Trevor S. Smith

Cerebral blood volume, genotype and chemosensitivity in oligodendroglial tumours.

IntroductionThe biological factors responsible for differential chemoresponsiveness in oligodendroglial tumours with or without the −1p/−19q genotype are unknown, but tumour vascularity may contribute. We aimed to determine whether dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) could distinguish molecular subtypes of oligodendroglial tumour, and examined the relationship between relative cerebral blood volume (rCBV) and outcome following procarbazine, lomustine and vincristine (PCV) chemotherapy.MethodsPretherapy rCBV was calculated and inter- and intraobserver variability assessed. Allelic imbalance in 1p36, 19q13, 17p13, 10p12–15, and 10q22–26 and p53 mutation (exons 5–8) were determined. rCBV was compared with genotype and clinicopathological characteristics (n=37) and outcome following PCV chemotherapy (n=33).Results1p/19q loss was seen in 6/9 grade II oligodendrogliomas, 6/14 grade II oligoastrocytomas, 4/4 grade III oligodendrogliomas, and 3/10 grade III oligoastrocytomas. rCBV measurements had good inter- and intraobserver variability, but did not distinguish histology subtype or grade. Tumours with 1p/19q loss had higher rCBV values (Student’s t-test P=0.001). Receiver operating characteristic analysis revealed a cut-off of 1.59 for identifying genotype (sensitivity 92%, specificity 76%). Tumours with high and low rCBV showed response to chemotherapy. The −1p/−19q genotype, but not rCBV, was strongly associated with response, progression-free and overall survival following PCV chemotherapy. Tumours with high rCBV and intact 1p/19q were associated with shorter progression-free and overall patient survival than those with intact 1p/19q and low rCBV or high rCBV and 1p/19q loss.ConclusionrCBV identifies oligodendroglial tumours with 1p/19q loss, but does not predict chemosensitivity. The prognostic significance of rCBV may differ in oligodendroglial tumours with or without the −1p/−19q genotype.

Molecular pathology and clinical characteristics of oligodendroglial neoplasms

To evaluate the role of molecular genetics in the routine clinic, we investigated allelic imbalance at 1p36, 19q13, 17p13, 10p12‐15, and 10q22‐26 and p53 mutation in 100 oligodendroglial neoplasms diagnosed at a single treatment center between 2000 and 2003. The ‐1p/‐19q genotype, seen in 64, 34, 77, and 30% of OII, OAII, OIII, and OAIII respectively, was inversely related to p53 mutation and 17p13 loss. Genotype was unrelated to tumor location and could not distinguish high‐grade tumors that presented de novo from those that progressed from a previous lower grade malignancy. Presentation with seizures was more common in cases with the ‐1p/‐19q genotype, and these remained stable for longer before treatment. In longitudinal samples, 74% retained their initial histological differentiation, whereas 29% showed new genetic alterations, the ‐1p/‐19q genotype being acquired in three cases. Loss of 1p36 and 19q13, 17p13, chromosome 10, and p53 mutation were significantly associated with survival from presentation in Kaplan–Meier analysis (p < 0.01), and loss of 1p36 and 19q13 and loss of 17p13 retained significance in multivariate analysis. In this recently diagnosed unselected series, clinical differences in tumors with and without the ‐1p/‐19q genotype support a genetic approach to aid diagnosis and prognostication for oligodendroglial neoplasms. Ann Neurol 2005;57:855–865

Advanced MRI in the management of adult gliomas

Gliomas are a heterogeneous group that account for ∼86% of primary brain neoplasms, and include astrocytic and oligodendroglial tumours, as well as a variety of less common histopathological subtypes. Magnetic resonance imaging has become the accepted mode of imaging for the clinical management of these tumours. MRI features bear close resemblance to the histopathology grading and prognosis of these tumours. Currently, conventional MRI is used to aid diagnosis, plan neurosurgical approaches, and monitor response to therapy and disease progression. More recent developments in the field of MRI include MR spectroscopy, perfusion MRI, diffusion-weighted imaging, intraoperative MRI and functional MRI. These newer techniques have been adopted with varying success in the management of adult gliomas. This review focuses on the application of advanced MR imaging in the clinical management of adult gliomas.

Apparent diffusion coefficients in oligodendroglial tumors characterized by genotype.

To investigate whether oligodendroglial tumors with or without 1p/19q loss differ in their diffusion‐weighted imaging characteristics. Oligodendroglial tumors with or without 1p/19q loss differ in their therapeutic responsiveness and prognosis, and recent reports also suggest that these tumors may differ in their magnetic resonance characteristics and blood volume.

Correlation of Molecular Genetics with Molecular and Morphological Imaging in Gliomas with an Oligodendroglial Component

Purpose: Since the recognition that oligodendrogliomas may be chemosensitive, their diagnosis and clinical management has become highly controversial. Histopathology diagnosis remains challenging and new tools such as molecular genetics or molecular imaging require evaluation. Experimental Design: In a single-center, population-based prospective study, allelic imbalance in chromosomes 1p36, 19q13, 17p13, 10p12–15, and 10q22–26 has been investigated in 19 oligodendroglioma WHO grade 2 (OII), 20 oligoastrocytoma WHO grade 2 (OAII), 8 oligodendroglioma WHO grade 3 (OIII), and 12 oligoastrocytoma WHO grade 3 (OAIII), and compared with pretherapy histopathology, computed tomography and/or magnetic resonance (CT and/or MR), [fluorine-18]fluoro-2-deoxyglucose (18F-FDG), and thallium-201 single-photon emission computed tomography (201Tl SPECT). Results: In 50 cases, 18F-FDG uptake correlated with 201Tl uptake; however, 8 cases had increased 201Tl uptake but were hypometabolic for 18F-FDG, and 1 case was hypermetabolic with normal 201Tl uptake. Sixteen cases enhanced on CT/MR but failed to show 201Tl uptake; and 2 low-grade non-enhancing oligodendrogliomas had increased 201Tl uptake. Increased metabolism was more likely in high-grade cases, with 201Tl uptake more strongly correlated with grade than was 18F-FDG uptake. Tumors with 1p/19q loss were more likely to show increased 201Tl uptake and, to a lesser degree, increased 18F-FDG uptake than those without these losses. Elevated metabolism in 28% of low-grade tumors was significantly more common in tumors with 1p/19q loss, and increased uptake of both 18F-FDG and 201Tl in low-grade cases was found only in those with 1p/19q loss. Conclusions: In this study, dissociation of uptake of contrast agents and radiotracers suggests independent deregulation of the blood–brain barrier breakdown and metabolism during disease progression of oligodendroglial neoplasms, and the association of elevated metabolism with 1p/19q loss, particularly in low-grade tumors, may have implications for clinical management.

MRS of oligodendroglial tumors Correlation with histopathology and genetic subtypes

Background: Oligodendroglial neoplasms with combined loss of chromosomes 1p and 19q may have a good prognosis and respond to procarbazine-lomustine (CCNU)-vincristine (PCV) chemotherapy. Objective: To determine whether single voxel magnetic resonance spectroscopy (SV-MRS) obtained through routine clinical practice distinguishes between histopathologic and genetic subtypes of oligodendroglial tumors. Methods: Forty-eight patients with oligodendroglial tumors (19 oligodendrogliomas and 29 oligoastrocytomas) underwent molecular genetic analysis to determine allelic imbalance in chromosomes 1p36 and 19q13. SV-MRS was obtained pretherapy to determine tumor metabolite ratios. Results: Grade III oligodendroglial tumors had higher choline (Mann–Whitney; p = 0.002), methyl lipid (Mann–Whitney; p = 0.002), and combined methylene lipid and lactate ratios (Mann–Whitney; p < 0.001) than grade II tumors. Lactate did not distinguish between tumor types (Fisher exact test; p = 0.342) or grade (Fisher exact test; p = 0.452). There were no significant associations when tumors were analyzed according to histopathology or genetic subtypes. Conclusion: As a noninvasive diagnostic tool used in routine clinical practice, SV-MRS has the potential benefit of determining oligodendroglial tumor grade but not subtypes classified by histopathology or molecular genetics. MRS may be useful for determining the timing of therapy but is unlikely to predict chemosensitivity.

Clinical use of genotype to predict chemosensitivity in oligodendroglial tumors

Background: The −1p/−19q genotype has been associated with prolonged survival and chemosensitivity in oligodendroglial neoplasms, but the predictive and prognostic significance of genotype in the routine clinic is not established. Methods: The authors investigated allelic imbalance in 1p36, 19q13, 17p13, 10p12-15, and 10q22-26 and p53 mutation in a cohort representative of clinical practice at their center (50 primary, 26 recurrent cases) given PCV chemotherapy between 2000 and 2003 and compared with response and outcome following PCV. Results: 1p/19q loss was found in 12/19 OII, 10/23 OAII, 11/13 OIII, and 6/21 OAIII. Response, seen in 92% with 1p/19q loss, was associated with the −1p/−19q genotype (Fisher exact: p < 0.001) regardless of WHO grade or whether primary or recurrent. 1p/19q loss was an independent prognostic factor associated with longer progression-free (PFS) and overall survival (OS) (Cox regression: PFS and OS p < 0.001), with greater impact on PFS than OS in primary tumors, and OS at recurrence. 17p13 loss and p53 mutation were associated with poor prognosis in recurrent tumors and chromosome 10 loss was associated with short PFS and OS in primary tumors. Histologic subtype did not influence outcome in tumors of equivalent genotype. Genotype had greater association with response and outcome than conventional clinical factors. A total of 29% with intact 1p/19q and a variety of genetic or clinicopathologic characteristics responded in association with increased PFS and OS. Conclusions: The −1p/−19q genotype predicted response and favorable outcome following PCV chemotherapy corroborating genetic analysis to guide routine clinical management. However, some cases with intact 1p/19q also had clinical benefit.

Vanishing contrast enhancement in malignant glioma after corticosteroid treatment

SummaryMalignant gliomas of the brain typically exhibit on CT or MRI a strong peripheral contrast enhancement area with a variable central zone of necrosis. These tumours are not known to change their radiological appearance and contrast enhancement pattern under systemic steroid treatment – a feature usually associated with primary CNS lymphoma. We report two cases of adult patients with glioblastoma multiforme and atypical hemispherical contrast enhancement initially demonstrated on MRI or CT, which disappeared after dexamethasone administration. At the same time, however, another tumour focus became visible, in both cases localised in the corpus callosum. Histological diagnosis was confirmed by stereotactic biopsy in both cases. This unusual changing pattern of contrast enhancement seems to be associated with multifocal malignant glioma with partial blood-brain barrier disruption modified by dexamethasone, and may present diagnostic difficulties in respect to neuroimaging and selection of target areas for tumour biopsy.

Acute confusional state following a whiplash injury: a case of multiple cervical artery dissection.

Sirs: Cervical arterial dissection is an important cause of stroke in young people and has been described as a consequence of both trivial and severe neck trauma. Whiplash neck injuries are a common sequel of road traffic accidents and may be defined as a musculo-ligamentous sprain resulting from forced acceleration/ deceleration flexion/extension neck injury [6]. Single vessel cervical arterial dissection has been reported as a rare consequence of whiplash [1]. We describe the first case to our knowledge, of cervical arterial dissection involving four vessels (both carotid and both vertebral arteries) arising as a consequence of otherwise uncomplicated whiplash neck injury. A 33-year-old woman was involved in a high-speed motor vehicle collision. She sustained whiplash neck injuries and a minor head injury. Four days after the accident she presented to the emergency department (ED) with worsening occipital headaches, vomiting, and an episode of transient dysarthria with left hemiparesis and right-sided limb jerking. She was discharged from the ED without deficit following a normal computerized tomography (CT) of brain. She represented four days later with drowsiness, disorientation, and memory problems. There was no history of fever, rash, visual disturbances, recent foreign travel, vaccination or recreational drug abuse. There were no risk factors for stroke. She was of normal built and there was no history or clinical markers of marfan’s syndrome in the patient or the family. On physical examination she was obtunded with a Glasgow Coma Scale fluctuating between 11 and 9/15. There was an up-gaze palsy and left facial and left limb weakness with left extensor plantar response. She was normotensive. Cardio-respiratory and general physical examinations were unremarkable. Full blood count, blood glucose, renal and liver function tests, lipid profile and septic screen were normal. Erythrocyte sedimentation rate was 13 mm at 1 hour and C-reactive protein was mildly raised at 10.3. A full autoantibody screen (including anti-nuclear antibody, double stranded DNA antibody and perinuclear and cytoplasmic anti-neutrophil-cytoplasmic antibody) was negative. She was biochemically euthyroid. An electrocardiogram and chest radiograph were normal. Cerebrospinal fluid cytology and biochemistry were normal and Gram stain negative. Cerebrospinal fluid polymerase chain reaction for Herpes simplex was negative. Magnetic resonance imaging (MRI) of the brain showed an ischemic stroke in the right caudate nucleus and an additional right cerebral peduncle infarct. Carotid Doppler was abnormal with damped common carotid flow and bilateral internal carotid occlusion/critical stenosis; The vertebral artery velocities were not damped. CT angiography confirmed bilateral carotid dissection with right internal carotid artery (ICA) occlusion, and severe left ICA stenosis, and also demonstrated bilateral vertebral artery dissection (Figure 1). Immediate complete MRI studies including MR Angiogram were not possible because of the patients poor clinical state. However the fat suppressed axial T1 weighted MRI of Fig. 1 Reconstruction CT angiogram (sagittal section) obtained 11 days after injury showing bifurcation of left common carotid artery (left arrow head) and narrowed left internal carotid artery lumen( right arrow head) consistent with dissection (‘‘string sign‘‘)

A radiologic “alcohol breathalyzer” test

A 52-year-old man with 3 years of progressive unsteadiness admitted to previous alcohol excess but denied ongoing consumption. Magnetic resonance spectroscopy (MRS) (figure) was performed looking for changes of subclinical hepatic encephalopathy, which was not found. Instead, …