Unravelling the tumour genome: The evolutionary and clinical impacts of structural variants in tumourigenesis.

Structural variants (SVs) represent a major source of aberration in tumour genomes. Given the diversity in the size and type of SVs present in tumours, the accurate detection and interpretation of SVs in tumours is challenging. New classes of complex structural events in tumours are discovered frequently, and the definitions of the genomic consequences of complex events are constantly being refined. Detailed analyses of short-read whole-genome sequencing (WGS) data from large tumour cohorts facilitate the interrogation of SVs at orders of magnitude greater scale and depth. However, the inherent technical limitations of short-read WGS prevent us from accurately detecting and investigating the impact of all the SVs present in tumours. The expanded use of long-read WGS will be critical for improving the accuracy of SV detection, and in fully resolving complex SV events, both of which are crucial for determining the impact of SVs on tumour progression and clinical outcome. Despite the present limitations, we demonstrate that SVs play an important role in tumourigenesis. In particular, SVs contribute significantly to late-stage tumour development and to intratumoural heterogeneity. The evolutionary trajectories of SVs represent a window into the clonal dynamics in tumours, a comprehensive understanding of which will be vital for influencing patient outcomes in the future. Recent findings have highlighted many clinical applications of SVs in cancer, from early detection to biomarkers for treatment response and prognosis. As the methods to detect and interpret SVs improve, elucidating the full breadth of the complex SV landscape and determining how these events modulate tumour evolution will improve our understanding of cancer biology and our ability to capitalise on the utility of SVs in the clinical management of cancer patients. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Compression of a giant pseudomeningocele causing transient anoxic seizures-a case report.

Transient anoxic seizure upon application of pressure on a giant pseudomeningocele has never been reported in the literature; such abrupt changes in intracranial pressure due to large volume of cerebrospinal fluid (CSF) translocation, if left untreated may lead to permanent cerebral hypoxic injury and death. Here we describe a case of a 26-year-old woman who had undergone lumbar disc surgery in another unit few months ago and developed a large lump around her back. Any pressure on the lump resulted in headaches and at times episodes of seizures. Clinical examination revealed a very large fluid-filled lump consistent with a giant pseudomeningocele, confirmed by an MRI. A video EEG while applying pressure on the lump was recorded. The patient developed a typical seizure attack with a characteristic pattern of cerebral anoxia, and a paired ECG showed irregular rhythm with junctional and ventricular ectopic beats during the latter part of the attack, raising a suspicion of asystole. Upon relieving the pressure off the lump, the patient gradually regained consciousness with no permanent neurological deficit. We then discuss the pathophysiology of anoxic seizures and highlight the need to be vigilant in managing patients with such lesions in order to prevent permanent cerebral hypoxic injury and death.

Counting the cost of negligence in neurosurgery: Lessons to be learned from 10 years of claims in the NHS.

INTRODUCTION: Despite substantial progress in modernising neurosurgery, the specialty still tops the list of medico-legal claims. Understanding the factors associated with negligence claims is vital if we are to identify areas of underperformance and subsequently improve patient safety. Here we provide data on trends in neurosurgical negligence claims over a 10-year period in England. METHODS: We used data provided by the National Health Service Litigation Authority to analyse negligence claims related to neurosurgery from the financial years 2002/2003 to 2011/2012. Using the abstracts provided, we extracted information pertaining to the underlying pathology, injury severity, nature of misadventure and claim value. RESULTS: Over the 10-year period, the annual number of claims increased significantly. In total, there were 794 negligence claims (range 50-117/year); of the 613 closed cases, 405 (66.1%) were successful. The total cost related to claims during the 10 years was £65.7 million, with a mean claim per successful case of £0.16 million (total damages, defence and claimant costs of £45.1, £6.36 and £14.3 million, respectively). Claims related to emergency cases were more costly compared to those of elective cases (£209,327 vs. £112,627; P=0.002). Spinal cases represented the most frequently litigated procedures (350; 44.1% of total), inadequate surgical performance the most common misadventure (231; 29.1%) and fatality the commonest injury implicated in claims (102; 12.8%). Negligence claims related to wrong-site surgery and cauda equina syndrome were frequently successful (26/26; 100% and 14/16; 87.5% of closed cases, respectively). CONCLUSION: In England, the number of neurosurgical negligence claims is increasing, the financial cost substantial, and the burden significant. Lessons to be learned from the study are of paramount importance to reduce future cases of negligence and improve patient care.

Spin-echo echo-planar perfusion prior to chemoradiation is a strong independent predictor of progression-free and overall survival in newly diagnosed glioblastoma.

Spin-echo echo planar (EP) perfusion weighted imaging (SE-PWI) has been demonstrated to be more selective than gradient-echo EP PWI for blood volume in microvessels the size of glioma neocapillaries, but it has not been comprehensively studied in human clinical use. We assessed whether SE-PWI before and after initiating chemoradiation can stratify patients with respect to progression free survival (PFS) and overall survival (OS). Sixty-eight patients with newly diagnosed glioblastoma (mean age 58.3, 36 males) were included in analysis. SE EP cerebral blood volumes (SE-CBVs) in enhancing and nonenhancing tumor, normalized to contralateral normal appearing white matter (SE-nCBV), were assessed at baseline and after initial chemoradiation. SE-nCBV parameters predictive of PFS and OS were identified in univariate and multivariate Cox proportional hazards models. Multivariate analysis demonstrated that baseline tumor mean SE-nCBV was predictive of PFS (p = 0.038) and OS (p = 0.004). Within the patient sample, baseline tumor mean SE-nCBV <2.0 predicted longer patient PFS (median 47.0 weeks, p < 0.001) and OS (median 98.6 weeks, p = 0.003) compared with baseline mean SE-nCBV >2.0 (median PFS 25.3, median OS 56.0 weeks). Exploratory multi-group stratification demonstrated that very high (>4.0) tumor SE-nCBV was associated with worse patient OS than intermediate high (>2.0, <4.0) SE-nCBV (p = 0.025). Baseline mean SE-nCBV can stratify patients for PFS and OS prior to initiation of chemoradiation, which may help select patients who require closer surveillance. Our exploratory analysis indicates a magnitude-dependent relationship between baseline SE-nCBV and OS.

Histogram analysis of apparent diffusion coefficient within enhancing and nonenhancing tumor volumes in recurrent glioblastoma patients treated with bevacizumab.

While patients with recurrent glioblastoma receiving anti-angiogenic therapy demonstrate significant response rates, the benefit on patient survival is less clear. We assessed whether histogram analysis of diffusion weighted MRI can stratify for progression-free and overall survival. Baseline and 3-6 week post-treatment MRI exams of 91 patients with recurrent glioblastoma treated with bevacizumab were retrospectively evaluated. Histograms of apparent diffusion coefficient (ADC) within the volume of contrast enhancing and nonenhancing T2/FLAIR lesions were analyzed using curve-fit analysis. Overall survival (OS) and progression-free survival (PFS) were assessed using ADC parameters in a Cox proportional hazards model adjusted for clinical variables. Baseline ADC(L)/ADC(M) within nonenhancing T2/FLAIR volume (> or ≤0.64) can stratify OS (HR = 2.24, p = 0.002) and PFS (HR = 1.90, p = 0.005). %ADC(H) within enhancing T1+C volume (> or ≤25 %) can also stratify OS (HR = 0.59, p = 0.034) and PFS (HR = 0.56, p = 0.01). Stratification of patient survival can be improved by merging these two ADC parameters into a single combined ADC factor (HR = 0.17, p < 0.0001). The median OS ratio of patient groups stratified by this combined factor was 2.03, larger than median OS ratio when stratifying by either %ADC(H) within T1+C volume alone (1.3) or ADC(L)/ADC(M) within T2/FLAIR alone (1.86). ADC histogram analysis within both enhancing and nonenhancing components of tumor can be used to stratify for PFS and OS in patients with recurrent glioblastoma.

Hippocampal capillary pericytes in post-stroke and vascular dementias and Alzheimer's disease and experimental chronic cerebral hypoperfusion.

Neurovascular unit mural cells called 'pericytes' maintain the blood-brain barrier and local cerebral blood flow. Pathological changes in the hippocampus predispose to cognitive impairment and dementia. The role of hippocampal pericytes in dementia is largely unknown. We investigated hippocampal pericytes in 90 post-mortem brains from post-stroke dementia (PSD), vascular dementia (VaD), Alzheimer's disease (AD), and AD-VaD (Mixed) subjects, and post-stroke non-demented survivors as well as similar age controls. We used collagen IV immunohistochemistry to determine pericyte densities and a mouse model of VaD to validate the effects of chronic cerebral hypoperfusion. Despite increased trends in hippocampal microvascular densities across all dementias, mean pericyte densities were reduced by ~25-40% in PSD, VaD and AD subjects compared to those in controls, which calculated to 14.1 ± 0.7 per mm capillary length, specifically in the cornu ammonis (CA) 1 region (P = 0.01). In mice with chronic bilateral carotid artery occlusion, hippocampal pericyte loss was ~60% relative to controls (P < 0.001). Pericyte densities were correlated with CA1 volumes (r = 0.54, P = 0.006) but not in any other sub-region. However, mice subjected to the full-time environmental enrichment (EE) paradigm showed remarkable attenuation of hippocampal CA1 pericyte loss in tandem with CA1 atrophy. Our results suggest loss of hippocampal microvascular pericytes across common dementias is explained by a vascular aetiology, whilst the EE paradigm offers significant protection.

Recurrent glioblastoma: volumetric assessment and stratification of patient survival with early posttreatment magnetic resonance imaging in patients treated with bevacizumab.

BACKGROUND: Despite a high radiographic response rate in patients with recurrent glioblastoma following bevacizumab therapy, survival benefit has been relatively modest. We assess whether tumor volume measurements based on baseline and early posttreatment MRI can stratify patients in terms of progression-free survival (PFS) and overall survival (OS). METHODS: Baseline (-4 +/- 4 days) and posttreatment (30 +/- 6 days) MRI exams of 91 patients with recurrent glioblastoma treated with bevacizumab were retrospectively evaluated for volume of enhancing tumor as well as volume of the T2/FLAIR hyperintensity. Overall survival (OS) and progression-free survival (PFS) were assessed using volume parameters in a Cox regression model adjusted for significant clinical parameters. RESULTS: In univariable analysis, residual tumor volume, percentage change in tumor volume, steroid change from baseline to posttreatment scan, and number of recurrences were associated with both OS and PFS. With dichotomization by sample median of 52% change of enhancing volume can stratify OS (52 weeks vs. 31 weeks, P = .013) and PFS (21 weeks vs. 12 weeks, P = .009). Residual enhancing volume, dichotomized by sample median of 7.8 cm(3) , can also stratify for OS (64 weeks vs. 28 weeks, P < .001) and PFS (21 weeks vs. 12 weeks, P = .036). CONCLUSIONS: Volumetric percentage change and absolute early posttreatment volume of enhancing tumor can stratify survival for patients with recurrent glioblastoma receiving bevacizumab therapy.

Oncogene expression from extrachromosomal DNA is driven by copy number amplification and does not require spatial clustering in glioblastoma stem cells.

Extrachromosomal DNA (ecDNA) are frequently observed in human cancers and are responsible for high levels of oncogene expression. In glioblastoma (GBM), ecDNA copy number correlates with poor prognosis. It is hypothesized that their copy number, size, and chromatin accessibility facilitate clustering of ecDNA and colocalization with transcriptional hubs, and that this underpins their elevated transcriptional activity. Here, we use super-resolution imaging and quantitative image analysis to evaluate GBM stem cells harbouring distinct ecDNA species (EGFR, CDK4, PDGFRA). We find no evidence that ecDNA routinely cluster with one another or closely interact with transcriptional hubs. Cells with EGFR-containing ecDNA have increased EGFR transcriptional output, but transcription per gene copy is similar in ecDNA compared to the endogenous chromosomal locus. These data suggest that it is the increased copy number of oncogene-harbouring ecDNA that primarily drives high levels of oncogene transcription, rather than specific interactions of ecDNA with each other or with high concentrations of the transcriptional machinery.

Intramedullary hemorrhage from a thoracolumbar dural arteriovenous fistula.

BACKGROUND CONTEXT: Spinal dural arteriovenous fistulas (AVFs) are acquired lesions presenting typically with neurologic deficits secondary to chronic congestive myelopathy. The low-flow and low-volume nature of these lesions makes hemorrhage very unlikely, and intramedullary hemorrhage caused by thoracolumbar dural AVFs is exceedingly rare. PURPOSE: The purpose of this study was to report a case of intramedullary hemorrhage caused by a thoracolumbar dural AVF. STUDY DESIGN/SETTING: The study design included a case report and review of literature. METHODS: A case of intramedullary hemorrhage from a thoracolumbar dural AVF was reported, and the literature regarding hemorrhagic presentations of dural AVF was reviewed. RESULTS: A 66-year-old woman presented with a sudden onset of abdominal pain, paraplegia, sensory loss below the costal margins, and urinary retention. Magnetic resonance imaging scan showed intramedullary hemorrhage with abnormal flow voids raising suspicion of an intramedullary AV malformation. However, subsequent selective spinal angiography demonstrated a spinal dural AVF fed by the T7 intercostal artery and a varix within the draining vein. Complete obliteration of the dural AVF and the varix was achieved via embolization. As far as we are aware, there are only two other similar cases in the literature. Literature review revealed that presentation of thoracolumbar dural AVFs with hemorrhage is frequently associated with accelerated venous flow and the presence of a venous varix. CONCLUSIONS: Although very unusual, a spinal dural AVF may present with intramedullary hemorrhage, and hemorrhage in such conditions may be associated with an accelerated venous flow and the presence of a venous varix.

Subarachnoid hemorrhage and the female sex: analysis of risk factors, aneurysm characteristics, and outcomes.

OBJECT: The pathophysiology of aneurysmal subarachnoid hemorrhage (aSAH) is unclear. Sex may play a role in the outcome of patients with aSAH. METHODS: The authors retrospectively identified 617 patients with aSAH (April 2005 to February 2010) and analyzed sex differences in risk factors (age, hypertension, smoking, alcohol consumption, and family history), admission-related factors (World Federation of Neurosurgical Societies grade and admission delay), aneurysm characteristics (site, side, location, and multiplicity), and outcomes (treatment modalities [coiling/clipping/both/conservative], complications [vasospasm and hydrocephalus], length of stay, and modified Rankin Scale score at 3 months). RESULTS: The female patients with aSAH were older than the male patients (mean age 56.6 vs 51.9 years, respectively, p < 0.001), and more women than men were ≥ 55 years old (56.2% vs 40.4%, respectively, p < 0.001). Women exhibited higher rates of bilateral (6.8% vs 2.6%, respectively, p < 0.05), multiple (11.5% vs 5.2%, respectively, p < 0.05), and internal carotid artery (ICA) (36.9% vs 17.5%, respectively, p < 0.001) aneurysms and a lower rate of anterior cerebral artery aneurysms (26.3% vs 44.8%, respectively, p < 0.001) than the men, but no side differences were noted. There were no sex differences in risk factors, admission-related factors, or outcome measures. For both sexes, outcomes varied according to aneurysm location, with odds ratios for a poor outcome of 1.62 (95% CI 0.91-2.86, p = 0.1) for middle cerebral artery, 2.41 (95% CI 1.29-4.51, p = 0.01) for ICA, and 2.41 (95% CI 1.29-4.51, p = 0.006) for posterior circulation aneurysms compared with those for anterior cerebral artery aneurysms. The odds ratio for poor outcome (modified Rankin Scale score of 4-6) in women compared with men after adjusting for significant prognostic factors was 0.71 (95% CI 0.45-1.11, p > 0.05). CONCLUSIONS: The overall outcomes after aSAH between women and men are similar.

Modified Lund concept versus cerebral perfusion pressure-targeted therapy: a randomised controlled study in patients with secondary brain ischaemia.

PURPOSE: Secondary brain ischaemia (SBI) usually develops after aneurysmal subarachnoid haemorrhage (SAH) and severe traumatic brain injury (TBI). Current approaches to managing these conditions are based either on intracranial pressure-targeted therapy (ICP-targeted) with cerebral microdialysis (CM) monitoring according to the modified Lund concept or cerebral perfusion pressure-targeted therapy (CPP-targeted). We present a prospective, randomised controlled study comparing relative effectiveness of the two management strategies. METHODS: Sixty comatose operated patients with SBI following aneurysmal SAH and severe TBI were randomised into ICP-targeted therapy with CM monitoring and CPP-targeted therapy groups. Mortality rates in both groups were calculated and tissue biochemical signs of cerebral ischaemia were analysed using CM. Measured CM data were related to outcome (Glasgow Outcome Scale [GOS] score 1, 2 and 3 for poor outcome or GOS score 4 and 5 for good outcome). RESULTS: Patients treated with ICP-targeted therapy with CM monitoring had significantly lower mortality rate as compared with those treated with CPP-targeted therapy (P=0.03). Patients monitored with CM who had poor outcome had lower mean values of glucose and higher mean values of glycerol and lactate/pyruvate ratio as compared with those who had good outcome (glucose: P=0.003; glycerol: P=0.02; lactate/pyruvate ratio: P=0.01). There was no difference in the mortality outcome between aneurysmal SAH and severe TBI in the two groups (P=0.28 for ICP-targeted therapy with CM monitoring, P=0.36 for CPP-targeted therapy). Also, there were no differences in the CM values between patients with aneurysmal SAH and severe TBI who underwent ICP-targeted therapy (glucose: P=0.23; glycerol: P=0.41; lactate/pyruvate ratio: P=0.40). CONCLUSION: The modified Lund concept, directed at bedside real-time monitoring of brain biochemistry by CM showed better results compared to CPP-targeted therapy in the treatment of comatose patients sustaining SBI after aneurysmal SAH and severe TBI.