Tissue mechanics promote IDH1-dependent HIF1α-tenascin C feedback to regulate glioblastoma aggression.

Increased overall survival for patients with glioma brain tumours is associated with mutations in the metabolic regulator isocitrate dehydrogenase 1 (IDH1). Gliomas develop within a mechanically challenged microenvironment that is characterized by a dense extracellular matrix (ECM) that compromises vascular integrity to induce hypoxia and activate HIF1α. We found that glioma aggression and patient prognosis correlate with HIF1α levels and the stiffness of a tenascin C (TNC)-enriched ECM. Gain- and loss-of-function xenograft manipulations demonstrated that a mutant IDH1 restricts glioma aggression by reducing HIF1α-dependent TNC expression to decrease ECM stiffness and mechanosignalling. Recurrent IDH1-mutant patient gliomas had a stiffer TNC-enriched ECM that our studies attributed to reduced miR-203 suppression of HIF1α and TNC mediated via a tension-dependent positive feedback loop. Thus, our work suggests that elevated ECM stiffness can independently foster glioblastoma aggression and contribute to glioblastoma recurrence via bypassing the protective activity of IDH1 mutational status.

Characterization of a diffuse intrinsic pontine glioma cell line: implications for future investigations and treatment.

Diffuse intrinsic pontine gliomas arise almost exclusively in children, and despite advances in treatment, the majority of patients die within 2 years after initial diagnosis. Because of their infiltrative nature and anatomic location in an eloquent area of the brain, most pontine gliomas are treated without a surgical biopsy. The corresponding lack of tissue samples has resulted in a limited understanding of the underlying genetic and molecular biologic abnormalities associated with pontine gliomas, and is a substantial obstacle for the preclinical testing of targeted therapeutic agents for these tumors. We have established a human glioma cell line that originated from surgical biopsy performed on a patient with a pontine glioma. To insure sustainable in vitro propagation, tumor cells were modified with hTERT (human telomerase ribonucleoprotein reverse transcriptase), and with a luciferase reporter to enable non-invasive bioluminescence imaging. The hTERT modified cells are tumorigenic in athymic rodents, and produce brainstem tumors that recapitulate the infiltrative growth of brainstem gliomas in patients.

MRI apparent diffusion coefficient reflects histopathologic subtype, axonal disruption, and tumor fraction in diffuse-type grade II gliomas.

The apparent diffusion coefficient (ADC) determined from MR diffusion tensor imaging (DTI) has shown promise for distinguishing World Health Organization grade II astrocytoma (AS) from the more prognostically favorable grade II oligodendroglioma (OD). Since mixed oligoastrocytomas (OAs) with codeletions in chromosomes 1p and 19q confer prognoses similar to those of OD, we questioned whether a previously determined ADC-based criterion for distinguishing OD and AS would hold on an independent set of gliomas that included OA with codeleted or intact 1p/19q chromosomes. We also questioned whether the ADC is associated with the tumor microstructure. ADC colormaps generated from presurgical DTI scans were used to guide the collection of biopsies from each tumor. The median normalized ADC distinguished OD from AS with 91% sensitivity and 92% specificity. 1p/19q codeleted OAs were always classified as ODs, while 1p/19q intact OAs were always classified as ASs. There were positive associations between the ADC and both the SMI-31 score of axonal disruption and the fraction of tumor cells in the biopsies. The ADC of OD and 1p/19q codeleted OA was more associated with tumor fraction, while the ADC of AS and 1p/19q intact OA was more associated with SMI-31 score. We conclude that our previously determined threshold median ADC can distinguish grade II OD and AS on a new patient cohort and that the distinctions extend to OA with codeleted and intact 1p/19q chromosomes. Further, the ADC in grade II gliomas is associated with the fraction of tumor cells and degree of axonal disruption in tumor subregions.

Choline metabolism, proliferation, and angiogenesis in nonenhancing grades 2 and 3 astrocytoma.

PURPOSE: To study choline metabolism in biopsies from nonenhancing Grade 2 (AS2) and Grade 3 (AS3) astrocytomas to determine whether (1) phosphocholine (PC) dominates in AS3, and (2) PC is associated with proliferation or angiogenesis. PC and glycerophosphocholine (GPC) are involved in phospholipid metabolism that accompanies mitosis. PC is the predominant peak in Grade 4 astrocytoma (GBM) while GPC dominates in AS2. MATERIALS AND METHODS: We used high resolution magic angle spinning magnetic resonance spectroscopy to compare the concentrations of 10 metabolites in 41 biopsies (16 AS2 and 25 AS3) from 24 tumors. Immunohistochemistry was performed on paired biopsies to determine the cell density, Ki-67 proliferation index, and vascular endothelial growth factor (VEGF) angiogenic marker expression. RESULTS: AS3 had higher PC than AS2; however, the PC:GPC was less than 1 in all cases irrespective of tumor grade. Within tumors, GPC increased with Ki-67 and PC and tCho increased with cell density. There was no association between any choline compound and VEGF. CONCLUSION: These data suggest that PC:GPC less than 1 is not unique to low grade glioma. Furthermore, the PC concentration that is a marker of aggressive glial tumors is not tightly linked to cell proliferation or angiogenesis in nonenhancing astrocytomas.

Non-stem cell origin for oligodendroglioma.

Malignant astrocytic brain tumors are among the most lethal cancers. Quiescent and therapy-resistant neural stem cell (NSC)-like cells in astrocytomas are likely to contribute to poor outcome. Malignant oligodendroglial brain tumors, in contrast, are therapy sensitive. Using magnetic resonance imaging (MRI) and detailed developmental analyses, we demonstrated that murine oligodendroglioma cells show characteristics of oligodendrocyte progenitor cells (OPCs) and are therapy sensitive, and that OPC rather than NSC markers enriched for tumor formation. MRI of human oligodendroglioma also suggested a white matter (WM) origin, with markers for OPCs rather than NSCs similarly enriching for tumor formation. Our results suggest that oligodendroglioma cells show hallmarks of OPCs, and that a progenitor rather than a NSC origin underlies improved prognosis in patients with this tumor.

Apparent diffusion coefficient and fractional anisotropy of newly diagnosed grade II gliomas.

Distinguishing between low-grade oligodendrogliomas (ODs) and astrocytomas (AC) is of interest for defining prognosis and stratifying patients to specific treatment regimens. The purpose of this study was to determine if the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) from diffusion imaging can help to differentiate between newly diagnosed grade II OD and AC subtypes and to evaluate the ADC and FA values for the mixed population of oligoastrocytomas (OA). Fifty-three patients with newly diagnosed grade II gliomas were studied using a 1.5T whole body scanner (23 ODs, 16 ACs, and 14 OAs). The imaging protocol included post-gadolinium T1-weighted images, T2-weighted images, and either three and/or six directional diffusion imaging sequence with b = 1000 s/mm(2). Diffusion-weighted images were analyzed using in-house software to calculate maps of ADC and for six directional acquisitions, FA. The intensity values were normalized by values from normal appearing white matter (NAWM) to generate maps of normalized apparent diffusion coefficient (nADC) and normalized fractional anisotropy (nFA). The hyperintense region in the T2 weighted image was defined as the T2All region. A Mann-Whitney rank-sum test was performed on the 25th, median, and 75th nADC and nFA among the three subtypes. Logistic regression was performed to determine how well the nADC and nFA predict subtype. Lesions diagnosed as being OD had significantly lower nADC and significantly higher nFA, compared to AC. The nADC and nFA values individually classified the data with an accuracy of 87%. Combining the two did not enhance the classification. The patients with OA had nADC and nFA values between those of OD and AC. This suggests that ADC and FA may be helpful in directing tissue sampling to the most appropriate regions for taking biopsies in order to make a definitive diagnosis.

Relationship between choline and apparent diffusion coefficient in patients with gliomas.

PURPOSE: To examine the relationship between apparent diffusion coefficients (ADC) from diffusion weighted imaging (DWI) and choline levels from proton magnetic resonance spectroscopic imaging (MRSI) in newly diagnosed Grade II and IV gliomas within distinct anatomic regions. MATERIALS AND METHODS: A total of 37 patients with Grade II and 28 patients with Grade IV glioma were scanned on a 1.5T system with 3D MRSI and DWI. Region level analysis included Spearman rank correlation between median normalized ADC and choline for each patient per grade within each distinct abnormal anatomical region. Voxel level analysis calculated a Spearman rank correlation per region, per patient. RESULTS: Grade II lesions showed no evidence of a correlation between normalized ADC and choline using either the region or voxel level analysis. Region level analysis of Grade IV lesions did not appear to correlate in the contrast enhancement or necrotic core, but did suggest a significant negative correlation in the more heterogeneous nonenhancing and combined regions. CONCLUSION: There appears to be differences in the relationship between ADC and choline levels in Grade II and Grade IV gliomas. Correlation within these regions in Grade IV lesions was strongest when all regions were included, suggesting heterogeneity may be driving the relationship.

Proton magnetic resonance spectroscopic imaging in newly diagnosed glioblastoma: predictive value for the site of postradiotherapy relapse in a prospective longitudinal study.

PURPOSE: To investigate the association between magnetic resonance spectroscopic imaging (MRSI)-defined, metabolically abnormal tumor regions and subsequent sites of relapse in data from patients treated with radiotherapy (RT) in a prospective clinical trial. METHODS AND MATERIALS: Twenty-three examinations were performed prospectively for 9 patients with newly diagnosed glioblastoma multiforme studied in a Phase I trial combining Tipifarnib and RT. The patients underwent magnetic resonance imaging (MRI) and MRSI before treatment and every 2 months until relapse. The MRSI data were categorized by the choline (Cho)/N-acetyl-aspartate (NAA) ratio (CNR) as a measure of spectroscopic abnormality. CNRs corresponding to T1 and T2 MRI for 1,207 voxels were evaluated before RT and at recurrence. RESULTS: Before treatment, areas of CNR2 (CNR > or =2) represented 25% of the contrast-enhancing (T1CE) regions and 10% of abnormal T2 regions outside T1CE (HyperT2). The presence of CNR2 was often an early indicator of the site of relapse after therapy. In fact, 75% of the voxels within the T1CE+CNR2 before therapy continued to exhibit CNR2 at relapse, compared with 22% of the voxels within the T1CE with normal CNR (p < 0.05). The location of new contrast enhancement with CNR2 corresponded in 80% of the initial HyperT2+CNR2 vs. 20.7% of the HyperT2 voxels with normal CNR (p < 0.05). CONCLUSION: Metabolically active regions represented a small percentage of pretreatment MRI abnormalities and were predictive for the site of post-RT relapse. The incorporation of MRSI data in the definition of RT target volumes for selective boosting may be a promising avenue leading to increased local control of glioblastomas.

Correlation of magnetic resonance spectroscopic and growth characteristics within Grades II and III gliomas.

OBJECT: The accurate diagnosis of World Health Organization Grades II and III gliomas is crucial for the effective treatment of patients with such lesions. Increased cell density and mitotic activity are histological features that distinguish Grade III from Grade II gliomas. Because increased cellular proliferation and density both contribute to the in vivo magnetic resonance (MR) spectroscopic peak corresponding to choline-containing compounds (Cho), the authors hypothesized that multivoxel MR spectroscopy might help identify the tumor regions with the most aggressive growth characteristics, which would be optimal locations for biopsy. They investigated the ability to use one or more MR spectroscopic parameters to predict the MIB-1 cell proliferation index (PI), the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling cell death index (DI), the cell density, and the ratio of proliferation to cell death (PI/DI) within different regions of the same tumor. METHODS: Patients with presumed Grades II or III glioma underwent 3D MR spectroscopic imaging prior to surgery, and two or three regions within the tumor were targeted for biopsy retrieval based on their spectroscopic features. Biopsy specimens were extracted from the tumor during image-guided resection, and the PI, DI, and cell density were assessed in the specimens using immunohistochemical methods. CONCLUSIONS: The authors found that the relative levels of Cho and N-acetylaspartate (NAA) correlated with the cell density, PI, and PI/DI ratio within different regions of the same tumor and that the association held for the subpopulation of nonenhancing tumors. The association was stronger in tumors with large ranges of Cho/NAA values, irrespective of the presence of contrast enhancement. The findings demonstrate the validity of using MR spectroscopy to identify regions of aggressive growth in presumed Grade II or III gliomas that would be suitable targets for retrieving diagnostic biopsy specimens.

Perfusion, diffusion and spectroscopy values in newly diagnosed cerebral gliomas.

PURPOSE: To evaluate perfusion, diffusion, and spectroscopy values in enhancing and non-enhancing lesions for patients with newly diagnosed gliomas of different grades. MATERIALS AND METHODS: Sixty-seven patients with newly diagnosed glioma were entered into the study 20 grade II, 26 grade III and 21 grade IV. MR data were acquired at 1.5T and included diffusion weighted images (59/67 patients), dynamic perfusion weighted images (30/67 patients) and 3D H-1 MR spectroscopy (64/67 patients). Enhancing and non-enhancing lesions were delineated by a neuroradiologist and applied to maps of relative cerebral blood volume (rCBV), apparent diffusion coefficient (ADC), relative anisotropy (RA) and metabolite intensities. RESULTS: The median rCBV within enhancing regions of grade IV gliomas was significantly elevated relative to enhancing regions in grade III gliomas and normal brain. ADC was elevated relative to normal brain, but was not significantly different between grades or between enhancing and non-enhancing regions. The RA was higher in the non-enhancing region of grade IV gliomas relative to grade II and grade III. Levels of lactate plus lipid were significantly elevated in grade IV relative to grade II and grade III gliomas. Both enhancing and non-enhancing regions in grade IV gliomas showed significant correlations between CBV, ADC and choline levels. CONCLUSION: The data were consistent with grade IV gliomas having higher membrane turnover, increased cell density and increased vascularity within enhancing lesions. Analysis of the correlations among parameters within grade IV gliomas suggested that high vascularity (high rCBV) was correlated with increased cellularity (low ADC) and increased membrane turnover (high choline) in these lesions. The non-enhancing region of grades II and III gliomas had MR parameters consistent with increased cellularity and/or membrane turnover.

Gadolinium-loaded liposomes allow for real-time magnetic resonance imaging of convection-enhanced delivery in the primate brain.

Drug delivery to brain tumors has long posed a major challenge. Convection-enhanced delivery (CED) has been developed as a drug delivery strategy to overcome this difficulty. Ideally, direct visualization of the tissue distribution of drugs infused by CED would assure successful delivery of therapeutic agents to the brain tumor while minimizing exposure of the normal brain. We previously developed a magnetic resonance imaging (MRI)-based method to visualize the distribution of liposomal agents after CED in rodent brains. In the present study, CED of liposomes was further examined in the non-human primate brain (n = 6). Liposomes containing Gadoteridol, DiI-DS, and rhodamine were infused in corona radiata, putamen nucleus, and brain stem. Volume of distribution was analyzed for all delivery locations by histology and MR imaging. Real-time MRI monitoring of liposomes containing gadolinium allowed direct visualization of a robust distribution. MRI of liposomal gadolinium was highly accurate at determining tissue distribution, as confirmed by comparison with histological results from concomitant administration of fluorescent liposomes. Linear correlation for liposomal infusions between infusion volume and distribution volume was established in all targeted locations. We conclude that an integrated strategy combining liposome/nanoparticle technology, CED, and MRI may provide new opportunities for the treatment of brain tumors. Our ability to directly monitor and to control local delivery of liposomal drugs will most likely result in greater clinical efficacy when using CED in management of patients.

Real-time visualization and characterization of liposomal delivery into the monkey brain by magnetic resonance imaging.

Liposomes loaded with Gadoteridol, in combination with convection-enhanced delivery (CED), offer an excellent option to monitor CNS delivery of therapeutic compounds with MRI. In previous studies, we investigated possible clinical applications of liposomes to the treatment of brain tumors. In this study, up to 700 microl of Gadoteridol/rhodamine-loaded liposomes were distributed in putamen, corona radiata and brainstem of non-human primates. Distribution was monitored by real-time MRI throughout infusion procedures and allowed accurate calculation of volume of distribution within anatomical structures. We found that different regions of the brain gave various volumes of distribution when infused with the same volume of liposome. Based on these findings, distinct distribution pathways within infused structures can be predicted. This work underlines the importance of monitoring drug delivery to CNS and enables accurate delivery of drug-loaded liposomes to specific brain regions with a standard MRI procedure. Findings presented in this manuscript may allow for modeling of parameters used for direct delivery of therapeutics into various regions of the brain.

Effects of the perivascular space on convection-enhanced delivery of liposomes in primate putamen.

Convection-enhanced delivery has recently entered the clinic and represents a promising new therapeutic option in the field of neurodegenerative diseases and treatment of brain tumors. Understanding of the principles governing delivery and flow of macromolecules within the CNS is still poorly understood and requires more investigation of the microanatomy and fluid dynamics of the brain. Our previously established, reflux-free convection-enhanced delivery (CED) technique and real-time imaging MR method for monitoring CED delivery of liposomes in primate CNS allowed us to closely monitor infusions of putamen. Our findings indicate that CED in putamen is associated with perivascular transport of liposomes, throughout CNS arteries. The results may explain side effects seen in current clinical trials using CED. In addition, they clearly show the necessity for a monitoring technique for future direct delivery of therapeutic agents to the human central nervous system. Based on these findings, we believe that the physiological concept that the perivascular space serves as a conduit for distribution of endogenous molecules within the CNS also applies to interstitially infused agents.

Longitudinal multivoxel MR spectroscopy study of pediatric diffuse brainstem gliomas treated with radiotherapy.

BACKGROUND AND PURPOSE: After radiotherapy (RT), children with diffuse intrinsic pontine gliomas (DIPG) are followed with sequential magnetic resonance imaging (MRI). However, MRI changes do not necessarily reflect tumor progression, and therefore additional noninvasive tools are needed to improve the definition of progression vs. treatment-related changes. In this study, we determined the feasibility and accuracy of multivoxel proton magnetic resonance spectroscopic imaging (1H-MRSI) for monitoring pediatric patients with DIPG. METHODS AND PATIENTS: Twenty-four serial examinations of MRI/MRSI (7 2D-MRSI and 17 3D-MRSI) were performed on 8 patients with DIPG who received local RT. A total of 1635 voxels were categorized as "normal" or "abnormal" based on corresponding imaging findings on contrast-enhanced T1- and T2-weighted MRI. The choline to N-acetyl-aspartate ratio (Cho:NAA) and choline to creatine ratios (Cho:Cr) within each category of MRI abnormality were compared to their counterpart in normal surrounding tissues. The changes in these ratios corresponding to each type of abnormality were evaluated before RT, at response, and at recurrence, as determined by the clinical status of the patients. The presence or absence of lactate and lipid peaks was noted for each voxel. MRI/MRSI was performed on posterior fossa and supratentorial tissue of 3 volunteer pediatric patients. RESULTS: The Cho:NAA and Cho:Cr values within the imaging abnormalities (3.8 +/- 0.93 and 3.55 +/- 1.37, respectively) were significantly higher than the mean values in normal-appearing regions (0.93 +/- 0.2 and 1.13 +/- 0.38, respectively) (p < 0.005). Cho:NAA values decreased from studies at diagnosis to the time of response to RT (3.12 +/- 0.5 and 2.08 +/- 0.73, respectively), followed by an increase at the time of relapse (from 1.83 +/- 0.92 to 4.29 +/- 1.08). Loss of lactate and lipid peaks correlated with response, and their presence and stability with relapse. In 3 patients, increased spectral abnormalities preceded the radiological and clinical deterioration by 2-5 months. CONCLUSION: Multivoxel MRSI is a feasible and reproducible noninvasive tool for assessing pediatric DIPG. Longitudinal multivoxel MRSI measurements have potential value in assessing response to radiation or other therapies, because they offer more coverage than single-voxel techniques and provide reliable spectral data.

1H-MRSI of radiation effects in normal-appearing white matter: dose-dependence and impact on automated spectral classification.

PURPOSE: To identify radiation-induced changes in healthy white-matter spectra in the first six months following radiotherapy, and assess the impact of these changes on an automated algorithm for detecting spectral abnormalities. MATERIALS AND METHODS: 1H-MRSI was performed on 10 patients with grade IV gliomas who were to undergo radiation therapy. Choline (Cho), creatine (Cr), and N-acetylaspartate (NAA) ratios were studied as a function of dose and time. The impact of these spectral changes on a spectral analysis algorithm was evaluated. RESULTS: The Cho/NAA ratios rose to values of 0.66 +/- 0.15, 0.75 +/- 0.21, and 0.73 +/- 0.15 two months after therapy, compared to immediate post-therapy values of 0.56 +/- 0.15, 0.60 +/- 0.16, and 0.61 +/- 0.15 for the < 25, 25-50, and > 50 Gy dose groups, respectively. These maxima were followed by a dose-dependent recovery. A similar trend was found in the Cho/Cr ratio. The automated spectral analysis system incorporated the changing Cho/NAA ratio into a global redefinition of healthy tissue, but did not account for dose-dependent spatial variations in Cho/NAA ratios. CONCLUSION: Radiation significantly alters the spectra of healthy tissues in the first six months after radiotherapy. This suggests that the radiation dose distribution should be considered during analysis of post-therapy spectra.

Distribution of liposomes into brain and rat brain tumor models by convection-enhanced delivery monitored with magnetic resonance imaging.

Although liposomes have been used as a vehicle for delivery of therapeutic agents in oncology, their efficacy in targeting brain tumors has been limited due to poor penetration through the blood-brain barrier. Because convection-enhanced delivery (CED) of liposomes may improve the therapeutic index for targeting brain tumors, we conducted a three-stage study: stage 1 established the feasibility of using in vivo magnetic resonance imaging (MRI) to confirm adequate liposomal distribution within targeted regions in normal rat brain. Liposomes colabeled with gadolinium (Gd) and a fluorescent indicator, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine-5,5'-disulfonic acid [DiI-DS; formally DiIC(18)(3)-DS], were administered by CED into striatal regions. The minimum concentration of Gd needed for monitoring, correlation of infused volume with distribution volume, clearance of infused liposome containing Gd and DiI-DS (Lip/Gd/DiI-DS), and potential local toxicity were evaluated. After determination of adequate conditions for MRI detection in normal brain, stage 2 evaluated the feasibility of in vivo MRI monitoring of liposomal distribution in C6 and 9L-2 rat glioma models. In both models, the distribution of Lip/Gd/DiI-DS covering the tumor mass was well defined and monitored with MRI. Stage 3 was designed to develop a clinically relevant treatment strategy in the 9L-2 model by infusing liposome containing Gd (Lip/Gd), prepared in the same size as Lip/Gd/DiI-DS, with Doxil, a liposomal drug of similar size used to treat several cancers. MRI detection of Lip/Gd coadministered with Doxil provided optimum CED parameters for complete coverage of 9L-2 tumors. By permitting in vivo monitoring of therapeutic distribution in brain tumors, this technique optimizes local drug delivery and may provide a basis for clinical applications in the treatment of malignant glioma.

Histopathological validation of a three-dimensional magnetic resonance spectroscopy index as a predictor of tumor presence.

OBJECT: Data obtained preoperatively from three-dimensional (3D)/proton magnetic resonance (MR) spectroscopy were compared with the results of histopathological assays of tissue biopsies obtained during surgery to verify the sensitivity and specificity of a choline-containing compound-N-acetylaspartate index (CNI) used to distinguish tumor from nontumorous tissue within T2-hyperintense and contrast-enhancing lesions of patients with untreated gliomas. The information gleaned from the biopsy correlation study was used to test the hypothesis that there is metabolically active tumor in nonenhancing regions of the T2-hyperintense lesion that can be detected using MR spectroscopy. METHODS: Patients suspected of harboring a glioma underwent 3D MR spectroscopy during their preoperative MR imaging examination. Surgical navigation techniques were used to record the location of tissue biopsies collected during open resection of the tumor. A receiver operating curve analysis of the CNI and histological characteristics of specimens at each biopsy location was performed to determine the optimal threshold of the CNI required to separate tumor from nontumorous tissue. Histograms of the CNIs within enhancing and nonenhancing regions of lesions appearing on MR images were generated to determine the spatial distribution of CNIs consistent with tumor. CONCLUSIONS: Biopsy samples containing tumor were distinguished from those containing a mixture of normal, edematous, gliotic, and necrotic tissue with 90% sensitivity and 86% specificity by using a CNI threshold of 2.5. The CNIs of nontumorous specimens were significantly different from those of biopsy specimens containing Grade II (p < 0.03), Grade III (p < 0.005), and Grade IV (p < 0.01) tumors. On average, one third to one half of the T2-hyperintense lesion outside the contrast-enhancing lesion contained CNI greater than 2.5.

In vivo molecular imaging for planning radiation therapy of gliomas: an application of 1H MRSI.

Gliomas are infiltrative lesions that typically have poorly defined margins on conventional magnetic resonance (MR) and computed tomography (CT) images. This presents a considerable challenge for planning radiation and other forms of focal therapy, and introduces the possibility of both under-treating macroscopic tumor, and over-treating regions of normal brain tissue. New therapy systems are able to deliver radiation more precisely and accurately to irregular three-dimensional target volumes, and have placed a premium on definition of the spatial extent of the lesion. Proton MR spectroscopic imaging (H-MRSI) has been proposed as an in vivo molecular imaging technique that assists in targeting and predicts response to radiation therapy for patients with gliomas. The evidence that supports the use of H-MRSI for planning radiation treatment is reviewed, together with the technical requirements for implementing data acquisition and analysis procedures in a clinical setting. Although there is room for improvement in the spatial resolution and chemical specificity obtained at the conventional field strength of 1.5 T, there are clear benefits to integrating H-MRSI into treatment planning and follow-up examinations. Further work is required to integrate the results of the H-MRSI examination into the treatment planning workstation, and to improve the quality of the data using more sensitive phased array coils and higher field strength magnets.

Metabolic imaging of low-grade gliomas with three-dimensional magnetic resonance spectroscopy.

PURPOSE: The role of radiotherapy (RT) seems established for patients with low-grade gliomas with poor prognostic factors. Three-dimensional (3D) magnetic resonance spectroscopy imaging (MRSI) has been reported to be of value in defining the extent of glioma infiltration. We performed a study examining the impact MRSI would have on the routine addition of 2-3-cm margins around MRI T2-weighted hyperintensity to generate the treatment planning clinical target volume (CTV) for low-grade gliomas. METHODS AND MATERIALS: Twenty patients with supratentorial gliomas WHO Grade II (7 astrocytomas, 6 oligoastrocytomas, 7 oligodendrogliomas) underwent MRI and MRSI before surgery. The MRI was contoured manually; the regions of interest included T2 hyperintensity and, if present, regions of contrast enhancement on T1-weighted images. The 3D-MRSI peak parameters for choline and N-acetyl-aspartate, acquired voxel-by-voxel, were categorized using a choline/N-acetyl-aspartate index (CNI), a tool for quantitative assessment of tissue metabolite levels, with CNI 2 being the lowest value corresponding to tumor. CNI data were aligned to MRI and displayed as 3D contours. The relationship between the anatomic and metabolic information on tumor extent was assessed by comparing the CNI contours and other MRSI-derived metabolites to the MRI T2 volume. RESULTS: The limitations in the size of the region "excited" meant that MRSI could be used to evaluate only a median 68% of the T2 volume (range 38-100%), leaving the volume T2c. The CNI 2 volume (median 29 cm(3), range 10-73) was contained totally within the T2c in 55% of patients. In the remaining patients, the volume of CNI 2 extending beyond the T2c was quite small (median 2.3 cm(3), range 1.4-5.2), but was not distributed uniformly about the T2c, extending up to 22 mm beyond it. Two patients demonstrated small regions of contrast enhancement corresponding to the regions of highest CNI. Other metabolites, such as creatine and lactate, seem useful for determining less and more radioresistant areas, respectively. CONCLUSION: Metabolically active tumor, as detected by MRSI, is restricted mainly to the T2 hyperintensity in low-grade gliomas, but can extend outside it in a limited and nonuniform fashion up to 2 cm. Therefore, a CTV including T2 and areas of CNI extension beyond the T2 hyperintensity would result in a reduction in the size and a change in the shape of the standard clinical target volumes generated by adding uniform margins of 2-3 cm to the T2 hyperintensity.