Increased [18F]Fluorodeoxyglucose Uptake in the Left Pallidum in Military Veterans with Blast-Related Mild Traumatic Brain Injury: Potential as an Imaging Biomarker and Mediation with Executive Dysfunction and Cognitive Impairment.

Blast-related mild traumatic brain injury (blast-mTBI) can result in a spectrum of persistent symptoms leading to substantial functional impairment and reduced quality of life. Clinical evaluation and discernment from other conditions common to military service can be challenging and subject to patient recall bias and the limitations of available assessment measures. The need for objective biomarkers to facilitate accurate diagnosis, not just for symptom management and rehabilitation but for prognostication and disability compensation purposes is clear. Toward this end, we compared regional brain [18F]fluorodeoxyglucose-positron emission tomography ([18F]FDG-PET) intensity-scaled uptake measurements and motor, neuropsychological, and behavioral assessments in 79 combat Veterans with retrospectively recalled blast-mTBI with 41 control participants having no lifetime history of TBI. Using an agnostic and unbiased approach, we found significantly increased left pallidum [18F]FDG-uptake in Veterans with blast-mTBI versus control participants, p < 0.0001; q = 3.29 × 10-9 [Cohen's d, 1.38, 95% confidence interval (0.96, 1.79)]. The degree of left pallidum [18F]FDG-uptake correlated with the number of self-reported blast-mTBIs, r2 = 0.22; p < 0.0001. Greater [18F]FDG-uptake in the left pallidum provided excellent discrimination between Veterans with blast-mTBI and controls, with a receiver operator characteristic area under the curve of 0.859 (p < 0.0001) and likelihood ratio of 21.19 (threshold:SUVR ≥ 0.895). Deficits in executive function assessed using the Behavior Rating Inventory of Executive Function-Adult Global Executive Composite T-score were identified in Veterans with blast-mTBI compared with controls, p < 0.0001. Regression-based mediation analyses determined that in Veterans with blast-mTBI, increased [18F]FDG-uptake in the left pallidum-mediated executive function impairments, adjusted causal mediation estimate p = 0.021; total effect estimate, p = 0.039. Measures of working and prospective memory (Auditory Consonant Trigrams test and Memory for Intentions Test, respectively) were negatively correlated with left pallidum [18F]FDG-uptake, p < 0.0001, with mTBI as a covariate. Increased left pallidum [18F]FDG-uptake in Veterans with blast-mTBI compared with controls did not covary with dominant handedness or with motor activity assessed using the Unified Parkinson's Disease Rating Scale. Localized increased [18F]FDG-uptake in the left pallidum may reflect a compensatory response to functional deficits following blast-mTBI. Limited imaging resolution does not allow us to distinguish subregions of the pallidum; however, the significant correlation of our data with behavioral but not motor outcomes suggests involvement of the ventral pallidum, which is known to regulate motivation, behavior, and emotions through basal ganglia-thalamo-cortical circuits. Increased [18F]FDG-uptake in the left pallidum in blast-mTBI versus control participants was consistently identified using two different PET scanners, supporting the generalizability of this finding. Although confirmation of our results by single-subject-to-cohort analyses will be required before clinical deployment, this study provides proof of concept that [18F]FDG-PET bears promise as a readily available noninvasive biomarker for blast-mTBI. Further, our findings support a causative relationship between executive dysfunction and increased [18F]FDG-uptake in the left pallidum.

Repeatability of 18F-FDG uptake in metastatic bone lesions of breast cancer patients and implications for accrual to clinical trials.

BACKGROUND: Standard measures of response such as Response Evaluation Criteria in Solid Tumors are ineffective for bone lesions, often making breast cancer patients that have bone-dominant metastases ineligible for clinical trials with potentially helpful therapies. In this study we prospectively evaluated the test-retest uptake variability of 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) in a cohort of breast cancer patients with bone-dominant metastases to determine response criteria. The thresholds for 95% specificity of change versus no-change were then applied to a second cohort of breast cancer patients with bone-dominant metastases. METHODS: For this study, nine patients with 38 bone lesions were imaged with 18F-FDG in the same calibrated scanner twice within 14 days. Tumor uptake was quantified by the most commonly used PET parameter, the maximum tumor voxel normalized by dose and body weight (SUVmax) and also by the mean of a 1-cc maximal uptake volume normalized by dose and lean-body-mass (SULpeak). The asymmetric repeatability coefficients with confidence intervals for SUVmax and SULpeak were used to determine the limits of 18F-FDG uptake variability. A second cohort of 28 breast cancer patients with bone-dominant metastases that had 146 metastatic bone lesions was imaged with 18F-FDG before and after standard-of-care therapy for response assessment. RESULTS: The mean relative difference of SUVmax and SULpeak in 38 bone tumors of the first cohort were 4.3% and 6.7%. The upper and lower asymmetric limits of the repeatability coefficient were 19.4% and - 16.3% for SUVmax, and 21.2% and - 17.5% for SULpeak. 18F-FDG repeatability coefficient confidence intervals resulted in the following patient stratification using SULpeak for the second patient cohort: 11-progressive disease, 5-stable disease, 7-partial response, and 1-complete response with three inevaluable patients. The asymmetric repeatability coefficients response criteria for SULpeak changed the status of 3 patients compared to the standard Positron Emission Tomography Response Criteria in Solid Tumors of ± 30% SULpeak. CONCLUSION: In evaluating bone tumor response for breast cancer patients with bone-dominant metastases using 18F-FDG SUVmax, the repeatability coefficients from test-retest studies show that reductions of more than 17% and increases of more than 20% are unlikely to be due to measurement variability. Serial 18F-FDG imaging in clinical trials investigating bone lesions in these patients, such as the ECOG-ACRIN EA1183 trial, benefit from confidence limits that allow interpretation of response.

Equivalent uniform aerobic dose in radiotherapy for hypoxic tumors.

Objective.Equivalent uniform aerobic dose (EUAD) is proposed for comparison of integrated cell survival in tumors with different distributions of hypoxia and radiation dose.Approach.The EUAD assumes that for any non-uniform distributions of radiation dose and oxygen enhancement ratio (OER) within a tumor, there is a uniform distribution of radiation dose under hypothetical aerobic conditions with OER = 1 that produces equal integrated survival of clonogenic cells. This definition of EUAD has several advantages. First, the EUAD allows one to compare survival of clonogenic cells in tumors with intra-tumor and inter-tumor variation of radio sensitivity due to hypoxia because the cell survival is recomputed under the same benchmark oxygen level (OER = 1). Second, the EUAD for homogeneously oxygenated tumors is equal to the concept of equivalent uniform dose.Main results. We computed the EUAD using radiotherapy dose and the OER derived from the18F-Fluoromisonidazole PET (18F-FMISO PET) images of hypoxia in patients with glioblastoma, the most common and aggressive type of primary malignant brain tumor. The18F-FMISO PET images include a distribution of SUV (Standardized Uptake Value); therefore, the SUV is converted to partial oxygen pressure (pO2) and then to the OER. The prognostic value of EUAD in radiotherapy for hypoxic tumors is demonstrated using correlation between EUAD and overall survival (OS) in radiotherapy for glioblastoma. The correction to the EUAD for the absolute hypoxic volume that traceable to the tumor control probability improves the correlation with OS.Significance. While the analysis proposed in this research is based on the18F-FMISO PET images for glioblastoma, the EUAD is a universal radiobiological concept and is not associated with any specific cancer or any specific PET or MRI biomarker of hypoxia. Therefore, this research can be generalized to other cancers, for example stage III lung cancer, and to other hypoxia biomarkers.

Repeatability of 18F-FDG uptake in metastatic bone lesions of breast cancer patients and implications for accrual to clinical trials.

BACKGROUND: Standard measures of response such as Response Evaluation Criteria in Solid Tumors are ineffective for bone lesions, often making breast cancer patients with bone-dominant metastases ineligible for clinical trials with potentially helpful therapies. In this study we prospectively evaluated the test-retest uptake variability of 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) in a cohort of breast cancer patients with bone-dominant metastases to determine response criteria. The thresholds for 95% specificity of change versus no-change were then applied to a second cohort of breast cancer patients with bone-dominant metastases.In this study, nine patients with 38 bone lesions were imaged with 18F-FDG in the same calibrated scanner twice within 14 days. Tumor uptake was quantified as the maximum tumor voxel normalized by dose and body weight (SUVmax) and the mean of a 1-cc maximal uptake volume normalized by dose and lean-body-mass (SULpeak). The asymmetric repeatability coefficients with confidence intervals of SUVmax and SULpeak were used to determine limits of 18F-FDG uptake variability. A second cohort of 28 breast cancer patients with bone-dominant metastases that had 146 metastatic bone lesions was imaged with 18F-FDG before and after standard-of-care therapy for response assessment. RESULTS: The mean relative difference of SUVmax in 38 bone tumors of the first cohort was 4.3%. The upper and lower asymmetric limits of the repeatability coefficient were 19.4% and -16.3%, respectively. The 18F-FDG repeatability coefficient confidence intervals resulted in the following patient stratification for the second patient cohort: 11-progressive disease, 5-stable disease, 7-partial response, and 1-complete response with three inevaluable patients. The asymmetric repeatability coefficients response criteria changed the status of 3 patients compared to standard the standard Positron Emission Tomography Response Criteria in Solid Tumors of ±30% SULpeak. CONCLUSIONS: In evaluating bone tumor response for breast cancer patients with bone-dominant metastases using 18F-FDG uptake, the repeatability coefficients from test-retest studies show that reductions of more than 17% and increases of more than 20% are unlikely to be due to measurement variability. Serial 18F-FDG imaging in clinical trials investigating bone lesions from these patients, such as the ECOG-ACRIN EA1183 trial, benefit from confidence limits that allow interpretation of response.

Evaluation of Apparent Diffusion Coefficient Repeatability and Reproducibility for Preclinical MRIs Using Standardized Procedures and a Diffusion-Weighted Imaging Phantom.

Relevant to co-clinical trials, the goal of this work was to assess repeatability, reproducibility, and bias of the apparent diffusion coefficient (ADC) for preclinical MRIs using standardized procedures for comparison to performance of clinical MRIs. A temperature-controlled phantom provided an absolute reference standard to measure spatial uniformity of these performance metrics. Seven institutions participated in the study, wherein diffusion-weighted imaging (DWI) data were acquired over multiple days on 10 preclinical scanners, from 3 vendors, at 6 field strengths. Centralized versus site-based analysis was compared to illustrate incremental variance due to processing workflow. At magnet isocenter, short-term (intra-exam) and long-term (multiday) repeatability were excellent at within-system coefficient of variance, wCV [±CI] = 0.73% [0.54%, 1.12%] and 1.26% [0.94%, 1.89%], respectively. The cross-system reproducibility coefficient, RDC [±CI] = 0.188 [0.129, 0.343] µm2/ms, corresponded to 17% [12%, 31%] relative to the reference standard. Absolute bias at isocenter was low (within 4%) for 8 of 10 systems, whereas two high-bias (>10%) scanners were primary contributors to the relatively high RDC. Significant additional variance (>2%) due to site-specific analysis was observed for 2 of 10 systems. Base-level technical bias, repeatability, reproducibility, and spatial uniformity patterns were consistent with human MRIs (scaled for bore size). Well-calibrated preclinical MRI systems are capable of highly repeatable and reproducible ADC measurements.

Patient-Adaptive Population-Based Modeling of Arterial Input Functions.

Kinetic modeling of dynamic PET data requires knowledge of tracer concentration in blood plasma, described by the arterial input function (AIF). Arterial blood sampling is the gold standard for AIF measurement, but is invasive and labour intensive. A number of methods have been proposed to accurately estimate the AIF directly from blood sampling and/or imaging data. Here we consider fitting a patient-adaptive mixture of historical population time course profiles to estimate individual AIFs. Travel time of a tracer atom from the injection site to the right ventricle of the heart is modeled as a realization from a Gamma distribution, and the time this atom spends in circulation before being sampled is represented by a subject-specific linear mixture of population profiles. These functions are estimated from independent population data. Individual AIFs are obtained by projection onto this basis of population profile components. The model incorporates knowledge of injection duration into the fit, allowing for varying injection protocols. Analyses of arterial sampling data from 18F-FDG, 15O-H2O and 18F-FLT clinical studies show that the proposed model can outperform reference techniques. The statistically significant gain achieved by using population data to train the basis components, instead of fitting these from the single individual sampling data, is measured on the FDG cohort. Kinetic analyses of simulated data demonstrate the reliability and potential benefit of this approach in estimating physiological parameters. These results are further supported by numerical simulations that demonstrate convergence and stability of the proposed technique under varying training population sizes and noise levels.

Principles of Tracer Kinetic Analysis in Oncology, Part II: Examples and Future Directions.

Learning Objectives: On successful completion of this activity, participants should be able to (1) describe examples of the application of PET tracer kinetic analysis to oncology; (2) list applications research and possible clinical applications in oncology where kinetic analysis is helpful; and (3) discuss future applications of kinetic modeling to cancer research and possible clinical cancer imaging practice.Financial Disclosure: This work was supported by KL2 TR001879, R01 CA211337, R01 CA113941, R33 CA225310, Komen SAC130060, R50 CA211270, and K01 DA040023. Dr. Pantel is a consultant or advisor for Progenics and Blue Earth Diagnostics and is a meeting participant or lecturer for Blue Earth Diagnostics. Dr. Mankoff is on the scientific advisory boards of GE Healthcare, Philips Healthcare, Reflexion, and ImaginAb and is the owner of Trevarx; his wife is the chief executive officer of Trevarx. The authors of this article have indicated no other relevant relationships that could be perceived as a real or apparent conflict of interest.CME Credit: SNMMI is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing education for physicians. SNMMI designates each JNM continuing education article for a maximum of 2.0 AMA PRA Category 1 Credits. Physicians should claim only credit commensurate with the extent of their participation in the activity. For CE credit, SAM, and other credit types, participants can access this activity through the SNMMI website (http://www.snmmilearningcenter.org) through April 2025.Kinetic analysis of dynamic PET imaging enables the estimation of biologic processes relevant to disease. Through mathematic analysis of the interactions of a radiotracer with tissue, information can be gleaned from PET imaging beyond static uptake measures. Part I of this 2-part continuing education paper reviewed the underlying principles and methodology of kinetic modeling. In this second part, the benefits of kinetic modeling for oncologic imaging are illustrated through representative case examples that demonstrate the principles and benefits of kinetic analysis in oncology. Examples of the model types discussed in part I are reviewed here: a 1-tissue-compartment model (15O-water), an irreversible 2-tissue-compartment model (18F-FDG), and a reversible 2-tissue-compartment model (3'-deoxy-3'-18F-fluorothymidine). Kinetic approaches are contrasted with static uptake measures typically used in the clinic. Overall, this 2-part review provides the reader with background in kinetic analysis to understand related research and improve the interpretation of clinical nuclear medicine studies with a focus on oncologic imaging.

Principles of Tracer Kinetic Analysis in Oncology, Part I: Principles and Overview of Methodology.

Learning Objectives: On successful completion of this activity, participants should be able to describe (1) describe principles of PET tracer kinetic analysis for oncologic applications; (2) list methods used for PET kinetic analysis for oncology; and (3) discuss application of kinetic modeling for cancer-specific diagnostic needs.Financial Disclosure: This work was supported by KL2 TR001879, R01 CA211337, R01 CA113941, R33 CA225310, Komen SAC130060, R50 CA211270, and K01 DA040023. Dr. Pantel is a consultant or advisor for Progenics and Blue Earth Diagnostics and is a meeting participant or lecturer for Blue Earth Diagnostics. Dr. Mankoff is on the scientific advisory boards of GE Healthcare, Philips Healthcare, Reflexion, and ImaginAb and is the owner of Trevarx; his wife is the chief executive officer of Trevarx. The authors of this article have indicated no other relevant relationships that could be perceived as a real or apparent conflict of interest.CME Credit: SNMMI is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing education for physicians. SNMMI designates each JNM continuing education article for a maximum of 2.0 AMA PRA Category 1 Credits. Physicians should claim only credit commensurate with the extent of their participation in the activity. For CE credit, SAM, and other credit types, participants can access this activity through the SNMMI website (http://www.snmmilearningcenter.org) through March 2025PET enables noninvasive imaging of regional in vivo cancer biology. By engineering a radiotracer to target specific biologic processes of relevance to cancer (e.g., cancer metabolism, blood flow, proliferation, and tumor receptor expression or ligand binding), PET can detect cancer spread, characterize the cancer phenotype, and assess its response to treatment. For example, imaging of glucose metabolism using the radiolabeled glucose analog 18F-FDG has widespread applications to all 3 of these tasks and plays an important role in cancer care. However, the current clinical practice of imaging at a single time point remote from tracer injection (i.e., static imaging) does not use all the information that PET cancer imaging can provide, especially to address questions beyond cancer detection. Reliance on tracer measures obtained only from static imaging may also lead to misleading results. In this 2-part continuing education paper, we describe the principles of tracer kinetic analysis for oncologic PET (part 1), followed by examples of specific implementations of kinetic analysis for cancer PET imaging that highlight the added benefits over static imaging (part 2). This review is designed to introduce nuclear medicine clinicians to basic concepts of kinetic analysis in oncologic imaging, with a goal of illustrating how kinetic analysis can augment our understanding of in vivo cancer biology, improve our approach to clinical decision making, and guide the interpretation of quantitative measures derived from static images.

Multi-Site Concordance of Diffusion-Weighted Imaging Quantification for Assessing Prostate Cancer Aggressiveness.

BACKGROUND: Diffusion-weighted imaging (DWI) is commonly used to detect prostate cancer, and a major clinical challenge is differentiating aggressive from indolent disease. PURPOSE: To compare 14 site-specific parametric fitting implementations applied to the same dataset of whole-mount pathologically validated DWI to test the hypothesis that cancer differentiation varies with different fitting algorithms. STUDY TYPE: Prospective. POPULATION: Thirty-three patients prospectively imaged prior to prostatectomy. FIELD STRENGTH/SEQUENCE: 3 T, field-of-view optimized and constrained undistorted single-shot DWI sequence. ASSESSMENT: Datasets, including a noise-free digital reference object (DRO), were distributed to the 14 teams, where locally implemented DWI parameter maps were calculated, including mono-exponential apparent diffusion coefficient (MEADC), kurtosis (K), diffusion kurtosis (DK), bi-exponential diffusion (BID), pseudo-diffusion (BID*), and perfusion fraction (F). The resulting parametric maps were centrally analyzed, where differentiation of benign from cancerous tissue was compared between DWI parameters and the fitting algorithms with a receiver operating characteristic area under the curve (ROC AUC). STATISTICAL TEST: Levene's test, P < 0.05 corrected for multiple comparisons was considered statistically significant. RESULTS: The DRO results indicated minimal discordance between sites. Comparison across sites indicated that K, DK, and MEADC had significantly higher prostate cancer detection capability (AUC range = 0.72-0.76, 0.76-0.81, and 0.76-0.80 respectively) as compared to bi-exponential parameters (BID, BID*, F) which had lower AUC and greater between site variation (AUC range = 0.53-0.80, 0.51-0.81, and 0.52-0.80 respectively). Post-processing parameters also affected the resulting AUC, moving from, for example, 0.75 to 0.87 for MEADC varying cluster size. DATA CONCLUSION: We found that conventional diffusion models had consistent performance at differentiating prostate cancer from benign tissue. Our results also indicated that post-processing decisions on DWI data can affect sensitivity and specificity when applied to radiological-pathological studies in prostate cancer. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 3.

18F-fluorodeoxyglucose (FDG) PET or 18F-fluorothymidine (FLT) PET to assess early response to aromatase inhibitors (AI) in women with ER+ operable breast cancer in a window-of-opportunity study.

PURPOSE: This study evaluated the ability of 18F-Fluorodeoxyglucose (FDG) and 18F-Fluorothymidine (FLT) imaging with positron emission tomography (PET) to measure early response to endocrine therapy from baseline to just prior to surgical resection in estrogen receptor positive (ER+) breast tumors. METHODS: In two separate studies, women with early stage ER+ breast cancer underwent either paired FDG-PET (n = 22) or FLT-PET (n = 27) scans prior to endocrine therapy and again in the pre-operative setting. Tissue samples for Ki-67 were taken for all patients both prior to treatment and at the time of surgery. RESULTS: FDG maximum standardized uptake value (SUVmax) declined in 19 of 22 lesions (mean 17% (range -45 to 28%)). FLT SUVmax declined in 24 of 27 lesions (mean 26% (range -77 to 7%)). The Ki-67 index declined in both studies, from pre-therapy (mean 23% (range 1 to 73%)) to surgery [mean 8% (range < 1 to 41%)]. Pre- and post-therapy PET measures showed strong rank-order agreement with Ki-67 percentages for both tracers; however, the percent change in FDG or FLT SUVmax did not demonstrate a strong correlation with Ki-67 index change or Ki-67 at time of surgery. CONCLUSIONS: A window-of-opportunity approach using PET imaging to assess early response of breast cancer therapy is feasible. FDG and FLT-PET imaging following a short course of neoadjuvant endocrine therapy demonstrated measurable changes in SUVmax in early stage ER+ positive breast cancers. The percentage change in FDG and FLT-PET uptake did not correlate with changes in Ki-67; post-therapy SUVmax for both tracers was significantly associated with post-therapy Ki-67, an established predictor of endocrine therapy response.

Quantitation of multiple injection dynamic PET scans: an investigation of the benefits of pooling data from separate scans when mapping kinetics.

Multiple injection dynamic positron emission tomography (PET) scanning is used in the clinical management of certain groups of patients and in medical research. The analysis of these studies can be approached in two ways: (i) separate analysis of data from individual tracer injections, or (ii), concatenate/pool data from separate injections and carry out a combined analysis. The simplicity of separate analysis has some practical appeal but may not be statistically efficient. We use a linear model framework associated with a kinetic mapping scheme to develop a simplified theoretical understanding of separate and combined analysis. The theoretical framework is explored numerically using both 1D and 2D simulation models. These studies are motivated by the breast cancer flow-metabolism mismatch studies involving15O-water (H2O) and18F-Fluorodeoxyglucose (FDG) and repeat15O-H2O injections used in brain activation investigations. Numerical results are found to be substantially in line with the simple theoretical analysis: mean square error characteristics of alternative methods are well described by factors involving the local voxel-level resolution of the imaging data, the relative activities of the individual scans and the number of separate injections involved. While voxel-level resolution has dependence on scan dose, after adjustment for this effect, the impact of a combined analysis is understood in simple terms associated with the linear model used for kinetic mapping. This is true for both data reconstructed by direct filtered backprojection or iterative maximum likelihood. The proposed analysis has potential to be applied to the emerging long axial field-of-view PET scanners.

Whole-Body [18F]-Fluoride PET SUV Imaging to Monitor Response to Dasatinib Therapy in Castration-Resistant Prostate Cancer Bone Metastases: Secondary Results from ACRIN 6687.

ACRIN 6687, a multi-center clinical trial evaluating differential response of bone metastases to dasatinib in men with metastatic castration-resistant prostate cancer (mCRPC), used [18F]-fluoride (NaF) PET imaging. We extend previous ACRIN 6687 dynamic imaging results by examining NaF whole-body (WB) static SUV PET scans acquired after dynamic scanning. Eighteen patients underwent WB NaF imaging prior to and 12 weeks into dasatinib treatment. Regional VOI analysis of the most NaF avid bone metastases and an automated whole-body method using Quantitative Total Bone Imaging software (QTBI; AIQ Solutions, Inc., Madison, WI, USA) were used. We assessed differences in tumor and normal bone, between pre- and on-treatment dasatinib, and evaluated parameters in association with PFS and OS. Significant decrease in average SUVmax and average SUVpeak occurred in response to dasatinib. Univariate and multivariate analysis showed NaF uptake had significant association with PFS. Pharmacodynamic changes with dasatinib in tumor bone can be identified by WB NaF PET in men with mCRPC. WB PET has the benefit of examining the entire body and is less complicated than single FOV dynamic imaging.

Assessment of tumor hypoxia and perfusion in recurrent glioblastoma following bevacizumab failure using MRI and 18F-FMISO PET.

Tumoral hypoxia correlates with worse outcomes in glioblastoma (GBM). While bevacizumab is routinely used to treat recurrent GBM, it may exacerbate hypoxia. Evofosfamide is a hypoxia-targeting prodrug being tested for recurrent GBM. To characterize resistance to bevacizumab and identify those with recurrent GBM who may benefit from evofosfamide, we ascertained MRI features and hypoxia in patients with GBM progression receiving both agents. Thirty-three patients with recurrent GBM refractory to bevacizumab were enrolled. Patients underwent MR and 18F-FMISO PET imaging at baseline and 28 days. Tumor volumes were determined, MRI and 18F-FMISO PET-derived parameters calculated, and Spearman correlations between parameters assessed. Progression-free survival decreased significantly with hypoxic volume [hazard ratio (HR) = 1.67, 95% confidence interval (CI) 1.14 to 2.46, P = 0.009] and increased significantly with time to the maximum value of the residue (Tmax) (HR = 0.54, 95% CI 0.34 to 0.88, P = 0.01). Overall survival decreased significantly with hypoxic volume (HR = 1.71, 95% CI 1.12 to 12.61, p = 0.01), standardized relative cerebral blood volume (srCBV) (HR = 1.61, 95% CI 1.09 to 2.38, p = 0.02), and increased significantly with Tmax (HR = 0.31, 95% CI 0.15 to 0.62, p < 0.001). Decreases in hypoxic volume correlated with longer overall and progression-free survival, and increases correlated with shorter overall and progression-free survival. Hypoxic volume and volume ratio were positively correlated (rs = 0.77, P < 0.0001), as were hypoxia volume and T1 enhancing tumor volume (rs = 0.75, P < 0.0001). Hypoxia is a key biomarker in patients with bevacizumab-refractory GBM. Hypoxia and srCBV were inversely correlated with patient outcomes. These radiographic features may be useful in evaluating treatment and guiding treatment considerations.

Functional 4-D clustering for characterizing intratumor heterogeneity in dynamic imaging: evaluation in FDG PET as a prognostic biomarker for breast cancer.

PURPOSE: Probe-based dynamic (4-D) imaging modalities capture breast intratumor heterogeneity both spatially and kinetically. Characterizing heterogeneity through tumor sub-populations with distinct functional behavior may elucidate tumor biology to improve targeted therapy specificity and enable precision clinical decision making. METHODS: We propose an unsupervised clustering algorithm for 4-D imaging that integrates Markov-Random Field (MRF) image segmentation with time-series analysis to characterize kinetic intratumor heterogeneity. We applied this to dynamic FDG PET scans by identifying distinct time-activity curve (TAC) profiles with spatial proximity constraints. We first evaluated algorithm performance using simulated dynamic data. We then applied our algorithm to a dataset of 50 women with locally advanced breast cancer imaged by dynamic FDG PET prior to treatment and followed to monitor for disease recurrence. A functional tumor heterogeneity (FTH) signature was then extracted from functionally distinct sub-regions within each tumor. Cross-validated time-to-event analysis was performed to assess the prognostic value of FTH signatures compared to established histopathological and kinetic prognostic markers. RESULTS: Adding FTH signatures to a baseline model of known predictors of disease recurrence and established FDG PET uptake and kinetic markers improved the concordance statistic (C-statistic) from 0.59 to 0.74 (p = 0.005). Unsupervised hierarchical clustering of the FTH signatures identified two significant (p < 0.001) phenotypes of tumor heterogeneity corresponding to high and low FTH. Distributions of FDG flux, or Ki, were significantly different (p = 0.04) across the two phenotypes. CONCLUSIONS: Our findings suggest that imaging markers of FTH add independent value beyond standard PET imaging metrics in predicting recurrence-free survival in breast cancer and thus merit further study.

Quantifying bias and precision of kinetic parameter estimation on the PennPET Explorer, a long axial field-of-view scanner.

Long axial field-of-view (AFOV) PET scanners allow for full-body dynamic imaging in a single bed-position at very high sensitivity. However, the benefits for kinetic parameter estimation have yet to be studied. This work uses (1) a dynamic GATE simulation of [18F]-fluorothymidine (FLT) in a modified NEMA IQ phantom and (2) a lesion embedding study of spheres in a dynamic [18F]-fluorodeoxyglucose (FDG) human subject imaged on the PennPET Explorer. Both studies were designed using published kinetic data of lung and liver cancers and modeled using two tissue compartments. Data were reconstructed at various emulated doses. Sphere time-activity curves (TACs) were measured on resulting dynamic images, and TACs were fit using a two-tissue-compartment model (k4 ≠ 0) for the FLT study and both a two-tissue-compartment model (k4 = 0) and Patlak graphical analysis for the FDG study to estimate flux (Ki) and delivery (K1) parameters. Quantification of flux and K1 shows lower bias and better precision for both radiotracers on the long AFOV scanner, especially at low doses. Dynamic imaging on a long AFOV system can be achieved for a greater range of injected doses, as low as 0.5-2 mCi depending on the sphere size and flux, compared to a standard AFOV scanner, while maintaining good kinetic parameter estimation.

Chronic elevation of plasma vascular endothelial growth factor-A (VEGF-A) is associated with a history of blast exposure.

Mounting evidence points to the significance of neurovascular-related dysfunction in veterans with blast-related mTBI, which is also associated with reduced [18F]-fluorodeoxyglucose (FDG) uptake. The goal of this study was to determine whether plasma VEGF-A is altered in veterans with blast-related mTBI and address whether VEGF-A levels correlate with FDG uptake in the cerebellum, a brain region that is vulnerable to blast-related injury 72 veterans with blast-related mTBI (mTBI) and 24 deployed control (DC) veterans with no lifetime history of TBI were studied. Plasma VEGF-A was significantly elevated in mTBIs compared to DCs. Plasma VEGF-A levels in mTBIs were significantly negatively correlated with FDG uptake in cerebellum. In addition, performance on a Stroop color/word interference task was inversely correlated with plasma VEGF-A levels in blast mTBI veterans. Finally, we observed aberrant perivascular VEGF-A immunoreactivity in postmortem cerebellar tissue and not cortical or hippocampal tissues from blast mTBI veterans. These findings add to the limited number of plasma proteins that are chronically elevated in veterans with a history of blast exposure associated with mTBI. It is likely the elevated VEGF-A levels are from peripheral sources. Nonetheless, increasing plasma VEGF-A concentrations correlated with chronically decreased cerebellar glucose metabolism and poorer performance on tasks involving cognitive inhibition and set shifting. These results strengthen an emerging view that cognitive complaints and functional brain deficits caused by blast exposure are associated with chronic blood-brain barrier injury and prolonged recovery in affected regions.

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.

Evaluating the Use of rCBV as a Tumor Grade and Treatment Response Classifier Across NCI Quantitative Imaging Network Sites: Part II of the DSC-MRI Digital Reference Object (DRO) Challenge.

We have previously characterized the reproducibility of brain tumor relative cerebral blood volume (rCBV) using a dynamic susceptibility contrast magnetic resonance imaging digital reference object across 12 sites using a range of imaging protocols and software platforms. As expected, reproducibility was highest when imaging protocols and software were consistent, but decreased when they were variable. Our goal in this study was to determine the impact of rCBV reproducibility for tumor grade and treatment response classification. We found that varying imaging protocols and software platforms produced a range of optimal thresholds for both tumor grading and treatment response, but the performance of these thresholds was similar. These findings further underscore the importance of standardizing acquisition and analysis protocols across sites and software benchmarking.

Assessment of the Prognostic Value of Radiomic Features in 18F-FMISO PET Imaging of Hypoxia in Postsurgery Brain Cancer Patients: Secondary Analysis of Imaging Data from a Single-Center Study and the Multicenter ACRIN 6684 Trial.

Hypoxia is associated with resistance to radiotherapy and chemotherapy in malignant gliomas, and it can be imaged by positron emission tomography with 18F-fluoromisonidazole (18F-FMISO). Previous results for patients with brain cancer imaged with 18F-FMISO at a single center before conventional chemoradiotherapy showed that tumor uptake via T/Bmax (tissue SUVmax/blood SUV) and hypoxic volume (HV) was associated with poor survival. However, in a multicenter clinical trial (ACRIN 6684), traditional uptake parameters were not found to be prognostically significant, but tumor SUVpeak did predict survival at 1 year. The present analysis considered both study cohorts to reconcile key differences and examine the potential utility of adding radiomic features as prognostic variables for outcome prediction on the combined cohort of 72 patients with brain cancer (30 University of Washington and 42 ACRIN 6684). We used both 18F-FMISO intensity metrics (T/Bmax, HV, SUV, SUVmax, SUVpeak) and assessed radiomic measures that determined first-order (histogram), second-order, and higher-order radiomic features of 18F-FMISO uptake distributions. A multivariate model was developed that included age, HV, and the intensity of 18F-FMISO uptake. HV and SUVpeak were both independent predictors of outcome for the combined data set (P < .001) and were also found significant in multivariate prognostic models (P < .002 and P < .001, respectively). Further model selection that included radiomic features showed the additional prognostic value for overall survival of specific higher order texture features, leading to an increase in relative risk prediction performance by a further 5%, when added to the multivariate clinical model..