Invadopodia associated Thrombospondin-1 contributes to a post-therapy pro-invasive response in glioblastoma cells.

A critical challenge in the treatment of glioblastoma (GBM) is its highly invasive nature which promotes cell migration throughout the brain and hinders surgical resection and effective drug delivery. GBM cells demonstrate augmented invasive capabilities following exposure to the current gold standard treatment of radiotherapy (RT) and concomitant and adjuvant temozolomide (TMZ), resulting in rapid disease recurrence. Elucidating the mechanisms employed by post-treatment invasive GBM cells is critical to the development of more effective therapies. In this study, we utilized a Nanostring® Cancer Progression gene expression panel to identify candidate genes that may be involved in enhanced GBM cell invasion after treatment with clinically relevant doses of RT/TMZ. Our findings identified thrombospondin-1 (THBS1) as a pro-invasive gene that is upregulated in these cells. Immunofluorescence staining revealed that THBS1 localised within functional matrix-degrading invadopodia that formed on the surface of GBM cells. Furthermore, overexpression of THBS1 resulted in enhanced GBM cell migration and secretion of MMP-2, which was reduced with silencing of THBS1. The preliminary data demonstrates that THBS1 is associated with invadopodia in GBM cells and is likely involved in the invadopodia-mediated invasive process in GBM cells exposed to RT/TMZ treatment. Therapeutic inhibition of THBS1-mediated invadopodia activity, which facilitates GBM cell invasion, should be further investigated as a treatment for GBM.

Volume-based enteral feeding for ward patients with acute neurological conditions: a pilot prospective cohort study.

BACKGROUND: Patients requiring enteral nutrition (EN) after neurological insults experience feeding interruptions, contributing to inadequate nutrition delivery. This prospective cohort study investigated if volume-based enteral feeding (VBF) improved the delivery of prescribed EN volume in ward patients with acute neurological conditions. METHODS: Over two sequential periods, the usual care group received standard continuous rate-based feeding, and the intervention group received VBF with bi-daily EN rate adjustments to achieve target daily volume. The primary outcome was percentage of prescribed daily EN formula volume delivered. Differences in energy and protein provision, weight, malnutrition and safety were explored. An evaluation survey captured nurse acceptability of the protocol. RESULTS: The intervention group (n = 32) achieved greater median interquartile range (IQR) EN adequacy of prescribed volume at 92% (88-97) compared to 67% (54-78) for usual care (n = 35) (p < 0.001). VBF compared to rate-based feeding resulted in patients receiving more kilojoules (131 [121-138] kJ/kg vs. 84 [64-99] kJ/kg; p < 0.001) and protein (1.3 [1.2-1.5] g/kg vs. 0.9 [0.6-1.1] g/kg; p < 0.001). There were no differences in gastrointestinal intolerance between groups. Compliance to the VBF protocol was 90%, and 78% of staff reported high confidence using the protocol. The intervention group had less median weight loss at discharge (-1.4 [0.1 to -4.3] kg) than usual care (-3.6 [-1.3 to 8.4] kg; p < 0.011), but no differences in malnutrition status were observed. CONCLUSION: A VBF protocol delivered greater EN volume, energy and protein following neurological injury. The VBF protocol was feasible with high acceptability from nursing staff.

Somatic mutation landscape in a cohort of meningiomas that have undergone grade progression.

BACKGROUND: A subset of meningiomas progress in histopathological grade but drivers of progression are poorly understood. We aimed to identify somatic mutations and copy number alterations (CNAs) associated with grade progression in a unique matched tumour dataset. METHODS: Utilising a prospective database, we identified 10 patients with meningiomas that had undergone grade progression and for whom matched pre- and post-progression tissue (n = 50 samples) was available for targeted next-generation sequencing. RESULTS: Mutations in NF2 were identified in 4/10 patients, of these 94% were non-skull base tumours. In one patient, three different NF2 mutations were identified in four tumours. NF2 mutated tumours showed large-scale CNAs, with highly recurrent losses in 1p, 10, 22q, and frequent CNAs on chromosomes 2, 3 and 4. There was a correlation between grade and CNAs in two patients. Two patients with tumours without detected NF2 mutations showed a combination of loss and high gain on chromosome 17q. Mutations in SETD2, TP53, TERT promoter and NF2 were not uniform across recurrent tumours, however did not correspond with the onset of grade progression. CONCLUSION: Meningiomas that progress in grade generally have a mutational profile already detectable in the pre-progressed tumour, suggesting an aggressive phenotype. CNA profiling shows frequent alterations in NF2 mutated tumours compared to non NF2 mutated tumours. The pattern of CNAs may be associated with grade progression in a subset of cases.

Repurposing FDA-approved drugs as inhibitors of therapy-induced invadopodia activity in glioblastoma cells.

Glioblastoma (GBM) is the most prevalent primary central nervous system tumour in adults. The lethality of GBM lies in its highly invasive, infiltrative, and neurologically destructive nature resulting in treatment failure, tumour recurrence and death. Even with current standard of care treatment with surgery, radiotherapy and chemotherapy, surviving tumour cells invade throughout the brain. We have previously shown that this invasive phenotype is facilitated by actin-rich, membrane-based structures known as invadopodia. The formation and matrix degrading activity of invadopodia is enhanced in GBM cells that survive treatment. Drug repurposing provides a means of identifying new therapeutic applications for existing drugs without the need for discovery or development and the associated time for clinical implementation. We investigate several FDA-approved agents for their ability to act as both cytotoxic agents in reducing cell viability and as 'anti-invadopodia' agents in GBM cell lines. Based on their cytotoxicity profile, three agents were selected, bortezomib, everolimus and fludarabine, to test their effect on GBM cell invasion. All three drugs reduced radiation/temozolomide-induced invadopodia activity, in addition to reducing GBM cell viability. These drugs demonstrate efficacious properties warranting further investigation with the potential to be implemented as part of the treatment regime for GBM.

The role of spinal surgery in the treatment of low back pain.

Low back pain (LBP) is common and a leading cause of disability and lost productivity worldwide. Acute LBP is frequently self-resolving, but recurrence is common, and a significant proportion of patients will develop chronic pain. This transition is perpetuated by anatomical, biological, psychological and social factors. Chronic LBP should be managed with a holistic biopsychosocial approach of generally non-surgical measures. Spinal surgery has a role in alleviating radicular pain and disability resulting from neural compression, or where back pain relates to cancer, infection, or gross instability. Spinal surgery for all other forms of back pain is unsupported by clinical data, and the broader evidence base for spinal surgery in the management of LBP is poor and suggests it is ineffective. Emerging areas of interest include selection of a minority of patients who may benefit from surgery based on spinal sagittal alignment and/or nuclear medicine scans, but an evidence base is absent. Spinal surgery for back pain has increased substantially over recent decades, and disproportionately among privately insured patients, thus the contribution of industry and third-party payers to this increase, and their involvement in published research, requires careful consideration.

Health-Related Quality of Life in Intracranial Meningioma: Current Evidence and Future Directions.

Historically, largely due to the good prognosis for survival, there has been little attention paid to the possible impact of meningiomas and their treatment on health-related quality of life (HRQoL). However, in the last decade there has been increasing evidence that patients with intracranial meningiomas suffer from long-term decreases in their HRQoL. Compared with controls and normative data, meningioma patients have worse HRQoL scores both before and after intervention and continuing long term (even after >4 years of follow-up). Overall, surgery results in improvements in many aspects of HRQoL. The limited available studies investigating the impact of radiotherapy suggest that this type of treatment decreases HRQoL scores, especially in the long term. There is however only limited evidence on additional determinants of HRQoL. Patients with anatomically complex skull base meningiomas and severe comorbidities, including epilepsy, report the lowest HRQoL scores. Other tumor and sociodemographic characteristics have shown weak associations with HRQoL. Furthermore, about one-third of caregivers of meningioma patients report caregiver burden, warranting interventions to improve caregiver HRQoL. As antitumor interventions may not improve HRQoL scores to be comparable to those of the general population, more attention should be paid to the development of integrative rehabilitation and supportive care programs for meningioma patients.

Physical activity and glioma: a case-control study with follow-up for survival.

PURPOSE: High-grade disease accounts for ~ 70% of all glioma, and has a high mortality rate. Few modifiable exposures are known to be related to glioma risk or mortality. METHODS: We examined associations between lifetime physical activity and physical activity at different ages (15-18 years, 19-29 years, 30-39 years, last 10 years) with the risk of glioma diagnosis, using data from a hospital-based family case-control study (495 cases; 371 controls). We followed up cases over a median of 25 months to examine whether physical activity was associated with all-cause mortality. Physical activity and potential confounders were assessed by self-administered questionnaire. We examined associations between physical activity (metabolic equivalent [MET]-h/wk) and glioma risk using unconditional logistic regression and with all-cause mortality in cases using Cox regression. RESULTS: We noted a reduced risk of glioma for the highest (≥ 47 MET-h/wk) versus lowest (< 24 METh/wk) category of physical activity for lifetime activity (OR = 0.58, 95% CI: 0.38-0.89) and at 15-18 years (OR = 0.57, 95% CI: 0.39-0.83). We did not observe any association between physical activity and all-cause mortality (HR for lifetime physical activity = 0.91, 95% CI: 0.64-1.29). CONCLUSION: Our findings are consistent with previous research that suggested physical activity during adolescence might be protective against glioma. Engaging in physical activity during adolescence has many health benefits; this health behavior may also offer protection against glioma.

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.

Conventional MRI features can predict the molecular subtype of adult grade 2-3 intracranial diffuse gliomas.

PURPOSE: Molecular biomarkers are important for classifying intracranial gliomas, prompting research into correlating imaging with genotype ("radiogenomics"). A limitation of the existing radiogenomics literature is the paucity of studies specifically characterizing grade 2-3 gliomas into the three key molecular subtypes. Our study investigated the accuracy of multiple different conventional MRI features for genotype prediction. METHODS: Grade 2-3 gliomas diagnosed between 2007 and 2013 were identified. Two neuroradiologists independently assessed nine conventional MRI features. Features with better inter-observer agreement (κ ≥ 0.6) proceeded to consensus assessment. MRI features were correlated with genotype, classified as IDH-mutant and 1p/19q-codeleted (IDHmut/1p19qcodel), IDH-mutant and 1p/19q-intact (IDHmut/1p19qint), or IDH-wildtype (IDHwt). For IDHwt tumors, additional molecular markers of glioblastoma were noted. RESULTS: One hundred nineteen patients were included. T2-FLAIR mismatch (stratified as > 50%, 25-50%, or < 25%) was the most predictive feature across genotypes (p < 0.001). All 30 tumors with > 50% mismatch were IDHmut/1p19qint, and all seven with 25-50% mismatch. Well-defined margins correlated with IDHmut/1p19qint status on univariate analysis (p < 0.001), but this related to correlation with T2-FLAIR mismatch; there was no longer an association when considering only tumors with < 25% mismatch (p = 0.386). Enhancement (p = 0.001), necrosis (p = 0.002), and hemorrhage (p = 0.027) correlated with IDHwt status (especially "molecular glioblastoma"). Calcification correlated with IDHmut/1p19qcodel status (p = 0.003). A simple, step-wise algorithm incorporating these features, when present, correctly predicted genotype with a positive predictive value 91.8%. CONCLUSION: T2-FLAIR mismatch strongly predicts IDHmut/1p19qint even with a lower threshold of ≥ 25% mismatch and outweighs other features. Secondary features include enhancement, necrosis and hemorrhage (predicting IDHwt, especially "molecular glioblastoma"), and calcification (predicting IDHmut/1p19qcodel).

International Women in Neurosurgery.

The history of women in neurosurgery worldwide has been characterized by adversity and hardships in a male-dominated field, where resilient, tenacious, and ingenious women have nevertheless left their mark. The first women in neurosurgery appeared in Europe at the end of the 1920s, and since then have emerged in all continents in the world. Women neurosurgeons all over the globe have advanced the field in numerous directions, introducing neurosurgical subspecialties to their countries, making scientific and technical advances, and dedicating themselves to humanitarian causes, to name a few. The past 30 years, in particular, have been a period of increasing involvement and responsibility for women in neurosurgery. We must now focus on continual system improvements that will promote a diverse and talented workforce, building a welcoming environment for all aspiring neurosurgeons, in order to advance the specialty in the service of neurosurgical patients.

Healthcare professionals' experiences with education in short term medical missions: an inductive thematic analysis.

BACKGROUND: Short-term medical mission (STMM) providers supplement healthcare delivery and education in low- and middle-income countries (LMIC). Despite numerous providers working in this space, the views of volunteers who contribute their time and skills to these programs are rarely sought. METHOD: A qualitative study of 24 volunteers for Pangea Global Health Education (Pangea) was undertaken using semi-structured interviews to better understand their perspectives on program design and delivery, personal and professional outcomes of their volunteer experiences and the resulting implications for STMM program design. An inductive thematic analysis of their responses was completed. Social constructionist theory was utilised to contextualise themes and implications for program design. RESULTS: Participants highlighted the importance of co-creation with local learners and staff, the necessity to understand clinical context and the importance of relating to culture in the advancement of patient care. They reported personal growth, including a better understanding of others, and identifying commonalities between people. Professionally, participants reported learning from their colleagues, including new medical content, as well as refining their teaching practices. They also reported learning from those they taught and respecting the resourcefulness of medical and nursing staff working in LMIC. CONCLUSION: STMM providers may benefit from co-creation with their learners in the development of health professional education programs. A deep understanding of local context and culture provides for a richer learning environment and enables sustainable long-term program delivery. Utilising a social constructionist framework enables a better understanding of cultural barriers, which inhibit group learning, including the tendency to maintain hierarchical divides; addressing these will allow for optimised patient care.

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.

Challenges in the Australasian neurosurgery training program: who should be trained and where should they train?

OBJECTIVE: Neurosurgical training poses particular challenges in Australia and New Zealand, given the large landmass, small population, and widely separated, often small, neurosurgical units. Such factors have necessitated a move away from autonomous, single-institution-based training to the selection of trainees by a centralized binational process. The success of this system is based on rigorous standardized evaluation of candidates' academic achievements, anatomical knowledge, references, and interview performance. Similarly, the accreditation of hospitals to train successful candidates has been standardized. The authors review the evolution of trainee selection and the accreditation of training posts in Australia and New Zealand. METHODS: The records of the Neurosurgical Society of Australasia Surgical Education and Training Board were reviewed for documents pertaining to the selection of neurosurgical trainees and the accreditation of training posts. Application records and referee scores from 2014 to the present were reviewed to encompass process changes, in particular the change from written referee reports to standardized interviews of referees. Surgical logbook case numbers for 23 trainees completing training in 2016, 2017, and 2018 were collated and presented in an aggregated, de-identified form as a measure of adherence to accreditation standards. Written evaluations of the training experience were also sought from two trainees reflecting on the selection process, the quality of training posts, and training limitations. RESULTS: While a time-consuming process, the method of obtaining referee reports by interview has resulted in a wider spread of scores, more able to separate high- and low-scoring applicants than other components of the selection process. Review of the training post accreditation records for the last 2 years showed that adherence to standards has resulted in loss of accreditation for one unit and shortened periods of review for units with more minor deficiencies. Two applications for accreditation have been denied. Examination of caseload data showed that trainees more than fulfill minimum requirements in accredited training posts, confirming the robust nature of this aspect of unit accreditation. CONCLUSIONS: A key factor determining the success of neurosurgical training in Australia and New Zealand has been a willingness to evolve selection and other processes to overcome challenges as they become apparent. According to available analyses, the revised referee process and strict accreditation standards appear effective. The benefits and challenges of the current training system are discussed in the context of a paucity of international literature.

Extracellular vesicles and their role in glioblastoma.

Research on the role of extracellular vesicles (EVs) in disease pathogenesis has been rapidly growing over the last two decades. As EVs can mediate intercellular communication, they can ultimately facilitate both normal and pathological processes through the delivery of their bioactive cargo, which may include nucleic acids, proteins and lipids. EVs have emerged as important regulators of brain tumors, capable of transferring oncogenic proteins, receptors, and small RNAs that may support brain tumor progression, including in the most common type of brain cancer, glioma. Investigating the role of EVs in glioma is crucial, as the most malignant glioma, glioblastoma (GBM), is incurable with a dismal median survival of 12-15 months. EV research in GBM has primarily focused on circulating brain tumor-derived vesicles in biofluids, such as blood and cerebrospinal fluid (CSF), investigating their potential as diagnostic and prognostic biomarkers. Gaining a greater understanding of the role of EVs and their cargo in brain tumor progression may contribute to the discovery of novel diagnostics and therapeutics. In this review, we summarize the known and emerging functions of EVs in glioma biology and pathogenesis, as well as their emerging biomarker potential.

Outcomes after second surgery for recurrent glioblastoma: a retrospective case-control study.

Studies looking at the benefit of surgery at first relapse (second surgery) for recurrent glioblastoma were confounded by including patients with varying grades of glioma, performance status and extent of resection. This case-controlled study aims to remove these confounders to assess the survival impact of second surgery in recurrent glioblastoma. Retrospective data on patients with glioblastoma recurrence at two tertiary Australian hospitals from July 2009 to April 2015 was reviewed. Patients who had surgery at recurrence were matched with those who did not undergo surgery at recurrence, based on the extent of their initial resection and age. Overall survival (OS1 assessed from initial diagnosis and OS2 from the date of recurrence) as well as functional outcomes after resection were analysed. There were 120 patients (60 in each institution); median age at diagnosis was 56 years. Median OS1 was 14 months (95% CI 11.5-15.7) versus 22 months (95% CI 18-25) in patients who did not undergo second surgery and those with surgery at recurrence. OS2 was improved by second surgery (4.7 vs 9.6, HR 0.52, 95% CI 0.38-0.72, P < 0.001), and by chemotherapy, given at recurrence, (HR 0.47, 95% CI 0.24-0.92, P = 0.03). After second surgery, 80% did not require rehabilitation and 61% were independently mobile. Second surgery for recurrent glioblastoma was associated with a survival advantage. Chemotherapy independent of surgery, also improved survival. Functional outcomes were encouraging. More research is required in the era of improved surgical techniques and new antineoplastic therapies.

The 2016 revision of the WHO Classification of Central Nervous System Tumours: retrospective application to a cohort of diffuse gliomas.

The classification of central nervous system tumours has more recently been shaped by a focus on molecular pathology rather than histopathology. We re-classified 82 glial tumours according to the molecular-genetic criteria of the 2016 revision of the World Health Organization (WHO) Classification of Tumours of the Central Nervous System. Initial diagnoses and grading were based on the morphological criteria of the 2007 WHO scheme. Because of the impression of an oligodendroglial component on initial histological assessment, each tumour was tested for co-deletion of chromosomes 1p and 19q and mutations of isocitrate dehydrogenase (IDH-1 and 2) genes. Additionally, expression of proteins encoded by alpha-thalassemia X-linked mental retardation (ATRX) and TP53 genes was assessed by immunohistochemistry. We found that all but two tumours could be assigned to a specific category in the 2016 revision. The most common change in diagnosis was from oligoastrocytoma to specifically astrocytoma or oligodendroglioma. Analysis of progression free survival (PFS) for WHO grade II and III tumours showed that the objective criteria of the 2016 revision separated diffuse gliomas into three distinct molecular categories: chromosome 1p/19q co-deleted/IDH mutant, intact 1p/19q/IDH mutant and IDH wild type. No significant difference in PFS was found when comparing IDH mutant grade II and III tumours suggesting that IDH status is more informative than tumour grade. The segregation into distinct molecular sub-types that is achieved by the 2016 revision provides an objective evidence base for managing patients with grade II and III diffuse gliomas based on prognosis.

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.