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Driving is an integral part of adult life and losing a driving licence is potentially a major problem. Many neurological conditions may impact on driving, either by increasing the risk of a sudden disabling event or by affecting cognition, vision, reaction speed, motor coordination, peripheral sensation or visuospatial processing. In the UK, the Drivers Medical Group of the Driver and Vehicle Licensing Agency (DVLA) decides whether an individual’s medical condition meets the appropriate standards for driving. The licensing decision rests with the DVLA and is not at the clinician’s discretion. However, clinicians must inform patients of their legal obligations towards the DVLA and how their neurological symptoms may restrict their driving. We discuss risk assessment, how chronic disabling neurological disease may impact on driving and the general principles of applying medical standards for fitness to drive. We also highlight how legal driving eligibility varies around the world. Finally, we discuss the practical applications relating to a specific case.

Glioblastoma multiforme (GBM) is impossible to fully remove surgically and almost always recurs at the borders of the resection cavity, while systemic delivery of therapeutic drug levels to the brain tumour is limited by the blood-brain barrier. This research describes the development of a novel formulation of Irinotecan-loaded Drug Eluting Seeds (iDES) for insertion into the margin of the GBM resection cavity to provide a sustained high local dose with reduced systemic toxicities. We used primary GBM cells from both the tumour core and Brain Around the Tumour tissue from recurrent GBM patients to demonstrate that irinotecan is more effective than temozolomide. Irinotecan had a 75% response rate, while only 50% responded to temozolomide. With temozolomide the cell viability was never below 80% whereas irinotecan achieved cell viabilities of less than 44%. The iDES were manufactured using a hot melt extrusion process with accurate irinotecan drug loadings and the same cytotoxicity as unformulated irinotecan. The iDES released irinotecan in a sustained fashion for up to 7 days. However, only the 30, 40 and 50% w/w loaded iDES formulations released the 300 to 1000 μg of irinotecan needed to be effective in vivo. The 30 and 40% w/w iDES formulations containing 10% plasticizer and either 60 or 50% PLGA prolonged survival from 27 to 70 days in a GBM xenograft mouse resection model with no sign of tumour recurrence. The 30% w/w iDES formulations showed equivalent toxicity to a placebo in non-tumour bearing mice. This innovative drug delivery approach could transform the treatment of recurrent GBM patients by improving survival and reducing toxicity.

Background The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib potentiated radiation and temozolomide (TMZ) chemotherapy in preclinical glioblastoma models but brain penetration was poor. Clinically, PARP inhibitors exacerbate the hematological side effects of TMZ. The OPARATIC trial was conducted to measure penetration of recurrent glioblastoma by olaparib and assess the safety and tolerability of its combination with TMZ. Methods Preclinical pharmacokinetic studies evaluated olaparib tissue distribution in rats and tumor-bearing mice. Adult patients with recurrent glioblastoma received various doses and schedules of olaparib and low-dose TMZ in a 3 + 3 design. Suitable patients received olaparib prior to neurosurgical resection; olaparib concentrations in plasma, tumor core and tumor margin specimens were measured by mass spectrometry. A dose expansion cohort tested tolerability and efficacy of the recommended phase II dose (RP2D). Radiosensitizing effects of olaparib were measured by clonogenic survival in glioblastoma cell lines. Results Olaparib was a substrate for multidrug resistance protein 1 and showed no brain penetration in rats but was detected in orthotopic glioblastoma xenografts. Clinically, olaparib was detected in 71/71 tumor core specimens (27 patients; median, 496 nM) and 21/21 tumor margin specimens (9 patients; median, 512.3 nM). Olaparib exacerbated TMZ-related hematological toxicity, necessitating intermittent dosing. RP2D was olaparib 150 mg (3 days/week) with TMZ 75 mg/m2 daily for 42 days. Fourteen (36%) of 39 evaluable patients were progression free at 6 months. Olaparib radiosensitized 6 glioblastoma cell lines at clinically relevant concentrations of 100 and 500 nM. Conclusion Olaparib reliably penetrates recurrent glioblastoma at radiosensitizing concentrations, supporting further clinical development and highlighting the need for better preclinical models.

Gliomas are highly malignant brain tumours characterised by extensive areas of poor perfusion which subsequently leads to hypoxia and reduced survival. Therapies that address the hypoxic microenvironment are likely to significantly improve patient outcomes. Verteporfin, a benzoporphyrin-like drug, has been suggested to target the Yes-associated protein (YAP). Increased YAP expression and transcriptional activity has been proposed in other tumour types to promote malignant cell survival and thus YAP-inhibitor, verteporfin, may be predicted to impact glioma cell growth and viability. Due to the extensive hypoxic nature of gliomas, we investigated the effect of hypoxia on YAP expression and found that YAP transcription is increased under these conditions. Treatment of both primary and immortalised glioblastoma cell lines with verteporfin resulted in a significant decrease in viability but strikingly only under hypoxic conditions (1% O2). We discovered that cell death occurs through a YAP-independent mechanism, predominately involving binding of free iron and likely through redox cycling, contributes to production of reactive oxygen species. This results in disruption of normal cellular processes and death in cells already under oxidative stress – such as those in hypoxia. We suggest that through repurposing verteporfin, it represents a novel means of treating highly therapy-resistant, hypoxic cells in glioma.

This study aimed to evaluate the prevalence of glucocorticoid-induced adrenal insufficiency in a cohort of patients with brain and skull base tumours and to identify factors which may predict its occurrence. Patients with brain or skull base tumours attending for a short synacthen test (SST) (adrenocorticotropin hormone (ACTH) stimulation test) at a single institution over a 3-year period were retrospectively identified. Baseline demographics and dexamethasone exposure were examined. Only patients with dexamethasone exposure were included in the final analysis looking at the primary end point of SST failure. Fisher’s exact test, Student’s t test, Mann-Whitney test and the Kendall’s tau-b test were used to evaluate the influence of age, gender, diagnosis and mean pituitary radiation dose on the primary endpoint. Receiver operating characteristic (ROC) curves were generated to explore the impact of duration and total exposure to dexamethasone on likelihood of SST failure. Thirty-one of 51 patients with previous dexamethasone exposure failed their first SST (61%). No significant relationship was demonstrated between age, gender, diagnosis or mean pituitary radiation dose and SST failure. Duration of and total exposure to dexamethasone were significantly associated with SST failure (p = 0.001 and p = 0.007, respectively). ROC curves generated values of 78 days and 171 mg days to give a sensitivity of 94 and 97%, respectively, to detect SST failure. Duration of dexamethasone use and total exposure predict for adrenal insufficiency in patients with brain and skull base tumours. Values derived from this study may be useful to identify patients at higher risk of adrenal suppression who require empirical hydrocortisone pending formal testing of the hypothalamic-pituitary-adrenal axis.

There has been significant progress in the treatment of metastatic melanoma, however the impact of new agents on patients with brain metastases remains poorly understood. We report outcomes using SRS for patients with melanoma brain metastases exposed to BRAF targeted agents and/or immunotherapy. METHODS Consecutive patients with metastatic melanoma and brain metastases undergoing SRS without routine whole brain radiotherapy were identified. Selection was restricted to patients having systemic therapy within the same centre. Follow-up included 3monthly MRI scans. All patients were treated using Cyberknife. The target volume was neuroradiology approved without an uncertainty margin. A review of electronic records and follow up imaging was undertaken. Survival data were summarized using Kaplan-Meier curves and compared via a logrank test. RESULTS 49 patients with 148 target metastases were identified. Median number of lesions was 2 (range 1–12), median dose 21Gy, median volume 0.31cc (range 0.01–6.71cc) and 94% had extracranial disease at 2 or more sites. Three patients did not have follow up MRI. One patient required long-term steroids, 1 had transient symptomatic swelling at 11months and 3 patients experienced bleeds (1 symptomatic- post-SRS treated lesion). 12-month local disease free survival was 71% (CI 53, 84). Distant brain progression occurred in 28 patients (57%), with a median time to progression of 8months (95% CI 5, 15). Distant brain progression was less frequent in patients with a single metastasis (p=0.03). Median overall survival (OS) was 11months (95% CI 8, 17). Median OS was 20months (95% CI 5, NR), 10months (95% CI 4, 12) and 11months (95% CI 3, NR) for patients with 1, 2–4 and ≥ 5 metastases respectively (p=0.07). CONCLUSION Beyond a single metastasis, the number of brain metastases did not correlate with OS. Patients with multiple brain metastases and active systemic disease may benefit from SRS however prospective evaluation is recommended.

BACKGROUND: Following stereotactic radiosurgery (SRS), brain metastases initially increase in size in up to a third of cases, suggesting treatment failure. Current imaging using structural MRI cannot differentiate between tumour recurrence and SRS-induced changes, creating difficulties with patient management. Combining multiparametric MRI techniques, which assess tissue physiological and metabolic information has shown promise for answering this clinical question. MATERIALS AND METHODS: Multiparametric MRI techniques including spectroscopy, diffusion and perfusion imaging were used for differentiation of radiation-induced necrosis and tumour recurrence after SRS for intracranial metastases in six cases. All patients presented with enlargement of the treated lesion, an increase in perilesional brain oedema, and aggravation or appearance of neurological signs and symptoms from 7–29 weeks after primary treatment. RESULTS: Multiparametric imaging helped to differentiate features of tumour progression (n=4) from radiation-induced necrosis (n=2). A low apparent diffusion coefficient (ADC) 2.1, high choline:creatine (Cho:Cr) ratio >1.8 suggested tumour recurrence. A high ADC >1000 x 10(–6) mm(2)/s, low rCBV ratio

Stereotactic radiosurgery (SRS) and radiotherapy (SRT) are considered standard of care for patients with 1–3 brain metastases with favourable prognosis. The role of SRS/SRT for multiple metastases remains debated. This project evaluated SRS/SRT outcomes when treating 4 or more brain metastases up to a maximum volume of 20cc. METHODS: Treatment episodes for patients with 4 or more brain metastases were identified from a single centre prospective database from August 2013 to October 2017. All patients were WHO PS 0–1 and treated using Cyberknife. Target volumes were neuroradiology approved with no additional margin beyond the enhancing volume. A retrospective review of electronic records and imaging was undertaken. Overall survival (OS) and distant brain recurrence free survival were calculated using Kaplan-Meier method from the date of treatment, censoring at last clinic visit or MRI respectively. RESULTS: 69 episodes (61 SRS, 7 SRT) were identified with a total of 458 metastases. Primary sites were melanoma (31.9%), lung (29%), breast (27.5%), renal (5.8%), other (5.7%). Median number of targets per episode was 5 (range 4–36). Median SRS dose was 21Gy (range 15-24Gy). Median SRT dose was 24Gy in 3 fractions (range 17.7/3#-27/3#). Median OS was 9.4 months (95% CI 6.5–12.4 months). In patients 65 years (p65 years(p=0.001). Median OS was 14 months for breast cancer versus 8.4 months for other primary sites (p=0.094). Number of metastases was not predictive of OS or occurrence of distant brain metastases. DISCUSSION: Data supports the ongoing use of volume rather than number of metastases alongside established prognostic factors including age when selecting patients for SRS/SRT.

What you need to know Although primary malignant brain tumours represent only 3% of all cancers, they result in the most life-years lost of any cancer.1 Survival with malignant brain tumours has remained poor despite improvements in diagnosis and management (table 1), and it was believed that survival and quality of life could be improved by standardising care across the country with a guideline. Over 60% of people with primary brain tumours present at and are diagnosed by accident and emergency services rather than by general practitioners or in specialist settings.2 Brain metastases are the most common brain tumour to present in primary care, but other forms of brain cancer are seen. View this table: Table 1 Care requirements for brain tumours by approximate median survival Although brain tumours are usually managed by specialist teams, primary care and non-specialist teams have an important role in patients’ long term care, particularly when it comes to considering the longer term cognitive, physical, and mental health effects of the tumour and its treatment (table 1). This article summarises the most recent …

Aims Following stereotactic radiosurgery (SRS), brain metastases initially increase in size in up to a third of cases, suggesting treatment failure. Current imaging using structural magnetic resonance imaging (MRI) cannot differentiate between tumour recurrence and SRS-induced changes, creating difficulties with patient management. Combining multiparametric MRI techniques, which assess tissue physiological and metabolic information, has shown promise in answering this clinical question. Materials and methods Multiparametric MRI techniques, including spectroscopy, diffusion and perfusion imaging, were used for the differentiation of radiation-related changes and tumour recurrence after SRS for intracranial metastases in six cases. All patients presented with enlargement of the treated lesion, an increase in perilesional brain oedema and aggravation or appearance of neurological signs and symptoms from 7 to 29 weeks after primary treatment. Results Multiparametric imaging helped to differentiate features of tumour progression (n = 4) from radiation-related changes (n = 2). A low apparent diffusion coefficient (ADC) 2.1, high choline:creatine (Cho:Cr) ratio > 1.8 suggested tumour recurrence. A high ADC > 1000 × 10−6 mm2/s, low rCBV ratio Conclusion Multiparametric MRI was helpful in the early identification of radiation-related changes and tumour recurrence and may be useful for monitoring treatment changes in intracranial neoplasms after SRS treatment.

PurposeConventional MRI methods are insufficient to accurately differentiate between local tumour recurrence and radiation-induced necrosis. Advanced MRI techniques such as perfusion imaging, diffusion imaging and spectroscopy have individually been shown to aid the assessment of response following SRS treatment of brain metastases [1–3]. However, the potential added-value of a multi-parametric approach using a combination of these techniques has not been investigated. Materials and MethodsA retrospective analysis was performed on 10 multi-parametric MRI examinations following SRS for metastatic brain lesions in a cohort of 7 patients with varying primary malignant diseases (melanoma, n=3; breast, n=3; small cell lung, n=1). Multi-parametric MRI examination consisted of dynamic susceptibility contrast (DSC) perfusion imaging, diffusion weighted imaging (DWI) and both single- and multi-voxel MR spectroscopy (MRS) (TE = 30 ms). Relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) maps were calculated from DSC and DWI data respectively using Siemens Syngo software and an rCBV ratio (lesion: contralateral) calculated. Analysis of MRS was performed using TARQUIN [4]. Correlations between rCBV ratio, ADC and Cho:Cr were investigated. Predictions of response based on each parameter were tested using radiological and clinical follow up. ResultsCho:Cr demonstrates a strong positive correlation with rCBV ratio (r = 0.89, p < 0.01). This is in agreement with previous work in pre-treatment metastases [5]. No significant correlations were observed between ADC and rCBV or Cho:Cr. Applying a reported threshold for rCBV ratio of 2.1 [1], patients were divided into two groups showing suspected tumour recurrence (n=4) and suspected radiation necrosis (n=3). ConclusionPreliminary results suggest that a combination of high rCBV, low ADC and high Cho: Cr can clearly identify local tumour recurrence and that multi-parametric MRI may show improved accuracy compared with any of the techniques in isolation.

2022Background: Olaparib, a small molecule inhibitor of poly (ADP-ribose) polymerase (PARP), may improve GBM outcomes by enhancing cytotoxic effects of ionising radiation and TMZ. Clinical development of PARP inhibitors has been restricted by exacerbation of hematological toxicity. We investigated tumor pharmacokinetics (PK) of olaparib and safety and tolerability of its combination with TMZ. Methods: Dose escalation explored different schedules of olaparib (tablet formulation) with 42 day cycles of daily low dose TMZ. A dose expansion cohort evaluated the maximum tolerated schedule. PK analysis was performed on tumor and blood samples from patients undergoing neurosurgical resection, who received 4 olaparib doses pre-operatively. Results: 48 patients were recruited (median age 51(18-68); 29 male, 19 female) of whom 27 underwent surgery and 35 received olaparib/TMZ and were evaluable. 13 evaluable patients received expansion dose schedule (median age 54(21-67); 9 male, 4 female). Olaparib was detected in ...

Advances in both cranial surgery and radiosurgery now offer a range of therapy choices for patients with metastatic spread of their breast cancer to the brain. Clinical assessment of neurological performance, disease status, and metastatic load enables us to systematically offer more appropriate treatments or combinations of treatments to reduce toxicity and improve quality of life. Whilst whole brain irradiation (WBRT) remains the mainstay for patients with multiple metastases, its toxicity and suitability for larger lesions are in question. Radiosurgery (SRS) (with one or more fractions) offers a means of treating patients with single or a small number of metastases with brain sparing but becomes much less effective as lesions become greater than 2 cm. Neurosurgical removal using image-directed techniques and intraoperative @neuro-monitoring allows rapid removal of larger lesions, reduction in symptomatic mass effects, low morbidity and early reduction in the need for harmful steroids. Local recurrence rates are improving, and surgery, in combination with adjuvant or delayed radiosurgery, offers much improved quality of life for patients and in some cases improved survival where primary disease is controlled.

Aims To evaluate non-auditory toxicity and local control after linear accelerator stereotactic radiosurgery (SRS) for the treatment of vestibular schwannomas. Materials and methods The institutional policy was to use SRS for radiologically progressing vestibular schwannomas. Case notes and plans were retrospectively reviewed for all patients undergoing SRS for vestibular schwannomas between September 2002 and June 2012. All patients were surgically immobilised using a BrainLab stereotactic head frame. The treatment plan was generated using BrainLab software (BrainScan 5.03). The aim was to deliver 12 Gy to the surface of the target with no margin. Patients with a minimum of 12 months of follow-up were included for toxicity and local control assessment. Radiological progression was defined as growth on imaging beyond 2 years of follow-up. Overall local control was defined in line with other series as absence of surgical salvage. Results Ninety-nine patients were identified. Two patients were lost to follow-up. After a median follow-up interval of 2.4 years, the actuarial radiological progression-free survival at 3 years was 100% and overall local control was also 100%. However, two patients progressed radiologically at 3.3 and 4.5 years, respectively. Twenty-one of 97 (22%) evaluable patients suffered trigeminal toxicity and this was persistent in 8/97 (8%). Two of 97 (2%) suffered long-term facial nerve toxicity (one with associated radiological progression causing hemi-facial spasm alone). One of 97 (1%) required intervention for obstructive hydrocephalus. No statistically significant dosimetric relationship could be shown to cause trigeminal or facial nerve toxicity. However, 7/8 patients with persistent trigeminal nerve toxicity had tumours in contact with the trigeminal nerve. Conclusions SRS delivering 12 Gy using a linear accelerator leads to high local control rates, but only prospective evaluation will fully establish short-term toxicity. In this study, persistent trigeminal toxicity occurred almost exclusively in patients whose tumour was in contact with the trigeminal nerve.

Glioblastoma Multiforme –(GBM) are infiltrative, impossible to resect totally and consequently recur almost always at the borders of the resection margin. There is no established chemotherapy regimen available to patients who recur. Systemic treatment is hampered by the inability of many therapeutic agents to effectively cross the blood brain barrier and systemic toxicity, hence, loco- regional strategies aim to focus drug delivery within the resected tumour cavity wall. Implantable polymers releasing chemotherapeutic agents into the CNS, such as Gliadel® wafers, are a proven example of this approach. Here we report on the first evaluation in humans of the intraparenchymal injection of microspheres containing the topoisomerase II inhibitor irinotecan (Irinotecan Drug-eluting Beads, or IDEB) into the resection cavity after surgical resection of recurrent GBM. The drug-eluting beads (DEBs) used in this study are composed of a biocompatible biomedical polymer hydrogel loaded with chemotherapeutic agent. This drug delivery system is based on a product that is currently approved and available commercially- DC Beads™ that have a defined release characteristics. Irinotecan itself has demonstrated clinical efficacy in treating glioblastoma but with marked systemic drug-related toxicity. It was therefore considered logical that the combination of these products in the IDEB might offer a useful low-risk alternative therapy for patients, providing an improved method of delivery for an efficacious drug. METHODS: 10 Patients with single focus recurrent GBM Suitable for surgery were selected. 100mg of Irinotecan in 3ml was implanted with ~30 injections into resection margin to a depth of 1 cm in 100μ l per injection. Patients were assessed for clinical toxicity (CTC 3) immediately and over 6/12 for SAE, and MRI changes. Plasma Irinotecan levels and steroid use were recorded RESULTS: 9 patients underwent the treatment. There were no major early or late SAE despite the injection process. Wound healing was unaffected and imaging shows no overt brain swelling unlike other depot therapies. One patient had an increased seizure frequency for a few days. Steroid requirements were not increased overall or by comparison with resection only patients. Median survival was 228days with one patient still surviving. Plasma levels were negligible. CONCLUSION: This novel form of therapy using this bead/drug combination, can be simply and safely delivered to patients following resection for recurrent tumour with low risk of wound problems or tumour/brain swelling at these high concentrations of Irinotecan. Future work will establish a maximally tolerated dose delivered in this way

Glioblastoma (GBM) is the most common and malignant type of primary brain tumor in adults and prognosis of most GBM patients is poor. However, a small percentage of patients show a long term survival of 36 mo or longer after diagnosis. Epigenetic profiles can provide molecular markers for patient prognosis: recently, a G-CIMP positive phenotype associated with IDH1 mutations has been described for GBMs with good prognosis. In the present analysis we performed genome-wide DNA methylation profiling of short-term survivors (STS; overall survival < 1 y) and long-term survivors (LTS; overall survival > 3 y) by utilizing the HumanMethylation450K BeadChips to assess quantitative methylation at > 480,000 CpG sites. Cluster analysis has shown that a subset of LTS showed a G-CIMP positive phenotype that was tightly associated with IDH1 mutation status and was confirmed by analysis of the G-CIMP signature genes. Using high stringency criteria for differential hypermethylation between non-cancer brain and tumor samples, we identified 2,638 hypermethylated CpG loci (890 genes) in STS GBMs, 3,101 hypermethylated CpG loci (1,062 genes) in LTS (wild type IDH1) and 11,293 hypermethylated CpG loci in LTS (mutated for IDH1), reflecting the CIMP positive phenotype. The location of differentially hypermethylated CpG loci with respect to CpG content, neighborhood context and functional genomic distribution was similar in our sample set, with the majority of CpG loci residing in CpG islands and in gene promoters. Our preliminary study also identified a set of CpG loci differentially hypermethylated between STS and LTS cases, including members of the homeobox gene family (HOXD8, HOXD13 and HOXC4), the transcription factors NR2F2 and TFAP2A, and Dickkopf 2, a negative regulator of the wnt/β-catenin signaling pathway.

Objectives Headaches and facial pain have been identified as the most prevalent form of pain among patients with glioblastoma multiforme, the most common malignant primary brain tumour. Despite this, minimal research has been undertaken investigating the direct and indirect impact these headaches have on their quality of life. Therefore, in this study, we aimed at gaining a personal insight into the importance and impact that these headaches have on the quality of life of patients with glioblastoma multiforme. Design Exploratory study using face-to-face semistructured interviews. Interviews were audio-recorded, transcribed verbatim and then qualitatively analysed using thematic analysis. Setting Participants recruited from a tertiary referral hospital in Birmingham, UK. Participants Purposive sampling of 14 registered outpatients recently diagnosed with glioblastoma multiforme. Results 3 themes were identified: (1) an underlying attitude of determination and positivity; (2) impact of headache unpredictability on social interaction; (3) headaches found to act as a springboard onto thoughts regarding their disease and future. Conclusions While the quality of life of patients with glioblastoma multiforme is clearly multifactorial, headaches do indeed play a part for some. However, it is not the direct pain of the headache as one might expect that impacts on the quality of life of these patients, but the indirect effect of headaches through limiting patients' social lives and by serving as a painful psychological reminder of having a life-threatening illness. In clinical practice, using headache diaries for these patients may help provide a more comprehensive assessment and further aid management plans. Alongside acting as an important reminder of the potential secondary implications of this disease, suggestions for future research include quantitatively investigating whether headaches can act as a prognostic indicator for quality of life within this patient demographic and determining whether these conclusions also hold true for a wider spectrum of patients with brain tumour.

Arteriovenous malformations (AVMs) are the leading causing of intra-cerebral haemorrhage. Stereotactic radiosurgery (SRS) is an established treatment for arteriovenous malformations (AVM) and commonly delivered using Gamma Knife within dedicated radiosurgery units. Linear accelerator (LINAC) SRS is increasingly available however debate remains over whether it offers an equivalent outcome. The aim of this project is to evaluate the outcomes using LINAC SRS for AVMs used within a UK neurosciences unit and review the literature to aid decision making across various SRS platforms. Results have shown comparability across platforms and strongly supports that an adapted LINAC based SRS facility within a dynamic regional neuro-oncology department delivers similar outcomes (in terms of obliteration and toxicity) to any other dedicated radio-surgical platform. Locally available facilities can facilitate discussion between options however throughput will inevitably be lower than centrally based dedicated national radiosurgery units.

OBJECTIVE: Different methods for contouring target volumes are currently in use in the UK when irradiating glioblastomas post operatively. Both one- and two-phase techniques are offered at different centres. 90% of relapses are recognised to occur locally when using radiotherapy alone. The objective of this evaluation was to determine the pattern of relapse following concomitant radiotherapy with temozolomide (RT-TMZ). METHODS: A retrospective analysis of patients receiving RT-TMZ between 2006 and 2010 was performed. Outcome data including survival were calculated from the start of radiotherapy. Analysis of available serial cross-sectional imaging was performed from diagnosis to first relapse. The site of first relapse was defined by the relationship to primary disease. Central relapse was defined as progression of the primary enhancing mass or the appearance of a new enhancing nodule within 2 cm. RESULTS: 105 patients were identified as receiving RT-TMZ. 34 patients were not eligible for relapse analysis owing to either lack of progression or unsuitable imaging. Patterns of first relapse were as follows: 55 (77%) patients relapsed centrally within 2 cm of the original gadolinium-enhanced mass on MRI, 13 (18%) patients relapsed >4 cm from the original enhancement and 3 (4%) relapsed within the contralateral hemisphere. CONCLUSION: Central relapse remains the predominant pattern of failure following RT-TMZ. Single-phase conformal radiotherapy using a 2-cm margin from the original contrast-enhanced mass is appropriate for the majority of these patients. ADVANCES IN KNOWLEDGE: Central relapse remains the predominant pattern of failure following chemoradiotherapy for glioblastomas.

Background. Multidisciplinary team (MDT) working in oncology aims to improve outcomes for patients with cancer. One role is to ensure the implementation of best practice and National Institute for Health and Clinical Excellence (NICE) guidance. In this study, we have assessed the role of MDT in implementing the TA121 appraisal of the use of carmustine wafers in high grade gliomas. Methods. 296 patients with high-grade glioma suitable for maximal resection were recruited from 17 Neurosurgical Centres. The number of patients treated with carmustine wafers and reasons for not using this were recorded. Complications at 48 hours post-operatively and at 6 weeks post-radiotherapy were recorded. Results. 94/296 (32%) of suitable patients received carmustine wafers. In 55% of cases carmustine was not used due to either surgeon preference or a lack of an MDT decision. There was no increased complication rate with carmustine use at either 48 hours post-surgery or at 6 weeks post radiotherapy. Use of carmustine wafers did not decrease access to and use of chemoradiotherapy. Conclusions. One third of patients suitable for carmustine wafers received them. Their use was neither associated with more frequent complications, nor decreased use of chemoradiotherapy. Implementation of NICE TA121 Guidance is extremely variable in different MDTs across the United Kingdom.

Delayed cerebral ischemia resulting from extracellular hemoglobin is an important determinant of outcome in subarachnoid hemorrhage. Hemoglobin is scavenged by the CD163-haptoglobin system in the circulation, but little is known about this scavenging pathway in the human central nervous system. The components of this system were analyzed in normal cerebrospinal fluid and after subarachnoid hemorrhage. The intrathecal presence of the CD163-haptoglobin-hemoglobin scavenging system was unequivocally demonstrated. The resting capacity of the CD163-haptoglobin-hemoglobin system in the normal central nervous system was 50,000 fold lower than that of the circulation. After subarachnoid hemorrhage, the intrathecal CD163-haptoglobin-hemoglobin system was saturated, as shown by the presence of extracellular hemoglobin despite detectable haptoglobin. Hemoglobin efflux from the central nervous system was evident, enabling rescue hemoglobin scavenging by the systemic circulation. Therefore, the central nervous system is not capable of dealing with significant intrathecal hemolysis. Potential therapeutic options to prevent delayed cerebral ischemia ought to concentrate on augmenting the capacity of the intrathecal CD163-haptoglobin-hemoglobin scavenging system and strategies to encourage Hb efflux from the brain.

Background The aim of this study was to investigate possible delays in referral time for Glioblastoma multiforme (GBM) patients diagnosed at two similar neurosurgical centres (in Birmingham, UK and Strasbourg, France) and their impact on survival. Differences in the referral patterns for GBM patients within these healthcare systems may affect subsequent management and are potential targets to optimise the care of patients with GBM. Methods Medical case notes of 105 GBM patients in Birmingham and 81 in Strasbourg, admitted during October 2006 and April 2008, were reviewed. Data regarding demographic details, route of admission, presenting symptoms, date of initial presentation to a medical professional and dates of the first CT or MRI scan, first neurosurgical intervention, histological diagnosis and mortality was recorded. Results The median time taken from initial presentation to first neurosurgical intervention was lower in Birmingham compared to Strasbourg (13 vs. 21 days, respectively; p = 0.026). Similarly, the time taken from initial presentation to histological diagnosis was lower in Birmingham (15 vs. 24 days, respectively; p = 0.011). However, survival was poorer in Birmingham than Strasbourg (p = 0.001) and age (HR = 1.029; 95%CI 1.010–1.048; p = 0.003) and time from initial presentation to neurosurgical intervention (HR = 0.993; 95%CI 0.988–0.998; p = 0.011) were predictors of mortality in these groups. Conclusion Patients in Birmingham are diagnosed with GBM more rapidly than those in Strasbourg but they have poorer survival. Differences in disease severity may partially account for the observed results and further large scale work is required to support this study.

2018Background: The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib (O) has radio and chemosensitizing properties in GBM models. Clinical development of PARP inhibitor combinations has been r...

The system l-amino acid transporter-1 (LAT-1) imports p-boronophenylalanine (BPA) into cells and may play a major role in the effectiveness of BPA-based boron neutron capture therapy. The functional status of LAT-1 and its relationship to cell proliferation were simultaneously examined in the same section of human tumor material using a dual-labeling technique. The uptake of BPA (boron inductively coupled plasma mass spectrometry) was profiled in the presence of agonists and antagonists in fresh tumor explants. The number of LAT-1–expressing cells (mean ± SD) was three times higher than that of proliferating cell nuclear antigen (PCNA)–expressing cells (71.5 ± 17.02% versus 23.8 ± 16.5%; P < 0.0001; n = 38 glioblastoma and metastatic tumors). There was no correlation between PCNA cells and the number of LAT-1/PCNA double-stained cells, and not all PCNA-expressing cells coexpressed LAT-1. Boron uptake reached 30 ± 15 μg/g of wet weight of tissue by 4 hours both in tumor and brain around tumor tissue containing tumor cells compared with time 0 (P < 0.005; n = 4 glioblastoma tumors). This uptake was inhibited by both phenylalanine and 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid. These LAT-1 data indicate that BPA-based boron neutron capture therapy might affect up to 70% of tumor cells, representing a three times higher proportion of tumor cells than their cell cycle status might suggest. Cells expressing PCNA, but not LAT-1, will require a different therapeutic strategy. [Cancer Res 2009;69(5):2126–32]

INTRODUCTION: The recent identification of recurrent heterozygous somatic mutations in the isocitrate dehydrogenase (IDH1) gene in low-grade gliomas and secondary glioblastoma, provides a much-needed advance in our understanding of the drivers of these tumours. Patients with this mutation are generally younger and have improved prognosis. Mutations in IDH1 occur at an arginine residue at codon 132 (R132) and result in production of the putative oncometabolite - (R)-2-hydroxyglutarate (2HG). (R)-2HG production has subsequently been shown to induce changes in DNA and histone methylation. However, there are conflicting reports regarding the metabolic role of IDH1 mutations and subsequent production of (R)-2HG in hypoxia, which are yet to be reconciled. METHOD: To define the hypoxic metabolic phenotype of IDH1 mutations, we applied complementary techniques - gas chromatography mass spectrometry (GC-MS), and nuclear magnetic resonance (NMR) spectroscopy to probe differences in the metabolic adaptation to hypoxia using [13C6]-glucose and [13C5]-glutamine tracers. RESULTS: Employing a human oligodendroglioma (HOG) cell line model, infected with mutant IDH1 by lentivirus, we show that IDH1 mutations metabolically compromise the adaptation to hypoxia, despite observable HIF1alpha stabilisation. CONCLUSION: We hypothesise that the adaptive transcriptional responses of hypoxia is blunted in IDH1 mutants resulting in the inability ofHIF1alpha to fully regulate downstream targets and ultimately cell metabolism. These results may account for the improved prognosis associated with this subset of glial tumours. Increasing our understanding of metabolic redundancies in tumour cells will aid the development of more effective treatments.

Gliomas are the most common type of brain tumour, yet their biology is still poorly understood. Despite recent advances in our understanding of low grade gliomas through the discovery of mutations in isocitrate dehydrogenase (IDH) enzymes 1&2 in the majority of patients, this has only provided us with a single line of sight to new therapies to treat these devastating tumours. To further unpick the biology of grade 2 gliomas, we used an unbiased consensus clustering approach to identify biologically similar groups of tumours based on their gene expression profiles. Through this, we identified three clusters of tumours with significantly differing survival rates, which did not always correlate with IDH status. Importantly, this method of tumour stratification identified a population of patients with an overall survival of 6 years. We therefore report three novel biological groups of grade 2 tumours, and in doing so identified a high risk subgroup of patients who would likely benefit from aggressive early intervention.

BACKGROUND: Headaches and facial pain have been accredited as accounting for the most prevalent form of pain amongst patients with glioblastoma mulitforme (GBM) - the most common malignant primary brain tumour. Despite this, minimal research has previously been undertaken investigating the direct and indirect impact that headaches have upon the quality of life (QoL) of GBM patients. METHODS: Exploratory qualitative study utilising face-to-face semi-structured interviews, with GBM patients registered as outpatients at the Queen Elizabeth Hospital Birmingham (UK), to gain an insight into the factors impacting upon their QoL, specifically focusing upon the impact of headaches post-radiotherapy. Interviews were audio-recorded, transcribed verbatim and underwent qualitative thematic analysis to identify key themes, viewpoints and dynamics. RESULTS: From the 8 participants (median = 47.5 (44 - 57.5) years; 3 male) interviewed, 3 core themes were identified and developed: "Headache of social situations", "Underlying determination and positivity" and "Psychological springboard of headaches". Important to note, is that 5-7 more participants are still to be interviewed, with the research scheduled to finish by the end of July. CONCLUSION: Whilst the QoL of patients with GBM is clearly multifactorial, headaches do indeed play a part for some. However, it is not the direct pain of the headache as perhaps expected that impacts upon the QoL of these patients, but the indirect repercussive effect of the limitations headaches place upon social life and that they may serve as a painful psychological reminder to these patients of their prognosis and threat to autonomy. The findings from the remaining participant interviews will be incorporated into the current findings.

The neurotropic herpes simplex virus mutant HSV1716 lacks the gene encoding the virulence factor ICP34.5 and cannot replicate in non-dividing cells where proliferating cell nuclear antigen (PCNA) is not actively engaged in cellular DNA synthesis. In the brain, tumoral expression of PCNA therefore confers on it oncolytic specificity and may determine its efficacy. Three phase I trials in glioma patients and one in metastatic melanoma patients have established that HSV1716 is safe and replicates selectively in tumour tissue. Here we examine the in situ PCNA profiles of common human metastatic brain tumours and determine their in vitro permissivity for HSV1716 replication to ascertain their suitability for HSV1716 therapy.Histological sections of tumour biopsies obtained from patients undergoing craniotomies were stained for PCNA expression. The replicative ability of HSV wild-type (17(+)) and mutant (1716) viruses was assessed in tissue cultures of the same tumour biopsies and in cancer cell lines by plaque assay.Biopsies of all 10 metastatic tumours (3 melanoma, 4 carcinoma and 3 adenocarcinoma) as well as 4 glioblastoma multiforme were positive for PCNA immunoexpression and supported the replication of HSV1716. The PCNA-positive cells in the metastatic tumours were distributed comparatively in larger and more contiguous areas than in glioblastoma (1.69 +/- 1.61 mm(2) vs. 0.73 +/- 0.77 mm(2)) and numbered 29.0 +/- 12.4 and 12.6 +/- 4.7%, respectively.The results show that human cerebral metastatic tumours have generally larger and more contiguous proliferative areas, support efficient HSV1716 replication, and are thus potential candidates for such oncolytic viral therapy.

Direct drug delivery to a brain tumours offers the surety of access, together with the potential to realise at least therapeutic concentrations. With previously used systemic drugs toxicity and removal mechanisms are avoided. With new formulations drug activation and duration can be explored for low local toxicity, and tumour impact with sequential imaging. In this early study Irinotecan a drug with known efficacy against glioma but with limiting systemic toxicity has been incorporated into biodegradeable hydrogel microspheres and injected into the post-surgical cavity wall in patients with recurrent glioblastoma. 10 patients with focally recurrent GBM were recruited with 9 undergoing injection with up to 3mls of microbeads in alginate suspension in up to 60 ~ 8mm injection tracks after surgical resection (100mg). Patients were assessed for immediate (72hrs) toxicity with clinical assessment and imaging. Pharmacokinetic determination of Irinotecan and SN 38 active metabolite allowed confirmation of activation and comparator with known plasma toxicity profiles. Follow-up was planned for a minimum of 6/12 for SAE but continued to allow overall survival estimation. No overt SAE were determined for this group of patients with imaging and steroid use indicating less local swelling and wound healing issues than have been demonstrated for Carmustine wafers despite early offloading. Phamacokinetic measures (SN38 plasma curves) indicate a much higher activation of Irinotecan (>90%) than expected but shorter period of exposure. Survival curves suggest clinical benefit with 4/9 patient living longer than 8 months warranting further exploration of this safe approach

2022 Background: Olaparib, a small molecule inhibitor of poly (ADP-ribose) polymerase (PARP), may improve GBM outcomes by enhancing cytotoxic effects of ionising radiation and TMZ. Clinical development of PARP inhibitors has been restricted by exacerbation of hematological toxicity. We investigated tumor pharmacokinetics (PK) of olaparib and safety and tolerability of its combination with TMZ. Methods: Dose escalation explored different schedules of olaparib (tablet formulation) with 42 day cycles of daily low dose TMZ. A dose expansion cohort evaluated the maximum tolerated schedule. PK analysis was performed on tumor and blood samples from patients undergoing neurosurgical resection, who received 4 olaparib doses pre-operatively. Results: 48 patients were recruited (median age 51(18-68); 29 male, 19 female) of whom 27 underwent surgery and 35 received olaparib/TMZ and were evaluable. 13 evaluable patients received expansion dose schedule (median age 54(21-67); 9 male, 4 female). Olaparib was detected in 73 of 74 tumor core specimens from 27 patients; mean conc. 588nM (97-1374nM), and in 27 of 28 tumor margin specimens from 10 patients; mean conc. 500nM (97-1237nM). Margin: core ratios ranged from 0.2–3.9(mean 1.2); tumor: plasma ratios ranged from 0.01 to 0.9 (mean 0.25). Olaparib dosing on days 1-5 was hindered by myelosuppression. Expansion cohort dose was defined as TMZ 75 mg/m2daily plus olaparib 150 mg (OD) days 1-3 weekly. Of 13 evaluable patients receiving expansion dose-schedule, 9 completed cycle 1, 2 completed cycle 2 and 2 completed cycle 3. Currently 45% of the evaluable patients remain progression-free at 6 months, with 2 still on treatment (full data set May2017). Of 35 evaluable patients, 24 experienced AE Grade ≥3 (see Table). Conclusions: Olaparib penetrates both core and margins of recurrent GBM despite failing to penetrate the intact brain barrier in pre-clinical heathy rodent models. Combination with extended low dose TMZ is safe and well tolerated, yielding encouraging 6 month progression-free survival rates. Clinical trial information: NCT01390571. [Table: see text]

INTRODUCTION: Current treatments for Glioblastoma (GBM) are inadequate and immunotherapeutics may provide better outcomes for patients. Human recombinant Decorin is a glycoprotein that modulates inflammation & GBM growth by inhibiting Transforming Growth Factor, Vascular Endothelial Growth Factor and Epidermal Growth Factor Receptor. As Decorin is found in human tissue rich in fibrillar collagen (e.g. skin, heart, bone lung & liver) it is a potentially safe drug to be trialled in humans. METHOD: The local immune and microglial response to intracerebral injections of Decorin was investigated. Rats (n = 6 for each group) received either an injection of PBS (control) or 5¼l 5mg/ml Decorin and were sacrificed at 30min, 3 & 24 hrs or after continuous infusion of either PBS (control) or Decorin for 7 days. CSF samples were taken and analysed by ELISA and Luminex for presence of Decorin and change in inflammatory markers. Immunohistochemistry was also performed to investigate the effects of Decorin on microglia using OX42. RESULTS: There was no inflammatory reaction or cavity formation in brain. Decorin supressed the microglial response after direct injections into the brain compared to PBS control. At 30 mins, low levels of decorin were detected (with ELISA) in CSF and serum but none was detected at 3hrs and 24hrs after injection. CONCLUSION: Decorin showed no dose limiting toxicity, whilst maintaining its immunomodulatory effects in brain. These findings show a safe pharmacokinetic and toxicological profile.

INTRODUCTION: Low socioeconomic status is associated with increased frequency of chronic conditions, a higher frequency of mental health illness, greater use of primary care and hospital services and a lower relative cancer survival for some of the commonest cancers. The impact of social deprivation on the survival of patents with glial tumours however is poorly understood. We examine the role of social deprivation on the survival of patients with glial tumours METHOD: We performed a retrospective analysis of clinical records of patients with histologically confirmed glial tumours treated at our institution between 2009 and February 2013. The overall survival (from time of tissue diagnosis) and index of multiple deprivation (IMD - 2010) were obtained. Potential confounding factors incorporated into a multivariable Cox regression model included age, gender, ethnicity, tumour location, neurosurgical procedure, antiepileptic drug taken and past medical history. RESULTS: 485 patients with WHO Grade II, III and IV glioma were identified with all five quintiles of deprivation classes represented. 96 patients fell into the most deprived class (1), while 49 patients were found to be within the least deprived class (5). Patients in the lowest socioeconomic class had a significantly worse survival compared with those in the least deprived class. (p = 0.03) The significance of this finding persisted even after incorporation into a cox multivariable regression model to take account for other factors likely to affect survival. CONCLUSION:This study highlights the importance of addressing social deprivation and its effects in the effort to improve patient outcomes for patients with high grade glioma.

BACKGROUND: Grade IV glioblastomas exist in two forms, primary (de novo) glioblastomas (pGBM) that arise without precursor lesions, and the less common secondary glioblastomas (sGBM) which develop from earlier lower grade lesions. Genetic heterogeneity between pGBM and sGBM has been documented as have differences in the methylation of individual genes. A hypermethylator phenotype in grade IV GBMs is now well documented however there has been little comparison between global methylation profiles of pGBM and sGBM samples or of methylation profiles between paired early and late sGBM samples. METHODS: We performed genome-wide methylation profiling of 20 matched pairs of early and late gliomas using the Infinium HumanMethylation450 BeadChips to assess methylation at >485,000 cytosine positions within the human genome. RESULTS: Clustering of our data demonstrated a frequent hypermethylator phenotype that associated with IDH1 mutation in sGBM tumors. In 80% of cases, the hypermethylator status was retained in both the early and late tumor of the same patient, indicating limited alterations to genome-wide methylation during progression and that the CIMP phenotype is an early event. Analysis of hypermethylated loci identified 218 genes frequently methylated across grade II, III and IV tumors indicating a possible role in sGBM tumorigenesis. Comparison of our sGBM data with TCGA pGBM data indicate that IDH1 mutated GBM samples have very similar hypermethylator phenotypes, however the methylation profiles of the majority of samples with WT IDH1 that do not demonstrate a hypermethylator phenotype cluster separately from sGBM samples, indicating underlying differences in methylation profiles. We also identified 180 genes that were methylated only in sGBM. Further analysis of these genes may lead to a better understanding of the pathology of sGBM vs pGBM. CONCLUSION: This is the first study to have documented genome-wide methylation changes within paired early/late astrocytic gliomas on such a large CpG probe set, revealing a number of genes that maybe relevant to secondary gliomagenesis.

Wise reported that of 74% of the girls and young women who were offered vaccination against human papillomavirus (HPV) only half the women not in education, employment, or training were included in the offer.1 Much more concerning is the fact that oropharyngeal cancer driven by HPV has the fastest rising incidence of any cancer, yet no boys in the United Kingdom are offered vaccination. We …

The herpes simplex virus (HSV) ICP34.5 null mutant 1716 replicates selectively in actively dividing cells and has been proposed as a potential treatment for cancer, particularly brain tumours. We present a clinical study to evaluate the safety of 1716 in patients with relapsed malignant glioma. Following intratumoural inoculation of doses up to 10(5) p.f.u., there was no induction of encephalitis, no adverse clinical symptoms, and no reactivation of latent HSV. Of nine patients treated, four are currently alive and well 14-24 months after 1716 administration. This study demonstrates the feasibility of using replication-competent HSV in human therapy.

This paper describes results to-date from a human pharmacokinetic study which began recruitment in December 2007. Results are presented for a single patient recruited in December 2007. A second patient was recruited in July 2008 but detailed data are not available at the time of writing. The trial is an open-label, non-comparative, non-therapeutic study of BPA-mannitol in patients with high-grade glioma, who will be undergoing stereotactic brain biopsy as part of the diagnostic process before definitive treatment. The study investigates the route of infusion (intra-venous (IV) or intra-carotid artery) and in each case will assess the effect of administration of mannitol as a blood-brain barrier disrupter. All cohorts will receive a 2 h infusion of BPA-mannitol, and for some cohorts an additional mannitol bolus will be administered at the beginning of this infusion. Measurements are made by inductively coupled plasma mass spectrometry (ICP-MS) of10B concentration in samples of blood, urine, extra-cellular fluid in normal brain (via a dialysis probe), brain tissue around tumour and tumour tissue. Additional analysis of the tumour tissue is performed using secondary ion mass spectrometry (SIMS). The first patient was part of the cohort having intra-venous infusion without mannitol bolus. No serious clinical problems were experienced and the assay results can be compared with available patient data from other BNCT centres. In particular we note that the peak10B concentration in blood was 28.1 mg/ml for a total BPA administration of 350 mg/kg which is very consistent with the previous experience with BPA-fructose reported by the Helsinki group. Refereed/Peer-reviewed

BACKGROUND: Chemotherapy for brain tumours has been limited because of difficulty in achieving exposure to the tumour without systemic toxicity. Parenteral Irinotecan despite activity against glioma has an uncertain entry into the brain that has questioned its actual efficacy against glioma and a poor profile of enhanced systemic toxicity. In this study we have injected irinotecan sulphonated to PVA beads (1-1000 ) into the brain around tumour following resection of recurrent GBM to assess vehicle and drug safety from disease and procedure related problems. METHODS:10 patients who have failed available therapy for proven recurrent GBM with single focal recurrences as determined by gadolinium enhanced MRI with good performance and ages from 34 -76 were consented for this Phase I study. At operation tumour was removed and the cavity wall injected up to 5mm depth with up to 60 injections of beads suspended in alginate solution delivered using a 24 gauge flexible catheter to a total volume of 3mls and a drug dose of 100mg. Clinical assessments and blood samples were assessed for CTC criteria over 5/7 and imaging and clinical a assessment performed post operation at two and four and eight weekly to 6 months post surgery. RESULTS: To date one (6/15) patient has died at 4/12post treatment of progressive disease and there have been no CTC >2 or procedure related falls in performance despite these patients previous treatment and condition. We have no evidence from this study to suggest any local chemical meningitis or untoward swelling from the injection process. Follow-up is ongoing for survival comparison with other depot therapies. CONCLUSIONS: This novel form of depot therapy offers a stable safe drug loading platform and an accessible generic approach to ensuring local delivery of new agents or those with an uncertain access profile.

INTRODUCTION: MRI is used routinely to assess response to chemo-radiotherapy for glioblastoma (GBM). However, distinguishing between treatment effects and disease progression using published criteria based on contrast-enhancement on T1-weighted images is difficult. The phenomenon of pseudo-progression (psP) mimicking true progression (tP) is well known in this context. Early accurate diagnosis of tP versus psP is essential to optimise treatment strategies and improve outcome. This pilot study aims to evaluate the use of dynamic susceptibility (DSC-) MRI for differentiating between tP and psP by measuring cerebral blood volume (CBV). METHOD: Data were analysed from 5 patients who underwent MRI scans on a Siemens 3T scanner, including DSC-MRI (temporal resolution 2.1 s; injection of 0.1 mmol/kg Gadovist at 6 ml/s) and post-contrast T1-weighted scans at short intervals following surgery and chemo-radiotherapy for GBM. CE marked software (Olea Sphere) was used to obtain CBV maps with correction for T1 effects. Regions of interest were defined to calculate rCBV, the ratio of CBV in the lesion to that in normal contralateral tissue. RESULTS: Maximum rCBV varied widely across patients (mean ± standard deviation: 2.7 ± 2.0). Using a threshold of 1.8 from the literature 2 patients had hypo-perfused lesions suggesting psP and 3 patients had hyper-perfused lesions indicating tP. These findings will be correlated with follow-up scans and clinical data. CONCLUSION: This study confirms feasibility of measuring rCBV in patients undergoing treatment for GBM within a clinical workflow. Follow-up analysis will test the hypothesis that values of rCBV greater than 1.8 are indicative of tP.

This paper will review progress on two aspects of the Birmingham BNCT project. Firstly on evaluation of the effects of high and low LET radiations when delivered simultaneously, and secondly on attempts to optimise delivery of the boron carrier compound BPA through pharmacokinetic studies. Simultaneous or non-simultaneous irradiations of V79 cells with alpha-particle and X-ray irradiations were performed. Alpha doses of 2 and 2.5 Gy were chosen and the impact on survival when delivered separately or simultaneously with variable doses of X-rays was evaluated. The pharmacokinetics of the delivery of a new formulation of BPA (BPA-mannitol) are being investigated in brain tumour patients through a study with 2 × 2 design featuring intravenous and intracarotid artery infusion of BPA, with or without a mannitol bolus. On the combined effect of low and high LET radiations, a synergistic effect was observed when alpha and X-ray doses are delivered simultaneously. The effect is only present at the 2.5 Gy alpha dose and is a very substantial effect on both the shape of the survival curve and the level of cell killing. This indicates that the alpha component may have the effect of inhibiting the repair of damage from the low LET radiation dose delivered simultaneously. On the pharmacokinetics of BPA, data on the first three cohorts indicate that bioavailability of BPA in brain ECF is increased substantially through the addition of a mannitol bolus, as well as by the use of intracarotid artery route of infusion. In both cases, for some patients the levels after infusion approach those seen in blood, whereas the ECF levels for intravenous infusion without mannitol are typically less than 10% of the blood values.

BNCT is a biologically targeted radiotherapy where preferential boron uptake interacts with a neutron beam in cancerous cells causing irreparable alpha DNA damage. This requires the delivery of at least 30 parts per million (ppm) of 10B into tumour tissue and 30ppm boron) indicates potential BNCT targeting after surgery. Tumour boron uptake is governed by LAT-1 behaviour rather than BBB penetration and explains previous variable clinical results, whilst supporting the LAT1 determined selection of patients for BNCT

Few networks offer sufficient bandwidth for the transmission of high resolution two- and three-dimensional medical image sets without incurring significant latency. Traditional compression methods achieve bit-rate reduction based on pixel statistics and ignore visual cues that are important in identifying visually informative regions. This paper describes an approach to managing image transmission in which spatial regions are selected and prioritized for transmission so that visually informative data is received in a timely manner. This context-based image transmission (CBIT) scheme is a lossless form of progressive image transmission (PIT) in which gross structure, represented by an approximate iconic image, is transmitted first. Each part of this iconic image is progressively updated, using a simple set of rules that take into account viewing requirements. CBIT is realized using knowledge about image composition to segment, label, prioritize, and fit geometric models to regions of an image. Tests, using neurological images, show that, with CBIT, a valuable transmitted image is received with a latency that is about one-tenth that of traditional PIT schemes. Frequently, the necessary regions of the image are transmitted in about half the time taken to transmit the full image.

We present a transmission scheme that reduces the latency in transmitting high resolution medical image sets. Traditional compression methods use pixel statistics to reduce transmission bit-rate and ignore visual cues that are important in identifying visually informative regions. Context-based image transmission (CBIT) utilises gross structure, represented by an approximate iconic image, to provide initial information about image content. This iconic image is represented using a novel superelliptic shape-tree. Each part of the iconic image is progressively updated, using rules, to provide an informative image build-up, in a timely manner. CBIT is realised using knowledge about image composition to segment, label and prioritise regions of an image for transmission. Experiments using CT X-ray and MR images show that an informative structure delineation is obtained for the iconic image and that the progressive image build-up is beneficial.