Marcus Hacker

18F-FDG PET/CT Identifies Patients at Risk for Future Vascular Events in an Otherwise Asymptomatic Cohort with Neoplastic Disease

Our objective was to evaluate the association of arterial 18F-FDG uptake and calcifications in large arteries as detected by 18F-FDG PET/CT with the subsequent occurrence of vascular events in otherwise asymptomatic cancer patients. Methods: Clinical follow-up information was obtained for 932 cancer patients examined with whole-body 18F-FDG PET/CT (median follow-up time, 29 mo). Among this cohort, 279 patients had died from their oncologic disease. In 15 of 932 patients (1.6%), a vascular event, defined as ischemic stroke, myocardial infarction, or revascularization, was registered. The maximal standardized uptake value (SUV) was divided by the blood-pool SUV, yielding a target-to-background ratio (TBR) for each arterial segment. The mean TBR as well as a calcified plaque sum score per patient were calculated in the major vessels: ascending, descending, and abdominal aorta, aortic arch, as well as iliac and carotid arteries. Results: A significant correlation was observed between mean TBR and calcified plaque sum (P < 0.001). Although calcified plaque sum significantly correlated with all conventional risk factors for vascular events, mean TBR correlated only with age, the male sex, and hypertension. The Cox regression hazard model identified a mean TBR ≥ 1.7 and a calcified plaque sum ≥ 15 as independent predictors for the occurrence of a vascular event. Patients with both mean TBR and calcified plaque sum above these thresholds were identified as having the highest risk for a future vascular event. However, a mean TBR ≥ 1.7 had greater prognostic value than did a calcified plaque sum ≥ 15. Conclusion: In a large cohort of cancer patients, increased 18F-FDG uptake in major arteries emerged as the strongest predictor of a subsequent vascular event. Concomitant severe vascular calcifications seemed to impart a particularly high risk. Given the small event rate in the present study, larger, prospective trials of patients without cancer are required to substantiate these promising results.

68Ga-DOTATATE PET/CT for the Early Prediction of Response to Somatostatin Receptor–Mediated Radionuclide Therapy in Patients with Well-Differentiated Neuroendocrine Tumors

We aimed to evaluate 68Ga-DOTATATE PET/CT for the early prediction of time to progression and clinical outcome after a first cycle of peptide receptor radionuclide treatment (PRRT) in a cohort of patients with well-differentiated neuroendocrine tumors. Methods: Thirty-three consecutive patients (22 men and 11 women; mean age ± SD, 57.8 ± 12.1 y) were investigated at baseline and again 3 mo after initiation of the first cycle of PRRT. 68Ga-DOTATATE receptor expression was assessed using 2 measures of standardized uptake value (SUV): maximum SUV (SUVmax) and tumor-to-spleen SUV ratio (SUVT/S). Percentage change in SUV scores after PRRT relative to baseline (ΔSUV) was calculated. After completing 1–3 cycles of PRRT, patients entered the follow-up study, for estimation of time to progression. According to the Response Evaluation Criteria in Solid Tumors, progression was defined on the basis of contrast-enhanced CT. Clinical symptoms, as well as the tumor markers chromogranin A and neuron-specific enolase, were also recorded during regular follow-up visits. Results: The 23 of 31 patients with decreased SUVT/S after the first PRRT cycle had longer progression-free survival than did the 8 of 31 patients with stable or increased scores (median survival not reached vs. 6 mo, P = 0.002). For the 18 of 33 patients showing a reduction in SUVmax, there was no significant difference in progression-free survival (median survival not reached vs. 14 mo, P = 0.22). Multivariate regression analysis identified SUVT/S as the only independent predictor for tumor progression during follow-up. In the 17 of 33 patients with clinical symptoms before PRRT, ΔSUVT/S correlated with clinical improvement (r = 0.52, P < 0.05), whereas ΔSUVmax did not (r = 0.42, P = 0.10). Changes in the tumor markers (chromogranin A and neuron-specific enolase) did not predict ΔSUV scores, clinical improvement, or time to progression. Conclusion: Decreased 68Ga-DOTATATE uptake in tumors after the first cycle of PRRT predicted time to progression and correlated with an improvement in clinical symptoms among patients with well-differentiated neuroendocrine tumors; ΔSUVT/S was superior to ΔSUVmax for prediction of outcome.

In Vivo Imaging of Macrophage Activity in the Coronary Arteries Using 68Ga-DOTATATE PET/CT: Correlation with Coronary Calcium Burden and Risk Factors

We measured the uptake of the somatostatin receptor ligand 68Ga-[1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid]-d-Phe1,Tyr3-octreotate (DOTATATE) in the left anterior descending coronary artery (LAD) in association with calcified plaques (CPs) and cardiovascular risk factors. Methods: Seventy consecutive tumor patients were examined by whole-body 68Ga-DOTATATE contrast-enhanced PET/CT. Blood-pool–corrected standardized uptake value (target-to-background ratio) was measured in the LAD, and CT images were used to detect CP. Cardiovascular risk factors and history of prior cardiovascular events were recorded. Results: 68Ga-DOTATATE uptake was detectable in the LAD of all patients. Target-to-background ratio in the LAD correlated significantly with the presence of CP (R = 0.34; P < 0.01), prior vascular events (R = 0.26; P < 0.05), and male sex (R = 0.29; P < 0.05), whereas CP correlated with these parameters but also with age (R = 0.34; P < 0.01) and hypertension (R = 0.25; P < 0.05). Conclusion: In a series of oncologic patients, those with prior cardiovascular events and calcified atherosclerotic plaques showed significantly increased 68Ga-DOTATATE uptake in the LAD, suggesting a potential role of this tracer for plaque imaging in the coronary arteries.

EANM procedural guidelines for radionuclide myocardial perfusion imaging with SPECT and SPECT/CT : 2015 revision

Since the publication of the European Association of Nuclear Medicine (EANM) procedural guidelines for radionuclide myocardial perfusion imaging (MPI) in 2005, many small and some larger steps of progress have been made, improving MPI procedures. In this paper, the major changes from the updated 2015 procedural guidelines are highlighted, focusing on the important changes related to new instrumentation with improved image information and the possibility to reduce radiation exposure, which is further discussed in relation to the recent developments of new International Commission on Radiological Protection (ICRP) models. Introduction of the selective coronary vasodilator regadenoson and the use of coronary CT-contrast agents for hybrid imaging with SPECT/CT angiography are other important areas for nuclear cardiology that were not included in the previous guidelines. A large number of minor changes have been described in more detail in the fully revised version available at the EANM home page: http://eanm.org/publications/guidelines/2015_07_EANM_FINAL_myocardial_perfusion_guideline.pdf.

The intrinsic renal compartment syndrome: new perspectives in kidney transplantation.

Purpose. Inflammatory edema after ischemia-reperfusion may impair renal allograft function after kidney transplantation. This study examines the effect of edema-related pressure elevation on renal function and describes a simple method to relieve pressure within the renal compartment. Methods. Subcapsular pressure at 6, 12, 24, 48 hr, and 18 days after a 45 min warm ischemia was determined in a murine model of renal ischemia-reperfusion injury. Renal function was measured by 99mTc-MAG3 scintigraphy and laser Doppler perfusion. Structural damage was assessed by histologic analysis. As a therapeutic approach, parenchymal pressure was relieved by a standardized circular 0.3 mm incision at the lower pole of the kidney capsule. Results. Compared with baseline (0.9±0.3 mm Hg), prolonged ischemia was associated with a sevenfold increase in subcapsular pressure 6 hr after ischemia (7.0±1.0 mm Hg; P<0.001). Pressure levels remained significantly elevated for 24 hr. Without therapy, a significant decrease in functional parameters was found with considerably reduced tubular excretion rate (33±3.5%, P<0.001) and renal perfusion (64.5±6.8%, P<0.005). Histologically, severe tissue damage was found. Surgical pressure relief was able to significantly prevent loss of tubular excretion rate (62.5±6.8%, P<0.05) and renal blood flow (96.2±4.8%; P<0.05) and preserved the integrity of renal structures. Conclusions. Our data support the hypothesis of the existence of a renal compartment syndrome as a consequence of ischemia-reperfusion injury. Surgical pressure relief effectively prevented functional and structural renal impairment, and we speculate that this approach might be of value for improving graft function after renal transplantation.

18F-FDG PET/CT Predicts Survival After Radioembolization of Hepatic Metastases from Breast Cancer

90Y radioembolization (selective internal radiation therapy [SIRT]) has emerged as a valuable therapeutic option in unresectable, chemotherapy-refractory hepatic metastases from breast cancer. The objective of the present study was to evaluate 18F-FDG PET/CT for predicting survival in these patients. Methods: Fifty-eight consecutive patients with hepatic metastases from breast cancer were treated with SIRT. Before therapy, all patients underwent MRI of the liver. 18F-FDG PET/CT was performed at baseline and 3 mo after SIRT to calculate percentage changes in maximum 18F-FDG standardized uptake value (SUVmax) relative to baseline. A decrease of more than 30% in the follow-up scan, compared with the baseline examination, indicated therapy response. Treatment response at 3 mo was also assessed in 43 patients using contrast-enhanced MRI and CT on the basis of the Response Evaluation Criteria in Solid Tumors. All patients were followed to complete survival data. Results: Overall median survival after SIRT was 47 wk. Response as assessed with SUVmax correlated significantly with survival after radioembolization, with responders having significantly longer survival (65 wk) than nonresponders (43 wk; P < 0.05). In multivariate analysis the change in SUVmax was identified as the only independent predictor of survival (hazard ratio, 0.23; P < 0.005). Furthermore, a high pretherapeutic SUVmax (>20) was associated with a significantly shorter median survival than was an SUVmax of 20 or less (21 vs. 52 wk; P < 0.005). The presence of extrahepatic metastases (mean survival in both groups, 47 wk; P = 0.92), hormone receptor status (estrogen, P = 0.53; progesterone, P = 0.79; Her-2/neu, P = 0.49), and MRI/CT response (P = 0.91) did not predict survival. Conclusion: The change in SUVmax as assessed by 18F-FDG PET/CT before and 3 mo after SIRT was identified as the only independent predictor of survival in patients with hepatic metastases of breast cancer.

Kit-Like 18F-Labeling of Proteins: Synthesis of 4-(Di-tert-butyl[18F]fluorosilyl)benzenethiol (Si[18F]FA-SH) Labeled Rat Serum Albumin for Blood Pool Imaging with PET

Radiosyntheses of 18F-radiopharmaceuticals for positron emission tomography (PET) normally require an extraordinarily high effort of technical equipment and specially trained personnel. We recently reported a novel method for the introduction of fluorine-18 into peptides for PET-imaging based on silicon-18F-chemistry (SiFA technique). We herewith introduce the first SiFA-based Kit-like radio-fluorination of a protein (rat serum albumin,RSA) and demonstrate its usefulness for in vivo imaging with microPET in normal rats as well as in a rat heterotropic transplanted heart model. As a labeling agent, we prepared 4-(di-tert-butyl[18F]fluorosilyl)benzenethiol (Si[18F]FASH)by simple isotopic exchange in 40-60% radiochemical yield (RCY) and coupled it directly to a Sulfo-SMCC derivatized RSA in an overall RCY of 12% within 20-30 min. The technically simple labeling procedure does not require any elaborated purification procedures and is a straightforward example of a successful application of Si-18F chemistry for in vivo imaging with PET.

A Universally Applicable 68Ga-Labeling Technique for Proteins

Although protein-based PET imaging agents are projected to become important tracer molecules in the future, the labeling of complex biomolecules with PET radionuclides is inexpedient and, most of the time, challenging. Methods: Here we present a straightforward labeling chemistry to attach the versatile radionuclide 68Ga to proteins. Introducing the 68Ga chelating agent NODA-GA-T (2,2′-(7-(1-carboxy-4-(2-mercaptoethylamino)-4-oxobutyl)-1,4,7-triazonane-1,4-diyl)diacetic acid) by reaction with proteins chemically processed with sulfo-SMCC (4-(N-maleimidomethyl)cyclohexane-1-carboxylic acid 3-sulfo-N-hydroxysuccinimide ester sodium salt) results in labeling precursors, enabling a simple and rapid kit-labeling procedure that requires no workup of the radiolabeled proteins. Various 68Ga- proteins were labeled using this method, and the radiochemical yields and specific activities of the labeled proteins were determined. To show that the radiotracers are applicable for in vivo studies, proof-of-concept small-animal PET images were acquired in healthy rats using 68Ga rat serum albumin for blood-pool imaging and 68Ga-annexin V for apoptosis imaging in mice with a left ventricular myocardial infarction. Results: The proteins could be modified, yielding 1.2–1.7 68Ga-labeling sites per protein molecule. All investigated proteins could be labeled in high radiochemical yields of 95% or more in less than 10 min in 1 step, using acetate-buffered medium (pH 3.5–4.0) at room temperature without any further purification. The labeled proteins displayed specific activities of 20–45 GBq/μmol (540–1,200 Ci/mmol). In the proof-of-concept in vivo studies, 68Ga rat serum albumin and 68Ga-annexin V were successfully used for in vivo imaging. Both radiotracers showed a favorable biodistribution in the animal models, thus demonstrating the usefulness of the developed approach for the kit 68Ga labeling of proteins. Conclusion: The preprocessing of proteins proceeds in high chemical yields and with high protein recovery rates after purification. These precursors can be stored for several months at −20°C without degradation, and 68Ga labeling can be performed in a 1-step kit-labeling reaction in high radiochemical yields. Two of the derivatized model proteins were successfully used in proof-of-concept in vivo imaging studies to prove the applicability of this kit 68Ga-labeling technique.

Neuroendocrine Tumor Recurrence: Diagnosis with 68Ga-DOTATATE PET/CT

PURPOSE To evaluate diagnostic performance of gallium 68-tetraazacyclododecane tetraacetic acid-octreotate ((68)Ga-DOTATATE) in detection of recurrent neuroendocrine tumors (NETs). MATERIALS AND METHODS Approval was waived by the local ethics committee for this retrospective study. Between 2007 and 2011, 63 patients (mean age, 58 years) were examined with (68)Ga-DOTATATE positron emission tomography (PET)/computed tomography (CT) after primary NET curative resection. Reasons for PET/CT were regular follow-up examinations (n = 30), increased plasma levels of tumor markers (n = 27), or clinical suspicion of recurrence (n = 6). Final diagnosis was determined with histopathologic verification (n = 25) or clinical follow-up (n = 38). PET/CT scans were evaluated in consensus by two readers without blinding to clinical information and independently by two readers with blinding. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. RESULTS Final diagnosis of NET recurrence was determined in 29 patients. In three other patients, tumors of nonneuroendocrine origin were diagnosed. (68)Ga-DOTATATE PET/CT helped identify NET recurrence in 26 of 29 patients (sensitivity, 90%) and exclude presence of recurrent NET in 28 of 34 patients (specificity, 82% ). PET/CT provided false-positive and false-negative results in six and three patients (PPV, 81% [26 of 32]; NPV, 90% [28 of 31]; accuracy, 86% [54 of 63]). In gastroenteropancreatic NET (n = 45), sensitivity was 94% (17 of 18); specificity was 89% (24 of 27); PPV was 85% (17 of 20); NPV was 96% (24 of 25); and accuracy was 91% (41 of 45). Two blinded readers achieved sensitivity of 79% (23 of 29) and 76% (22 of 29); specificity of 85% (29 of 34) and 94% (32 of 34) (κ = 0.80); and accuracy of 83% and 86%. CONCLUSION (68)Ga-DOTATATE PET/CT is accurate in detection of recurrent NET. Blinded PET/CT review markedly decreased sensitivity, underlining importance of considering clinical parameters in NET recurrence. Present results must be further validated to substantiate use of (68)Ga-DOTATATE PET/CT in routine follow-up after curative resection of NET.

Stable Coronary Artery Disease: Prognostic Value of Myocardial Perfusion SPECT in Relation to Coronary Calcium Scoring—Long-term Follow-up

PURPOSE To evaluate the incremental prognostic value of coronary artery calcification (CAC) scoring over single photon emission computed tomographic (SPECT) myocardial perfusion imaging in long-term prognosis and survival of patients with stable coronary artery disease (CAD). MATERIALS AND METHODS All patients provided written informed consent to undergo CAC scoring according to a protocol that was approved by the local clinical institutional review board. Over a median follow-up time of 5.4 years, 260 patients with stable CAD were followed up for severe cardiac events (cardiac death or nonfatal myocardial infarction). CAC scanning and SPECT myocardial perfusion imaging were performed at enrollment. Patients were stratified on the basis of well-established cutoff points for CAC score, summed stress score (SSS), and summed rest score (SRS). Kaplan-Meier survival curves and the Cox proportional hazards model were used. RESULTS CAC score and SRS were identified as the only independent predictors of event-free survival. Patients with perfusion abnormalities at rest (SRS > or = 2), a CAC score greater than 400, or severe perfusion abnormalities under stress (SSS > or = 13) were identified as having significantly increased risk for subsequent severe cardiac events (P = .023, .0095, and .007, respectively). In addition, a CAC score greater than 400 offered incremental prognostic value over the scintigraphic scores alone (P = .028 with an SSS > 8; P = .008 with an SRS > or = 2). CONCLUSION CAC score and SRS were identified as independent predictors of severe cardiac events during long-term follow-up of patients with known CAD. CAC scores imparted superior risk stratification information as compared with SPECT myocardial perfusion imaging results alone.