Diagnostic Accuracy of Neuroimaging to Delineate Diffuse Gliomas within the Brain: A Meta-Analysis.

BACKGROUND: Brain imaging in diffuse glioma is used for diagnosis, treatment planning, and follow-up. PURPOSE: In this meta-analysis, we address the diagnostic accuracy of imaging to delineate diffuse glioma. DATA SOURCES: We systematically searched studies of adults with diffuse gliomas and correlation of imaging with histopathology. STUDY SELECTION: Study inclusion was based on quality criteria. Individual patient data were used, if available. DATA ANALYSIS: A hierarchic summary receiver operating characteristic method was applied. Low- and high-grade gliomas were analyzed in subgroups. DATA SYNTHESIS: Sixty-one studies described 3532 samples in 1309 patients. The mean Standard for Reporting of Diagnostic Accuracy score (13/25) indicated suboptimal reporting quality. For diffuse gliomas as a whole, the diagnostic accuracy was best with T2-weighted imaging, measured as area under the curve, false-positive rate, true-positive rate, and diagnostic odds ratio of 95.6%, 3.3%, 82%, and 152. For low-grade gliomas, the diagnostic accuracy of T2-weighted imaging as a reference was 89.0%, 0.4%, 44.7%, and 205; and for high-grade gliomas, with T1-weighted gadolinium-enhanced MR imaging as a reference, it was 80.7%, 16.8%, 73.3%, and 14.8. In high-grade gliomas, MR spectroscopy (85.7%, 35.0%, 85.7%, and 12.4) and 11C methionine-PET (85.1%, 38.7%, 93.7%, and 26.6) performed better than the reference imaging. LIMITATIONS: True-negative samples were underrepresented in these data, so false-positive rates are probably less reliable than true-positive rates. Multimodality imaging data were unavailable. CONCLUSIONS: The diagnostic accuracy of commonly used imaging is better for delineation of low-grade gliomas than high-grade gliomas on the basis of limited evidence. Improvement is indicated from advanced techniques, such as MR spectroscopy and PET.

Comparison of ventricular drain location and infusion test in hydrocephalus.

OBJECTIVES: Suspected cerebrospinal fluid shunt (CSF) dysfunction in hydrocephalic patients poses a diagnostic uncertainty. The clinical picture can be non-specific and CT imaging alone is not always pathognomonic. Infusion tests are an increasingly used investigation for real-time hydrodynamic assessment of shunt patency. We report the correlation between infusion test results with the quality of ventricular drain placement on CT scans in a large retrospective group of hydrocephalic patients. MATERIALS & METHODS: Three hundred and six infusion test results performed in 200 patients were correlated with 306 corresponding CT head scans. Nominal logistic regression was used to correlate shunt catheter position on CT imaging to patency of ventricular drain as determined by infusion tests. RESULTS: Infusion test results of shunt patency are statistically congruent with the analysis of shunt catheter position on CT head scans. Catheter tips completely surrounded by either parenchyma or CSF on CT imaging are strongly associated with evidence of occlusion or patency from infusion tests, respectively (χ² = 51.68, P < 0.0001, n = 306 and χ² = 31.04, P < 0.0001, n = 306). CONCLUSIONS: The most important anatomical factor for shunt patency is the catheter tip being completely surrounded by CSF. Infusion tests provide functional and reliable assessment of shunt patency in vivo and are strongly correlated with the position of the ventricular catheter on CT imaging.

Factors affecting temperature variation and habitat use in free-ranging diamondback terrapins.

Measuring the thermal conditions of aquatic reptiles with temperature dataloggers is a cost-effective way to study their behavior and habitat use. Temperature dataloggers are a particularly useful and informative approach to studying organisms such as the estuarine diamondback terrapin (Malaclemys terrapin) that inhabits a dynamic environment often inaccessible to researchers. We used carapace-mounted dataloggers to measure hourly carapace temperature (Tc) of free-ranging terrapins in South Carolina from October 2007 to 2008 to examine the effects of month, sex, creek site, and tide on Tc and to determine the effects of month, sex, and time of day on terrapin basking frequency. Simultaneous measurements of environmental temperatures (Te; shallow mud, deep mud, water) allowed us to make inferences about terrapin microhabitat use. Terrapin Tc differed significantly among months and creek and between sexes. Terrapin microhabitat use also varied monthly, with shallow mud temperature being the best predictor of Tc November-March and water temperature being the best predictor of Tc April-October. Terrapins basked most frequently in spring and fall and males basked more frequently than females. Our study contributes to a fuller understanding of terrapin thermal biology and provides support for using dataloggers to investigate behavior and habitat use of aquatic ectotherms inhabiting dynamic environments.

Current concepts in the surgical management of glioma patients.

The scientific basis for the surgical management of patients with glioma is rapidly evolving. The infiltrative nature of these cancers precludes a surgical cure, but despite this, cytoreductive surgery remains central to high-quality patient care. In addition to tissue sampling for accurate histopathological diagnosis and molecular genetic characterisation, clinical benefit from decompression of space-occupying lesions and microsurgical cytoreduction has been reported in patients with different grades of glioma. By integrating advanced surgical techniques with molecular genetic characterisation of the disease and targeted radiotherapy and chemotherapy, it is possible to construct a programme of personalised surgical therapy throughout the patient journey. The goal of therapeutic packages tailored to each patient is to optimise patient safety and clinical outcome and must be delivered in a multidisciplinary setting. Here we review the current concepts that underlie surgical subspecialisation in the management of patients with glioma.

Diffusion tensor invasive phenotypes can predict progression-free survival in glioblastomas.

INTRODUCTION: Glioblastomas multiformes (GBM) remain incurable in most cases. Their invasion into normal brain makes current therapies ineffective. Post-mortem studies suggest about a 25% of GBMs invade less than 1 cm from the tumour bulk and 20% invade more than 3 cm. AIM OF STUDY: The study aims to use DTI to assess tumour extension and determine how previously reported patterns relate to the progression-free survival (PFS). MATERIALS AND METHODS: Twenty-five patients with GBM treated according to the EORTC/NCIC protocol were retrospectively analysed. Patients were imaged post-operatively at 1.5 T. The sequences were composed of standard anatomical and a standard DTI sequence. As described earlier p and q maps were constructed. For each of the p and q maps, regions of interest were drawn around the visible abnormality. Patients were assigned a diffuse, localised or minimally invasive pattern. Progression was defined according to the RANO criteria (4) and PFS determined in days. Kaplan-Meier plots of survival for the three groups were plotted as were the proportion of patients who had not progressed at 24 months. RESULTS: The median PFS for the diffuse group was 278 days, for the localised group 605 days and 820 days for the minimally invasive group. Three-fourth of the minimally invasive group were progression-free at 24 months (LOG RANK 9.25; p = 0.010). CONCLUSION: It is possible to identify three invasive phenotypes in GBMs using Diffusion tensor imaging , and these three phenotypes have different progression free survival. A minimal phenotype (20% of patients) predicts a greater delay to progression.

Fluorescence-guided surgical sampling of glioblastoma identifies phenotypically distinct tumour-initiating cell populations in the tumour mass and margin.

BACKGROUND: Acquiring clinically annotated, spatially stratified tissue samples from human glioblastoma (GBM) is compromised by haemorrhage, brain shift and subjective identification of 'normal' brain. We tested the use of 5-aminolevulinic acid (5-ALA) fluorescence to objective tissue sampling and to derive tumour-initiating cells (TICs) from mass and margin. METHODS: The 5-ALA was administered to 30 GBM patients. Samples were taken from the non-fluorescent necrotic core, fluorescent tumour mass and non-fluorescent margin. We compared the efficiency of isolating TICs from these areas in 5-ALA versus control patients. HRMAS (1)H NMR was used to reveal metabolic alterations due to 5-ALA. We then characterised TICs for self-renewal in vitro and tumorigenicity in vivo. RESULTS: The derivation of TICs was not compromised by 5-ALA and the metabolic profile was similar between tumours from 5-ALA patients and controls. The TICs from the fluorescent mass were self-renewing in vitro and tumour-forming in vivo, whereas TICs from non-fluorescent margin did not self-renew in vitro but did form tumours in vivo. CONCLUSION: Our data show that 5-ALA does not compromise the derivation of TICs. It also reveals that the margin contains TICs, which are phenotypically different from those isolated from the corresponding mass.

Decision forests for tissue-specific segmentation of high-grade gliomas in multi-channel MR.

We present a method for automatic segmentation of high-grade gliomas and their subregions from multi-channel MR images. Besides segmenting the gross tumor, we also differentiate between active cells, necrotic core, and edema. Our discriminative approach is based on decision forests using context-aware spatial features, and integrates a generative model of tissue appearance, by using the probabilities obtained by tissue-specific Gaussian mixture models as additional input for the forest. Our method classifies the individual tissue types simultaneously, which has the potential to simplify the classification task. The approach is computationally efficient and of low model complexity. The validation is performed on a labeled database of 40 multi-channel MR images, including DTI. We assess the effects of using DTI, and varying the amount of training data. Our segmentation results are highly accurate, and compare favorably to the state of the art.

Implementation of neuro-oncology service reconfiguration in accordance with NICE guidance provides enhanced clinical care for patients with glioblastoma multiforme.

BACKGROUND: Brain tumours account for <2% of all primary neoplasms but are responsible for 7% of the years of life lost from cancer before age 70 years. The latest survival trends for patients with CNS malignancies have remained largely static. The objective of this study was to evaluate the change in practice as a result of implementing the Improving Outcomes Guidance from the UK National Institute for Health and Clinical Excellence (NICE). METHODS: Patients were identified from the local cancer registry and hospital databases. We compared time from diagnosis to treatment, proportion of patients discussed at multidisciplinary team (MDT) meetings, treatment received, length of inpatient stay and survival. Inpatient and imaging costs were also estimated. RESULTS: Service reconfiguration and implementation of NICE guidance resulted in significantly more patients being discussed by the MDT--increased from 66 to 87%, reduced emergency admission in favour of elective surgery, reduced median hospital stay from 8 to 4.5 days, increased use of post-operative MRI from 17 to 91% facilitating early discharge and treatment planning, and reduced cost of inpatient stay from £2096 in 2006 to £1316 in 2009. Patients treated with optimal surgery followed by radiotherapy with concomitant and adjuvant temozolomide achieved outcomes comparable to those reported in clinical trials: median overall survival 18 months (2-year survival 35%). CONCLUSIONS: Advancing the management of neuro-oncology patients by moving from an emergency-based system of patient referral and management to a more planned elective outpatient-based pattern of care improves patient experience and has the potential to deliver better outcomes and research opportunities.

Correlation of MR relative cerebral blood volume measurements with cellular density and proliferation in high-grade gliomas: an image-guided biopsy study.

BACKGROUND AND PURPOSE: As newer MR imaging techniques are used to assist with tumor grading, biopsy planning, and therapeutic response assessment, there is a need to relate the imaging characteristics to underlying pathologic processes. The aim of this study was to see how rCBV, a known marker of tumor vascularity, relates to cellular packing attenuation and cellular proliferation. MATERIALS AND METHODS: Nine patients with histologically proved high-grade gliomas and 1 with a supratentorial PNET requiring an image-guided biopsy were recruited. Patients underwent a DSC study. The rCBV at the intended biopsy sites was determined by using a histogram measure to derive the mean, maximum, and 75th centile and 90th centile values. This measure was correlated with histologic markers of the MIB-1 labeling index (as a marker of glioma cell proliferation) and the total number of neoplastic cells in a high-power field (cellular packing attenuation). RESULTS: There was a good correlation between rCBV and MIB-1 by using all the measures of rCBV. The mean rCBV provided the best results (r = 0.66, P < .001). The only correlation with cellular packing attenuation was with the 90% centile (rCBV(90%), r = 0.36, P = .03). The increase in rCBV could be seen over 1 cm from the edge of enhancement in 4/10 cases, and at 2 cm in 1/10. CONCLUSIONS: rCBV correlated with cellular proliferation in high-grade gliomas but not with cellular packing attenuation. The increase in rCBV extended beyond the contrast-enhancing region in 50% of our patients.

Methodology of diffusion-weighted, diffusion tensor and magnetisation transfer imaging.

MRI offers a number of opportunities to examine characteristics of tissue well below the spatial resolution of the imaging technique. The best known of these is diffusion imaging, which allows the production of images whose contrast reflects the ability of water molecules to move through the extravascular extracellular space. Less well-known, but increasingly important, is magnetisation transfer imaging, which produces contrast based on the ability of protons to move between the free water pool and local macromolecules. Both of these techniques offer unique information about the microscopic and molecular structure of tumour tissue. This article will briefly review the underlying theory and technical aspects associated with these imaging techniques.

Imaging biomarkers of brain tumour margin and tumour invasion.

Invasion of tumour cells into the normal brain is one of the major reasons of treatment failure for gliomas. Although there is a good understanding of the molecular and cellular processes that occur during this invasion, it is not possible to detect the extent of the tumour with conventional imaging. However, there is an understanding that the degree of invasion differs with individual tumours, and yet they are all treated the same. Newer imaging techniques that probe the pathological changes within tumours may be suitable biomarkers for invasion. Imaging methods are now available that can detect subtle changes in white matter organisation (diffusion tensor imaging), tumour metabolism and cellular proliferation (using MR spectroscopy and positron emission tomography) occurring in regions of tumour that cannot be detected by conventional imaging. The role of such biomarkers of invasion should allow better delineation of tumour margins, which should improve treatment planning (especially surgery and radiotherapy) and provide information on the invasiveness of an individual tumour to help select the most appropriate therapy and help stratify patients for clinical trials.

Imaging regional variation of cellular proliferation in gliomas using 3'-deoxy-3'-[18F]fluorothymidine positron-emission tomography: an image-guided biopsy study.

AIM: To compare regional variations in uptake of 3'-deoxy-3'- [(18)F]-fluorothymidine (FLT) images using positron-emission tomography (PET) with measures of cellular proliferation from biopsy specimens obtained by image-guided brain biopsies. MATERIALS AND METHODS: Fourteen patients with a supratentorial glioma that required an image-guided brain biopsy were imaged preoperatively with dynamic PET after the administration of FLT. Maps of FLT irreversible uptake rate (K(i)) and standardized uptake value (SUV) were calculated. These maps were co-registered to a gadolinium-enhanced T1-weighted spoiled gradient echo (SPGR) sequence that was used for biopsy guidance, and the mean and maximum K(i) and SUV determined for each biopsy site. These values were correlated with the MIB-1 labelling index (a tissue marker of proliferation) from these biopsy sites. RESULTS: A total of 57 biopsy sites were studied. Although all measures correlated with MIB-1 labelling index, K(i)(max) provided the best correlation (Pearson coefficient, r=0.68; p<0.001). In low-grade gliomas the K(i)(mean) (+/-SD) was significantly higher than in normal tissue (3.3+/-1.7x10(-3)ml(plasma)/min/ml(tissue) versus 1.2+/-0.7x10(-3)ml(plasma)/min/ml(tissue); p=0.001). High-grade gliomas showed heterogeneous uptake with a mean K(i) of 7.7+/-4x10(-3)ml(plasma)/min/ml(tissue). A threshold K(i)(mean) of 1.8x10(-3) differentiates between normal tissue and tumour (sensitivity 84%, specificity 88%); however, the latter threshold underestimated the extent of tumour in half the cases. SUV closely agreed with K(i) measurements. CONCLUSION: FLT PET is a useful marker of cellular proliferation that correlates with regional variation in cellular proliferation; however, it is unable to identify the margin of gliomas.

Radiotherapy as an adjuvant in the management of intracranial meningiomas: are we practising evidence-based medicine?

Although increasingly used, the precise role of radiotherapy in the management of meningiomas is still disputed. The objective of this study, therefore, was to appraise the evidence for adjuvant radiotherapy in benign and atypical intracranial meningiomas, and to compare and contrast it with the current opinion and practice of neurosurgeons in the United Kingdom and the Republic of Ireland. The use of radiotherapy as a primary treatment strategy or its use in the treatment of recurrence was not considered. We performed a systematic review of the evidence for adjuvant radiotherapy in benign and atypical intracranial meningiomas, surveyed current opinion amongst neurosurgeons involved in such cases and ascertained local practice using data from the regional cancer registry. Overall, 10 cohorts were identified that fulfilled our eligibility criteria. Four studies showed significantly improved local control in patients receiving adjuvant radiotherapy for incompletely resected grade I meningiomas. Our survey demonstrated that the vast majority (98%) of neurosurgeons would not recommend adjuvant radiotherapy in grade I meningioma. In grade II meningioma, most (80%) would not advocate adjuvant radiotherapy if completely excised, but the majority (59%) would recommend radiotherapy in cases of subtotal resection. Significant variation in opinion between centres exists, however, particularly in cases of completely resected atypical meningiomas (p = 0.02). Data from the Eastern Cancer Registration and Information Centre appears to be in line with these findings: less than 10% of patients with grade I meningiomas, but almost 30% of patients with grade II meningiomas received adjuvant radiotherapy in the Eastern region. In conclusion, our study has highlighted significant variation in opinion and practice, reflecting a lack of class 1 evidence to support the use of adjuvant radiotherapy in the treatment of meningiomas. Efforts are underway to address this with a randomized multicentre trial comparing a policy of watchful waiting versus adjuvant irradiation.

Early radiotherapy dose response and lack of hypersensitivity effect in normal brain tissue: a sequential dynamic susceptibility imaging study of cerebral perfusion.

AIMS: To determine if magnetic resonance perfusion markers can be used as an analytical marker of subclinical normal brain injury after radiotherapy, by looking for a dose-effect relationship. MATERIALS AND METHODS: Four patients undergoing conformal radiotherapy to 54Gy in 30 fractions for low-grade gliomas were imaged with conventional T(2)-weighted and fluid attenuated inversion recovery imaging as well as dynamic contrast susceptibility perfusion imaging. Forty regions of interest were determined from the periventricular white matter. All conventional sequences were examined for evidence of radiation-induced changes. Patients were imaged before radiotherapy, after one fraction, at the end of treatment and then at 1 and 3 months from the end of radiotherapy. For each region the relative cerebral blood volume (rCBV), relative cerebral blood flow (rCBF) and mean transit time (MTT) expressed as a ratio of the baseline value, and radiotherapy dose were determined. RESULTS: Of the 40 regions, seven occurred within the gross tumour volume and a further four occurred in regions later infiltrated by tumour, and were thus excluded. Regions within the 80% isodose showed a reduction in rCBV and rCBF over the 3 month period. There was no significant alteration in rCBV or rCBF in regions outside the 60% isodose (i.e. <32Gy). MTT did not alter in any region. There seemed to be a threshold effect at 132 days from the end of radiotherapy of 47% (standard error of the mean 11.5, about 25.4Gy) for rCBV and 59% (standard error of the mean 14.2, about 31.9Gy) for rCBF. CONCLUSIONS: There was a dose-related reduction in rCBV and rCBF in normal brain after radiotherapy at higher dose levels. Although this study used a limited number of patients, it suggests that magnetic resonance perfusion imaging seems to act as a marker of subclinical response of normal brain and that there is an absence of an early hypersensitivity effect with small doses per fraction. Further studies are required with larger groups of patients to show that these results are statistically robust.

Improved delineation of glioma margins and regions of infiltration with the use of diffusion tensor imaging: an image-guided biopsy study.

BACKGROUND AND PURPOSE: The efficacy of radiation therapy, the mainstay of treatment for malignant gliomas, is limited by our inability to accurately determine tumor margins. As a result, despite recent advances, the prognosis remains appalling. Because gliomas preferentially infiltrate along white matter tracks, methods that show white matter disruption should improve this delineation. In this study, results of histologic examination from samples obtained from image-guided brain biopsies were correlated with diffusion tensor images. METHODS: Twenty patients requiring image-guided biopsies for presumed gliomas were imaged preoperatively. Patients underwent image-guided biopsies with multiple biopsies taken along a single track that went into normal-appearing brain. Regions of interest were determined from the sites of the biopsies, and diffusion tensor imaging findings were compared with glioma histology. RESULTS: Using diffusion tissue signatures, it was possible to differentiate gross tumor (reduction of the anisotropic component, q > 12% from contralateral region), from tumor infiltration (increase in the isotropic component, p > 10% from contralateral region). This technique has a sensitivity of 98% and specificity of 81%. T2-weighted abnormalities failed to identify the margin in half of all specimens. CONCLUSION: Diffusion tensor imaging can better delineate the tumor margin in gliomas. Such techniques can improve the delineation of the radiation therapy target volume for gliomas and potentially can direct local therapies for tumor infiltration.

Enhanced visualization and quantification of magnetic resonance diffusion tensor imaging using the p:q tensor decomposition.

Many scalar measures have been proposed to quantify magnetic resonance diffusion tensor imaging (MR DTI) data in the brain. However, only two parameters are commonly used in the literature: mean diffusion (D) and fractional anisotropy (FA). We introduce a visualization technique which permits the simultaneous analysis of an additional five scalar measures. This enhanced diversity is important, as it is not known a priori which of these measures best describes pathological changes for brain tissue. The proposed technique is based on a tensor transformation, which decomposes the diffusion tensor into its isotropic (p) and anisotropic (q) components. To illustrate the use of this technique, diffusion tensor imaging was performed on a healthy volunteer, a sequential study in a patient with recent stroke, a patient with hydrocephalus and a patient with an intracranial tumour. Our results demonstrate a clear distinction between different anatomical regions in the normal volunteer and the evolution of the pathology in the patients. In the normal volunteer, the brain parenchyma values for p and q fell into a narrow band with 0.976

Diffusion tensor imaging: possible implications for radiotherapy treatment planning of patients with high-grade glioma.

AIMS: Radiotherapy treatment planning for high-grade gliomas (HGG) is hampered by the inability to image peri-tumoural white-matter infiltration. Diffusion tensor imaging (DTI) is an imaging technique that seems to show white-matter abnormalities resulting from tumour infiltration that cannot be visualised by conventional computed tomography or magnetic resonance imaging (MRI). We propose a new term, the image-based high-risk volume (IHV) for such abnormalities, which are distinct from the gross-tumour volume (GTV). For IHV based on DTI, we use the term IHVDTI. This study assesses the value of DTI for the individualisation of radiotherapy treatment planning for patients with HGG. METHODS: Seven patients with biopsy-proven HGG were included in a theoretical planning exercise, comparing standard planning techniques with individualised plans based on DTI. Standard plans were generated using a 2.5 cm clinical target volume (CTV) margin added to the GTV. For DTI-based plans, the CTV was generated by adding a 1 cm margin to the IHVDTI. Estimates of normal tissue complication probability (NTCP) were calculated and used to estimate the level of dose escalation that could be achieved using the DTI-based plans. RESULTS: The use of DTI resulted in non-uniform margins being added to the GTV to encompass areas at high risk of tumour involvement, but, in six out of seven cases, the IHVDTI was encapsulated by the standard CTV margin. In all cases, DTI could be used to reduce the size of the planning-target volume (PTV) (mean 35%, range 18-46%), resulting in escalated doses (mean 67 Gy, range 64-74 Gy), with NTCP levels that matched the conventional treatment plans. CONCLUSION: DTI can be used to individualise radiotherapy target volumes, and reduction in the CTV permits modest dose escalation without an increase in NTCP. DTI may also be helpful in stratifying patients according to the degree of white-matter infiltration.