Beyond standard data collection - the promise and potential of BRAIN (Brain tumour Registry Australia INnovation and translation registry).

BACKGROUND: Real-world data (RWD) is increasingly being embraced as an invaluable source of information to address clinical and policy-relevant questions that are unlikely to ever be answered by clinical trials. However, the largely unrealised potential of RWD is the value to be gained by supporting prospective studies and translational research. Here we describe the design and implementation of an Australian brain cancer registry, BRAIN, which is pursuing these opportunities. METHODS: BRAIN was designed by a panel of clinicians in conjunction with BIOGRID to capture comprehensive clinical data on patients diagnosed with brain tumours from diagnosis through treatment to recurrence or death. Extensive internal and external testing was undertaken, followed by implementation at multiple sites across Victoria and Tasmania. RESULTS: Between February 2021 and December 2021, a total of 350 new patients from 10 sites, including one private and two regional, were entered into BRAIN. Additionally, BRAIN supports the world's first registry trial in neuro-oncology, EX-TEM, addressing the optimal duration of post-radiation temozolomide; and BioBRAIN, a dedicated brain tumour translational program providing a pipeline for biospecimen collection matched with linked clinical data. CONCLUSIONS: Here we report on the first data collection effort in brain tumours for Australia, which we believe to be unique worldwide given the number of sites and patients involved and the extent to which the registry resource is being leveraged to support clinical and translational research. Further directions such as passive data flow and data linkages, use of artificial intelligence and inclusion of patient-entered data are being explored.

Correction to: Serum microRNA is a biomarker for post-operative monitoring in glioma.

For the reference citation '[57]' in the second paragraph of the Results section of the original article there was no corresponding entry in the References section. It should have referred to the below mentioned article by Ebrahimkhani et al. (2018).

Serum microRNA is a biomarker for post-operative monitoring in glioma.

PURPOSE: A circulating biomarker has potential to provide more accurate information for glioma progression post treatment, however no such biomarker is currently available. We aimed to discover a microRNA serum biomarker for longitudinal monitoring of glioma patients. METHODS: A prospectively collected cohort of 91 glioma patients and 17 healthy controls underwent pre and post-operative serum miRNA profiling using Nanostring®. Differentially expressed miRNAs were discovered using a machine learning random forest analysis. Candidate miRNAs were then assessed by droplet digital PCR in 11 patients with multiple follow up samples and compared to tumor volume based on magnetic resonance imaging. RESULTS: A 9-gene miRNA signature was identified that could distinguish between glioma and healthy controls with 99.8% accuracy. Two miRNAs miR-223 and miR-320e, best demonstrated dynamic changes that correlated closely with tumor volume in LGG and GBM respectively. Importantly, miRNA levels did not increase in two cases of pseudo-progression, indicating the potential utility of this test in guiding treatment decisions. CONCLUSIONS: We identified a highly accurate 9-miRNA signature associated with glioma serum. Additionally, we observed dynamic changes in specific miRNAs correlating with tumor volume over long-term follow up. These results support a large prospective validation study of serum miRNA biomarkers in glioma.

Early perfusion MRI predicts survival outcome in patients with recurrent glioblastoma treated with bevacizumab and carboplatin.

Bevacizumab, an anti-angiogenic agent, is FDA-approved for use in patients with recurrent glioblastoma multiforme (rGBM). The radiologic evaluation of tumor response to bevacizumab is complex and there is no validated method of monitoring tumor vascularity during therapy. We evaluated perfusion-weighted MR imaging (PWI) in our cohort of patients enrolled in the CABARET trial, which examined the effectiveness of bevacizumab with or without carboplatin in patients with rGBM. Pre-treatment and early follow-up (4- and 8-week) PWI were used to calculate relative cerebral blood volume (rCBV) histogram statistics of the contrast-enhancing and FLAIR hyperintense tumor volumes. A novel rCBV measurement (load) was developed to estimate the total volume of perfused tumor blood vessels. Changes in all rCBV measures were examined for correlations with progression-free (PFS) and overall survival (OS). All of our 15 patients enrolled in the CABARET trial were included. Median PFS and OS were 23 and 45 weeks respectively. Kaplan-Meier analysis of pre-treatment PWI revealed an 18 week reduction in median OS in patients with high tumor rCBV (p = 0.031). Changes in rCBV measures, especially load, correlated significantly with PFS and OS at both follow-up time-points. Patients with the greatest reduction in rCBVload by 8-weeks of therapy had a significantly increased median OS (30 weeks; p = 0.013). PWI may be of significant clinical utility in managing patients with rGBM, particularly those treated with anti-angiogenic agents such as bevacizumab. These findings need to be confirmed prospectively in larger studies.

Improving Clinical Registry Data Quality via Linkage With Survival Data From State-Based Population Registries.

PURPOSE: Real-world data (RWD) collected on patients treated as part of routine clinical care form the basis of cancer clinical registries. Capturing accurate death data can be challenging, with inaccurate survival data potentially compromising the integrity of registry-based research. Here, we explore the utility of data linkage (DL) to state-based registries to enhance the capture of survival outcomes. METHODS: We identified consecutive adult patients with brain tumors treated in the state of Victoria from the Brain Tumour Registry Australia: Innovation and Translation (BRAIN) database, who had no recorded date of death and no follow-up within the last 6 months. Full name and date of birth were used to match patients in the BRAIN registry with those in the Victorian Births, Deaths and Marriages (BDM) registry. Overall survival (OS) outcomes were compared pre- and post-DL. RESULTS: Of the 7,346 clinical registry patients, 5,462 (74%) had no date of death and no follow-up recorded within the last 6 months. Of the 5,462 patients, 1,588 (29%) were matched with a date of death in BDM. Factors associated with an increased number of matches were poor prognosis tumors, older age, and social disadvantage. OS was significantly overestimated pre-DL compared with post-DL for the entire cohort (pre- v post-DL: hazard ratio, 1.43; P < .001; median, 29.9 months v 16.7 months) and for most individual tumor types. This finding was present independent of the tumor prognosis. CONCLUSION: As revealed by linkage with BDM, a high proportion of patients in a brain cancer clinical registry had missing death data, contributed to by informative censoring, inflating OS calculations. DL to pertinent registries on an ongoing basis should be considered to ensure accurate reporting of survival data and interpretation of RWD outcomes.

An ovine model of cerebral catheter venography for implantation of an endovascular neural interface.

OBJECTIVE Neural interface technology may enable the development of novel therapies to treat neurological conditions, including motor prostheses for spinal cord injury. Intracranial neural interfaces currently require a craniotomy to achieve implantation and may result in chronic tissue inflammation. Novel approaches are required that achieve less invasive implantation methods while maintaining high spatial resolution. An endovascular stent electrode array avoids direct brain trauma and is able to record electrocorticography in local cortical tissue from within the venous vasculature. The motor area in sheep runs in a parasagittal plane immediately adjacent to the superior sagittal sinus (SSS). The authors aimed to develop a sheep model of cerebral venography that would enable validation of an endovascular neural interface. METHODS Cerebral catheter venography was performed in 39 consecutive sheep. Contrast-enhanced MRI of the brain was performed on 13 animals. Multiple telescoping coaxial catheter systems were assessed to determine the largest wide-bore delivery catheter that could be delivered into the anterior SSS. Measurements of SSS diameter and distance from the motor area were taken. The location of the motor area was determined in relation to lateral and superior projections of digital subtraction venography images and confirmed on MRI. RESULTS The venous pathway from the common jugular vein (7.4 mm) to the anterior SSS (1.2 mm) was technically challenging to selectively catheterize. The SSS coursed immediately adjacent to the motor cortex (< 1 mm) for a length of 40 mm, or the anterior half of the SSS. Attempted access with 5-Fr and 6-Fr delivery catheters was associated with longer procedure times and higher complication rates. A 4-Fr catheter (internal lumen diameter 1.1 mm) was successful in accessing the SSS in 100% of cases with no associated complications. Complications included procedure-related venous dissection in two major areas: the torcular herophili, and the anterior formation of the SSS. The bifurcation of the cruciate sulcal veins with the SSS was a reliable predictor of the commencement of the motor area. CONCLUSIONS The ovine model for cerebral catheter venography has generalizability to the human cerebral venous system in relation to motor cortex location. This novel model may facilitate the development of the novel field of endovascular neural interfaces that may include preclinical investigations for cortical recording applications such as paralysis and epilepsy, as well as other potential applications in neuromodulation.

Cryptococcal meningitis causing obstructive hydrocephalus in a patient on fingolimod.

Cryptococcosis is a recognised opportunistic infection in immunocompromised patients. The long-term adverse effect profile of fingolimod, an immunomodulating agent approved for use in multiple sclerosis in 2010, is only just emerging. We report the first case to our knowledge of a patient presenting with obstructive hydrocephalus secondary to cryptococcal meningitis in the setting of fingolimod therapy. Extensive posterior fossa leptomeningeal inflammation with associated cerebellar oedema resulted in effacement of the fourth ventricle and obstructive hydrocephalus requiring urgent ventriculostomy. Induction, consolidative and maintenance antifungal therapy was prescribed and subsequent conversion to a ventriculoperitoneal shunt was successful in relieving the patient's ventriculomegaly. Awareness of these rare, novel and life-threatening complications of fingolimod-associated immunocompromise is critical as the use of such drugs is expected to rise.

Methamphetamine-related brainstem haemorrhage.

We report the case of an otherwise healthy 29-year-old woman who presented with a brainstem haemorrhage following intravenous methamphetamine use. Extensive investigation did not reveal an underlying pathology, and the development of symptoms was temporally related to methamphetamine injection. Although intracerebral haemorrhage secondary to methamphetamine use is well documented, this report describes a haemorrhage within the brainstem which is a rare location. While animal studies have demonstrated the potential of methamphetamines to produce brainstem haemorrhages, there has only been one previous report describing a haemorrhage in this location due to amphetamine use in humans. We conclude with a brief discussion of the clinical features and aetiology of methamphetamine-related stroke.

Minimally invasive endovascular stent-electrode array for high-fidelity, chronic recordings of cortical neural activity.

High-fidelity intracranial electrode arrays for recording and stimulating brain activity have facilitated major advances in the treatment of neurological conditions over the past decade. Traditional arrays require direct implantation into the brain via open craniotomy, which can lead to inflammatory tissue responses, necessitating development of minimally invasive approaches that avoid brain trauma. Here we demonstrate the feasibility of chronically recording brain activity from within a vein using a passive stent-electrode recording array (stentrode). We achieved implantation into a superficial cortical vein overlying the motor cortex via catheter angiography and demonstrate neural recordings in freely moving sheep for up to 190 d. Spectral content and bandwidth of vascular electrocorticography were comparable to those of recordings from epidural surface arrays. Venous internal lumen patency was maintained for the duration of implantation. Stentrodes may have wide ranging applications as a neural interface for treatment of a range of neurological conditions.

Preoperative biomarkers of tumour vascularity are elevated in patients with glioblastoma multiforme.

We investigated the correlation between the circulating and imaging biomarkers of tumour vascularity, and examined whether they are prognostic of outcomes in patients with glioblastoma multiforme (GBM). Despite the increasing use of anti-angiogenic agents within neuro-oncology, there are still no validated biomarkers to monitor for a treatment response or relapse. The pre- and postoperative circulating endothelial cell (CEC) and progenitor cell (CEP) levels were assessed. Preoperative perfusion-weighted MRI (PWI) was also performed, and the relative cerebral blood volume (rCBV) histogram statistics of the contrast-enhancing tumour were analysed. A novel PWI parameter (rCBVload) was developed to estimate the total volume of perfused tumour vessels, and it was hypothesised that this parameter would correlate with CEC and CEP concentrations. In total, 24 GBM patients were included. The mean preoperative CEC concentration was significantly higher in GBM patients than the controls (p=0.019), and it then declined significantly postoperatively (p=0.009). The preoperative CEP levels were significantly correlated with the median tumour rCBV (Spearman rank-order coefficient=0.526; p=0.039). Neither CEC nor CEP was correlated with the total tumour vessel volume, as measured by rCBVload. None of the biomarkers that were investigated showed a significant correlation with progression-free or overall survival. We conclude that CEC are potentially useful biomarkers to monitor GBM patients during treatment. We found that CEC are increased in the presence of GBM, and that CEP levels appear to be proportional to tumour vascularity, as measured on PWI. However, in this study, none of the biomarkers of GBM vascularity were highly prognostic of patient outcomes.