Preclinical Evaluation of 18F-ML-10 to Determine Timing of Apoptotic Response to Chemotherapy in Solid Tumors.

PURPOSE: We investigated 2-(5-fluoro-pentyl)-2-methyl-malonic acid (18F-ML-10) positron emission tomography (PET) imaging of apoptosis posttherapy to determine optimal timing for predicting chemotherapy response in a mouse head/neck xenograft cancer model. PROCEDURES: BALB/c nude mice (4-8 weeks old) were implanted with UM-SCC-22B tumors. The treatment group received 2 doses of doxorubicin (10 mg/kg, days 0, 2). Small animal 18F-ML-10 PET/computed tomography was performed before and on days 1, 3, and 7 postchemotherapy. Using regions of interest around tumors, 18F-ML-10 uptake change was measured as %ID/g and uptake relative to liver. Terminal Uridine Nick-End Labeling (TUNEL) immunohistochemistry assay was performed using tumor samples of baseline and on days 1, 3, and 7 posttreatment. RESULTS: Treated mice demonstrated increased 18F-ML-10 uptake compared to baseline and controls, and 10 of 13 mice showed tumor volume decreases. All control mice showed tumor volume increases. Tumor-to-liver (T/L) ratios from the control group mice did not show significant change from baseline ( P > .05); however, T/L ratios of the treatment group showed significant 18F-ML-10 uptake differences from baseline compared to days 3 and 7 posttreatment ( P < .05), but no significant difference at 1 day posttreatment. CONCLUSION: 2-(5-Fluoro-pentyl)-2-methyl-malonic acid PET imaging has the potential for early assessment of treatment-induced apoptosis. Timing and image analysis strategies may require optimization, depending on the type of tumor and cancer treatment.

In vivo brain rosette spectroscopic imaging (RSI) with LASER excitation, constant gradient strength readout, and automated LCModel quantification for all voxels.

PURPOSE: To optimize the Rosette trajectories for high-sensitivity in vivo brain spectroscopic imaging and reduced gradient demands. METHODS: Using LASER localization, a rosette based sampling scheme for in vivo brain spectroscopic imaging data on a 3 Tesla (T) system is described. The two-dimensional (2D) and 3D rosette spectroscopic imaging (RSI) data were acquired using 20 × 20 in-plane resolution (8 × 8 mm(2) ), and 1 (2D) -18 mm (1.1 cc) or 12 (3D) -8 mm partitions (0.5 cc voxels). The performance of the RSI acquisition was compared with a conventional spectroscopic imaging (SI) sequence using LASER localization and 2D or 3D elliptical phase encoding (ePE). Quantification of the entire RSI data set was performed using an LCModel based pipeline. RESULTS: The RSI acquisitions took 32 s for the 2D scan, and as short as 5 min for the 3D 20 × 20 × 12 scan, using a maximum gradient strength Gmax=5.8 mT/m and slew-rate Smax=45 mT/m/ms. The Bland-Altman agreement between RSI and ePE CSI, characterized by the 95% confidence interval for their difference (RSI-ePE), is within 13% of the mean (RSI+ePE)/2. Compared with the 3D ePE at the same nominal resolution, the effective RSI voxel size was three times smaller while the measured signal-to-noise ratio sensitivity, after normalization for differences in effective size, was 43% greater. CONCLUSION: 3D LASER-RSI is a fast, high-sensitivity spectroscopic imaging sequence, which can acquire medium-to-high resolution SI data in clinically acceptable scan times (5-10 min), with reduced stress on the gradient system. Magn Reson Med 76:380-390, 2016. © 2015 Wiley Periodicals, Inc.

Short-T2 imaging for quantifying concentration of sodium (23 Na) of bi-exponential T2 relaxation.

PURPOSE: This work intends to demonstrate a new method for quantifying concentration of sodium (23 Na) of bi-exponential T2 relaxation in patients on MRI scanners at 3.0 Tesla. THEORY AND METHODS: Two single-quantum (SQ) sodium images acquired at very-short and short echo times (TE = 0.5 and 5.0 ms) are subtracted to produce an image of the short-T2 component of the bi-exponential (or bound) sodium. An integrated calibration on the SQ and short-T2 images quantifies both total and bound sodium concentrations. Numerical models were used to evaluate signal response of the proposed method to the short-T2 components. MRI scans on agar phantoms and brain tumor patients were performed to assess accuracy and performance of the proposed method, in comparison with a conventional method of triple-quantum filtering. RESULTS: A good linear relation (R2 = 0.98) was attained between the short-T2 image intensity and concentration of bound sodium. A reduced total scan time of 22 min was achieved under the SAR restriction for human studies in quantifying both total and bound sodium concentrations. CONCLUSION: The proposed method is feasible for quantifying bound sodium concentration in routine clinical settings at 3.0 Tesla. Magn Reson Med 74:162-174, 2015. © 2014 Wiley Periodicals, Inc.

Classification of amyloid-positivity in controls: comparison of visual read and quantitative approaches.

UNLABELLED: An important research application of amyloid imaging with positron emission tomography (PET) is detection of the earliest evidence of fibrillar amyloid-beta (Aß) deposition. Use of amyloid PET for this purpose, requires a reproducible method for defining a cutoff that separates individuals with no significant Aß deposition from those in which Aß deposition has begun. We previously reported the iterative outlier approach (IO) for the analysis of Pittsburgh Compound-B (PiB) PET data. Developments in amyloid imaging since the initial report of IO have led us to re-examine the generalizability of this method. IO was developed using full-dynamic atrophy-corrected PiB PET data obtained from a group of control subjects with a fairly distinct separation between PiB-positive [PiB(+)] and PiB-negative [PiB(-)] subjects. METHODS: We tested the performance of IO using late-summed tissue ratio data with atrophy correction or with an automated template method without atrophy correction and tested the robustness of the method when applied to a cohort of older subjects in which separation between PiB(+) and PiB(-) subjects was not so distinct. RESULTS: The IO method did not perform consistently across analyses and performed particularly poorly when separation was less clear. We found that a sparse k-means (SKM) cluster analysis approach performed significantly better; performing more consistently across methods and subject cohorts. We also compared SKM to a consensus visual read approach and found very good correspondence. CONCLUSION: The visual read and SKM methods, applied together, may optimize the identification of early Aß deposition. These methods have the potential to provide a standard approach to the detection of PiB-positivity that is generalizable across centers.

Efficacy and safety of metronidazole for pulmonary multidrug-resistant tuberculosis.

Pulmonary lesions from active tuberculosis patients are thought to contain persistent, nonreplicating bacilli that arise from hypoxic stress. Metronidazole, approved for anaerobic infections, has antituberculosis activity against anoxic bacilli in vitro and in some animal models and may target persistent, nonreplicating bacilli. In this double-blind, placebo-controlled trial, pulmonary multidrug-resistant tuberculosis subjects were randomly assigned to receive metronidazole (500 mg thrice daily) or placebo for 8 weeks in addition to an individualized background regimen. Outcomes were measured radiologically (change on high-resolution computed tomography [HRCT]), microbiologically (time to sputum smear and culture conversion), and clinically (status 6 months after stopping therapy). Enrollment was stopped early due to excessive peripheral neuropathies in the metronidazole arm. Among 35 randomized subjects, 31 (15 metronidazole, 16 placebo) were included in the modified intent-to-treat analysis. There were no significant differences by arm in improvement of HRCT lesions from baseline to 2 or 6 months. More subjects in the metronidazole arm converted their sputum smear (P = 0.04) and liquid culture (P = 0.04) to negative at 1 month, but these differences were lost by 2 months. Overall, 81% showed clinical success 6 months after stopping therapy, with no differences by arm. However, 8/16 (50%) of subjects in the metronidazole group and 2/17 (12%) of those in the placebo group developed peripheral neuropathy. Subjects who received metronidazole were 4.3-fold (95% confidence interval [CI], 1.1 to 17.1) more likely to develop peripheral neuropathies than subjects who received placebo. Metronidazole may have increased early sputum smear and culture conversion but was too neurotoxic to use over the longer term. Newer nitroimidazoles with both aerobic and anaerobic activity, now in clinical trials, may increase the sterilizing potency of future treatment regimens.

Quantitative Sodium (23Na) MRI in Pediatric Gliomas: Initial Experience.

Background: 23Na MRI correlates with tumor proliferation, and studies in pediatric patients are lacking. The purpose of the study: (1) to compare total sodium concentration (TSC) between pediatric glioma and non-neoplastic brain tissue using 23Na MRI; (2) compare tissue conspicuity of bound sodium concentration (BSC) using 23Na MRI dual echo relative to TSC imaging. Methods: TSC was measured in: (1) non-neoplastic brain tissues and (2) three types of manually segmented gliomas (diffuse intrinsic brainstem glioma (DIPG), recurrent supratentorial low-grade glioma (LGG), and high-grade glioma (HGG)). In a subset of patients, serial changes in both TSC and BSC (dual echo 23Na MRI) were assessed. Results: Twenty-six pediatric patients with gliomas (median age of 12.0 years, range 4.9−23.3 years) were scanned with 23Na MRI. DIPG treated with RT demonstrated higher TSC values than the uninvolved infratentorial tissues (p < 0.001). Recurrent supratentorial LGG and HGG exhibited higher TSC values than the uninvolved white matter (WM) and gray matter (GM) (p < 0.002 for LGG, and p < 0.02 for HGG). The dual echo 23Na MRI suppressed the sodium signal within both CSF and necrotic foci. Conclusion: Quantitative 23Na MRI of pediatric gliomas demonstrates a range of values that are higher than non-neoplastic tissues. Dual echo 23Na MRI of BCS improves tissue conspicuity relative to TSC imaging.

Direct Comparison of the Tau PET Tracers 18F-Flortaucipir and 18F-MK-6240 in Human Subjects.

Tau PET tracers exhibit varying levels of specific signal and distinct off-target binding patterns that are more diverse than amyloid PET tracers. This study compared 2 frequently used tau PET tracers, 18F-flortaucipir and 18F-MK-6240, in the same subjects. Methods:18F-flortaucipir and 18F-MK-6240 scans were collected within 2 mo in 15 elderly subjects varying in clinical diagnosis and cognition. FreeSurfer, version 5.3, was applied to 3-T MR images to segment Braak pathologic regions (I-VI) for PET analyses. Off-target binding was assessed in the choroid plexus, meninges, and striatum. SUV ratio (SUVR) outcomes were determined over 80-100 min (18F-flortaucipir) or 70-90 min (18F-MK-6240) normalized to cerebellar gray matter. Masked visual interpretation of images was performed by 5 raters for both the medial temporal lobe and the neocortex, and an overall (majority) rating was determined. Results: Overall visual ratings showed complete concordance between radiotracers for both the medial temporal lobe and the neocortex. SUVR outcomes were highly correlated (r2 > 0.92; P ≪ 0.001) for all Braak regions except Braak II. The dynamic range of SUVRs in target regions was approximately 2-fold higher for 18F-MK-6240 than for 18F-flortaucipir. Cerebellar SUVs were similar for 18F-MK-6240 and 18F-flortaucipir, suggesting that differences in SUVRs are driven by specific signals. Apparent off-target binding was observed often in the striatum and choroid plexus with 18F-flortaucipir and most often in the meninges with 18F-MK-6240. Conclusion: Both 18F-MK-6240 and 18F-flortaucipir are capable of quantifying signal in a common set of brain regions that develop tau pathology in Alzheimer disease; these tracers perform equally well in visual interpretations. Each also shows distinct patterns of apparent off-target binding. 18F-MK-6240 showed a greater dynamic range in SUVR estimates, which may be an advantage in detecting early tau pathology or in performing longitudinal studies to detect small interval changes.

Effect of automatic injectors on the injection latency, safety, and seizure onset zone localization of ictal single photon emission computed tomography studies in adult epilepsy monitoring unit.

BACKGROUND: Ictal Single Photon Emission Computed Tomography (iSPECT) is one of the established tools utilized in the presurgical evaluation of patients with drug-resistant epilepsy (DRE). Timely isotope injection for an iSPECT is critical for optimal yield but poses logistical challenges when done manually. We aim to evaluate the added value of automatic iSPECT injectors (ASIs) in overcoming such challenges. METHODS: We retrospectively reviewed all cases admitted to the University of Pittsburgh Medical Center (UPMC) Epilepsy Monitoring Unit from Jan 1, 2010, through Dec 31, 2016, who underwent an iSPECT. We compared the manually injected iSPECTs with those performed with ASIs. RESULTS: A total of 123 iSPECTs were reviewed. The manually injected iSPECT group consisted of 35 patients (median age, 35 years; and 19 males). The automatically injected iSPECT group consisted of 88 patients (median age, 36 years; and 46 males). The two groups were comparable in age, gender, epilepsy treatment, focal features on neuropsychological testing (NPT), EEG, and MRI, and temporal origin of seizures (p > 0.05). Compared to manually injected iSPECTs, automatically injected ISPECTs' median injection latency (IL) was shorter (18.5 vs. 60 s, p < 0.001); the ratio of IL/total duration of seizure was lower (0.395 vs. 0.677, p < 0.001); postictal injections were less frequent (4 (4.5 %) vs. 7 (20 %), p = 0.007); the number of isotope spills was less (zero vs. 3, p = 0.022); and successfully localizing iSPECTs were more prevalent (81.8 % vs. 62.9 %, p = 0.025), even after adjusting for focal features on NPT, EEG, and MRI, the temporal origin of seizures, and seizure duration (OR of 5.539, 95 %CI = 1.653-18.563, p = 0.006). CONCLUSIONS: Utilization of ASIs leads to a significant shortening of iSPECT IL with less postictal injections, provides a safer injection option for the EMU staff, and leads to a significant improvement in the number of successfully localizing iSPECTs.

PET and SPECT Imaging of Brain Tumors.

Neuroimaging plays a vital role in the diagnosis and post-treatment assessment of brain tumors, aiding in treatment optimization, prognostication, and patient management. New clinical treatments have resulted in increased complexity of imaging interpretation, thus integrating complementary information from multiple imaging modalities (computed tomography, magnetic resonance imaging, and nuclear medicine) contributes to a thorough and more accurate evaluation. In review, we discuss current strategies of brain tumor imaging, specifically detailing the role of nuclear medicine single-photon emission computed tomography and positron emission tomography with utilization of both common and uncommon radiotracers in tumor grading, diagnosis, and treatment response.

Differential 18F-FDG and 18F-Fluciclovine Uptake Pattern in a Patient With Poorly Differentiated Adenocarcinoma of the Lung and Prostate Cancer Biochemical Recurrence.

A 72-year-old man with a history of T1cN0M0 prostate adenocarcinoma and rising prostate-specific antigen underwent a fluciclovine PET/CT scan that showed high uptake in several para-aortic nodes, suspicious for prostate cancer. A right upper lobe single pulmonary nodule (SPN), demonstrated only mild uptake, which raised the suspicion for a lung primary. Subsequent FDG PET/CT showed high uptake in the SPN, revealing poorly differentiated adenocarcinoma at biopsy, but with no abnormal uptake in the para-aortic nodes. This case highlights the complementary potential of fluciclovine and FDG PET in patients with a history of prostate cancer biochemical recurrence and SPN.

18F-FDG PET/MRI Primary Staging of Cervical Cancer: A Pilot Study with PET/CT Comparison.

We report our PET/MRI experience from a pilot study that compared the diagnostic performance of 18F-FDG PET/MRI versus PET/CT in staging of cervical cancer. Methods: Six adults with newly diagnosed cervical cancer underwent a single 18F-FDG injection with a dual-imaging protocol: standard-of-care PET/CT followed by research PET/MRI. The diagnostic interpretation and SUVmax for the 2 modalities were compared. Results: Both modalities detected all primary tumors (median size, 3.9 cm) and all 4 metastases present in 2 of the 6 patients (median size, 0.9 cm). PET/MRI provided greater diagnostic confidence than PET/CT and upstaged the disease in 4 patients. On the basis of the imaging findings alone, the additional information from PET/MRI would have led to a change in clinical management in 3 of 6 patients. The primary lesion showed a median SUV of 12.8 on PET/CT and 18.2 on PET/MRI (P = 0.03). SUVs, however, correlated strongly between the 2 modalities (ρ = 0.96, P < 0.001). Conclusion: Our pilot study supports the notion that PET/MRI has the potential to impact clinical decisions and treatment strategies in women with cervical cancer. Further studies are, however, warranted to define the value that PET/MRI adds to PET/CT.

Diagnostic Value of FDG PET/MRI in Females With Pelvic Malignancy-A Systematic Review of the Literature.

Hybrid imaging with F-18 fludeoxyglucose positron emission tomography/magnetic resonance imaging (FDG PET/MRI) has increasing clinical applications supplementing conventional ultrasound, CT, and MRI imaging as well as hybrid PET/CT imaging in assessing cervical, endometrial, and ovarian cancer. This article summarizes the existing literature and discusses the emerging role of hybrid PET/MRI in gynecologic malignancies. Thus, far, the published literature on the applications of FDG PET/MRI shows that it can have a significant impact on patient management by improving the staging of the cancers compared with PET/CT, influencing clinical decision and treatment strategy. For disease restaging, current literature indicates that PET/MRI performs equivalently to PET/CT. There appears to be a mild-moderate inverse correlation between standard-uptake-value (SUV) and apparent-diffusion-coefficient (ADC) values, which could be used to predict tumor grading and risk stratification. It remains to be seen as to whether multi-parametric PET/MRI imaging could prove valuable for prognostication and outcome. PET/MRI provides the opportunity for reduced radiation exposure, which is particularly relevant for a young female in need of multiple scans for treatment monitoring and follow-up. Fast acquisition protocols and optimized methods for attenuation correction are still evolving. Major limitations of PET/MRI remains such as suboptimal detection of small pulmonary nodules and lack of utility for radiation treatment planning, which pose an impediment in making PET/MRI a viable one-stop-shop imaging option to compete with PET/CT.

Multisite Technical and Clinical Performance Evaluation of Quantitative Imaging Biomarkers from 3D FDG PET Segmentations of Head and Neck Cancer Images.

Quantitative imaging biomarkers (QIBs) provide medical image-derived intensity, texture, shape, and size features that may help characterize cancerous tumors and predict clinical outcomes. Successful clinical translation of QIBs depends on the robustness of their measurements. Biomarkers derived from positron emission tomography images are prone to measurement errors owing to differences in image processing factors such as the tumor segmentation method used to define volumes of interest over which to calculate QIBs. We illustrate a new Bayesian statistical approach to characterize the robustness of QIBs to different processing factors. Study data consist of 22 QIBs measured on 47 head and neck tumors in 10 positron emission tomography/computed tomography scans segmented manually and with semiautomated methods used by 7 institutional members of the NCI Quantitative Imaging Network. QIB performance is estimated and compared across institutions with respect to measurement errors and power to recover statistical associations with clinical outcomes. Analysis findings summarize the performance impact of different segmentation methods used by Quantitative Imaging Network members. Robustness of some advanced biomarkers was found to be similar to conventional markers, such as maximum standardized uptake value. Such similarities support current pursuits to better characterize disease and predict outcomes by developing QIBs that use more imaging information and are robust to different processing factors. Nevertheless, to ensure reproducibility of QIB measurements and measures of association with clinical outcomes, errors owing to segmentation methods need to be reduced.

Human biodistribution and dosimetry of the D2/3 agonist 11C-N-propylnorapomorphine (11C-NPA) determined from PET.

UNLABELLED: We measured the whole-body distribution of intravenously injected (11)C-N-propylnorapomorphine ((11)C-NPA), a dopamine agonist PET tracer, in human subjects and determined the resulting absorbed radiation doses. METHODS: Six subjects (3 women, 3 men) were injected with (11)C-NPA (nominal dose, 370 MBq). A total of 9 consecutive whole-body PET scans were obtained for each subject. In addition, time-activity curves for 12 organs were determined, and residence times were computed for each subject. Dosimetry was determined for the various body organs and the whole body. RESULTS: The average NPA whole-body radiation dose was 3.17 x 10(-3) mSv per MBq of injected (11)C-NPA. The organ receiving the highest dose was the gallbladder wall, with an average of 2.81 x 10(-2) mSv.MBq(-1). CONCLUSION: On the basis of averaged dosimetry results, an administration of less than 1,780 MBq (<48 mCi) of (11)C-NPA yields an organ dose of under 50 mSv (5 rem) to all organs.

Positron emission tomography imaging of D(2/3) agonist binding in healthy human subjects with the radiotracer [(11)C]-N-propyl-norapomorphine: preliminary evaluation and reproducibility studies.

OBJECTIVE: (-)-N-[(11)C]-propyl-norapomorphine (NPA) is a full dopamine D(2/3) receptor agonist radiotracer suitable for imaging D(2/3) receptors configured in a state of high affinity for agonists using positron emission tomography. The aim of the present study was to define the optimal analytic method to derive accurate and reliable D(2/3) receptor parameters with [(11)C]NPA. METHODS: Six healthy subjects (four females/two males) underwent two [(11)C]NPA scans in the same day. D(2/3) receptor-binding parameters were estimated using kinetic analysis (using one- and two-tissue compartment models) as well as simplified reference tissue method in the three functional subdivisions of the striatum (associative striatum, limbic striatum, and sensorimotor striatum). The test-retest variability and intraclass correlation coefficient were assessed for distribution volume (V(T)), binding potential relative to plasma concentration (BP(P)), and binding potential relative to nondisplaceable uptake (BP(ND)). RESULTS: A two-tissue compartment kinetic model adequately described the functional subdivisions of the striatum as well as cerebellum time-activity data. The reproducibility of V(T) was excellent (0.75) in the three functional subdivisions of the striatum. Although SRTM led to an underestimation of BP(ND) values relative to that estimated by kinetic analysis by 8-13%, the values derived using both the methods were reasonably well correlated (r(2) = 0.89, n = 84). Both methods were similarly effective in detecting the differences in [(11)C]NPA BP(ND) between subjects. CONCLUSION: The results of this study indicate that [(11)C]NPA can be used to measure D(2/3) receptors configured in a state of high affinity for the agonists with high reliability and reproducibility in the functional subdivisions of the human striatum.

Localization of parathyroid adenomas by sonography and technetium tc 99m sestamibi single-photon emission computed tomography before minimally invasive parathyroidectomy: are both studies really needed?

OBJECTIVE: The purpose of this study was to determine the utility of radiologist-performed sonography as the principal modality for parathyroid localization before minimally invasive parathyroidectomy. METHODS: Both sonography and technetium Tc 99m sestamibi single-photon emission computed tomography (SPECT) are commonly performed during imaging evaluation of patients with primary hyperparathyroidism (HPTH). Sonographic examinations ordered during the study period were performed by 1 author (M.E.T.), and results were immediately reported. Findings of a subsequent Tc 99m sestamibi study were recorded blinded to the sonographic results. The sensitivity and specificity of sonography and Tc 99m sestamibi SPECT were assessed with the use of surgery and pathology reports as a reference standard. The 2007 global Medicare reimbursement rates were used to assess the costs of preoperative localization. RESULTS: Parathyroidectomy was performed in 144 of 172 patients evaluated by both modalities. The sensitivity, specificity, and positive predictive value of sonography for identifying abnormal parathyroid glands were 74%, 96%, and 90%, respectively. Sonography correctly localized a single adenoma or suggested multiglandular disease in 112 of 144 patients (78%). The sensitivity, specificity, and positive predictive value of SPECT were 58%, 96%, and 89%. Technetium 99m sestamibi SPECT correctly predicted an adenoma or multiglandular disease in 88 of 144 patients (61%). Five patients with negative sonographic findings were shown to have uniglandular disease on Tc 99m sestamibi SPECT. Selective use of Tc 99m sestamibi SPECT (ie, when sonographic findings were negative or equivocal) would have decreased the cost of imaging by 53%. CONCLUSIONS: Radiologist-performed sonography may potentially be used as a principal imaging modality for patients with HPTH. Selective use of Tc 99m sestamibi in cases with negative or equivocal sonographic findings can decrease the cost of imaging before parathyroid resection considerably.

Complementary Molecular and Metabolic Characterization of Meningiomas With DOTATATE and FDG-PET: Advancing Treatment Planning and Prognostication.

Ga-DOTATATE imaging for meningiomas is gaining clinical use for selecting patients that may benefit from targeted therapy (eg, Lu-DOTATATE). We present an image of a 67-year-old man with an intracranial WHO grade III anaplastic meningioma. He underwent tumor resection followed by intensity-modulated radiation therapy but experienced a recurrence 25 months later. He received an F-(FDG) and Ga-DOTATATE PET/MR to evaluate for the presence of somatostatin receptor expression and guide subsequent treatment. The scans showed both concordant and discordant regions of uptake, indicating that high somatostatin receptor (SSTR2) expression may not coincide with areas of increased metabolic rate.

[18F]FDG, [11C]PiB, and [18F]AV-1451 PET Imaging of Neurodegeneration in Two Subjects With a History of Repetitive Trauma and Cognitive Decline.

Background: Trauma-related neurodegeneration can be difficult to differentiate from multifactorial neurodegenerative syndromes, both clinically and radiographically. We have initiated a protocol for in vivo imaging of patients with suspected TBI-related neurodegeneration utilizing volumetric MRI and PET studies, including [18F]FDG indexing cerebral glucose metabolism, [11C]PiB for Aß deposition, and [18F]AV-1451 for tau deposition. Objective: To present results from a neuroimaging protocol for in vivo evaluation of TBI-related neurodegeneration in patients with early-onset cognitive decline and a history of TBI. Methods: Patients were enrolled in parallel TBI studies and underwent a comprehensive neuropsychological test battery as well as an imaging protocol of volumetric MRI and PET studies. Findings from two patients were compared with two age-matched control subjects without a history of TBI. Results: Both chronic TBI patients demonstrated cognitive deficits consistent with early-onset dementia on neuropsychological testing, and one patient self-reported a diagnosis of probable early-onset AD. Imaging studies demonstrated significant [18F]AV-1451 uptake in the bilateral occipital lobes, substantial [11C]PiB uptake throughout the cortex in both TBI patients, and abnormally decreased [18F]FDG uptake in the posterior temporoparietal areas of the brain. One TBI patient also had subcortical volume loss. Control subjects demonstrated no appreciable [18F]AV-1451 or [11C]PiB uptake, had normal cortical volumes, and had normal cognition profiles on neuropsychological testing. Conclusions: In the two patients presented, the [11C]PiB and [18F]FDG PET scans demonstrate uptake patterns characteristic of AD. [11C]PiB PET scans showed widespread neocortical uptake with less abnormal uptake in the occipital lobes, whereas there was significant [18F]AV-1451 uptake in both occipital lobes.

The Impact of Arterial Input Function Determination Variations on Prostate Dynamic Contrast-Enhanced Magnetic Resonance Imaging Pharmacokinetic Modeling: A Multicenter Data Analysis Challenge, Part II.

This multicenter study evaluated the effect of variations in arterial input function (AIF) determination on pharmacokinetic (PK) analysis of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data using the shutter-speed model (SSM). Data acquired from eleven prostate cancer patients were shared among nine centers. Each center used a site-specific method to measure the individual AIF from each data set and submitted the results to the managing center. These AIFs, their reference tissue-adjusted variants, and a literature population-averaged AIF, were used by the managing center to perform SSM PK analysis to estimate Ktrans (volume transfer rate constant), ve (extravascular, extracellular volume fraction), kep (efflux rate constant), and τi (mean intracellular water lifetime). All other variables, including the definition of the tumor region of interest and precontrast T1 values, were kept the same to evaluate parameter variations caused by variations in only the AIF. Considerable PK parameter variations were observed with within-subject coefficient of variation (wCV) values of 0.58, 0.27, 0.42, and 0.24 for Ktrans, ve, kep, and τi, respectively, using the unadjusted AIFs. Use of the reference tissue-adjusted AIFs reduced variations in Ktrans and ve (wCV = 0.50 and 0.10, respectively), but had smaller effects on kep and τi (wCV = 0.39 and 0.22, respectively). kep is less sensitive to AIF variation than Ktrans, suggesting it may be a more robust imaging biomarker of prostate microvasculature. With low sensitivity to AIF uncertainty, the SSM-unique τi parameter may have advantages over the conventional PK parameters in a longitudinal study.

Targeted Therapy and Immunotherapy Response Assessment with F-18 Fluorothymidine Positron-Emission Tomography/Magnetic Resonance Imaging in Melanoma Brain Metastasis: A Pilot Study.

INTRODUCTION: This pilot study aimed at exploring the utility of the proliferation tracer F-18 fluorothymidine (FLT) and positron-emission tomography (PET)/magnetic resonance imaging (MRI) (FLT-PET/MRI) for early treatment monitoring in patients with melanoma brain metastasis (MBM) who undergo targeted therapy or immunotherapy. MATERIAL AND METHODS: Patients with newly diagnosed MBM underwent baseline and follow-up FLT-PET/MRI scans at 3-4 weeks of targeted therapy or immunotherapy. Up to six measurable brain lesions ≥1.0 cm per subject, as identified on T1-weighted post-gadolinium images, were included for quantitative analyses. The maximum SUV of each lesion was divided by the mean SUV of the pons to obtain the SUV ratio (SUVR). RESULTS: Five enrolled subjects underwent the baseline FLT-PET/MRI study in which the MBM showed a median size of 1.7 cm (range 1.0-2.9) and increased metabolic activity with SUVR of 9.9 (range 3.2-18.4). However, only two subjects (cases #1 and #2) returned for a follow-up scan. At baseline, a total of 22 lesions were analyzed in all five subjects, which showed a median size of 1.7 cm (range 1.0-2.9) and median SUVR of 9.9 (range 3.2-18.4). At follow-up, case #1 was a 55-year-old man who received targeted BRAF inhibitor and MEK inhibitor therapy with dabrafenib and trametinib. Fused PET/MRI data of six measured lesions demonstrated a significant reduction in MBM proliferative activity (median -68%; range -38 to -77%) and size (median -23%; range -4 to -55%) at three weeks of therapy. Nevertheless, the subject eventually progressed and died 13 months after therapy initiation. Case #2 was a 36-year-old man who received immunotherapy with nivolumab and ipilimumab. The five measured MBM lesions showed a mixed response at both proliferative and morphologic imaging at 1-month follow-up. Some lesions demonstrated interval decrease while others interval increase in proliferative activity with a median -44% (range -77 to +68%). On MRI, the size change was +7% (range -64 to +50%). The therapy was switched to dabrafenib and trametinib, which led to a partial response. The patient is still alive 16 months following therapy initiation. CONCLUSION: The five cases presented show the potential benefit of hybrid FLT-PET/MRI for the diagnosis of MBM and treatment monitoring of targeted therapy and immunotherapy. However, further studies are required to assess their complementary role in distinguishing true progression from pseudoprogression.