Paul Grundy

The effects of the NICE Technology Appraisal 121 (Gliadel and Temozolomide) on survival in high-grade glioma

Objective. The prognosis of high-grade glioma (HGG) is poor with a median survival of about 1 year for glioblastoma. In 2007, NICE published a technology appraisal (TA121) recommending the use of carmustine wafers (Gliadel) and systemic therapy with temozolomide for selected patients with HGG. Outcomes for HGG surgery in the United Kingdom with these combined treatments have not been published. Design. Retrospective audit of consecutive patients in a single unit with carmustine wafer implantation. Subjects. Fifty-nine patients had carmustine wafers implanted at primary surgery, between October 2005 and October 2010 at Wessex Neurological Centre, Southampton, UK. Methods. Patients were given chemotherapeutic treatments strictly according to NICE TA121. Survival was calculated using Kaplan-Meier method. Results. Fifty-five patients had WHO grade IV tumours and four had grade III. Median age was 61 years. At follow-up, 39 patients had died. Median survival was 15.3 months. Eight patients (13.5%) experienced post-operative complications (including five infections) for which four had the carmustine wafers removed. Forty-seven (80%) patients were treated with radical radiotherapy (55–60 Gy) and six (10%) patients received palliative radiotherapy (30 Gy). Thirty-seven patients (63%) received concomitant temozolomide chemotherapy. In the subset of 37 patients receiving multimodal treatment with radical radiotherapy and concomitant temozolomide, median survival was 15.8 months compared with 7.4 months in those not receiving multimodal treatment. Discussion. Carmustine wafers for primary HGG surgery in accordance with the NICE TA121 were associated with a median survival of 15.3 months; this is improved compared with previously reported randomised trials. Multimodal treatment with carmustine wafers, radical radiotherapy and concomitant temozolomide was associated with improved survival. Increased incidence of infections was observed in cases receiving carmustine wafers.

Novel association between microglia and stem cells in human gliomas: A contributor to tumour proliferation?

Brain tumour stem cells and microglia both promote the growth of astrocytomas, the commonest form of primary brain tumour, with recent emerging evidence that these cell types may interact in glioma models. It is unclear whether microglia and stem cells are associated in human gliomas. To investigate this question, we used the technique of tissue microarrays to perform a correlative study of a large number of tumour samples. We quantified immunostaining of human astrocytic tumour tissue microarrays (86 patients; World Health Organisation grade II–IV) for microglia Ionized calcium binding adaptor molecule 1 (Iba1) and CD68, and stem cell nestin, SOX2 and CD133. Ki67 was used to assess proliferation and GFAP for astrocytic differentiation. Immunoreactivity for both microglial markers and stem cell markers nestin and SOX2 significantly increased with increasing tumour grade. GFAP was higher in low grade astrocytomas. There was a positive correlation between: (i) both microglial markers and nestin and CD133, (ii) nestin and tumour cell proliferation Ki67 and (iii) both microglial markers and Ki67. SOX2 was not associated with microglia or tumour proliferation. To test the clinical relevance, we investigated the putative association of these markers with clinical outcomes. High expression for nestin and Iba1 correlated with significantly shorter survival times, and high expression for nestin, Iba1, CD68 and Ki67 was associated with faster tumour progression on univariate analysis. On multivariate analysis, nestin, CD133 and Ki67 remained significant predictors of poorer survival, after adjustment for other markers. These results confirm previous in vitro findings, demonstrating their functional relevance as a therapeutic target in humans. This is the first report of a novel correlation between microglia and stem cells that may drive human astrocytic tumour development.

Phenytoin-induced methaemoglobinaemia in a patient with glioblastoma multiforme

Received for publication 4 March 2014; accepted 27 July 2014 A 76-year old man presented to the emergency department with a first seizure (generalised tonic-clonic seizure). He was loaded with phenytoin at 15 mg/kg and treated thereafter with oral phenytoin (150 mg twice daily), and later discharged. The MRI head demonstrated a left frontal ringenhancing lesion typical of high-grade glioma and frontal craniotomy for tumour resection was planned. Five weeks later, two days prior to the scheduled surgery, his wife noticed widespread blue-purple discolouration of his skin affecting his upper arms, chest, abdomen, back and face, which seemingly resembled cyanosis and was particularly prominent post-showering (Fig. 1). It was non-itchy and caused no discomfort. He was systemically well with no symptoms of phenytoin toxicity. His drug history also included dexamethasone and omeprazole. There was no previous history of drug allergies. He had a past medical history of a hiatus hernia. Phenytoin was discontinued, as the presumed cause of the skin changes, and replaced with sodium valproate. On admission two days later, the blue-purple skin discolouration had begun to resolve. Arterial blood gas analysis revealed no hypoxia but a mildly raised methaemoglobin (0.9%), more consistent with methaemoglobinaemia than cyanosis as the underlying cause. His phenytoin level was 7 mg/L (lower end of therapeutic range). He underwent complete macroscopic excision of the tumour, confirmed as glioblastoma multiforme on histopathology. On follow up 7 days later, there was no recurrence of skin discolouration. Phenytoin can cause a variety of skin reactions, typically an early red rash, and more rarely StevensJohnson syndrome and purple glove syndrome.1 An increased frequency of reactions to anti-seizure medication in brain tumour patients is noted, compared to other patient groups.2–4 We initially considered this distinctive blue-purple discolouration a manifestation of central cyanosis secondary to phenytoin, but given the lack of systemic effects and no hypoxia, methaemoglobinaemia was felt more likely. Importantly, it resolved on phenytoin discontinuation. This is an unusual side-effect of phenytoin,5 not previously well highlighted in the literature.