Early minimally invasive intracerebral hemorrhage evacuation: a phase 2a feasibility, safety, and promise of surgical efficacy study.

BACKGROUND: Surgical treatment of intracerebral hemorrhage (ICH) is unproven, although meta-analyses suggest that both early conventional surgery with craniotomy and minimally invasive surgery (MIS) may be beneficial. We aimed to demonstrate the safety, feasibility, and promise of efficacy of early MIS for ICH using the Aurora Surgiscope and Evacuator. METHODS: We performed a prospective, single arm, phase IIa Simon's two stage design study at two stroke centers (10 patients with supratentorial ICH volumes ≥20 mL and National Institutes of Health Stroke Scale (NIHSS) score of ≥6, and surgery commencing <12 hours after onset). Positive outcome was defined as ≥50% 24 hour ICH volume reduction, with the safety outcome lack of significant ICH reaccumulation. RESULTS: From December 2019 to July 2020, we enrolled 10 patients at two Australian Comprehensive Stroke Centers, median age 70 years (IQR 65-74), NIHSS score 19 (IQR 19-29), ICH volume 59 mL (IQR 25-77), at a median of 227 min (IQR 175-377) post-onset. MIS was commenced at a median time of 531 min (IQR 437-628) post-onset, had a median duration of 98 min (IQR 77-110), with a median immediate postoperative hematoma evacuation of 70% (IQR 67-80%). A positive outcome was achieved in 5/5 first stage patients and in 4/5 second stage patients. One patient developed significant 24 hour ICH reaccumulation; otherwise, 24 hour stability was observed (median reduction 71% (IQR 61-80), 5/9 patients <15 mL residual). Three patients died, unrelated to surgery. There were no surgical safety concerns. At 6 months, the median modified Rankin Scale score was 4 (IQR 3-6) with 30% achieving a score of 0-3. CONCLUSION: In this study, early ICH MIS using the Aurora Surgiscope and Evacuator appeared to be feasible and safe, warranting further exploration. TRIAL REGISTRATION NUMBER: ACTRN12619001748101.

How has the COVID-19 pandemic impacted clinical care and research in Neuro-Oncology?

The COVID-19 pandemic has challenged the continued delivery of healthcare globally. Due to disease risk, clinicians were forced to re-evaluate the safety and priorities of pre-pandemic care. Neuro-oncology presents unique challenges, as patients can deteriorate rapidly without intervention. These challenges were also observed in countries with reduced COVID-19 burden with centres required to rapidly develop strategies to maintain efficient and equitable care. This review aims to summarise the impact of the pandemic on clinical care and research within the practice of Neuro-oncology. A narrative review of the literature was performed using MEDLINE and EMBASS and results screened using PRISMA guidelines with relevant inclusion and exclusion criteria. Search strategies included variations of 'Neuro-oncology' combined with COVID-19 and other clinical-related terms. Most adult and paediatric neurosurgical centres experienced reductions in new referrals and operations for brain malignancies, and those who did present for treatment frequently had operations cancelled or delayed. Many radiation therapy and medical oncology centres altered treatment plans to mitigate COVID-19 risk for patients and staff. New protocols were developed that aimed to reduce in-person visits and reduce the risk of developing severe complications from COVID-19. The COVID-19 pandemic has presented many challenges to the provision of safe and accessible healthcare. Despite these challenges, some benefits to healthcare provision such as the use of telemedicine are likely to remain in future practice. Neuro-oncology staff must remain vigilant to ensure patient and staff safety.

Scalpel sign: Dorsal thoracic arachnoid web, thoracic arachnoid cyst and ventral cord herniation.

The "Scalpel sign" is a radiological sign which can be identified on magnetic resonance imaging and indicates dorsal compression of the spinal cord [1]. Prior descriptions of a "Scalpel sign" have been reported in the literature and the awareness and identification of this pathognomonic sign may aid in the rapid diagnosis and treatment of patients with dorsal arachnoid web, dorsal arachnoid cyst or ventral cord herniation. We describe 3 cases which highlight these rare conditions for which this sign is pathognomonic and summarize the pertinent literature related to these disorders [1,2].

Lipid droplets and ferroptosis as new players in brain cancer glioblastoma progression and therapeutic resistance.

A primary brain tumor glioblastoma is the most lethal of all cancers and remains an extremely challenging disease. Apparent oncogenic signaling in glioblastoma is genetically complex and raised at any stage of the disease's progression. Many clinical trials have shown that anticancer drugs for any specific oncogene aberrantly expressed in glioblastoma show very limited activity. Recent discoveries have highlighted that alterations in tumor metabolism also contribute to disease progression and resistance to current therapeutics for glioblastoma, implicating an alternative avenue to improve outcomes in glioblastoma patients. The roles of glucose, glutamine and tryptophan metabolism in glioblastoma pathogenesis have previously been described. This article provides an overview of the metabolic network and regulatory changes associated with lipid droplets that suppress ferroptosis. Ferroptosis is a newly discovered type of nonapoptotic programmed cell death induced by excessive lipid peroxidation. Although few studies have focused on potential correlations between tumor progression and lipid droplet abundance, there has recently been increasing interest in identifying key players in lipid droplet biology that suppress ferroptosis and whether these dependencies can be effectively exploited in cancer treatment. This article discusses how lipid droplet metabolism, including lipid synthesis, storage, and use modulates ferroptosis sensitivity or tolerance in different cancer models, focusing on glioblastoma.

Perioperative clinical trials for glioma: Raising the bar.

Gliomas are a heterogeneous group of primary brain cancers with poor survival despite multimodality therapy that includes surgery, radiation and chemotherapy. Numerous clinical trials have investigated systemic therapies in glioma, but have largely been negative. Multiple factors have contributed to the lack of progress including tumour heterogeneity, the tumour micro-environment and presence of the blood-brain barrier, as well as extrinsic factors relating to trial design, such as the lack of a contemporaneous biopsy at the time of treatment. A number of strategies have been proposed to progress new agents into the clinic. Here, we review the progress of perioperative, including phase 0 and 'window of opportunity', studies and provide recommendations for trial design in the development of new agents for glioma. The incorporation of pre- and post-treatment biopsies in glioma early phase trials will provide valuable pharmacokinetic and pharmacodynamic data and also determine the target or biomarker effect, which will guide further development of new agents. Perioperative 'window of opportunity' studies must use drugs with a recommended-phase-2-dose, known safety profile and adequate blood-brain barrier penetration. Drugs shown to have on-target effects in perioperative trials can then be evaluated further in a larger cohort of patients in an adaptive trial to increase the efficiency of drug development.

The biological and clinical basis for early referral of low grade glioma patients to a surgical neuro-oncologist.

The discovery of IDH1/2 (isocitrate dehydrogenase) mutation in large scale, genomewide mutational analyses of gliomas has led to profound developments in understanding tumourigenesis, and restructuring of the classification of both high and low grade gliomas. Owing to this progress made in the recognition of molecular markers which predict tumour behavior and treatment response, the increasing importance of adjuvant treatments such as chemo- and radiotherapy, and the tremendous advances in surgical technique and intraoperative monitoring which have facilitated superior extents of resection whilst preserving neurological functioning and quality of life, contemporary management of low grade glioma (LGG) has switched from a passive, observant approach to a more active, interventional one. Furthermore, this has implications for the manner in which patients with incidentally discovered and/or asymptomatic LGG are managed, and this review of the biological behaviour of LGG, as well as its clinical investigation and management, should act as a timely reminder to all clinicians of the importance of referring LGG patients early to a surgical neuro-oncologist who is not only familiar and acquainted with the vagaries of this disease process, but who, in addition, is devoted to delivering care to these patients with the support of a multi-disciplinary clinical decision-making unit, comprising medical neuro-oncologists, radiation oncologists and allied health professionals.

Supramaximal resection: A systematic review of its safety, efficacy and feasibility in glioblastoma.

The philosophy of 'supramaximal resection' (SMR) beyond the T1-enhanced margin holds some potential in glioblastoma surgery, but the quality of available literature has not been elucidated. A systematic review of published studies of SMR in glioblastoma surgery was performed. Articles were sought in MEDLINE, EMBASE, Scopus and Cochrane Central Register for Clinical Trials. The search items were grouped into three themes; supramaximal resection, glioblastoma and outcomes. Cases were included wherein the initial extent of resection was described as exceeding gross total resection, that is to say, beyond the area of T1-enhancement on MRI. Only newly diagnosed glioblastoma was considered. Articles containing primary patient data, including outcome data, were included; reviews, editorials, descriptive articles and systematic reviews were excluded. Subsequently, 1123 unique articles were initially retrieved. After screening article titles and abstracts for relevance to SMR in glioblastoma, seven articles remained, and were all included post-full text review. No randomized controlled trials were discovered. Almost all studies were of Level 4 quality, according to Oxford Center for Evidence-Based Medicine guidelines. The included articles yielded a total of 2019 surgically treated glioblastoma patients, 13.5% of whom underwent SMR. Preliminary results suggest SMR of glioblastoma positively impacts overall and progression free survival. However, the contemporaneous literature supporting glioblastoma SMR is of low quality, with neither anatomical nor radiographic definitional consensus for what constitutes SMR. Prospective studies of larger pooled populations with standardized technical, radiological and outcome measures in designated centers would help minimize bias and validate SMR in appropriately selected glioblastoma patients.

Invasive central nervous system aspergillosis in a patient with Crohn's disease after treatment with infliximab and corticosteroids.

Aspergillus species are emerging as a significant cause of pneumonia mortality in immune compromised hosts, with haematological spread being a rare and life-threatening complication. The central nervous system (CNS) as a site for extrapulmonary spread is rarer still. We report a case of CNS disseminated aspergillosis in a patient treated with corticosteroids and infliximab, an immunomodulatory agent commonly used in the treatment of inflammatory bowel disease, and review the available literature regarding this rare pathology.

Regulation of glycogen synthase kinase-3 beta (GSK-3ß) by the Akt pathway in gliomas.

Gliomas are aggressive brain tumours that, despite advances in multimodal therapies, continue to portend a dismal prognosis. Glioblastoma multiforme (GBM) represents the most aggressive glioma and patients have a median survival of 14 months, even with the best available treatments. The phosphoinositide 3-kinase/Akt/glycogen synthase kinase-3 beta (GSK-3ß) and Wnt/ß-catenin pathways are dysregulated in a number of cancers, and these two pathways share a common node protein, GSK-3ß. This protein is responsible for the regulation/degradation of ß-catenin, which reduces ß-catenin's translocation to the nucleus and influences the subsequent transcription of oncogenes. The non-specific small-molecule GSK-3ß inhibitor, lithium chloride (LiCl), and the specific Akt inhibitor, AktX, were used to treat U87MG and U87MG.Δ2-7 human glioma cell lines. LiCl treatment significantly affected cell morphology of U87MG and U87MG.Δ2-7 cells, while also increasing levels of phospho-GSK-3ß in a dose-dependent manner. Increased cell proliferation was observed at low-to-mid LiCl concentrations as determined by MTT cell growth assays. Treatment of U87MG and U87MG.Δ2-7 cells with AktX resulted in reduced levels of phospho-GSK-3ß through its inhibition of Akt, in addition to decreased levels of phosphorylated (active) Akt in a dose-dependent fashion. We have shown in this study that GSK-3ß regulation by phosphorylation is important for cell morphology and growth, and that LiCl enhances growth of U87MG and U87MG.Δ2-7 cells by inhibiting GSK-3ß through its phosphorylation, whereas AktX reduces growth via activation of GSK-3ß by inhibiting Akt's kinase activity.

Metastatic olfactory neuroblastoma invading a radiation-induced meningioma.

Olfactory neuroblastomas are malignant, neuroectodermal nasal tumours. We describe a 62-year-old patient with a recurrent olfactory neuroblastoma invading a radiation-induced meningioma. Given the temporal and spatial relationship between the primary lesion and the described recurrence, this was due to metastatic rather than direct contiguous spread, fulfilling all the criteria for true tumour-to-tumour metastasis. To our knowledge, this is the first description of an olfactory neuroblastoma metastasising to a meningioma.

Primary diffuse leptomeningeal gliosarcomatosis with a sphenoid/sellar mass: confirmation of the ectopic glial tissue theory?

Gliosarcoma is a rare glioblastoma variant, classically arising in the cerebral hemispheres. We report a patient with primary diffuse leptomeningeal gliomatosis (PDLG) with a sphenoid sinus and sellar mass. An 84-year-old woman presented with progressive headache and right-sided visual failure, associated with ipsilateral oculomotor nerve palsy and left temporal field loss. Neuraxial MRI showed a large lesion within the sphenoid sinus and sella resulting in chiasmal compression, and diffuse cranial and spinal leptomeningeal enhancement. Endoscopic transphenoidal biopsy and debulking of the sphenosellar lesion was performed, and gliosarcoma was diagnosed on histopathological examination. The patient was palliated due to poor performance status. To our knowledge, this is the only report of gliosarcoma within the paranasal sinuses and the second report of PDLG where the histological analysis has confirmed gliosarcoma. We believe this adds significant weight to the theory that heterotopic nests of glial tissue, in this instance within the sphenoid or sella, are the putative origin of PDLG.

Spontaneous spinal epidural haematoma in a geriatric patient on aspirin.

Spontaneous spinal epidural haematoma (SSEH) is a rare cause of spinal cord compression in adults, especially in the elderly. We report an independent 88-year-old female, on aspirin only for chronic atrial fibrillation, who presented with a 12-hour history of acute lumbar back pain, urinary incontinence and progressive bilateral lower limb paresis. Examination revealed saddle anaesthesia and reduced anal tone. Urgent spinal MRI demonstrated an epidural haematoma extending from T7 to L5. The patient made a poor initial post-operative recovery, but four months later had begun to mobilise independently after intensive physiotherapy. The case highlights the significance of clinical suspicion, especially in those patients on anti-platelet therapy, rapid spinal radiography and emergent decompressive surgery in SSEH patients, as well as the importance of ongoing rehabilitation in restoring neurological function.

Spinal cord compression as the initial presentation of acute biphenotypic leukaemia.

Acute biphenotypic leukaemia (BAL) is an uncommon haematological malignancy with features of myeloid and lymphoid origin and poor overall prognosis. We report a 68-year-old man who presented with rapidly progressive upper thoracic spinal cord compression secondary to an extradural lesion. A T2-3 decompressive laminectomy with tumour excision was performed. Histopathology confirmed the diagnosis of acute biphenotypic (B/myeloid) leukaemia. The patient had only minor post-operative improvement in pyramidal lower limb weakness. He succumbed to the disease three months post-diagnosis after failing induction chemotherapy. While central nervous system involvement with acute leukaemia is well recognised, this is the first reported patient with spinal cord compression secondary to this leukaemia subtype.

Sacral ganglioneuroma in a 19-year-old woman.

Ganglioneuroma is a rare benign neural crest tumour, located usually in the posterior mediastinum and retroperitoneum. It tends to acquire significant size before symptoms or clinical signs become apparent. We report a 19-year-old female who underwent excision of a pelvisacral ganglioneuroma via a Pfannenstiel incision, after an abdominopelvic CT scan for investigation of left iliac fossa pain and menorrhagia detected a pelvic mass. This report highlights the importance of complete surgical excision of these lesions and the collaboration of multiple surgical units in managing these often large, variably located tumours.