Newly identified biologically active and proteolysis-resistant VEGF-A isoform VEGF111 is induced by genotoxic agents

Ultraviolet B and genotoxic drugs induce the expression of a vascular endothelial growth factor A (VEGF-A) splice variant (VEGF111) encoded by exons 1–4 and 8 in many cultured cells. Although not detected in a series of normal human and mouse tissue, VEGF111 expression is induced in MCF-7 xenografts in nude mice upon treatment by camptothecin. The skipping of exons that contain proteolytic cleavage sites and extracellular matrix–binding domains makes VEGF111 diffusible and resistant to proteolysis. Recombinant VEGF111 activates VEGF receptor 2 (VEGF-R2) and extracellularly regulated kinase 1/2 in human umbilical vascular endothelial cells and porcine aortic endothelial cells expressing VEGF-R2. The mitogenic and chemotactic activity and VEGF111's ability to promote vascular network formation during embyonic stem cell differentiation are similar to those of VEGF121 and 165. Tumors in nude mice formed by HEK293 cells expressing VEGF111 develop a more widespread network of numerous small vessels in the peritumoral tissue than those expressing other isoforms. Its potent angiogenic activity and remarkable resistance to proteolysis makes VEGF111 a potential adverse factor during chemotherapy but a beneficial therapeutic tool for ischemic diseases

Quantitative SPECT: the time is now

Abstract Background Quantification is one of the key benefits of nuclear medicine imaging. Recently, driven by the demand for post radionuclide therapy imaging, quantitative SPECT has moved from relative and semiquantitative measures to absolute quantification in terms of activity concentration, and yet further to normalised uptake using the standard uptake value (SUV). This expansion of quantitative SPECT has the potential to be a useful tool in the nuclear medicine armoury, but key factors must be addressed before it can meet its full potential. Discussion Quantitative SPECT should address an unmet clinical need and give metrics that are clinically meaningful. Using the technique in a similar manner to PET with longitudinal assessments of disease in terms of SUV is one example that meets these criteria. Having metrics that are evaluated to ensure that they are correct, that are optimised to maximise their sensitivity, and that are transferrable to allow multi-centre learning and applicability to all users of the technology are other areas of quantitative SPECT that need to be addressed and that have specific challenges associated with them. Finally, ensuring quantitative SPECT is cost-effective in times when healthcare budgets are being squeezed is also very important. Conclusion Quantitative SPECT offers the possibility to continue and expand the potential of quantitative nuclear medicine applications. The time is now to ensure that our community works together to make this potential a reality

SPECT and PET imaging of angiogenesis and arteriogenesis in pre-clinical models of myocardial ischemia and peripheral vascular disease

PURPOSE: The extent of neovascularization determines the clinical outcome of coronary artery disease and other occlusive cardiovascular disorders. Monitoring of neovascularization is therefore highly important. This review article will elaborately discuss preclinical studies aimed at validating new nuclear angiogenesis and arteriogenesis tracers. Additionally, we will briefly address possible obstacles that should be considered when designing an arteriogenesis radiotracer. METHODS: A structured medline search was the base of this review, which gives an overview on different radiopharmaceuticals that have been evaluated in preclinical models. RESULTS: Neovascularization is a collective term used to indicate different processes such as angiogenesis and arteriogenesis. However, while it is assumed that sensitive detection through nuclear imaging will facilitate translation of successful therapeutic interventions in preclinical models to the bedside, we still lack specific tracers for neovascularization imaging. Most nuclear imaging research to date has focused on angiogenesis, leaving nuclear arteriogenesis imaging largely overlooked. CONCLUSION: Although angiogenesis is the process which is best understood, there is no scarcity in theoretical targets for arteriogenesis imaging

Severity of pulmonary involvement and 18F-FDG PET activity in sarcoidosis

SummaryBackgroundAssessing inflammatory activity is useful in the management of persistent symptomatic sarcoidosis patients. 18F-FDG PET (PET) has been shown to be a sensitive technique to assess inflammatory activity in sarcoidosis. The aim of this study was to evaluate whether the severity of pulmonary involvement is associated with PET activity in persistent symptomatic sarcoidosis patients.MethodsOver a 5-year period, relevant clinical data including laboratory and lung function test results were gathered from the medical records of 95 sarcoidosis patients with persistent disabling symptoms who underwent both a PET and HRCT. HRCT scans were classified using a semiquantitative scoring system and PET findings as positive or negative, respectively.ResultsPET was positive in 77/95 patients, of whom 56 demonstrated pulmonary PET-positivity. HRCT scores were high (7.1 ± 3.6) in patients with positive pulmonary PET findings (n = 56) compared to patients with negative pulmonary PET findings (n = 39; 3.0 ± 2.9; p < 0.001). DLCO (65 ± 20% predicted) and FVC (85 ± 24% predicted) were low in patients with pulmonary PET-positivity versus those with negative pulmonary PET findings (79 ± 16% predicted; p = 0.001 and 96 ± 22% predicted; p = 0.044, respectively). Interestingly, out of the 26 patients with fibrotic changes, 22 (85%) had positive pulmonary PET findings, of whom 18/22 (82%) showed extrathoracic PET-positive lesions and 16/22 (73%) showed signs of serological inflammation.ConclusionsThe severity of the pulmonary involvement, assessed by HRCT features and lung function parameters, appeared to be associated with PET activity in sarcoidosis. The majority of patients with fibrotic changes demonstrated inflammatory activity at pulmonary and extrathoracic sites

Cardiac shockwave therapy in patients with chronic refractory angina pectoris

BACKGROUND: Cardiac shockwave therapy (CSWT) might improve symptoms and decrease ischaemia burden by stimulating collateral growth in chronic ischaemic myocardium. This prospective study was performed to evaluate the feasibility and safety of CSWT. METHODS: We included 33 patients (mean age 70 ± 7 years, mean left ventricular ejection fraction 55 ± 12 %) with end-stage coronary artery disease, chronic angina pectoris and reversible ischaemia on myocardial scintigraphy. CSWT was applied to the ischaemic zones (3–7 spots/session, 100 impulses/spot, 0.09 mJ/mm(2)) in an echocardiography-guided and ECG-triggered fashion. The protocol included a total of 9 treatment sessions (3 treatment sessions within 1 week at baseline, and after 1 and 2 months). Clinical assessment was performed using exercise testing, angina score (CCS class), nitrate use, myocardial scintigraphy, and cardiac magnetic resonance (CMR) 1 and 4 months after the last treatment session. RESULTS: One and 4 months after CSWT, sublingual nitrate use decreased from 10/week to 2/week (p < 0.01) and the angina symptoms diminished from CCS class III to CCS class II (p < 0.01). This clinical improvement was accompanied by an improved myocardial uptake on stress myocardial scintigraphy (54.2 ± 7.7 % to 56.4 ± 9.4 %, p = 0.016) and by increased exercise tolerance at 4-month follow-up (from 7.4 ± 2.8 to 8.8 ± 3.6 min p = 0.015). No clinically relevant side effects were observed. CONCLUSION: CSWT improved symptoms and reduced ischaemia burden in patients with end-stage coronary artery disease without relevant side effects. The study provides a solid basis for a randomised multicentre trial to establish CSWT as a new treatment option in end-stage coronary artery disease

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

(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. 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). 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. URL: http://www.clinicaltrials.gov. Unique identifier: NCT0189901