DNA methylation-based profiling for paediatric CNS tumour diagnosis and treatment: a population-based study.

BACKGROUND: Marked variation exists in the use of genomic data in tumour diagnosis, and optimal integration with conventional diagnostic technology remains uncertain despite several studies reporting improved diagnostic accuracy, selection for targeted treatments, and stratification for trials. Our aim was to assess the added value of molecular profiling in routine clinical practice and the impact on conventional and experimental treatments. METHODS: This population-based study assessed the diagnostic and clinical use of DNA methylation-based profiling in childhood CNS tumours using two large national cohorts in the UK. In the diagnostic cohort-which included routinely diagnosed CNS tumours between Sept 1, 2016, and Sept 1, 2018-we assessed how the methylation profile altered or refined diagnosis in routine clinical practice and estimated how this would affect standard patient management. For the archival cohort of diagnostically difficult cases, we established how many cases could be solved using modern standard pathology, how many could only be solved using the methylation profile, and how many remained unsolvable. FINDINGS: Of 484 patients younger than 20 years with CNS tumours, 306 had DNA methylation arrays requested by the neuropathologist and were included in the diagnostic cohort. Molecular profiling added a unique contribution to clinical diagnosis in 107 (35%; 95% CI 30-40) of 306 cases in routine diagnostic practice-providing additional molecular subtyping data in 99 cases, amended the final diagnosis in five cases, and making potentially significant predictions in three cases. We estimated that it could change conventional management in 11 (4%; 95% CI 2-6) of 306 patients. Among 195 historically difficult-to-diagnose tumours in the archival cohort, 99 (51%) could be diagnosed using standard methods, with the addition of methylation profiling solving a further 34 (17%) cases. The remaining 62 (32%) cases were unresolved despite specialist pathology and methylation profiling. INTERPRETATION: Together, these data provide estimates of the impact that could be expected from routine implementation of genomic profiling into clinical practice, and indicate limitations where additional techniques will be required. We conclude that DNA methylation arrays are a useful diagnostic adjunct for childhood CNS tumours. FUNDING: The Brain Tumour Charity, Children with Cancer UK, Great Ormond Street Hospital Children's Charity, Olivia Hodson Cancer Fund, Cancer Research UK, and the National Institute of Health Research.

The role of the renin-angiotensin system in malignant vascular injury affecting the systemic and cerebral circulations.

Malignant hypertension is a rare but serious syndrome complicating 1% of essential hypertension and causing neurological, renal and cardiac complications. Despite improved anti-hypertensive medication, the incidence of this condition fails to decline. In the first part of this review, we discuss transgenic rat models of malignant hypertension, generated by over-expressing renin, to illustrate the role of the renin-angiotensin system in the development of systemic hypertensive vascular remodelling and hypertension. In the second part, we focus on the cerebrovascular response to hypertension and discuss new data using a conditional, transgenic model of malignant hypertension, the inducible hypertensive rat (IHR). Cerebral infarction associates strongly with hypertension in man and the mechanisms by which hypertension predisposes to different types of stroke remains poorly understood. Rats have similar cerebrovascular anatomy and structure to humans and as such provide a good experimental tool. To date, such models lack controllability and blood-pressure matched controls. Using the IHR, we have manipulated dietary salt and water intake to generate a novel, controllable stroke phenotype. Hypertensive small-vessel stroke develops over a predictable time period, permitting the study of developing cerebrovascular lesions. Systemic end-organ injury and hypertension are not affected. Dissociation of the systemic and central vascular responses in this way, will allow for comparative study of animals with equivalent hypertension, genetic background and systemic features of hypertension with or without stroke.

Hypertensive cerebral small vessel disease and stroke.

Lacunar infarcts and "hypertensive" primary intracerebral hemorrhages, collectively often referred to as hypertensive small vessel strokes, constitute about one third of all strokes. However, despite their public health importance, their etiopathogenesis remains ill-understood. Like all strokes, they are a heterogeneous entity, but the autopsy pathology evidence suggests that the majority are caused by a limited number of cerebral small vessel lesions. Small vessel atherosclerosis is causally implicated in a proportion of lacunar infarcts, although modern concepts of atherosclerotic plaque biology and natural history have yet to be applied to small cerebral vessels. A lesion characterized in its acute form by fibrinoid necrosis appears to be important in causing both lacunar infarcts and primary intracerebral bleeds. Advances in molecular genetics may prove instrumental in understanding the cause of this lesion and therefore in designing its targeted prevention.

Apolipoprotein E (APOE) and lipoprotein lipase (LPL) gene variants and carotid atherosclerotic lesions in the oldest old: a population-based autopsy study.

We investigated the association between histologically defined atherosclerotic lesions in the carotid arteries and the genetic variants of APOE and LPL in a population-based sample of Finns aged 85 or over. Post-mortem analysis of carotid arteries was performed in 240 subjects. Atherosclerotic lesions were categorized according to the modified American Heart Association criteria, and classified into four different categories: pathological intimal thickening (PIT), fibrous cap atheromas (FCA), calcified lesions (CL), and atherosclerotic burden (AB) (a combination of the other three categories). APOE epsilon4 genetic variant was associated with PIT (p=0.018) and AB (p=0.006) in the carotid arteries, and its effect was independent of the serum lipid levels. The genetic variant LPL Ser447Ter was protective against FCA (p=0.031) and AB (p=0.012), while APOE epsilon2 was protective against FCA (p=0.035). Our results suggest that the APOE epsilon4, epsilon2 and LPL Ser447Ter variants may have different roles in the atherosclerotic process and their effects are seen even in the oldest old population.

Tuberculous cerebrovascular disease: a review.

Cerebrovascular complications of tuberculous meningitis are common, and may represent its most serious legacy. They present in clinically diverse ways, and continue to develop during the initial stages of treatment. Magnetic resonance imaging is the imaging modality of choice in detecting brain infarcts, typically revealing multiple or bilateral lesions in the territories of the middle cerebral artery perforating vessels. Vessel pathology appears to be a consequence of its immersion in the local inflammatory exudate. Infiltrative, proliferative and necrotising vessel pathologies have been described, but the relative contributions of each and of luminal thrombosis to brain damage remain unclear. There is some evidence that vasospasm may mediate strokes early in the course of the disease and proliferative intimal disease later strokes. Anti-tuberculous chemotherapy appears to be relatively ineffective in preventing vascular complications, perhaps suggesting an immune mechanism. However, a preventive role for corticosteroids remains to be proven. Study of the molecular pathogenesis of TBM vasculopathy is in its infancy. This review focuses in particular on pathogenetic aspects of tuberculous cerebrovascular disease, with a view to its future targeted prevention.

CNS lupus: a study of 41 patients.

BACKGROUND: CNS lupus is a serious but potentially treatable illness, which, though long recognized, may still present very difficult diagnostic challenges. We believed that further detailed study of patients with neuropsychiatric lupus would yield clinical information of practical value in improving both recognition and management of this difficult illness. METHODS: A retrospective case analysis of 41 patients with CNS systemic lupus erythematosus (CNS-SLE) was performed largely in the southwest of England and South Wales, covering the period 1990 to 2002. RESULTS: We found that primary neurologic presentation of SLE was not rare (10/41 patients), and there was an unexpected emergence of movement disorders (particularly parkinsonism and myoclonus) early in the disease course (4/10 patients). These showed a good response to immunosuppressants, but not to standard dopaminergic therapy. Typically, the erythrocyte sedimentation rate (ESR) or plasma viscosity was elevated during neurologic episodes while C-reactive protein levels were normal, and lupus-related serum antibody tests usually supportive. But, significantly, neither a normal ESR nor negative serology excluded CNS lupus. MR brain imaging is more commonly abnormal in patients with focal neurologic deficits and normal or shows wholly nonspecific change with more diffuse manifestations (cognitive decline, epilepsy). Abnormal CSF correlated significantly with poorer outcome. At the end of the period of study, 54% had no more than minor functional disability, the remainder having a severe or fatal outcome. CONCLUSIONS: Our observations, particularly the emergence of non-choreic movement disorders, the blood, serum, and imaging findings, and the prognostic importance of CSF abnormalities, should help improve both the recognition of CNS systemic lupus erythematosus, perhaps particularly in elderly individuals, and its management.

Tuberculous encephalopathy: a reappraisal.

Forty years ago Dastur and Udani described a form of diffuse cerebral damage in tuberculosis, which they called tuberculous encephalopathy. Their pathological and clinical observations led them to propose an immune pathogenesis. Although there have been no convincing independently reported series, the entity is now established in the tuberculosis literature. We review the literature on tuberculous encephalopathy, and suggest alternative aetiopathogenetic explanations for the appearances of the brain in these cases. We propose that tuberculosis is one of many infections which may be associated with a range of immune, drug-related, hypoxic-ischaemic and toxic diffuse brain pathologies.