Isocitrate dehydrogenase gene variants in cancer and their clinical significance.

Human isocitrate dehydrogenase (IDH) genes encode for the IDH1, 2 & 3 isoenzymes which catalyse the formation of 2-oxoglutarate from isocitrate and are essential for normal mammalian metabolism. Although mutations in these genes in cancer were long thought to lead to a 'loss of function', combined genomic and metabolomic studies led to the discovery that a common IDH 1 mutation, present in low-grade glioma and acute myeloid leukaemia (AML), yields a variant (R132H) with a striking change of function leading to the production of (2R)-hydroxyglutarate (2HG) which consequently accumulates in large quantities both within and outside cells. Elevated 2HG is proposed to promote tumorigenesis, although the precise mechanism by which it does this remains uncertain. Inhibitors of R132H IDH1, and other subsequently identified cancer-linked 2HG producing IDH variants, are approved for clinical use in the treatment of chemotherapy-resistant AML, though resistance enabled by additional substitutions has emerged. In this review, we provide a current overview of cancer linked IDH mutations focussing on their distribution in different cancer types, the effects of substitution mutations on enzyme activity, the mode of action of recently developed inhibitors, and their relationship with emerging resistance-mediating double mutations.

High field structural MRI in the management of degenerative cervical myelopathy.

Introduction: This is a narrative overview of the pathophysiology, investigation and management of Degenerative Cervical Myelopathy (DCM). This review article also takes a look ahead to the impact high resolution MRI may have on treatment.Background: DCM is the most common cause of spinal dysfunction and yet it remains poorly understood. It is becoming increasingly common in our ageing population. Disc and facet joint abnormalities, osteophytes, spondylothisthesis and ligamentous hypertrophy all act together to produce spinal canal and neuronal foramina stenosis which in turn causes neural compromise. Its impact on the quality of life of this patient group and the wider economy is vast. Some patients with overt cord compression and MRI signal change in their cervical cord may only have subtle clinical signs whilst others with less striking imaging may be profoundly myelopathic. Who to operate on and when remains a neurosurgical dilemma in this group of patients.Methods: A number of articles with a broad variation in methodology were reviewed and referenced during the production of this paper.Results: This paper is a narrative review. The results presented in all the referenced articles were considered.Conclusion: The process of developing new imaging techniques will give a greater understanding of the causes of the symptoms of DCM and in a wider context facilitate further surgical and medical strategies that are more cost effective and beneficial to patients. The advent of 7T MRI or further optimisation of safer 3T MRI sequences may soon provide this opportunity and the diagnostic gap in spinal cord imaging can begin to close.

Routine radiographs one day after anterior cervical discectomy and fusion are neither necessary nor cost-effective.

OBJECTIVES: Anterior cervical discectomy and fusion (ACDF) is a common operative treatment of compressive pathology of the cervical spinal cord, when caused by one or more degenerated intervertebral discs or related osteophytes. In addition to intra-operative radiographs to confirm spinal level before discectomy and implant position after insertion, traditional practice is to obtain post-operative antero-posterior and lateral plain radiographs (XR) before hospital discharge, despite a paucity of evidence supporting their benefit to patient care. Minimising unnecessary radiation to radiosensitive neck structures is desirable, and furthermore, with increasing financial pressure on healthcare resources, routine investigations should be clinically justified and evidence-based. We aim to compare the utility of routine post-operative cervical spine X-rays following ACDF. METHODS: We compare two groups of consecutive patients undergoing ACDF in a single UK neurosurgical centre. The first group (n = 109) received routine post-operative XR imaging, and the second group (n = 113) received radiographs only when clinically indicated. RESULTS: There were no differences in post-operative complication rates (4.6% vs. 5.3%), or requirement for further imaging or of further operative intervention (1.8% vs. 0.9%). The group that did not have routine post-operative radiographs had a significantly shorter stay in hospital (median two days vs. three days). There were no patients in either group where post-operative XR changed clinical management and mandated revision surgery or further imaging. All cases requiring surgery or further imaging were identified by clinical deterioration. CONCLUSIONS: We suggest that the practice of obtaining routine radiographs of the cervical spine following ACDF should be abandoned, unless there is a clear clinical indication.

Multi-modal MRI in normal pressure hydrocephalus identifies pre-operative haemodynamic and diffusion coefficient changes in normal appearing white matter correlating with surgical outcome.

Magnetic resonance techniques were used to investigate haemodynamic abnormalities and their consequences in normal pressure hydrocephalus (NPH) and to assess changes in these parameters following surgery. Eleven patients with NPH were studied pre- and post-operatively using perfusion and diffusion weighted imaging and compared with ten age-matched controls. Pre-operative periventricular relative cerebral blood volume (rCBV) was reduced in patients (0.76+/-0.11) compared with control (1.16+/-0.16, P<0.01). There was no difference between outcome groups and no change in haemodynamic parameters following surgery. The periventricular apparent diffusion coefficient (ADC) was elevated in the poor outcome group (1.67+/-0.3 x 10(-3) mm(2) s(-1)) compared with both controls (1.04+/-0.4 x 10(-3) mm(2) s(-1), P<0.05) and the good outcome group (0.99+/-0.3 x 10(-3) mm(2) s(-1), P<0.05) despite appearing normal on conventional imaging. In white matter hyperintensities (WMH), rCBV was reduced (0.70+/-0.12 vs. 1.00+/-0.10, P<0.01), and the ADC was increased (1.98+/-0.6 vs. 1.04+/-0.4 x 10(-3) mm(2) s(-1), P<0.05) compared with the same anatomical location in controls. As low rCBV and high ADC is characteristic of chronic infarction, the findings in WMH regions suggest they are irreversibly damaged. Normal appearing periventricular tissue rCBV was reduced, implying that significant haemodynamic consequences contribute to symptoms in NPH. The elevated pre-operative ADC of the same region, was correlated with poor outcome, and may, therefore, be useful in selecting patients for surgery.

Platelets play an essential role in the aetiology of cerebral vasospasm after subarachnoid haemorrhage.

Platelets have long been implicated in the aetiology of cerebral vasospasm (CV) after subarachnoid haemorrhage (SAH). It was noticed that vasospastic CSF (CSF(V)) could be formed in vitro by the mixing of control blood (with platelets) and non-SAH CSF. We also propose a hypothesis for the aetiology of CV after SAH based on this and previous research. This study also aims to determine which blood fraction is responsible for the stimulation of O(2) consumption and vasospasm of blood vessels. Control blood was separated into various fractions and mixed with non-SAH CSF. The activity of the resulting mixture and the blood fraction alone were assessed. Only the fractions containing platelets mixed with CSF showed vasoactivity. These data suggest that platelets plus some component in the CSF produce vasoactive factors with actions similar to CSF(V). This study may help to elucidate the aetiology of CV after SAH.