Quantitative Delta T1 (dT1) as a Replacement for Adjudicated Central Reader Analysis of Contrast-Enhancing Tumor Burden: A Subanalysis of the American College of Radiology Imaging Network 6677/Radiation Therapy Oncology Group 0625 Multicenter Brain Tumor Trial.

BACKGROUND AND PURPOSE: Brain tumor clinical trials requiring solid tumor assessment typically rely on the 2D manual delineation of enhancing tumors by ≥2 expert readers, a time-consuming step with poor interreader agreement. As a solution, we developed quantitative dT1 maps for the delineation of enhancing lesions. This retrospective analysis compares dT1 with 2D manual delineation of enhancing tumors acquired at 2 time points during the post therapeutic surveillance period of the American College of Radiology Imaging Network 6677/Radiation Therapy Oncology Group 0625 (ACRIN 6677/RTOG 0625) clinical trial. MATERIALS AND METHODS: Patients enrolled in ACRIN 6677/RTOG 0625, a multicenter, randomized Phase II trial of bevacizumab in recurrent glioblastoma, underwent standard MR imaging before and after treatment initiation. For 123 patients from 23 institutions, both 2D manual delineation of enhancing tumors and dT1 datasets were evaluable at weeks 8 (n = 74) and 16 (n = 57). Using dT1, we assessed the radiologic response and progression at each time point. Percentage agreement with adjudicated 2D manual delineation of enhancing tumor reads and association between progression status and overall survival were determined. RESULTS: For identification of progression, dT1 and adjudicated 2D manual delineation of enhancing tumor reads were in perfect agreement at week 8, with 73.7% agreement at week 16. Both methods showed significant differences in overall survival at each time point. When nonprogressors were further divided into responders versus nonresponders/nonprogressors, the agreement decreased to 70.3% and 52.6%, yet dT1 showed a significant difference in overall survival at week 8 (P = .01), suggesting that dT1 may provide greater sensitivity for stratifying subpopulations. CONCLUSIONS: This study shows that dT1 can predict early progression comparable with the standard method but offers the potential for substantial time and cost savings for clinical trials.

Moving Toward a Consensus DSC-MRI Protocol: Validation of a Low-Flip Angle Single-Dose Option as a Reference Standard for Brain Tumors.

BACKGROUND AND PURPOSE: DSC-MR imaging using preload, intermediate (60°) flip angle and postprocessing leakage correction has gained traction as a standard methodology. Simulations suggest that DSC-MR imaging with flip angle = 30° and no preload yields relative CBV practically equivalent to the reference standard. This study tested this hypothesis in vivo. MATERIALS AND METHODS: Eighty-four patients with brain lesions were enrolled in this 3-institution study. Forty-three patients satisfied the inclusion criteria. DSC-MR imaging (3T, single-dose gadobutrol, gradient recalled-echo-EPI, TE = 20-35 ms, TR = 1.2-1.63 seconds) was performed twice for each patient, with flip angle = 30°-35° and no preload (P-), which provided preload (P+) for the subsequent intermediate flip angle = 60°. Normalized relative CBV and standardized relative CBV maps were generated, including postprocessing with contrast agent leakage correction (C+) and without (C-) contrast agent leakage correction. Contrast-enhancing lesion volume, mean relative CBV, and contrast-to-noise ratio obtained with 30°/P-/C-, 30°/P-/C+, and 60°/P+/C- were compared with 60°/P+/C+ using the Lin concordance correlation coefficient and Bland-Altman analysis. Equivalence between the 30°/P-/C+ and 60°/P+/C+ protocols and the temporal SNR for the 30°/P- and 60°/P+ DSC-MR imaging data was also determined. RESULTS: Compared with 60°/P+/C+, 30°/P-/C+ had closest mean standardized relative CBV (P = .61), highest Lin concordance correlation coefficient (0.96), and lowest Bland-Altman bias (µ = 1.89), compared with 30°/P-/C- (P = .02, Lin concordance correlation coefficient = 0.59, µ = 14.6) and 60°/P+/C- (P = .03, Lin concordance correlation coefficient = 0.88, µ = -10.1) with no statistical difference in contrast-to-noise ratios across protocols. The normalized relative CBV and standardized relative CBV were statistically equivalent at the 10% level using either the 30°/P-/C+ or 60°/P+/C+ protocols. Temporal SNR was not significantly different for 30°/P- and 60°/P+ (P = .06). CONCLUSIONS: Tumor relative CBV derived from low-flip angle, no-preload DSC-MR imaging with leakage correction is an attractive single-dose alternative to the higher dose reference standard.

Multisite Concordance of DSC-MRI Analysis for Brain Tumors: Results of a National Cancer Institute Quantitative Imaging Network Collaborative Project.

BACKGROUND AND PURPOSE: Standard assessment criteria for brain tumors that only include anatomic imaging continue to be insufficient. While numerous studies have demonstrated the value of DSC-MR imaging perfusion metrics for this purpose, they have not been incorporated due to a lack of confidence in the consistency of DSC-MR imaging metrics across sites and platforms. This study addresses this limitation with a comparison of multisite/multiplatform analyses of shared DSC-MR imaging datasets of patients with brain tumors. MATERIALS AND METHODS: DSC-MR imaging data were collected after a preload and during a bolus injection of gadolinium contrast agent using a gradient recalled-echo-EPI sequence (TE/TR = 30/1200 ms; flip angle = 72°). Forty-nine low-grade (n = 13) and high-grade (n = 36) glioma datasets were uploaded to The Cancer Imaging Archive. Datasets included a predetermined arterial input function, enhancing tumor ROIs, and ROIs necessary to create normalized relative CBV and CBF maps. Seven sites computed 20 different perfusion metrics. Pair-wise agreement among sites was assessed with the Lin concordance correlation coefficient. Distinction of low- from high-grade tumors was evaluated with the Wilcoxon rank sum test followed by receiver operating characteristic analysis to identify the optimal thresholds based on sensitivity and specificity. RESULTS: For normalized relative CBV and normalized CBF, 93% and 94% of entries showed good or excellent cross-site agreement (0.8 ≤ Lin concordance correlation coefficient ≤ 1.0). All metrics could distinguish low- from high-grade tumors. Optimum thresholds were determined for pooled data (normalized relative CBV = 1.4, sensitivity/specificity = 90%:77%; normalized CBF = 1.58, sensitivity/specificity = 86%:77%). CONCLUSIONS: By means of DSC-MR imaging data obtained after a preload of contrast agent, substantial consistency resulted across sites for brain tumor perfusion metrics with a common threshold discoverable for distinguishing low- from high-grade tumors.

Progressing Bevacizumab-Induced Diffusion Restriction Is Associated with Coagulative Necrosis Surrounded by Viable Tumor and Decreased Overall Survival in Patients with Recurrent Glioblastoma.

BACKGROUND AND PURPOSE: Patients with recurrent glioblastoma often exhibit regions of diffusion restriction following the initiation of bevacizumab therapy. Studies suggest that these regions represent either diffusion-restricted necrosis or hypercellular tumor. This study explored postmortem brain specimens and a population analysis of overall survival to determine the identity and implications of such lesions. MATERIALS AND METHODS: Postmortem examinations were performed on 6 patients with recurrent glioblastoma on bevacizumab with progressively growing regions of diffusion restriction. ADC values were extracted from regions of both hypercellular tumor and necrosis. A receiver operating characteristic analysis was performed to define optimal ADC thresholds for differentiating tissue types. A retrospective population study was also performed comparing the overall survival of 64 patients with recurrent glioblastoma treated with bevacizumab. Patients were separated into 3 groups: no diffusion restriction, diffusion restriction that appeared and progressed within 5 months of bevacizumab initiation, and delayed or stable diffusion restriction. An additional analysis was performed assessing tumor O6-methylguanine-DNA-methyltransferase methylation. RESULTS: The optimal ADC threshold for differentiation of hypercellularity and necrosis was 0.736 × 10-3mm2/s. Progressively expanding diffusion restriction was pathologically confirmed to be coagulative necrosis surrounded by viable tumor. Progressive lesions were associated with the worst overall survival, while stable lesions showed the greatest overall survival (P < .05). Of the 40% of patients with O6-methylguanine-DNA-methyltransferase methylated tumors, none developed diffusion-restricted lesions. CONCLUSIONS: Progressive diffusion-restricted lesions were pathologically confirmed to be coagulative necrosis surrounded by viable tumor and associated with decreased overall survival. Stable lesions were, however, associated with increased overall survival. All lesions were associated with O6-methylguanine-DNA-methyltransferase unmethylated tumors.

In vivo detection of postictal perturbations of cerebral metabolism by use of proton MR spectroscopy: preliminary results in a canine model of prolonged generalized seizures.

BACKGROUND AND PURPOSE: Biochemical studies of seizures in patients and laboratory animals have monitored postictal perturbations in cerebral metabolism with either invasive techniques or with such noninvasive techniques as nuclear medicine, MR imaging, in vivo phosphorus MR spectroscopy (MRS), and in vivo proton MRS at field strengths of 1.5 T or above. We investigated postictal metabolic changes in a generalized seizure model with in vivo proton MRS at 0.5 T, in which the combination of glutamate and glutamine resonances (denoted glx) can be modeled as a singlet. METHODS: Five adult mongrel dogs underwent control and postictal experiments in which single-voxel proton MR spectra were obtained from the right frontal lobe cortex with a point-resolved spectroscopy technique approximately every 20 minutes for 3 hours. N-acetylaspartate (NAA), glx, and creatine (Cr) were quantified in absolute millimolar units with a cerebral water-referenced algorithm. Inter- and intrasubject differences in mean metabolite concentrations collected throughout the 3-hour period were compared using an unpaired, two-tailed Student's t test at a.05 level of significance. RESULTS: We found a significant increase (15.4%) in the postictal intersubject mean glx concentration, as well as a 23.7% postictal decrease in the intersubject mean Cr concentration. A trend toward a subtle decrease in postictal intersubject mean NAA concentration was not statistically significant. We also observed a substantial qualitative increase in the combination of postictal lactate and free fatty acid peaks. CONCLUSIONS: The glx, NAA, lactate, and free fatty acid results are in general agreement with previous studies of postictal perturbations in cerebral metabolism measured with invasive biochemical or noninvasive high-field-strength in vivo MRS detection assays. Given a high sensitivity for glx at 0.5 T relative to 1.5 T, further studies of postictal mesial temporal lobe structures are warranted in chronic animal preparations that model temporal lobe epilepsy.

Utility of simultaneously acquired gradient-echo and spin-echo cerebral blood volume and morphology maps in brain tumor patients.

An interleaved gradient-echo (GE) / spin-echo (SE) EPI sequence was used to acquire images during the first pass of a susceptibility contrast agent, in patients with brain tumors. Maps of 1) GE (total) rCBV (relative cerebral blood volume), 2) SE (microvascular) rCBV, both corrected for T(1) leakage effects, and 3) (DeltaR(2)*/DeltaR(2)), a potential marker of averaged vessel diameter, were determined. Both GE rCBV and DeltaR(2)*/DeltaR(2) correlated strongly with tumor grade (P = 0.01, P = 0.01, n = 15), while SE rCBV did not (P = 0.24, n = 15). When the GE rCBV data were not corrected for leakage effects, the correlation with tumor grade was no longer significant (P = 0.09, n = 15). These findings suggest that MRI measurements of total blood volume fraction (corrected for agent extravasation) and DeltaR(2)*/DeltaR(2), as opposed to maps of microvascular volume, may prove to be the most appropriate markers for the evaluation of tumor angiogenesis (the induction of new blood vessels) and antiangiogenic therapies. Magn Reson Med 43:845-853, 2000.

Applicability of American College of Radiology appropriateness criteria in a general internal medicine clinic.

OBJECTIVE: The American College of Radiology (ACR) Appropriateness Criteria for Imaging and Treatment Decisions are intended to help radiologists and referring physicians use imaging procedures appropriately and cost-effectively, but these criteria have not undergone empirical testing. To assess how readily the ACR appropriateness criteria can be applied to clinical practice, we retrospectively examined their applicability in a general ambulatory care setting. MATERIALS AND METHODS: From all requests during an 8-month period for noninterventional CT, sonography, MR imaging, and nuclear medicine imaging procedures received from a general internal medicine clinic, we excluded cases for which relevant clinic notes were unavailable or incomplete. Three experienced radiologists classified cases by consensus, using data from radiology requests and clinic notes. Cases were classified as a "complete match" if the features matched a clinical condition and variant included in the ACR appropriateness criteria; as a "partial match" if the features matched a clinical condition but did not match all features of a variant; or as "unmatched." RESULTS: Of 316 cases, there were 202 complete matches (64%) and 37 partial matches (12%). Of the 77 unmatched cases (24%), 14 pertained to asymptomatic patients. CONCLUSION: The ACR appropriateness criteria could be applied to 76% of the imaging procedure requests that we received from a general internal medicine clinic. These results suggest that the ACR appropriateness criteria can be applied to diagnostic imaging in a general ambulatory-care setting.

Proton MR spectroscopy of the brain.

Over the past five decades, MR spectroscopy has evolved from an analytical chemistry tool to a noninvasive clinical examination on FDA approved equipment with an AMA billing code. While proton MR spectroscopy has dominated current clinical studies, interest in other nucleii has arisen, particularly P-31 for the evaluation of membrane lipids, and C-13 for the evaluation of glutamate neurotransmission and excitotoxicity. Currently, the most common neuroradiological diagnostic indication is the differentation of suspected cerebral neoplasms for post-treatment effects, abcesses, subacute infarcts, demyelinating disease, and other non-neoplastic processes. Recent recommendations for monitoring multiple sclerosis treatment suggest an increasing role for MR spectroscopy in the future.

Single-voxel proton MR spectroscopy of nonneoplastic brain lesions suggestive of a neoplasm.

BACKGROUND AND PURPOSE: MR spectroscopy is used to characterize biochemical components of normal and abnormal brain tissue. We sought to evaluate common histologic findings in a diverse group of nonneoplastic diseases in patients with in vivo MR spectroscopic profiles suggestive of a CNS neoplasm. METHODS: During a 2-year period, 241 patients with suspected neoplastic CNS lesions detected on MR images were studied with MR spectroscopy. Of these, five patients with a nonneoplastic diagnosis were identified retrospectively; a sixth patient without tissue diagnosis was added. MR spectroscopic findings consistent with a neoplasm included elevated choline and decreased N-acetylaspartate and creatine, with or without detectable mobile lipid and lactate peaks. RESULTS: The histologic specimens in all five patients for whom tissue diagnoses were available showed significant WBC infiltrates, with both interstitial and perivascular accumulations of lymphocytes, macrophages, histiocytes, and (in one case) plasma cells. Reactive astrogliosis was also prominent in most tissue samples. This cellular immune response was an integral component of the underlying disorder in these patients, including fulminant demyelination in two patients, human herpesvirus 6 encephalitis in one patient, organizing hematoma from a small arteriovenous malformation in one patient, and inflammatory pseudotumor in one patient. Although no histologic data were available in the sixth patient, neoplasm was considered unlikely on the basis of ongoing clinical and neuroradiologic improvement without specific therapy. CONCLUSION: Nonneoplastic disease processes in the CNS may elicit a reactive proliferation of cellular elements of the immune system and of glial tissue that is associated with MR spectroscopic profiles indistinguishable from CNS neoplasms with current in vivo MR spectroscopic techniques. Such false-positive findings substantiate the need for histologic examination of tissue as the standard of reference for the diagnosis of intracranial mass lesions.

Focal brain lesions: effect of single-voxel proton MR spectroscopic findings on treatment decisions.

PURPOSE: To determine the influence of single-voxel proton magnetic resonance (MR) spectroscopic findings on the treatment of patients suspected of having a brain tumor. MATERIALS AND METHODS: Medical records were reviewed in 78 patients who underwent MR spectroscopy for evaluation of a focal brain mass suspected of being neoplastic. MR spectroscopic findings were positive for neoplasm in 49 patients and negative in 29. Treatment with or without performance of biopsy was noted. In patients with positive findings who underwent irradiation or chemotherapy without biopsy and in patients with negative findings who were treated medically or followed up for interval changes, MR spectroscopy was classified as having a potential positive influence on treatment. In patients with positive findings with subsequently proved nonneoplastic lesions and in patients with negative findings with subsequently proved tumors, MR spectroscopy was classified as having a potential negative influence. RESULTS: MR spectroscopy in eight (16%) patients with positive findings and in 15 (52%) patients with negative findings had a potential positive influence on treatment. In two (3%) patients, MR spectroscopy had a potential negative influence. CONCLUSION: MR spectroscopy may play a beneficial role in the management of suspected brain tumors. Prospective studies are needed to test the effect of MR spectroscopy on clinical practice and to measure costs and benefits.

Recent advances in MR spectroscopy expand its applications in neurologic disease.

MRS extends the diagnostic power of MRI by displaying the biochemical composition of a selected tissue or region. When MR imaging shows a lesion, the evaluation of the chemical composition by MRS can help determine whether biopsy, observation or medical treatment is indicated. It can save some patients from biopsy prior to radiation or chemotherapy. In the future, both the image information and the spatial distribution of chemical constituents throughout the brain will be displayed with techniques such as chemical shift imaging (CSI). MRS improves the accuracy of MRI diagnosis and prognosis. MRS is performed at many sites in the country and is reimbursed by many insurers. MRS has been approved by the AMA for a CPT-4 code for reimbursement.

Accuracy of single-voxel proton MR spectroscopy in distinguishing neoplastic from nonneoplastic brain lesions.

PURPOSE: To measure the accuracy of single-voxel, image-guided proton MR spectroscopy in distinguishing normal from abnormal brain tissue and neoplastic from nonneoplastic brain disease. METHODS: MR spectroscopy was performed at 0.5 T with the point-resolved spectroscopic pulse sequence and conventional postprocessing techniques. Subjects consisted of a consecutive series of patients with suspected brain neoplasms or recurrent neoplasia and 10 healthy adult volunteers. Fifty-five lesions in 53 patients with subsequently verified final diagnoses were included. Spectra were interpreted qualitatively by visual inspection by nonblinded readers (prospectively) with the benefit of prior clinical data and imaging studies, and by blinded readers (retrospectively). The nonblinded readers interpreted the spectra as diagnostic or not, and, if diagnostic, as neoplastic or nonneoplastic. The blinded readers classified the spectra as diagnostic or not, and, if diagnostic, as normal or abnormal and as neoplastic or nonneoplastic (when abnormal). The sensitivity, specificity, positive and negative predictive values, and accuracy were calculated from blinded and nonblinded MR spectroscopy interpretations. A receiver operator characteristic (ROC) curve analysis was performed on blinded MR spectroscopy interpretations. RESULTS: The diagnostic accuracy averaged across four blinded readers in differentiating patients from control subjects was .96, while the area under the aggregate (pooled interpretations) ROC curve approached unity. Accuracy in the nonblinded and blinded discrimination of neoplastic from nonneoplastic disease was .96 and .83, respectively. The area under the aggregate ROC curve in the blinded discrimination of neoplasm from nonneoplasm was .89. CONCLUSIONS: Image-guided proton spectra obtained at 0.5 T from patients with suspected neoplasia can be distinguished from spectra in healthy control subjects, and neoplastic spectra can be distinguished from nonneoplastic spectra with a high degree of diagnostic accuracy.

Appropriateness of imaging procedure requests: do radiologists agree?

OBJECTIVE: We explored the agreement among radiologists in their evaluation of the appropriateness of individual requests for imaging procedures. MATERIALS AND METHODS: We reviewed 318 noninterventional CT, sonographic, MR imaging, and nuclear medicine procedures ordered at a general internal medicine clinic during 8 months in 1995. Five subspecialty radiologists used data from the radiology request from and clinic notes to independently rate the appropriateness of each requested imaging procedure on a four-point scale. The radiologists were unaware of the results achieved by each procedure. Each case was reviewed by at least three radiologists, of whom at least one had relevant subspecialty expertise. Agreement among radiologists was analyzed using Cohen's kappa statistic and weighted kappa statistics and Cronbach's alpha statistic. RESULTS: Nonchance agreement (kappa) was .19 +/- .05; weighted kappa was .24 +/- .05. Interrater agreement was significantly greater than that expected from chance alone (p < .01). The composite score, defined as the average of the radiologists' scores for each case, showed moderate reliability, as evidenced by a value for Cronbach's alpha of 70. CONCLUSION: In the absence of explicit criteria, we found modest but statistically significant agreement among radiologists about the appropriateness of individual requests for imaging procedures. The disagreement among radiologists highlights the importance of developing well-reasoned, explicit criteria by which to judge the appropriateness of diagnostic radiology procedures. Further study is needed to elucidate the relationship between appropriateness and actual patient outcomes.

A Nyquist modulated echo-to-view mapping scheme for fast spin-echo imaging.

A new scheme for assignment of echoes to views in fast spin-echo imaging was developed. The scheme places early and late echoes in alternating lines of the periphery of k-space; continued alternation of echoes arising closer to the middle of the echo train encodes the central portion of k-space. The scheme has two effects: a) The echo-to-echo signal decay that usually gives rise to multiple faint ghosts, now yields a single Nyquist ghost that is removed by phase over-sampling. b) Mapping earlier echoes (and thus more energy) to the periphery of k-space yields sharper edges.

Three-dimensional fast spin-echo imaging: pulse sequence and in vivo image evaluation.

Three-dimensional (3D) magnetic resonance imaging allows thin-section acquisition and therefore more accurate multiplanar reconstruction than conventional two-dimensional spin-echo imaging. Unfortunately, addition of a third acquisition plane extends imaging time greatly. With gradient-echo techniques, 3D acquisitions have become clinically useful. These techniques are limited, however, by susceptibility and other field inhomogeneity artifacts and decreased signal-to-noise ratios compared with spin-echo techniques. The authors describe implementation of a true spin-echo 3D technique that, by using fast spin-echo parameters, reduces acquisition time to a clinically useful level. Potential applications of the technique are demonstrated.

Rapid projection MRI of short T(2) species with multiple small angle excitations and oscillatory-rotary field gradients.

The use of images weighted by transverse relaxation time T(2) in the identification of pathology in many organ systems is reported. Recent applications by R.C. Hawkes and S. Patz (1987) of steady-state free precision (SSFP) excitation to both static readout gradient (2DFT) and cosinusoidal readout gradient techniques have investigated species with T(2) values on the order of several milliseconds. This work is extended with a one-dimensional cosinusoidal gradient to a two-dimensional projection format through a gradient that simultaneously oscillates and rotates, proposed by S.J. Norton (1987). Each position of interest is encoded (and decoded) during free decay through the unique phase modulation (demodulation) determined by the continuously time-varying gradient. Ideal reconstruction consists of long term integration of the product of the observed signal and a phase demodulation kernel. The approach for a single (or set of independent) FID(s) following a nonselective 90 degrees pulse is modified to image short as well as long T(2) species with the periodic steady state obtained by SSFP excitation.

Rapid MRI of short t2 species with multiple small angle excitations and time-varying gradients.

Images weighted by transverse relaxation time T2 have established efficacy in tissue characterization and enhanced the sensitivity and specificity of the diagnosis of pathology in many organ systems. While relatively long echo times (TE) on the order of 50-100 ms appear to improve image contrast, they do so at the expense of a loss of information, namely short T2 species. This precludes the correlation of complex determinants of tissue T2 decay such as the modulation of intrinsic dipolar interactions by molecular processes like proton exchange, proton transfer, and diffusion, with biological factors such as the degree of tissue hydration (compartmentalization), oxygen content, and temperature. We present a rapid MRI technique that employs multiple small angle excitations synchronized to periodic gradient fields to image both a short T2 species that is not visualized and several long T2 species that are seen with a current spin echo and gradient recalled echo technique (TE = 12.5 ms). The unique phase modulation to which each point in space is subjected is decoded through long term integration of the product of the observed periodic steady-state (dynamic equilibrium) signal and a phase demodulation kernel. Whereas gradient recalled echo techniques with static readout gradients are extremely sensitive to main magnet inhomogeneities, susceptibility changes, and chemical shifts, the decoding operation above can be modified to provide a relatively high degree of immunity to these variations. Furthermore, continuous cosinusoidal gradients enable the use of resonant gradient circuitry to eliminate switching transients and to dissipate less power for comparable amplitudes.

Mechanisms for excited state relaxation and dissociation of oxymyoglobin and carboxymyoglobin.

The dissociation of carboxymyoglobin (MbCO) and oxymyoglobin (MbO2) induced by 530-nm picosecond excitation in the beta band or the 355-nm delta band has been measured by monitoring the absorbance changes at 420 and 440 nm corresponding to ligand-bound and ligand-detached species, respectively. We find that MbO2 and MbCO dissociate with very similar rates, which do not reflect the 30-fold difference between the quantum yields of the two reactions. Kinetic data suggest that a short-lived intermediate is formed that is responsible for the low quantum efficiency of the MbO2 dissociation.