Kal Natarajan

Identification and characterisation of childhood cerebellar tumours by in vivo proton MRS.

1H MRS has great potential for the clinical investigation of childhood brain tumours, but the low incidence in, and difficulties of performing trials on, children have hampered progress in this area. Most studies have used a long‐TE, thus limiting the metabolite information obtained, and multivariate analysis has been largely unexplored. Thirty‐five children with untreated cerebellar tumours (18 medulloblastomas, 12 pilocytic astrocytomas and five ependymomas) were investigated using a single‐voxel short‐TE PRESS sequence on a 1.5 T scanner. Spectra were analysed using LCModelTM to yield metabolite profiles, and key metabolite assignments were verified by comparison with high‐resolution magic‐angle‐spinning NMR of representative tumour biopsy samples. In addition to univariate metabolite comparisons, the use of multivariate classifiers was investigated. Principal component analysis was used for dimension reduction, and linear discriminant analysis was used for variable selection and classification. A bootstrap cross‐validation method suitable for estimating the true performance of classifiers in small datasets was used. The discriminant function coefficients were stable and showed that medulloblastomas were characterised by high taurine, phosphocholine and glutamate and low glutamine, astrocytomas were distinguished by low creatine and high N‐acetylaspartate, and ependymomas were differentiated by high myo‐inositol and glycerophosphocholine. The same metabolite features were seen in NMR spectra of ex vivo samples. Successful classification was achieved for glial‐cell (astrocytoma + ependymoma) versus non‐glial‐cell (medulloblastoma) tumours, with a bootstrap 0.632 + error, eB.632+, of 5.3%. For astrocytoma vs medulloblastoma and astrocytoma vs medulloblastoma vs ependymoma classification, the eB.632+ was 6.9% and 7.1%, respectively. The study showed that 1H MRS detects key differences in the metabolite profiles for the main types of childhood cerebellar tumours and that discriminant analysis of metabolite profiles is a promising tool for classification. The findings warrant confirmation by larger multi‐centre studies. Copyright

Non-invasive detection of glycine as a biomarker of malignancy in childhood brain tumours usingin-vivo1H MRS at 1.5 Tesla confirmed byex-vivohigh-resolution magic-angle spinning NMR

Management of brain tumours in children would benefit from improved non‐invasive diagnosis, characterisation and prognostic biomarkers. Metabolite profiles derived from in‐vivo MRS have been shown to provide such information. Studies indicate that using optimum a priori information on metabolite contents in the construction of linear combination (LC) models of MR spectra leads to improved metabolite profile estimation. Glycine (Gly) is usually neglected in such models due to strong overlap with myo‐inositol (mI) and a low concentration in normal brain. However, biological studies indicate that Gly is abundant in high‐grade brain tumours. This study aimed to investigate the quantitation of Gly in paediatric brain tumours using MRS analysed by LCModel™, and its potential as a non‐invasive biomarker of malignancy. Single‐voxel MRS was performed using PRESS (TR 1500 ms, TE 30 ms/135 ms) on a 1.5 T scanner. Forty‐seven cases (18 high grade (HG), 17 low grade (LG), 12 ungraded) were retrospectively selected if both short‐TE and long‐TE MRS (n = 33) or short‐TE MRS and high‐resolution magic‐angle spinning (HRMAS) of matched surgical samples (n = 15) were available. The inclusion of Gly in LCModel™ analyses led to significantly reduced fit residues for both short‐TE and long‐TE MRS (p < 0.05). The Gly concentrations estimated from short‐TE MRS were significantly correlated with the long‐TE values (R = 0.91, p < 0.001). The Gly concentration estimated by LCModel™ was significantly higher in HG versus LG tumours for both short‐TE (p < 1e‐6) and long‐TE (p = 0.003) MRS. This was consistent with the HRMAS results, which showed a significantly higher normalised Gly concentration in HG tumours (p < 0.05) and a significant correlation with the normalised Gly concentration measured from short‐TE in‐vivo MRS (p < 0.05). This study suggests that glycine can be reliably detected in paediatric brain tumours using in‐vivo MRS on standard clinical scanners and that it is a promising biomarker of tumour aggressiveness. Copyright

Accurate classification of childhood brain tumours by in vivo 1H MRS – A multi-centre study

AIMS To evaluate the accuracy of single-voxel Magnetic Resonance Spectroscopy ((1)H MRS) as a non-invasive diagnostic aid for paediatric brain tumours in a multi-national study. Our hypotheses are (1) that automated classification based on (1)H MRS provides an accurate non-invasive diagnosis in multi-centre datasets and (2) using a protocol which increases the metabolite information improves the diagnostic accuracy. METHODS Seventy-eight patients under 16 years old with histologically proven brain tumours from 10 international centres were investigated. Discrimination of 29 medulloblastomas, 11 ependymomas and 38 pilocytic astrocytomas (PILOAs) was evaluated. Single-voxel MRS was undertaken prior to diagnosis (1.5 T Point-Resolved Spectroscopy (PRESS), Proton Brain Exam (PROBE) or Stimulated Echo Acquisition Mode (STEAM), echo time (TE) 20-32 ms and 135-136 ms). MRS data were processed using two strategies, determination of metabolite concentrations using TARQUIN software and automatic feature extraction with Peak Integration (PI). Linear Discriminant Analysis (LDA) was applied to this data to produce diagnostic classifiers. An evaluation of the diagnostic accuracy was performed based on resampling to measure the Balanced Accuracy Rate (BAR). RESULTS The accuracy of the diagnostic classifiers for discriminating the three tumour types was found to be high (BAR 0.98) when a combination of TE was used. The combination of both TEs significantly improved the classification performance (p<0.01, Tukeys test) compared with the use of one TE alone. Other tumour types were classified accurately as glial or primitive neuroectodermal (BAR 1.00). CONCLUSION (1)H MRS has excellent accuracy for the non-invasive diagnosis of common childhood brain tumours particularly if the metabolite information is maximised and should become part of routine clinical assessment for these children.

Magnetic resonance spectroscopy metabolite profiles predict survival in paediatric brain tumours

Background Brain tumours cause the highest mortality and morbidity rate of all childhood tumour groups and new methods are required to improve clinical management. 1H magnetic resonance spectroscopy (MRS) allows non-invasive concentration measurements of small molecules present in tumour tissue, providing clinically useful imaging biomarkers. The primary aim of this study was to investigate whether MRS detectable molecules can predict the survival of paediatric brain tumour patients. Patients and methods Short echo time (30 ms) single voxel 1H MRS was performed on children attending Birmingham Children’s Hospital with a suspected brain tumour and 115 patients were included in the survival analysis. Patients were followed-up for a median period of 35 months and Cox-Regression was used to establish the prognostic value of individual MRS detectable molecules. A multivariate model of survival was also investigated to improve prognostic power. Results Lipids and scyllo-inositol predicted poor survival whilst glutamine and N-acetyl aspartate predicted improved survival (p < 0.05). A multivariate model of survival based on three MRS biomarkers predicted survival with a similar accuracy to histologic grading (p < 5e–5). A negative correlation between lipids and glutamine was found, suggesting a functional link between these molecules. Conclusions MRS detectable biomolecules have been identified that predict survival of paediatric brain tumour patients across a range of tumour types. The evaluation of these biomarkers in large prospective studies of specific tumour types should be undertaken. The correlation between lipids and glutamine provides new insight into paediatric brain tumour metabolism that may present novel targets for therapy.

Skull base growth in children with Chiari malformation Type I

OBJECT The goal of this study was to establish whether children with Chiari malformation Type I (CM-I) have abnormal skull base geometry. METHODS Distances and angles between skull base landmarks were measured on preoperative magnetic resonance images obtained in 30 children (age range 36-204 months) with symptomatic isolated CM-I; 16 of them (53%) had syringomyelia. Comparisons were made with 42 children of similar age who comprised the control group by using one-way analysis of variance. RESULTS The angle formed by the crista galli (CG), dorsum sellae (DS), and foramen magnum (FM) was larger than normal in individuals with CM-I than in those without (145 degrees in patients with CM-I but no syringomyelia and 151 degrees in those with CM-I and syringomyelia compared with 135 degrees in controls; p = 0.000). The angle formed by the left internal auditory meatus (IAM), FM, and right IAM was also larger than normal in the patients (122 degrees in patients with CM-I but no syringomyelia and 123 degrees in those with CM-I and syringomyelia compared with 110 degrees in controls; p = 0.001). The angle formed by the anterior clinoid process (ACP), CG, and right ACP was smaller than normal (29 degrees in all patients with CM-I compared with 34 degrees in controls; p = 0.000). The distance between the two IAMs was longer than normal (75 mm in patients with CM-I but no syringomyelia and 63 mm in those with CM-I and syringomyelia compared with 58 mm in controls; p = 0.000). The distance between the two ACPs was shorter than normal in the syringomyelia group (31 mm in patients with CM-I but no syringomyelia and 27 mm in those with CM-I and syrinx compared with 32 mm in controls; p = 0.001). Within the group of patients with CM-I, the DS-FM and left ACP-right ACP distances were smaller in the syringomyelia group (p = 0.009 and p = 0.037, respectively). CONCLUSIONS Children with CM-I have abnormal geometrical measurements of their entire skull base, not only the posterior fossa, irrespective of presence of syringomyelia. This may indicate a mesodermal defect as a possible cause of the malformation.

The value of magnetic resonance spectroscopy in tumour imaging

Magnetic resonance (MR) imaging has a key role in the management of many childhood tumours. There is increasing interest in extending these investigations to MR techniques that give information on tumour biology in vivo . Magnetic resonance spectroscopy (MRS) is one such method and it provides information on tissue biochemistry. Promising results have been obtained from many preclinical and clinical studies, leading to an expectation that MRS will play a valuable clinical role. However, the role of MRS is not yet well defined and there is a paucity of data from multi-centre clinical trials. In this article we concentrate on MRS in paediatric oncology and provide some general guidance on current applications and outline areas that need to be developed further. Certain atomic nuclei (eg, 1H, 31P and 13C) possess a magnetic moment and when placed in a strong magnetic field will resonate at a particular radiofrequency that subtly depends upon the chemical environment. In MR spectroscopy, the frequencies and intensities of these resonances are measured and represented graphically in an MR spectrum. The most commonly available method clinically is 1H MRS, and the 1H spectrum is a biochemical profile of the small mobile metabolites and macromolecules present in the tissue. 1H MRS can be performed with a standard clinical MRI scanner as part of a conventional MRI investigation. An example 1H spectrum from normal brain is given in figure 1. The horizontal scale, in units of parts per million (ppm), represents signal frequency adjusted to be invariant to the strength of the magnetic field of the MR scanner. Each metabolite is identified by one or more peaks at specific ppm values with the areas under the peaks being proportional to the metabolite concentration. The main metabolites observed are N-acetyl aspartate (NAA), …

1H magnetic resonance spectroscopy in the diagnosis of paediatric low grade brain tumours

INTRODUCTION Low grade gliomas are the commonest brain tumours in children but present in a myriad of ways, each with its own treatment challenges. Conventional MRI scans play an important role in their management but have limited ability to identify likely clinical behaviour. The aim of this study is to investigate (1)H magnetic resonance spectroscopy (MRS) as a method for detecting differences between the various low grade gliomas and related tumours in children. PATIENTS AND METHODS Short echo time single voxel (1)H MRS at 1.5 or 3.0 T was performed prior to treatment on children with low grade brain tumours at two centres and five MR scanners, 69 cases had data which passed quality control. MRS data was processed using LCModel to give mean spectra and metabolite concentrations which were compared using T-tests, ANOVA, Receiver Operator Characteristic curves and logistic regression in SPSS. RESULTS Significant differences were found in concentrations of key metabolites between glioneuronal and glial tumours (T-test p<0.05) and between most of the individual histological subtypes of low grade gliomas. The discriminatory metabolites identified, such as choline and myoinositol, are known tumour biomarkers. In the set of pilocytic astrocytomas and unbiopsied optic pathway gliomas, significant differences (p<0.05, ANOVA) were found in metabolite profiles of tumours depending on location and patient neurofibromatosis type 1 status. Logistic regression analyses yielded equations which could be used to assess the probability of a tumour being of a specific type. CONCLUSIONS MRS can detect subtle differences between low grade brain tumours in children and should form part of the clinical assessment of these tumours.

Predictive value of preoperative ventricular volume on the need for permanent hydrocephalus treatment immediately after resection of posterior fossa medulloblastomas in children

OBJECT In this study, the authors investigated whether preoperative ventricular volume can be used to predict the need for permanent treatment of hydrocephalus in children with posterior fossa medulloblastomas. METHODS Ventricular volumes were measured on magnetic resonance imaging studies obtained preoperatively and immediately postoperatively in 20 children who had undergone resection for medulloblastomas between 1999 and 2007. Comparison of mean values was performed using the one-way analysis of variance test. The association between ventricular and tumor volume was also investigated. RESULTS All patients had obstructive hydrocephalus preoperatively, and 4 patients required postoperative shunt placement. The mean preoperative ventricular volume was 252 ml for those who required shunt placement, and 106 ml for those who did not (p = 0.000). The postoperative ventricular volume was 157 and 78 ml, respectively (p = 0.039), larger than normal in both groups. The mean postoperative and preoperative ratios were 0.69 and 0.70, respectively (p = 0.932). There was no correlation of ventricular volumes with age at operation (older or younger than 3 years), presence of metastasis, or amount of residual tumor. There was a statistical correlation between the preoperative ventricular volume and the tumor volume, related to the need for permanent shunt placement. CONCLUSIONS Preoperative ventricular volume has predictive value for the later need for shunt placement, but in clinical practice this may be difficult to appreciate because all patients have significant hydrocephalus at presentation. The rate of ventricular size reduction in response to tumor excision does not have predictive value because ventricular volume is related to tumor volume. It appears that the removal of cerebellar medulloblastoma converts hydrocephalus from obstructive to communicating, which requires surgical treatment if it exceeds a certain level of cerebrospinal fluid volume.

Short echo time single voxel 1H magnetic resonance spectroscopy in the diagnosis and characterisation of pineal tumours in children

Magnetic resonance spectroscopy (MRS) has been successful in characterising a range of brain tumours and is a useful aid to non‐invasive diagnosis. The pineal region poses considerable surgical challenges and a major surgical resection is not required in the management of all tumours. Improved non‐invasive assessment of pineal region tumours would be of considerable benefit.

A comparison between simulated and experimental basis sets for assessing short-TE in vivo1H MRS data at 1.5 T

A number of algorithms designed to determine metabolite concentrations from in vivo 1H MRS require a collection of single metabolite spectra, known as a basis set, which can be obtained experimentally or by simulation. It has been assumed that basis sets can be used interchangeably, but no systematic study has investigated the effects of small variations in basis functions on the metabolite values obtained. The aim of this study was to compare the results of simulated with experimental basis sets when used to fit short‐TE 1H MRS data of variable quality at 1.5 T. Two hundred and twelve paediatric brain tumour spectra were included in the analysis, and each was analysed twice with LCModel™ using a simulated and experimental basis set. To determine the influence of data quality on quantification, each spectrum was assessed and 152 were classified as being of ‘good’ quality. Bland–Altman statistics were used to measure the agreement between the two basis sets for all available spectra and only ‘good’‐quality spectra. Monte‐Carlo simulations were performed to investigate the influence of minor shifts in metabolite frequencies on metabolite concentration estimates. All metabolites showed good agreement between the two basis sets, and the average metabolite limits of agreement were approximately ±3.84 mM for all available data and ±0.99 mM for good‐quality data. Errors obtained from the Monte‐Carlo analysis were found to be more accurate than the Cramer–Rao lower bounds (CRLB) for 12 of 15 metabolites when metabolite frequency shifting was considered. For the majority of purposes, a level of agreement of ±0.99 mM between simulated and experimental basis sets is sufficiently small for them to be used interchangeably. Multiple analyses using slightly modified basis sets may be useful in estimating fitting errors, which are not predicted by CRLBs. Copyright