Metabolic adaptations in cancers expressing isocitrate dehydrogenase mutations.

The most frequently mutated metabolic genes in human cancer are those encoding the enzymes isocitrate dehydrogenase 1 (IDH1) and IDH2; these mutations have so far been identified in more than 20 tumor types. Since mutations were first reported in glioma over a decade ago, extensive research has revealed their association with altered cellular processes. Mutations in lead to a change in enzyme function, enabling efficient conversion of 2-oxoglutarate to 2-hydroxyglutarate (2-HG).

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.

Roles of metal ions in the selective inhibition of oncogenic variants of isocitrate dehydrogenase 1.

Cancer linked isocitrate dehydrogenase (IDH) 1 variants, notably R132H IDH1, manifest a 'gain-of-function' to reduce 2-oxoglutarate to 2-hydroxyglutarate. High-throughput screens have enabled clinically useful R132H IDH1 inhibitors, mostly allosteric binders at the dimer interface. We report investigations on roles of divalent metal ions in IDH substrate and inhibitor binding that rationalise this observation.

Isocitrate dehydrogenase variants in cancer - Cellular consequences and therapeutic opportunities.

Abnormal metabolism is common in cancer cells and often correlates with mutations in genes encoding for enzymes involved in small-molecule metabolism. Isocitrate dehydrogenase 1 (IDH1) is the most frequently mutated metabolic gene in cancer. Cancer-associated substitutions in IDH1 and IDH2 impair wild-type production of 2-oxoglutarate and reduced nicotinamide adenine dinucleotide phosphate (NADPH) from isocitrate and oxidised nicotinamide adenine dinucleotide phosphate (NADP ), and substantially promote the IDH variant catalysed conversion of 2-oxoglutarate to d-2-hydroxyglutarate (d-2HG).

Anion-exchange chromatography mass spectrometry provides extensive coverage of primary metabolic pathways revealing altered metabolism in IDH1 mutant cells.

Altered central carbon metabolism is a hallmark of many diseases including diabetes, obesity, heart disease and cancer. Identifying metabolic changes will open opportunities for better understanding aetiological processes and identifying new diagnostic, prognostic, and therapeutic targets. Comprehensive and robust analysis of primary metabolic pathways in cells, tissues and bio-fluids, remains technically challenging.

MRS and DTI evidence of progressive posterior cingulate cortex and corpus callosum injury in the hyper-acute phase after Traumatic Brain Injury.

The posterior cingulate cortex (PCC) and corpus callosum (CC) are susceptible to trauma, but injury often evades detection. PCC Metabolic disruption may predict CC white matter tract injury and the secondary cascade responsible for progression. While the time frame for the secondary cascade remains unclear in humans, the first 24 h (hyper-acute phase) are crucial for life-saving interventions.

A Noninvasive Comparison Study between Human Gliomas with IDH1 and IDH2 Mutations by MR Spectroscopy.

The oncogenes that are expressed in gliomas reprogram particular pathways of glucose, amino acids, and fatty acid metabolism. Mutations in isocitrate dehydrogenase genes (IDH1/2) in diffuse gliomas are associated with abnormally high levels of 2-hydroxyglutarate (2-HG) levels. The aim of this study was to determine whether metabolic reprogramming associated with IDH mutant gliomas leads to additional ¹H MRS-detectable differences between IDH1 and IDH2 mutations, and to identify metabolites correlated with 2-HG.

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

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. DCM is the most common cause of spinal dysfunction and yet it remains poorly understood.

A comparison of 2-hydroxyglutarate detection at 3 and 7 T with long-TE semi-LASER.

Abnormally high levels of the 'oncometabolite' 2-hydroxyglutarate (2-HG) occur in many grade II and III gliomas, and correlate with mutations in the genes of isocitrate dehydrogenase (IDH) isoforms. In vivo measurement of 2-HG in patients, using magnetic resonance spectroscopy (MRS), has largely been carried out at 3 T, yet signal overlap continues to pose a challenge for 2-HG detection. To combat this, several groups have proposed MRS methods at ultra-high field (≥7 T) where theoretical increases in signal-to-noise ratio and spectral resolution could improve 2-HG detection.

Early detection of cerebral microbleeds following traumatic brain injury using MRI in the hyper-acute phase.

Background: Traumatic brain injury (TBI) is a leading cause of death and disability in people under 45. Advanced imaging techniques to identify injury and classify severity in the first few hours and days following trauma could improve patient stratification and aid clinical decision making. Traumatic cerebral microbleeds (TCMBs), detectable on magnetic resonance susceptibility weighted imaging (SWI), can be used as markers of long-term clinical outcome.

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.

Improved localisation for 2-hydroxyglutarate detection at 3T using long-TE semi-LASER.

2-hydroxyglutarate (2-HG) has emerged as a biomarker of tumour cell IDH mutations that may enable the differential diagnosis of glioma patients. At 3 Tesla, detection of 2-HG with magnetic resonance spectroscopy is challenging because of metabolite signal overlap and a spectral pattern modulated by slice selection and chemical shift displacement. Using density matrix simulations and phantom experiments, an optimised semi-LASER scheme (TE = 110 ms) improves localisation of the 2-HG spin system considerably compared to an existing PRESS sequence.

Optimising treatment strategies in spinal ependymoma based on 20years of experience at a single centre.

Spinal ependymomas are rare tumours, with total resection favoured where possible. Several case series assessing the outcome following neurosurgical treatment for spinal ependymoma advocate the usage of adjuvant radiotherapy in cases of subtotal resection, or in unencapsulated tumours. We assessed the outcome of 61 consecutive cases of spinal ependymoma in a single centre over a 20year period using a variety of outcome measures.

Noninvasive Quantification of 2-Hydroxyglutarate in Human Gliomas with IDH1 and IDH2 Mutations.

Mutations in the isocitrate dehydrogenase genes (IDH1/2) occur often in diffuse gliomas, where they are associated with abnormal accumulation of the oncometabolite 2-hydroxyglutarate (2-HG). Monitoring 2-HG levels could provide prognostic information in this disease, but detection strategies that are noninvasive and sufficiently quantitative have yet to be developed. In this study, we address this need by presenting a proton magnetic resonance spectroscopy ((1)H-MRS) acquisition scheme that uses an ultrahigh magnetic field (≥ 7T) capable of noninvasively detecting 2-HG with quantitative measurements sufficient to differentiate mutant cytosolic IDH1 and mitochondrial IDH2 in human brain tumors.

Idiopathic normal pressure hydrocephalus: an important differential diagnosis.

Idiopathic normal pressure hydrocephalus, an uncommon but important differential diagnosis for ataxia, cognitive impairment and urinary incontinence, is surgically treatable, unlike many of its differential diagnoses. This article discusses its assessment, investigation and therapeutic interventions.

Anterior cervical discectomy plus intervertebral polyetheretherketone cage fusion over three and four levels without plating is safe and effective long-term.

Anterior cervical discectomy and fusion (ACDF) is an established treatment for single-level cervical spondylotic myelopathy and radiculopathy, yet its stand-alone use for multi-level disease of the subaxial cervical spine remains controversial. We report a prospectively studied case series of 30 patients receiving polyetheretherketone (PEEK) cage fusion over three and four cervical levels without anterior plating. Seven (23.

Acute foramen magnum syndrome from acquired Chiari I malformation relieved by ventriculoperitoneal shunt revision.

An adult case of shunt malfunction presenting with acute quadriparesis as a manifestation of foramen magnum syndrome with acquired Chiari type I malformation is described in this study. The corticospinal function was restored after shunt revision. MRI showing considerable ascent of cerebellar tonsils after surgery is shown.

La maladie de Grisel treated by combined C1-2 transarticular and C1 lateral mass screw fixation.

The authors describe a novel posterior approach to atlantoaxial stabilization combining C1-2 transarticular and C1 lateral mass screws with vertical connecting rods to create a strong construct with four-point fixation. They present here a case of atlanto-axial instability secondary to infection, Grisel's syndrome, necessitating instrumented stabilization after a period of close clinical and radiological observation following the initial cervical decompression and evacuation of retropharyngeal and epidural abscesses.

Acute vasospasm following transcallosal resection of a xanthogranulomatous colloid cyst of the 3rd ventricle.

We present the first case of a 57 year old man who developed severe, acute vasospasm following transcallosal resection of an unusual, xanthogranulomatous colloid cyst. The 16 year history of growth of this cyst may have resulted in its unusual pathology, and the subsequent vasospastic reaction to its excision. We discuss the potential pathological relationship between the inflammatory nature of the cyst, chemical meningitis and vasospasm, and what this implies about vasospasm in general.

Posterior occipitocervical instrumented fusion for dropped head syndrome after deep brain stimulation.

We describe dropped head syndrome in a patient with Parkinson's disease receiving subthalamic nucleus deep brain stimulation (DBS). Posterior occipitocervical instrumented fusion after transarticular screw fixation of an odontoid fracture is shown and its rationale explained. Pedunculopontine nucleus DBS as treatment for fall-predominant Parkinson's disease, and globus pallidus interna DBS for dystonia-predominant Parkinson's disease, are discussed.

A resistant case of spontaneous intracranial hypotension.

The case of a 39-year-old with intractable spontaneous intracranial hypotension (SIH) is presented. He developed bilateral and symptomatic subdural hygromas that were drained in response to clinical deterioration, but proved ineffective. An initial MRI of the lumbar region suggested a lumbosacral CSF leak, but he failed to respond to local blood patching.

Recurrent dural based cystic cerebellar haemangioblastoma in a patient with von Hippel-Lindau disease.

Surgical excision of cerebellar haemangioblastomas, once they become Symptomatic, is the standard treatment in patients with von Hippel-Lindau disease. This case report describes a von Hippel-Lindau disease patient with a rare recurrent symptomatic dural based cystic haemangioblastoma.

Lateral medullary syndrome caused by penetrating head injury.

Herein, we report a rare case of a patient surviving penetrating trauma to the brainstem. Low velocity penetrating head injuries may be occult and are associated with a high incidence of vascular injury.