Fast-track pathway for early diagnosis and management of giant cell arteritis: the combined role of vascular ultrasonography and [18F]-fluorodeoxyglucose PET-computed tomography imaging.

Giant cell arteritis (GCA) is a medical emergency, which can lead to irreversible blindness and other ischaemic vascular events if left untreated. Prompt access to specialist assessment, diagnostics in the form of a fast-track pathway (FTP) and access to appropriate treatment are key factors in preventing morbidity associated with this disease. Recent developments in vascular imaging prompted review of our management of GCA patients. Here, we present the newly implemented FTP in GCA at the University College London Hospital, with added vascular imaging in the form of temporal artery ultrasound (TAUS) and [18F]-fluorodeoxyglucose PET-computed tomography ( 18 F-FDG PET-CT) with temporal artery biopsy. The initial pilot data on the FTP showed a significant negative predictive value of the combined TAUS and 18 F-FDG PET-CT, and the vast majority of cases positive on imaging were confirmed by biopsy. Through the new FTP in GCA, the diagnosis was completed within 48-72 h, compared with the conventional pathway time of up to 2-3 weeks awaiting biopsy results. Prompt and accurate diagnosis of GCA enables commencement of corticosteroid (prednisolone) treatment in the appropriate patient population while avoiding unnecessary steroid exposure and toxicity in GCA-negative patients.

Renal protection during 177lutetium DOTATATE molecular radiotherapy in children: a proposal for safe amino acid infusional volume during peptide receptor radionuclide therapy.

Peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues such as 177-lutetium DOTATATE is an effective treatment modality for neuroendocrine tumours, paragangliomas, and neuroblastomas. However, renal and haematopoietic toxicities are the major limitations of this therapeutic approach. The renal toxicity of PRRT is mediated by renal proximal tubular reabsorption and interstitial retention of the radiolabelled peptides resulting in excessive renal irradiation that can be dose-limiting. To protect the kidneys from PRRT-induced radiation nephropathy, basic amino acids are infused during PRRT as they competitively bind to the proximal tubular cells and prevent uptake of the radionuclide. In adults, 1 L of a basic amino acid solution consisting of arginine and lysine is infused over 4 h commencing 30 min prior to PRRT. However, this volume of amino acids infused over 4 h is excessive in small children and can result in hemodynamic overload. This is all the more relevant in paediatric oncology, as many of the children may have been heavily pretreated and so may have treatment-related renal and or cardiac impairment. We have therefore developed the following guidelines for safe paediatric dosing of renal protective amino acid infusions during PRRT. Our recommendations have been made taking into consideration the renal physiology in small children and the principles of safe fluid management in children.

Is It Time to Call Time on Bone Marrow Biopsy for Staging Ewing Sarcoma (ES)?

Primary malignant bone sarcomas are rare and Ewing sarcoma (ES), along with osteosarcoma, predominates in teenagers and young adults. The well-established multimodality treatment incorporates systemic chemotherapy with local control in the form of surgery, with or without radiation. The presence and extent of metastases at diagnosis remains the most important prognostic factor in determining patient outcome; patients with skeletal metastases or bone marrow infiltration having a significantly worse outcome than those with lung metastases alone. There is, however, no accepted staging algorithm for ES. Large cooperative groups and national guidelines continue to advocate bone marrow biopsy (BMB) for staging but functional imaging techniques, such as 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) with computerised tomography (CT) have been increasingly used for staging cancers and whole-body magnetic resonance imaging (WB-MRI) for staging skeletal metastases. This review outlines the current literature, from which we conclude that BMB is no longer required for the staging of ES as it does not influence the standard of care management. BMB may, however, provide prognostic information and insights into the biology of ES in selected patients on prospective clinical trials.

Revalidation of PET/computed tomography criteria (Hopkins criteria) for the assessment of therapeutic response in lung cancer patients: inter-reader reliability, accuracy and survival outcomes.

BACKGROUND/AIM: Systematic reporting using qualitative evaluation of PET/computed tomography (CT) results has been demonstrated to be very accurate and reproducible in posttherapy assessment of lung cancer (so-called Hopkins criteria). Our aim was to test, in a different cohort of patients, the Hopkins criteria for assessment of therapeutic response in lung cancer and to compare the results with those obtained using a semi-quantitative evaluation of uptake. METHODS: This is a retrospective study. A total of 85 patients with known lung cancer who underwent fluorine-18 fluorodeoxyglucose PET/CT assessment within 24 weeks (mean 7.9 weeks) of completion of treatment were included. Treatments included surgical resection, chemotherapy, radiation therapy, immunotherapy or combinations thereof. PET/CT interpretation was done by two nuclear medicine physicians, and discrepancies were resolved by a third interpreter. Studies were scored both according to the Hopkins criteria using qualitative assessment of tracer uptake for the primary tumour, locoregional disease in the mediastinum and distant metastatic sites and by applying the same five-point score using a semi-quantitative measure, maximum standardized uptake value. Overall scores of 1, 2 and 3 were considered negative for residual disease, while scores of 4 and 5 were considered positive. Patients were followed up for a median of 18.5 months (range 2-139 months). Kaplan-Meier plots with a Mantel-Cox log-rank test were performed, considering death as the endpoint. Inter-reader variability was assessed using percent agreement and kappa statistics. RESULTS: The Cohen κ coefficient analysis showed substantial agreement between the two interpreters on the five-point Hopkins criteria scoring, with a κ of 0.73. There was almost perfect agreement between the interpreters with respect to classification as positive or negative according to the Hopkins criteria, with a κ of 0.89. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of the Hopkins criteria were 88.5% [95% confidence interval (CI) 80.6-96.5%), 79.2% (95% CI 63.2-95.1%), 91.5% (95% CI 84.4-98.6%), 73.1% (95% CI 61.8-84.4%) and 85.9% (95% CI 78.5-93.3%), respectively. There was almost perfect agreement between the qualitative and semi-quantitative scoring with a κ of 0.87, with sensitivity, specificity, positive predictive value, negative predictive value and accuracy of the semi-quantitative Hopkin's criteria of 86.9% (95% CI 78.4-95.4%), 79.2% (95% CI 62.9-95.4%), 91.4% (95% CI 84.2-98.6%), 70.4% (95% CI 58.6-82.1%) and 84.7% (95% CI 80.8-92.4%), respectively. CONCLUSION: The use of Hopkins criteria for posttherapy assessment in patients with lung cancer represents an easy and reproducible method with substantial to almost perfect interobserver agreement and high positive predictive value and accuracy; moreover, it is easily understood by referring physicians. Additionally, there was no significant difference when applying a semi-quantitative measure to the same five-point score.

Performing clinical 18F-FDG-PET/MRI of the mediastinum optimising a dedicated, patient-friendly protocol.

OBJECTIVE: To construct a mediastinal-specific fluorine-18-fluorodeoxyglucose (F-FDG)-PET/MR protocol with high-quality MRI of minimal acquisition-time and comparable diagnostic value to F-FDG-PET/computed tomography (CT). MATERIALS AND METHODS: Fifteen healthy participants received PET/MRI and 10 patients with mediastinal tumours (eight non-small-cell lung, two oesophageal cancer) received F-FDG-PET/MRI immediately after F-FDG-PET/CT. Sequences volume interpolated breath-hold examination (T1-VIBE) and Half-Fourier acquisition single-shot turbo spin echo (T2-HASTE) were optimised by varying the parameters: breath-hold (BH, end-expiration), fat suppression (spectral adiabatic inversion recovery), and ECG-triggering (ECG, end-diastole). Image quality (IQ) of each sequence-variation was qualitatively scored by medical experts and quantitatively assessed by calculating signal-to-noise ratios, contrast relative to muscle, standardized-uptake-value, and tumour-to-blood ratios. Patient comfort was evaluated on patients' experience. Diagnostic accuracy of F-FDG-PET/MRI was compared to F-FDG-PET/CT, in reference to histopathology/cytopathology. RESULTS: ECG-triggered T1-VIBE images showed the highest signal-to-noise ratio (P < 0.01) and the largest contrast between mediastinal soft-tissues, regardless of BH or free-breathing acquisition. IQ of ECG-triggered T1-VIBE scans in BH were scored qualitatively highest with good reader agreement (κ = 0.62). IQ of T2-HASTE was not significantly affected by BH acquisition (P > 0.9). Qualitative IQ of T1-VIBE and T2-HASTE declined after spectral adiabatic inversion recovery fat-suppression. All patients could maintain BH at end-expiration and reported no discomfort. Diagnostic performance of F-FDG-PET/MR was not significantly different from F-FDG-PET/CT with comparable staging, standardized-uptake-values, and tumour-to-blood ratios. However, T-status was more often over-staged on F-FDG-PET/CT, while N-status was more frequently under-staged on F-FDG-PET/MR. CONCLUSION: ECG-triggered T1-VIBE sequences acquired during short, multiple BHs are recommended for mediastinal imaging using F-FDG-PET/MR. With dedicated protocols, F-FDG-PET/MRI will be useful in thoracic oncology and aid in diagnostic evaluation and tailored treatment decision-making.

The role of bone SPECT/CT in patients with persistent or recurrent lumbar pain following lumbar spine stabilization surgery.

PURPOSE: Despite recent advances in lumbar spine stabilization surgery (LSSS), a high number of patients continue to complain of persistent/recurrent lumbar pain after LSSS. Conventional imaging (plain radiography, CT and MRI) is commonly performed to assess potential lumbar pain generators, but findings are equivocal in approximately 20% of patients. The purpose of this study was to assess the diagnostic performance of 99mTc-HDP bone SPECT/CT in identifying potential pain generators in patients with persistent/recurrent lumbar pain after LSSS but in whom conventional diagnostic imaging is inconclusive. METHODS: A total of 187 patients (median age 56 years, 70 men) with persistent/recurrent lumbar pain following LSSS with inconclusive conventional imaging (plain radiography, CT and/or MRI) underwent 99mTc-HDP bone SPECT/CT and were included in the study. Tracer uptake on SPECT/CT, as an indicator of ongoing or altered osteoblastic activity, was assessed in the lumbar spine stabilization segment(s) and in adjacent segments. Uptake intensity was graded as (1) high (the same as or more than iliac crest uptake), (2) mild (the same as or more than nondiseased vertebral uptake but less than iliac crest uptake), or (3) negative (normal scan). Mild and high uptake were regarded as positive. RESULTS: In 160 of the 187 patients (85.6%), SPECT/CT showed positive mild or high tracer uptake in the LSSS region. More than half of the patients had abnormal tracer uptake in the stabilized segments (56.7%) and/or in the adjacent segments (55.6%). Although positive stabilized segment findings were commonly seen at <2 years (70.3%) and the rate decreased with time after LSSS, they were seen at >6 years after surgery in 38.2% of patients. In 51.4% of patients, abnormal activity was seen in the adjacent segments <2 years after LSSS, suggesting early/accelerated degeneration after surgery. The proportion of patients with abnormal activity in the adjacent segments increased to 67.3% at >6 years after LSSS (p < 0.05). Positive SPECT/CT findings in the stabilized segments were more frequent in patients with three or more stabilized segments (p < 0.05), but were not more frequent in the adjacent segments. Overall, positive SPECT/CT guided therapy in 64% of patients, which included facet joint/nerve root injections or re-do surgery at active sites and/or adjacent sites. CONCLUSION: Bone SPECT/CT is a sensitive diagnostic tool for identifying altered osteoblastic activity, which might be a pain generator in patients with persistent/recurrent pain after lumbar surgery especially when conventional imaging is inconclusive.

Additional Clinical Value for PET/MRI in Oncology: Moving Beyond Simple Diagnosis.

Initial clinical research comparing the diagnostic performance of PET/MRI and PET/CT has largely shown equivalent diagnostic capabilities for these modalities in oncology. These uncertainties about the magnitude of diagnostic benefit are compounded by the considerable health economic challenges associated with clinical implementation. Therefore, there is a need to identify ways to extend the use of this technology beyond simple diagnosis so that PET/MRI can add sufficient clinical value beyond PET/CT or MRI alone and become a cost-effective imaging modality in clinical practice. A major advantage of PET/MRI over other imaging modalities is the ability to generate multiple quantitative images from a single examination. This article describes how a multiparametric PET/MRI approach not only can add clinical value through contributing to precision medicine but also can establish PET/MRI as a potentially cost-effective imaging modality in oncology.

Hybrid 18F-FDG PET/MRI might improve locoregional staging of breast cancer patients prior to neoadjuvant chemotherapy.

PURPOSE: Our purpose in this study was to assess the added clinical value of hybrid 18F-FDG-PET/MRI compared to conventional imaging for locoregional staging in breast cancer patients undergoing neoadjuvant chemotherapy (NAC). METHODS: In this prospective study, primary invasive cT2-4 N0 or cT1-4 N+ breast cancer patients undergoing NAC were included. A PET/MRI breast protocol was performed before treatment. MR images were evaluated by a breast radiologist, blinded for PET images. PET images were evaluated by a nuclear physician. Afterwards, a combined PET/MRI report was written. PET/MRI staging was compared to conventional imaging, i.e., mammography, ultrasound and MRI. The proportion of patients with a modified treatment plan based on PET/MRI findings was analyzed. RESULTS: A total of 40 patients was included. PET/MRI was of added clinical value in 20.0% (8/40) of patients, changing the treatment plan in 10% and confirming the malignancy of suspicious lesions on MRI in another 10%. In seven (17.5%) patients radiotherapy fields were extended because of additional or affirmative PET/MRI findings being lymph node metastases (n = 5) and sternal bone metastases (n = 2). In one (2.5%) patient radiotherapy fields were reduced because of fewer lymph node metastases on PET/MRI compared to conventional imaging. Interestingly, all treatment changes were based on differences in number of lymph nodes suspicious for metastasis or number of distant metastasis, whereas differences in intramammary tumor extent were not observed. CONCLUSION: Prior to NAC, PET/MRI shows promising results for locoregional staging compared to conventional imaging, changing the treatment plan in 10% of patients and potentially replacing PET/CT or tissue sampling in another 10% of patients.

Imaging Intraplaque Inflammation in Carotid Atherosclerosis With 18F-Fluorocholine Positron Emission Tomography-Computed Tomography: Prospective Study on Vulnerable Atheroma With Immunohistochemical Validation.

BACKGROUND: (18)F-fluorocholine ((18)F-FCH) uptake is associated with cell proliferation and activity in tumor patients. We hypothesized that (18)F-FCH could similarly be a valuable imaging tool to identify vulnerable plaques and associated intraplaque inflammation and atheroma cell proliferation. METHODS AND RESULTS: Ten consecutive stroke patients (90% men, median age 66.5 years, range, 59.4-69.7) with ipsilateral >70% carotid artery stenosis and who underwent carotid endarterectomy were included in the study. Before carotid endarterectomy, all patients underwent positron emission tomography to assess maximum (18)F-FCH uptake in ipsilateral symptomatic carotid plaques and contralateral asymptomatic carotid arteries, which was corrected for background activity, resulting in a maximum target-to-background ratio (TBRmax). Macrophage content was assessed in all carotid endarterectomy specimens as a percentage of CD68(+)-staining per whole plaque area (plaqueCD68(+)) and as a maximum CD68(+) percentage (maxCD68(+)) in the most inflamed section/plaque. Dynamic positron emission tomography imaging demonstrated that an interval of 10 minutes between (18)F-FCH injection and positron emission tomography acquisition is appropriate for carotid plaque imaging. TBRmax in ipsilateral symptomatic carotid plaques correlated significantly with plaqueCD68(+) (Spearman's ρ=0.648, P=0.043) and maxCD68(+) (ρ=0.721, P=0.019) in the 10 corresponding carotid endarterectomy specimens. TBRmax was significantly higher (P=0.047) in ipsilateral symptomatic carotid plaques (median: 2.0; interquartile range [Q1-Q3], 1.5-2.5) compared with the contralateral asymptomatic carotid arteries (median: 1.4; Q1-Q3, 1.3-1.6). TBRmax was not significantly correlated to carotid artery stenosis (ρ=0.506, P=0.135). CONCLUSIONS: In vivo uptake of (18)F-FCH in human carotid atherosclerotic plaques correlated strongly with degree of macrophage infiltration and recent symptoms, thus (18)F-FCH positron emission tomography is a promising tool for the evaluation of vulnerable plaques. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01899014.

Extent of disease in recurrent prostate cancer determined by [(68)Ga]PSMA-HBED-CC PET/CT in relation to PSA levels, PSA doubling time and Gleason score.

PURPOSE: To examine the relationship between the extent of disease determined by [(68)Ga]PSMA-HBED-CC-PET/CT and the important clinical measures prostate-specific antigen (PSA), PSA doubling time (PSAdt) and Gleason score. METHODS: We retrospectively studied the first 155 patients with recurrent prostate cancer (PCA) referred to our university hospital for [(68)Ga]PSMA-HBED-CC PET/CT. RESULTS: PET/CT was positive in 44%, 79% and 89% of patients with PSA levels of ≤1, 1-2 and ≥2 ng/ml, respectively. Patients with high PSA levels showed higher rates of local prostate tumours (p < 0.001), and extrapelvic lymph node (p = 0.037) and bone metastases (p = 0.013). A shorter PSAdt was significantly associated with pelvic lymph node (p = 0.026), extrapelvic lymph node (p = 0.001), bone (p < 0.001) and visceral (p = 0.041) metastases. A high Gleason score was associated with more frequent pelvic lymph node metastases (p = 0.039). In multivariate analysis, both PSA and PSAdt were independent determinants of scan positivity and of extrapelvic lymph node metastases. PSAdt was the only independent marker of bone metastases (p = 0.001). Of 20 patients with a PSAdt <6 months and a PSA ≥2 ng/ml, 19 (95%) had a positive scan and 12 (60%) had M1a disease. Of 14 patients with PSA <1 ng/ml and PSAdt >6 months, only 5 (36%) had a positive scan and 1 (7%) had M1a disease. CONCLUSION: [(68)Ga]PSMA-HBED-CC PET/CT will identify PCA lesions even in patients with very low PSA levels. Higher PSA levels and shorter PSAdt are independently associated with scan positivity and extrapelvic metastases, and can be used for patient selection for [(68)Ga]PSMA-HBED-CC PET/CT.

Aortic ¹8F-FDG uptake in patients suffering from granulomatosis with polyangiitis.

PURPOSE: The objective of the study was to systematically assess aortic inflammation in patients with granulomatosis with polyangiitis (GPA) using (18)F-2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) positron emission tomography (PET)/CT. METHODS: Aortic inflammation was studied in PET/CT scans obtained from 21 patients with GPA; 14 patients with sarcoidosis were included as disease controls, 7 patients with stage I or II head and neck carcinoma ascertained during routine clinical practice were used as healthy controls (HC) and 5 patients with large vessel vasculitis (LVV) were used as positive controls. Aortic (18)F-FDG uptake was expressed as the blood-normalized maximum standardized uptake value (SUVmax), known as the target to background ratio (mean TBRmax). RESULTS: The mean TBRmax (interquartile range) of the aorta in patients with GPA, sarcoidosis, HC and LVV were 1.75 (1.32-2.05), 1.62 (1.54-1.74), 1.29 (1.22-1.52) and 2.03 (1.67-2.45), respectively. The mean TBRmax was significantly higher in patients suffering from GPA or LVV compared to HC (p < 0.05 and p < 0.005, respectively) and tended to be higher in patients suffering from sarcoidosis, but this did not reach statistical significance (p = 0.098). The mean TBRmax of the most diseased segment was significantly higher compared to HC [1.57 (1.39-1.81)] in LVV patients [2.55 (2.22-2.82), p < 0.005], GPA patients [2.17 (1.89-2.83), p < 0.005] and patients suffering from sarcoidosis [2.04 (1.88-2.20), p < 0.05]. In GPA patients, the mean TBRmax of the aorta was significantly higher in patients with previous renal involvement [2.01 (1.69-2.53)] compared to patients without renal involvement in the past [1.60 (1.51-1.80), p < 0.05]. Interrater reproducibility with a second reader was high (all intraclass correlation coefficients >0.9). CONCLUSION: Patients suffering from GPA show marked aortic FDG uptake.

Positron emission tomography scanning in anti-neutrophil cytoplasmic antibodies-associated vasculitis.

Tools for evaluation of disease activity in patients with anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) include scoring clinical manifestations, determination of biochemical parameters of inflammation, and obtaining tissue biopsies. These tools, however, are sometimes inconclusive. 2-deoxy-2-[F]-fluoro-D-glucose (FDG) positron emission tomography (PET) scans are commonly used to detect inflammatory or malignant lesions. Our objective is to explore the ability of PET scanning to assess the extent of disease activity in patients with AAV.Consecutive PET scans made between December 2006 and March 2014 in Maastricht (MUMC) and between July 2008 and June 2013 in Brussels (EUH) to assess disease activity in patients with AAV were retrospectively included. Scans were re-examined and quantitatively scored using maximum standard uptake values (SUVmax). PET findings were compared with C-reactive protein (CRP) and ANCA positivity at the time of scanning.Forty-four scans were performed in 33 patients during a period of suspected active disease. All but 2 scans showed PET-positive sites, most commonly the nasopharynx (n = 22) and the lung (n = 22). Forty-one clinically occult lesions were found, including the thyroid gland (n = 4 patients), aorta (n = 8), and bone marrow (n = 7). The amount of hotspots, but not the highest observed SUVmax value, was higher if CRP levels were elevated. Seventeen follow-up scans were made in 13 patients and showed decreased SUVmax values.FDG PET scans in AAV patients with active disease show positive findings in multiple sites of the body even when biochemical parameters are inconclusive, including sites clinically unsuspected and difficult to assess otherwise.

Extent of disease activity assessed by 18F-FDG PET/CT in a Dutch sarcoidosis population.

BACKGROUND: Sarcoidosis is characterized by a wide range of disease manifestations. In the management and follow-up of sarcoidosis patients, knowledge of extent of disease, activity and severity is crucial. Objectives The aim of this study was to assess the extent, distribution and consistency of inflammatory organ involvement using 18F-FDG PET/CT (PET) in sarcoidosis patients with persistent disabling symptoms. METHODS: Retrospectively, sarcoidosis patients who underwent a PET between 2005 and 2011 (n=158) were included. Clinical data were gathered from medical records and PET scans were evaluated. Positive findings were classified as thoracic and/or extrathoracic. RESULTS :Of the studied PET positive sarcoidosis patients (n=118/158; 75%), 93% had intrathoracic activity (79% mediastinal and 64% pulmonary activity, respectively) and 75% displayed extrathoracic activity (mainly peripheral lymph nodes, bone/bone marrow, and spleen). Hepatic positivity was always accompanied by splenic activity, whereas the majority of patients with parotid gland, splenic or bone/bone marrow activity showed lymph node activity. A substantial number of patients with PET positive pulmonary findings (86%) had signs of respiratory functional impairment. No obvious association between hepatic, splenic or bone/bone marrow activity and their corresponding laboratory abnormalities suggestive of specific organ involvement, was found. CONCLUSIONS: The majority of studied patients appeared to have PET positive findings (75%), of which a high proportion (75%) displayed extrathoracic activity. Hence, PET can be especially useful in the assessment of extent, distribution and consistency of inflammatory activity in sarcoidosis to provide an explanation for persistent disabling symptoms and/or to provide a suitable location for biopsy.

I-131-MIBG therapies.

Metaiodobenzylguanidine (MIBG) is a tracer that selectively targets neuroendocrine cells. On this basis, radiolabeled iodinated-MIBG (I-131-MIBG) has been introduced as a molecular nuclear therapy in the management of neuroendocrine tumors, including neuroblastoma, pheochromocytoma, paraganglioma, neuroendocrine carcinomas, and other rare neuroendocrine tumors. Extensive work has been addressed to develop I-131-MIBG therapy: doses, therapeutic schemes, and efficiency. In this paper, we present an overview on I-131-MIBG therapy, with main focus on different aspects how to perform this treatment.

VEGF-A-induced chemotaxis of CD16+ monocytes is decreased secondary to lower VEGFR-1 expression.

BACKGROUND: Monocyte recruitment into the vessel wall is a crucial initial step in vascular repair, arteriogenesis and atherogenesis. Two distinct human monocyte subpopulations can be classified according to their CD14/16 surface expression, namely CD14++CD16-monocytes (CD16-mo) and CD14+CD16+ monocytes (CD16+mo). We investigated different functional properties of the two monocyte subsets. METHODS: CD16-/CD16+mo were isolated from human blood by an immunological selection. We assessed monocyte chemokinesis, chemotaxis, adhesion and Vascular-Endothelial Growth Factor (VEGF) receptor expression. Furthermore, generation of reactive oxygen species (ROS) as well as expression of antioxidant enzymes was investigated. RESULTS: Chemokinesis of CD16+mo was decreased compared to CD16-mo (p<0.01). Likewise, adhesion capacity of CD16+mo was weaker (p<0.05). CD16+mo chemotaxis towards the angiogenic ligands vascular endothelial growth factor-A (VEGF-A) and placenta growth factor-1 (PlGF-1) was reduced compared to CD16-mo. VEGFR-1 is the receptor for VEGF-A and PlGF-1 on monocytes. VEGFR-1 protein expression was lower in CD16+mo than in CD16-mo (p<0.05). The impaired VEGF-A- and PlGF-1-induced CD16+mo chemotaxis might therefore be attributed to the reduced VEGFR-1 expression. CD16+mo exhibited less spontaneous ROS production than CD16-mo. Additionally, the antioxidant enzyme manganese superoxide dismutase was expressed at higher levels in CD16+mo (p<0.05); this might partly explain the higher oxidative resistance of CD16+mo. CONCLUSION: These novel functional differences between CD16-mo and CD16+mo may predict different functional roles of both monocyte subsets in vascular repair, arteriogenesis and atherogenesis.

Metaiodobenzylguanidine scintigraphy in pulmonary and cardiac disease.

PURPOSE OF REVIEW: Nuclear medicine techniques have the capacity to investigate neuronal dysfunction at the synapse level. For instance, metaiodobenzylguanidine (MIBG) shows a similar uptake, storage and release as norepinephrine. Intravenously injected radiolabeled MIBG is able to reflect neuronal damage induced by inflammation and tumors. The purpose of this review is to evaluate the results and the limitation of these neuronal imaging techniques in patients with pulmonary and cardiac diseases and to give an opinion about the clinical value of these new diagnostic tools. RECENT FINDINGS: MIBG neuronal images of the lungs and heart can show heterogeneous distribution patterns with either diminished or increased MIBG uptake and/or washout. These changes reflect changes in endothelial integrity, neuronal innervations and clearance of norepinephrine. Interest in the role of neurotransmitter involvement and the relation between endothelial cell integrity and vascularization is growing and of utmost importance to understand the effect on pathophysiology of diseases. SUMMARY: At this moment, there is no added clinical value to routinely use MIBG scanning of the lungs and the heart. This is partly due to the many unresolved questions such as what actually happens and which factors influence MIBG uptake and washout under normal physiological circumstances. But the technique, if standardized and when dynamic time acquisition is performed with the latest equipment, such as PET and single photon emission computed tomography-computed tomography (SPECT-CT), has a tremendous potential. It can unravel upto now unknown relationships between innervation, vascularization and endothelial integrity. Other diagnostic tools such as MRI and CT do not have this capacity, so the future looks bright for these new neuronal imaging techniques.

Sonic hedgehog is a potent chemoattractant for human monocytes: diabetes mellitus inhibits Sonic hedgehog-induced monocyte chemotaxis.

The aim of the present study was to evaluate the expression of hedgehog (Hh) signaling molecules and the chemotactic activity of Sonic hedgehog (Shh) in monocytes from control (CTR) and diabetic patients with or without coronary artery disease (CAD). Previously several studies demonstrated that exogenous administration of Shh can induce angiogenesis and accelerate repair of ischemic myocardium and skeletal muscles. Blood samples were collected from (1) CTR (n = 25); (2) patients with stable CAD without diabetes mellitus (CAD-DM, n = 10); and (3) with stable CAD with DM (CAD+DM, n = 15). Monocytes were isolated by Percoll gradient and subjected to PCR and chemotaxis analysis. Hh signaling molecules were expressed in human monocytes, and Shh-induced monocyte chemotaxis. Shh-stimulated migration of monocytes from CTR measured 172.5 +/- 90% and a maximal stimulation was observed at Shh concentration of 1 microg/ml. However, Shh failed to induce migration of monocytes from CAD+DM (94.3 +/- 27%, P < 0.001 vs. CTR). The impaired response to Shh was associated with strong transcriptional upregulation of the receptor Ptc, while expression of downstream molecules was not altered. Moreover, Ptc is strongly expressed in macrophages of human aortic atherosclerotic plaque. Thus, Shh is a potent chemoattractant for monocytes and it activates classical signaling pathways related to migration. The Shh signaling was negatively affected by DM which might be involved in the pathogenesis of DM-related complications.

Enhanced functional response of CD133+ circulating progenitor cells in patients early after acute myocardial infarction.

AIMS: Circulating progenitor cells (PC) may contribute to myocardial recovery following infarction. Growth factors including VEGF are produced during ischaemia and stimulate PC release and activation. In this study, we focused on the functional chemotactic response of PC to VEGF in subjects early after myocardial ischaemia. METHODS AND RESULTS: Number and phenotype of PC were characterized using flow-cytometry. CD133(+)PC were isolated from peripheral blood using positive MACS isolation. The chemotactic response towards members of the VEGF family (VEGF-A, PlGF-1, and VEGF-E) was analysed in three groups: (i) early period following acute myocardial infarction (days 2-4) treated with primary PCI (AMI) (n = 35), (ii) stable coronary artery disease (CAD) (n = 35), and (iii) controls (CTR) (n = 20). CD133(+)PC number was 2-fold higher in AMI when compared with CAD and CTR (P = 0.0001), whereas CAD was not different from CTR. The chemotactic response of CD133(+)PC to VEGF-A, PlGF-1, and VEGF-E was significantly enhanced (2-fold) in AMI when compared with CAD (P = 0.0001). While the increase of the VEGFR-1-mediated/PlGF-triggered response was rapid (2 days following infarction), the VEGFR-2-mediated/VEGF-E-triggered response was maximally increased on day 4 post-AMI, thus correlating with the kinetics of maximal inflammatory activation reflected by increased CRP levels (P = 0.019). CONCLUSION: The enhanced chemotactic response of CD133(+)PC following myocardial infarction represents a novel principle potentially involved in cardiovascular repair early after myocardial infarction. Acute inflammatory processes are closely associated with this increased cellular function.