Comparing Magnetic Resonance Imaging and Prostate-Specific Membrane Antigen-Positron Emission Tomography for Prediction of Extraprostatic Extension of Prostate Cancer and Surgical Guidance: A Prospective Nonrandomized Clinical Trial.

PURPOSE: Survivors of surgically managed prostate cancer may experience urinary incontinence and erectile dysfunction. Our aim was to determine if 68Ga-prostate-specific membrane antigen-11 positron emission tomography CT (PSMA-PET) in addition to multiparametric (mp) MRI scans improved surgical decision-making for nonnerve-sparing or nerve-sparing approach. MATERIALS AND METHODS: We prospectively enrolled 50 patients at risk for extraprostatic extension (EPE) who were scheduled for prostatectomy. After mpMRI and PSMA-PET images were read for EPE prediction, surgeons prospectively answered questionnaires based on mpMRI and PSMA-PET scans on the decision for nerve-sparing or nonnerve-sparing approach. Final whole-mount pathology was the reference standard. Sensitivity, specificity, positive predictive value, negative predictive value, and receiver operating characteristic curves were calculated and McNemar's test was used to compare imaging modalities. RESULTS: The median age and PSA were 61.5 years and 7.0 ng/dL. The sensitivity for EPE along the posterior neurovascular bundle was higher for PSMA-PET than mpMRI (86% vs 57%, P = .03). For MRI, the specificity, positive predictive value, negative predictive value, and area under the curve for the receiver operating characteristic curves were 77%, 40%, 87%, and 0.67, and for PSMA-PET were 73%, 46%, 95%, and 0.80. PSMA-PET and mpMRI reads differed on 27 nerve bundles, with PSMA-PET being correct in 20 cases and MRI being correct in 7 cases. Surgeons predicted correct nerve-sparing approach 74% of the time with PSMA-PET scan in addition to mpMRI compared to 65% with mpMRI alone (P = .01). CONCLUSIONS: PSMA-PET scan was more sensitive than mpMRI for EPE along the neurovascular bundles and improved surgical decisions for nerve-sparing approach. Further study of PSMA-PET for surgical guidance is warranted in the unfavorable intermediate-risk or worse populations. CLINICALTRIALS.GOV IDENTIFIER: NCT04936334.

A Comparison of Arterial Input Function Interpolation Methods for Patlak Plot Analysis of 68Ga-PSMA-11 PET Prostate Cancer Studies.

Positron emission tomography (PET) imaging enables quantitative assessment of tissue physiology. Dynamic pharmacokinetic analysis of PET images requires accurate estimation of the radiotracer plasma input function to derive meaningful parameter estimates, and small discrepancies in parameter estimation can mimic subtle physiologic tissue variation. This study evaluates the impact of input function interpolation method on the accuracy of Patlak kinetic parameter estimation through simulations modeling the pharmacokinetic properties of [68Ga]-PSMA-11. This study evaluated both trained and untrained methods. Although the mean kinetic parameter accuracy was similar across all interpolation models, the trained node weighting interpolation model estimated accurate kinetic parameters with reduced overall variability relative to standard linear interpolation. Trained node weighting interpolation reduced kinetic parameter estimation variance by a magnitude approximating the underlying physiologic differences between normal and diseased prostatic tissue. Overall, this analysis suggests that trained node weighting improves the reliability of Patlak kinetic parameter estimation for [68Ga]-PSMA-11 PET.

Comparison of tracer kinetic models for 68Ga-PSMA-11 PET in intermediate-risk primary prostate cancer patients.

BACKGROUND: 68Ga-PSMA-11 positron emission tomography enables the detection of primary, recurrent, and metastatic prostate cancer. Regional radiopharmaceutical uptake is generally evaluated in static images and quantified as standard uptake values (SUVs) for clinical decision-making. However, analysis of dynamic images characterizing both tracer uptake and pharmacokinetics may offer added insights into the underlying tissue pathophysiology. This study was undertaken to evaluate the suitability of various kinetic models for 68Ga-PSMA-11 PET analysis. Twenty-three lesions in 18 patients were included in a retrospective kinetic evaluation of 55-min dynamic 68Ga-PSMA-11 pre-prostatectomy PET scans from patients with biopsy-demonstrated intermediate- to high-risk prostate cancer. Three kinetic models-a reversible one-tissue compartment model, an irreversible two-tissue compartment model, and a reversible two-tissue compartment model, were evaluated for their goodness of fit to lesion and normal reference prostate time-activity curves. Kinetic parameters obtained through graphical analysis and tracer kinetic modeling techniques were compared for reference prostate tissue and lesion regions of interest. RESULTS: Supported by goodness of fit and information loss criteria, the irreversible two-tissue compartment model optimally fit the time-activity curves. Lesions exhibited significant differences in kinetic rate constants (K1, k2, k3, Ki) and semiquantitative measures (SUV and %ID/kg) when compared with reference prostatic tissue. The two-tissue irreversible tracer kinetic model was consistently appropriate across prostatic zones. CONCLUSIONS: An irreversible tracer kinetic model is appropriate for dynamic analysis of 68Ga-PSMA-11 PET images. Kinetic parameters estimated by Patlak graphical analysis or full compartmental analysis can distinguish tumor from normal prostate tissue.

Comparison of Tracer Kinetic Models for 68Ga-PSMA-11 PET in Intermediate Risk Primary Prostate Cancer Patients.

BACKGROUND: 68Ga-PSMA-11 positron emission tomography enables the detection of primary, recurrent, and metastatic prostate cancer. Regional radiopharmaceutical uptake is generally evaluated in static images and quantified as standard uptake values (SUV) for clinical decision-making. However, analysis of dynamic images characterizing both tracer uptake and pharmacokinetics may offer added insights into the underlying tissue pathophysiology. This study was undertaken to evaluate the suitability of various kinetic models for 68Ga-PSMA-11 PET analysis. Twenty-three lesions in 18 patients were included in a retrospective kinetic evaluation of 55-minute dynamic 68Ga-PSMA-11 pre-prostatectomy PET scans from patients with biopsy-demonstrated intermediate to high-risk prostate cancer. A reversible one-tissue compartment model, irreversible two-tissue compartment model, and a reversible two-tissue compartment model were evaluated for their goodness-of-fit to lesion and normal reference prostate time-activity curves. Kinetic parameters obtained through graphical analysis and tracer kinetic modeling techniques were compared for reference prostate tissue and lesion regions of interest. RESULTS: Supported by goodness-of-fit and information loss criteria, the irreversible two-tissue compartment model was selected as optimally fitting the time-activity curves. Lesions exhibited significant differences in kinetic rate constants (K1, k2, k3, Ki) and semiquantitative measures (SUV) when compared with reference prostatic tissue. The two-tissue irreversible tracer kinetic model was consistently appropriate across prostatic zones. CONCLUSIONS: An irreversible tracer kinetic model is appropriate for dynamic analysis of 68Ga-PSMA-11 PET images. Kinetic parameters estimated by Patlak graphical analysis or full compartmental analysis can distinguish tumor from normal prostate tissue.

Hybrid 18F-Fluoroethyltyrosine PET and MRI with Perfusion to Distinguish Disease Progression from Treatment-Related Change in Malignant Brain Tumors: The Quest to Beat the Toughest Cases.

Conventional MRI has important limitations when assessing for progression of disease (POD) versus treatment-related changes (TRC) in patients with malignant brain tumors. We describe the observed impact and pitfalls of implementing 18F-fluoroethyltyrosine (18F-FET) perfusion PET/MRI into routine clinical practice. Methods: Through expanded-access investigational new drug use of 18F-FET, hybrid 18F-FET perfusion PET/MRI was performed during clinical management of 80 patients with World Health Organization central nervous system grade 3 or 4 gliomas or brain metastases of 6 tissue origins for which the prior brain MRI results were ambiguous. The diagnostic performance with 18F-FET PET/MRI was dually evaluated within routine clinical service and for retrospective parametric evaluation. Various 18F-FET perfusion PET/MRI parameters were assessed, and patients were monitored for at least 6 mo to confirm the diagnosis using pathology, imaging, and clinical progress. Results: Hybrid 18F-FET perfusion PET/MRI had high overall accuracy (86%), sensitivity (86%), and specificity (87%) for difficult diagnostic cases for which conventional MRI accuracy was poor (66%). 18F-FET tumor-to-brain ratio static metrics were highly reliable for distinguishing POD from TRC (area under the curve, 0.90). Dynamic tumor-to-brain intercept was more accurate (85%) than SUV slope (73%) or time to peak (73%). Concordant PET/MRI findings were 89% accurate. When PET and MRI conflicted, 18F-FET PET was correct in 12 of 15 cases (80%), whereas MRI was correct in 3 of 15 cases (20%). Clinical management changed after 88% (36/41) of POD diagnoses, whereas management was maintained after 87% (34/39) of TRC diagnoses. Conclusion: Hybrid 18F-FET PET/MRI positively impacted the routine clinical care of challenging malignant brain tumor cases at a U.S. institution. The results add to a growing body of literature that 18F-FET PET complements MRI, even rescuing MRI when it fails.

Assessing extra-prostatic extension for surgical guidance in prostate cancer: Comparing two PSMA-PET tracers with the standard-of-care.

BACKGROUND: Incontinence and impotence occur following radical prostatectomy due to injury to nerves and sphincter muscle. Preserving nerves and muscle adjacent to prostate cancer risks positive surgical margins. Advanced imaging with MRI has improved cancer localization but limitations exist. OBJECTIVE: To measure the accuracy for assessing extra-prostatic extension at nerve bundles for 2 PSMA-PET tracers and to compare the PET accuracy to standard-of-care predictors including MRI and biopsy results. MATERIALS AND METHODS: We studied men with PSMA-targeted PET imaging, performed prior to prostatectomy in men largely with intermediate to high-risk prostate cancer, and retrospectively evaluated for assessment of extra-prostatic extension with whole-mount analysis as reference standard. Two different PSMA-PET tracers were included: 68Ga-PSMA-11 and 68Ga-P16-093. Blinded reviews of the PET and MRI scans were performed to assess extra-prostatic extension (EPE). Sensitivity and specificity for extra-prostatic extension were compared using McNemar's Chi2. RESULTS: Pre-operative PSMA-PET imaging was available for 71 patients with either 68Ga-P16-093 (n = 25) or 68Ga-PSMA-11 (n = 46). There were 24 (34%) with pT3a (EPE) and 16 (23%) with pT3b (SVI). EPE Sensitivity (87% vs. 92%), Specificity (77% vs. 76%), and ROC area (0.82 vs. 0.84) were similar between P16-093 and PSMA-11, respectively (P = 0.87). MRI (available in only 45) found high specificity (83%) but low sensitivity (60%) for EPE when using a published grading system. MRI sensitivity was significantly lower than the PSMA-PET (60% vs. 90%, P = 0.02), but similar to PET when using a >5 mm capsular contact (76% vs. 90%, P = 0.38). A treatment change to "nerve sparing" was recommended in 21 of 71 (30%) patients based on PSMA-PET imaging. CONCLUSIONS: Presurgical PSMA-PET appeared useful as a tool for surgical planning, changing treatment plans in men with ≥4+3 or multi-core 3+4 prostate cancer resulting in preservation of nerve-bundles.

Use of multimodality imaging, histology, and treatment feasibility to characterize a transgenic Rag2-null rat model of glioblastoma.

Many drugs that show potential in animal models of glioblastoma (GBM) fail to translate to the clinic, contributing to a paucity of new therapeutic options. In addition, animal model development often includes histologic assessment, but multiparametric/multimodality imaging is rarely included despite increasing utilization in patient cancer management. This study developed an intracranial recurrent, drug-resistant, human-derived glioblastoma tumor in Sprague-Dawley Rag2-Rag2 tm1Hera knockout rat and was characterized both histologically and using multiparametric/multimodality neuroimaging. Hybrid 18F-fluoroethyltyrosine positron emission tomography and magnetic resonance imaging, including chemical exchange saturation transfer (18F-FET PET/CEST MRI), was performed for full tumor viability determination and characterization. Histological analysis demonstrated human-like GBM features of the intracranially implanted tumor, with rapid tumor cell proliferation (Ki67 positivity: 30.5 ± 7.8%) and neovascular heterogeneity (von Willebrand factor VIII:1.8 to 5.0% positivity). Early serial MRI followed by simultaneous 18F-FET PET/CEST MRI demonstrated consistent, predictable tumor growth, with exponential tumor growth most evident between days 35 and 49 post-implantation. In a second, larger cohort of rats, 18F-FET PET/CEST MRI was performed in mature tumors (day 49 post-implantation) for biomarker determination, followed by evaluation of single and combination therapy as part of the model development and validation. The mean percentage of the injected dose per mL of 18F-FET PET correlated with the mean %CEST (r = 0.67, P < 0.05), but there was also a qualitative difference in hot spot location within the tumor, indicating complementary information regarding the tumor cell demand for amino acids and tumor intracellular mobile phase protein levels. Finally, the use of this glioblastoma animal model for therapy assessment was validated by its increased overall survival after treatment with combination therapy (temozolomide and idasanutlin) (P < 0.001). Our findings hold promise for a more accurate tumor viability determination and novel therapy assessment in vivo in a recently developed, reproducible, intracranial, PDX GBM.

The Brain: Is it a Next Frontier to Better Understand the Regulation and Control of Hematopoiesis for Future Modulation and Treatment?

We wish to suggest the possibility there is a link between the brain and hematopoiesis in the bone marrow and that in the future it may be possible to use such information for better understanding of the regulation of hematopoiesis, and for efficacious treatment of hematopoietic disorders.

Advanced imaging techniques for neuro-oncologic tumor diagnosis, with an emphasis on PET-MRI imaging of malignant brain tumors.

PURPOSE OF REVIEW: This review will explore the latest in advanced imaging techniques, with a focus on the complementary nature of multiparametric, multimodality imaging using magnetic resonance imaging (MRI) and positron emission tomography (PET). RECENT FINDINGS: Advanced MRI techniques including perfusion-weighted imaging (PWI), MR spectroscopy (MRS), diffusion-weighted imaging (DWI), and MR chemical exchange saturation transfer (CEST) offer significant advantages over conventional MR imaging when evaluating tumor extent, predicting grade, and assessing treatment response. PET performed in addition to advanced MRI provides complementary information regarding tumor metabolic properties, particularly when performed simultaneously. 18F-fluoroethyltyrosine (FET) PET improves the specificity of tumor diagnosis and evaluation of post-treatment changes. Incorporation of radiogenomics and machine learning methods further improve advanced imaging. The complementary nature of combining advanced imaging techniques across modalities for brain tumor imaging and incorporating technologies such as radiogenomics has the potential to reshape the landscape in neuro-oncology.

[68Ga]Ga-P16-093 as a PSMA-Targeted PET Radiopharmaceutical for Detection of Cancer: Initial Evaluation and Comparison with [68Ga]Ga-PSMA-11 in Prostate Cancer Patients Presenting with Biochemical Recurrence.

PURPOSE: This study was undertaken to evaluate radiation dosimetry for the prostate-specific membrane antigen targeted [68Ga]Ga-P16-093 radiopharmaceutical, and to initially assess agent performance in positron emission tomography (PET) detection of the site of disease in prostate cancer patients presenting with biochemical recurrence. PROCEDURES: Under IND 133,222 and an IRB-approved research protocol, we evaluated the biodistribution and pharmacokinetics of [68Ga]Ga-P16-093 with serial PET imaging following intravenous administration to ten prostate cancer patients with biochemical recurrence. The recruited subjects were all patients in whom a recent [68Ga]Ga-PSMA-11 PET/X-ray computed tomography (CT) exam had been independently performed under IND 131,806 to assist in decision-making with regard to their clinical care. Voided urine was collected from each subject at ~ 60 min and ~ 140 min post-[68Ga]Ga-P16-093 injection and assayed for Ga-68 content. Following image segmentation to extract tissue time-activity curves and corresponding cumulated activity values, radiation dosimetry estimates were calculated using IDAC Dose 2.1. The prior [68Ga]Ga-PSMA-11 PET/CT exam (whole-body PET imaging at 60 min post-injection, performed with contrast-enhanced diagnostic CT) served as a reference scan for comparison to the [68Ga]Ga-P16-093 findings. RESULTS: [68Ga]Ga-P16-093 PET images at 60 min post-injection provided diagnostic information that appeared equivalent to the subject's prior [68Ga]Ga-PSMA-11 scan. With both radiopharmaceuticals, sites of tumor recurrence were found in eight of the ten patients, identifying 16 lesions. The site of recurrence was not detected with either agent for the other two subjects. Bladder activity was consistently lower with [68Ga]Ga-P16-093 than [68Ga]Ga-PSMA-11. The kidneys, spleen, salivary glands, and liver receive the highest radiation exposure from [68Ga]Ga-P16-093, with estimated doses of 1.7 × 10-1, 6.7 × 10-2, 6.5 × 10-2, and 5.6 × 10-2 mGy/MBq, respectively. The corresponding effective dose from [68Ga]Ga-P16-093 is 2.3 × 10-2 mSv/MBq. CONCLUSIONS: [68Ga]Ga-P16-093 provided diagnostic information that appeared equivalent to [68Ga]Ga-PSMA-11 in this limited series of ten prostate cancer patients presenting with biochemical recurrence, with the kidneys found to be the critical organ. Diminished tracer appearance in the urine represents a potential advantage of [68Ga]Ga-P16-093 over [68Ga]Ga-PSMA-11 for detection of lesions in the pelvis.

Prostate Specific Membrane Antigen Targeted Positron Emission Tomography of Primary Prostate Cancer: Assessing Accuracy with Whole Mount Pathology.

PURPOSE: We evaluated which lesions are detected and missed on [68Ga]Ga-PSMA (prostate specific membrane antigen)-11 positron emission tomography in patients with primary prostate cancer. MATERIALS AND METHODS: Patients undergoing radical prostatectomy were enrolled in this prospective observational study. Patients underwent [68Ga]Ga-PSMA-11 positron emission tomography/computerized tomography or positron emission tomography/magnetic resonance imaging prior to surgery and received a dose of [68Ga]Ga-PSMA-11 intraoperatively for positron emission tomography of extirpated specimens. Whole mount pathology was performed with lesion and intralesion based analysis to determine the characteristics of lesions detected or not detected by PSMA positron emission tomography. Lesion volume was determined by planimetry and clinically significant lesion volume was calculated as lesion volume × fraction pattern 4/5. RESULTS: On whole mount analysis 30 cancerous lesions were found in a total of 15 patients, including 4, 15, 4, 1 and 6 which were Grade Group 1, 2, 3, 4 and 5, respectively. PSMA-positron emission tomography detected 100% of primary/index lesions and 8 of 11 (82%) secondary lesions. All Grade Group 3-5 lesions were detected vs 12 of 15 Grade Group 2 lesions. When comparing Grade Group 2 vs 3-5, lesion size was similar (p=0.48) but the standardized uptake value was lower for Grade Group 2 vs 3-5 (5.3 vs 7.9, p=0.03). The 3 missed lesions showed 10% or less of pattern 4 and a Gleason pattern 4/5 volume of less than 0.1 cm3. CONCLUSIONS: PSMA positron emission tomography detected 100% of primary/index lesions in this study. The 3 missed secondary lesions were small and had a low percent of pattern 4. This argues for further study to better understand what defines clinically significant prostate cancer, which would assist in determining whether small lesions that become challenging to detect by [68Ga]Ga-PSMA-11 positron emission tomography confer a risk to the patient.

Synthesis and preliminary biological evaluation of radiolabeled 5-BDBD analogs as new candidate PET radioligands for P2X4 receptor.

P2X4 receptor has become an interesting molecular target for treatment and PET imaging of neuroinflammation and associated brain diseases such as Alzheimer's disease. This study reports the first design, synthesis, radiolabeling and biological evaluation of new candidate PET P2X4 receptor radioligands using 5-BDBD, a specific P2X4 receptor antagonist, as a scaffold. 5-(3-Hydroxyphenyl)-1-[11C]methyl-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one (N-[11C]Me-5-BDBD analog, [11C]9) and 5-(3-Bromophenyl)-1-[11C]methyl-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one (N-[11C]Me-5-BDBD, [11C]8c) were prepared from their corresponding desmethylated precursors with [11C]CH3OTf through N-[11C]methylation and isolated by HPLC combined with SPE in 30-50% decay corrected radiochemical yields with 370-1110GBq/µmol specific activity at EOB. 5-(3-[18F]Fluorophenyl)-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one ([18F]F-5-BDBD, [18F]5a) and 5-(3-(2-[18F]fluoroethoxy)phenyl)-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one ([18F]FE-5-BDBD, [18F]11) were prepared from their corresponding nitro- and tosylated precursors by nucleophilic substitution with K[18F]F/Kryptofix 2.2.2 and isolated by HPLC-SPE in 5-25% decay corrected radiochemical yields with 111-740GBq/µmol specific activity at EOB. The preliminary biological evaluation of radiolabeled 5-BDBD analogs indicated these new radioligands have similar biological activity with their parent compound 5-BDBD.

Estimation of radiation dosimetry for 68Ga-HBED-CC (PSMA-11) in patients with suspected recurrence of prostate cancer.

INTRODUCTION: This study was performed to estimate the human radiation dosimetry for [68Ga]Ga-HBED-CC (PSMA-11) (68Ga PSMA-11). METHODS: Under an RDRC-approved research protocol, we evaluated the biodistribution and pharmacokinetics of 68Ga PSMA-11 with serial PET imaging following intravenous administration to nine prostate cancer patients in whom clinical [11C]acetate PET/CT exams had been independently performed under Expanded Access IND 118,204. List-mode imaging was performed over the initial 0-10min post-injection with the pelvis in the field-of-view. Whole-body images were acquired, pelvis-to-head, at 15, 60, and 90-min post-injection. Additional images of the pelvis were acquired at 40-min and 115-min, and voided urine collected from each subject at 48-min and 120-min post-injection. Radiation dosimetry estimates were calculated from these data using the OLINDA software package. RESULTS: Renal uptake was high and relatively invariant, ranging from 11% to 14% of the injected dose between 15 and 90-min post-injection. Radioactivity collected in the voided urine accounted for 14% of the injected dose over a period of 120-min. Lymph nodes and skeletal metastases suspicious for prostate cancer recurrence were detected in a greater number of patients using 68Ga PSMA-11 than using 11C-acetate. CONCLUSION: Kidneys are the critical organ following 68Ga PSMA-11 administration, receiving an estimated dose of 0.413mGy/MBq. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: This study confirms that the kidneys will be the critical organ following intravenous administration of 68Ga PSMA-11, and provided data consistent with the expectation that 68Ga PSMA-11 will be superior to [11C]acetate for defining sites of recurrence in prostate cancer patients presenting with biochemical relapse.

Measurement of cardiovascular function using a novel view-sharing PET reconstruction method and tracer kinetic analysis.

Recent advancements in PET instrumentation have made the non-invasive assessment of cardiovascular function in small animals a reality. The majority of small animal PET systems use stationary detector gantries, thus affording high temporal resolution imaging of cardiac function. Systems designed to maximize spatial resolution and detection sensitivity employing rotating gantry designs are suboptimal when high temporal resolution imaging is needed. To overcome this limitation, the current work developed a novel view-sharing data analysis scheme suitable for dynamic cardiac PET imaging using 18F-NaF as the tracer and tracer kinetic model analysis. This scheme was tested in a rat model of cardiovascular function where the relationship between direct transonic flow measures of cardiac output were highly correlated (f(x) = 1.0216x - 24.233, R = 0.9158, p < 0.001) with the new model. Similarly, derived measures of stroke volume were also highly correlated (f(x) = 0.9655x - 0.0428, R = 0.9453, p < 0.001) with the current approach. Administration of xylazine caused a statistically significant increase in stroke volume (0.32 ± 0.07 ml, p = 0.003, n = 4) and a significant decrease in both heart rate (-155 ± 7.1 beats/min, p < 0.001, n = 4) and cardiac output (-75.9 ± 23.0 ml/kg min, p = 0.01, n = 4). These findings suggest that the new sinogram binning and kinetic modeling methods produce reliable cardiac function measures suitable for longitudinal monitoring of cardiovascular function.

Novel application of complementary imaging techniques to examine in vivo glucose metabolism in the kidney.

The metabolic status of the kidney is a determinant of injury susceptibility and a measure of progression for many disease processes; however, noninvasive modalities to assess kidney metabolism are lacking. In this study, we employed positron emission tomography (PET) and intravital multiphoton microscopy (MPM) to assess cortical and proximal tubule glucose tracer uptake, respectively, following experimental perturbations of kidney metabolism. Applying dynamic image acquisition PET with 2-18fluoro-2-deoxyglucose (18F-FDG) and tracer kinetic modeling, we found that an intracellular compartment in the cortex of the kidney could be distinguished from the blood and urine compartments in animals. Given emerging literature that the tumor suppressor protein p53 is an important regulator of cellular metabolism, we demonstrated that PET imaging was able to discern a threefold increase in cortical 18F-FDG uptake following the pharmacological inhibition of p53 in animals. Intravital MPM with the fluorescent glucose analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose (2-NBDG) provided increased resolution and corroborated these findings at the level of the proximal tubule. Extending our observation of p53 inhibition on proximal tubule glucose tracer uptake, we demonstrated by intravital MPM that pharmacological inhibition of p53 diminishes mitochondrial potential difference. We provide additional evidence that inhibition of p53 alters key metabolic enzymes regulating glycolysis and increases intermediates of glycolysis. In summary, we provide evidence that PET is a valuable tool for examining kidney metabolism in preclinical and clinical studies, intravital MPM is a powerful adjunct to PET in preclinical studies of metabolism, and p53 inhibition alters basal kidney metabolism.

Differential dopamine function in fibromyalgia.

Approximately 30 % of Americans suffer from chronic pain disorders, such as fibromyalgia (FM), which can cause debilitating pain. Many pain-killing drugs prescribed for chronic pain disorders are highly addictive, have limited clinical efficacy, and do not treat the cognitive symptoms reported by many patients. The neurobiological substrates of chronic pain are largely unknown, but evidence points to altered dopaminergic transmission in aberrant pain perception. We sought to characterize the dopamine (DA) system in individuals with FM. Positron emission tomography (PET) with [(18)F]fallypride (FAL) was used to assess changes in DA during a working memory challenge relative to a baseline task, and to test for associations between baseline D2/D3 availability and experimental pain measures. Twelve female subjects with FM and 11 female controls completed study procedures. Subjects received one FAL PET scan while performing a "2-back" task, and one while performing a "0-back" (attentional control, "baseline") task. FM subjects had lower baseline FAL binding potential (BP) in several cortical regions relative to controls, including anterior cingulate cortex. In FM subjects, self-reported spontaneous pain negatively correlated with FAL BP in the left orbitofrontal cortex and parahippocampal gyrus. Baseline BP was significantly negatively correlated with experimental pain sensitivity and tolerance in both FM and CON subjects, although spatial patterns of these associations differed between groups. The data suggest that abnormal DA function may be associated with differential processing of pain perception in FM. Further studies are needed to explore the functional significance of DA in nociception and cognitive processing in chronic pain.

Whole-body PET/CT evaluation of tumor perfusion using generator-based 62Cu-ethylglyoxal bis(thiosemicarbazonato)copper(II): validation by direct comparison to 15O-water in metastatic renal cell carcinoma.

UNLABELLED: This study was undertaken to demonstrate the feasibility of whole-body (62)Cu-ethylglyoxal bis(thiosemicarbazonato)copper(II) ((62)Cu-ETS) PET/CT tumor perfusion imaging in patients with metastatic renal carcinoma and to validate (62)Cu-ETS as a quantitative marker of tumor perfusion by direct comparison with (15)O-water perfusion imaging. METHODS: PET/CT imaging of 10 subjects with stage IV renal cell cancer was performed after intravenous administration of (15)O-water (10-min dynamic list-mode study) with the heart and at least 1 tumor in the PET field of view, followed 10 min later by intravenous (62)Cu-ETS (6-min list-mode study). Whole-body (62)Cu imaging was then performed from 6 to 20 min at 2-3 min/bed position. Blood flow (K1) was quantified with both agents for normal and malignant tissues in the 21.7-cm dynamic field of view. The required arterial input functions were derived from the left atrium and, in the case of (62)Cu-ETS, corrected for partial decomposition of the agent by blood with data from an in vitro analysis using a sample of each patient's blood. This imaging protocol was repeated at an interval of 3-4 wk after initiation of a standard clinical treatment course of the antiangiogenic agent sunitinib. RESULTS: All subjects received the scheduled (62)Cu-ETS doses for the dynamic and subsequent whole-body PET/CT scans, but technical issues resulted in no baseline (15)O-water data for 2 subjects. Direct comparisons of the perfusion estimates for normal tissues and tumor metastases were made in 18 paired baseline and treatment studies (10 subjects; 8 baseline studies, 10 repeated studies during treatment). There was an excellent correlation between the blood flow estimates made with (62)Cu-ETS and (15)O-water for normal tissues (muscle, thyroid, myocardium) and malignant lesions (pulmonary nodules, bone lesions); the regression line was y = 0.85x + 0.15, R(2) = 0.83, for the 88 regions analyzed. CONCLUSION: (62)Cu-ETS provided high-quality whole-body PET/CT images, and (62)Cu-ETS measures of blood flow were highly and linearly correlated with (15)O-water-derived K1 values (mL(-1) ⋅ min(-1) ⋅ g). This tracer is suitable for use as a PET tracer of tumor perfusion in patients with metastatic renal cell carcinoma.

The HMGB1-RAGE axis mediates traumatic brain injury-induced pulmonary dysfunction in lung transplantation.

Traumatic brain injury (TBI) results in systemic inflammatory responses that affect the lung. This is especially critical in the setting of lung transplantation, where more than half of donor allografts are obtained postmortem from individuals with TBI. The mechanism by which TBI causes pulmonary dysfunction remains unclear but may involve the interaction of high-mobility group box-1 (HMGB1) protein with the receptor for advanced glycation end products (RAGE). To investigate the role of HMGB1 and RAGE in TBI-induced lung dysfunction, RAGE-sufficient (wild-type) or RAGE-deficient (RAGE(-/-)) C57BL/6 mice were subjected to TBI through controlled cortical impact and studied for cardiopulmonary injury. Compared to control animals, TBI induced systemic hypoxia, acute lung injury, pulmonary neutrophilia, and decreased compliance (a measure of the lungs' ability to expand), all of which were attenuated in RAGE(-/-) mice. Neutralizing systemic HMGB1 induced by TBI reversed hypoxia and improved lung compliance. Compared to wild-type donors, lungs from RAGE(-/-) TBI donors did not develop acute lung injury after transplantation. In a study of clinical transplantation, elevated systemic HMGB1 in donors correlated with impaired systemic oxygenation of the donor lung before transplantation and predicted impaired oxygenation after transplantation. These data suggest that the HMGB1-RAGE axis plays a role in the mechanism by which TBI induces lung dysfunction and that targeting this pathway before transplant may improve recipient outcomes after lung transplantation.

Microsphere localization and dose quantification using positron emission tomography/CT following hepatic intraarterial radioembolization with yttrium-90 in patients with advanced hepatocellular carcinoma.

PURPOSE: To characterize the distribution of absorbed radiation dose after glass microsphere radioembolization for hepatocellular carcinoma (HCC) using yttrium-90 ((90)Y) positron emission tomography/computed tomography (PET/CT). MATERIALS AND METHODS: In this retrospective study, 64 (90)Y PET/CT scans performed after treatment were evaluated following (90)Y glass-bead radioembolization in patients with advanced HCC. The intended dose to the target volume ranged from 83-129 Gy. Three-dimensional "dose maps" were created from reconstructed PET images using a voxel-based S-value transformation. Liver parenchyma and liver tumors were contoured on cross-sectional imaging and aligned with the created dose maps. RESULTS: There were 113 tumors examined as part of 64 lobar treatments. The average tumor size was 4.8 cm ± 4.0 with an average tumor dose of 173 Gy ± 109. The average dose to the nontumor parenchyma within the target volume was 93.4 Gy ± 32.6, with on average 50% of the parenchymal voxels receiving > 79 Gy ± 23 and 10% receiving > 173 Gy ± 55. The average and median tumor-to-parenchymal weighted dose ratios were 2.2 and 1.9, respectively. CONCLUSIONS: Using recommended dosimetry and administration techniques for lobar glass microsphere radioembolization, high doses to target tumors as well as background parenchyma were achieved on average with modest preferential uptake within tumors. There was wide variation in measured tumor and parenchymal doses after hepatic radioembolization for HCC, suggesting the need for continued development of patient-specific dosimetry.

The impact of image reconstruction bias on PET/CT 90Y dosimetry after radioembolization.

UNLABELLED: PET/CT imaging after radioembolization is a viable method for determining the posttreatment (90)Y distribution in the liver. Low true-to-random coincidence ratios in (90)Y PET studies limit the quantitative accuracy of these studies when reconstruction algorithms optimized for traditional PET imaging are used. This study examined these quantitative limitations and assessed the feasibility of generating radiation dosimetry maps in liver regions with high and low (90)Y concentrations. METHODS: (90)Y PET images were collected on a PET/CT scanner and iteratively reconstructed with the vendor-supplied reconstruction algorithm. PET studies on a Jaszczak cylindric phantom were performed to determine quantitative accuracy and minimum detectable concentration (MDC). (90)Y and (18)F point-source studies were used to investigate the possible increase in detected random coincidence events due to bremsstrahlung photons. Retrospective quantitative analyses were performed on (90)Y PET/CT images obtained after 65 right or left hepatic artery radioembolizations in 59 patients. Quantitative image errors were determined by comparing the measured image activity with the assayed (90)Y activity. PET images were converted to dose maps through convolution with voxel S values generated using MCNPX, a Monte Carlo N-particle transport code system for multiparticle and high-energy applications. Tumor and parenchyma doses and potential bias based on measurements found below the MDC were recorded. RESULTS: Random coincidences were found to increase in (90)Y acquisitions, compared with (18)F acquisitions, at similar positron emission rates because of bremsstrahlung photons. Positive bias was observed in all images. Quantitative accuracy was achieved for phantom inserts above the MDC of 1 MBq/mL. The mean dose to viable tumors was 183.6 ± 156.5 Gy, with an average potential bias of 3.3 ± 6.4 Gy. The mean dose to the parenchyma was 97.1 ± 22.1 Gy, with an average potential bias of 8.9 ± 4.9 Gy. CONCLUSION: The low signal-to-noise ratio caused by low positron emission rates and high bremsstrahlung photon production resulted in a positive bias on (90)Y PET images reconstructed with conventional iterative algorithms. However, quantitative accuracy was good at high activity concentrations, such as those found in tumor volumes, allowing for adequate tumor (90)Y PET/CT dosimetry after radioembolization.