. We show that a remote electrical input regulates electron transport between these redox molecules, which results in quantum biological tunnelling for electron transfer to trigger apoptosis in patient-derived cancer cells in a selective manner. Transcriptomics data show that the electric-field-induced bio-nanoantenna targets the cancer cells in a unique manner, representing electrically induced control of molecular signalling. The work shows the potential of quantum-based medical diagnostics and treatments.

Lesion detection in epilepsy surgery: Lessons from a prospective evaluation of a machine learning algorithm.

AIM: To evaluate a lesion detection algorithm designed to detect focal cortical dysplasia (FCD) in children undergoing stereoelectroencephalography (SEEG) as part of their presurgical evaluation for drug-resistant epilepsy. METHOD: This was a prospective, single-arm, interventional study (Idea, Development, Exploration, Assessment, and Long-Term Follow-Up phase 1/2a). After routine SEEG planning, structural magnetic resonance imaging sequences were run through an FCD lesion detection algorithm to identify putative clusters. If the top three clusters were not already sampled, up to three additional SEEG electrodes were added. The primary outcome measure was the proportion of patients who had additional electrode contacts in the SEEG-defined seizure-onset zone (SOZ). RESULTS: Twenty patients (median age 12 years, range 4-18 years) were enrolled, one of whom did not undergo SEEG. Additional electrode contacts were part of the SOZ in 1 out of 19 patients while 3 out of 19 patients had clusters that were part of the SOZ but they were already implanted. A total of 16 additional electrodes were implanted in nine patients and there were no adverse events from the additional electrodes. INTERPRETATION: We demonstrate early-stage prospective clinical validation of a machine learning lesion detection algorithm used to aid the identification of the SOZ in children undergoing SEEG. We share key lessons learnt from this evaluation and emphasize the importance of robust prospective evaluation before routine clinical adoption of such algorithms. WHAT THIS PAPER ADDS: The focal cortical dysplasia detection algorithm collocated with the seizure-onset zone (SOZ) in 4 out of 19 patients. The algorithm changed the resection boundaries in 1 of 19 patients undergoing stereoelectroencephalography for drug-resistant epilepsy. The patient with an altered resection due to the algorithm was seizure-free 1 year after resective surgery. Overall, the algorithm did not increase the proportion of patients in whom SOZ was identified.

Spatially resolved transcriptomic profiles reveal unique defining molecular features of infiltrative 5ALA-metabolizing cells associated with glioblastoma recurrence.

BACKGROUND: Spatiotemporal heterogeneity originating from genomic and transcriptional variation was found to contribute to subtype switching in isocitrate dehydrogenase-1 wild-type glioblastoma (GBM) prior to and upon recurrence. Fluorescence-guided neurosurgical resection utilizing 5-aminolevulinic acid (5ALA) enables intraoperative visualization of infiltrative tumors outside the magnetic resonance imaging contrast-enhanced regions. The cell population and functional status of tumor responsible for enhancing 5ALA-metabolism to fluorescence-active PpIX remain elusive. The close spatial proximity of 5ALA-metabolizing (5ALA +) cells to residual disease remaining post-surgery renders 5ALA + biology an early a priori proxy of GBM recurrence, which is poorly understood. METHODS: We performed spatially resolved bulk RNA profiling (SPRP) analysis of unsorted Core, Rim, Invasive margin tissue, and FACS-isolated 5ALA + /5ALA - cells from the invasive margin across IDH-wt GBM patients (N = 10) coupled with histological, radiographic, and two-photon excitation fluorescence microscopic analyses. Deconvolution of SPRP followed by functional analyses was performed using CIBEROSRTx and UCell enrichment algorithms, respectively. We further investigated the spatial architecture of 5ALA + enriched regions by analyzing spatial transcriptomics from an independent IDH-wt GBM cohort (N = 16). Lastly, we performed survival analysis using Cox Proportinal-Hazards model on large GBM cohorts. RESULTS: SPRP analysis integrated with single-cell and spatial transcriptomics uncovered that the GBM molecular subtype heterogeneity is likely to manifest regionally in a cell-type-specific manner. Infiltrative 5ALA + cell population(s) harboring transcriptionally concordant GBM and myeloid cells with mesenchymal subtype, -active wound response, and glycolytic metabolic signature, was shown to reside within the invasive margin spatially distinct from the tumor core. The spatial co-localization of the infiltrating MES GBM and myeloid cells within the 5ALA + region indicates PpIX fluorescence can effectively be utilized to resect the immune reactive zone beyond the tumor core. Finally, 5ALA + gene signatures were associated with poor survival and recurrence in GBM, signifying that the transition from primary to recurrent GBM is not discrete but rather a continuum whereby primary infiltrative 5ALA + remnant tumor cells more closely resemble the eventual recurrent GBM. CONCLUSIONS: Elucidating the unique molecular and cellular features of the 5ALA + population within tumor invasive margin opens up unique possibilities to develop more effective treatments to delay or block GBM recurrence, and warrants commencement of such treatments as early as possible post-surgical resection of the primary neoplasm.

The Regulation of m6A Modification in Glioblastoma: Functional Mechanisms and Therapeutic Approaches.

Glioblastoma is the most prevalent primary brain tumour and invariably confers a poor prognosis. The immense intra-tumoral heterogeneity of glioblastoma and its ability to rapidly develop treatment resistance are key barriers to successful therapy. As such, there is an urgent need for the greater understanding of the tumour biology in order to guide the development of novel therapeutics in this field. N6-methyladenosine (m6A) is the most abundant of the RNA modifications in eukaryotes. Studies have demonstrated that the regulation of this RNA modification is altered in glioblastoma and may serve to regulate diverse mechanisms including glioma stem-cell self-renewal, tumorigenesis, invasion and treatment evasion. However, the precise mechanisms by which m6A modifications exert their functional effects are poorly understood. This review summarises the evidence for the disordered regulation of m6A in glioblastoma and discusses the downstream functional effects of m6A modification on RNA fate. The wide-ranging biological consequences of m6A modification raises the hope that novel cancer therapies can be targeted against this mechanism.

Stimuli-Responsive Multifunctional Nanomedicine for Enhanced Glioblastoma Chemotherapy Augments Multistage Blood-to-Brain Trafficking and Tumor Targeting.

Minimal therapeutic advances have been achieved over the past two decades for glioblastoma (GBM), which remains an unmet clinical need. Here, hypothesis-driven stimuli-responsive nanoparticles (NPs) for docetaxel (DTX) delivery to GBM are reported, with multifunctional features that circumvent insufficient blood-brain barrier (BBB) trafficking and lack of GBM targeting-two major hurdles for anti-GBM therapies. NPs are dual-surface tailored with a i) brain-targeted acid-responsive Angiopep-2 moiety that triggers NP structural rearrangement within BBB endosomal vesicles, and ii) L-Histidine moiety that provides NP preferential accumulation into GBM cells post-BBB crossing. In tumor invasive margin patient cells, the stimuli-responsive multifunctional NPs target GBM cells, enhance cell uptake by 12-fold, and induce three times higher cytotoxicity in 2D and 3D cell models. Moreover, the in vitro BBB permeability is increased by threefold. A biodistribution in vivo trial confirms a threefold enhancement of NP accumulation into the brain. Last, the in vivo antitumor efficacy is validated in GBM orthotopic models following intratumoral and intravenous administration. Median survival and number of long-term survivors are increased by 50%. Altogether, a preclinical proof of concept supports these stimuli-responsive multifunctional NPs as an effective anti-GBM multistage chemotherapeutic strategy, with ability to respond to multiple fronts of the GBM microenvironment.

Development of nanoparticle loaded microneedles for drug delivery to a brain tumour resection site.

Systemic drug delivery to the central nervous system (CNS) has been historically impeded by the presence of the blood brain barrier rendering many therapies inefficacious to any cancer cells residing within the brain. Therefore, local drug delivery systems are being developed to overcome this shortfall. Here we have manufactured polymeric microneedle (MN) patches, which can be anchored within a resection cavity site following surgical removal of a tumour such as isocitrate dehydrogenase wild type glioblastoma (GBM). These MN patches have been loaded with polymer coated nanoparticles (NPs) containing cannabidiol (CBD) or olaparib (OLA) and applied to an in vitro brain simulant and ex vivo rat brain tissue to assess drug release and distance of penetration. MN patches loaded with methylene blue dye were placed into a cavity of 0.6 % agarose to simulate brain tissue. The results showed that clear channels were generated by the MNs and the dye spread laterally throughout the agarose. When loaded with CBD-NPs, the agarose showed a CBD concentration of 12.5 µg/g at 0.5 cm from the MN insertion site. Furthermore, high performance liquid chromatography of ex vivo brain tissue following CBD-NP/MN patch insertion showed successful delivery of 59.6 µg/g into the brain tissue. Similarly, OLA-NP loaded MN patches showed delivery of 5.2 µg/g OLA into agarose gel at 0.5 cm distance from the insertion site. Orbitrap secondary ion mass spectrometry (OrbiSIMS) analysis confirmed the presence of OLA and the MN patch at up to 6 mm away from the insertion site following its application to a rat brain hemisphere. This data has provided insight into the capabilities and versatility of MN patches for use in local brain drug delivery, giving promise for future research.

Coughing on the coil; a case report and literature review of eight cases of endovascularly treated ICA pseudoaneurysms with coil migration into the oropharnyx.

We report a case of coil migration into the oropharynx five years after treatment of a left internal carotid pseudoaneurysm following abandoned transsphenoidal resection of a pituitary macroadenoma. Eight other cases were found on literature review, with coil migration occurring between 2 and 120 months often after a history of transsphenoidal surgery. The majority of these were treated with trimming in a day case setting. This report highlights the need for careful extended follow up when a pseudoaneurysm forms with a concurrent skull base deficit.

Electric field responsive nanotransducers for glioblastoma.

BACKGROUND: Electric field therapies such as Tumor Treating Fields (TTFields) have emerged as a bioelectronic treatment for isocitrate dehydrogenase wild-type and IDH mutant grade 4 astrocytoma Glioblastoma (GBM). TTFields rely on alternating current (AC) electric fields (EF) leading to the disruption of dipole alignment and induced dielectrophoresis (DEP) during cytokinesis. Although TTFields have a favourable side effect profile, particularly compared to cytotoxic chemotherapy, survival benefits remain limited (~ 4.9 months) after an extensive treatment regime (20 hours/day for 18 months). The cost of the technology also limits its clinical adoption worldwide. Therefore, the discovery of new technology that can enhance both the therapeutic efficiency and efficacy of these TTFields will be of great benefit to cancer treatment and decrease healthcare costs worldwide. METHODS: In this work, we report the role of electrically conductive gold (GNPs), dielectric silica oxide (SiO2), and semiconductor zinc oxide (ZnO) nanoparticles (NPs) as transducers for enhancing EF mediated anticancer effects on patient derived GBM cells. Physicochemical properties of these NPs were analyzed using spectroscopic, electron microscopy, and light-scattering techniques. RESULTS: In vitro TTFields studies indicated an enhanced reduction in the metabolic activity of patient-derived Glioma INvasive marginal (GIN 28) and Glioma contrast enhanced core (GCE 28) GBM As per our journal style, article titles should not include capitalised letters unless these are proper nouns/acronyms. We have therefore used the article title "Electric field responsive nanotransducers for glioblastoma" as opposed to "Electric Field Responsive Nanotransducers for Glioblastoma" as given in the submission system. Please check if this is correct.cells in groups treated with NPs vs. control groups, irrespective of NPs dielectric properties. Our results indicate the inorganic NPs used in this work enhance the intracellular EF effects that could be due to the virtue of bipolar dielectrophoretic and electrophoretic effects. CONCLUSIONS: This work presents preliminary evidence which could help to improve future EF applications for bioelectronic medicine. Furthermore, the merits of spherical morphology, excellent colloidal stability, and low toxicity, make these NPs ideal for future studies for elucidating the detailed mechanism and efficacy upon their delivery in GBM preclinical models.

Genome-Wide Expression and Anti-Proliferative Effects of Electric Field Therapy on Pediatric and Adult Brain Tumors.

The lack of treatment options for high-grade brain tumors has led to searches for alternative therapeutic modalities. Electrical field therapy is one such area. The Optune™ system is an FDA-approved novel device that delivers continuous alternating electric fields (tumor treating fields-TTFields) to the patient for the treatment of primary and recurrent Glioblastoma multiforme (GBM). Various mechanisms have been proposed to explain the effects of TTFields and other electrical therapies. Here, we present the first study of genome-wide expression of electrotherapy (delivered via TTFields or Deep Brain Stimulation (DBS)) on brain tumor cell lines. The effects of electric fields were assessed through gene expression arrays and combinational effects with chemotherapies. We observed that both DBS and TTFields significantly affected brain tumor cell line viability, with DBS promoting G0-phase accumulation and TTFields promoting G2-phase accumulation. Both treatments may be used to augment the efficacy of chemotherapy in vitro. Genome-wide expression assessment demonstrated significant overlap between the different electrical treatments, suggesting novel interactions with mitochondrial functioning and promoting endoplasmic reticulum stress. We demonstrate the in vitro efficacy of electric fields against adult and pediatric high-grade brain tumors and elucidate potential mechanisms of action for future study.

Feasibility of Photodynamic Therapy for Glioblastoma with the Mitochondria-Targeted Photosensitizer Tetramethylrhodamine Methyl Ester (TMRM).

One of the most challenging problems in the treatment of glioblastoma (GBM) is the highly infiltrative nature of the disease. Infiltrating cells that are non-resectable are left behind after debulking surgeries and become a source of regrowth and recurrence. To prevent tumor recurrence and increase patient survival, it is necessary to cleanse the adjacent tissue from GBM infiltrates. This requires an innovative local approach. One such approach is that of photodynamic therapy (PDT) which uses specific light-sensitizing agents called photosensitizers. Here, we show that tetramethylrhodamine methyl ester (TMRM), which has been used to asses mitochondrial potential, can be used as a photosensitizer to target GBM cells. Primary patient-derived GBM cell lines were used, including those specifically isolated from the infiltrative edge. PDT with TMRM using low-intensity green light induced mitochondrial damage, an irreversible drop in mitochondrial membrane potential and led to GBM cell death. Moreover, delayed photoactivation after TMRM loading selectively killed GBM cells but not cultured rat astrocytes. The efficacy of TMRM-PDT in certain GBM cell lines may be potentiated by adenylate cyclase activator NKH477. Together, these findings identify TMRM as a prototypical mitochondrially targeted photosensitizer with beneficial features which may be suitable for preclinical and clinical translation.

Improved survival outcomes despite older age at diagnosis: an era-by-era analysis of patients with primary central nervous system lymphoma treated at a single referral centre in the United Kingdom.

Observational studies with long-term follow-up of patients with primary central nervous system lymphoma (PCNSL) are scarce. Patient data over a period of four decades were retrospectively analysed from databases at Nottingham University Hospitals Trust, UK. The cohort was delineated by two distinct therapeutic eras; the first from 01/01/1982 to 31/12/2010 (n = 147) and the second 01/01/2011 to 31/07/2020 (n = 125). The median age at diagnosis was significantly older in the second era compared to the first (69 and 65 years respectively, P = 0·003). The 3-, 6- and 12-month overall survival (OS) rates in the second era were significantly higher compared to the first, at 85%, 77%, 62% versus 56%, 49%, 38% respectively (log-rank test P < 0·0001). On multivariate analysis, high-dose methotrexate (HD-MTX)-based induction protocols employed in the second era were associated with improved OS compared to those used in the first [hazard ratio (HR) 0·40, 95% confidence interval (CI) 0·28-0·57]. Within the second era, superior OS rates were seen with the use of intensive HD-MTX protocols (including consolidation with high-dose chemotherapy and autologous stem cell transplantation) compared to non-intensive HD-MTX schedules (HR 0·47, 95% CI 0·22-0·99). Initiating chemotherapy within 14 days of biopsy and use of rituximab were independently associated with improved OS and progression-free survival during the second era. These data suggest that prompt treatment initiation and use of intensive HD-MTX- and rituximab-based protocols have resulted in improved survival outcomes for patients.

Intratumour heterogeneity in microRNAs expression regulates glioblastoma metabolism.

While specific microRNA (miRNA) signatures have been identified in glioblastoma (GBM), the intratumour heterogeneity in miRNA expression has not yet been characterised. In this study, we reveal significant alterations in miRNA expression across three GBM tumour regions: the core, rim, and invasive margin. Our miRNA profiling analysis showed that miR-330-5p and miR-215-5p were upregulated in the invasive margin relative to the core and the rim regions, while miR-619-5p, miR-4440 and miR-4793-3p were downregulated. Functional analysis of newly identified miRNAs suggests their involvement in regulating lipid metabolic pathways. Subsequent liquid chromatography-mass spectrometry (LC-MS) and tandem mass spectroscopy (LC-MS/MS) profiling of the intracellular metabolome and the lipidome of GBM cells with dysregulated miRNA expression confirmed the alteration in the metabolite levels associated with lipid metabolism. The identification of regional miRNA expression signatures may underlie the metabolic heterogeneity within the GBM tumour and understanding this relationship may open new avenues for the GBM treatment.

CovidNeuroOnc: A UK multicenter, prospective cohort study of the impact of the COVID-19 pandemic on the neuro-oncology service.

BACKGROUND: The COVID-19 pandemic has profoundly affected cancer services. Our objective was to determine the effect of the COVID-19 pandemic on decision making and the resulting outcomes for patients with newly diagnosed or recurrent intracranial tumors. METHODS: We performed a multicenter prospective study of all adult patients discussed in weekly neuro-oncology and skull base multidisciplinary team meetings who had a newly diagnosed or recurrent intracranial (excluding pituitary) tumor between 01 April and 31 May 2020. All patients had at least 30-day follow-up data. Descriptive statistical reporting was used. RESULTS: There were 1357 referrals for newly diagnosed or recurrent intracranial tumors across 15 neuro-oncology centers. Of centers with all intracranial tumors, a change in initial management was reported in 8.6% of cases (n = 104/1210). Decisions to change the management plan reduced over time from a peak of 19% referrals at the start of the study to 0% by the end of the study period. Changes in management were reported in 16% (n = 75/466) of cases previously recommended for surgery and 28% of cases previously recommended for chemotherapy (n = 20/72). The reported SARS-CoV-2 infection rate was similar in surgical and non-surgical patients (2.6% vs. 2.4%, P > .9). CONCLUSIONS: Disruption to neuro-oncology services in the UK caused by the COVID-19 pandemic was most marked in the first month, affecting all diagnoses. Patients considered for chemotherapy were most affected. In those recommended surgical treatment this was successfully completed. Longer-term outcome data will evaluate oncological treatments received by these patients and overall survival.

Polymer Pro-Drug Nanoparticles for Sustained Release of Cytotoxic Drugs Evaluated in Patient-Derived Glioblastoma Cell Lines and In Situ Gelling Formulations.

Glioblastoma (GBM) is the most common, malignant and aggressive brain tumour in adults. Despite the use of multimodal treatments, involving surgery, followed by concomitant radiotherapy and chemotherapy, the median survival for patients remains less than 15 months from diagnosis. Low penetration of drugs across the blood-brain barrier (BBB) is a dose-limiting factor for systemic GBM therapies, and as a result, post-surgical intracranial drug delivery strategies are being developed to ensure local delivery of drugs within the brain. Here we describe the effects of PEGylated poly(lactide)-poly(carbonate)-doxorubicin (DOX) nanoparticles (NPs) on the metabolic activity of primary cancer cell lines derived from adult patients following neurosurgical resection, and the commercially available GBM cell line, U87. The results showed that non-drug-loaded NPs were well tolerated at concentrations of up to 100 µg/mL while tumour cell-killing effects were observed for the DOX-NPs at the same concentrations. Further experiments evaluated the release of DOX from polymer-DOX conjugate NPs when incorporated in a thermosensitive in situ gelling poly(DL-lactic-co-glycolic acid) and poly(ethylene glycol) (PLGA/PEG) matrix paste, in order to simulate the clinical setting of a locally injected formulation for GBM following surgical tumour resection. These assays demonstrated drug release from the polymer pro-drugs, when in PLGA/PEG matrices of two formulations, over clinically relevant time scales. These findings encourage future in vivo assessment of the potential capability of polymer-drug conjugate NPs to penetrate brain parenchyma efficaciously, when released from existing interstitial delivery systems.

Biomedical engineering approaches to enhance therapeutic delivery for malignant glioma.

We review the challenges of next-generation therapeutics for both systemic and localised delivery to brain tumours and discuss how recent engineering advances may be used to enhance brain penetration of systemic delivery therapies. The unmet clinical need which drug delivery seeks to address is discussed with reference to the therapy obstacles that the intra-tumour heterogeneity of glioma present. The unmet chemistry and biomedical engineering challenge to develop controlled release therapeutics is appraised, with commentary on current success/failures in systemic carrier-mediated delivery, including receptor-targeted, cell-based, blood-brain-barrier disrupting and MRI-guided focused ultrasound. Localised therapeutic delivery is a relatively under-studied research avenue and is discussed with reference to existing technologies in preclinical development. These include convection-enhanced delivery, alternative catheter delivery, and neuro-surgically applied delivery systems such as polymeric hydrogels and interstitial spray. A myriad of nano-scale therapeutic delivery systems is emerging as potential future medicines for malignant brain tumours. Such biomedically-engineered systems will increasingly feature in next-generation neuro-oncological clinical trials to deliver repurposed and experimental therapeutics, aimed at achieving therapeutic drug concentrations in the brain, with associated mortality and morbidity benefits for patients.

Ion Channels as Therapeutic Targets in High Grade Gliomas.

Glioblastoma multiforme (GBM) is a lethal brain cancer with an average survival of 14-15 months even with exhaustive treatment. High grade gliomas (HGG) represent the leading cause of CNS cancer-related death in children and adults due to the aggressive nature of the tumour and limited treatment options. The scarcity of treatment available for GBM has opened the field to new modalities such as electrotherapy. Previous studies have identified the clinical benefit of electrotherapy in combination with chemotherapeutics, however the mechanistic action is unclear. Increasing evidence indicates that not only are ion channels key in regulating electrical signaling and membrane potential of excitable cells, they perform a crucial role in the development and neoplastic progression of brain tumours. Unlike other tissue types, neural tissue is intrinsically electrically active and reliant on ion channels and their function. Ion channels are essential in cell cycle control, invasion and migration of cancer cells and therefore present as valuable therapeutic targets. This review aims to discuss the role that ion channels hold in gliomagenesis and whether we can target and exploit these channels to provide new therapeutic targets and whether ion channels hold the mechanistic key to the newfound success of electrotherapies.

Etoposide and olaparib polymer-coated nanoparticles within a bioadhesive sprayable hydrogel for post-surgical localised delivery to brain tumours.

Glioblastoma is a malignant brain tumour with a median survival of 14.6 months from diagnosis. Despite maximal surgical resection and concurrent chemoradiotherapy, reoccurrence is inevitable. To try combating the disease at a stage of low residual tumour burden immediately post-surgery, we propose a localised drug delivery system comprising of a spray device, bioadhesive hydrogel (pectin) and drug nanocrystals coated with polylactic acid-polyethylene glycol (NCPPs), to be administered directly into brain parenchyma adjacent to the surgical cavity. We have repurposed pectin for use within the brain, showing in vitro and in vivo biocompatibility, bio-adhesion to mammalian brain and gelling at physiological brain calcium concentrations. Etoposide and olaparib NCPPs with high drug loading have shown in vitro stability and drug release over 120 h. Pluronic F127 stabilised NCPPs to ensure successful spraying, as determined by dynamic light scattering and transmission electron microscopy. Successful delivery of Cy5-labelled NCPPs was demonstrated in a large ex vivo mammalian brain, with NCPP present in the tissue surrounding the resection cavity. Our data collectively demonstrates the pre-clinical development of a novel localised delivery device based on a sprayable hydrogel containing therapeutic NCPPs, amenable for translation to intracranial surgical resection models for the treatment of malignant brain tumours.