A Randomised Phase II Trial of Hippocampal Sparing Versus Conventional Whole Brain Radiotherapy After Surgical Resection or Radiosurgery in Favourable Prognosis Patients With 1-10 Brain Metastases.

AIMS: To assess in patients with 1-10 brain metastases, each of which has been treated by neurosurgery or stereotactic radiosurgery, whether hippocampal sparing whole brain radiotherapy (HS-WBRT) better spares neurocognitive function (NCF) than standard WBRT. Further, to assess whether a phase III randomised trial of HS-WBRT would be feasible in the UK. MATERIALS AND METHODS: A multicentre, randomised, open label phase II trial was undertaken, randomising patients to 30Gy in 10 fractions of WBRT or HS-WBRT. The primary endpoint was decline in Total recall using Hopkins Verbal Learning Test Revised (HVLT-R) at 4 months post treatment. To assess this, we aimed to recruit 84 patients over 3 years. Secondary endpoints included further measures of NCF, quality of life, duration of functional independence, local control of treated metastases, development of new metastases, disease control within the hippocampal regions, overall survival, steroid and antiepileptic medication requirements, and toxicity. RESULTS: The trial closed prematurely due to slower than anticipated recruitment. From April 2016 to January 2018, 23 patients were randomised. Follow up was a median of 25 months. Fifteen patients (6 WBRT, 9 HS-WBRT) were assessed for the primary endpoint; of these, 1 in each arm experienced significant decline in the 4-month HVLT-R Total recall score (p = 0.8). Patients in the HS-WBRT arm experienced less insomnia (p < 0.01) and drowsiness (p < 0.01). There were no differences in other secondary endpoints. CONCLUSION: A phase III randomised trial of HS-WBRT was shown not to be feasible at this time in the UK. As most randomised trials of HS-WBRT reported to date share common endpoints, including NCF, an individual patient data meta-analysis should be undertaken.

Characterisation of the immune microenvironment of primary breast cancer and brain metastasis reveals depleted T-cell response associated to ARG2 expression.

BACKGROUND: Immune checkpoint inhibition is an established treatment in programmed death-ligand 1 (PD-L1)-positive metastatic triple-negative (TN) breast cancer (BC). However, the immune landscape of breast cancer brain metastasis (BCBM) remains poorly defined. MATERIALS AND METHODS: The tumour-infiltrating lymphocytes (TILs) and the messenger RNA (mRNA) levels of 770 immune-related genes (NanoString™, nCounter™ Immuno-oncology IO360) were assessed in primary BCs and BCBMs. The prognostic role of ARG2 transcripts and protein expression in primary BCs and its association with outcome was determined. RESULTS: There was a significant reduction of TILs in the BCBMs in comparison to primary BCs. 11.5% of BCs presented a high immune infiltrate (hot), 46.2% were altered (immunosuppressed/excluded) and 34.6% were cold (no/low immune infiltrate). 3.8% of BCBMs were hot, 23.1% altered and 73.1% cold. One hundred and twelve immune-related genes including PD-L1 and CTLA4 were decreased in BCBM compared to the primary BCs (false discovery rate <0.01, log2 fold-change >1.5). These genes are involved in matrix remodelling and metastasis, cytokine-chemokine signalling, lymphoid compartment, antigen presentation and immune cell adhesion and migration. Immuno-modulators such as PD-L1 (CD274), CTLA4, TIGIT and CD276 (B7H3) were decreased in BCBMs. However, PD-L1 and CTLA4 expression was significantly higher in TN BCBMs (P = 0.01), with CTLA4 expression also high in human epidermal growth factor receptor 2-positive (P < 0.01) compared to estrogen receptor-positive BCBMs. ARG2 was one of four genes up-regulated in BCBMs. High ARG2 mRNA expression in primary BCs was associated with worse distant metastasis-free survival (P = 0.038), while ARG2 protein expression was associated with worse breast-brain metastasis-free (P = 0.027) and overall survival (P = 0.019). High transcript levels of ARG2 correlated to low levels of cytotoxic and T cells in both BC and BCBM (P < 0.01). CONCLUSION: This study highlights the immunological differences between primary BCs and BCBMs and the potential importance of ARG2 expression in T-cell depletion and clinical outcome.

Chlorhexidine dressings could reduce external ventricular drain infections: results from a systematic review and meta-analysis.

The incidence of external ventricular drain (EVD) infections remains high. Chlorhexidine dressings have demonstrated efficacy in reducing infections associated with indwelling catheters at other body sites, although evidence for their use with EVDs is limited. The aim of this systematic review and meta-analysis was to evaluate the efficacy of chlorhexidine dressings in reducing EVD-associated cerebrospinal fluid infection (EVDAI). MEDLINE, EMBASE and the Cochrane library were queried for articles from inception. The primary outcome was the incidence of EVDAI. Secondary outcomes included device safety, microbiological outcomes and shunt-dependency. From 896 unique records, five studies were included of which four presented suitable data for quantitative analysis including three case series and one underpowered randomized controlled trial. There was a high risk of bias in all studies. A total of 880 patients were included with a mean age of 57.7 years (95% confidence interval (CI) 57.4-58.0 years). In primary outcome analysis, the chlorhexidine dressing group had a significantly lower incidence of EVDAI (1.7% vs 7.9%, risk difference (RD) = 0.07, 95% CI 0.00-0.13, P=0.04). In conclusion, chlorhexidine dressings may reduce the incidence of EVDAI but require future study in randomized trials to definitively determine efficacy.

Second surgery for progressive glioblastoma: a multi-centre questionnaire and cohort-based review of clinical decision-making and patient outcomes in current practice.

PURPOSE: Glioblastoma prognosis is poor. Treatment options are limited at progression. Surgery may benefit, but no quality guidelines exist to inform patient selection. We sought to describe variations in surgical management at progression, highlight where further evidence is needed, and build towards a consensus strategy. METHODS: Current practice in selection of patients with progressive GBM for second surgery was surveyed online amongst specialists in the UK and Europe. We complemented this with an assessment of practice in a retrospective cohort study from six United Kingdom neurosurgical units. We used descriptive statistics to analyse the data. RESULTS: 234 questionnaire responses were received. Maintaining or improving patient quality of life was key to decision making, with variation as to whether patient age, performance status or intended extent of resection was relevant. MGMT methylation status was not important. Half considered no minimum time after first surgery. 288 patients were reported in the cohort analysis. Median time to second surgery from first surgery 390 days. Median overall survival 815 days, with no association between time to second surgery and time to death (p = 0.874). CONCLUSIONS: This is the most wide-ranging examination of contemporaneous practice in management of GBM progression. Without evidence-based guidelines, the variation is unsurprising. We propose consensus guidelines for consideration, to reduce heterogeneity in decision making, support data collection and analysis of factors influencing outcomes, and to inform clinical trials to establish whether second surgery improves patient outcomes, or simply selects to patients already performing well.

Epilepsy and adverse quality of life in surgically resected meningioma.

OBJECTIVES: Meningiomas are common intracranial tumors, and despite surgery or therapy with anti-epileptic drugs (AEDs), many patients suffer from seizures. Epilepsy has a significant impact on quality of life (QoL) in non-tumor populations, but the impact of epilepsy on QoL in patients with meningioma is unknown. Our aim was to evaluate the impact of epilepsy on QoL in patients that have undergone resection of a benign meningioma. MATERIALS AND METHODS: We recruited meningioma patients without epilepsy (n=109), meningioma patients with epilepsy (n=56), and epilepsy patients without meningioma (n=64). QoL was measured with the Short Form 36 version 2 (SF-36), the Functional Assessment of Cancer Therapy (FACT-BR), and the Liverpool Adverse Events Profile (LAEP). Regression analyses identified significant determinants of QoL. RESULTS: Patients with meningioma and epilepsy had poorer QoL scores than meningioma patients without epilepsy in all measures. In FACT-BR, this difference was significant. Multiple regression analyses demonstrated that current AED use had a greater impact on QoL scores than recent seizures. Other variables associated with impaired QoL included depression, unemployment, and meningioma attributed symptoms. CONCLUSIONS: Epilepsy has a negative impact on quality of life in patients with benign meningioma. AED use is correlated with impaired QoL and raised LAEP scores, suggesting that AEDs and adverse effects may have led to impaired QoL in our meningioma patients with epilepsy. The severity of epilepsy in our meningioma population was comparatively mild; therefore, a more conservative approach to AED therapy may be indicated in an attempt to minimize adverse effects.

The role of the corpus callosum in seizure spread: MRI lesion mapping in oligodendrogliomas.

BACKGROUND: Some patients with oligodendrogliomas have generalized tonic-clonic seizures (GTCS) while others have only partial seizures (PS). We investigated the relationship between tumour localization and seizure generalization using quantitative lesion mapping on magnetic resonance images. METHODS: Twenty one patients with histologically proven oligodendrogliomas and GTCS (n=11) or PS (n=10) were studied. Data were acquired on a 3 Tesla MRI System. We performed lesion mapping techniques to compare the spatial distribution of oligodendrogliomas between patient groups, and quantitatively determined the extent to which lesions intersected each probabilistic regions-of-interest, including the cerebral lobes, thalamus, striatum, and genu of the corpus callosum. RESULTS: In patients experiencing GTCS, the greatest lesion load was observed in mesial frontal regions, including cortex connected to the genu. In contrast, the greatest lesion load in patients experiencing PS was observed more caudo-laterally in orbitofrontal and temporal lobes, but typically sparing cortex connected to the genu. The number of lesion intersections with genu region of interest was significantly greater in patients experiencing GTCS relative to patients with PS (p=0.03). There were no significant differences between patient groups with respect to lesion intersection with the individual cerebral lobes, thalamus and striatum, or with respect to overall oligodendroglioma size. CONCLUSION: Our data suggest that the genu of the corpus callosum may be a major pathway for seizure generalization in patients with oligodendrogliomas.

The reliability of routine clinical post-processing software in assessing potential diffusion-weighted MRI "biomarkers" in brain metastases.

BACKGROUND AND PURPOSE: Diffusion MRI characteristics have been used as biomarkers to guide prognosis in cerebral pathologies including brain metastases. The measurement of ADC is often described poorly in clinical and research studies with little detail given to the practical considerations of where to place ROIs, which post processing software package to use and how reproducible the resulting metrics will be. METHOD: We investigated a series of 12 patients with brain metastases and preoperative DWI. Three post processing platforms were used. ROI were placed over the tumour, peritumoural region and across the brain-tumour interface. These recordings were made by a neurosurgeon and a neuroradiologist. Inter-intra-observer variability was assessed using Bland-Altman analysis. An exploratory analysis of DWI with overall survival and tumour type was made. RESULTS: There was excellent correlation between the software packages used for all measures including assessing the whole tumour, selective regions with lowest ADC, the change of ADC across the brain-tumour interface and the relation of the tumour ADC to peritumoural regions and the normal white matter. There was no significant inter- or intra-observer variability for repeated readings. There were significant differences in the mean values obtained using different methodologies and different metrics had differing relationships to overall survival and primary tumour of origin. CONCLUSION: Diffusion weighted MRI metrics offer promise as potential non-invasive biomarkers in brain metastases and a variety of metrics have been shown to be reliably measured using differing platforms and observers.

Is stereotactic radiosurgery under-utilised in the treatment of surgically excisable cerebral metastases?

BACKGROUND/OBJECTIVE: Brain metastases are a significant cause of morbidity and mortality. Treatment options included surgery, whole brain radiotherapy and stereotactic radiosurgery alone or in combination. There has been a significant increase in stereotactic radiosurgery (SRS) provision in the UK over the last 5 years. We investigated the proportion of surgically resected brain metastases that would be suitable for SRS. METHODS: We retrospectively collected data on 116 consecutive patients undergoing surgical resection of brain metastases. Suitable radiological targets for SRS were defined as solid tumours < 30 mm maximum diameter with no hydrocephalus and no symptomatic mass effect. RESULTS: One hundred and two cases (88%) were solitary metastasis and fourteen (12%) had multiple metastases. Median maximum tumour diameter was 34 mm (range: 12-70 mm). Approximately one-third of patients (n = 41) had surgically resected brain metastasis suitable for SRS. Median OS was 7.7 months for those suitable for SRS and 5.4 months for those not suitable for SRS (Fig. 3; Log Rank: P = 0.52). CONCLUSIONS: In surgically amenable tumours, day case SRS could also be used in approximately one-third of cases, thereby avoiding craniotomy and reducing length of stay. These data may be useful in planning service provision, and for drawing up business plans for a new SRS services. Nationally agreed guidelines for SRS for brain metastases have been developed and a full health economic analysis warrants further investigation to determine the cost effectiveness of SRS compared to craniotomy.

Biology, genetics and imaging of glial cell tumours.

Despite advances in therapy, gliomas remain associated with poor prognosis. Clinical advances will be achieved through molecularly targeted biological therapies, for which knowledge of molecular genetic and gene expression characteristics in relation to histopathology and in vivo imaging are essential. Recent research supports the molecular classification of gliomas based on genetic alterations or gene expression profiles, and imaging data supports the concept that molecular subtypes of glioma may be distinguished through non-invasive anatomical, physiological and metabolic imaging techniques, suggesting differences in the baseline biology of genetic subtypes of infiltrating glioma. Furthermore, MRI signatures are now being associated with complex gene expression profiles and cellular signalling pathways through genome-wide microarray studies using samples obtained by image guidance which may be co-registered with clinical imaging. In this review we describe the pathobiology, molecular pathogenesis, stem cells and imaging characteristics of gliomas with emphasis on astrocytomas and oligodendroglial neoplasms.