Heart-brain axis: Pushing the boundaries of cardiovascular molecular imaging.

Despite decades of research, the heart-brain axis continues to challenge investigators seeking to unravel its complex pathobiology. Strong epidemiologic evidence supports a link by which insult or injury to one of the organs increases the risk of pathology in the other. The putative pathways have important differences between sexes and include alterations in autonomic function, metabolism, inflammation, and neurohormonal mechanisms that participate in crosstalk between the heart and brain and contribute to vascular changes, the development of shared risk factors, and oxidative stress. Recently, given its unique ability to characterize biological processes in multiple tissues simultaneously, molecular imaging has yielded important insights into the interplay of these organ systems under conditions of stress and disease. Yet, additional research is needed to probe further into the mechanisms underlying the heart-brain axis and to evaluate the impact of targeted interventions.

PSMA-heterogeneity in metastatic castration-resistant prostate cancer: Circulating tumor cells, metastatic tumor burden, and response to targeted radioligand therapy.

BACKGROUND: We explored the interrelation between prostate-specific membrane antigen (PSMA) expression on circulating tumor cells (CTCs) and that of solid metastatic lesions as determined by whole-body PSMA-targeted positron emission tomography (PET) to refine the prediction of response to subsequent PSMA-targeted radioligand therapy (RLT). METHODS: A prospective study was performed in 20 patients with advanced mCRPC. Of these, 16 underwent subsequent RLT with [177 Lu]Lu-PSMA-617 at a dose of 7.4 GBq every 6-8 weeks. PSMA expression on CTCs using the CellSearch system was compared to clinical and serological results, and to marker expression in targeted imaging and available histological sections of prostatectomy specimens (19% of RLT patients). Clinical outcome was obtained after two cycles of RLT. RESULTS: Marked heterogeneity of PSMA expression was observed already at first diagnosis in available histological specimens. Targeted whole-body imaging also showed heterogeneous inter- and intra-patient PSMA expression between metastases. Heterogeneity of CTC PSMA expression was partially paralleled by heterogeneity of whole-body tumor burden PSMA expression. Twenty percent of CTC samples showed no PSMA expression, despite unequivocal PSMA expression of solid metastases at PET. A high fraction of PSMA-negative CTCs emerged as the sole predictor of poor RLT response (odds ratio [OR]: 0.9379 [95% confidence interval, CI, 0.8558-0.9902]; p = 0.0160), and was prognostic for both shorter progression-free survival (OR: 1.236 [95% CI, 1.035-2.587]; p = 0.0043) and overall survival (OR: 1.056 [95% CI, 1.008-1.141]; p = 0.0182). CONCLUSION: This proof-of-principle study suggests that liquid biopsy for CTC PSMA expression is complementary to PET for individual PSMA phenotyping of mCRPC.

Individual radiosensitivity reflected by γ-H2AX and 53BP1 foci predicts outcome in PSMA-targeted radioligand therapy.

PURPOSE: γ-H2AX and 53BP1 are fundamental for cellular DNA damage response (DDR) after radiation exposure and are linked to cell repair, arrest, or apoptosis. We aimed to evaluate whether DDR-markers in peripheral blood lymphocytes (PBLs) may have predictive potential for outcome in metastatic castration-resistant prostate cancer (mCRPC) patients receiving [177Lu]Lu-prostate-specific membrane antigen (PSMA) radioligand therapy (RLT). METHODS: We prospectively enrolled 20 men with advanced mCRPC scheduled for PSMA-targeted RLT. Prior to the first cycle of [177Lu]Lu-PSMA RLT, all patients underwent [18F]F-PSMA-1007 positron emission tomography (PET)/computed tomography (CT) for assessment of tumor PSMA expression (assessing maximum standardized uptake value (SUVmax) of all tumor lesions). Blood samples were collected prior to, + 1 h after, and + 24 h after administration of [177Lu]Lu-PSMA, and DDR-markers γ-H2AX and 53BP1 were determined in PBLs through immunocytofluorescence. We then tested the predictive performance of DDR-markers relative to clinical and PET-based parameters for progressive disease (PSA-PD) after 2 cycles. In addition, the predictive value for progression-free survival (PSA-PFS, provided as median and 95% confidence interval [CI]) was explored. RESULTS: Low baseline 53BP1 and γ-H2AX foci (P = 0.17) tended to predict early PSA-PD, whereas low SUVmax was significantly associated with higher risk for PSA-PD (P = 0.04). In Kaplan-Meier analysis, there was a trend towards prolonged PSA-PFS in patients with higher baseline 53BP1 of 6 months (mo; 95%CI, 4-9 mo) compared to 3 mo in patients with low 53BP1 (95% CI, 2-3 mo; P = 0.12). Comparable results were recorded for higher γ-H2AX expression (6 mo [95% CI, 3-9 mo] relative to 3 mo [95% CI, 2-4 mo] in patients with low γ-H2AX; P = 0.12). SUVmax, however, did not demonstrate predictive value (P = 0.29). Consistently, in univariate Cox-regression analysis, baseline 53BP1 foci demonstrated borderline significance for predicting PSA-PFS under [177Lu]Lu-PSMA RLT (P = 0.05). CONCLUSION: In this prospective study investigating mCRPC patients undergoing [177Lu]Lu-PSMA RLT, low baseline DDR-markers in PBLs tended to predict poor outcome. Although the study group was small and results need further confirmation, these preliminary findings lay the foundation for exploring additive radiosensitizing or treatment intensification in future studies with high-risk individuals scheduled for RLT.

Molecular Imaging of Inflammation and Fibrosis in Pressure Overload Heart Failure.

[Figure: see text].

Pretherapeutic estimated glomerular filtration rate predicts development of chronic kidney disease in patients receiving PSMA-targeted radioligand therapy.

BACKGROUND: Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) may be associated with renal toxicity. We aimed to identify predictive parameters for the development of chronic kidney disease (CKD) in patients with metastatic castration resistant prostate cancer (mCRPC) undergoing RLT. METHODS: In 46 mCRPC patients scheduled for Lu-177-PSMA-RLT, pretherapeutic estimated glomerular filtration rate (eGFR [ml/min/1.73 m2 ]), Tc-99m-mercaptoacetyltriglycine (Tc-99m-MAG3) clearance and baseline Ga-68-PSMA-ligand positron emission tomography (PET)-derived renal cortical uptake and PSMA-tumor volume (TV) were determined. We tested the predictive capability of these parameters and clinical risk factors for the occurrence of CKD (defined as CTCAE vers. 5.0 grade 2 or higher) during follow-up. RESULTS: After 4 ± 3 cycles of RLT average eGFR declined from 76 ± 17 to 72 ± 20 ml/min/1.73 m2 (p = 0.003). Increased estimated renal radiation dose (eRRD) was significantly associated with renal functional decline (p = 0.008). During follow-up, 16/46 (30.4%) developed CKD grade 2 (no grade 3 or higher). In receiver operating characteristic (ROC) analysis, pretherapeutic eGFR was highly accurate in identifying the occurrence of CKD vs no CKD with an area under the curve (AUC) of 0.945 (p < 0.001; best threshold, 77 ml/min/1.73 m2 ), followed by Tc-99m-MAG3-derived tubular extraction rate (TER; AUC, 0.831, p < 0.001; best threshold, 200 ml/min/1.73 m2 ). Renal PET signal (p = 0.751) and PSMA-TV (p = 0.942), however, were not predictive. Kaplan-Meier analyses revealed adverse renal outcome for patients with lower eGFR (p = 0.001) and lower scintigraphy-derived TER (p = 0.009), with pretherapeutic eGFR emerging as the sole predictive parameter in multivariate analysis (p = 0.007). CONCLUSION: Serious adverse renal events are not a frequent phenomenon after PSMA-targeted RLT. However, in patients developing moderate CKD after RLT, pretherapeutic eGFR is an independent predictor for renal impairment during follow-up.

Characterizing the transition from immune response to tissue repair after myocardial infarction by multiparametric imaging.

Persistent inflammation following myocardial infarction (MI) precipitates adverse outcome including acute ventricular rupture and chronic heart failure. Molecular imaging allows longitudinal assessment of immune cell activity in the infarct territory and predicts severity of remodeling. We utilized a multiparametric imaging platform to assess the immune response and cardiac healing following MI in mice. Suppression of circulating macrophages prior to MI paradoxically resulted in higher total leukocyte content in the heart, demonstrated by increased CXC motif chemokine receptor 4 (CXCR4) positron emission tomography imaging. This supported the formation of a thrombus overlying the injured region, as identified by magnetic resonance imaging. The injured and thrombotic region in macrophage depeleted mice subsequently showed active calcification, as evidenced by accumulation of 18F-fluoride and by cardiac computed tomography. Importantly, macrophage suppression triggered a prolonged inflammatory response confirmed by post-mortem tissue analysis that was associated with higher mortality from ventricular rupture early after occlusion and with increased infarct size and worse chronic contractile function at 6 weeks after reperfusion. These findings establish a molecular imaging toolbox for monitoring the interplay between adverse immune response and tissue repair after MI. This may serve as a foundation for development and monitoring of novel targeted therapies that may include immune modulation and endogenous healing support.

Molecular imaging of the brain-heart axis provides insights into cardiac dysfunction after cerebral ischemia.

Ischemic stroke imparts elevated risk of heart failure though the underlying mechanisms remain poorly described. We aimed to characterize the influence of cerebral ischemic injury on cardiac function using multimodality molecular imaging to investigate brain and cardiac morphology and tissue inflammation in two mouse models of variable stroke severity. Transient middle cerebral artery occlusion (MCAo) generated extensive stroke damage (56.31 ± 40.39 mm3). Positron emission tomography imaging of inflammation targeting the mitochondrial translocator protein (TSPO) revealed localized neuroinflammation at 7 days after stroke compared to sham (3.8 ± 0.8 vs 2.6 ± 0.7 %ID/g max, p < 0.001). By contrast, parenchyma topical application of vasoconstrictor endothelin-1 did not generate significant stroke damage or neuroinflammatory cell activity. MCAo evoked a modest reduction in left ventricle ejection fraction at both 1 weeks and 3 weeks after stroke (LVEF at 3 weeks: 54.3 ± 5.7 vs 66.1 ± 3.5%, p < 0.001). This contractile impairment was paralleled by elevated cardiac TSPO PET signal compared to sham (8.6 ± 2.4 vs 5.8 ± 0.7%ID/g, p = 0.022), but was independent of leukocyte infiltration defined by flow cytometry. Stroke size correlated with severity of cardiac dysfunction (r = 0.590, p = 0.008). Statistical parametric mapping identified a direct association between neuroinflammation at 7 days in a cluster of voxels including the insular cortex and reduced ejection fraction (ρ = - 0.396, p = 0.027). Suppression of microglia led to lower TSPO signal at 7 days which correlated with spared late cardiac function after MCAo (r = - 0.759, p = 0.029). Regional neuroinflammation early after cerebral ischemia influences subsequent cardiac dysfunction. Total body TSPO PET enables monitoring of neuroinflammation, providing insights into brain-heart inter-organ communication and may guide therapeutic intervention to spare cardiac function post-stroke.

Volumetric 68Ga-DOTA-TATE PET/CT for assessment of whole-body tumor burden as a quantitative imaging biomarker in patients with metastatic gastroenteropancreatic neuroendocrine tumors.

BACKGROUND: A quantitative imaging biomarker is desirable to provide a comprehensive measure of whole-body tumor burden in patients with metastatic neuroendocrine tumors, and to standardize the evaluation of treatment-related changes. Therefore, we evaluated volumetric parameters for quantification of whole-body tumor burden from somatostatin receptor (SSR)-targeted PET/CT. METHODS: Thirty-two patients with metastastic grade1/grade 2 gastroenteropancreatic neuroendocrine tumors who underwent a 68Ga-DOTA-TATE PET/CT for staging of disease before initiation of peptide receptor radionuclide therapy were included in this retrospective cohort analysis. Volumetric parameters of tumor lesions, SSR-derived tumor volume (SSR-TV) and total lesion SSR (TL-SSR), were calculated for each patient using a computerized volumetric technique with a 40% SUVmax cut-off, and compared with serum chromogranin A (CgA) levels. Progression-free survival (PFS) was determined in relation to volumetric parameters. In a subgroup of 18 patients, the feasibility of volumetric parameters for treatment monitoring was evaluated. RESULTS: Mean SSR-TV was 178±214 cm3 (range, 9-797 cm3), whereas mean TL-SSR was 4096±5191 cm3 (range, 61-19,203 cm3). Baseline CgA levels were associated with whole-body tumor burden (SSR-TV, r=0.57, P=0.0008; and TL-SSR, r=0.43, P=0.01, respectively). PFS was shorter in patients with high SSR-TV and high TL-SSR (HR 5.16, 95% CI, 1.61-29.67), P=0.009), and SSR-TV (P=0.0067) and TL-SSR (P=0.0215) emerged as the sole predictors of progression in regression analysis. Changes in CgA did not correctly identify treatment response (P=0.25). CONCLUSIONS: SSR-derived volumetric parameters provide a quantitative imaging biomarker for whole-body tumor burden, and may hold potential as a clear-cut measure for assessment of treatment response.

Comparison of pretherapeutic osseous tumor volume and standard hematology for prediction of hematotoxicity after PSMA-targeted radioligand therapy.

PURPOSE: Hematotoxicity is a potentially dose-limiting adverse event in patients with metastasized castration-resistant prostate cancer (mCRPC) undergoing prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT). We aimed to identify clinical or PSMA-targeted imaging-derived parameters to predict hematological adverse events at early and late stages in the treatment course. METHODS: In 67 patients with mCRPC scheduled for 177Lu-PSMA-617 RLT, pretherapeutic osseous tumor volume (TV) from 68Ga-PSMA-11 PET/CT and laboratory values were assessed. We then tested the predictive capability of these parameters for early and late hematotoxicity (according to CTCAE vers. 5.0) after one cycle of RLT and in a subgroup of 32/67 (47.8%) patients after four cycles of RLT. RESULTS: After one cycle, 10/67 (14.9%) patients developed leukocytopenia (lymphocytopenia, 39/67 [58.2%]; thrombocytopenia, 17/67 [25.4%]). A cut-off of 5.6 × 103/mm3 for baseline leukocytes was defined by receiver operating characteristics (ROC) and separated between patients with and without leukocytopenia (P < 0.001). Baseline leukocyte count emerged as a stronger predictive factor in multivariate analysis (hazard ratio [HR], 33.94, P = 0.001) relative to osseous TV (HR, 14.24, P = 0.01). After four cycles, 4/32 (12.5%) developed leukocytopenia and the pretherapeutic leukocyte cut-off (HR, 9.97, P = 0.082) tended to predict leukocytopenia better than TV (HR, 8.37, P = 0.109). In addition, a cut-off of 1.33 × 103/mm3 for baseline lymphocytes separated between patients with and without lymphocytopenia (P < 0.001), which was corroborated in multivariate analysis (HR, 21.39, P < 0.001 vs. TV, HR, 4.57, P = 0.03). After four cycles, 19/32 (59.4%) developed lymphocytopenia and the pretherapeutic cut-off for lymphocytes (HR, 46.76, P = 0.007) also demonstrated superior predictive performance for late lymphocytopenia (TV, HR, 5.15, P = 0.167). Moreover, a cut-off of 206 × 103/mm3 for baseline platelets separated between patients with and without thrombocytopenia (P < 0.001) and also demonstrated superior predictive capability in multivariate analysis (HR, 115.02, P < 0.001 vs.TV, HR, 12.75, P = 0.025). After four cycles, 9/32 (28.1%) developed thrombocytopenia and the pretherapeutic cut-off for platelets (HR, 5.44, P = 0.048) was also superior for the occurrence of late thrombocytopenia (TV, HR, 1.44, P = 0.7). CONCLUSIONS: Pretherapeutic leukocyte, lymphocyte, and platelet levels themselves are strong predictors for early and late hematotoxicity under PSMA-directed RLT, and are better suited than PET-based osseous TV for this purpose.

Reduced microglia activity in patients with long-term immunosuppressive therapy after liver transplantation.

PURPOSE: Calcineurin inhibitors (CNI) can cause long-term impairment of brain function. Possible pathomechanisms include alterations of the cerebral immune system. This study used positron emission tomography (PET) imaging with the translocator protein (TSPO) ligand 18F-GE-180 to evaluate microglial activation in liver-transplanted patients under different regimens of immunosuppression. METHODS: PET was performed in 22 liver-transplanted patients (3 CNI free, 9 with low-dose CNI, 10 with standard-dose CNI immunosuppression) and 9 healthy controls. The total distribution volume (VT) estimated in 12 volumes-of-interest was analyzed regarding TSPO genotype, CNI therapy, and cognitive performance. RESULTS: In controls, VT was about 80% higher in high affinity binders (n = 5) compared to mixed affinity binders (n = 3). Mean VT corrected for TSPO genotype was significantly lower in patients compared to controls, especially in patients in whom CNI dose had been reduced because of nephrotoxic side effect. CONCLUSION: Our results provide evidence of chronic suppression of microglial activity in liver-transplanted patients under CNI therapy especially in patients with high sensitivity to CNI toxicity.

Dissecting the target leukocyte subpopulations of clinically relevant inflammation radiopharmaceuticals.

BACKGROUND: Leukocyte subtypes bear distinct pro-inflammatory, reparative, and regulatory functions. Imaging inflammation provides information on disease prognosis and may guide therapy, but the cellular basis of the signal remains equivocal. We evaluated leukocyte subtype specificity of characterized clinically relevant inflammation-targeted radiotracers. METHODS AND RESULTS: Leukocyte populations were purified from blood- and THP-1-derived macrophages were polarized into M1-, reparative M2a-, or M2c-macrophages. In vitro uptake assays were conducted using tracers of enhanced glucose or amino acid metabolism and molecular markers of inflammatory cells. Both 18F-deoxyglucose (18F-FDG) and the labeled amino acid 11C-methionine (11C-MET) displayed higher uptake in neutrophils and monocytes compared to other leukocytes (P = 0.005), and markedly higher accumulation in pro-inflammatory M1-macrophages compared to reparative M2a-macrophages (P < 0.001). Molecular tracers 68Ga-DOTATATE targeting the somatostatin receptor type 2 and 68Ga-pentixafor targeting the chemokine receptor type 4 (CXCR4) exhibited broad uptake by leukocyte subpopulations and polarized macrophages with highest uptake in T-cells/natural killer cells and B-cells compared to neutrophils. Mitochondrial translocator protein (TSPO)-targeted 18F-flutriciclamide selectively accumulated in monocytes and pro-inflammatory M1 macrophages (P < 0.001). Uptake by myocytes and fibroblasts tended to be higher for metabolic radiotracers. CONCLUSIONS: The different in vitro cellular uptake profiles may allow isolation of distinct phases of the inflammatory pathway with specific inflammation-targeted radiotracers. The pathogenetic cell population in specific inflammatory diseases should be considered in the selection of an appropriate imaging agent.

99mTc-HMPAO SPECT imaging reveals brain hypoperfusion during status epilepticus.

Status epilepticus (SE) is a clinical emergency with high mortality. SE can trigger neuronal death or injury and alteration of neuronal networks resulting in long-term cognitive decline or epilepsy. Among the multiple factors contributing to this damage, imbalance between oxygen and glucose requirements and brain perfusion during SE has been proposed. Herein, we aimed to quantify by neuroimaging the spatiotemporal course of brain perfusion during and after lithium-pilocarpine-induced SE in rats. To this purpose, animals underwent 99mTc-HMPAO SPECT imaging at different time points during and after SE using a small animal SPECT/CT system. 99mTc-HMPAO regional uptake was normalized to the injected dose. In addition, voxel-based statistical parametric mapping was performed. SPECT imaging showed an increase of cortical perfusion before clinical seizure activity onset followed by regional hypo-perfusion starting with the first convulsive seizure and during SE. Twenty-four hours after SE, brain 99mTc-HMPAO uptake was widely decreased. Finally, chronic epileptic animals showed regionally decreased perfusion affecting hippocampus and cortical sub-regions. Despite elevated energy and oxygen requirements, brain hypo-perfusion is present during SE. Our results suggest that insufficient compensation of required blood flow might contribute to neuronal damage and neuroinflammation, and ultimately to chronic epilepsy generated by SE.

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

AIMS: 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. METHODS AND RESULTS: 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. CONCLUSION: 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.

Influence of short-term dexamethasone on the efficacy of 177 Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer.

BACKGROUND AND AIM: Corticosteroids alone or in combination therapy are associated with favorable biochemical responses in metastatic castration-resistant prostate cancer (mCRPC). We speculated that the intermittent addition of dexamethasone may also enhance the antitumor effect of radioligand therapy (RLT) with 177 Lu-prostate-specific membrane antigen (PSMA)-617. PATIENTS AND METHODS: Seventy-one patients with mCRPC were treated with 1 to 5 cycles of 177 Lu-PSMA-617 (6.0-7.4 GBq per cycle) at 6 to 8 weeks intervals. Based on the clinical decision (eg, in the case of vertebral metastases), 56% of patients received 4 mg of dexamethasone for the first 5 days of each cycle. Biochemical response rates, PSA decline and progression-free survival (PFS) were analyzed after one, three, and five cycles of RLT. RESULTS: PSA response rates were not significantly different between patients receiving 177 Lu-PSMA-617 plus dexamethasone and those receiving 177 Lu-PSMA-617 alone after one, three, and five cycles (33% vs 39%, P = .62; 45% vs 45%, P = 1.0; and 38% vs 42%, P = .81). However, there was a nonsignificant trend for a more pronounced PSA decline in patients with bone metastases receiving adjunct dexamethasone (-21% ± 50% vs +11% ± 90%, P = .08; -21% ± 69% vs +22% ± 116%, P = .07; -13% ± 76% vs +32% ± 119%, P = .07). Median PFS tended to be longer in patients with bone metastases receiving 177 Lu-PSMA-617 plus dexamethasone (146 vs 81 days; hazard ratio: 0.87 [95% confidence interval: 0.47-1.61]; P = .20). Multiple regression analysis showed that age (P = .0110), alkaline phosphatase levels (P = .0380) and adjunct dexamethasone (P = .0285) were independent predictors of changes in PSA in patients with bone metastases. CONCLUSIONS: We observed high response rates to 177 Lu-PSMA-617 RLT in men with mCRPC. The short-term addition of dexamethasone to 177 Lu-PSMA-617 had no striking antitumor effect but might enhance biochemical responses in patients with bone metastases. Future trials are warranted to test this hypothesis in a prospective setting.

Angiotensin-converting enzyme inhibitor treatment early after myocardial infarction attenuates acute cardiac and neuroinflammation without effect on chronic neuroinflammation.

PURPOSE: Myocardial infarction (MI) triggers a local inflammatory response which orchestrates cardiac repair and contributes to concurrent neuroinflammation. Angiotensin-converting enzyme (ACE) inhibitor therapy not only attenuates cardiac remodeling by interfering with the neurohumoral system, but also influences acute leukocyte mobilization from hematopoietic reservoirs. Here, we seek to dissect the anti-inflammatory and anti-remodeling contributions of ACE inhibitors to the benefit of heart and brain outcomes after MI. METHODS: C57BL/6 mice underwent permanent coronary artery ligation (n = 41) or sham surgery (n = 9). Subgroups received ACE inhibitor enalapril (20 mg/kg, oral) either early (anti-inflammatory strategy; 10 days treatment beginning 3 days prior to surgery; n = 9) or delayed (anti-remodeling; continuous from 7 days post-MI; n = 16), or no therapy (n = 16). Cardiac and neuroinflammation were serially investigated using whole-body macrophage- and microglia-targeted translocator protein (TSPO) PET at 3 days, 7 days, and 8 weeks. In vivo PET signal was validated by autoradiography and histopathology. RESULTS: Myocardial infarction evoked higher TSPO signal in the infarct region at 3 days and 7 days compared with sham (p < 0.001), with concurrent elevation in brain TSPO signal (+ 18%, p = 0.005). At 8 weeks after MI, remote myocardium TSPO signal was increased, consistent with mitochondrial stress, and corresponding to recurrent neuroinflammation. Early enalapril treatment lowered the acute TSPO signal in the heart and brain by 55% (p < 0.001) and 14% (p = 0.045), respectively. The acute infarct signal predicted late functional outcome (r = 0.418, p = 0.038). Delayed enalapril treatment reduced chronic myocardial TSPO signal, consistent with alleviated mitochondrial stress. Early enalapril therapy tended to lower TSPO signal in the failing myocardium at 8 weeks after MI (p = 0.090) without an effect on chronic neuroinflammation. CONCLUSIONS: Whole-body TSPO PET identifies myocardial macrophage infiltration and neuroinflammation after MI, and altered cardiomyocyte mitochondrial density in chronic heart failure. Improved chronic cardiac outcome by enalapril treatment derives partially from acute anti-inflammatory activity with complementary benefits in later stages. Whereas early ACE inhibitor therapy lowers acute neuroinflammation, chronic alleviation is not achieved by early or delayed ACE inhibitor therapy, suggesting a more complex mechanism underlying recurrent neuroinflammation in ischemic heart failure.

Reliable quantification of 18F-GE-180 PET neuroinflammation studies using an individually scaled population-based input function or late tissue-to-blood ratio.

PURPOSE: Tracer kinetic modeling of tissue time activity curves and the individual input function based on arterial blood sampling and metabolite correction is the gold standard for quantitative characterization of microglia activation by PET with the translocator protein (TSPO) ligand 18F-GE-180. This study tested simplified methods for quantification of 18F-GE-180 PET. METHODS: Dynamic 18F-GE-180 PET with arterial blood sampling and metabolite correction was performed in five healthy volunteers and 20 liver-transplanted patients. Population-based input function templates were generated by averaging individual input functions normalized to the total area under the input function using a leave-one-out approach. Individual population-based input functions were obtained by scaling the input function template with the individual parent activity concentration of 18F-GE-180 in arterial plasma in a blood sample drawn at 27.5 min or by the individual administered tracer activity, respectively. The total 18F-GE-180 distribution volume (VT) was estimated in 12 regions-of-interest (ROIs) by the invasive Logan plot using the measured or the population-based input functions. Late ROI-to-whole-blood and ROI-to-cerebellum ratio were also computed. RESULTS: Correlation with the reference VT (with individually measured input function) was very high for VT with the population-based input function scaled with the blood sample and for the ROI-to-whole-blood ratio (Pearson correlation coefficient = 0.989 ± 0.006 and 0.970 ± 0.005). The correlation was only moderate for VT with the population-based input function scaled with tracer activity dose and for the ROI-to-cerebellum ratio (0.653 ± 0.074 and 0.384 ± 0.177). Reference VT, population-based VT with scaling by the blood sample, and ROI-to-whole-blood ratio were sensitive to the TSPO gene polymorphism. Population-based VT with scaling to the administered tracer activity and the ROI-to-cerebellum ratio failed to detect a polymorphism effect. CONCLUSION: These results support the use of a population-based input function scaled with a single blood sample or the ROI-to-whole-blood ratio at a late time point for simplified quantitative analysis of 18F-GE-180 PET.

Baseline and interim PET-based outcome prediction in peripheral T-cell lymphoma: A subgroup analysis of the PETAL trial.

The prospective randomized Positron Emission Tomography (PET)-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL) trial was designed to test the ability of interim PET (iPET) to direct therapy. As reported previously, outcome remained unaffected by iPET-based treatment changes. In this subgroup analysis, we studied the prognostic value of baseline total metabolic tumor volume (TMTV) and iPET response in 76 patients with T-cell lymphoma. TMTV was measured using the 41% maximum standardized uptake value (SUV41max ) and SUV4 thresholding methods. Interim PET was performed after two treatment cycles and evaluated using the ΔSUVmax approach and the Deauville scale. Because of significant differences in outcome, patients with anaplastic lymphoma kinase (ALK)-positive lymphoma were analyzed separately from patients with ALK-negative lymphoma. In the latter, TMTV was statistically significantly correlated with progression-free survival, with thresholds best dichotomizing the population, of 232 cm3 using SUV41max and 460 cm3 using SUV4 . For iPET response, the respective thresholds were 46.9% SUVmax reduction and Deauville score 1-4 vs 5. The proportion of poor prognosis patients was 46% and 29% for TMTV by SUV41max and SUV4 , and 29% and 25% for iPET response by ΔSUVmax and Deauville, respectively. At diagnosis, the hazard ratio (95% confidence interval) for poor prognosis vs good prognosis patients according to TMTV was 2.291 (1.135-4.624) for SUV41max and 3.206 (1.524-6.743) for SUV4 . At iPET, it was 3.910 (1.891-8.087) for ΔSUVmax and 4.371 (2.079-9.187) for Deauville. On multivariable analysis, only TMTV and iPET response independently predicted survival. Patients with high baseline TMTV and poor iPET response (22% of the population) invariably progressed or died within the first year (hazard ratio, 9.031 [3.651-22.336]). Due to small numbers and events, PET did not predict survival in ALK-positive lymphoma. Baseline TMTV and iPET response are promising tools to select patients with ALK-negative T-cell lymphoma for early allogeneic transplantation or innovative therapies.

Accuracy of cardiac functional parameters measured from gated radionuclide myocardial perfusion imaging in mice.

BACKGROUND: Quantitative cardiac contractile function assessment is the primary indicator of disease progression and therapeutic efficacy in small animals. Operator dependency is a major challenge with commonly used echocardiography. Simultaneous assessment of cardiac perfusion and function in nuclear scans would reduce burden on the animal and facilitate longitudinal studies. We evaluated the accuracy of contractile function measurements obtained from electrocardiogram-gated nuclear perfusion imaging compared with anatomic imaging. METHODS AND RESULTS: In healthy C57Bl/6N mice (n = 11), 99mTc-sestamibi SPECT and 13N-ammonia PET underestimated left ventricular volumes (23 to 28%, P = 0.02) compared to matched anatomic images, though ejection fraction (LVEF) was comparable (%, SPECT: 73 ± 8 vs CMR: 72 ± 6, P = 0.1). At 1 week after myocardial infarction (n = 13), LV volumes were significantly lower in perfusion images compared to CMR and contrast CT (P = 0.003), and LVEF was modestly overestimated (%, SPECT: 37 ± 8, vs CMR: 27 ± 7, P = 0.003). Nuclear images exhibited good intra- and inter-reader agreement. Perfusion SPECT accurately calculated infarct size compared to histology (r = 0.95, P < 0.001). CONCLUSIONS: Cardiac function can be calculated by gated nuclear perfusion imaging in healthy mice. After infarction, perfusion imaging overestimates LVEF, which should be considered for comparison to other modalities. Combined functional and infarct size analysis may optimize imaging protocols and reduce anaesthesia duration for longitudinal studies.

[Theranostics and hybrid imaging for somatostatin receptor-expressing tumors]. / Theranostics und Hybridbildgebung für somatostatinrezeptor-exprimierende Tumore.

CLINICAL/METHODICAL ISSUE: Conventional imaging tests like computed tomography (CT) cannot visualize somatostatin receptor (SSTR) expression on the tumor cell surface. STANDARD RADIOLOGICAL METHODS: For imaging of SSTR-expressing tumors conventional morphological imaging tests such as CT or magnetic resonance imaging (MRI) are employed. METHODICAL INNOVATIONS: Molecular imaging of SSTR expression on the tumor cell surface, in particular by using (whole body) single photon emission computed tomography (SPECT) and positron emission tomography (PET), are considered the current standard of care. Only the use of CT enables for exact localization of putative sites of disease (hybrid imaging). PERFORMANCE: Hybrid SPECT/CT and PET/CT are of utmost importance for staging and monitoring of treatment efficacy. SSTR-PET is superior to SPECT and the PET radiotracer 68Ga-DOTATATE has been approved in multiple countries. In addition, SSTR positivity revealed by SPECT or PET pave the way for a peptide receptor radionuclide therapy (PRRT). Such a theranostic approach enables for systemic or locoregional radiation with ß­emitting radionuclides, which are linked to the identical amino acid peptide used for PET or SPECT imaging. The prospective, randomized Netter­1 trial has shown significant benefit for patients receiving PRRT. ACHIEVEMENTS: A combined use of conventional and functional imaging tests is superior to conventional imaging alone and allows for identification of suitable candidates for a theranostic approach. PRACTICAL RECOMMENDATIONS: In case of clinical suspicion or after having obtained histological evidence, hybrid SSTR-SPECT/CT or -PET/CT should be performed, preferably in a dedicated molecular imaging center.

Comparison of 68 Ga-PSMA ligand PET/CT versus conventional cross-sectional imaging for target volume delineation for metastasis-directed radiotherapy for metachronous lymph node metastases from prostate cancer.

PURPOSE: To assess the differences in the target volume (TV) delineation of metachronous lymph node metastases between 68 Ga-PSMA ligand PET/CT and conventional imaging in a comparative retrospective contouring study. PATIENTS AND METHODS: Twenty-five patients with biochemical prostate cancer recurrence after primary prostatectomy underwent 68 Ga-PSMA ligand PET/CT in addition to conventional imaging techniques such as CT and/or MR imaging for restaging. All patients were diagnosed with at least one lymph node metastasis. TVs were manually delineated in two different ways: (a) based on conventional imaging (CT/MRI) and (b) based on conventional imaging (CT/MRI) plus 68 Ga-PSMA ligand PET/CT. The size of TVs, overlap rates, and subjective assessment of the difficulty of TV delineation reported by the radiation oncologist (easy/moderate/difficult) were compared. RESULTS: With the additional information from PSMA ligand PET, 47 lymph node metastases were identified and included in the gross tumor volume (GTV). The median clinical target volume (CTV) of non-PET-based TV delineation was statistically larger than the CTV based on PET imaging (134.8 ml [range 6.9-565.2] versus 44.9 ml [range 4.9-481.3; p = 0.001]). The CTV based on CT/MRI enclosed only 81.3% (39/48) of PET-positive lymph nodes. The CT/MRI-based CTV did not enclose all PET-positive lymph nodes in 24% (6/25) of patients. In 12% (3/25) of patients, all PET-positive lymph nodes were outside of the CT/MRI-based CTV. The median overlap rates (TVPET/TVCT/MRIâ€¯× 100) were 45.7% (range 0-96.9) for the GTV and 71.7% (range 9.8-98.2) for the CTV. The assessment of difficulty of contouring revealed that contouring with the additional imaging information of the PET was categorized as easy/moderate in 92% (23/25) and as difficult in 8% (2/25) of the cases, whereas contouring based on CT/MRI without PET was categorized as difficult in 56% (14/25) and as easy/moderate in 44% of the cases (11/25; p = 0.003). CONCLUSION: 68 Ga-PSMA ligand PET/CT is superior to conventional cross-sectional imaging for the delineation of lymph node metastases from prostate cancer. PET-based TV delineation allows for smaller target volumes and should be considered the standard for irradiation of metachronous lymph node metastases in recurrent prostate cancer. Conventional imaging is not sufficiently sensitive for radio-oncological treatment concepts in oligometastatic prostate cancer.