PET imaging of the neurovascular interface in cerebrovascular disease

Cerebrovascular disease encompasses a range of pathologies affecting different components of the cerebral vasculature and brain parenchyma. Large artery atherosclerosis, acute cerebral ischaemia, and intracerebral small vessel disease all demonstrate metabolic processes that are key to pathogenesis. Although structural imaging has been a mainstay of stroke clinical care and research, it has limited ability to detect these pathophysiological processes in vivo. Positron emission tomography (PET) provides a means to detect and quantify metabolic processes in each facet of cerebrovascular disease non-invasively. The use of PET has helped shape the understanding of key concepts in cerebrovascular medicine, including the vulnerable atherosclerotic plaque, salvageable ischaemic penumbra, neuroinflammation and selective neuronal loss after ischaemic insult, and the relationships between chronic hypoxia, neuroinflammation, and amyloid deposition in cerebral small vessel disease. This review considers how the ability to image these processes at the neurovascular interface has contributed to our understanding of cerebrovascular disease and facilitated translational research to advance clinical care.N.R.E. is supported by a research training fellowship from The Dunhill Medical Trust (grant number RTF44/0114). J.M.T. is supported by a Wellcome Trust research training fellowship (104492/Z/14/Z). J.H.F.R. is part-supported by the Higher Education Funding Council for England (HEFCE), the British Heart Foundation, and the Wellcome Trust. H.S.M. is supported by the Medical Research Council (MRC) as a National Institute for Health Research (NIHR) Senior Investigator. E.A.W. is supported by the British Heart Foundation. H.S.M., J.H.F.R., and E.A.W. are supported by the NIHR Cambridge Biomedical Research Centre

Targeted Molecular Imaging in Adrenal Disease—An Emerging Role for Metomidate PET-CT

Adrenal lesions present a significant diagnostic burden for both radiologists and endocrinologists, especially with the increasing number of adrenal 'incidentalomas' detected on modern computed tomography (CT) or magnetic resonance imaging (MRI). A key objective is the reliable distinction of benign disease from either primary adrenal malignancy (e.g., adrenocortical carcinoma or malignant forms of pheochromocytoma/paraganglioma (PPGL)) or metastases (e.g., bronchial, renal). Benign lesions may still be associated with adverse sequelae through autonomous hormone hypersecretion (e.g., primary aldosteronism, Cushing's syndrome, phaeochromocytoma). Here, identifying a causative lesion, or lateralising the disease to a single adrenal gland, is key to effective management, as unilateral adrenalectomy may offer the potential for curing conditions that are typically associated with significant excess morbidity and mortality. This review considers the evolving role of positron emission tomography (PET) imaging in addressing the limitations of traditional cross-sectional imaging and adjunctive techniques, such as venous sampling, in the management of adrenal disorders. We review the development of targeted molecular imaging to the adrenocortical enzymes CYP11B1 and CYP11B2 with different radiolabeled metomidate compounds. Particular consideration is given to iodo-metomidate PET tracers for the diagnosis and management of adrenocortical carcinoma, and the increasingly recognized utility of $^{11}$C-metomidate PET-CT in primary aldosteronism.NIHR Cambridge Biomedical Research Centr

99mTc-IgG-Lung Scintigraphy in the Assessment of Pulmonary Involvement in Interstitial Lung Disease and Its Comparison With Pulmonary Function Tests and High-Resolution Computed Tomography: A Preliminary Study

Background: The discrimination of inactive inflammatory processes from the active form of the disease is of great importance in the management of interstitial lung disease (ILD). Objectives: The aim of this study was to determine the efficacy of 99mTc-IgG scan for the detection of severity of disease compared to high-resolution computed tomography (HRCT) and pulmonary function test (PFT). Patients and Methods: Eight known cases of ILD including four cases of Mustard gas (MG) intoxication and four patients with ILD of unknown cause were included in this study. A population of six patients without lung disease was considered as the control group. The patients underwent PFT and high-resolution computed tomography scan, followed by 99mTc-IgG scan. They were followed up for one year. 99mTc-IgG scan assessment of IgG uptake was accomplished both qualitatively (subjectively) and semiquantitatively. Results: All eight ILD patients demonstrated a strong increase in 99mTc-IgG uptake in the lungs, compared to the control patients. The 99mTc-IgG scan scores were higher in the patient group (0.64[95% confidence interval (CI)=0.61-0.69])) than the control group (0.35 (0.35[95% CI=0.28-0.40]), (P 0.05). There were no significant correlations between 99mTc-IgG score and HRCT patterns including ground glass opacity, reticular fibrosis and honeycombing (P value > 0.05). Conclusion: The present results confirmed that 99mTc-IgG scan could be applied to detect the severity of pulmonary involvement, which was well correlated with HRCT findings. This data also showed that the 99mTc-IgG scan might be used as a complement to HRCT in the functional evaluation of the clinical status in ILD; however, further studies are recommended

Combined approach of perioperative 18F-FDG PET/CT imaging and intraoperative 18F-FDG handheld gamma probe detection for tumor localization and verification of complete tumor resection in breast cancer

<p>Abstract</p> <p>Background</p> <p>¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography/computed tomography (PET/CT) has become an established method for detecting hypermetabolic sites of known and occult disease and is widely used in oncology surgical planning. Intraoperatively, it is often difficult to localize tumors and verify complete resection of tumors that have been previously detected on diagnostic PET/CT at the time of the original evaluation of the cancer patient. Therefore, we propose an innovative approach for intraoperative tumor localization and verification of complete tumor resection utilizing ¹⁸F-FDG for perioperative PET/CT imaging and intraoperative gamma probe detection.</p> <p>Methods</p> <p>Two breast cancer patients were evaluated. ¹⁸F-FDG was administered and PET/CT was acquired immediately prior to surgery. Intraoperatively, tumors were localized and resected with the assistance of a handheld gamma probe. Resected tumors were scanned with specimen PET/CT prior to pathologic processing. Shortly after the surgical procedure, patients were re-imaged with PET/CT utilizing the same preoperatively administered ¹⁸F-FDG dose.</p> <p>Results</p> <p>One patient had primary carcinoma of breast and a metastatic axillary lymph node. The second patient had a solitary metastatic liver lesion. In both cases, preoperative PET/CT verified these findings and demonstrated no additional suspicious hypermetabolic lesions. Furthermore, intraoperative gamma probe detection, specimen PET/CT, and postoperative PET/CT verified complete resection of the hypermetabolic lesions.</p> <p>Conclusion</p> <p>Immediate preoperative and postoperative PET/CT imaging, utilizing the same ¹⁸F-FDG injection dose, is feasible and image quality is acceptable. Such perioperative PET/CT imaging, along with intraoperative gamma probe detection and specimen PET/CT, can be used to verify complete tumor resection. This innovative approach demonstrates promise for assisting the oncologic surgeon in localizing and verifying resection of ¹⁸F-FDG positive tumors and may ultimately positively impact upon long-term patient outcomes.</p

Assessment of the efficacy and toxicity of 131I-metaiodobenzylguanidine therapy for metastatic neuroendocrine tumours

131I-metaiodobenzylguanidine (131I-MIBG) is a licensed palliative treatment for patients with metastatic neuroendocrine tumours. We have retrospectively assessed the consequences of 131I-MIBG therapy in 48 patients (30 gastroenteropancreatic, 6 pulmonary, 12 unknown primary site) with metastatic neuroendocrine tumours attending Royal Liverpool University Hospital between 1996 and 2006. Mean age at diagnosis was 57.6 years (range 34–81). 131I-MIBG was administered on 88 occasions (mean 1.8 treatments, range 1–4). Twenty-nine patients had biochemical markers measured before and after 131I-MIBG, of whom 11 (36.7%) showed >50% reduction in levels post-therapy. Forty patients had radiological investigations performed after 131I-MIBG, of whom 11(27.5%) showed reduction in tumour size post-therapy. Twenty-seven (56.3%) patients reported improved symptoms after 131I-MIBG therapy. Kaplan–Meier analysis showed significantly increased survival (P=0.01) from the date of first 131I-MIBG in patients who reported symptomatic benefit from therapy. Patients with biochemical and radiological responses did not show any statistically significant alteration in survival compared to non-responders. Eleven (22.9%) patients required hospitalisation as a consequence of complications, mostly due to mild bone marrow suppression. 131I-MIBG therefore improved symptoms in more than half of the patients with metastatic neuroendocrine tumours and survival was increased in those patients who reported a symptomatic response to therapy

Planar Tc99m – sestamibi scintimammography should be considered cautiously in the axillary evaluation of breast cancer protocols: Results of an international multicenter trial

BACKGROUND: Lymph node status is the most important prognostic indicator in breast cancer in recently diagnosed primary lesion. As a part of an interregional protocol using scintimammography with Tc99m compounds, the value of planar Tc99m sestamibi scanning for axillary lymph node evaluation is presented. Since there is a wide range of reported values, a standardized protocol of planar imaging was performed. METHODS: One hundred and forty-nine female patients were included prospectively from different regions. Their mean age was 55.1 ± 11.9 years. Histological report was obtained from 2.987 excised lymph nodes from 150 axillas. An early planar chest image was obtained at 10 min in all patients and a delayed one in 95 patients, all images performed with 740–925 MBq dose of Tc99m sestamibi. Blind lecture of all axillary regions was interpreted by 2 independent observers considering any well defined focal area of increased uptake as an involved axilla. Diagnostic values, 95% confidence intervals [CI] and also likelihood ratios (LR) were calculated. RESULTS: Node histology demonstrated tumor involvement in 546 out of 2987 lymph nodes. Sestamibi was positive in 30 axillas (25 true-positive) and negative in 120 (only 55 true-negative). The sensitivity corresponded to 27.8% [CI = 18.9–38.2] and specificity to 91.7% [81.6–97.2]. The positive and negative LR were 3.33 and 0.79, respectively. There was no difference between early and delayed images. Sensitivity was higher in patients with palpable lesions. CONCLUSION: This work confirmed that non tomographic Tc99m sestamibi scintimammography had a very low detection rate for axillary lymph node involvement and it should not be applied for clinical assessment of breast cancer

Neoadjuvant chemotherapy in breast cancer: early response prediction with quantitative MR imaging and spectroscopy.

A prospective study was undertaken in women undergoing neoadjuvant chemotherapy for locally advanced breast cancer in order to determine the ability of quantitative magnetic resonance imaging (MRI) and proton spectroscopy (MRS) to predict ultimate tumour response (percentage decrease in volume) or to detect early response. Magnetic resonance imaging and MRS were carried out before treatment and after the second of six treatment cycles. Pharmacokinetic parameters were derived from T1-weighted dynamic contrast-enhanced MRI, water apparent diffusion coefficient (ADC) was measured, and tissue water:fat peak area ratios and water T2 were measured using unsuppressed one-dimensional proton spectroscopic imaging (30 and 135 ms echo times). Pharmacokinetic parameters and ADC did not detect early response; however, early changes in water:fat ratios and water T2 (after cycle two) demonstrated substantial prognostic efficacy. Larger decreases in water T2 accurately predicted final volume response in 69% of cases (11/16) while maintaining 100% specificity and positive predictive value. Small/absent decreases in water:fat ratios accurately predicted final volume non-response in 50% of cases (3/6) while maintaining 100% sensitivity and negative predictive value. This level of accuracy might permit clinical application where early, accurate prediction of non-response would permit an early change to second-line treatment, thus sparing patients unnecessary toxicity, psychological morbidity and delay of initiation of effective treatment

Gastrin-releasing peptide receptor-based targeting using bombesin analogues is superior to metabolism-based targeting using choline for in vivo imaging of human prostate cancer xenografts

Purpose: Prostate cancer (PC) is a major health problem. Overexpression of the gastrin-releasing peptide receptor (GRPR) in PC, but not in the hyperplastic prostate, provides a promising target for staging and monitoring of PC. Based on the assumption that cancer cells have increased metabolic activity, metabolism-based tracers are also being used for PC imaging. We compared GRPR-based targeting using the68Ga-labelled bombesin analogue AMBA with metabolism-based tar

Detection of Atherosclerotic Inflammation by 68^{68}Ga-DOTATATE PET Compared to [18^{18}F]FDG PET Imaging

$\textbf{Background}$ Inflammation drives atherosclerotic plaque rupture. Although inflammation can be measured using fluorine-18-labeled fluorodeoxyglucose positron emission tomography ([$^{18}$F]FDG PET), [$^{18}$F]FDG lacks cell specificity, and coronary imaging is unreliable because of myocardial spillover. $\textbf{Objectives}$ Objectives This study tested the efficacy of gallium-68-labeled DOTATATE ($^{68}$Ga-DOTATATE), a somatostatin receptor subtype-2 (SST2)-binding PET tracer, for imaging atherosclerotic inflammation. $\textbf{Methods}$ We confirmed $^{68}$Ga-DOTATATE binding in macrophages and excised carotid plaques. $^{68}$Ga-DOTATATE PET imaging was compared to [$^{18}$F]FDG PET imaging in 42 patients with atherosclerosis. $\textbf{Results}$ Target $\textit{SSTR2}$ gene expression occurred exclusively in “proinflammatory” M1 macrophages, specific $^{68}$Ga-DOTATATE ligand binding to SST$_{2}$ receptors occurred in CD68-positive macrophage-rich carotid plaque regions, and carotid $\textit{SSTR2}$ mRNA was highly correlated with in vivo $^{68}$Ga-DOTATATE PET signals (r = 0.89; 95% confidence interval [CI]: 0.28 to 0.99; p = 0.02). $^{68}$Ga-DOTATATE mean of maximum tissue-to-blood ratios (mTBR$_{max}$) correctly identified culprit versus nonculprit arteries in patients with acute coronary syndrome (median difference: 0.69; interquartile range [IQR]: 0.22 to 1.15; p = 0.008) and transient ischemic attack/stroke (median difference: 0.13; IQR: 0.07 to 0.32; p = 0.003). $^{68}$Ga-DOTATATE mTBR$_{max}$ predicted high-risk coronary computed tomography features (receiver operating characteristics area under the curve [ROC AUC]: 0.86; 95% CI: 0.80 to 0.92; p < 0.0001), and correlated with Framingham risk score (r = 0.53; 95% CI: 0.32 to 0.69; p <0.0001) and [$^{18}$F]FDG uptake (r = 0.73; 95% CI: 0.64 to 0.81; p < 0.0001). [$^{18}$F]FDG mTBR$_{max}$ differentiated culprit from nonculprit carotid lesions (median difference: 0.12; IQR: 0.0 to 0.23; p = 0.008) and high-risk from lower-risk coronary arteries (ROC AUC: 0.76; 95% CI: 0.62 to 0.91; p = 0.002); however, myocardial [$^{18}$F]FDG spillover rendered coronary [$^{18}$F]FDG scans uninterpretable in 27 patients (64%). Coronary $^{68}$Ga-DOTATATE PET scans were readable in all patients. $\textbf{Conclusions}$ We validated $^{68}$Ga-DOTATATE PET as a novel marker of atherosclerotic inflammation and confirmed that $^{68}$Ga-DOTATATE offers superior coronary imaging, excellent macrophage specificity, and better power to discriminate high-risk versus low-risk coronary lesions than [$^{18}$F]FDG. (Vascular Inflammation Imaging Using Somatostatin Receptor Positron Emission Tomography [VISION]; NCT02021188)This study was funded by the Wellcome Trust and supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre and the Cambridge Clinical Trials Unit. Dr. Tarkin is supported by a Wellcome Trust research training fellowship (104492/Z/14/Z). Dr. Evans is supported by a Dunhill Medical Trust fellowship (RTF44/0114). Dr. Chowdhury is supported by Royal College of Surgeons of England and British Heart Foundation (BHF) fellowships (FS/16/29/31957). Drs. Manavaki and Warburton are supported by the NIHR Biomedical Research Centres. Drs. Yu and Frontini are supported by the BHF (RE/13/6/30180). Dr. Fryer is supported by Higher Education Funding Council for England (HEFCE). Dr. Groves is supported by the University College London Hospital NIHR Biomedical Research Centre; and has received grant support from GlaxoSmithKline. Dr. Ouwehand’s laboratory is funded by EU-FP7 project Blueprint (Health-F5-2011-282510), BHF (PG-0310-1002 and RG/09/12/28096), and National Health Service Blood and Transplant. Dr. Bennett is supported by NIHR and BHF. Dr. Davenport is supported by research grants from Wellcome Trust (107715/Z/15/Z), Medical Research Council (MC_PC_14116), and BHF (RE-13-6-3180). Dr. Rudd is supported by the NIHR, BHF, Wellcome Trust, and HEFCE

Impact of solitary pulmonary nodule size on qualitative and quantitative assessment using 18F-fluorodeoxyglucose PET/CT: the SPUTNIK trial

Purpose: To compare qualitative and semi-quantitative PET/CT criteria, and the impact of nodule size on the diagnosis of solitary pulmonary nodules in a prospective multicentre trial. / Methods: Patients with an SPN on CT ≥ 8 and ≤ 30 mm were recruited to the SPUTNIK trial at 16 sites accredited by the UK PET Core Lab. Qualitative assessment used a five-point ordinal PET-grade compared to the mediastinal blood pool, and a combined PET/CT grade using the CT features. Semi-quantitative measures included SUVmax of the nodule, and as an uptake ratio to the mediastinal blood pool (SURBLOOD) or liver (SURLIVER). The endpoints were diagnosis of lung cancer via biopsy/histology or completion of 2-year follow-up. Impact of nodule size was analysed by comparison between nodule size tertiles. / Results: Three hundred fifty-five participants completed PET/CT and 2-year follow-up, with 59% (209/355) malignant nodules. The AUCs of the three techniques were SUVmax 0.87 (95% CI 0.83;0.91); SURBLOOD 0.87 (95% CI 0.83; 0.91, p = 0.30 versus SUVmax); and SURLIVER 0.87 (95% CI 0.83; 0.91, p = 0.09 vs. SUVmax). The AUCs for all techniques remained stable across size tertiles (p > 0.1 for difference), although the optimal diagnostic threshold varied by size. For nodules  16 mm, an SUVmax ≥ 3.6 or visual PET uptake greater than the mediastinum was the most accurate. / Conclusion: In this multicentre trial, SUVmax was the most accurate technique for the diagnosis of solitary pulmonary nodules. Diagnostic thresholds should be altered according to nodule size. / Trial registration: ISRCTN - ISRCTN30784948. ClinicalTrials.gov - NCT0201306