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Background: Mitral regurgitation (MR) and cardiac amyloidosis (CA) both primarily affect older patients. Data on coexistence and prognostic implications of MR and CA are currently lacking., Objectives: This study sought to identify the prevalence, clinical characteristics, and outcomes of MR CA compared with lone MR., Methods: Consecutive patients undergoing transcatheter edge-to-edge repair (TEER) for MR at 2 sites were screened for concomitant CA using a multiparametric approach including core laboratory 99m Tc-3,3-diphosphono-1,2-propanodicarboxylic acid bone scintigraphy and echocardiography and immunoglobulin light chain assessment. Transthyretin CA (ATTR) was diagnosed by 99m Tc-3,3-diphosphono-1,2-propanodicarboxylic acid (Perugini grade 1: early infiltration; grades 2/3: clinical CA) and the absence of monoclonal protein, and light chain (AL) CA via tissue biopsy. All-cause mortality and hospitalization for heart failure (HHF) served as the endpoints., Results: A total of 120 patients (age 76.9 ± 8.1 years, 55.8% male) were recruited. Clinical CA was diagnosed in 14 patients (11.7%; 12 ATTR, 1 AL, and 1 combined ATTR/AL) and early amyloid infiltration in 9 patients (7.5%). Independent predictors of MR CA were increased posterior wall thickness and the presence of a left anterior fascicular block on electrocardiography. Procedural success and periprocedural complications of TEER were similar in MR CA and lone MR (P for all = NS). After a median of 1.7 years, 25.8% had experienced death and/or HHF. MR CA had worse outcomes compared with lone MR (HR: 2.2; 95% CI: 1.0-4.7; P = 0.034), driven by a 2.5-fold higher risk for HHF (HR: 2.5; 95% CI: 1.1-5.9), but comparable mortality (HR: 1.6; 95% CI: 0.4-6.1)., Conclusions: Dual pathology of MR CA is common in elderly patients with MR undergoing TEER and has worse postinterventional outcomes compared with lone MR., Competing Interests: Funding Support and Author Disclosures This study received financial support from Pfizer. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Positron emission tomography (PET) has been widely used in paediatric oncology. 2-Deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG) is the most commonly used radiopharmaceutical for PET imaging. For oncological brain imaging, different amino acid PET radiopharmaceuticals have been introduced in the last years. The purpose of this document is to provide imaging specialists and clinicians guidelines for indication, acquisition, and interpretation of [ 18 F]FDG and radiolabelled amino acid PET in paediatric patients affected by brain gliomas. There is no high level of evidence for all recommendations suggested in this paper. These recommendations represent instead the consensus opinion of experienced leaders in the field. Further studies are needed to reach evidence-based recommendations for the applications of [ 18 F]FDG and radiolabelled amino acid PET in paediatric neuro-oncology. These recommendations are not intended to be a substitute for national and international legal or regulatory provisions and should be considered in the context of good practice in nuclear medicine. The present guidelines/standards were developed collaboratively by the EANM and SNMMI with the European Society for Paediatric Oncology (SIOPE) Brain Tumour Group and the Response Assessment in Paediatric Neuro-Oncology (RAPNO) working group. They summarize also the views of the Neuroimaging and Oncology and Theranostics Committees of the EANM and reflect recommendations for which the EANM and other societies cannot be held responsible., (© 2022. The Author(s).)

Background: Blood-based biomarkers may add a great benefit in detecting the earliest neuropathological changes in patients with Alzheimer's disease (AD). We examined the utility of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) regarding clinical diagnosis and differentiation between amyloid positive and negative patients. To evaluate the practical application of these biomarkers in a routine clinical setting, we conducted this study in a heterogeneous memory-clinic population. Methods: We included 167 patients in this retrospective cross-sectional study, 123 patients with an objective cognitive decline [mild cognitive impairment (MCI) due to AD, n = 63, and AD-dementia, n = 60] and 44 age-matched healthy controls (HC). Cerebrospinal fluid (CSF) and plasma concentrations of NfL and GFAP were measured with single molecule array (SIMOA ® ) technology using the Neurology 2-Plex B kit from Quanterix. To assess the discriminatory potential of different biomarkers, age- and sex-adjusted receiver operating characteristic (ROC) curves were calculated and the area under the curve (AUC) of each model was compared. Results: We constructed a panel combining plasma NfL and GFAP with known AD risk factors (Combination panel: age+sex+ APOE4 +GFAP+NfL). With an AUC of 91.6% (95%CI = 0.85-0.98) for HC vs. AD and 81.7% (95%CI = 0.73-0.90) for HC vs. MCI as well as an AUC of 87.5% (95%CI = 0.73-0.96) in terms of predicting amyloid positivity, this panel showed a promising discriminatory power to differentiate these populations. Conclusion: The combination of plasma GFAP and NfL with well-established risk factors discerns amyloid positive from negative patients and could potentially be applied to identify patients who would benefit from a more invasive assessment of amyloid pathology. In the future, improved prediction of amyloid positivity with a noninvasive test may decrease the number and costs of a more invasive or expensive diagnostic approach., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Parvizi, König, Wurm, Silvaieh, Altmann, Klotz, Rommer, Furtner, Regelsberger, Lehrner, Traub- Weidinger, Gelpi and Stögmann.)

Purpose: Curative treatment for primary hyperparathyroidism (PHPT) is parathyroidectomy (PTX) with removal of the hyperfunctioning gland(s). In an endemic goitre region, 35-78% of PHPT patients show concomitant thyroid disease. This study aimed to evaluate if 99m Tc-sestamibi (MIBI)-positive thyroid nodules decrease sensitivity in regard to localising the hyperfunctioning parathyroid gland(s) in PHPT patients., Methods: Within 5 years, 497 consecutive patients with biochemically proven PHPT were included in this study. The data was analysed retrospectively., Results: In total, 198 patients underwent PTX with thyroid surgery and 299 patients underwent sole PTX. Sensitivity of MIBI scan for PTX with and without thyroid surgery was 72.1% and 73.6%, respectively. A statistically significant difference in sensitivity of ultrasound for PTX with and without thyroid surgery (57.0% and 70.9%, respectively) was observed (p = 0.029). Thyroid nodule histology did not have a significant effect on the MIBI scan. Unilateral neck exploration (UNE) was performed in 110 patients and bilateral neck exploration (BNE) in 177 patients. The probability of surgical conversion from UNE to BNE due to incorrect localisation was 1.733 times higher in patients with thyroid nodules., Conclusions: Concomitant benign thyroid nodules did not influence MIBI sensitivity. No correlation between thyroid carcinoma and MIBI uptake was determined. However, MIBI detection of thyroid malignancy is important in patients initially being considered for minimal invasive parathyroidectomy. Sensitivity and positive predictive value of ultrasound were significantly lower in patients with thyroid nodules. The probability of conversion from UNE to BNE due to incorrect localisation was 1.733 times higher in patients with thyroid nodules., (© 2022. The Author(s).)

(1) Background: Recent developments in 7T magnetic resonance spectroscopic imaging (MRSI) made the acquisition of high-resolution metabolic images in clinically feasible measurement times possible. The amino acids glutamine (Gln) and glycine (Gly) were identified as potential neuro-oncological markers of importance. For the first time, we compared 7T MRSI to amino acid PET in a cohort of glioma patients. (2) Methods: In 24 patients, we co-registered 7T MRSI and routine PET and compared hotspot volumes of interest (VOI). We evaluated dice similarity coefficients (DSC), volume, center of intensity distance (CoI), median and threshold values for VOIs of PET and ratios of total choline (tCho), Gln, Gly, myo-inositol (Ins) to total N-acetylaspartate (tNAA) or total creatine (tCr). (3) Results: We found that Gln and Gly ratios generally resulted in a higher correspondence to PET than tCho. Using cutoffs of 1.6-times median values of a control region, DSCs to PET were 0.53 ± 0.36 for tCho/tNAA, 0.66 ± 0.40 for Gln/tNAA, 0.57 ± 0.36 for Gly/tNAA, and 0.38 ± 0.31 for Ins/tNAA. (4) Conclusions: Our 7T MRSI data corresponded better to PET than previous studies at lower fields. Our results for Gln and Gly highlight the importance of future research (e.g., using Gln PET tracers) into the role of both amino acids.

Prostate-specific membrane antigen (PSMA) is present in the tumor-associated neovasculature of many cancer types. Current data in ovarian cancer are limited and controversial; thus, the aim of this study was to investigate PSMA expression in a larger and homogenous patient cohort. This might lead to further studies investigating the use of imaging and therapeutic modalities targeting PSMA. Eighty patients with advanced stage high-grade serous ovarian cancers were included. Using immunohistochemistry, PSMA and CD31, a marker for endothelial cells, were examined in whole tissue sections. Percentage and intensity of PSMA expression were determined in the neovasculature. Expression levels were correlated with clinicopathological parameters and survival. Low (≤10%), medium (20-80%), and high (≥90%) PSMA expression was found in 14, 46, and 20 ovarian cancer samples, respectively. PSMA expression was confined to tumor-associated neovasculature and significantly correlated with progression-free (HR 2.24, 95% CI 1.32-3.82, p = 0.003) and overall survival (HR 2.73, 95% CI 1.41-5.29, p = 0.003) in multivariate models, considering age, FIGO stage, and residual disease. This is the first study showing a clinical relevance for PSMA in patients with ovarian cancer. PSMA was detected in the vast majority of cancer samples and showed an impact on survival.

The present procedural guidelines summarize the current views of the EANM Neuro-Imaging Committee (NIC). The purpose of these guidelines is to assist nuclear medicine practitioners in making recommendations, performing, interpreting, and reporting results of [ 18 F]FDG-PET imaging of the brain. The aim is to help achieve a high-quality standard of [ 18 F]FDG brain imaging and to further increase the diagnostic impact of this technique in neurological, neurosurgical, and psychiatric practice. The present document replaces a former version of the guidelines that have been published in 2009. These new guidelines include an update in the light of advances in PET technology such as the introduction of digital PET and hybrid PET/MR systems, advances in individual PET semiquantitative analysis, and current broadening clinical indications (e.g., for encephalitis and brain lymphoma). Further insight has also become available about hyperglycemia effects in patients who undergo brain [ 18 F]FDG-PET. Accordingly, the patient preparation procedure has been updated. Finally, most typical brain patterns of metabolic changes are summarized for neurodegenerative diseases. The present guidelines are specifically intended to present information related to the European practice. The information provided should be taken in the context of local conditions and regulations., (© 2021. The Author(s).)

The sex hormones testosterone and estradiol influence brain structure and function and are implicated in the pathogenesis, prevalence and disease course of major depression. Recent research employing gender-affirming hormone treatment (GHT) of gender dysphoric individuals and utilizing positron emission tomography (PET) indicates increased serotonin transporter binding upon high-dosages of testosterone treatment. Here, we investigated the effects of GHT on levels of monoamine oxidase A (MAO-A), another key target of antidepressant treatment. Participants underwent PET with the radioligand [ 11 C]harmine to assess cerebral MAO-A distribution volumes (V T ) before and four months after initiation of GHT. By the time this study was terminated for technical reasons, 18 transgender individuals undergoing GHT (11 transmen, TM and 7 transwomen, TW) and 17 cis-gender subjects had been assessed. Preliminary analysis of available data revealed statistically significant MAO-A V T reductions in TM under testosterone treatment in six of twelve a priori defined regions of interest (middle frontal cortex (-10%), anterior cingulate cortex (-9%), medial cingulate cortex (-10.5%), insula (-8%), amygdala (-9%) and hippocampus (-8.5%, all p<0.05)). MAO-A V T did not change in TW receiving estrogen treatment. Despite the limited sample size, pronounced MAO-A V T reduction could be observed, pointing towards a potential effect of testosterone. Considering MAO-A's central role in regulation of serotonergic neurotransmission, changes to MAO-A V T should be further investigated as a possible mechanism by which testosterone mediates risk for, symptomatology of, and treatment response in affective disorders., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Apart from its expression in benign and malignant prostate tissue, prostate specific membrane antigen (PSMA) was shown to be expressed specifically in the neovasculature of solid tumors. For gliomas only little information exists. Therefore, we aimed to correlate PSMA expression in gliomas to tumor metabolism by L-[S-methyl- 11 C]methionine (MET) PET and survival. Therefore, immunohistochemical staining (IHC) for isocitrate dehydrogenase 1-R132H (IDH1-R132H) mutation and PSMA expression was performed on the paraffin embedded tissue samples of 122 treatment-naive glioma patients. The IHC results were then related to the pre-therapeutic semiquantitative MET PET data and patients' survival. Vascular PSMA expression was observed in 26 of 122 samples and was rather specific for high-grade gliomas ([HGG] 81% of glioblastoma multiforme, 10% of WHO grade III and just 2% of grade II gliomas). Significantly higher amounts of gliomas without verifiable IDH1-R132H mutation showed vascular PSMA expression. Significantly shorter median survival times were seen for patients with vascular PSMA staining in all tumors as well as HGG only. Additionally, significantly higher numbers of PSMA staining vessels were found in tumors with high amino acid metabolic rates. Vascular PSMA expression in gliomas was seen as a high-grade specific feature associated with elevated amino acid metabolism and short survival.

This work set out to develop a motion-correction approach aided by conditional generative adversarial network (cGAN) methodology that allows reliable, data-driven determination of involuntary subject motion during dynamic 18 F-FDG brain studies. Methods: Ten healthy volunteers (5 men/5 women; mean age ± SD, 27 ± 7 y; weight, 70 ± 10 kg) underwent a test-retest 18 F-FDG PET/MRI examination of the brain ( n = 20). The imaging protocol consisted of a 60-min PET list-mode acquisition contemporaneously acquired with MRI, including MR navigators and a 3-dimensional time-of-flight MR angiography sequence. Arterial blood samples were collected as a reference standard representing the arterial input function (AIF). Training of the cGAN was performed using 70% of the total datasets ( n = 16, randomly chosen), which was corrected for motion using MR navigators. The resulting cGAN mappings (between individual frames and the reference frame [55-60 min after injection]) were then applied to the test dataset (remaining 30%, n = 6), producing artificially generated low-noise images from early high-noise PET frames. These low-noise images were then coregistered to the reference frame, yielding 3-dimensional motion vectors. Performance of cGAN-aided motion correction was assessed by comparing the image-derived input function (IDIF) extracted from a cGAN-aided motion-corrected dynamic sequence with the AIF based on the areas under the curves (AUCs). Moreover, clinical relevance was assessed through direct comparison of the average cerebral metabolic rates of glucose (CMRGlc) values in gray matter calculated using the AIF and the IDIF. Results: The absolute percentage difference between AUCs derived using the motion-corrected IDIF and the AIF was (1.2% + 0.9%). The gray matter CMRGlc values determined using these 2 input functions differed by less than 5% (2.4% + 1.7%). Conclusion: A fully automated data-driven motion-compensation approach was established and tested for 18 F-FDG PET brain imaging. cGAN-aided motion correction enables the translation of noninvasive clinical absolute quantification from PET/MR to PET/CT by allowing the accurate determination of motion vectors from the PET data itself., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Primary diffuse leptomeningeal melanomatosis (PDLMM) is an extremely rare and aggressive cancer type for which best treatment strategies remain to be elucidated. Herein, we present current and prospective diagnostic strategies and treatment management of PDLMM. Against the background of an extensive literature review of published PDLMM cases and currently employed therapeutic strategies, we present an illustrative case of a pediatric patient suffering from PDLMM. We report the first case of a pediatric patient with PDLMM who received combination treatment including trametinib and everolimus, followed by intravenous nivolumab and ipilimumab with concomitant intensive intraventricular chemotherapy, resulting in temporary significant clinical improvement and overall survival of 7 months. Following this clinical experience, we performed a comprehensive literature review, identifying 26 additional cases. By these means, we provide insight into current knowledge on clinical and molecular characteristics of PDLMM. Analysis of these cases revealed that the unspecific clinical presentation, such as unrecognized increased intracranial pressure (present in 67%), is a frequent reason for the delay in diagnosis. Mortality remains substantial despite diverse therapeutic approaches with a median overall survival of 4 months from diagnosis. On the molecular level, to date, the only oncogenic driver reported so far is mutation of NRAS ( n = 3), underlining a close biological relation to malignant melanoma and neurocutaneous melanosis. We further show, for the first time, that this somatic mutation can be exploited for cerebrospinal fluid liquid biopsy detection, revealing a novel potential biomarker for diagnosis and monitoring of PDLMM. Last, we use a unique patient derived PDLMM cell model to provide first insights into in vitro drug sensitivities. In summary, we provide future diagnostic and therapeutic guidance for PDLMM and first insights into the use of liquid biopsy and in vitro models for this orphan cancer type.

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with a robust genetic influence. The norepinephrine transporter (NET) is of particular interest as it is one of the main targets in treatment of the disorder. As ADHD is a complex and polygenetic condition, the possible regulation by epigenetic processes has received increased attention. We sought to determine possible differences in NET promoter DNA methylation between patients with ADHD and healthy controls. DNA methylation levels in the promoter region of the NET were determined in 23 adult patients with ADHD and 23 healthy controls. A subgroup of 18 patients with ADHD and 18 healthy controls underwent positron emission tomography (PET) with the radioligand (S,S)-[ 18 F]FMeNER-D 2 to quantify the NET in several brain areas in vivo. Analyses revealed significant differences in NET methylation levels at several cytosine-phosphate-guanine (CpG) sites between groups. A defined segment of the NET promoter ("region 1") was hypermethylated in patients in comparison with controls. In ADHD patients, a negative correlation between methylation of a CpG site in this region and NET distribution in the thalamus, locus coeruleus, and the raphe nuclei was detected. Furthermore, methylation of several sites in region 1 was negatively associated with the severity of hyperactivity-impulsivity symptoms. Our results point to an epigenetic dysregulation in ADHD, possibly due to a compensatory mechanisms or additional factors involved in transcriptional processing.

The diagnosis of parkinsonian syndromes in patients with severe depression may be challenging due to overlapping clinical phenomena, especially regarding psychomotor and affective symptoms. [ 123 I]FP-CIT-SPECT is a useful method to detect degenerative parkinsonian disorders. However, some drugs may influence the tracer binding and thus alter the result. We present a case of 56-year-old female inpatient with difficult-to-treat late-onset depression. Since the current major depressive episode (MDE) was accompanied by psychotic features including delusions and hallucinations as well as hypokinesia, stooped posture and hypomimia, underlying degenerative parkinsonism was suspected. The pathologic [ 123 I]FP-CIT-SPECT scan under ongoing antidepressant therapy with bupropion 300 mg/die (serum level of bupropion 43 ng/ml and hydroxybupropion 2,332 ng/ml) showed reduced [ 123 I]FP-CIT binding throughout the striatum. The scan normalized upon a wash-out phase of four half-time periods (serum level of bupropion was 0.4 ng/ml and for hydroxybupropion 80.5 ng/ml). Our report should serve as a cautionary note for use of [ 123 I]FP-CIT in depressed patients, particularly in those treated with drugs interfering with the dopamine transporter. Furthermore, our case argues for a need of consultation of a movement disorder specialist prior to dopamine transporter imaging., Competing Interests: IM received grant from Takeda. LB received travel grants and consultant/speaker honoraria from AOP Orphan, Medizin Medien Austria, Vertretungsnetz, Schwabe Austria, Janssen, and Angelini. KP received honoraria from AOP Orphan Pharmaceuticals, Germania Pharmaceuticals, Lundbeck, and Janssen-Cilag. SK received grants/research support, consulting fees, and/or honoraria from Angelini, AOP Orphan Pharmaceuticals, Celegne GmbH, Eli Lilly, Janssen-Cilag Pharma GmbH, KRKA-Pharma, Lundbeck A/S, Mundipharma, Neuraxpharm, Pfizer, Sanofi, Schwabe, Servier, Shire, Sumitomo Dainippon Pharma Co. Ltd. and Takeda. DW received lecture fees/authorship honoraria from Angelini, Lundbeck, and Medizin Medien Austria. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Milenkovic, Bartova, Papageorgiou, Kasper, Traub-Weidinger and Winkler.)

Purpose of the Report: F-FDG PET is limited for assessment of central nervous system lymphoma (CNSL) due to physiologic tracer accumulation in the brain. We prospectively evaluated the novel PET tracer Ga-pentixafor, which targets the C-X-C chemokine receptor 4 (CXCR4), for lesion visualization and response assessment of CNSL., Materials and Methods: Seven CNSL patients underwent Ga-pentixafor PET/MRI with contrast enhancement (CE-MRI) and diffusion-weighted sequences. The accuracy of Ga-pentixafor PET for CNSL lesion detection relative to the CE-MRI reference standard was determined. Standardized uptake values (SUVmean and SUVmax), PET-based (PTV) and MRI-based (VOLMRI) tumor volumes, and apparent diffusion coefficients (ADCs) were assessed, and correlation coefficients were calculated. Three SUVmax thresholds (41%, 50%, and 70%) were evaluated for PTV definitions (PTV41%, PTV50%, and PTV70%) and tested against VOLMRI using paired sample t tests., Results: Twelve Ga-pentixafor PET/MRI examinations (including 5 follow-up scans) of 7 patients were evaluated. Ga-pentixafor PET demonstrated 18 lesions, all of which were confirmed by CE-MRI; there were no false-positive lesions on PET (accuracy, 100%). PTV41% showed the highest concordance with lesion morphology, with no significant difference compared with VOLMRI (mean difference, -0.24 cm; P = 0.45). The correlation between ADCmean and SUVmean41% (r = 0.68) was moderate. Changes in PTV41% on follow-up PET/MRI showed the same trend as VOLMRI changes, including progression of 1 lesion each in patient 1 (+456.0% PTV41% and +350.8% VOLMRI) and patient 3 (+110.4% PTV41% and +85.1% VOLMRI)., Conclusions: Ga-pentixafor PET may be feasible for assessment and follow-up of CNSL. Future studies need to focus on testing its clinical value to distinguish between glioma and CNSL, and between radiation-induced inflammation and viable residual tumor.

Purpose: There is evidence that mild cognitive impairment (MCI) or Alzheimer's disease (AD) is accompanied by alterations in the retina. The current study was performed to investigate structural and functional changes in patients with systemic neurodegenerative disease., Methods: A total of 47 patients with either MCI or AD and 43 healthy age- and sex-matched control subjects were included. Inclusion criteria for MCI were abnormal memory function and a mini-mental state examination (MMSE) score >26 points, for patients with AD a diagnosis of probable AD of mild to moderate degree and an MMSE score in the range of 20-26. Retinal blood flow was measured using a Doppler optical coherence tomography (OCT) system. Retinal vessel diameter, oxygen saturation and flicker-induced vasodilatation were measured using a Vessel Analyzer. Retinal nerve fibre layer thickness (RNFLT) was assessed using an OCT system., Results: Global RNFLT was lower in patients compared to healthy controls (93.7 ± 12.8 µm versus 99.1 ± 9.0 µm, p = 0.02). The same was found in regards to retinal arterial blood flow, which was 9.3 ± 2.4 and 12.3 ± 3.2 μl/min in the patient and control groups, respectively (p < 0.001). Mean retinal arterial diameter was reduced in patients (76.0 ± 8.9 µm versus 80.6 ± 8.0 µm, p = 0.03). Arteriovenous difference in oxygen saturation was lower in patients (20.4 ± 5.1% versus 23.5 ± 4.0%, p < 0.01). No difference in the flicker response was observed., Conclusion: In patients with MCI and AD, arteriovenous difference in oxygen saturation, retinal blood flow and arterial vessel diameter was reduced. No difference was found in flicker response between groups. This indicates alterations in retinal oxygen metabolism in patients with neurodegenerative disease., (© 2020 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Background: Current diagnosis of Transthyretin-related Amyloidosis (ATTR) using bone scintigraphy is primarily based on visual scoring and semi-quantitative indices. With the introduction of new potential life-prolonging drugs for ATTR, a more precise quantification of myocardial amyloid burden is desirable for improved response prediction and therapy monitoring., Methods: At first, quantification experiments using an anthropomorphic thorax phantom were performed. Second, 32 patients underwent both planar whole body [ 99m Tc]- 3,3-Diphosphono-1,2-Propanodicarboxylic Acid (DPD)-scintigraphy and quantitative Single-Photon Emission Computed Tomography/Computed Tomography (SPECT/CT) of the thorax. SPECT/CT standardized myocardial uptake values SUVpeak and SUVpeak normalized to bone uptake (nSUVpeak) were determined., Results: Phantom measurements showed a strong linear relationship between the activity in the myocardial insert and the measured activity (r = 0.9998, p = 0.01), but the measured activity was systematically underestimated by approximately 30%. Receiver operating characteristics (ROC) analysis revealed a 100% sensitivity and specificity at a cut-off of 3.1 for SUVpeak for the differentiation of both patient groups., Conclusion: SUV quantification of ATTR amyloid burden is feasible using novel SPECT/CT technology. With a SUVpeak cut-off of 3.1, patients with Perugini grade 2 and 3 could be clearly separated from those with Perugini grade 0 and 1. Besides ATTR diagnostics, quantification of amyloid deposits could potentially be used for therapy monitoring and prognostication in patients with cardiac ATTR.

In the past, determination of absolute values of cerebral metabolic rate of glucose (CMRGlc) in clinical routine was rarely carried out due to the invasive nature of arterial sampling. With the advent of combined PET/MR imaging technology, CMRGlc values can be obtained non-invasively, thereby providing the opportunity to take advantage of fully quantitative data in clinical routine. However, CMRGlc values display high physiological variability, presumably due to fluctuations in the intrinsic activity of the brain at rest. To reduce CMRGlc variability associated with these fluctuations, the objective of this study was to determine whether functional connectivity measures derived from resting-state fMRI (rs-fMRI) could be used to correct for these fluctuations in intrinsic brain activity., Methods: We studied 10 healthy volunteers who underwent a test-retest dynamic [18F]FDG-PET study using a fully integrated PET/MR system (Siemens Biograph mMR). To validate the non-invasive derivation of an image-derived input function based on combined analysis of PET and MR data, arterial blood samples were obtained. Using the arterial input function (AIF), parametric images representing CMRGlc were determined using the Patlak graphical approach. Both directed functional connectivity (dFC) and undirected functional connectivity (uFC) were determined between nodes in six major networks (Default mode network, Salience, L/R Executive, Attention, and Sensory-motor network) using either a bivariate-correlation (R coefficient) or a Multi-Variate AutoRegressive (MVAR) model. In addition, the performance of a regional connectivity measure, the fractional amplitude of low frequency fluctuations (fALFF), was also investigated., Results: The average intrasubject variability for CMRGlc values between test and retest was determined as (14 ±8%) with an average inter-subject variability of 25% at test and 15% at retest. The average CMRGlc value (umol/100 g/min) across all networks was 39 ±10 at test and increased slightly to 43 ±6 at retest. The R, MVAR and fALFF coefficients showed relatively large test-retest variability in comparison to the inter-subjects variability, resulting in poor reliability (intraclass correlation in the range of 0.11-0.65). More importantly, no significant relationship was found between the R coefficients (for uFC), MVAR coefficients (for dFC) or fALFF and corresponding CMRGlc values for any of the six major networks., Discussion: Measurement of functional connectivity within established brain networks did not provide a means to decrease the inter- or intrasubject variability of CMRGlc values. As such, our results indicate that connectivity measured derived from rs-fMRI acquired contemporaneously with PET imaging are not suited for correction of CMRGlc variability associated with intrinsic fluctuations of resting-state brain activity. Thus, given the observed substantial inter- and intrasubject variability of CMRGlc values, the relevance of absolute quantification for clinical routine is presently uncertain., (Copyright © 2020 Shiyam Sundar, Baajour, Beyer, Lanzenberger, Traub-Weidinger, Rausch, Pataraia, Hahn, Rischka, Hienert, Klebermass and Muzik.)

We describe a fully automated processing pipeline to support the noninvasive absolute quantification of the cerebral metabolic rate for glucose (CMRGlc) in a clinical setting. This pipeline takes advantage of "anatometabolic" information associated with fully integrated PET/MRI. Methods: Ten healthy volunteers (5 men and /5 women; 27 ± 7 y old; 70 ± 10 kg) underwent a test-retest 18 F-FDG PET/MRI examination of the brain. The imaging protocol consisted of a 60-min PET list-mode acquisition with parallel MRI acquisitions, including 3-dimensional time-of-flight MR angiography, MRI navigators, and a T1-weighted MRI scan. State-of-the-art MRI-based attenuation correction was derived from T1-weighted MRI (pseudo-CT [pCT]). For validation purposes, a low-dose CT scan was also performed. Arterial blood samples were collected as the reference standard (arterial input function [AIF]). The developed pipeline allows the derivation of an image-derived input function (IDIF), which is subsequently used to create CMRGlc maps by means of a Patlak analysis. The pipeline also includes motion correction using the MRI navigator sequence as well as a novel partial-volume correction that accounts for background heterogeneity. Finally, CMRGlc maps are used to generate a normative database to facilitate the detection of metabolic abnormalities in future patient scans. To assess the performance of the developed pipeline, IDIFs extracted by both CT-based attenuation correction (CT-IDIF) and MRI-based attenuation correction (pCT-IDIF) were compared with the reference standard (AIF) using the absolute percentage difference between the areas under the curves as well as the absolute percentage difference in regional CMRGlc values. Results: The absolute percentage differences between the areas under the curves for CT-IDIF and pCT-IDIF were determined to be 1.4% ± 1.0% and 3.4% ± 2.6%, respectively. The absolute percentage difference in regional CMRGlc values based on CT-IDIF and pCT-IDIF differed by less than 6% from the reference values obtained from the AIF. Conclusion: By taking advantage of the capabilities of fully integrated PET/MRI, we developed a fully automated computational pipeline that allows the noninvasive determination of regional CMRGlc values in a clinical setting. This methodology might facilitate the proliferation of fully quantitative imaging into the clinical arena and, as a result, might contribute to improved diagnostic efficacy., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

The purpose of this study was to establish a non-invasive clinical PET/MR protocol using [ 18 F]-labeled deoxyglucose (FDG) that provides physicians with regional metabolic rate of glucose (MRGlc) values and to clarify the contribution of absolute quantification to clinical management of patients with non-lesional extratemporal lobe epilepsy (ETLE). The study included a group of 15 patients with non-lesional ETLE who underwent a dynamic FDG PET study using a fully-integrated PET/MRI system (Siemens Biograph). FDG tracer uptake images were converted to MRGlc (μmol/100 g/min) maps using an image derived input function that was extracted based on the combined analysis of PET and MRI data. In addition, the same protocol was applied to a group of healthy controls, yielding a normative database. Abnormality maps for ETLE patients were created with respect to the normative database, defining significant hypo- or hyper-metabolic regions that exceeded ±2 SD of normal regional mean MRGlc values. Abnormality maps derived from MRGlc images of ETLE patients contributed to the localization of hypo-metabolic areas against visual readings in 53% and increased the confidence in the original clinical readings in 33% of all cases. Moreover, quantification allowed identification of hyper-metabolic areas that are associated with frequently spiking cortex, rarely acknowledged in clinical readings. Overall, besides providing some confirmatory information to visual readings, quantitative PET imaging demonstrated only a moderate impact on clinical management of patients with complex pathology that leads to epileptic seizures, failing to provide new decisive information that would have changed classification of patients from being rejected to being considered for surgical intervention., (Copyright © 2020 Traub-Weidinger, Muzik, Sundar, Aull-Watschinger, Beyer, Hacker, Hahn, Kasprian, Klebermass, Lanzenberger, Mitterhauser, Pilz, Rausch, Rischka, Wadsak and Pataraia.)

Aim: To assess if tumour grading based on dynamic [18F]FET positron emission tomography/magnetic resonance imaging (PET/MRI) studies is affected by different MRI-based attenuation correction (AC) methods., Methods: Twenty-four patients with suspected brain tumours underwent dynamic [18F]FET-PET/MRI examinations and subsequent low-dose computed tomography (CT) scans of the head. The dynamic PET data was reconstructed using the following AC methods: standard Dixon-based AC and ultra-short echo time MRI-based AC (MR-AC) and a model-based AC approach. All data were reconstructed also using CT-based AC (reference). For all lesions and reconstructions, time-activity curves (TACs) and time to peak (TTP) were extracted using different region-of-interest (ROI) and volume-of-interest (VOI) definitions. According to the most common evaluation approaches, TACs were categorised into two or three distinct curve patterns. Changes in TTP and TAC patterns compared to PET using CT-based AC were reported., Results: In the majority of cases, TAC patterns did not change. However, TAC pattern changes as well as changes in TTP were observed in up to 8% and 17% of the cases when using different MR-AC methods and ROI/VOI definitions, respectively. However, these changes in TTP and TAC pattern were attributed to different delineations of the ROIs/VOIs in PET corrected with different AC methods., Conclusion: PET/MRI using different MR-AC methods can be used for the assessment of TAC patterns in dynamic [18F]FET studies, as long as a meaningful delineation of the area of interest within the tumour is ensured., Key Points: • PET/MRI using different MR-AC methods can be used for dynamic [18F]FET studies. • A meaningful segmentation of the area of interest needs to be ensured, mandating a visual validation of the delineation by an experienced reader.

Absolute quantification of PET brain imaging requires the measurement of an arterial input function (AIF), typically obtained invasively via an arterial cannulation. We present an approach to automatically calculate an image-derived input function (IDIF) and cerebral metabolic rates of glucose (CMRGlc) from the [18F]FDG PET data using an integrated PET/MRI system. Ten healthy controls underwent test-retest dynamic [18F]FDG-PET/MRI examinations. The imaging protocol consisted of a 60-min PET list-mode acquisition together with a time-of-flight MR angiography scan for segmenting the carotid arteries and intermittent MR navigators to monitor subject movement. AIFs were collected as the reference standard. Attenuation correction was performed using a separate low-dose CT scan. Assessment of the percentage difference between area-under-the-curve of IDIF and AIF yielded values within ±5%. Similar test-retest variability was seen between AIFs (9 ± 8) % and the IDIFs (9 ± 7) %. Absolute percentage difference between CMRGlc values obtained from AIF and IDIF across all examinations and selected brain regions was 3.2% (interquartile range: (2.4-4.3) %, maximum < 10%). High test-retest intravariability was observed between CMRGlc values obtained from AIF (14%) and IDIF (17%). The proposed approach provides an IDIF, which can be effectively used in lieu of AIF.

Introduction: Radiochemists/radiopharmacists, involved in the preparation of radiopharmaceuticals are regularly confronted with the requirement of continuous high quality productions in their day-to-day business. One of these requirements is high specific or molar activity of the radiotracer in order to avoid e.g. receptor saturation and pharmacological or even toxic effects of the applied tracer for positron emission tomography. In the case of 11 C-labeled radiotracers, the reasons for low molar activity are manifold and often the search for potential 12 C-contaminations is time-consuming., Methods: In this study, diverse 12 C-contaminations were analyzed and quantified, which occurred during >450 syntheses of six PET tracers using [ 11 C]CO 2 or [ 11 C]CH 3 I generated via the gas phase method in a commercially available synthesizer. Additionally, non-radioactive syntheses were performed in order to identify the origins of carbon-12., Results: The manifold contributions to low molar activity can be attributed to three main categories, namely technical parameters (e.g. quality of target gases, reagents or tubings), inter/intralaboratory parameters (e.g. maintenance interval, burden of the module, etc.) and interoperator parameters (e.g. handling of the module)., Conclusion: Our study provides a better understanding of different factors contributing to the overall carbon load of a synthesis module, which facilitates maintenance of high molar activity of carbon-11-labeled radiopharmaceuticals., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Recent studies have shown that tumor vascular endothelial cells and various tumor cells overexpress receptors for vascular endothelial growth factor (VEGF). The aim of this study was to investigate the prognostic value of [ 123 I]-VEGF scintigraphy in patients with histologically verified brain tumors., Methods: 23 consecutive patients (9 women and 14 men aged 30-83 years, mean age 56.6 ± 14.4 years) with histopathologically-verified primary brain tumors were included in the study. All patients had undergone [ 123 I]-VEGF scintigraphy. SPECT examinations of brain were performed 30 min and 18 h after injection. Additional [ 11 C]-methionine PET ([ 11 C]-MET PET) was performed in eight of the 23 patients. Both [ 123 I]-VEGF and [ 11 C]-MET PET were evaluated visually and semiquantitatively by tumor-to-normal brain uptake ratio (T/N ratio). Thresholds of the T/N ratio were evaluated by analysis of receiver operating characteristics (ROC). Overall survival (OS) was estimated using the Kaplan-Meier method., Results: World Health Organization (WHO) grade IV glioma lesions showed [ 123 I]-VEGF uptake 18 h after the injection, whereas other brain tumors of grade II or III showed negative results. There was no significant difference in the tumor size between VEGF positive and VEGF negative tumors. Patients with [ 123 I]-VEGF T/N ratio threshold <1.32 showed significantly longer survival than patients with T/N ratio ≥ 1.32 (2680 days vs 295 days; P < 0.05). In the subgroup of 16 grade IV glioma patients, significant OS differences were found using a T/N ratio of 1.75 as threshold (T/N ratio < 1.75: 720 days; T/N ≥ 1.75: 183 days; P < 0.05). Significant difference (P < 0.05) was also found in [ 11 C]-MET PET T/N ratios between the grade IV glioma (mean T/N ratio: 3.71) and the grade II or III glioma (mean T/N ratio: 1.74)., Conclusion: Our results suggest that [ 123 I]-VEGF scintigraphy may be useful for visualization of tumor angiogenesis. In addition, [ 123 I]-VEGF may provide relevant prognostic information in patients with glioma.

Radiosynthetic optimization is crucial in routine PET production but is often neglected in literature. Small changes in the radiochemical procedure can increase the yield significantly and reduce time fluctuation within the synthetic procedure enabling better planning and product release on time. Therefore, a highly reproducible production method for L-[S-methyl- 11 C]methionine is presented, which uses a fully automated GE TRACERlab FX C Pro synthesizer. Evolution of the synthetic procedure lead to a protocol with a nearly doubled absolute yield., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background and Purpose: Asymmetry of the corticospinal tract in congenital lesions is a good prognostic marker for preserved motor function after hemispherectomy. This study aimed to assess this marker and provide a clinically feasible approach in selected cases of unilateral polymicrogyria., Materials and Methods: Corticospinal tract asymmetry of 9 patients with unilateral polymicrogyria substantially affecting the central region was retrospectively assessed on axial T1WI and DTI. Volumes of the brain stem and thalamus and DTI parameters of the internal capsule were measured. Two neuroradiologists independently rated the right-left asymmetry at 4 levels along the corticospinal tract. DTI tractography was used to determine the motor cortex within polymicrogyria, with task-based functional MR imaging available in 3/9 cases., Results: Visual assessment of the brain stem asymmetry showed excellent correlation with quantitative measures on both T1WI and color-coded DTI maps ( P = .007 and P = .023). Interrater reliability regarding structural and DTI-based corticospinal tract asymmetry was best at the midbrain (Cohen κ = 0.77, P = .018). Three patients underwent functional hemispherectomy with postsurgical stable motor function, all showing marked corticospinal tract asymmetry preoperatively. Following the DTI-based corticospinal tract trajectories allowed identifying the presumed primary motor region within the dysplastic cortex in 9/9 patients, confirmed by functional MR imaging in 3/3 cases., Conclusions: Visual assessment of corticospinal tract asymmetry in unilateral polymicrogyria involving the motor cortex is most reliable with T1WI and color-coded DTI maps at the level of the midbrain. Pronounced asymmetry predicts preserved motor function after hemispherectomy. DTI-based tractography can be used as a guidance tool to the motor cortex within polymicrogyria., (© 2018 by American Journal of Neuroradiology.)

Gliomas are the most common type of tumor in the brain. Although the definite diagnosis is routinely made ex vivo by histopathologic and molecular examination, diagnostic work-up of patients with suspected glioma is mainly done using MRI. Nevertheless, l- S -methyl- 11 C-methionine ( 11 C-MET) PET holds great potential in the characterization of gliomas. The aim of this study was to establish machine-learning-driven survival models for glioma built on in vivo 11 C-MET PET characteristics, ex vivo characteristics, and patient characteristics. Methods: The study included 70 patients with a treatment-naïve glioma that was 11 C-MET-positive and had histopathology-derived ex vivo feature extraction, such as World Health Organization 2007 tumor grade, histology, and isocitrate dehydrogenase 1 R132H mutational status. The 11 C-MET-positive primary tumors were delineated semiautomatically on PET images, followed by the extraction of tumor-to-background-based general and higher-order textural features by applying 5 different binning approaches. In vivo and ex vivo features, as well as patient characteristics (age, weight, height, body mass index, Karnofsky score), were merged to characterize the tumors. Machine-learning approaches were used to identify relevant in vivo, ex vivo, and patient features and their relative weights for predicting 36-mo survival. The resulting feature weights were used to establish 3 predictive models per binning configuration: one model based on a combination of in vivo, ex vivo, and clinical patient information (M36 IEP ); another based on in vivo and patient information only (M36 IP ); and a third based on in vivo information only (M36 I ). In addition, a binning-independent model based on ex vivo and patient information only (M36 EP ) was created. The established models were validated in a Monte Carlo cross-validation scheme. Results: The most prominent machine-learning-selected and -weighted features were patient-based and ex vivo-based, followed by in vivo-based. The highest areas under the curve for our models as revealed by the Monte Carlo cross-validation were 0.9 for M36 IEP , 0.87 for M36 EP , 0.77 for M36 IP , and 0.72 for M36 I Conclusion: Prediction of survival in amino acid PET-positive glioma patients was highly accurate using computer-supported predictive models based on in vivo, ex vivo, and patient features., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Few data exist regarding the prognostic value of L-[S-methyl-11C]methionine (MET) PET for treatment-naïve gliomas., Methods: A total of 160 glioma patients (89 men, 71 women; mean age: 45, range 18-84 y) underwent a MET PET prior to any therapy. The PET scans were evaluated visually and semiquantitatively by tumor-to-background (T/N) ratio thresholds chosen by analysis of receiver operating characteristics. Additionally, isocitrate dehydrogenase 1-R132H (IDH1-R132H) immunohistochemistry was performed. Survival analysis was done using Kaplan-Meier estimates and the Cox proportional hazards model., Results: Significantly shorter mean survival times (7.2 vs 8.6 y; P = 0.024) were seen in patients with amino acid avid gliomas (n = 137) compared with visually negative tumors (n = 33) in MET PET. T/N ratio thresholds of 2.1 and 3.5 were significantly associated with survival (10.3 vs 7 vs 4.3 y; P < 0.001). Mean survival differed significantly using the median T/N ratio of 2.4 as cutoff, independent of histopathology (P < 0.01; mean survival: 10.2 ± 0.8 y vs 5.5 ± 0.6 y). In the subgroup of 142 glioma patients characterized by IDH1-R132H status, METT/N ratio demonstrated a significant prognostic impact in IDH1-R132H wildtype astrocytomas and glioblastoma (P = 0.001). Additionally, multivariate testing revealed semiquantitative MET PET as an independent prognostic parameter for treatment-naïve glioma patients without (P = 0.031) and with IDH1-R132H characterization of gliomas (P = 0.024; odds ratio 1.57)., Conclusion: This retrospective analysis demonstrates the value of MET PET as a prognostic parameter on survival in treatment-naïve glioma patients., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Purpose: About 10% of patients with neurofibromatosis type 1 (NF-1) develop malignant peripheral nerve sheath tumours (MPNST) mostly arising in plexiform neurofibroma (PN); 15% of MPNST arise in children and adolescents. 2-[ 18 F]fluoro-2-deoxy-d-glucose ([ 18 F]FDG)-PET (where PET is positron emission tomography) is a sensitive method in differentiating PN and MPNST in symptomatic patients with NF-1. This study assesses the value of [ 18 F]FDG-PET imaging in detecting malignant transformation in symptomatic and asymptomatic children with PN., Methods: Forty-one patients with NF-1 and extensive PN underwent prospective [ 18 F]FDG imaging from 2003 to 2014. Thirty-two of the patients were asymptomatic. PET data, together with histological results and clinical course were re-evaluated retrospectively. Maximum standardised uptake values (SUVmax) and lesion-to-liver ratio were assessed., Results: A total of 104 examinations were performed. Mean age at first PET was 13.5 years (2.6-22.6). Eight patients had at least one malignant lesion; four of these patients were asymptomatic. Two of four symptomatic patients died, while all patients with asymptomatic malignant lesions are alive. All malignant tumours could be identified by PET imaging in both symptomatic and asymptomatic patients. All lesions judged as benign by [ 18 F]FDG imaging and clinical judgment were either histologically benign if removed or remained clinically silent during follow-up. SUVmax of malignant and benign lesions overlapped, but no malignant lesion showed FDG uptake ≤3.15. Asymptomatic malignant lesions were detected with a sensitivity of 100%, a negative predictive value of 100% and a specificity of 45.1%., Conclusion: Malignant transformation of PN also occurs in asymptomatic children and adolescents. Detection of MPNST at early stages could increase the possibility of oncologically curative resections., (© 2017 Wiley Periodicals, Inc.)

Purpose: To investigate whether elevated glucose metabolism in neurofibroma, determined by [F18]-FDG-PET, is correlated with cell density in MRI, as expressed through the apparent diffusion coefficient., Materials and Methods: Patients diagnosed with neurofibromatosis type 1 and peripheral nerve sheath tumors (PNST) were enrolled in this prospective, IRB-approved study. After a single [F18]-FDG injection, patients consecutively underwent [F18]-FDG-PET/CT and [F18]-FDG-PET/MRI on the same day. Maximum and mean standardized uptake values (SUVmax, SUVmean) on [F18]-FDG-PET/CT and [F18]-FDG-PET/MRI were compared, and correlated with minimum and mean apparent diffusion coefficients (ADCmean, ADCmin)., Results: A total of 12 (6 male/6 female, mean age was 16.2 ± 5.2 years) patients were prospectively included and analyzed on a per-lesion (n = 39) basis. The SUVmean of examined PNST showed a moderate negative correlation with the ADCmean (r = -.441) and ADCmin (r = -.477), which proved to be statistically significant (p = .005 and p = .002). The SUVmax of the respective lesions, however, showed a weaker negative correlation for ADCmean (r: -.311) and ADCmin (r: -.300) and did not reach statistical significance (p = .054 and p = .057). Lesion-based correlation between [F18]-FDG-PET/MRI and [F18]-FDG-PET/CT showed a moderate correlation for SUVmax (r = .353; p = .027) and a strong one for SUVmean (r = .879; p = .001)). Patient-based liver uptake (SUVmax and mean) of [F18]-FDG-PET/MRI and [F18]-FDG-PET/CT were strongly positively correlated (r = .827; p < .001 and r = .721; p < .001) but differed significantly (p < .001)., Conclusions: We found a statistically significant, negative correlation between glucose metabolism and cell density in PNST. Thus, ADCmean and ADCmin could possibly add complimentary information to the SUVmax and SUVmean and may serve as a potential determinant of malignant transformation of PNST.

Objectives: To evaluate and compare the effect of reduced acquisition time, as a surrogate of injected activity, on the PET quantification accuracy in PET/CT and PET/MR imaging., Methods: Twenty min 18 F-FDG phantom measurements and 10min 18 F-FET brain scans were acquired in a Biograph-True-Point-True-View PET/CT (n=8) and a Biograph mMR PET/MR (n=16). Listmode data were repeatedly split into frames of 1min to 10min length and reconstructed using two different reconstruction settings of a 3D-OSEM algorithm: with post-filtering ("OSEM"), and without post-filtering but with resolution recovery ("PSF"). Recovery coefficients (RC max , RC A50 ) and standard uptake values (SUV max , SUV A50 ) were evaluated., Results: RC max (phantom) and SUV max (patients) increased significantly when reducing the frame duration. Significantly lower deviations were observed for RC A50 and SUV A50 , respectively, making them more appropriate to compare PET studies at different number of counts. No statistical significant differences were observed when using post-filtering and reducing the frame time to 4min (RC A50 , reference 20min, phantom) and to 3min (SUV A50 , reference 10min, patients)., Conclusions: For hybrid aminoacid brain imaging, frame duration (or injected activity) can potentially be reduced to 30% of the standard used in clinical routine without significant changes on the quantification accuracy of the PET images if adequate reconstruction settings and quantitative measures are used. Frame times below 4min in the NEMA phantom are not advisable to obtain quantitative and reproducible measures., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The aim of this study was to compare attenuation-correction (AC) approaches for PET/MRI in clinical neurooncology. Methods: Forty-nine PET/MRI brain scans were included: brain tumor studies using 18 F-fluoro-ethyl-tyrosine ( 18 F-FET) ( n = 31) and 68 Ga-DOTANOC ( n = 7) and studies of healthy subjects using 18 F-FDG ( n = 11). For each subject, MR-based AC maps (MR-AC) were acquired using the standard DIXON- and ultrashort echo time (UTE)-based approaches. A third MR-AC was calculated using a model-based, postprocessing approach to account for bone attenuation values (BD, noncommercial prototype software by Siemens Healthcare). As a reference, AC maps were derived from patient-specific CT images (CTref). PET data were reconstructed using standard settings after AC with all 4 AC methods. We report changes in diagnosis for all brain tumor patients and the following relative differences values (RDs [%]), with regards to AC-CTref: for 18 F-FET (A)-SUVs as well as volumes of interest (VOIs) defined by a 70% threshold of all segmented lesions and lesion-to-background ratios; for 68 Ga-DOTANOC (B)-SUVs as well as VOIs defined by a 50% threshold for all lesions and the pituitary gland; and for 18 F-FDG (C)-RD of SUVs of the whole brain and 10 anatomic regions segmented on MR images. Results: For brain tumor imaging (A and B), the standard PET-based diagnosis was not affected by any of the 3 MR-AC methods. For A, the average RDs of SUV mean were -10%, -4%, and -3% and of the VOIs 1%, 2%, and 7% for DIXON, UTE, and BD, respectively. Lesion-to-background ratios for all MR-AC methods were similar to that of CTref. For B, average RDs of SUV mean were -11%, -11%, and -3% and of the VOIs 1%, -4%, and -3%, respectively. In the case of 18 F-FDG PET/MRI (C), RDs for the whole brain were -11%, -8%, and -5% for DIXON, UTE, and BD, respectively. Conclusion: The diagnostic reading of PET/MR patients with brain tumors did not change with the chosen AC method. Quantitative accuracy of SUVs was clinically acceptable for UTE- and BD-AC for group A, whereas for group B BD was in accordance with CTref. Nevertheless, for the quantification of individual lesions large deviations to CTref can be observed independent of the MR-AC method used., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Introduction: In-vivo quantification of serotonin transporters (SERT) in human brain has been a mainstay of molecular imaging in the field of neuropsychiatric disorders and helped to explore the underpinnings of several medical conditions, therapeutic and environmental influences. The emergence of PET/MR hybrid systems and the heterogeneity of SERT binding call for the development of efficient methods making the investigation of larger or vulnerable populations with limited scanner time and simultaneous changes in molecular and functional measures possible. We propose [ 11 C]DASB bolus plus constant infusion for these applications and validate it against standard analyses of dynamic PET data., Methods: [ 11 C]DASB bolus/infusion optimization was performed on data acquired after [ 11 C]DASB bolus in 8 healthy subjects. Subsequently, 16 subjects underwent one scan using [ 11 C]DASB bolus plus constant infusion with K bol 160-179min and one scan after [ 11 C]DASB bolus for inter-method reliability analysis. Arterial blood sampling and metabolite analysis were performed for all scans. Distribution volumes (V T ) were obtained using Logan plots for bolus scans and ratios between tissue and plasma parent activity for bolus plus infusion scans for different time spans of the scan (V T-70 for 60-70min after start of tracer infusion, V T-90 for 75-90min, V T-120 for 100-120min) in 9 subjects. Omitting blood data, binding potentials (BP ND ) obtained using multilinear reference tissue modeling (MRTM2) and cerebellar gray matter as reference region were compared in 11 subjects., Results: A K bol of 160min was observed to be optimal for rapid equilibration in thalamus and striatum. V T-70 showed good intraclass correlation coefficients (ICCs) of 0.61-0.70 for thalamus, striatal regions and olfactory cortex with bias ≤5.1% compared to bolus scans. ICCs increased to 0.72-0.78 for V T-90 and 0.77-0.93 for V T-120 in these regions. BP ND-90 had negligible bias ≤2.5%, low variability ≤7.9% and ICCs of 0.74-0.87; BP ND-120 had ICCs of 0.73-0.90. Low-binding cortical regions and cerebellar gray matter showed a positive bias of ~8% and ICCs 0.57-0.68 at V T-90 . Cortical BP ND suffered from high variability and bias, best results were obtained for olfactory cortex and anterior cingulate cortex with ICC=0.74-0.75 for BP ND-90 . High-density regions amygdala and midbrain had a negative bias of -5.5% and -22.5% at V T-90 with ICC 0.70 and 0.63, respectively., Conclusions: We have optimized the equilibrium method with [ 11 C]DASB bolus plus constant infusion and demonstrated good inter-method reliability with accepted standard methods and for SERT quantification using both V T and BP ND in a range of different brain regions. With as little as 10-15min of scanning valid estimates of SERT V T and BP ND in thalamus, amygdala, striatal and high-binding cortical regions could be obtained. Blood sampling seems vital for valid quantification of SERT in low-binding cortical regions. These methods allow the investigation of up to three subjects with a single radiosynthesis., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Selective serotonin reuptake inhibitors (SSRIs) modulate serotonergic neurotransmission by blocking reuptake of serotonin from the extracellular space. Up to now, it remains unclear how SSRIs achieve their antidepressant effect. However, task-based and resting state functional magnetic resonance imaging studies, have demonstrated connectivity changes between brain regions. Here, we use positron emission tomography (PET) to quantify SSRI's main target, the serotonin transporter (SERT), and assess treatment-induced molecular changes in the interregional relation of SERT binding potential (BP ND ). Nineteen out-patients with major depressive disorder (MDD) and 19 healthy controls (HC) were included in this study. Patients underwent three PET measurements with the radioligand [ 11 C]DASB: (1) at baseline, (2) after a first SSRI dose; and (3) following at least 3 weeks of daily intake. Controls were measured once with PET. Correlation analyses were restricted to brain regions repeatedly implicated in MDD pathophysiology. After 3 weeks of daily SSRI administration a significant increase in SERT BP ND correlations of anterior cingulate cortex and insula with the amygdala, midbrain, hippocampus, pallidum and putamen ( p < 0.05; false discovery rate, FDR corrected) was revealed. No significant differences were found when comparing MDD patients and HC at baseline. These findings are in line with the clinical observation that treatment response to SSRIs is often achieved only after a latency of several weeks. The elevated associations in interregional SERT associations may be more closely connected to clinical outcomes than regional SERT occupancy measures and could reflect a change in the regional interaction of serotonergic neurotransmission during antidepressant treatment.

Altered serotonergic neurotransmission has been found to cause impulsive and aggressive behavior, as well as increased motor activity, all exemplifying key symptoms of ADHD. The main objectives of this positron emission tomography (PET) study were to investigate the serotonin transporter binding potential (SERT BP ND ) in patients with ADHD and to assess associations of SERT BP ND between the brain regions. 25 medication-free patients with ADHD (age ± SD; 32.39 ± 10.15; 10 females) without any psychiatric comorbidity and 25 age and sex matched healthy control subjects (33.74 ± 10.20) were measured once with PET and the highly selective and specific radioligand [ 11 C]DASB. SERT BP ND maps in nine a priori defined ROIs exhibiting high SERT binding were compared between groups by means of a linear mixed model. Finally, adopted from structural and functional connectivity analyses, we performed correlational analyses using regional SERT binding potentials to examine molecular interregional associations between all selected ROIs. We observed significant differences in the interregional correlations between the precuneus and the hippocampus in patients with ADHD compared to healthy controls, using SERT BP ND of the investigated ROIs (P < 0.05; Bonferroni corrected). When correlating SERT BP ND and age in the ADHD and the healthy control group, we confirmed an age-related decline in brain SERT binding in the thalamus and insula (R 2  = 0.284, R 2  = 0.167, Ps < 0.05; Bonferroni corrected). The results show significantly different interregional molecular associations of the SERT expression for the precuneus with hippocampus in patients with ADHD, indicating presumably altered functional coupling. Altered interregional coupling between brain regions might be a sensitive approach to demonstrate functional and molecular alterations in psychiatric conditions. Hum Brain Mapp 38:792-802, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Bioimaging of brain tumors using nuclear medicine techniques complements computed tomography (CT) and magnetic resonance imaging (MRI), thus allowing more accurate diagnosis in clinically ambiguous situations. Special tracers for positron emission tomography (PET) have been developed which allow monitoring and planning of therapy. PET data may provide also presurgical evidence with regard to the presence of clinically relevant molecular brain tumor biomarkers. Combined PET/CT and PET/MR hybrid imaging systems will further enhance bioimaging-based brain tumor analysis. The main aim of brain tumor surgery is maximal safe tumor resection with preservation of neurologic functions, and to relieve tumor-related symptoms. In deep-seated unresectable tumors, diagnostic biopsy may be the main surgical goal. Special pre- and intraoperative techniques and approaches, including multidisciplinary team approaches, have been developed to optimize these surgical goals. Differences in spectrum, biology, and clinical presentation of brain tumors in the pediatric patient population demand special surgical expertise to warrant optimal postoperative patient outcome., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Regional differences in posttranscriptional mechanisms may influence in vivo protein densities. The association of positron emission tomography (PET) imaging data from 112 healthy controls and gene expression values from the Allen Human Brain Atlas, based on post-mortem brains, was investigated for key serotonergic proteins. PET binding values and gene expression intensities were correlated for the main inhibitory (5-HT1A) and excitatory (5-HT2A) serotonin receptor, the serotonin transporter (SERT) as well as monoamine oxidase-A (MAO-A), using Spearman's correlation coefficients (rs) in a voxel-wise and region-wise analysis. Correlations indicated a strong linear relationship between gene and protein expression for both the 5-HT1A (voxel-wise rs = 0.71; region-wise rs = 0.93) and the 5-HT2A receptor (rs = 0.66; 0.75), but only a weak association for MAO-A (rs = 0.26; 0.66) and no clear correlation for SERT (rs = 0.17; 0.29). Additionally, region-wise correlations were performed using mRNA expression from the HBT, yielding comparable results (5-HT1Ars = 0.82; 5-HT2Ars = 0.88; MAO-A rs = 0.50; SERT rs = -0.01). The SERT and MAO-A appear to be regulated in a region-specific manner across the whole brain. In contrast, the serotonin-1A and -2A receptors are presumably targeted by common posttranscriptional processes similar in all brain areas suggesting the applicability of mRNA expression as surrogate parameter for density of these proteins., (© The Author 2016. Published by Oxford University Press.)

OBJECTIVE The objective of this study was to investigate whether fluorine-18 fluorodeoxyglucose PET ( 18 F-FDG PET) can help to predict seizure outcome after hemispherotomy and therefore may be useful in decision making and patient selection. METHODS Children and adolescents less than 18 years of age who underwent 18 F-FDG PET studies during presurgical evaluation prior to hemispherotomy and had follow-up data of at least 12 months after surgery were included. Seizure outcome was classified according to the recommendations of the International League Against Epilepsy. PET data were reevaluated by two specialists in nuclear medicine blinded to clinical data and to MRI. MRI studies were also reinterpreted visually by an experienced neuroradiologist blinded to clinical data and PET findings. RESULTS Thirty-five patients (17 girls) with a median age of 5 years (range 0.4-17.8 years) were evaluable. Of the 35 patients, 91.4% were seizure free after surgery, including 100% of those with unilateral 18 F-FDG-PET hypometabolism compared with only 75% of those with bilateral hypometabolism. With respect to MRI, seizure freedom after surgery was observed in 96.4% of the patients with unilateral lesions compared with only 71.4% in those with bilateral MRI lesions. The best seizure outcomes were noted in patients with unilateral findings in both PET and MRI (100% seizure freedom) whereas only 50% of those with bilateral findings in both imaging techniques were seizure free. Furthermore, 100% of the patients with unilateral PET hypometabolism and bilateral MRI findings were also seizure free, but only 87.5% of those with bilateral PET hypometabolism and unilateral MRI findings. CONCLUSIONS According to these results, candidate selection for hemispherotomy can be optimized by the use of 18 F-FDG PET as part of a multimodal presurgical evaluation program, especially in patients with inconsistent (bilateral) MRI findings.

The human brain exhibits marked hemispheric differences, though it is not fully understood to what extent lateralization of the epileptic focus is relevant. Preoperative [(18)F]FDG-PET depicts lateralization of seizure focus in patients with temporal lobe epilepsy and reveals dysfunctional metabolic brain connectivity. The aim of the present study was to compare metabolic connectivity, inferred from inter-regional [(18)F]FDG PET uptake correlations, in right-sided (RTLE; n = 30) and left-sided TLE (LTLE; n = 32) with healthy controls (HC; n = 31) using graph theory based network analysis. Comparing LTLE and RTLE and patient groups separately to HC, we observed higher lobar connectivity weights in RTLE compared to LTLE for connections of the temporal and the parietal lobe of the contralateral hemisphere (CH). Moreover, especially in RTLE compared to LTLE higher local efficiency were found in the temporal cortices and other brain regions of the CH. The results of this investigation implicate altered metabolic networks in patients with TLE specific to the lateralization of seizure focus, and describe compensatory mechanisms especially in the CH of patients with RTLE. We propose that graph theoretical analysis of metabolic connectivity using [(18)F]FDG-PET offers an important additional modality to explore brain networks.

Attention deficit hyperactivity disorder (ADHD) is a heterogeneous disorder with a strong genetic component. The norepinephrine transporter (NET) is a key target for ADHD treatment and the NET gene has been of high interest as a possible modulator of ADHD pathophysiology. Therefore, we conducted an imaging genetics study to examine possible effects of single nucleotide polymorphisms (SNPs) within the NET gene on NET nondisplaceable binding potential (BPND ) in patients with ADHD and healthy controls (HCs). Twenty adult patients with ADHD and 20 HCs underwent (S,S)-[18F]FMeNER-D2 positron emission tomography (PET) and were genotyped on a MassARRAY MALDI-TOF platform using the Sequenom iPLEX assay. Linear mixed models analyses revealed a genotype-dependent difference in NET BPND between groups in the thalamus and cerebellum. In the thalamus, a functional promoter SNP (-3081 A/T) and a 5'-untranslated region (5'UTR) SNP (-182 T/C), showed higher binding in ADHD patients compared to HCs depending on the major allele. Furthermore, we detected an effect of genotype in HCs, with major allele carriers having lower binding. In contrast, for two 3'UTR SNPs (*269 T/C, *417 A/T), ADHD subjects had lower binding in the cerebellum compared to HCs depending on the major allele. Additionally, symptoms of hyperactivity and impulsivity correlated with NET BPND in the cerebellum depending on genotype. Symptoms correlated positively with cerebellar NET BPND for the major allele, while symptoms correlated negatively to NET BPND in minor allele carriers. Our findings support the role of genetic influence of the NE system on NET binding to be pertubated in ADHD., (© 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.)

Purpose: Radiolabelled somatostatin (SST) analogues have proven useful in diagnosing tumours positive for SST receptor (SSTR). As different subtypes of SSTR are expressed on the tumour cell surface, the choice of appropriate therapeutic SST analogue is crucial. We evaluated the SSTR status of thyroid cancer patients who had signs of progressive disease comparing different SSTR ligands for PET imaging to evaluate possible further therapeutic options., Methods: PET with (68)Ga-radiolabelled SSTR ligands DOTA lanreotide (DOTA-LAN), DOTA-Tyr(3) octreotide (DOTA-TOC) and (18)F-FDG was performed in 31 patients with thyroid cancer (TC). These 31 patients comprised 18 with radioiodine non-avid differentiated TC (DTC) including 6 papillary TC (PTC), 8 follicular TC (FTC) and 4 oxyphilic TC (oxyTC), 5 with anaplastic TC (ATC), and 8 with medullary TC (MTC). The PET results were compared in a region-based evaluation., Results: All patients underwent a PET study with (68)Ga-DOTA-LAN, 28 patients with (68)Ga-DOTA-TOC and 28 patients with (18)F-FDG. A lack of SSTR expression was found in 13 of the 31 patients (42%) with negative results with both SSTR tracers in 12 patients. Ambiguous results with both SSTR tracers were observed in one patient. High tracer uptake in SSTR PET images was seen in seven DTC patients (39%; two PTC, three FTC, two oxyTC), in four ATC patients (80%) and in six MTC patients (75%). Lesions showing aerobic glycolysis on (18)F-FDG PET were found in 24 of 28 patients (86%) with corresponding positive results with (68)Ga-DOTA-LAN in 35% and with (68)Ga-DOTA-TOC in 29%., Conclusion: The heterogeneous SSTR profile of TC tumour lesions needs to be evaluated using different SSTR PET tracers to characterize more closely the SSTR subtype affinities in patients with progressive TC in order to further stratify therapy with SSTR therapeutics.

Background: Corticobasal degeneration (CBD) is characterized by neuronal and glial deposition of 4-repeat tau in the frontal and parietal cerebral cortex, white matter and striatum. There is neuronal loss in affected cortical regions and in the substantia nigra (SN). Recent single photon emission tomography (SPECT) studies have reported normal striatal dopamine transporter (DAT) binding in individual patients with CBD., Objective: To study the pattern and course of DAT binding loss in CBD., Methods: We retrospectively analyzed DAT SPECT studies in two patients presenting with a corticobasal syndrome in whom a diagnosis of CBD was later confirmed pathologically., Results: Baseline scans at 1.5 years after symptom onset revealed only mild abnormalities (reduced uptake in one putamen). Follow up scans at 4.5 years (Case 1) and 5 years (Case 2) after symptom onset showed a marked decline of striatal DAT binding. In both cases, there was a 37% binding reduction from the age-expected striatal binding value. Asymmetry of striatal DAT binding had increased from mild in the first SPECT studies to moderate at the time of their final imaging., Conclusion: CBD patients can have delayed neuronal loss in the SN. Follow up DAT imaging may be of value in patients with possible CBD and a normal baseline scan.

Dopamine transporter imaging is widely used for the differential diagnosis of parkinsonism. Only limited data are available on the relationship between striatal dopamine transporter binding and dopaminergic cell loss in the substantia nigra (SN). We analyzed postmortem SN cell counts in patients who had previously undergone dopamine transporter single-photon emission computed tomography (SPECT). Pathological diagnoses included Parkinson's disease (n = 1), dementia with Lewy bodies (n = 2), multiple system atrophy (n = 1), corticobasal degeneration (n = 2), atypical parkinsonism with multiple pathological conditions (n = 1), Alzheimer's disease (n = 1), and Creutzfeldt-Jakob disease (n = 1). [(12) (3) I]β-CIT SPECT had been performed in all subjects using a standardized protocol on the same triple-head gamma camera. The density of neuromelanin-containing and tyrosine hydroxylase-positive substantia nigra neurons/mm(2) was evaluated in paraffin-embedded tissue sections by morphometric methods. Mean disease duration at the time of dopamine transporter imaging was 2.3 years, and the mean interval from imaging to death was 29.3 months (range, 4-68 months). Visual analysis of dopamine transporter images showed reduced striatal uptake in all seven patients with neurodegenerative parkinsonism, but not in Alzheimer's and Creutzfeldt-Jakob disease cases. Averaged [(right+left)/2] striatal uptake was highly correlated with averaged SN cell counts (rs  = 0.98, P < 0.0005 for neuromelanin- and rs  = 0.96, P < 0.0005 for tyrosine hydroxylase-positive cells). Similar strong correlations were found in separate analyses for the right and left sides. Striatal dopamine transporter binding highly correlated with postmortem SN cell counts, confirming the validity of dopamine transporter imaging as an excellent in vivo marker of nigrostriatal dopaminergic degeneration., (© 2014 International Parkinson and Movement Disorder Society.)

Importance: Attention-deficit/hyperactivity disorder (ADHD) research has long focused on the dopaminergic system's contribution to pathogenesis, although the results have been inconclusive. However, a case has been made for the involvement of the noradrenergic system, which modulates cognitive processes, such as arousal, working memory, and response inhibition, all of which are typically affected in ADHD. Furthermore, the norepinephrine transporter (NET) is an important target for frequently prescribed medication in ADHD. Therefore, the NET is suggested to play a critical role in ADHD., Objective: To explore the differences in NET nondisplaceable binding potential (NET BPND) using positron emission tomography and the highly selective radioligand (S,S)-[18F]FMeNER-D2 [(S,S)-2-(α-(2-[18F]fluoro[2H2]methoxyphenoxy)benzyl)morpholine] between adults with ADHD and healthy volunteers serving as controls., Design, Setting, and Participants: Twenty-two medication-free patients with ADHD (mean [SD] age, 30.7 [10.4] years; 15 [68%] men) without psychiatric comorbidities and 22 age- and sex-matched healthy controls (30.9 [10.6] years; 15 [68%] men) underwent positron emission tomography once. A linear mixed model was used to compare NET BPND between groups., Main Outcomes and Measures: The NET BPND in selected regions of interest relevant for ADHD, including the hippocampus, putamen, pallidum, thalamus, midbrain with pons (comprising a region of interest that includes the locus coeruleus), and cerebellum. In addition, the NET BPND was evaluated in thalamic subnuclei (13 atlas-based regions of interest)., Results: We found no significant differences in NET availability or regional distribution between patients with ADHD and healthy controls in all investigated brain regions (F1,41<0.01; P=.96). Furthermore, we identified no significant association between ADHD symptom severity and regional NET availability. Neither sex nor smoking status influenced NET availability. We determined a significant negative correlation between age and NET availability in the thalamus (R2=0.29; P<.01 corrected) and midbrain with pons, including the locus coeruleus (R2=0.18; P<.01 corrected), which corroborates prior findings of a decrease in NET availability with aging in the human brain., Conclusions and Relevance: Our results do not indicate involvement of changes in brain NET availability or distribution in the pathogenesis of ADHD. However, the noradrenergic transmitter system may be affected on a different level, such as in cortical regions, which cannot be reliably quantified with this positron emission tomography ligand. Alternatively, different key proteins of noradrenergic neurotransmission might be affected.

Context: (99m)Tc-Methoxy-isobutyl-isonitrile (MIBI) scintigraphy is a standard preoperative localization imaging modality in patients with primary hyperparathyroidism (pHPT). Its accuracy in localizing a hyperactive parathyroid gland after previous cervical surgery is limited. Recently, (11)C-methionine has been introduced as a promising radiotracer for pHPT imaging. Yet, few data exist for this technique in patients with persisting or recurrent pHPT before reoperation., Objectives: We aimed to investigate the ability of (11)C-methionine positron emission tomography (PET)/computed tomography (CT) to localize a parathyroid disorder after cervical surgery and negative postsurgical (99m)Tc-MIBI single-photon emission CT (SPECT)/CT., Design, Setting, and Participants: Fifteen patients (6 males, 9 females; age range, 36-85 years) with pHPT and negative (99m)Tc-MIBI SPECT/CT who had undergone earlier neck surgery because of pHPT and/or thyroid disorder were recruited. Twelve of the 15 patients had thyroidectomy for goiter or differentiated thyroid carcinoma. Ten patients had previous parathyroid surgery for pHPT, and 2 patients had a history of parathyroid carcinoma. Thirteen of 15 patients showed elevated levels of intact PTH at the time of PET/CT imaging, whereas all patients had elevated serum calcium values., Main Outcome Measurements: Pathological results of contrast-enhanced (11)C-methionine PET/CT and surgical results were evaluated., Results: In 6 of 15 patients (11)C-methionine PET/CT showed a hypermetabolic focus in the upper mediastinum in 2 patients, in the thoracic outlet in 1 patient, and in the cervical region in 3 patients. In 9 of the 15 patients, no hyperactive parathyroid gland could be visualized. Reoperation was performed in 5 of 6 patients without surgical complications. One patient refused surgery. In 2 of the 5 patients, a transsternal procedure was performed. Correlating with the (11)C-methionine PET/CT results, a single parathyroid adenoma was found in 4 patients and parathyroid carcinoma metastasis in 1 patient., Conclusion: (11)C-Methionine PET/CT is a useful complementary imaging technique to localize parathyroid adenoma or carcinoma in (99m)Tc-MIBI SPECT/CT-negative patients.