Serial Positron Emission Tomography Research Articles

Role of serial 18F-fludeoxyglucose positron emission tomography in determining the therapeutic efficacy of immunosuppression and clinical outcome in patients with cardiac sarcoidosis

BackgroundMyocardial inflammation and perfusion defects detected by 18F-fludeoxyglucose (FDG) and Rubidium-82 positron emission tomography (PET) may be associated with ventricular arrhythmias (VAs) in cardiac sarcoidosis (CS). The role of serial quantitative PET in determining the effect of treatment on myocardial inflammation and clinical outcomes is yet to be defined. MethodsNewly diagnosed CS patients with active myocardial inflammation (maximum standardised uptake value (SUVmax) ≥ 2.5) were treated with immunosuppression, then underwent repeat FDG-PET, Rubidium-82, and echocardiographic imaging 6–12 months later. Serial changes in SUVmax, SUVmean, inflammatory extent, perfusion defect (PD) extent, metabolism/perfusion mismatch extent, global cardiac metabolic activity, and left ventricular ejection fraction (LVEF) were assessed. The primary endpoint was a composite of all-cause mortality, serious VA and heart-failure (HF) hospitalisation. Event data were recorded from the date of the second FDG-PET. ResultsThe study population consisted of 113 patients (66% male, age: 55 ± 11 years, LVEF: 54 ± 13%). SUVmax reduced from 4.5 (interquartile range: 3.3–7.1) to 2.7 (2.2–3.6). Overall, 94 (83%) patients saw serial reduction in SUVmax, with 42 (37%) demonstrating complete response (SUVmax <2.5).Following a median of 46 (25–57) months, 28 (25%) patients reached the endpoint (8 deaths, 17 VAs, and 3 HF hospitalisations). PD extent (Hazard ratio 1.03, 95% confidence interval: 1.01–1.05; p = 0.035) was a significant predictor of outcome following treatment, even after accounting for LVEF and change in SUVmean. The risk of adverse events was the greatest in those with a pre-treatment or post-treatment PD extent of >10%. ConclusionIn our cohort with active CS, following a treatment-induced reduction in myocardial inflammation, PD extent was the main predictor of adverse events.

Cardiac noradrenergic deficiency revealed by 18F-dopamine positron emission tomography identifies preclinical central Lewy body diseases.

In Lewy body diseases (LBDs) Parkinson disease (PD), and dementia with Lewy bodies (DLB), by the time parkinsonism or cognitive dysfunction manifests clinically, substantial neurodegeneration has already occurred. Biomarkers are needed to identify central LBDs in a preclinical phase, when neurorescue strategies might forestall symptomatic disease. This phase may involve catecholamine deficiency in the autonomic nervous system. We analyzed data from the prospective, observational, long-term PDRisk study to assess the predictive value of low versus normal cardiac 18F-dopamine positron emission tomography (PET), an index of myocardial content of the sympathetic neurotransmitter norepinephrine, in at-risk individuals. Participants self-reported risk factor information (genetics, olfactory dysfunction, dream enactment behavior, and orthostatic intolerance or hypotension) at a protocol-specific website. Thirty-four with 3 or more confirmed risk factors underwent serial cardiac 18F-dopamine PET at 1.5-year intervals for up to 7.5 years or until PD was diagnosed. Nine participants had low initial myocardial 18F-dopamine-derived radioactivity (<6,000 nCi-kg/cc-mCi) and 25 had normal radioactivity. At 7 years of follow-up, 8 of 9 with low initial radioactivity and 1 of 11 with normal radioactivity were diagnosed with a central LBD (LBD+) (P = 0.0009 by Fisher's exact test). Conversely, all 9 LBD+ participants had low 18F-dopamine-derived radioactivity before or at the time of diagnosis of a central LBD, whereas among 25 participants without a central LBD only 1 (4%) had persistently low radioactivity (P < 0.0001 by Fisher's exact test). Cardiac 18F-dopamine PET highly efficiently distinguishes at-risk individuals who are diagnosed subsequently with a central LBD from those who are not. gov NCT00775853. Division of Intramural Research, NIH, NINDS.

Abstract 17309: Assessing the Effect of Corticosteroid Taper Rate and Repeat Pet Imaging on Cardiovascular Outcomes Among a Homogenously Treated Cohort of Patients With Suspected Cardiac Sarcoidosis

Introduction: Serial positron emission tomography (PET) imaging is utilized to monitor disease activity and treatment response in patients with suspected cardiac sarcoidosis (CS). However, there is no data available on the cardiovascular outcomes associated with corticosteroid taper rates and timing of repeat PET imaging in patients with CS. Methods: We identified 70 patients with suspected CS (Age: 56.3 ± 9, 31% female, LVEF 45.6 ± 13.6, median follow-up time: 6.3 months [4-7.6]) who were treatment naïve and displayed inflammation on baseline FDG-PET, subsequently started on a moderate-dose of prednisone only (i.e., 30-40 mg/day), and had a diagnostic follow-up PET. Patients were divided into two groups based on median follow-up time between PET scans; early (&lt;6.3 months, n=35) or delayed (≥6.3 months, n=35) surveillance imaging. Corticosteroid taper was captured by measuring weekly changes in prednisone from treatment initiation to follow-up PET. Major adverse cardiovascular events (MACE) were defined as sustained ventricular tachycardia/ventricular fibrillation (VT/VF), heart failure (HF) admission, and death. Results: In this homogenously treated cohort, overall, we observed no significant difference in MACE between early vs delayed imaging groups (p=0.117, Figure 1A). Furthermore, there were no significant differences in corticosteroid taper rates between early and delayed groups (-0.927 ± 1.15 vs -0.618 ± 0.58, p=0.163). As such, we observed no difference in MACE associated with taper rate (p=0.647, Figure 1B). Conclusion: Patients with suspected CS undergoing repeat PET imaging had similar adverse cardiovascular outcomes despite variations in follow-up time and taper rates of prednisone. We suggest to adopt an early imaging strategy to allow for timely optimization of immunosuppression and clinical surveillance.

Quantitative Analysis of Serial Positron Emission Tomography Imaging in Men with Metastatic Castration-resistant Prostate Cancer Treated with Enzalutamide

BackgroundThe emergence of positron emission tomography (PET) in prostate cancer is impacting clinical practice, but little is known about PET imaging as a tool to determine treatment failure in metastatic castration-resistant prostate cancer (mCRPC). ObjectiveTo evaluate PET imaging dynamics in mCRPC patients on enzalutamide with stable computed tomography (CT) and technetium-99m (Tc99) bone scans. Design, setting, and participantsAll patients were on treatment with enzalutamide for first-line mCRPC in a clinical trial at the National Cancer Institute (Bethesda, MD, USA). A volunteer sample had serial 18F-sodium fluoride (NaF) PET in parallel with CT and Tc99. Regions of interest (ROIs) on NaF were analyzed quantitatively for response. InterventionPatients were randomized to enzalutamide with/without a cancer immunotherapy, Prostvac. Outcome measurements and statistical analysisA post hoc, descriptive analysis was performed comparing the changes seen on CT and Tc99 as per RECIST 1.1 with NaF PET scans including the use of a quantitative analysis. Results and limitationsEighteen mCRPC patients had 67 NaF scans. A total of 233 ROIs resolved after treatment, 52 (22%) of which eventually retuned while on therapy. In all, 394 new ROIs were seen, but 112(28%) resolved subsequently. Of 18 patients, 14 had new ROIs that ultimately resolved after appearing. Many patients experienced progression in a minority of lesions, and one patient with radiation intervention to oligoprogression had a remarkable response. This study is limited by its small number of patients and post hoc nature. ConclusionsThese data highlight the dynamic nature of NaF PET in mCRPC patients treated with enzalutamide, where not all new findings were ultimately related to disease progression. This analysis also provides a potential strategy to identify and intervene in oligoprogression in prostate cancer. Patient summaryIn this small analysis of patients with prostate cancer on enzalutamide, changes on 18F-sodium fluoride positron emission tomography (PET) imaging were not always associated with treatment failure. Caution may be indicated when using PET imaging to determine whether new therapy is needed.

Outcomes of Patients Treated With RCHOP With a PET-Adapted Approach for Consolidative Radiotherapy: A Retrospective Single-Center Study at the Royal Marsden Hospital

BackgroundTreatment with CHOP-based chemotherapy with consolidative radiotherapy (CRT) for primary mediastinal B cell lymphoma (PMBCL) has been the standard approach in the pre-rituximab era. Overtreatment with CRT for patients who may have already been cured by primary immunochemotherapy in the rituximab era is a significant concern due to the long-term toxicity associated with radiotherapy. Positron emission tomography (PET) may help to identify patients who may not benefit from further CRT. MethodsWe conducted a retrospective review of patients treated at the Royal Marsden Hospital between 2003 and 2020 for PMBCL to assess CRT use and survival outcomes. ResultsForty-three patients were identified, with 95% of the patients receiving R-CHOP. CRT was given in 5 patients. Five-year event-free survival was 79% (95% confidence interval: 64%-89%) and 5-year overall survival was 88% (95% confidence interval: 73%-95%). Seven of 9 patients with DS4 did not receive CRT and instead monitored with serial PET scans. None of these 7 patients relapsed in the mediastinum. ConclusionCRT may be omitted in patients with a negative end of treatment PET scans; however, careful observation may also obviate the need for CRT in PET positive patients.

Abstract 581: Peptide-based theranostics targeting ANTXR1 in cancer stroma

Abstract Background: ANTXR1 is one of the pancreatic ductal adenocarcinoma (PDAC) stroma-specific cell surface markers (Ref 1), which is also overexpressed in the stroma of various cancer types. Radiotheranostics refers to the combination of molecular imaging with targeted radionuclide therapy. Recent success of radiotheranostic agents such as 177Lu-DOTATATE and 177Lu-PSMA617 heralds the vibrant expansion of radiotheranostics. Herein, we sought to develop ANTXR1 targeting peptide as a cancer stroma-targeting radiotheranostic agent. Methods: We selected A549 and NCI-H460 as ANTXR1 positive cell lines and NCI-H1437 and NCI-H358 as negative cell lines based on a proteomics database for cancer cell lines. ANTXR1-targeting peptide (PC01) was discovered using Chemistry-based Ultra-high-throughput Screening (CUSTM) platform. PC01 was conjugated with either fluorescence dye (Cy5-PC01) or chelator (DOTA-PC01). DOTA-PC01 was labeled with 68Ga. Flow cytometry and confocal microscopy were utilized to assess specific binding of the peptide. Subcutaneous tumor-bearing mice were intravenously injected with Cy5-PC01 or 68Ga-DOTA-PC01. In vivo/ex vivo fluorescence imaging (IVIS) and positron emission tomography (PET) imaging were performed. Results: In western blot analysis, H460 and A549 demonstrated high levels of expression of ANTXR1, while H1437 and H358 showed negligible levels of expression, consistent with the proteomics database. The mean fluorescence intensity of H460 was significantly higher than that of H1437 after incubation with Cy5-PC01 in flow cytometry. In confocal microscopy, the two ANTXR1 positive cell lines demonstrated higher fluorescence signals compared to the two ANTXR1 negative cell lines, which indicates the specific binding of PC01 to ANTXR1. As for in vivo experiments, timepoints of image acquisition for both IVIS and PET were 0h, 1h, 2h, and 4h after injection of the peptide. In in vivo IVIS images, tumor uptake was more prominent in H460 tumors than in H1437 tumors. Furthermore, tumor/kidney uptake ratio and tumor/liver uptake ratio of Cy5-PC01 were significantly higher in H460 tumors compared to those of H1437 tumors (P &amp;lt; 0.05, P &amp;lt; 0.05, respectively). Radiolabeling efficiency of 68Ga-DOTA-PC01 was measured to be over 95% by thin-layer chromatography. Serial PET images of 68Ga-DOTA-PC01 demonstrated an initial intense renal uptake and subsequent fast renal clearance, which is a typical biodistribution of peptide-based radiotheranostic agents. Also, the tumor uptake was more pronounced in the H460 tumors than in the H1437 tumors. Conclusion: We developed an ANTXR1 targeting peptide conjugated with DOTA for radiotheranostics. We found that PC01 demonstrated favorable biodistribution and specific in vitro/in vivo binding to ANTXR1, which prompts us to further optimize and develop a peptide-based ANTXR1 targeting radiotheranostic agent. Ref 1. Cancer Res (2022) 82 (12_Supplement): 5007 Citation Format: Shengjun Li, Jin Yeong Choi, Hye Sook Ha, Yoo Joung Oh, Song-Gil Lee, Hongyoon Choi, Hyung-Jun Im. Peptide-based theranostics targeting ANTXR1 in cancer stroma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 581.

Development of 89Zr-anti-CD103 PET imaging for non-invasive assessment of cancer reactive T cell infiltration

PurposeCD103, an integrin specifically expressed on the surface of cancer-reactive T cells, is significantly increased during successful immunotherapy across human malignancies. In this study, we describe the generation and zirconium-89...

Chronic fluoxetine enhances extinction therapy for PTSD by evaluating brain glucose metabolism in rats: an [18F]FDG PET study.

Recent studies suggest that selective serotonin reuptake inhibitors (SSRIs) and exposure therapies have been used to reduced footshock-induced posttraumatic stress disorder (PTSD) symptoms. However, the therapeutic effect of the combination of SSRIs treatment with exposure therapy remains a matter of debate. This study aimed to evaluate these therapeutic effect through the behavioural and the neuroimaging changes by positron emission tomography (PET) in model rats. Pavlovian fear conditioning paradigm to establish model rats, and serial PET imaging with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) was performed during the control, fear-conditioning, and extinction-retrieval phases. The expression of c-Fos was used to identify neural activity. We report that fear conditioning increased glucose metabolism in the right amygdala and left primary visual cortex but decreased glucose metabolism in the left primary somatosensory cortex. After extinction retrieval, there was increased [18F]FDG uptake in the left striatum, left cochlear nucleus and right primary visual cortex but decreased uptake in the anterior cingulate cortex in the extinction group. Fluoxetine increased [18F]FDG uptake in the left hippocampus and right primary visual cortex but decreased uptake in the bilateral primary somatosensory cortex, left primary/secondary motor cortex and cuneiform nucleus. The combined therapy increased [18F]FDG uptake in the left hippocampus, left striatum, right insular cortex, left posterior parietal cortex, and right secondary visual cortex but reduced uptake in the cerebellar lobule. c-Fos expression in the hippocampal dentate gyrus and anterior cingulate cortex in the fluoxetine and combined groups was significantly higher than that in the extinction group, with no significant difference between the two groups. Chronic fluoxetine enhanced the effects of extinction training in a rat model of PTSD. In vivo PET imaging may provide a promising approach for evaluation chronic fluoxetine treatment of PTSD.

Risk Assessment in Diffuse Large B-Cell Lymphoma by Combining Baseline Metabolic Tumor Volume and Peking Criteria When Evaluating Series 18F-Fluorodeoxyglucose Positron Emission Tomography Scans.

This study aimed to determine the predictive and prognostic value of baseline metabolic tumor volume (MTV) and the Peking criteria from serial positron emission tomography (PET) scans in diffuse large B-cell lymphoma, including 300 newly diagnosed patients who were prospectively treated with 2–4 cycles of standard first-line treatment (clinicaltrials.gov identifier: NCT02928861). PET/computed tomography (CT) examinations were performed at baseline, after two (PET-2) or four cycles (PET-4). PET during the interim was evaluated using Deauville 5-point scales (5-PS), ΔSUVmax criteria, and the Peking criteria which interpreted based on the maximum standard uptake of the liver (SUVmax-liver). Peking criteria had better accuracy, positive predictive value (PPV), and specificity than other two methods. The MTV and Peking criteria both significantly predicted progression-free survival (PFS) and overall survival (OS). An MTV > 191 cm2 and Peking criteria of PET-2 and PET-4 > 1.6-fold SUVmax-liver was used as the cutoff for a positive result. PET-4 achieved higher accuracy, PPV, and specificity for 2-year PFS (83.3%, 86.7%, and 98.4%, respectively) and OS (92.6%, 73.3%, and 97.2%, respectively) than PET-2. Various prognostic models containing different risk factors were established via Cox regression analysis. The MTV and PET-2/PET-4 results were used to categorized patients into low-risk, intermediate-risk, and high-risk prognostic groups (with 0, 1, and 2 risk factors, respectively) (P < 0.0001). High burden MTV and positive PET-2 and PET-4 (>1.6-fold SUVmax-liver) could identify high-risk patients with 2-year PFS and OS of 0.0% and 26.3% (95% confidence interval [CI]: N/A to 54.3%). When PET-2 and PET-4 were evaluated by 5-PS, the 2-year PFS and OS from high risk patients of three-parameters model achieved 31.4% (95%CI: 6.9%–55.9%) and 42.7% (95%CI: 14.6%–70.7%). In conclusion, combining baseline MTV and any regular response on PET/CT evaluated using the Peking criteria can improve prognostic value. Serial PET/CT from baseline MTV to PET-4 may have relatively greater predictive power for poor prognosis in diffuse large B-cell lymphoma.Clinical Trial Registration ClinicalTrials.gov, identifier (NCT02928861).

Prognostic utility of longitudinal quantification of PET myocardial blood flow early post heart transplantation

BackgroundMyocardial blood flow (MBF) quantification by Rubidium-82 positron emission tomography (PET) has shown promise for cardiac allograft vasculopathy (CAV) surveillance and risk stratification post heart transplantation. The objective was to determine the prognostic value of serial PET performed early post transplantation. Methods and ResultHeart transplant (HT) recipients at the University of Ottawa Heart Institute with 2 PET examinations (PET1 = baseline, PET2 = follow-up) within 6 years of transplant were included in the study. Evaluation of PET flow quantification included stress MBF, coronary vascular resistance (CVR), and myocardial flow reserve (MFR). The primary composite outcome was all-cause death, re-transplant, myocardial infarction, revascularization, allograft dysfunction, cardiac allograft vasculopathy (CAV), or heart failure hospitalization. A total of 121 patients were evaluated (79% male, mean age 56 ± 11 years) with consecutive scans performed at mean 1.4 ± 0.7 and 2.6 ± 1.0 years post HT for PET1 and PET2, respectively. Over a mean follow-up of 3.0 (IQR 1.8, 4.6) years, 26 (22%) patients developed the primary outcome: 1 death, 11 new or progressive angiographic CAV, 2 percutaneous coronary interventions, 12 allograft dysfunction. Unadjusted Cox analysis showed a significant reduction in event-free survival in patients with PET1 stress MBF < 2.1 (HR: 2.43, 95% CI 1.11-5.29 P = 0.047) and persistent abnormal PET1 to PET2 CVR > 76 (HR: 2.19, 95% CI 0.87-5.51 P = 0.045). There was no association between MFR and outcomes. ConclusionLow-stress MBF and persistent increased CVR on serial PET imaging early post HT are associated with adverse cardiovascular outcomes. Early post-transplant and longitudinal assessment by PET may identify at-risk patients for increased surveillance post HT.

The Overlap Index: A new means for early detection of serial tau PET signal change

AbstractBackgroundIn longitudinal tau (flortaucipir) positron emission tomography (PET), a reliable method to detect a tau accumulation while minimizing a random variability is crucial. Variability can be a problem especially in the early stages of tau pathology in which only small regions and low levels of accumulation may exist relative to the range of random noise fluctuation.MethodWe recruited 76 participants who had serial scans for a total of 234 tau PET scans. In this cohort we tested a PET signal measurement method we developed called the “overlap index” (OI). The OI was calculated by identifying voxels that have elevated tau PET signal that overlap on two successive tau PET scans in the same participant (Figure 1). This analysis procedure tests the hypothesis that voxel‐wise, elevated‐uptake consistency might be more sensitive for early detection of tau tangles than standard ROI based measures. We compared OI to ROI based measures for early detection of increasing tau PET signal and detection clinical progression. A meta ROI used in this analysis included the amygdala, entorhinal cortex, fusiform, parahippocampal, and inferior temporal and middle temporal gyri.ResultOI showed regional progression of tau in the temporal lobe followed by increases throughout the brain at relatively low standardized uptake value ratio (SUVr) levels (Figure 2A and B). The topographical pattern of OI was in agreement in some respects with the sequential appearance of tau aggregation (Figure 2B and C). The high‐OI group (OI&gt;0.5) had a significantly higher ΔSUVr compared to the low‐OI group (OI&lt;0.5) (Figure 3A and B). OI identified subjects that did or didn’t have tau accumulation within meta SUVr subgroups even when below the meta ROI SUVr threshold. OI was associated with early clinical disease stage progression vs meta‐ROI SUVr measures (Figure 3C‐E).ConclusionIn this study, we found that OI tau PET measurement was able to quantify voxel‐wise consistency using a set of serial scans. OI may detect earlier tau tangle accumulation and earlier disease progression than standard SUVr measurements in tau PET.

PEGylated Nanoscale Metal-Organic Frameworks for Targeted Cancer Imaging and Drug Delivery.

Nanoscale metal-organic frameworks (nMOFs) are a unique type of hybrid materials, which are broadly applicable as cargo delivery systems. However, the relatively low material stability and insufficient cancer cell interacting capacity have limited nMOFs' applications in cancer theranostics. Herein, a zirconium-based nMOF UiO-66-N3 was synthesized, and its surface was covalently functionalized with alkyne-containing polyethylene glycol (PEG) via the azide-alkyne click chemistry. After that, F3 peptide was attached for targeting of cancer cells (the material was denoted as UiO-66-PEG-F3). Doxorubicin (DOX) served as a therapeutic drug and a fluorescent label in this study, and it was transported into UiO-66-PEG conjugates with sufficient drug loading efficiency. pH-responsive release of DOX from UiO-66 conjugates was witnessed. The structural integrity of UiO-66-N3 was maintained post the surface modification process. Flow cytometry and confocal fluorescence microscopy revealed that DOX/UiO-66-PEG-F3 had stronger accumulation in MDA-MB-231 cells (nucleolin+) compared with DOX/UiO-66-PEG. In order to track the pharmacokinetic behavior (organ distribution profile) in vivo, the positron-emitting zirconium-89 (89Zr) was incorporated into UiO-66-N3. Similar PEGylation and F3 peptide conjugation resulted in the formation of 89Zr-UiO-66-PEG-F3. Serial positron emission tomography (PET) imaging demonstrated that the preferential accumulation of 89Zr-UiO-66-PEG-F3 in MDA-MB-231 tumors, and their liver clearance was faster than PEGylated UiO-66 using noncovalent methods. Thus, the PEGylated nMOFs using covalent strategies may find broad application in future cancer theranostics.

Multimodality Imaging of the Brain-Heart-Axis after Ischemic Stroke Reveals Acute and Chronic Cardiac Dysfunction after Cerebral Ischemia

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): DFG; Ev Studienwerk Villigst Introduction Cerebral ischemia remains a major contributor to global morbidity and mortality. Beyond neurological dysfunction, cerebral stroke also increases risk of subsequent cardiac events and development of chronic heart failure. The mechanisms underlying this brain-heart communication are poorly characterized, but systemic inflammation is thought to play a role. Purpose We hypothesized that cerebral ischemic stroke evokes systemic inflammation contributing to acute cardiac stress and persistent contractile dysfunction, which may be monitored by serial molecular imaging by positron emission tomography (PET). Methods C57Bl6 mice underwent transient (30min) intraluminal middle cerebral artery occlusion (MCAo, n = 88) to induce stroke or sham surgery (n = 18). Serial 18F-GE180 PET at 24h, 7d, and 21d after injury identified translocator protein (TSPO) in brain microglia and peripheral macrophages as a marker of inflammation. Magnetic resonance imaging (MRI) determined stroke size and characterized cardiac function at 1 and 3wk after MCAo. Imaging signals were confirmed by autoradiography, immunohistochemistry and fluorescence-activated cell sorting. Results MCAo in mice induced cerebral stroke of variable size (median 44.68mm3, range:5.12-139.60mm3). Localized inflammation in the injured hemisphere was observed by TSPO PET covering territory consistent to the stroke location, with marked increase in the neuroinflammatory signal at 7d relative to the contralateral hemisphere (% injected dose (ID)/g max: 3.82 ± 0.84 vs 2.51 ± 0.32, p &amp;lt; 0.001). TSPO signal was similarly elevated in the stroke region compared to sham animals (%ID/g max: 3.82 ± 0.84 vs 2.59 ± 0.72, p &amp;lt; 0.001). Corresponding with neuroinflammation, a heightened global myocardial TSPO signal was observed 7d after MCAo compared to sham (%ID/g: 7.75 ± 2.79 vs 5.61 ± 1.98, p = 0.041). TSPO PET signal remained elevated 21d after stroke in brain (3.20 ± 1.15 vs 2.46 ± 0.37, p = 0.012) and heart (8.62 ± 2.43 vs 5.85 ± 0.66, p = 0.022). Cerebral stroke was associated with reduced contractile function compared to sham at 1wk (ejection fraction, EF: 49.58 ± 16.90 vs 62.17 ± 5.25%, p = 0.025) and 3wk (54.30 ± 5.70 vs 66.06 ± 3.48%, p = 0.009). Larger stroke size identified early after injury by T2 weighted MRI, reflecting the focal injury and penumbra edema, correlated with worse subsequent cardiac function at 21d (r = 0.745, p = 0.009). Despite increased TSPO signal, flow cytometry showed comparable CD45+ leukocyte content in the left ventricle after MCAo compared to sham at 7d (p = 0.749). Conclusions Ischemic stroke evoked parallel cerebral and cardiac TSPO upregulation and persistent contractile dysfunction, beginning early after injury. The extent and severity of brain injury predicts left ventricle dysfunction, but the role of inflammation requires further investigation. Molecular imaging may identify risk and guide novel therapies to improve cardiac outcome after stroke.

Use of Chromogranin A for Monitoring Patients With Pancreatic Neuroendocrine Neoplasms.

We aimed to assess the role of serum chromogranin A (CgA) in monitoring disease status and treatment response in patients with pancreatic neuroendocrine neoplasms (pNENs). We included posttherapy pNENs patients with measured serum CgA levels who underwent 68Ga-labeled tetraazacyclododecanetetraacetic acid-peptide positron emission tomography (PET) imaging between April 2017 and January 2020. Serum CgA levels were determined by enzyme-linked immunosorbent assay. Tumor response was assessed according to the PET response evaluation criteria in solid tumors. Seventy-seven patients with 101 events were included in this study. Serum CgA levels were significantly higher in patients with active disease and metastasis. The optimal cutoff values for CgA for active and metastatic pNENs diagnosis after treatment were 52.39 (77.8% sensitivity, 80.7% specificity) and 60.18 ng/mL (73.9% sensitivity, 73.1% specificity), respectively. Based on 18 patients with serial CgA measurements and PET imaging, the optimal changes in CgA levels for predicting disease remission and progression were a 28.5% decrease (71.4% sensitivity, 88.2% specificity) and a 21.0% increase (100.0% sensitivity, 75.0% specificity), respectively. We concluded that serum CgA levels are associated with disease status and treatment response and may thus provide a helpful biomarker for the monitoring and clinical management of patients with pNENs.

Molecular imaging of fibroblast activation protein after myocardial infarction using the novel radiotracer [68Ga]MHLL1.

Background: Myocardial infarction (MI) evokes an organized remodeling process characterized by the activation and transdifferentiation of quiescent cardiac fibroblasts to generate a stable collagen rich scar. Early fibroblast activation may be amenable to targeted therapy, but is challenging to identify in vivo. We aimed to non-invasively image active fibrosis by targeting the fibroblast activation protein (FAP) expressed by activated (myo)fibroblasts, using a novel positron emission tomography (PET) radioligand [68Ga]MHLL1 after acute MI.Methods: One-step chemical synthesis and manual as well as module-based radiolabeling yielded [68Ga]MHLL1. Binding characteristics were evaluated in murine and human FAP-transfected cells, and stability tested in human serum. Biodistribution in healthy animals was interrogated by dynamic PET imaging, and metabolites were measured in blood and urine. The temporal pattern of FAP expression was determined by serial PET imaging at 7 d and 21 d after coronary artery ligation in mice as percent injected dose per gram (%ID/g). PET measurements were validated by ex vivo autoradiography and immunostaining for FAP and inflammatory macrophages.Results: [68Ga]MHLL1 displayed specific uptake in murine and human FAP-positive cells (p = 0.0208). In healthy mice the tracer exhibited favorable imaging characteristics, with low blood pool retention and dominantly renal clearance. At 7 d after coronary artery ligation, [68Ga]MHLL1 uptake was elevated in the infarct relative to the non-infarcted remote myocardium (1.3 ± 0.3 vs. 1.0 ± 0.2 %ID/g, p < 0.001) which persisted to 21 d after MI (1.3 ± 0.4 vs. 1.1 ± 0.4 %ID/g, p = 0.013). Excess unlabeled compound blocked tracer accumulation in both infarct and non-infarct remote myocardium regions (p < 0.001). Autoradiography and histology confirmed the regional uptake of [68Ga]MHLL1 in the infarct and especially border zone regions, as identified by Masson trichrome collagen staining. Immunostaining further delineated persistent FAP expression at 7 d and 21 d post-MI in the border zone, consistent with tracer distribution in vivo.Conclusion: The simplified synthesis of [68Ga]MHLL1 bears promise for non-invasive characterization of fibroblast activation protein early in remodeling after MI.

Molecular imaging-guided repair after acute myocardial infarction by targeting the chemokine receptor CXCR4

Balance between inflammatory and reparative leucocytes allows optimal healing after myocardial infarction (MI). Interindividual heterogeneity evokes variable functional outcome complicating targeted therapy. We aimed to characterize infarct chemokine CXC-motif receptor 4 (CXCR4) expression using positron emission tomography (PET) and establish its relationship to cardiac outcome. We tested whether image-guided early CXCR4 directed therapy attenuates chronic dysfunction. Mice (n = 180) underwent coronary ligation or sham surgery and serial PET imaging over 7 days. Infarct CXCR4 content was elevated over 3 days after MI compared with sham (%ID/g, Day 1:1.1 ± 0.2; Day 3:0.9 ± 0.2 vs. 0.6 ± 0.1, P < 0.001), confirmed by flow cytometry and histopathology. Mice that died of left ventricle (LV) rupture exhibited persistent inflammation at 3 days compared with survivors (1.2 ± 0.3 vs. 0.9 ± 0.2% ID/g, P < 0.001). Cardiac magnetic resonance measured cardiac function. Higher CXCR4 signal at 1 and 3 days independently predicted worse functional outcome at 6 weeks (rpartial = -0.4, P = 0.04). Mice were treated with CXCR4 blocker AMD3100 following the imaging timecourse. On-peak CXCR4 blockade at 3 days lowered LV rupture incidence vs. untreated MI (8% vs. 25%), and improved contractile function at 6 weeks (+24%, P = 0.01). Off-peak CXCR4 blockade at 7 days did not improve outcome. Flow cytometry analysis revealed lower LV neutrophil and Ly6Chigh monocyte content after on-peak treatment. Patients (n = 50) early after MI underwent CXCR4 PET imaging and functional assessment. Infarct CXCR4 expression in acute MI patients correlated with contractile function at time of PET and on follow-up. Positron emission tomography imaging identifies early CXCR4 up-regulation which predicts acute rupture and chronic contractile dysfunction. Imaging-guided CXCR4 inhibition accelerates inflammatory resolution and improves outcome. This supports a molecular imaging-based theranostic approach to guide therapy after MI.

Longitudinal validity of PET-based staging of regional amyloid deposition.

Positron emission tomography (PET)‐based staging of regional amyloid deposition has recently emerged as a promising tool for sensitive detection and stratification of pathology progression in Alzheimer's Disease (AD). Here we present an updated methodological framework for PET‐based amyloid staging using region–specific amyloid‐positivity thresholds and assess its longitudinal validity using serial PET acquisitions. We defined region‐specific thresholds of amyloid‐positivity based on Florbetapir‐PET data of 13 young healthy individuals (age ≤ 45y), applied these thresholds to Florbetapir‐PET data of 179 cognitively normal older individuals to estimate a regional amyloid staging model, and tested this model in a larger sample of patients with mild cognitive impairment (N = 403) and AD dementia (N = 85). 2‐year follow‐up Florbetapir‐PET scans from a subset of this sample (N = 436) were used to assess the longitudinal validity of the cross‐sectional model based on individual stage transitions and data‐driven longitudinal trajectory modeling. Results show a remarkable congruence between cross‐sectionally estimated and longitudinally modeled trajectories of amyloid accumulation, beginning in anterior temporal areas, followed by frontal and medial parietal areas, the remaining associative neocortex, and finally primary sensory‐motor areas and subcortical regions. Over 98% of individual amyloid deposition profiles and longitudinal stage transitions adhered to this staging scheme of regional pathology progression, which was further supported by corresponding changes in cerebrospinal fluid biomarkers. In conclusion, we provide a methodological refinement and longitudinal validation of PET‐based staging of regional amyloid accumulation, which may help improving early detection and in‐vivo stratification of pathologic disease progression in AD.

A preclinical PET dual-tracer imaging protocol for ER and HER2 phenotyping in breast cancer xenografts

BackgroundNuclear medicine is on the constant search of precision radiopharmaceutical approaches to improve patient management. Although discordant expression of the estrogen receptor (ER) and the human epidermal growth factor receptor 2 (HER2) in breast cancer is a known dilemma for appropriate patient management, traditional tumor sampling is often difficult or impractical. While 2-deoxy-2[18F]fluoro-D-glucose (18F-FDG)-positron emission tomography (PET) is an option to detect subclinical metastases, it does not provide phenotype information. Radiolabeled antibodies are able to specifically target expressed cell surface receptors. However, their long circulating half-lives (days) require labeling with long-lived isotopes, such as 89Zr, in order to allow sufficient time for tracer clearance from the blood compartment and to accumulate adequately in target tumors and, thus, generate high-quality PET images. The aim of this study was to develop a dual-tracer PET imaging approach consisting of a fast-clearing small molecule and a slow-clearing antibody. This approach was evaluated in a model consisting of mice harboring separate breast cancer xenografts with either an ER+/HER2− or ER−/HER2+ phenotype, comparable to human metastatic disease with intertumor heterogeneity. Lastly, the aim of our study was to determine the feasibility of specifically identifying these two important phenotypes in an acceptable time window.MethodsFemale nude mice were subcutaneously implanted on opposite shoulders with the ER+/HER2− and ER−/HER2+ MCF-7 and JIMT-1 tumor cell lines, respectively. A second model was developed consisting of mice implanted orthotopically with either MCF-7 or JIMT-1 cells. Pharmacokinetic analysis, serial PET imaging, and biodistribution were first performed for [89Zr]Zr-DFO-trastuzumab (89Zr-T) up to 8 days post-injection (p.i.) in JIMT-1 bearing mice. Region-of-interest (ROI) and biodistribution-derived uptake (% injected-activity/gram of tissue [%IA/g]) values and tumor-to-background ratios were obtained. Results were compared in order to validate ROI and identify early time points that provided high contrast tumor images. For the dual-tracer approach, cohorts of tumor-bearing mice were then subjected to sequential tracer PET imaging. On day 1, mice were administered 4-fluoro-11β-methoxy-16α-[18F]-fluoroestradiol (4FMFES) which targets ER and imaged 45 min p.i. This was immediately followed by the injection of 89Zr-T. Mice were then imaged on day 3 or day 7. ROI analysis was performed, and uptake was calculated in tumors and selected healthy organs for all radiotracers. Quality of tumor targeting for all tracers was evaluated by tumor contrast visualization, tumor and normal tissue uptake, and tumor-to-background ratios.Results89Zr-T provided sufficiently high tumor and low background uptake values that furnished high contrast tumor images by 48 h p.i. For the dual-tracer approach, 4FMFES provided tumor uptake values that were significantly increased in MCF-7 tumors. When 89Zr-T-PET was combined with 18F-4FMFES-PET, the entire dual-tracer sequential-imaging procedure provided specific high-quality contrast images of ER+/HER2− MCF-7 and ER−/HER2+ JIMT-1 tumors for 4FMFES and 89Zr-T, respectively, as short as 72 h from start to finish.ConclusionsThis protocol can provide high contrast images of tumors expressing ER or HER2 within 3 days from injection of 4FMFES to final scan of 89Zr-T and, hence, provides a basis for future dual-tracer combinations that include antibodies.

In Vivo Tracking of Adoptively Transferred Natural Killer Cells in Rhesus Macaques Using 89Zirconium-Oxine Cell Labeling and PET Imaging.

Trials of adoptive natural killer (NK)-cell immunotherapy for hematologic malignancies have thus far shown only marginal effects, despite the potent in vitro antitumor activity of these cells. Homing of infused cells to tumor microenvironments is critical for efficacy, but has not been well characterized. We established a novel method to track and quantify the distribution of adoptively transferred NK cells using rhesus macaques (RM) as a clinically relevant preclinical model. RM NK cells were expanded ex vivo for 14-21 days, labeled with 89Zr-oxine complex, and assessed for phenotype, function, and survival. Trafficking of 89Zr-labeled ex vivo-expanded NK cells infused into RMs was monitored and quantitated by serial positron emission tomography (PET)/CT (n = 3, 2.05 ± 0.72 MBq, 23.5 ± 2.0 × 106 NK cells/kg) and compared with that of 89Zr-labeled nonexpanded NK cells, apoptotic NK cells, and hematopoietic stem and progenitor cells (HSPC). NK cells retained sufficient levels of 89Zr for accurate in vivo tracking for 7 days. 89Zr labeling did not alter cellular phenotype, viability, or function. PET/CT showed NK cells initially localized in the lungs, followed by their migration to the liver, spleen, and, at low levels, bone marrow. One day following transfer, only 3.4% of infused NK cells localized to the BM versus 22.1% of HSPCs. No clinical side effects were observed, and dosimetry analysis indicated low organ radioexposures of 6.24 mSv/MBq (spleen) or lower. These data support translation of this technique to humans to track the distribution of adoptively infused cells and to develop novel techniques to improve immune cell homing to tumor microenvironments.

The relationships between neuroinflammation, beta-amyloid and tau deposition in Alzheimer\u2019s disease: a longitudinal PET study

BackgroundThe aim of this longitudinal study was to assess with positron emission tomography (PET) the relationship between levels of inflammation and the loads of aggregated β-amyloid and tau at baseline and again after 2 years in prodromal Alzheimer's disease.MethodsForty-three subjects with mild cognitive impairment (MCI) had serial 11C-PK11195 PET over 2 years to measure inflammation changes, and 11C-PiB PET to determine β-amyloid fibril load; 22 also had serial 18F-Flortaucipir PET to determine tau tangle load. Cortical surface statistical mapping was used to localise areas showing significant changes in tracer binding over time and to interrogate correlations between tracer binding of the tracers at baseline and after 2 years.ResultsThose MCI subjects with high 11C-PiB uptake at baseline (classified as prodromal Alzheimer’s disease) had raised inflammation levels which significantly declined across cortical regions over 2 years although their β-amyloid levels continued to rise. Those MCI cases who had low/normal 11C-PiB uptake at baseline but their levels then rose over 2 years were classified as prodromal AD with low Thal phase 1-2 amyloid deposition at baseline. They showed levels of cortical inflammation which correlated with their rising β-amyloid load. Those MCI cases with baseline low 11C-PiB uptake that remained stable were classified as non-AD, and they showed no correlated inflammation levels. Finally, MCI cases which showed both high 11C-PiB and 18F-Flortaucipir uptake at baseline (MCI due to AD) showed a further rise in their tau tangle load over 2 years with a correlated rise in levels of inflammation.ConclusionsOur baseline and 2-year imaging findings are compatible with a biphasic trajectory of inflammation in Alzheimer’s disease: MCI cases with low baseline but subsequently rising β-amyloid load show correlated levels of microglial activation which then later decline when the β-amyloid load approaches AD levels. Later, as tau tangles form in β-amyloid positive MCI cases with prodromal AD, the rising tau load is associated with higher levels of inflammation.