Blood Volume Fraction Research Articles

Pharmacokinetic analysis of [68Ga]Ga-DOTA-TOC PET in meningiomas for assessment of in vivo somatostatin receptor subtype 2.

DOTA-D-Phe1-Tyr3-octreotide with gallium-68 ([68Ga]Ga-DOTA-TOC) is one of the PET tracers that forms the basis for peptide receptor radionuclide therapy based on somatostatin receptor subtype 2 (SSTR2) expression in meningiomas. Yet, the quantitative relationship between [68Ga]Ga-DOTA-TOC accumulation and SSTR2 is unknown. We conducted a correlative analysis of a range of [68Ga]Ga-DOTA-TOC PET metric(s) as imaging surrogate(s) of the receptor binding in meningiomas by correlating the PET results with SSTR2 expression from surgical specimens. We additionally investigated possible influences of secondary biological factors such as vascularization, inflammation and proliferation. Fifteen patients with MRI-presumed or recurrent meningiomas underwent a 60-min dynamic [68Ga]Ga-DOTA-TOC PET/CT before surgery. The PET data comprised maximum and mean standardized uptake values (SUVmax, SUVmean) with and without normalization to reference regions, and quantitative measurements derived from kinetic modelling using a reversible two-tissue compartment model with the fractional blood volume (VB). Expressions of SSTR2 and proliferation (Ki-67, phosphohistone-H3, proliferating cell nuclear antigen) were determined by immunohistochemistry and/or quantitative polymerase chain reaction (qPCR), while biomarkers of vascularization (vascular endothelial growth factor A (VEGFA), endothelial marker CD34) and inflammation (cytokine interleukin-18, microglia/macrophage-specific marker CD68) by qPCR. Histopathology revealed 12 World Health Organization (WHO) grade I and three WHO grade II meningiomas showing no link to SSTR2. The majority of [68Ga]Ga-DOTA-TOC PET metrics showed significant associations with SSTR2 protein, while all PET metrics were positively correlated with SSTR2 mRNA with the best results for mean tumour-to-blood ratio (TBRmean) (r = 0.757, P = 0.001) and SUVmean (r = 0.714, P = 0.003). Significant positive correlations were also found between [68Ga]Ga-DOTA-TOC PET metrics, and VEGFA and VB. SSTR2 mRNA was moderately correlated with VEGFA (r = 0.539, P = 0.038). Neither [68Ga]Ga-DOTA-TOC PET metrics nor SSTR2 were correlated with proliferation or inflammation. [68Ga]Ga-DOTA-TOC accumulation in meningiomas is associated with SSTR2 binding and vascularization with TBRmean being the best PET metric for assessing SSTR2.

4D blood flow model for dose calculation to circulating blood and lymphocytes

To better understand how radiotherapy delivery parameters affect the depletion of circulating lymphocytes in patients treated for intra-cranial tumors, we developed a computational human body blood flow model (BFM), that enables to estimate the dose to the circulating blood during the course of fractionated radiation therapy.A hemodynamic cardiovascular system based on human body reference values was developed to distribute the cardiac output to 24 different organs, described by a discrete Markov Chain. For explicit intracranial blood flow modeling, we extracted major cerebral vasculature from MRI data of a patient and complemented them with an extension network of generic vessels in the frontal and occipital lobes to guarantee even overall blood supply to the entire brain volume. An explicit Monte Carlo simulation was implemented to track the propagation of each individual blood particle (BP) through the brain and time-dependent radiation fields, accumulating dose along their trajectories.The cerebral model includes 1050 path lines and explicitly simulates more than 266 000 BP at any given time that are tracked with a time resolution of 10 ms. The entire BFM for the whole body contains 22 178 000 BP, corresponding to 4200 BP per ml of blood. We have used the model to investigate the difference between proton and photon therapy, and the effect of different dose rates and patient characteristics on the dose to the circulating blood pool.The mean dose to the blood pool is estimated to be 0.06 and 0.13 Gy after 30 fractions of proton and photon therapy, respectively, and the highest dose to 1% of blood was found to be 0.19 Gy and 0.34 Gy. The fraction of blood volume receiving any dose after the first fraction is significantly lower for proton therapy, 10.1% compared to 18.4% for the photon treatment plan. 90% of the blood pool will have received dose after the 11th fraction using photon therapy compared to the 21st fraction with proton therapy. Higher dose rates can effectively reduce the fraction of blood irradiated to low doses but increase the amount of blood receiving high doses. Patient characteristics such as blood pressure, gender and age lead to smaller effects than variations in the dose rate.We developed a 4D human BFM including recirculating to estimate the radiation dose to the circulating blood during intracranial treatment and demonstrate its application to proton- versus photon-based delivery, various dose rates and patient characteristics. The radiation dose estimation to the circulating blood provides us better insight into the origins of radiation-induced lymphopenia.

Quantification of PD-L1 Expression with 18F-BMS-986192 PET/CT in Patients with Advanced-Stage Non-Small Cell Lung Cancer.

The aim of this work was to quantify the uptake of 18F-BMS-986192, a programmed cell death ligand 1 (PD-L1) adnectin PET tracer, in patients with non-small cell lung cancer. To this end, plasma input kinetic modeling of dynamic tumor uptake data with online arterial blood sampling was performed. In addition, the accuracy of simplified uptake metrics such as SUV was investigated. Methods: Data from a study with 18F-BMS-986192 in patients with advanced-stage non-small cell lung cancer eligible for nivolumab treatment were used if a dynamic scan was available and lesions were present in the field of view of the dynamic scan. After injection of 18F-BMS-986192, a 60-min dynamic PET/CT scan was started, followed by a 30-min whole-body PET/CT scan. Continuous arterial and discrete arterial and venous blood sampling were performed to determine a plasma input function. Tumor time-activity curves were fitted by several plasma input kinetic models. Simplified uptake parameters included tumor-to-blood ratio as well as several SUV measures. Results: Twenty-two tumors in 9 patients were analyzed. The arterial plasma input single-tissue reversible compartment model with fitted blood volume fraction seems to be the most preferred model as it best fitted 11 of 18 tumor time-activity curves. The distribution volume (VT ) ranged from 0.4 to 4.8 mL⋅cm-3 Similar values were obtained with an image-derived input function. From the simplified measures, SUV normalized for body weight at 50 and 67 min after injection correlated best with VT , with an R2 of more than 0.9. Conclusion: A single-tissue reversible model can be used to quantify tumor uptake of the PD-L1 PET tracer 18F-BMS-986192. SUV at 60 min after injection, normalized for body weight, is an accurate simplified parameter for uptake assessment of baseline studies. To assess its predictive value for response evaluation during programmed cell death protein 1 or PD-L1 immune checkpoint inhibition, further validation of SUV against VT based on an image-derived input function is recommended.

Mechanical Ventilation Redistributes Blood to Poorly Ventilated Areas in Experimental Lung Injury.

Determine the intra-tidal regional gas and blood volume distributions at different levels of atelectasis in experimental lung injury. Test the hypotheses that pulmonary aeration and blood volume matching is reduced during inspiration in the setting of minimal tidal recruitment/derecruitment and that this mismatching is an important determinant of hypoxemia. Preclinical study. Research laboratory. Seven anesthetized pigs 28.7 kg (SD, 2.1 kg). All animals received a saline-lavage surfactant depletion lung injury model. Positive end-expiratory pressure was varied between 0 and 20 cm H2O to induce different levels of atelectasis. Dynamic dual-energy CT images of a juxtadiaphragmatic slice were obtained, gas and blood volume fractions within three gravitational regions calculated and normalized to lung tissue mass (normalized gas volume and normalized blood volume, respectively). Ventilatory conditions were grouped based upon the fractional atelectatic mass in expiration (< 20%, 20-40%, and ≥ 40%). Tidal recruitment/derecruitment with fractional atelectatic mass in expiration greater than or equal to 40% was less than 7% of lung mass. In this group, inspiration-related increase in normalized gas volume was greater in the nondependent (818 µL/g [95% CI, 729-908 µL/g]) than the dependent region (149 µL/g [120-178 µL/g]). Normalized blood volume decreased in inspiration in the nondependent region (29 µL/g [12-46 µL/g]) and increased in the dependent region (39 µL/g [30-48 µL/g]). Inspiration-related changes in normalized gas volume and normalized blood volume were negatively correlated in fractional atelectatic mass in expiration greater than or equal to 40% and 20-40% groups (r = 0.56 and 0.40), but not in fractional atelectatic mass in expiration less than 20% group (r = 0.01). Both the increase in normalized blood volume in the dependent region and fractional atelectatic mass in expiration negatively correlated with PaO2/FIO2 ratio (ρ = -0.77 and -0.93, respectively). In experimental atelectasis with minimal tidal recruitment/derecruitment, mechanical inspiratory breaths redistributed blood volume away from well-ventilated areas, worsening PaO2/FIO2.

Effect of Radiation on DCE-MRI Pharmacokinetic Parameters in a Rabbit Model of Compromised Maxillofacial Wound Healing: A Pilot Study

Osteoradionecrosis (ORN), a potentially debilitating complication of maxillofacial radiation, continues to present a challenging clinical scenario, with limited treatment options that often fail. Translational animal models that can accurately mimic the human characteristics of the condition are lacking. In the present pilot study, we aimed to characterize the effects of radiation on the dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) pharmacokinetic parameters in a rabbit model of compromised maxillofacial wound healing to determine its potential as a translational model of ORN. An experimental group underwent fractionated radiation of the mandible totaling 36Gy. At 4weeks after irradiation, the experimental and control groups (n=8 rabbits each) underwent a surgical procedure to create a critical size defect in the mandibular bone. DCE-MRI scans were acquired 1week after arrival (baseline; time point 1), 4weeks after completion of irradiation in the experimental group (just before surgery, time point 2), and 4weeks after surgery (time point 3). No differences in the analyzed DCE-MRI parameters were noted within the experimental or control group between the baseline values (time point 1) and those after irradiation (time point 2). The whole blood volume fraction (vb) in the experimental group was increased compared with that in the control group after irradiation (time point 2; P<.05). After surgery (time point 3), both the forward flux rate of contrast from blood plasma and the extracellular extravascular space and the vb were increased in the control group compared with the experimental group (P<.05). The results of the present study suggest that DCE-MRI of a rabbit model of compromised maxillofacial wound healing could reflect the DCE-MRI characteristics of human patients with ORN and those at risk of developing the condition. Future studies will focus on further characterization of this rabbit model as a translational preclinical model of ORN.

Probing renal blood volume with magnetic resonance imaging

Damage to the kidney substantially reduces life expectancy. Renal tissue hypoperfusion and hypoxia are key elements in the pathophysiology of acute kidney injury and its progression to chronic kidney disease. In vivo assessment of renal haemodynamics and tissue oxygenation remains a challenge. Blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) is sensitive to changes in the effective transversal relaxation time (T2 *) in vivo, and is non-invasive and indicative of renal tissue oxygenation. However, the renal T2 * to tissue pO2 relationship is not governed exclusively by renal blood oxygenation, but is affected by physiological confounders with alterations in renal blood volume fraction (BVf) being of particular relevance. To decipher this interference probing renal BVf is essential for the pursuit of renal MR oximetry. Superparamagnetic iron oxide nanoparticle (USPIO) preparations can be used as MRI visible blood pool markers for detailing alterations in BVf. This review promotes the opportunities of MRI-based assessment of renal BVf. Following an outline on the specifics of renal oxygenation and perfusion, changes in renal BVf upon interventions and their potential impact on renal T2 * are discussed. We also describe the basic principles of renal BVf assessment using ferumoxytol-enhanced MRI in the equilibrium concentration regimen. We demonstrate that ferumoxytol does not alter control of renal haemodynamics and oxygenation. Preclinical applications of ferumoxytol enhanced renal MRI as well as considerations for its clinical implementation for examining renal BVf changes are provided alongside practical considerations. Finally, we explore the future directions of MRI-based assessment of renal BVf.

Forecasting tumor and vasculature response dynamics to radiation therapy via image based mathematical modeling

BackgroundIntra-and inter-tumoral heterogeneity in growth dynamics and vascularity influence tumor response to radiation therapy. Quantitative imaging techniques capture these dynamics non-invasively, and these data can initialize and constrain predictive models of response on an individual basis.MethodsWe have developed a family of 10 biologically-based mathematical models describing the spatiotemporal dynamics of tumor volume fraction, blood volume fraction, and response to radiation therapy. To evaluate this family of models, rats (n = 13) with C6 gliomas were imaged with magnetic resonance imaging (MRI) three times before, and four times following a single fraction of 20 Gy or 40 Gy whole brain irradiation. The first five 3D time series data of tumor volume fraction, estimated from diffusion-weighted (DW-) MRI, and blood volume fraction, estimated from dynamic contrast-enhanced (DCE-) MRI, were used to calibrate tumor-specific model parameters. The most parsimonious and well calibrated of the 10 models, selected using the Akaike information criterion, was then utilized to predict future growth and response at the final two imaging time points. Model predictions were compared at the global level (percent error in tumor volume, and Dice coefficient) as well as at the local or voxel level (concordance correlation coefficient).ResultThe selected model resulted in < 12% error in tumor volume predictions, strong spatial agreement between predicted and observed tumor volumes (Dice coefficient > 0.74), and high level of agreement at the voxel level between the predicted and observed tumor volume fraction and blood volume fraction (concordance correlation coefficient > 0.77 and > 0.65, respectively).ConclusionsThis study demonstrates that serial quantitative MRI data collected before and following radiation therapy can be used to accurately predict tumor and vasculature response with a biologically-based mathematical model that is calibrated on an individual basis. To the best of our knowledge, this is the first effort to characterize the tumor and vasculature response to radiation therapy temporally and spatially using imaging-driven mathematical models.

Interstitial diffuse optical probe with spectral fitting to measure dynamic tumor hypoxia

Understanding the dynamic nature of tumor hypoxia is vital for cancer therapy. The presence of oxygen within a tumor during radiation therapy increases the likelihood of local control. We used a novel interstitial diffuse optical probe to make real-time measurements of blood volume fraction and hemoglobin oxygen saturation within a tumor at a high temporal resolution. This device was initially characterized and benchmarked using a customized vessel designed to control hemoglobin oxygen saturation and blood volume in a solution of blood with different concentrations of an oxygen scavenger, tetrakis (hydroxymethyl) phosphonium chloride. The optical device was found to consistently monitor the changes in oxygen saturation and these changes correlated to the concentration of the oxygen scavenger added. In near-simultaneous measurements of blood volume and oxygen saturation in tumor-bearing mice, the changes in blood volume fraction and oxygen saturation measured with the interstitial diffuse optical probe were benchmarked against photoacoustic imaging system to track and compare temporal dynamics of oxygen saturation and blood volume in a patient-derived xenograft model of hypopharyngeal carcinoma. Positive correlations between our device and photoacoustic imaging in measuring blood volume and oxygen saturation were observed.

Reproducibility of compartmental modelling of 18F-FDG PET/CT to evaluate lung inflammation

IntroductionCompartmental modelling is an established method of quantifying 18F-FDG uptake; however, only recently has it been applied to evaluate pulmonary inflammation. Implementation of compartmental models remains challenging in the lung, partly due to the low signal-to-noise ratio compared to other organs and the lack of standardisation. Good reproducibility is a key requirement of an imaging biomarker which has yet to be demonstrated in pulmonary compartmental models of 18F-FDG; in this paper, we address this unmet need.MethodsRetrospective subject data were obtained from the EVOLVE observational study: Ten COPD patients (age =66±9; 8M/2F), 10 α1ATD patients (age =63±8; 7M/3F) and 10 healthy volunteers (age =68±8; 9M/1F) never smokers. PET and CT images were co-registered, and whole lung regions were extracted from CT using an automated algorithm; the descending aorta was defined using a manually drawn region. Subsequent stages of the compartmental analysis were performed by two independent operators using (i) a MIAKATTM based pipeline and (ii) an in-house developed pipeline. We evaluated the metabolic rate constant of 18F-FDG (Kim) and the fractional blood volume (Vb); Bland-Altman plots were used to compare the results. Further, we adjusted the in-house pipeline to identify the salient features in the analysis which may help improve the standardisation of this technique in the lung.ResultsThe initial agreement on a subject level was poor: Bland-Altman coefficients of reproducibility for Kim and Vb were 0.0031 and 0.047 respectively. However, the effect size between the groups (i.e. COPD, α1ATD and healthy subjects) was similar using either pipeline. We identified the key drivers of this difference using an incremental approach: ROI methodology, modelling of the IDIF and time delay estimation. Adjustment of these factors led to improved Bland-Altman coefficients of reproducibility of 0.0015 and 0.027 for Kim and Vb respectively.ConclusionsDespite similar methodology, differences in implementation can lead to disparate results in the outcome parameters. When reporting the outcomes of lung compartmental modelling, we recommend the inclusion of the details of ROI methodology, input function fitting and time delay estimation to improve reproducibility.

Mechanism-Based Modeling of Tumor Growth and Treatment Response Constrained by Multiparametric Imaging Data.

Multiparametric imaging is a critical tool in the noninvasive study and assessment of cancer. Imaging methods have evolved over the past several decades to provide quantitative measures of tumor and healthy tissue characteristics related to, for example, cell number, blood volume fraction, blood flow, hypoxia, and metabolism. Mechanistic models of tumor growth also have matured to a point where the incorporation of patient-specific measures could provide clinically relevant predictions of tumor growth and response. In this review, we identify and discuss approaches that use multiparametric imaging data, including diffusion-weighted magnetic resonance imaging, dynamic contrast-enhanced magnetic resonance imaging, diffusion tensor imaging, contrast-enhanced computed tomography, [18F]fluorodeoxyglucose positron emission tomography, and [18F]fluoromisonidazole positron emission tomography to initialize and calibrate mechanistic models of tumor growth and response. We focus the discussion on brain and breast cancers; however, we also identify three emerging areas of application in kidney, pancreatic, and lung cancers. We conclude with a discussion of the future directions for incorporating multiparametric imaging data and mechanistic modeling into clinical decision making for patients with cancer.

Nanoparticle Contrast-enhanced T1-Mapping Enables Estimation of Placental Fractional Blood Volume in a Pregnant Mouse Model

Non-invasive methods for estimating placental fractional blood volume (FBV) are of great interest for characterization of vascular perfusion in placentae during pregnancy to identify placental insufficiency that may be indicative of local ischemia or fetal growth restriction (FGR). Nanoparticle contrast-enhanced magnetic resonance imaging (CE-MRI) may enable direct placental FBV estimation and may provide a reliable, 3D alternative to assess maternal-side placental perfusion. In this pre-clinical study, we investigated if placental FBV at 14, 16, and 18 days of gestation could be estimated through contrast-enhanced MRI using a long circulating blood-pool liposomal gadolinium contrast agent that does not penetrate the placental barrier. Placental FBV estimates of 0.47 ± 0.06 (E14.5), 0.50 ± 0.04 (E16.5), and 0.52 ± 0.04 (E18.5) were found through fitting pre-contrast and post-contrast T1 values in placental tissue using a variable flip angle method. MRI-derived placental FBV was validated against nanoparticle contrast-enhanced computed tomography (CE-CT) derived placental FBV, where signal is directly proportional to the concentration of iodine contrast agent. The results demonstrate successful estimation of the placental FBV, with values statistically indistinguishable from the CT derived values.

Triple-marker cardiac MRI detects sequential tissue changes of healing myocardium after a hydrogel-based therapy

Regenerative therapies based on injectable biomaterials, hold an unparalleled potential for treating myocardial ischemia. Yet, noninvasive evaluation of their efficacy has been lagging behind. Here, we report the development and longitudinal application of multiparametric cardiac magnetic resonance imaging (MRI) to evaluate a hydrogel-based cardiac regenerative therapy. A pH-switchable hydrogel was loaded with slow releasing insulin growth factor 1 and vascular endothelial growth factor, followed by intramyocardial injection in a mouse model of ischemia reperfusion injury. Longitudinal cardiac MRI assessed three hallmarks of cardiac regeneration: angiogenesis, resolution of fibrosis and (re)muscularization after infarction. The multiparametric approach contained dynamic contrast enhanced MRI that measured improved vessel features by assessing fractional blood volume and permeability*surface area product, T1-mapping that displayed reduced fibrosis, and tagging MRI that showed improved regional myocardial strain in hydrogel treated infarcts. Finally, standard volumetric MRI demonstrated improved left ventricular functioning in hydrogel treated mice followed over time. Histology confirmed MR-based vessel features and fibrotic measurements. Our novel triple-marker strategy enabled detection of ameliorated regeneration in hydrogel treated hearts highlighting the translational potential of these longitudinal MRI approaches.

Improvement and validation of high precision ocular oximetry using a convolutional neural network algorithm and a phantom eye

AbstractRetinal oximetry is a non‐invasive imaging technology that enables the measurement of oxygen saturation (StO2) in the eye fundus. The goal of this research was to validate a convolutional neural network (CNN) algorithm designed to calculate and improve the precision of StO2 measurements from diffuse reflectance spectra (DRS) taken on the optic nerve head (ONH). Zilia’s multi‐wavelength retinal oximetry device was used to acquire experimental spectra from the ONH which allowed us to simulate reasonable digital spectra replicates with known absorber concentrations. These spectra were used to train a novel machine learning algorithm based on CNN. The device was then used to acquire diffuse reflectance spectra on several ONH‐mimicking liquid optical phantoms (phantom eye) with dynamic oxygenation cycles between 0% ‐ 100% in order to validate the improvements of this CNN on experimental data. Measurements were made simultaneously with gold standard devices for comparison. The procedure was then repeated with several cataract‐simulating contact lenses integrated in the optical path to show the robustness of oximetry measurements. We found good agreement in StO2 measurements between the results obtained with the Zilia device using the CNN algorithm and the gold standard references in all phantom cases. Applying the various algorithms to data acquired on the validation phantom show the marked improvements in using the CNN on experimental data, validating its high potential for clinical use. We specifically show strong robustness in precision, even when cataract‐simulating lenses were used. We present further validation that the oximetry device and CNN algorithm produces reliable, precise measurements even under conditions where blood volume fractions vary, optical scattering changes, and cataract‐simulating contact lenses are included.

Correlation of histological marrow characteristics and intravoxel incoherent motion-derived parameters in benign and malignant hematological disorders

PurposeTo investigate the relationship between intravoxel incoherent motion (IVIM) parameters and histological parameters of vascularity and cellularity in marrow of hyperplasia disease and compare the difference between benign and malignant marrow disorders. MethodsFrom August 2016 to March 2017, 43 newly diagnosed patients were recruited, which included 15 anemia patients (benign hemopathy) and 28 patients with acute leukemia (AL) (malignant hemopathy). All patients underwent IVIM in the lumbar marrow and the D, D*, f values were measured. The microvessel density (MVD) and cellularity of marrow were calculated from the sample of iliac crest biopsy. Pearson correlation analysis was used to study the relationship between IVIM-derived and histology-derived parameters. We performed unpaired t test to analyze the differences of all parameters between AL and anemia. ResultThe MVD was positively correlated with f in patients with AL, anemia and both of them (r = 0.692, P < 0.001; r = 0.595, P = 0.019; r = 0.673, P < 0.001, respectively). But there was no correlation between D* and MVD in three groups. D was not related to bone marrow cellularity (BMC) in all groups. In addition, the f and MVD were higher in AL than anemia (t = 3.546, P = 0.001; t = 6.695, P < 0.001, respectively). The BMC was significantly higher in AL than in anemia (t = 3.330, P = 0.004), but D and D* value had no significant difference between the two groups. ConclusionThe blood volume fraction f was positively correlated with the histological features of marrow in hematological disorders, while f can show the difference of vascularity between benign and malignant marrow disease.

MNGI-13. DYNAMIC IMAGING OF MENINGIOMA WITH 3’-DEOXY-3’-[18F]-FLUOROTHYMIDINE USING POSITRON EMISSION TOMOGRAPHY: A POSSIBLE PREDICTOR OF TUMOR GROWTH

Abstract BACKGROUND Positron emission tomography (PET) with 3’-deoxy-3’-[18F]-fluorothymidine (18F-FLT) provides a non-invasive assessment of in vivo tumor proliferation that could be useful for predicting growth potential in meningiomas. We aimed to study static and dynamic 18F-FLT PET metrics prospectively to assess metabolic activity of meningioma, and their associations to potential tumor growth on subsequent MRI scans. METHODS Between April 2017 and December 2018, 44 patients harboring MRI-suspected (n = 37) and histologically-verified residual meningiomas (n = 7) underwent a 60-minute dynamic 18F-FLT PET prior to imaging surveillance. Maximum and mean standardized uptake values (SUVmax, SUVmean) with/without normalisation to blood radioactivity obtained from a 40-60-minute static PET image and a 60-minute venous blood sampling were calculated. Total volume of distribution (VT) was estimated by kinetic modeling using a two-tissue reversible compartmental model with a fractional blood volume and metabolite-corrected image-derived input function. Tumor growth rate was calculated by volumetric analysis of subsequent MRI scans. RESULTS At the time of this writing, a total of 53 follow-up MRI scans from 33 patients were available for review, with a median follow-up time of 11 months (range, 4–22.5 months). Tumor growth/progression was observed in 12 cases with a monthly median growth rate of 0.10 cm3 (range, 0.03–3.41 cm3). All 18F-FLT metrics were significantly higher in patients with radiological progression compared to patients with stable findings with maximum tumor-to-blood-ratio (TBRmax) as the most promising imaging biomarker (4.9 ± 1.4 vs. 3.4 ± 1.0, P = .003; Mann-Whitney) and the strongest predictor for tumor progression (hazard ratio, 3.125; 95% confidence interval, 1.390–7.028; P = .006; univariate binary logistic regression). Age, gender, previous residual remnant(s) and initial tumor volume (median, 3.1 cm3; range, 0.2–55.3 cm3) had no influence. CONCLUSION 18F-FLT PET imaging could be a valuable tool in designing a patient-tailored surveillance strategy for patients with asymptomatic meningiomas.

MNGI-08. PHARMACOKINETIC ANALYSIS OF 68GA-DOTATOC IN MENINGIOMAS USING PET/CT FOR ASSESSMENT OF SOMATOSTATIN RECEPTORS AND CORRELATION WITH ANGIOGENESIS, INFLAMMATION AND PROLIFERATION

Abstract BACKGROUND A quantitative correlative analysis between 68Ga-DOTATOC accumulation using PET/CT and somatostatin receptor subtype 2 (SSTR2) in meningiomas was conducted. The possible contributions of angiogenesis and inflammation were investigated as well. METHODS Fifteen patients with newly (n = 12) and recurrent (n = 3) meningiomas were prospectively assigned to a 60-minute dynamic 68Ga-DOTATOC PET/CT scan prior to surgery. PET data included measurements of maximum and mean standardized uptake value (SUVmax, SUVmean) with/without normalisation to different reference tissues, and quantitative measures derived from kinetic modeling using a reversible two-tissue compartment model with the fractional blood volume (VB) included in the model. The SSTR2-expression was determined by immunohistochemistry and quantitative polymerase chain reaction (qPCR), while biomarkers of inflammation (macrophage-specific marker CD68, interleukin-18 [IL18]) and angiogenesis (endothelial marker CD34, vascular endothelial growth factor-A [VEGF-A]), were assessed by qPCR only. RESULTS Twelve patients (80%) were diagnosed with World Health Organization (WHO) grade I meningioma and three with WHO grade II (20%). No significant differences in SSTR2-expression was seen between WHO grades or subtypes (P ≥ 0.05; Mann-Whitney, Kruskal-Wallis). Upon stratification of patients based on the median SUVs (SUVmax, 20.9; SUVmean, 9.9), SSTR2-expression was seven-fold increased in patients with SUVs above the medians compared to patients with SUVs below the medians. Spearman’s rank correlation coefficient revealed significant correlations between SSTR2-expression, and SUVmean (r = 0.532, P = .041) and mean tumor-to-neck muscle ratio (TNMRmean) (r = 0.593, P = .020). 68Ga-DOTATOC uptake was additionally associated with VB and VEGF-A (P &lt; 0.01), while no association with inflammatory biomarkers were found. In univariate linear regression analysis, SUVmean and TNMRmean remained the optimal surrogate biomarkers for SSTR2-expression (P &lt; .0001). CONCLUSIONS 68Ga-DOTATOC accumulation in meningiomas is more complex than previously reported, and may not be limited to the SSTR2-density but also be associated with the vascular component.

High spatiotemporal vessel-specific hemodynamic mapping with multi-echo single-vessel fMRI

High-resolution fMRI enables noninvasive mapping of the hemodynamic responses from individual penetrating vessels in animal brains. Here, a 2D multi-echo single-vessel fMRI (MESV-fMRI) method has been developed to map the fMRI signal from arterioles and venules with a 100 ms sampling rate at multiple echo times (TE, 3–30 ms) and short acquisition windows (<1 ms). The T2*-weighted signal shows the increased extravascular effect on venule voxels as a function of TE. In contrast, the arteriole voxels show an increased fMRI signal with earlier onset than venules voxels at the short TE (3 ms) with increased blood inflow and volume effects. MESV-fMRI enables vessel-specific T2* mapping and presents T2*-based fMRI time courses with higher contrast-to-noise ratios (CNRs) than the T2*-weighted fMRI signal at a given TE. The vessel-specific T2* mapping also allows semi-quantitative estimation of the oxygen saturation levels (Y) and their changes (ΔY) at a given blood volume fraction upon neuronal activation. The MESV-fMRI method enables vessel-specific T2* measurements with high spatiotemporal resolution for better modeling of the fMRI signal based on the hemodynamic parameters.

Physiological model using diffuse reflectance spectroscopy for nonmelanoma skin cancer diagnosis.

Diffuse reflectance spectroscopy (DRS) is a noninvasive, fast, and low-cost technology with potential to assist cancer diagnosis. The goal of this study was to test the capability of our physiological model, a computational Monte Carlo lookup table inverse model, for nonmelanoma skin cancer diagnosis. We applied this model on a clinical DRS dataset to extract scattering parameters, blood volume fraction, oxygen saturation and vessel radius. We found that the model was able to capture physiological information relevant to skin cancer. We used the extracted parameters to classify (basal cell carcinoma [BCC], squamous cell carcinoma [SCC]) vs actinic keratosis (AK) and (BCC, SCC, AK) vs normal. The area under the receiver operating characteristic curve achieved by the classifiers trained on the parameters extracted using the physiological model is comparable to that of classifiers trained on features extracted via Principal Component Analysis. Our findings suggest that DRS can reveal physiologic characteristics of skin and this physiologic model offers greater flexibility for diagnosing skin cancer than a pure statistical analysis. Physiological parameters extracted from diffuse reflectance spectra data for nonmelanoma skin cancer diagnosis.

Early Changes of Diffusion MRI Predict Radiation Therapy Effects in Esophageal Cancer

Concurrent chemoradiation (CRT) is the standard therapy for inoperable locally advanced esophageal cancer (LAEC). However, patients who are insensitive to CRT (20∼30%) may be harmed unnecessarily by the treatment toxicity without survival benefit. An early prediction of treatment response during therapy using non-invasive imaging could identify the patients at high-risk of poor response for individualized adaptive treatment. This study aimed to investigate physiological changes in LAEC using diffusion and perfusion MRI for early predicting treatment response to CRT. Sixty-seven LAEC patients (median age of 64 years) treated with CRT were enrolled in an IRB approved study. All patients received definite thoracic radiotherapy (RT) with a median dose of 60Gy and 30fx, and 73% received concurrent chemotherapy. MRI scans were performed pre-RT and at week 3 during RT (mid-RT), including diffusion weighed images to derive apparent diffusion coefficient (ADC) and dynamic contrast-enhanced images to quantify the fractional blood volume (BV). Gross tumor volume (GTV) was delineated on T2 weighted images. Within the GTV, the hypercellularity volume (VHC) was defined as ADC <1.86x10-3 mm2/s, and the high BV volume (VHBV) as BV >18.2 ml/(100g). ROC curve was applied to assess the prediction abilities of the imaging metrics for CRT outcomes. Associations of the imaging metrics pre-RT and mid-RT and their changes during RT with progression-free survival (PFS) of patients were analyzed by Cox proportional hazards regression analysis. With a median follow-up period of 35.1 months (range 20–41 months), median PFS was 10.1 months. For all patients, the median pre-RT GTV was 28cc±3.2cc, with decreasing of -32.5% ±7.2% to 16.5cc±2.2cc at mid RT. Respectively, VHC and VHBV decreased from 6cc±1.1cc and 4.5cc±1.1cc at pre-RT to 4.1cc±0.7cc and 3.2cc±0.7cc at mid-RT. Smaller VHC at mid-RT (AUC=0.65, p=0.03) and more decreasing in VHC at mid-RT (AUC=0.7, p=0.007) were associated with longer PFS (Table 1). No significant predictive effects were shown in GTV and VHBV. This study suggests that VHC may represent aggressive subvolumes in LAEC. Further analysis will be carried out to correlate the changes in image-phenotype subvolumes with local failure to determine the radiation-resistant tumor subvolumes, which may benefit from treatment intensification.Abstract 1033; Table 1Univariable and multivariable Cox proportional hazards regression analysisCut-off valuesHR95%CIP valueHR95%CIP valueGTVPre-RT33.1cc1.590.88-2.880.13GTVMid-RT13.3cc1.060.63-1.740.89GTVchange-54%1.090.55-2.160.80VHCPre-RT7.3cc1.470.81-2.680.21VHCMid-RT1.1cc2.281.10-4.770.03*2.020.95-4.280.66VHCchange-63%1.950.99-3.820.05*1.680.85-3.330.14VHBVPre-RT10.4cc1.470.94-2.740.14VHBVMid-RT3.3cc1.290.71-2.340.39VHBVchange-54%1.450.75-2.790.27* Statistically significant. Open table in a new tab

Multi-parametric analysis reveals metabolic and vascular effects driving differences in BOLD-based cerebrovascular reactivity associated with a history of sport concussion

ABSTRACTObjective: Identify alterations in cerebrovascular reactivity (CVR) based on the history of sport-related concussion (SRC). Further explore possible mechanisms underlying differences in vascular physiology using hemodynamic parameters modeled using calibrated magnetic resonance imaging (MRI).Method: End-tidal targeting and dual-echo MRI were combined to probe hypercapnic and hyperoxic challenges in athletes with (n = 32) and without (n = 31) a history of SRC. Concurrent blood oxygenation level dependent (BOLD) and arterial spin labeling (ASL) data were used to compute BOLD-CVR, ASL-CVR, and other physiological parameters including resting oxygen extraction fraction (OEF0) and cerebral blood volume (CBV0). Multiple linear and logistic regressions were then used to identify dominant parameters driving group-differences in BOLD-CVR.Results: Robust evidence for elevated BOLD-CVR were found in athletes with SRC history spreading over parts of the cortical hemispheres. Follow-up analyses showed co-localized differences in ASL-CVR (representing modulation of cerebral blood flow) and hemodynamic factors representing static vascular (i.e., CBV0) and metabolic (i.e., OEF0) effects suggesting that group-based differences in BOLD-CVR may be driven by a mixed effect from factors with vascular and metabolic origins.Conclusion: These results emphasize that while BOLD-CVR offers promises as a surrogate non-specific biomarker for cerebrovascular health following SRC, multiple hemodynamic parameters can affect its relative measurements.Abbreviations: [dHb]: concentration of deoxyhemoglobin; AFNI: Analysis of Functional NeuroImages (https://afni.nimh.nih.gov); ASL: arterial spin labeling; BIG: position group: defensive and offensive linemen; BIG-SKILL: position group: full backs, linebackers, running backs, tight-ends; BOLD: blood oxygen level dependent; CBF: cerebral blood flow; CMRO2: cerebral metabolic rate of oxygen consumption; CTL: group of control subjects; CVR: cerebrovascular reactivity; fMRI: functional magnetic resonance imaging; FSL: FMRIB software library (https://fsl.fmrib.ox.ac.uk/fsl/fslwiki/); HC: hypercapnia; HO: hyperoxia; HX: group with history of concussion; M: maximal theoretical BOLD signal upon complete removal of venous dHb; pCASL: pseudo-continuous arterial spin labeling; PETCO2: end-tidal carbon dioxide; PETO2: end-tidal oxygen; SCAT: sport-concussion assessment tool; SKILL: position group: defensive backs, kickers, quarterbacks, safeties, wide-receivers; SRC: sport-related concussion.