Delay of Aortic Arterial Input Function Time Improves Detection of Malignant Vertebral Body Lesions on Dynamic Contrast-Enhanced MRI Perfusion.

Dynamic contrast-enhanced MRI (DCE) is an emerging modality in the study of vertebral body malignancies. DCE-MRI analysis relies on a pharmacokinetic model, which assumes that contrast uptake is simultaneous in the feeding of arteries and tissues of interest. While true in the highly vascularized brain, the perfusion of the spine is delayed. This delay of contrast reaching vertebral body lesions can affect DCE-MRI analyses, leading to misdiagnosis for the presence of active malignancy in the bone marrow. To overcome the limitation of delayed contrast arrival to vertebral body lesions, we shifted the arterial input function (AIF) curve over a series of phases and recalculated the plasma volume values (Vp) for each phase shift. We hypothesized that shifting the AIF tracer curve would better reflect actual contrast perfusion, thereby improving the accuracy of Vp maps in metastases. We evaluated 18 biopsy-proven vertebral body metastases in which standard DCE-MRI analysis failed to demonstrate the expected increase in Vp. We manually delayed the AIF curve for multiple phases, defined as the scan-specific phase temporal resolution, and analyzed DCE-MRI parameters with the new AIF curves. All patients were found to require at least one phase-shift delay in the calculated AIF to better visualize metastatic spinal lesions and improve quantitation of Vp. Average normalized Vp values were 1.78 ± 1.88 for zero phase shifts (P0), 4.72 ± 4.31 for one phase shift (P1), and 5.59 ± 4.41 for two phase shifts (P2). Mann-Whitney U tests obtained p-values = 0.003 between P0 and P1, and 0.0004 between P0 and P2. This study demonstrates that image processing analysis for DCE-MRI in patients with spinal metastases requires a careful review of signal intensity curve, as well as a possible adjustment of the phase of aortic AIF to increase the accuracy of Vp.

CNS Metastases in Patients With MET Exon 14-Altered Lung Cancers and Outcomes With Crizotinib.

PURPOSE: Although MET exon 14 (METex14)-altered lung cancers were first identified more than a decade and a half ago, the frequency of CNS metastatic disease remains poorly defined. Furthermore, the seminal trial of crizotinib in these patients (PROFILE 1001) did not report patterns of CNS response or progression. PATIENTS AND METHODS: Patients with pathologically confirmed, advanced non-small-cell lung cancers (NSCLC) harboring a METex14 alteration by targeted DNA/RNA sequencing were studied. The incidence of brain metastases and the outcomes of MET inhibition with crizotinib were analyzed. RESULTS: Eighty-three patients with METex14-altered metastatic NSCLC were identified. The incidence of CNS metastases at diagnosis was 17% (95% CI, 10% to 27%). The lifetime incidence was 36% (95% CI, 26% to 47%); 83% of patients had parenchymal disease, and 17% had leptomeningeal disease. The probability of having brain metastasis at 1, 2, and 3 years was 24%, 35%, and 38%, respectively. Fifty-four patients received crizotinib. The median time to radiologic CNS progression was 5.8 months (range, 3.7-20.0 months). Patterns of crizotinib progression were as follows: intracranial only in 10% of patients, intracranial and extracranial in 12%, and extracranial only in 78%. In patients with brain metastases before treatment, the median time on crizotinib was 7.5 months (range, 7.2-11.7 months). CONCLUSION: CNS metastases, including leptomeningeal disease, occurred in more than a third of patients with METex14-altered lung cancers. In crizotinib-treated patients with or without CNS metastases, CNS failure was seen in less than a quarter of patients on progression.

Comparison of Glioblastomas and Brain Metastases using Dynamic Contrast-Enhanced Perfusion MRI.

PURPOSE: To compare glioblastoma and brain metastases using T1-weighted dynamic contrast-enhanced (DCE)-MRI perfusion technique. METHODS: 26 patients with glioblastoma and 32 patients with metastatic brain lesions with no treatment who underwent DCE-MRI were, retrospectively, analyzed. DCE perfusion parameters K(trans) and Vp were calculated for the whole tumor. Signal intensity time curves were quantified by calculating the area under the curve (AUC) and the logarithmic slope of the washout phase to explore the heterogeneous tumor characteristics. RESULTS: Glioblastoma did not differ from all brain metastases in K(trans) (P = .34) or Vp (P = .47). Glioblastoma and melanoma metastases differed from hypovascular metastases in AUC and log slope of the washout phase of the signal intensity time curve (P < .05); however, glioblastoma and melanoma metastases did not differ from each other (AUC: P = .78, Log slope: P = .77). Glioblastoma and melanoma metastases differed from hypovascular metastases in the ratio of Voxelneg /Voxelpos (P< .03); however, they did not differ from each other. Glioblastoma and melanoma metastases differed from each other in Voxelneg_threshold at higher negative log slope threshold. CONCLUSION: DCE-MRI showed that it has a potential to differentiate glioblastomas, melanoma metastases and hypovascular brain tumors. Logarithmic slope of the washout phase and AUC of the signal intensity time curve were shown to be the best discriminator between hypervascular and hypovascular neoplasms.

Early magnetic resonance imaging biomarkers to predict local control after high dose stereotactic body radiotherapy for patients with sarcoma spine metastases.

BACKGROUND CONTEXT: Recent advances in image guidance and stereotactic body radiotherapy (SBRT) have resulted in unprecedented local control for spinal metastases of all histologies. However, little is known about early imaging biomarkers of local control. PURPOSE: This study aimed to identify early magnetic resonance imaging (MRI) biomarkers to predict local control after SBRT for patients with sarcoma spine metastases. STUDY DESIGN/SETTING: This study used a retrospective case series at a large tertiary cancer center. PATIENT SAMPLE: From 2011 to 2014, 9 consecutive patients with 12 metastatic sarcoma lesions to the spine were treated with SBRT and underwent evaluation with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) both pre- and post-SBRT. OUTCOME MEASURE: Changes in perfusion metrics, including the wash-in rate constant (Ktrans), plasma volume (Vp), composite multiparametric magnetic resonance imaging (mpMRI) score, bi-dimensional tumor size, and a graded response assessment were performed and correlated to local control. METHODS: All measurements were independent and blinded by two neuroradiologists. R2 statistics were performed to document correlation, and two-tailed t tests were used to compare groups. p<.05 was deemed statistically significant. RESULTS: The median time from SBRT until posttreatment MRI was 57 days. Local failure developed in one lesion (8.3%) 10 months after SBRT. The Vp mean, Ktrans mean, Vp max, and Ktrans max were significantly decreased post-SBRT as compared with pre-SBRT (58.7%, 63.2%, 59.0%, and 55.2%; all p-values <.05). Bi-dimensional tumor measurements demonstrated an average increase in size across the cohort, and 50%, 25%, and 25% of the treated lesions demonstrated features of "worsening," "no change," or "improvement," respectively, by both radiologists' graded impressions. There was good inter-reader reliability for both size and subjective disease response scores (R2=0.84). The mpMRI score had 100% accuracy in predicting local control at time of last follow-up. There was no apparent correlation with size changes compared with the mpMRI score change post-SBRT (R2=0.026). CONCLUSIONS: We report the first analysis on the utility of DCE-MRI for metastatic sarcoma spine metastases treated with SBRT. We demonstrate that early assessment at 2 months post-SBRT using size and subjective neuroradiology impressions is insufficient to judge ultimate disease progression, and that a combination of perfusion parameters provides excellent correlation to local control.

Corpus Callosum Diffusion and Language Lateralization in Patients with Brain Tumors: A DTI and fMRI Study.

BACKGROUND AND PURPOSE: Examining how left-hemisphere brain tumors might impact both the microstructure of the corpus callosum (CC) as measured by fractional anisotropy (FA) values in diffusion tensor imaging (DTI) as well as cortical language lateralization measured with functional MRI (fMRI). METHODS: fMRI tasks (phonemic fluency and verb generation) were performed in order to detect activation in Broca's and Wernicke's area. Twenty patients with left-hemisphere brain tumors were investigated. fMRI results were divided into left dominant (LD), right dominant (RD), or codominant (CD) for language function. DTI was performed to generate FA maps in the anterior and posterior CC. FA values were correlated with the degree of language dominance. RESULTS: Patients who were LD or RD for language in Broca's area had lower FA in the anterior CC than those who were CD for language (median for CD = .72, LD = .66, RD = .65, P < .09). Lateralized versus CD group level analysis also showed that CD patients had higher FA in the anterior CC than patients who displayed strong lateralization in either hemisphere (median for CD = .72, lateralized = .65, P < .05). CONCLUSION: Our preliminary observations indicate that the greater FA in CD patients may reflect a more directional microstructure for the CC in this region, suggesting a greater need for interhemispheric transfer of information. Because brain tumors can cause compensatory codominance, our findings may suggest a mechanism by which interhemispheric transfer is facilitated during plasticity in the presence of a tumor.

Pre-operative fMRI localization of the supplementary motor area and its relationship with postoperative speech deficits.

INTRODUCTION: Neurosurgery of the supplementary motor area (SMA) is associated with transient speech defects. We investigated whether SMA laterality correlates with postoperative speech defects. MATERIALS AND METHODS: The authors reviewed 17 patients with SMA-area lesion resection and preoperative language fMRI. SMA laterality was calculated by comparison of voxel activation in paired SMAs by hand-drawn regions of interest (ROIs) (drawn by a neuroradiologist), and compared with qualitative assessment by two neuroradiologists. Postoperative speech defects before and after surgery were assessed by chart review. RESULTS: Six patients developed new speech defects that resolved within several months. Two of the patients had a pre-existing speech defect that had developed after prior SMA-area surgery. All these patients had left-sided lesions, while none of the four patients with a right-sided lesion developed a speech defect. Neuroradiologists' assessment of SMA laterality agreed with ROI calculation for the SMAs that were lateralized. However, for the SMAs in the "codominant" range by ROI, the neuroradiologists felt that all but one of the cases clearly lateralized, with the exception deemed indeterminate or codominant. No correlation between laterality of SMA and speech defect was identified. Twelve patients showed lateralization contralateral to the lesion. CONCLUSIONS: fMRI lateralization does not correlate with transient speech defects that developed from SMA-area surgery. Qualitative/visual assessment of SMA laterality was superior to ROI calculation because of the close proximity and possible overlap of signal from midline SMA. A majority of patients showed SMA lateralization contralateral to the SMA lesion.

Dynamic Contrast-Enhanced Perfusion MRI and Diffusion-Weighted Imaging in Grading of Gliomas.

PURPOSE: Accurate glioma grading is crucial for treatment planning and predicting prognosis. We performed a quantitative volumetric analysis to assess the diagnostic accuracy of histogram analysis of diffusion-weighted imaging (DWI) and dynamic contrast-enhanced (DCE) T1-weighted perfusion imaging in the preoperative evaluation of gliomas. METHODS: Sixty-three consecutive patients with pathologically confirmed gliomas who underwent baseline DWI and DCE-MRI were enrolled. The patients were classified by histopathology according to tumor grade: 20 low-grade gliomas (grade II) and 43 high-grade gliomas (grades III and IV). Volumes-of-interest were calculated and transferred to DCE perfusion and apparent diffusion coefficient (ADC) maps. Histogram analysis was performed to determine mean and maximum values for Vp and Ktrans , and mean and minimum values for ADC. Comparisons between high-grade and low-grade gliomas, and between grades II, III, and IV, were performed. A Mann-Whitney U test at a significance level of corrected P ≤ .01 was used to assess differences. RESULTS: All perfusion parameters could differentiate between high-grade and low-grade gliomas (P < .001) and between grades II and IV, grades II and III, and grades III and IV. Significant differences in minimum ADC were also found (P < .01). Mean ADC only differed significantly between high and low grades and grades II and IV (P < .01). There were no differences between grades II and III (P = .1) and grades III and IV (P = .71). CONCLUSION: When derived from whole-tumor histogram analysis, DCE-MRI perfusion parameters performed better than ADC in noninvasively discriminating low- from high-grade gliomas.

Differentiating benign from malignant vertebral fractures using T1 -weighted dynamic contrast-enhanced MRI.

PURPOSE: To differentiate pathologic from benign vertebral fractures, which can be challenging. We hypothesized that dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can aid in the noninvasive distinction between pathologic and benign fractures. MATERIALS AND METHODS: Consecutive patients with vertebral fractures who underwent DCE-MRI, biopsy, and kyphoplasty were reviewed. Forty-seven fractures were separated into pathologic and benign fractures. Benign fractures were in turn separated into acute and chronic fractures for further comparison. Regions of interest (ROIs) were placed over fractured vertebral bodies. Perfusion parameters: plasma volume (Vp ), K(trans) , wash-in slope, peak enhancement, and area under the curve (AUC) were measured and compared between the three different groups of fractures. A Mann-Whitney U-test was conducted to assess the difference between the groups. RESULTS: Pathologic fractures had significantly higher (P < 0.01) perfusion parameters (Vp , K(trans) , wash-in slope, peak enhancement, and AUC) compared with benign fractures. We also found significant differences (P < 0.001) in all parameters between chronic and acute fractures. Vp and K(trans) were able to differentiate between pathologic and acute fractures (P < 0.01). No significant differences were found with peak enhancement (P = 0.21) and AUC (P = 0.4) between pathologic and acute fractures. CONCLUSION: Our data demonstrate that T1 -weighted DCE-MRI has potential to differentiate between pathologic vs. benign, acute vs. chronic, and most important, benign acute vs. pathologic vertebral fractures.

A phase II study of pralatrexate with vitamin B12 and folic acid supplementation for previously treated recurrent and/or metastatic head and neck squamous cell cancer.

BACKGROUND: Pralatrexate (Fotolyn(TM); Allos Therapeutics Inc.) is an antifolate dihydrofolate reductase (DHFR) inhibitor. We conducted a phase II study of pralatrexate with folic acid and B12 supplementation in patients with recurrent and/or metastatic head and neck squamous cell cancer (R/M HNSCC). PATIENTS AND METHODS: This was a single-arm, Simon optimal two stage phase II study. Patients with R/M HNSCC previously treated with chemotherapy were eligible. The study was initiated with a dosing schedule of pralatrexate 190 mg/m(2) biweekly on a 4-week cycle with vitamin supplementation. Due to toxicity concerns, the dosing was modified to 30 mg/m(2) weekly for 3 weeks in a 4-week cycle with vitamin supplementation. Radiologic imaging was to be obtained about every 2 cycles. RESULTS: Thirteen subjects were enrolled; 12 were treated. Seven of the twelve patients had previously received ≥2 lines of chemotherapy. The most common grade 3 toxicity was mucositis (3 patients). Seven patients did not complete two cycles of therapy due to progression of disease (4), toxicity (1), death (1), and withdrawal of consent (1). Two deaths occurred: one due to disease progression and the other was an unwitnessed event that was possibly related to pralatrexate. No clinical activity was observed. The median overall survival was 3.1 months. The study was closed early due to lack of efficacy. CONCLUSIONS: Pralatrexate does not possess clinical activity against previously treated R/M HNSCC. Evaluation of pralatrexate in other clinical settings of HNSCC management with special considerations for drug toxicity may be warranted.

Skeletal muscle BOLD MRI: from underlying physiological concepts to its usefulness in clinical conditions.

Blood oxygenation-level dependent (BOLD) MRI has gained particular attention in functional brain imaging studies, where it can be used to localize areas of brain activation with high temporal resolution. To a higher degree than in the brain, skeletal muscles show extensive but transient alterations of blood flow between resting and activation state. Thus, there has been interest in the application of the BOLD effect in studying the physiology of skeletal muscles (healthy and diseased) and its possible application to clinical practice. This review outlines the potential of skeletal muscle BOLD MRI as a diagnostic tool for the evaluation of physiological and pathological alterations in the peripheral limb perfusion, such as in peripheral arterial occlusive disease. Moreover, current knowledge is summarized regarding the complex mechanisms eliciting BOLD effect in skeletal muscle. We describe technical fundaments of the procedure that should be taken into account when performing skeletal muscle BOLD MRI, including the most often applied paradigms to provoke BOLD signal changes and key parameters of the resulting time courses. Possible confounding effects in muscle BOLD imaging studies, like age, muscle fiber type, training state, and drug effects are also reviewed in detail.

Clinical implications of skeletal muscle blood-oxygenation-level-dependent (BOLD) MRI.

Blood-oxygenation-level-dependent (BOLD) contrast in magnetic resonance (MR) imaging of skeletal muscle mainly depends on changes of oxygen saturation in the microcirculation. In recent years, an increasing number of studies have evaluated the clinical relevance of skeletal muscle BOLD MR imaging in vascular diseases, such as peripheral arterial occlusive disease, diabetes mellitus, and chronic compartment syndrome. BOLD imaging combines the advantages of MR imaging, i.e., high spatial resolution, no exposure to ionizing radiation, with functional information of local microvascular perfusion. Due to intrinsic contrast provoked via changes in hemoglobin oxygen saturation, it is a safe and easy applicable procedure on standard whole-body MR devices. Therefore, BOLD MR imaging of skeletal muscle is a potential new diagnostic tool in the clinical evaluation of vascular, inflammatory, and muscular pathologies. Our review focuses on the current evidence concerning the use of BOLD MR imaging of skeletal muscle under pathological conditions and highlights ways for future clinical and scientific applications.

Effects of covert and overt paradigms in clinical language fMRI.

RATIONALE AND OBJECTIVES: The aim of this study was to assess the intrasubject and intersubject reproducibility of functional magnetic resonance imaging (fMRI) language paradigms on language localization and lateralization. MATERIALS AND METHODS: Fourteen healthy volunteers were enrolled prospectively and underwent language fMRI using visually triggered covert and overt sentence generation (SG) and word generation (WG) paradigms. Semiautomated analysis of all functional data was performed using Brain Voyager on an individual basis. Regions of interest for Broca's area, Wernicke's area, and their contralateral homologues were drawn. The Euclidean coordinates of the center of gravidity (x, y, and z) of the respective blood oxygenation level-dependent (BOLD) activation cluster, and the correlation of the measured hemodynamic response to the applied reference function (r), relative BOLD signal change as BOLD signal characteristics were measured in each region of interest. Regional lateralization indexes were calculated for Broca's area, Wernicke's area, and their contralateral homologues separately. Wilcoxon's signed-rank test was applied for statistical comparisons (P values < .05 were considered significant). Ten of the 14 volunteers had three repeated measurements to test intrasession reproducibility and intersession reproducibility. RESULTS: Overall activation rates for the four paradigms were 89% for covert SG, 82% for overt SG, 89% for covert WG, and 100% for overt WG. When comparing covert and overt paradigms, language localization was significantly different in 17% (Euclidean coordinates) and 19% (BOLD signal characteristics), respectively. Language lateralization was significantly different in 75%. Intrasubject and intersubject reproducibility was excellent, with 3.3% significant differences among all five parameters for language localization and 0% significant differences for language lateralization using covert paradigms. CONCLUSIONS: Covert language paradigms (SG and WG) provided highly robust and reproducible localization and lateralization of essential language centers for scans performed on the same and different days. Their overt counterparts achieved confirmatory localization but lower lateralization capabilities. Reference data for presurgical application are provided.

Imaging of metastatic CNS neuroblastoma.

OBJECTIVE: Although neuroblastoma is a common childhood malignancy, which frequently metastasizes, involvement of the CNS is rarely reported in the literature. However, over the past several years, we have encountered an increasing number of cases of metastatic neuroblastoma to the CNS. This metastatic potential and changing metastatic pattern may, in part, be due to advances in medical treatment, leading to prolonged survival. This article will review the common and uncommon manifestations of metastatic neuroblastoma with an emphasis on the skull, dura, brain, ventricles, and leptomeninges. CONCLUSION: Neuroblastoma has diverse manifestations including masquerading as primary neurologic disease. This disease must be considered in a child with any unexplained neurologic disorder. Realizing that neuroblastoma may represent the cause of neurologic disease in a child will lead to earlier diagnosis.

Close packing of Listeria monocytogenes ActA, a natively unfolded protein, enhances F-actin assembly without dimerization.

Studies of the biochemistry of Listeria monocytogenes virulence protein ActA have typically focused on the behavior of bacteria in complex systems or on the characterization of the protein after expression and purification. Although prior in vivo work has proposed that ActA forms dimers on the surface of L. monocytogenes, dimerization has not been demonstrated in vitro, and little consideration has been given to the surface environment where ActA performs its pivotal role in bacterial actin-based motility. We have synthesized and characterized an ActA dimer and provide evidence that the two ActA molecules do not interact with each other even when tethered together. However, we also demonstrate that artificial dimers provide superior activation of actin nucleation by the Arp2/3 complex compared with monomers and that increased activation of the Arp2/3 complex by dimers may be a general property of Arp2/3 activators. It appears that the close packing ( approximately 19 nm) of ActA molecules on the surface of L. monocytogenes is so dense that the kinetics of actin nucleation mimic that of synthetic ActA dimers. We also present observations indicating that ActA is a natively unfolded protein, largely random coil that is responsible for many of the unique physical properties of ActA including its extended structure, aberrant mobility during SDS-PAGE, and ability to resist irreversible denaturation upon heating.

Pulmonary nodules on multi-detector row CT scans: performance comparison of radiologists and computer-aided detection.

PURPOSE: To compare the performance of radiologists and of a computer-aided detection (CAD) algorithm for pulmonary nodule detection on thin-section thoracic computed tomographic (CT) scans. MATERIALS AND METHODS: The study was approved by the institutional review board. The requirement of informed consent was waived. Twenty outpatients (age range, 15-91 years; mean, 64 years) were examined with chest CT (multi-detector row scanner, four detector rows, 1.25-mm section thickness, and 0.6-mm interval) for pulmonary nodules. Three radiologists independently analyzed CT scans, recorded the locus of each nodule candidate, and assigned each a confidence score. A CAD algorithm with parameters chosen by using cross validation was applied to the 20 scans. The reference standard was established by two experienced thoracic radiologists in consensus, with blind review of all nodule candidates and free search for additional nodules at a dedicated workstation for three-dimensional image analysis. True-positive (TP) and false-positive (FP) results and confidence levels were used to generate free-response receiver operating characteristic (ROC) plots. Double-reading performance was determined on the basis of TP detections by either reader. RESULTS: The 20 scans showed 195 noncalcified nodules with a diameter of 3 mm or more (reference reading). Area under the alternative free-response ROC curve was 0.54, 0.48, 0.55, and 0.36 for CAD and readers 1-3, respectively. Differences between reader 3 and CAD and between readers 2 and 3 were significant (P < .05); those between CAD and readers 1 and 2 were not significant. Mean sensitivity for individual readings was 50% (range, 41%-60%); double reading resulted in increase to 63% (range, 56%-67%). With CAD used at a threshold allowing only three FP detections per CT scan, mean sensitivity was increased to 76% (range, 73%-78%). CAD complemented individual readers by detecting additional nodules more effectively than did a second reader; CAD-reader weighted kappa values were significantly lower than reader-reader weighted kappa values (Wilcoxon rank sum test, P < .05). CONCLUSION: With CAD used at a level allowing only three FP detections per CT scan, sensitivity was substantially higher than with conventional double reading.