AimsWe sought to evaluate the mechanism of angiotensin receptor–neprilysin inhibitor (ARNI) sacubitril/valsartan therapy and compare it with a valsartan-only control group in patients with heart... Show moreAimsWe sought to evaluate the mechanism of angiotensin receptor–neprilysin inhibitor (ARNI) sacubitril/valsartan therapy and compare it with a valsartan-only control group in patients with heart failure with reduced ejection fraction (HFrEF).Methods and resultsThe study was a phase IV, prospective, randomized, double-blind, parallel-group study in patients with New York Heart Association class II–III heart failure and left ventricular ejection fraction (LVEF) ≤35%. During a 6-week run-in period, all patients received valsartan therapy, which was up-titrated to the highest tolerated dose level (80 mg bid or 160 mg bid) and then randomized to either valsartan or sacubitril/valsartan. Myocardial oxygen consumption, energetic efficiency of cardiac work, cardiac and systemic haemodynamics were quantified using echocardiography and 11C-acetate positron emission tomography before and after 6 weeks of therapy (on stable dose) in 55 patients (ARNI group: n = 27, mean age 63 ± 10 years, LVEF 29.2 ± 10.4%; and valsartan-only control group: n = 28, mean age 64 ± 8 years, LVEF 29.0 ± 7.3%; all p = NS). The energetic efficiency of cardiac work remained unchanged in both treatment arms. However, both diastolic (−4.5 mmHg; p = 0.026) and systolic blood pressure (−9.8 mmHg; p = 0.0007), myocardial perfusion (−0.054 ml/g/min; p = 0.045), and left ventricular mechanical work (−296; p = 0.038) decreased significantly in the ARNI group compared to the control group. Although myocardial oxygen consumption decreased in the ARNI group (−5.4%) compared with the run-in period and remained unchanged in the control group (+0.5%), the between-treatment group difference was not significant (p = 0.088).ConclusionsWe found no differences in the energetic efficiency of cardiac work between ARNI and valsartan-only groups in HFrEF patients. However, ARNI appears to have haemodynamic and cardiac mechanical effects over valsartan in heart failure patients. Show less
Delgado, V.; Marsan, N.; Waha, S. de; Bonaros, N.; Brida, M.; Burri, H.; ... ; ESC Sci Document Grp 2023
Background: The various plaque components have been associated with ischemia and outcomes in patients with coronary artery disease (CAD). The main goal of this analysis was to test the hypothesis... Show moreBackground: The various plaque components have been associated with ischemia and outcomes in patients with coronary artery disease (CAD). The main goal of this analysis was to test the hypothesis that, at patient level, the fraction of non-calcified plaque volume (PV) of total PV is associated with ischemia and outcomes in patients with CAD. This ratio could be a simple and clinically useful parameter, if predicting outcomes. Methods: Consecutive patients with suspected CAD undergoing coronary computed tomography angiography with selective positron emission tomography perfusion imaging were selected. Plaque components were quantitatively analyzed at patient level. The fraction of various plaque components were expressed as percentage of total PV and examined among patients with non-obstructive CAD, suspected stenosis with normal perfusion, and those with reduced myocardial perfusion. Clinical outcomes included all-cause mortality and myocardial infarction. Results: In total, 494 patients (age 63 & PLUSMN; 9 years, 55% male) were included. Total PV and all plaque components were significantly larger in patients with reduced myocardial perfusion compared to patients with normal perfusion and those with non-obstructive CAD. During follow-up 35 events occurred. Patients with any plaque component & GE; median showed worse outcomes (log-rank p < 0.001 for all). In addition, low-attenuation plaque & GE; median was associated with worse outcomes independent of total PV (adjusted HR: 2.754, 95% CI: 1.022-7.0419, p = 0.045). The fractions of the various plaque components were not associated with outcomes. Conclusion: Larger total PV or any plaque component at patient level are associated with abnormal myocardial perfusion and adverse events. The various plaque components as fraction of total PV lack additional prognostic value. Show less
Background: Additional strategies are needed to refine the referral for diagnostic testing of symptomatic patients with suspected coronary artery disease (CAD). We aimed to compare various models... Show moreBackground: Additional strategies are needed to refine the referral for diagnostic testing of symptomatic patients with suspected coronary artery disease (CAD). We aimed to compare various models to predict hemodynamically obstructive CAD. Methods and results: Symptomatic patients with suspected CAD who underwent coronary artery calcium scoring (CACS) and sequential coronary computed tomography angiography (CCTA) and [O-15]H2O positron emission tomography (PET) myocardial perfusion imaging were analyzed. Obstructive CAD was defined as a suspected coronary artery stenosis on CCTA with myocardial ischemia on PET (absolute stress myocardial perfusion <= 2.4 mL/g/min in >= 1 segment). Three models were developed to predict obstructive CAD-induced myocardial ischemia using logistic regression analysis: (1) basic model: including age, sex and cardiac symptoms, (2) risk factor model: adding number of risk factors to the basic model, and (3) CACS model: adding CACS to the risk factor model. Model performance was evaluated using discriminatory ability with area under the receiver-operating characteristic curves (AUC). A total of 647 patients (mean age 62 +/- 9 years, 45% men) underwent CACS and sequential CCTA and PET myocardial perfusion imaging. Obstructive CAD with myocardial ischemia on PET was present in 151 (23%) patients. CACS was independently associated with myocardial ischemia (P < .001). AUC for the discrimination of ischemia for the CACS model was superior over the basic model and risk factor model (P < .001). Conclusions: Adding CACS to the model including age, sex, cardiac symptoms and number of risk factors increases the accuracy to predict obstructive CAD with myocardial ischemia on PET in symptomatic patients with suspected CAD. Show less
Unterrainer, M.; Deroose, C.M.; Herrmann, K.; Moehler, M.; Blomqvist, L.; Cannella, R.; ... ; European Soc Gastrointestinal Abdominal Radiology (ESGAR) 2022
Background: Treatment monitoring in metastatic colorectal cancer (mCRC) relies on imaging to evaluate the tumour burden. Response Evaluation Criteria in Solid Tumors provide a framework on... Show moreBackground: Treatment monitoring in metastatic colorectal cancer (mCRC) relies on imaging to evaluate the tumour burden. Response Evaluation Criteria in Solid Tumors provide a framework on reporting and interpretation of imaging findings yet offer no guidance on a standardised imaging protocol tailored to patients with mCRC. Imaging protocol hetero-geneity remains a challenge for the reproducibility of conventional imaging end-points and is an obstacle for research on novel imaging end-points. Patients and methods: Acknowledging the recently highlighted potential of radiomics and arti-ficial intelligence tools as decision support for patient care in mCRC, a multidisciplinary, international and expert panel of imaging specialists was formed to find consensus on mCRC imaging protocols using the Delphi method. Results: Under the guidance of the European Organisation for Research and Treatment of Cancer (EORTC) Imaging and Gastrointestinal Tract Cancer Groups, the European Society of Oncologic Imaging (ESOI) and the European Society of Gastrointestinal and Abdominal Radiology (ESGAR), the EORTC-ESOI-ESGAR core imaging protocol was identified. Conclusion: This consensus protocol attempts to promote standardisation and to diminish variations in patient preparation, scan acquisition and scan reconstruction. We anticipate that this standardisation will increase reproducibility of radiomics and artificial intelligence studies and serve as a catalyst for future research on imaging end-points. For ongoing and future mCRC trials, we encourage principal investigators to support the dissemination of these im-aging standards across recruiting centres. (c) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
Rotteveel, L.; Kurakula, K.; Kooijman, E.J.M.; Schuit, R.C.; Verlaan, M.; Schreurs, M.; ... ; Windhorst, A.D. 2022
The transforming growth factor beta (TGF beta) pathway plays a complex role in cancer biology, being involved in both tumour suppression as well as promotion. Overactive TGF beta signalling has... Show moreThe transforming growth factor beta (TGF beta) pathway plays a complex role in cancer biology, being involved in both tumour suppression as well as promotion. Overactive TGF beta signalling has been linked to multiple diseases, including cancer, pulmonary arterial hypertension, and fibrosis. One of the key meditators within this pathway is the TGF beta type I receptor, also termed activin receptor-like kinase 5 (ALK5). ALK5 expression level is a key determinant of TGF beta signalling intensity and duration, and perturbation has been linked to diseases. A validated ALK5 positron emission tomography (PET) tracer creates an opportunity, therefore, to study its role in human diseases. To develop ALK5 PET tracers, two small molecule ALK5 kinase inhibitors were selected as lead compounds, which were labelled with carbon-11 and fluorine-18, respectively. [C-11]LR111 was synthesized with a yield of 17 +/- 6%, a molar activity of 126 +/- 79 GBq. mol(-1) and a purity of > 95% (n = 44). [18F]EW-7197 was synthesized with a yield of 10 +/- 5%, a molar activity of 183 & PLUSMN; 126 GBq. mol(-1) and a purity of > 95% (n = 11). Metabolic stability was evaluated in vivo in mice, showing 39 +/- 2% of intact [11C]LR111 and 21 +/- 2% of intact [F-18]EW-7197 in blood plasma at 45 min p.i. In vitro binding experiments were conducted in breast cancer MDAMB-231 and lung cancer A431 cell lines. In addition, both tracers were used for PET imaging in MDA-MB-231 xenograft models. Selective uptake of [F-18]EW-7197 and [C-11]LR111 was observed in MDA-MB-231 cells, in the MDA-MB-231 tumour xenografts in vivo and in the autoradiograms. As [C-11]LR111 and [F-18]EW-7197 showed selectivity of binding to ALK5 in vivo and in vitro. Both tracers are thereby valuable tools for the detection of ALK5 activity. Show less
Purpose: To report the first experience of our multidisciplinary team with functional imaging using C-11-methionine positron emission tomography-computed tomography (C-11-methionine PET-CT) co... Show morePurpose: To report the first experience of our multidisciplinary team with functional imaging using C-11-methionine positron emission tomography-computed tomography (C-11-methionine PET-CT) co-registered with MRI (Met-PET/MRICR) in clinical decision making and surgical planning of patients with difficult to treat prolactinoma. Methods: In eighteen patients with prolactinoma, referred to our tertiary referral centre because of intolerance or resistance for dopamine agonists (DA), Met-PET/MRICR was used to aid decision-making regarding therapy. Results: Met-PET/MRICR was positive in 94% of the patients. MRI and Met-PET/MRICR findings were completely concordant in five patients, partially concordant in nine patients, and non-concordant in four patients. In five patients Met-PET/MRICR identified lesion(s) that were retrospectively also visible on MRI. Met-PET/MRICR was false negative in one patient, with a cystic adenoma on conventional MRI. Thirteen patients underwent transsphenoidal surgery, with nine achieving full biochemical remission, two clinical improvement and near normalized prolactin levels, and one patient clinical improvement with significant tumour reduction. Hence, nearly all patients (94%) were considered to have a positive outcome. Permanent complication rate was low. Three patients continued DA, two patients have a wait and scan policy. Conclusion: Met-PET/MRICR can provide additional information to guide multidisciplinary preoperative and intraoperative decision making in selected cases of prolactinoma. This approach resulted in a high remission rate with a low rate of complications in our expert centre. Show less
Inflammatory musculoskeletal diseases represent a group of chronic and disabling conditions that evolve from a complex interplay between genetic and environmental factors that cause perturbations... Show moreInflammatory musculoskeletal diseases represent a group of chronic and disabling conditions that evolve from a complex interplay between genetic and environmental factors that cause perturbations in innate and adaptive immune responses. Understanding the pathogenesis of inflammatory musculoskeletal diseases is, to a large extent, derived from preclinical and basic research experiments. In vivo molecular imaging enables us to study molecular targets and to measure biochemical processes non-invasively and longitudinally, providing information on disease processes and potential therapeutic strategies, e.g. efficacy of novel therapeutic interventions, which is of complementary value next to ex vivo (post mortem) histopathological analysis and molecular assays. Remarkably, the large body of preclinical imaging studies in inflammatory musculoskeletal disease is in contrast with the limited reports on molecular imaging in clinical practice and clinical guidelines. Therefore, in this EANM-endorsed position paper, we performed a systematic review of the preclinical studies in inflammatory musculoskeletal diseases that involve radionuclide imaging, with a detailed description of the animal models used. From these reflections, we provide recommendations on what future studies in this field should encompass to facilitate a greater impact of radionuclide imaging techniques on the translation to clinical settings. Show less
Purpose We evaluated the value of reduced global and segmental absolute stress myocardial blood flow (sMBF) quantified by [O-15] water positron emission tomography (PET) for predicting cardiac... Show morePurpose We evaluated the value of reduced global and segmental absolute stress myocardial blood flow (sMBF) quantified by [O-15] water positron emission tomography (PET) for predicting cardiac events in patients with suspected obstructive coronary artery disease (CAD). Methods Global and segmental sMBF during adenosine stress were retrospectively quantified in 530 symptomatic patients who underwent [O-15] water PET for evaluation of coronary stenosis detected by coronary computed tomography angiography. Results Cardiovascular death, myocardial infarction, or unstable angina occurred in 28 (5.3%) patients at a 4-year follow-up. Reduced global sMBF was associated with events (area under the receiver operating characteristic curve 0.622, 95% confidence interval (95% CI) 0.538-0.707, p = 0.006). Reduced global sMBF (< 2.2 ml/g/min) was found in 22.8%, preserved global sMBF despite segmentally reduced sMBF in 35.3%, and normal sMBF in 41.9% of patients. Compared with normal sMBF, reduced global sMBF was associated with the highest risk of events (adjusted hazard ratio (HR) 6.970, 95% CI 2.271-21.396, p = 0.001), whereas segmentally reduced sMBF combined with preserved global MBF predicted an intermediate risk (adjusted HR 3.251, 95% CI 1.030-10.257, p = 0.044). The addition of global or segmental reduction of sMBF to clinical risk factors improved risk prediction (net reclassification index 0.498, 95% CI 0.118-0.879, p = 0.010, and 0.583, 95% CI 0.203-0.963, p = 0.002, respectively). Conclusion In symptomatic patients evaluated for suspected obstructive CAD, reduced global sMBF by [O-15] water PET identifies those at the highest risk of adverse cardiac events, whereas segmental reduction of sMBF with preserved global sMBF is associated with an intermediate event risk. Show less
Purpose To compare cardiac magnetic resonance imaging (CMR) with [O-15]H2O positron emission tomography (PET) for quantification of absolute myocardial blood flow (MBF) and myocardial flow reserve ... Show morePurpose To compare cardiac magnetic resonance imaging (CMR) with [O-15]H2O positron emission tomography (PET) for quantification of absolute myocardial blood flow (MBF) and myocardial flow reserve (MFR) in patients with coronary artery disease (CAD). Methods Fifty-nine patients with stable CAD underwent CMR and [O-15]H2O PET. The CMR imaging protocol included late gadolinium enhancement to rule out presence of scar tissue and perfusion imaging using a dual sequence, single bolus technique. Absolute MBF was determined for the three main vascular territories at rest and during vasodilator stress. Results CMR measurements of regional stress MBF and MFR showed only moderate correlation to those obtained using PET (r = 0.39; P < 0.001 for stress MBF and r = 0.36; P < 0.001 for MFR). Bland-Altman analysis revealed a significant bias of 0.2 +/- 1.0 mL/min/g for stress MBF and - 0.5 +/- 1.2 for MFR. CMR-derived stress MBF and MFR demonstrated area under the curves of respectively 0.72 (95% CI: 0.65 to 0.79) and 0.76 (95% CI: 0.69 to 0.83) and had optimal cutoff values of 2.35 mL/min/g and 2.25 for detecting abnormal myocardial perfusion, defined as [O-15]H2O PET-derived stress MBF <= 2.3 mL/min/g and MFR <= 2.5. Using these cutoff values, CMR and PET were concordant in 137 (77%) vascular territories for stress MBF and 135 (80%) vascular territories for MFR. Conclusion CMR measurements of stress MBF and MFR showed modest agreement to those obtained with [O-15]H2O PET. Nevertheless, stress MBF and MFR were concordant between CMR and [O-15]H2O PET in 77% and 80% of vascular territories, respectively. Show less
PurposeTo compare cardiac magnetic resonance imaging (CMR) with [15O]H2O positron emission tomography (PET) for quantification of absolute myocardial blood flow (MBF) and myocardial flow reserve ... Show morePurposeTo compare cardiac magnetic resonance imaging (CMR) with [15O]H2O positron emission tomography (PET) for quantification of absolute myocardial blood flow (MBF) and myocardial flow reserve (MFR) in patients with coronary artery disease (CAD).MethodsFifty-nine patients with stable CAD underwent CMR and [15O]H2O PET. The CMR imaging protocol included late gadolinium enhancement to rule out presence of scar tissue and perfusion imaging using a dual sequence, single bolus technique. Absolute MBF was determined for the three main vascular territories at rest and during vasodilator stress.ResultsCMR measurements of regional stress MBF and MFR showed only moderate correlation to those obtained using PET (r = 0.39; P < 0.001 for stress MBF and r = 0.36; P < 0.001 for MFR). Bland-Altman analysis revealed a significant bias of 0.2 ± 1.0 mL/min/g for stress MBF and − 0.5 ± 1.2 for MFR. CMR-derived stress MBF and MFR demonstrated area under the curves of respectively 0.72 (95% CI: 0.65 to 0.79) and 0.76 (95% CI: 0.69 to 0.83) and had optimal cutoff values of 2.35 mL/min/g and 2.25 for detecting abnormal myocardial perfusion, defined as [15O]H2O PET-derived stress MBF ≤ 2.3 mL/min/g and MFR ≤ 2.5. Using these cutoff values, CMR and PET were concordant in 137 (77%) vascular territories for stress MBF and 135 (80%) vascular territories for MFR.ConclusionCMR measurements of stress MBF and MFR showed modest agreement to those obtained with [15O]H2O PET. Nevertheless, stress MBF and MFR were concordant between CMR and [15O]H2O PET in 77% and 80% of vascular territories, respectively. Show less
Maurer, T.; Robu, S.; Schottelius, M.; Schwamborn, K.; Rauscher, I.; Bereg, N.S. van den; ... ; Eibere, M. 2019
Background: Prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) can visualize metastatic lesions in recurrent prostate cancer (PC). However, reliable... Show moreBackground: Prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) can visualize metastatic lesions in recurrent prostate cancer (PC). However, reliable identification of small and/or atypically localized lesions during salvage surgery procedures is challenging.Objective: To describe the technique, feasibility, and short-term outcomes of (99m)Technetium (Tc-99m)-based PSMA-radioguided surgery (Tc-99m-PSMA-RGS) for removal of recurrent PC lesions.Design, setting, and participants: Thirty-one consecutive patients with evidence of recurrent PC on Ga-68-PSMA N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl] ethylenediamine-N,N'-diacetic acid (Ga-68-PSMA-11) PET after radical prostatectomy undergoing Tc-99m-PSMA-RGS were retrospectively analyzed.Surgical procedure: Salvage surgery with intraoperative radioguidance using a gamma probe was performed after intravenous application of Tc-99m-PSMA investigation and surgery (mean activity 571 MBq, mean time to surgery 19.7 h).Measurements: Radioactive rating (positive vs negative) of resected tissue was compared with the findings of postoperative histopathological analysis. Best prostate-specific antigen (PSA) response without additional treatment was determined after 8-16 wk postoperatively. Biochemical recurrence- and treatment-free survival was evaluated.Results and limitations: In total,132 tissue specimens were removed, of which 58 showed metastatic involvement on histological analysis. On a specimen basis, radioactive rating yielded a sensitivity of 83.6% (confidence interval [CI]: 70.9-91.5%), a specificity of 100%, and an accuracy of 93.0% (CI: 85.5-96.7%). With Tc-99m-PSMA-RGS, all lesions visualized on preoperative Ga-68-PSMA-11 PET could be removed. Moreover, Tc-99m-PSMA-RGS detected additional metastases as small as 3 mm in two patients. Thirteen patients suffered from complications related to surgery (Clavien-Dindo grade 1: 12 patients; grade 3a: one patient). A PSA reduction below 0.2 ng/ml was observed in 20 patients. Thirteen patients remained biochemical recurrence free after a median follow-up of 13.8 (range: 4.6-18.3) mo. Twenty patients continued to be treatment free after a median follow-up of 12.2 (range: 5.5-18.3) mo.Conclusions: As a new technique for surgical guidance, Tc-99m-PSMA-RGS is feasible, and has been proved to be of high value for successful intraoperative detection and removal of metastatic lesions in PC patients scheduled for salvage surgery. Its long-term impact on outcome has to be evaluated.Patient summary: In this report, we evaluated a novel technique to identify metastatic lesions intraoperatively in patients with recurrent prostate cancer to facilitate surgical removal. After intravenous injection of radioactive molecules that specifically bind to prostate cancer cells that show increased expression of the prostate-specific membrane antigen, we were able to detect and remove these metastatic lesions during surgery. Following salvage surgery, 41.9% of patients remained biochemical recurrence free (median follow-up of 13.8 mo) and 64.5% continued to be treatment free (median follow-up of 12.2 mo). (C) 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved. Show less
Willemsen, A.E.C.A.B.; Vlenterie, M.; Herpen, C.M.L. van; Erp, N.P. van; Graaf, W.T.A. van der; Geus-Oei, L.F. de; Oyen, W.J.G. 2016
The Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder in which patients have muscle weakness and autonomic dysfunction. Half of the patients have small cell lung cancer (SCLC).... Show moreThe Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder in which patients have muscle weakness and autonomic dysfunction. Half of the patients have small cell lung cancer (SCLC). SCLC is a very aggressive lung tumour with a median survival of only 9 months. Quick discovery and treatment is of uttermost importance for both patient and physician to improve the chance of cure. SCLC-LEMS is related to smoking, a higher age at onset and weight loss. The clinical symptoms develop more quickly and more severely if the LEMS is related to SCLC. The discovery of SOX antibodies is described specific for SCLC-LEMS. Based on simple epidemiological and clinical parameters, we created the DELTA-P score and validated it in an independent second cohort. The DELTA-P score predicts already shortly after onset of symptoms with 95% accuracy who has or will have an SCLC. The reliability of imaging to detect SCLC is analyzed in 100 patients, creating a new screening protocol. For other paraneoplastic syndromes, screening guidelines are updated. SOX and Hu antibodies are also found in 43% of SCLC patients (without LEMS). Combination of different antibodies might lead to reliable screening strategies in high-risk patients. Show less
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