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1.  PET/MR: a paradigm shift 
Cancer Imaging  2013;13(1):36-52.
More than a decade ago, multimodality imaging was introduced into clinical routine with the development of the positron emission tomography (PET)/computed tomography (CT) technique. Since then, PET/CT has been widely accepted in clinical imaging and has emerged as one of the main cancer imaging modalities. With the recent development of combined PET/magnetic resonance (MR) systems for clinical use, a promising new hybrid imaging modality is now becoming increasingly available. The combination of functional information delivered by PET with the morphologic and functional imaging of MR imaging (e.g., diffusion-weighted imaging, dynamic contrast-enhanced MR imaging and MR spectroscopy) offers exciting possibilities for clinical applications as well as basic research. However, the differences between CT and MR imaging are fundamental. This also leads to distinct differences between PET/CT and PET/MR not only regarding image interpretation but also concerning data acquisition, data processing and image reconstruction. This article provides an overview of the principal differences between PET/CT and PET/MR in terms of scanner design and technology, attenuation correction, speed, acquisition protocols, radiation exposure and safety aspects. PET/MR is expected to show advantages over PET/CT in clinical applications in which MR is known to be superior to CT due to its high intrinsic soft tissue contrast. However, as of now, only assumptions can be made about the future clinical role of PET/MR, as data about the performance of PET/MR in the clinical setting are still limited. The possible future clinical use of PET/MR in oncology, neurology and neurooncology, cardiology and imaging of inflammation is discussed.
PMCID: PMC3584300  PMID: 23446110
Positron emission tomography; magnetic resonance tomography; PET/MR; oncology; neurology; cardiology
3.  Multisite Kinetic Modeling of 13C Metabolic MR Using [1-13C]Pyruvate 
Hyperpolarized 13C imaging allows real-time in vivo measurements of metabolite levels. Quantification of metabolite conversion between [1-13C]pyruvate and downstream metabolites [1-13C]alanine, [1-13C]lactate, and [13C]bicarbonate can be achieved through kinetic modeling. Since pyruvate interacts dynamically and simultaneously with its downstream metabolites, the purpose of this work is the determination of parameter values through a multisite, dynamic model involving possible biochemical pathways present in MR spectroscopy. Kinetic modeling parameters were determined by fitting the multisite model to time-domain dynamic metabolite data. The results for different pyruvate doses were compared with those of different two-site models to evaluate the hypothesis that for identical data the uncertainty of a model and the signal-to-noise ratio determine the sensitivity in detecting small physiological differences in the target metabolism. In comparison to the two-site exchange models, the multisite model yielded metabolic conversion rates with smaller bias and smaller standard deviation, as demonstrated in simulations with different signal-to-noise ratio. Pyruvate dose effects observed previously were confirmed and quantified through metabolic conversion rate values. Parameter interdependency allowed an accurate quantification and can therefore be useful for monitoring metabolic activity in different tissues.
PMCID: PMC4274847  PMID: 25548671
4.  Diagnostic value of retrospective PET-MRI fusion in head-and-neck cancer 
BMC Cancer  2014;14(1):846.
To assess the diagnostic value of retrospective PET-MRI fusion and to compare the results with side-by-side analysis and single modality use of PET and of MRI alone for locoregional tumour and nodal staging of head-and-neck cancer.
Thirty-three patients with head-and-neck cancer underwent preoperative contrast-enhanced MRI and PET/CT for staging. The diagnostic data of MRI, PET, side-by-side analysis of MRI and PET images and retrospective PET-MRI fusion were systematically analysed for tumour and lymph node staging using receiver operating characteristic (ROC) analysis. The results were correlated to the histopathological evaluation.
The overall sensitivity/specificity for tumour staging for MRI, PET, side-by-side analysis and retrospective PET-MRI fusion was 79%/66%, 82%/100%, 86%/100% and 89%/100%, respectively. The overall sensitivity/specificity for nodal staging on a patient basis for MRI, PET, side-by-side analysis and PET-MRI fusion was 94%/64%, 94%/91%, 94%/82% and 94%/82%, respectively. MRI, PET, side-by-side analysis and retrospective image fusion were associated with correct diagnosis/over-staging/under-staging of N-staging in 70.4%/18.5%/11.1%, 81.5%/7.4%/11.1%, 81.5%/11.1%/7.4% and 81.5%/11.1%/7.4%, respectively.
ROC analysis showed no significant differences in tumor detection between the investigated methods. The Area Under the Curve (AUC) for MRI, PET, side-by-side analysis and retrospective PET-MRI fusion were 0.667/0.667/0.702/0.708 (p > 0.05). The most reliable technique in detection of cervical lymph node metastases was PET imaging (AUC: 0.95), followed by side-by-side analysis and retrospective image fusion technique (AUC: 0.941), which however, was not significantly better then the MRI (AUC 0.935; p > 0.05).
We found a beneficial use of multimodal imaging, compared with MRI or PET imaging alone, particular in individual cases of recurrent tumour disease. Side-by-side analysis and retrospective image fusion analysis did not perform significantly differently.
PMCID: PMC4252007  PMID: 25407100
Multimodal imaging; PET-MRI fusion; Retrospective image fusion; Side-by-side analysis; Head-and-neck cancer; Staging
5.  PET / MR as tool for ”precision medicine” 
Cancer Imaging  2014;14(Suppl 1):O34.
PMCID: PMC4242757
6.  Week one FLT-PET response predicts complete remission to R-CHOP and survival in DLBCL 
Oncotarget  2014;5(12):4050-4059.
Despite improved survival in the Rituximab (R) era, a considerable number of patients with diffuse large B-cell lymphoma (DLBCL) ultimately die from the disease. Functional imaging using [18F]fluorodeoxyglucose-PET is suggested for assessment of residual viable tumor very early during treatment but is compromised by non-specific tracer retention in inflammatory lesions. The PET tracer [18F]fluorodeoxythymidine (FLT) as surrogate marker of tumor proliferation may overcome this limitation. We present results of a prospective clinical study testing FLT-PET as superior and early predictor of response to chemotherapy and outcome in DLBCL. 54 patients underwent FLT-PET prior to and one week after the start of R-CHOP chemotherapy. Repetitive FLT-PET imaging was readily implemented into the diagnostic work-up. Our data demonstrate that the reduction of FLT standard uptake valuemean (SUVmean) and SUVmax one week after chemotherapy was significantly higher in patients achieving complete response (CR, n=48; non-CR, n=6; p<0.006). Martingale-residual and Cox proportional hazard analyses showed a significant monotonous decrease of mortality risk with increasing change in SUV. Consistent with these results, early FLT-PET response showed relevant discriminative ability in predicting CR. In conclusion, very early FLT-PET in the course of R-CHOP chemotherapy is feasible and enables identification of patients at risk for treatment failure.
PMCID: PMC4147305  PMID: 24979177
Lymphoma; DLBCL; Positron emission tomography; [18F]Fluorodeoxythymidine; FLT-PET
7.  Positron emission tomographic monitoring of dual phosphatidylinositol-3-kinase and mTOR inhibition in anaplastic large cell lymphoma 
OncoTargets and therapy  2014;7:789-798.
Dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibition offers an attractive therapeutic strategy in anaplastic large cell lymphoma depending on oncogenic nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) signaling. We tested the efficacy of a novel dual PI3K/mTOR inhibitor, NVP-BGT226 (BGT226), in two anaplastic large cell lymphoma cell lines in vitro and in vivo and performed an early response evaluation with positron emission tomography (PET) imaging using the standard tracer, 2-deoxy-2-[18F]fluoro-D-glucose (FDG) and the thymidine analog, 3′-deoxy-3′-[18F] fluorothymidine (FLT).
The biological effects of BGT226 were determined in vitro in the NPM-ALK positive cell lines SU-DHL-1 and Karpas299 by 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay, propidium iodide staining, and biochemical analysis of PI3K and mTOR downstream signaling. FDG-PET and FLT-PET were performed in immunodeficient mice bearing either SU-DHL-1 or Karpas299 xenografts at baseline and 7 days after initiation of treatment with BGT226. Lymphomas were removed for immunohistochemical analysis of proliferation and apoptosis to correlate PET findings with in vivo treatment effects.
SU-DHL-1 cells showed sensitivity to BGT226 in vitro, with cell cycle arrest in G0/G1 phase and an IC50 in the low nanomolar range, in contrast with Karpas299 cells, which were mainly resistant to BGT226. In vivo, both FDG-PET and FLT-PET discriminated sensitive from resistant lymphoma, as indicated by a significant reduction of tumor-to-background ratios on day 7 in treated SU-DHL-1 lymphoma-bearing animals compared with the control group, but not in animals with Karpas299 xenografts. Imaging results correlated with a marked decrease in the proliferation marker Ki67, and a slight increase in the apoptotic marker, cleaved caspase 3, as revealed by immunostaining of explanted lymphoma tissue.
Dual PI3K/mTOR inhibition using BGT226 is effective in ALK-positive anaplastic large cell lymphoma and can be monitored with both FDG-PET and FLT-PET early on in the course of therapy.
PMCID: PMC4043809  PMID: 24920919
lymphoma; phosphatidylinositol-3-kinase; mammalian target of rapamycin; inhibition; positron emission tomography
8.  Multimodality Multiparametric Imaging of Early Tumor Response to a Novel Antiangiogenic Therapy Based on Anticalins 
PLoS ONE  2014;9(5):e94972.
Anticalins are a novel class of targeted protein therapeutics. The PEGylated Anticalin Angiocal (PRS-050-PEG40) is directed against VEGF-A. The purpose of our study was to compare the performance of diffusion weighted imaging (DWI), dynamic contrast enhanced magnetic resonance imaging (DCE)-MRI and positron emission tomography with the tracer [18F]fluorodeoxyglucose (FDG-PET) for monitoring early response to antiangiogenic therapy with PRS-050-PEG40. 31 mice were implanted subcutaneously with A673 rhabdomyosarcoma xenografts and underwent DWI, DCE-MRI and FDG-PET before and 2 days after i.p. injection of PRS-050-PEG40 (n = 13), Avastin (n = 6) or PBS (n = 12). Tumor size was measured manually with a caliper. Imaging results were correlated with histopathology. In the results, the tumor size was not significantly different in the treatment groups when compared to the control group on day 2 after therapy onset (P = 0.09). In contrast the imaging modalities DWI, DCE-MRI and FDG-PET showed significant differences between the therapeutic compared to the control group as early as 2 days after therapy onset (P<0.001). There was a strong correlation of the early changes in DWI, DCE-MRI and FDG-PET at day 2 after therapy onset and the change in tumor size at the end of therapy (r = −0.58, 0.71 and 0.67 respectively). The imaging results were confirmed by histopathology, showing early necrosis and necroptosis in the tumors. Thus multimodality multiparametric imaging was able to predict therapeutic success of PRS-050-PEG40 and Avastin as early as 2 days after onset of therapy and thus promising for monitoring early response of antiangiogenic therapy.
PMCID: PMC4011746  PMID: 24801709
9.  Molecular imaging for early prediction of response to Sorafenib treatment in sarcoma 
The role of [18F]fluorodeoxyglucose ([18F]FDG) PET in staging of sarcoma is well established. The aim of this preclinical study was to compare [18F]fluorothymidine ([18F]FLT) PET to [18F]FDG PET regarding early metabolic changes of sarcoma in the course of targeted cancer therapy. SCID mice bearing sarcoma A673 xenotransplants were used for investigation of tumor response after treatment with the multikinase inhibitor Sorafenib. [18F]FLT and/or [18F]FDG-PET were performed prior to and early after initiation of treatment. Tumoral uptake (% Injected Dose per gram (%ID/g) of [18F]FLT-PET was compared to [18F]FDG-PET. Results were correlated with histopathology and in vitro data including cellular uptake, cell cycle-related protein expression, cell cycle distribution and apoptosis. In vitro experiments showed that A673 cells were sensitive to Sorafenib. In vivo, tumor growth was inhibited in comparison to a 4-fold increase of the tumor volume in control mice. Using [18F]FDG as tracer, a moderate reduction in tracer uptake (n=15, mean relative %ID/g 74%, range 35%-121%, p=0.03) was observed. The decrease in %ID/g using [18F]FLT-PET was significantly higher (p=0.003). The mean relative %ID/g in [18F]FLT uptake on day + 5 was significantly reduced to 54% compared to baseline (n=15, range 24%-125%, SD=29%). The PET analysis 24 hr after therapy showed a significant reduction of the mean [18F]FLT-%ID/g (p=0.04). The reduction of %ID/g on day + 1 in [18F]FDG-PET was not statistically significant (p=0.99). In conclusion, both [18F]FDG- and [18F]FLT-PET were able to predict response to Sorafenib treatment. In contrast to [18F]FDG-PET, [18F]FLT-PET was more predictive for very early response to treatment.
PMCID: PMC3867731  PMID: 24380047
Molecular imaging; sarcoma; PET; proliferation; [18F]FLT; [18F]FDG
10.  EGFR-Targeted Adenovirus Dendrimer Coating for Improved Systemic Delivery of the Theranostic NIS Gene 
We recently demonstrated tumor-selective iodide uptake and therapeutic efficacy of combined radiovirotherapy after systemic delivery of the theranostic sodium iodide symporter (NIS) gene using a dendrimer-coated adenovirus. To further improve shielding and targeting we physically coated replication-selective adenoviruses carrying the hNIS gene with a conjugate consisting of cationic poly(amidoamine) (PAMAM) dendrimer linked to the peptidic, epidermal growth factor receptor (EGFR)-specific ligand GE11. In vitro experiments demonstrated coxsackie-adenovirus receptor-independent but EGFR-specific transduction efficiency. Systemic injection of the uncoated adenovirus in a liver cancer xenograft mouse model led to high levels of NIS expression in the liver due to hepatic sequestration, which were significantly reduced after coating as demonstrated by 123I-scintigraphy. Reduction of adenovirus liver pooling resulted in decreased hepatotoxicity and increased transduction efficiency in peripheral xenograft tumors. 124I-PET-imaging confirmed EGFR-specificity by significantly lower tumoral radioiodine accumulation after pretreatment with the EGFR-specific antibody cetuximab. A significantly enhanced oncolytic effect was observed following systemic application of dendrimer-coated adenovirus that was further increased by additional treatment with a therapeutic dose of 131I. These results demonstrate restricted virus tropism and tumor-selective retargeting after systemic application of coated, EGFR-targeted adenoviruses therefore representing a promising strategy for improved systemic adenoviral NIS gene therapy.
PMCID: PMC3889187  PMID: 24193032
11.  Myeloablative Anti-CD20 Radioimmunotherapy +/- High-Dose Chemotherapy Followed by Autologous Stem Cell Support for Relapsed/Refractory B-Cell Lymphoma Results in Excellent Long-Term Survival 
Oncotarget  2013;4(6):899-910.
Radioimmunotherapy (RIT) has been used to treat relapsed/refractory CD20+ Non-Hodgkin lymphoma (NHL). Myeloablative anti-CD20 RIT followed by autologous stem cell infusion (ASCT) enables high radiation doses to lymphoma sites. We performed a phase I/II trial to assess feasibility and survival.
Twenty-three patients with relapsed/refractory NHL without complete remission (CR) to salvage chemotherapy were enrolled to evaluate RIT with Iodine-131 labelled rituximab (131I-rituximab) in a myeloablative setting. Biodistribution and dosimetric studies were performed to determine 131I activity required to induce a total body dose of 21-27Gy to critical organs. In 6/23 patients RIT was combined with high-dose chemotherapy. 8/23 patients received a sequential high-dose chemotherapy with a second ASCT. The median follow-up is 9.5 years.
6.956-19.425GBq of 131I was delivered to achieve the limiting organ dose to lungs or kidneys. No grade III/IV non-hematologic toxicity was seen with RIT alone. Significant grade III/IV toxicity (mucositis, fever, infection, one therapy related death) was observed in patients treated with RIT combined with high-dose chemotherapy. The overall response rate was 87% (64% CR). The median progression-free (PFS) and overall survival (OS) is 47.5 and 101.5 months. An international prognostic index score >1 was predictive for OS.
Myeloablative RIT with 131I-rituximab followed by ASCT is feasible, well-tolerated and effective in high risk CD20+ NHL. Combination of RIT and high-dose chemotherapy increased toxicity significantly. Long-term results for PFS and OS are encouraging.
PMCID: PMC3757247  PMID: 23765188
Non-Hodgkin lymphoma; Radioimmunotherapy; CD20; High-dose chemotherapy; Autologous stem cell transplantation
12.  Comparison of cyclic RGD peptides for αvβ3 integrin detection in a rat model of myocardial infarction 
EJNMMI Research  2013;3:38.
Expression of αvβ3 integrin is increased after myocardial infarction as part of the repair process. Increased expression of αvβ3 has been shown by molecular imaging with 18F-galacto-RGD in a rat model. The 68Ga-labelled RGD compounds 68Ga-NODAGA-RGD and 68Ga-TRAP(RGD)3 have high specificity and affinity, and may therefore serve as alternatives of 18F-galacto-RGD for integrin imaging.
Left coronary artery ligation was performed in rats. After 1 week, rats were imaged with [13N]NH3, followed by 18F-galacto-RGD, 68Ga-NODAGA-RGD or 68Ga-TRAP(RGD)3 using a dedicated animal PET/CT device. Rats were killed, and the activity in tissues was measured by gamma counting. The heart was sectioned for autoradiography and histology. Immunohistochemistry was performed on consecutive sections using CD31 for the endothelial cells and CD61 for β3 expression (as part of the αvβ3 receptor).
In vivo imaging showed focal RGD uptake in the hypoperfused area of infarcted myocardium as defined with [13N]NH3 scan. In autoradiography images, augmented uptake of all RGD tracers was observed within the infarct area as verified by the HE staining. The tracer uptake ratios (infarct vs. remote) were 4.7 ± 0.8 for 18F-galacto-RGD, 5.2 ± 0.8 for 68Ga-NODAGA-RGD, and 4.1 ± 0.7 for 68Ga-TRAP(RGD)3. The 68Ga-NODAGA-RGD ratio was higher compared to 68Ga-TRAP(RGD)3 (p = 0.04), but neither of the 68Ga tracers differed from 18F-galacto-RGD (p > 0.05). The area of augmented 68Ga-RGD uptake was associated with β3 integrin expression (CD61).
68Ga-NODAGA-RGD and 68Ga-TRAP(RGD)3 uptake was equally increased in the infarct area at 1 week post infarction as 18F-galacto-RGD. These results show the potential of 68Ga-labelled RGD peptides to monitor integrin expression as a part of myocardial repair and angiogenesis after ischaemic injury in vivo.
PMCID: PMC3658936  PMID: 23663426
18F-galacto-RGD; 68Ga-NODAGA-RGD; 68Ga-TRAP(RGD)3; PET; Myocardial infarction
13.  Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo 
Deep vein thrombosis initiation is mediated by cross talk between monocytes, neutrophils, and platelets.
Deep vein thrombosis (DVT) is a major cause of cardiovascular death. The sequence of events that promote DVT remains obscure, largely as a result of the lack of an appropriate rodent model. We describe a novel mouse model of DVT which reproduces a frequent trigger and resembles the time course, histological features, and clinical presentation of DVT in humans. We demonstrate by intravital two-photon and epifluorescence microscopy that blood monocytes and neutrophils crawling along and adhering to the venous endothelium provide the initiating stimulus for DVT development. Using conditional mutants and bone marrow chimeras, we show that intravascular activation of the extrinsic pathway of coagulation via tissue factor (TF) derived from myeloid leukocytes causes the extensive intraluminal fibrin formation characteristic of DVT. We demonstrate that thrombus-resident neutrophils are indispensable for subsequent DVT propagation by binding factor XII (FXII) and by supporting its activation through the release of neutrophil extracellular traps (NETs). Correspondingly, neutropenia, genetic ablation of FXII, or disintegration of NETs each confers protection against DVT amplification. Platelets associate with innate immune cells via glycoprotein Ibα and contribute to DVT progression by promoting leukocyte recruitment and stimulating neutrophil-dependent coagulation. Hence, we identified a cross talk between monocytes, neutrophils, and platelets responsible for the initiation and amplification of DVT and for inducing its unique clinical features.
PMCID: PMC3328366  PMID: 22451716
14.  A Novel 18F-Labeled Imidazo[2,1-b]benzothiazole (IBT) for High-Contrast PET Imaging of β-Amyloid Plaques 
ACS Medicinal Chemistry Letters  2011;2(9):673-677.
18F-labeled imidazo[2,1-b]benzothiazole ([18F]8) was synthesized and evaluated as a tracer for cerebral β-amyloid deposits (Aβ) by means of positron emission tomography (PET). [18F]8 exhibits a high affinity to Aβ and suitable brain uptake kinetics combined with a high metabolic stability in the brain. In a double transgenic APP/PS1 mouse model of Alzheimer's disease, we demonstrated a specific uptake of [18F]8 in Aβ-containing telencephalic brain regions. The specific binding of [18F]8 to Aβ was confirmed by regional brain biodistribution and autoradiography and correlated to immunohistochemistry staining. Analysis of brain sections of APP/PS1 mouse injected with a cocktail of [18F]8 and reference compound [3H]PiB revealed that the two tracers bind to Aβ plaques in the brain of mouse in a comparable binding pattern. [18F]8 represents the first high-contrast PET imaging agent for detection of Aβ plaques in transgenic mouse model of Alzheimer's disease and holds promise for transfer to a clinical evaluation.
PMCID: PMC4018122  PMID: 24900362
Alzheimer's disease; 18F-labeled tracer for β-amyloid; IBT; β-amyloid plaques; positron emission tomography; autoradiography; APP/PS1transgenic mice; neuroimaging
15.  Small-Animal PET Imaging of Amyloid-Beta Plaques with [11C]PiB and Its Multi-Modal Validation in an APP/PS1 Mouse Model of Alzheimer's Disease 
PLoS ONE  2012;7(3):e31310.
In vivo imaging and quantification of amyloid-β plaque (Aβ) burden in small-animal models of Alzheimer's disease (AD) is a valuable tool for translational research such as developing specific imaging markers and monitoring new therapy approaches. Methodological constraints such as image resolution of positron emission tomography (PET) and lack of suitable AD models have limited the feasibility of PET in mice. In this study, we evaluated a feasible protocol for PET imaging of Aβ in mouse brain with [11C]PiB and specific activities commonly used in human studies. In vivo mouse brain MRI for anatomical reference was acquired with a clinical 1.5 T system. A recently characterized APP/PS1 mouse was employed to measure Aβ at different disease stages in homozygous and hemizygous animals. We performed multi-modal cross-validations for the PET results with ex vivo and in vitro methodologies, including regional brain biodistribution, multi-label digital autoradiography, protein quantification with ELISA, fluorescence microscopy, semi-automated histological quantification and radioligand binding assays. Specific [11C]PiB uptake in individual brain regions with Aβ deposition was demonstrated and validated in all animals of the study cohort including homozygous AD animals as young as nine months. Corresponding to the extent of Aβ pathology, old homozygous AD animals (21 months) showed the highest uptake followed by old hemizygous (23 months) and young homozygous mice (9 months). In all AD age groups the cerebellum was shown to be suitable as an intracerebral reference region. PET results were cross-validated and consistent with all applied ex vivo and in vitro methodologies. The results confirm that the experimental setup for non-invasive [11C]PiB imaging of Aβ in the APP/PS1 mice provides a feasible, reproducible and robust protocol for small-animal Aβ imaging. It allows longitudinal imaging studies with follow-up periods of approximately one and a half years and provides a foundation for translational Alzheimer neuroimaging in transgenic mice.
PMCID: PMC3302888  PMID: 22427802
16.  Functional Imaging of Pheochromocytoma with 68Ga-DOTATOC and 68C-HED in a Genetically Defined Rat Model of Multiple Endocrine Neoplasia 
Rats affected by the MENX multitumor syndrome develop pheochromocytoma (100%). Pheochromocytomas are uncommon tumors and animal models are scarce, hence the interest in MENX rats to identify and preclinically evaluate novel targeted therapies. A prerequisite for such studies is a sensitive and noninvasive detection of MENXassociated pheochromocytoma. We performed positron emission tomography (PET) to determine whether rat pheochromocytomas are detected by tracers used in clinical practice, such as 68Ga-DOTATOC (somatostatin analogue) or 11C-Hydroxyephedrine (HED), a norepinephrine analogue. We analyzed four affected and three unaffected rats. The PET scan findings were correlated to histopathology and immunophenotype of the tumors, their proliferative index, and the expression of genes coding for somatostatin receptors or the norepinephrine transporter. We observed that mean 68Ga-DOTATOC standard uptake value (SUV) in adrenals of affected animals was 23.3 ± 3.9, significantly higher than in control rats (15.4 ± 7.9; P = .03). The increase in mean tumor-to-liver ratio of 11C-HED in the MENX-affected animals (1.6 ± 0.5) compared to controls (0.7 ± 0.1) was even more significant (P = .0016). In a unique animal model, functional imaging depicting two pathways important in pheochromocytoma biology discriminated affected animals from controls, thus providing the basis for future preclinical work with MENX rats.
PMCID: PMC3132633  PMID: 21755051
18.  PET Imaging of Integrin αVβ3 Expression 
Theranostics  2011;1:48-57.
PET imaging of integrin αvβ3 expression has been studied intensely by the academia and recently also by the industry. Imaging of integrin αvβ3 expression is of great potential value, as the integrin αvβ3 is a key player in tumor metastasis and angiogenesis. Therefore PET imaging of this target might be a suitable in-vivo biomarker of angiogenesis and metastatic potential of tumors. In this manuscript, the various strategies for PET imaging of the integrin αvβ3 will be summarized, including monomeric and multimeric radiolabelled RGD peptides and nanoparticles. While most experiments have been performed using preclinical tumor models, more and more clinical results on PET imaging of αvβ3 expression are available and will be discussed in detail. However, while a multitude of radiotracer strategies have been successfully evaluated for PET imaging of αvβ3, the ultimate clinical value of this new imaging biomarker still has to be evaluated in large clinical trials.
PMCID: PMC3086612  PMID: 21547152
PET; integrin αvβ3; molecular imaging; angiogenesis; metastasis
19.  Imaging of integrin αvβ3 expression in patients with malignant glioma by [18F] Galacto-RGD positron emission tomography 
Neuro-Oncology  2009;11(6):861-870.
Inhibitors targeting the integrin αvβ3 are promising new agents currently tested in clinical trials for supplemental therapy of glioblastoma multiforme (GBM). The aim of our study was to evaluate 18F-labeled glycosylated Arg-Gly-Asp peptide ([18F]Galacto-RGD) PET for noninvasive imaging of αvβ3 expression in patients with GBM, suggesting eligibility for this kind of additional treatment. Patients with suspected or recurrent GBM were examined with [18F]Galacto-RGD PET. Standardized uptake values (SUVs) of tumor hotspots, galea, and blood pool were derived by region-of-interest analysis. [18F]Galacto-RGD PET images were fused with cranial MR images for image-guided surgery. Tumor samples taken from areas with intense tracer accumulation in the [18F]Galacto-RGD PET images and were analyzed histologically and immunohistochemically for αvβ3 integrin expression. While normal brain tissue did not show significant tracer accumulation (mean SUV, 0.09 ± 0.04), GBMs demonstrated significant but heterogeneous tracer uptake, with a maximum in the highly proliferating and infiltrating areas of tumors (mean SUV, 1.6 ± 0.5). Immunohistochemical staining was prominent in tumor microvessels as well as glial tumor cells. In areas of highly proliferating glial tumor cells, tracer uptake (SUVs) in the [18F]Galacto-RGD PET images correlated with immunohistochemical αvβ3 integrin expression of corresponding tumor samples. These data suggest that [18F] Galacto-RGD PET successfully identifies αvβ3 expression in patients with GBM and might be a promising tool for planning and monitoring individualized cancer therapies targeting this integrin.
PMCID: PMC2802406  PMID: 19401596
αvβ3; [18F]Galacto-RGD; malignant glioma; PET; integrins
20.  Impact of preoperative positron emission tomography in patients with severely impaired LV-function undergoing surgical revascularization 
In patients with ischemic cardiomyopathy, coronary artery bypass grafting (CABG) offers an important therapeutic option but is still associated with high perioperative mortality. Although previous studies suggest a benefit from revascularization for patients with defined viability by a non-invasive technique, the role of viability assessment to determine suitability for revascularization in patients with ischemic cardiomyopathy has not yet been defined. This study evaluates the hypothesis that the use of PET imaging in the decision-making process for CABG will improve postoperative patient survival. We reviewed 476 patients with ischemic cardiomyopathy (LV ejection fraction ≤0.35) who were considered candidates for CABG between 1994 and 2004 on the basis of clinical presentation and angiographic data. In a Standard Care Group, 298 patients underwent CABG. In a second PET-assisted management group of 178 patients, 152 patients underwent CABG (PET-CABG) and 26 patients were excluded from CABG because of lack of viability (PET-Alternatives). Primary endpoint was postoperative survival. There were two in hospital deaths in the PET-CABG (1.3%) and 30 (10.1%) in the Standard Care Group (P = 0.018). The survival rate after 1, 5 and 9.3 years was 92.0, 73.3 and 54.2% in the PET-CABG and 88.9, 62.2 and 35.5% in the Standard Care Group, respectively (P = 0.005). Cox-regression analysis revealed a significant influence on long-term survival of patient selection by viability assessment via PET (P = 0.008), of LV-function (P = 0.017), and age >70 (P = 0.016). Preoperative assessment of myocardial viability via PET identifies patients, who will benefit most from CABG.
PMCID: PMC2852592  PMID: 20091350
Ischemic cardiomyopathy; PET; Coronary artery bypass grafting (CABG)
22.  Clinical Applications of FDG PET and PET/CT in Head and Neck Cancer 
Journal of Oncology  2009;2009:208725.
18F-FDG PET plays an increasing role in diagnosis and management planning of head and neck cancer. Hybrid PET/CT has promoted the field of molecular imaging in head and neck cancer. This modality is particular relevant in the head and neck region, given the complex anatomy and variable physiologic FDG uptake patterns. The vast majority of 18F-FDG PET and PET/CT applications in head and neck cancer related to head and neck squamous cell carcinoma. Clinical applications of 18F-FDG PET and PET/CT in head and neck cancer include diagnosis of distant metastases, identification of synchronous 2nd primaries, detection of carcinoma of unknown primary and detection of residual or recurrent disease. Emerging applications are precise delineation of the tumor volume for radiation treatment planning, monitoring treatment, and providing prognostic information. The clinical role of 18F-FDG PET/CT in N0 disease is limited which is in line with findings of other imaging modalities. MRI is usually used for T staging with an intense discussion concerning the preferable imaging modality for regional lymph node staging as PET/CT, MRI, and multi-slice spiral CT are all improving rapidly. Is this review, we summarize recent literature on 18F-FDG PET and PET/CT imaging of head and neck cancer.
PMCID: PMC2730473  PMID: 19707528
23.  Positron detection for the intraoperative localisation of cancer deposits 
The study investigated the feasibility of a positron-sensitive hand-held detector system for the intraoperative localisation of tumour deposits resulting from intravenous [18F]FDG administration.
A total of 17 patients (12 receiving preoperative [18F]FDG PET imaging) with various histologically proven malignancies were included. Radioactivity from tumours and surrounding normal tissue was measured on average 3 h after administration of 36–110 MBq [18F]FDG and the tumour-to-background (T/B) ratio was calculated. In addition, phantom studies were performed to evaluate the spatial resolution and sensitivity of the probe.
All known targeted tumour sites were identified by the positron probe. T/B ratios were generally high, with a mean T/B ratio of 6.6, allowing easy identification of most tumour sites. In one case of a hepatic metastasis, the T/B ratio of 1.34 was below expectations, since the preoperative [18F]FDG PET scan was positive. The probe was instrumental in the localisation of three additional tumour lesions (two lymph nodes, one anastomotic ring) that were not immediately apparent at surgery. Phantom studies revealed that [18F]FDG-containing gel (simulating tumour tissue), having 10 times more [18F]FDG than surrounding “normal” background gel, was clearly detectable in quantities as low as 15 mg. As measured in two cases, the absorbed radiation doses ranged from 2.5 to 8.6 μSv/h for the surgical team to 0.8 μSv/h for the aesthetician.
[18F]FDG-accumulating tumour tissues can be localised with positron probes intraoperatively with a low radiation burden to the patient and medical personnel. The methodology holds promise for further clinical testing.
PMCID: PMC2562440  PMID: 17431612
Positron probe; 18F-2-fluoro-2-deoxy-D-glucose; Tumour imaging; Intraoperative tumour localisation
24.  Impaired Cross-Modal Inhibition in Alzheimer Disease 
PLoS Medicine  2005;2(10):e288.
Successful cognitive performance depends not only on the activation of specific neuronal networks but also on selective suppression of task-irrelevant modalities, i.e., deactivation of non-required cerebral regions. This ability to suppress the activation of specific brain regions has, to our knowledge, never been systematically evaluated in patients with Alzheimer disease (AD). The aim of the current study was to evaluate both cerebral activation and deactivation in (1) healthy volunteers, (2) patients with mild cognitive impairment (MCI) who are at risk for AD, and (3) patients with moderate AD during active navigation, representing a cognitive task typically affected in AD.
Methods and Findings
Changes in regional cerebral blood flow (rCBF) were assessed with PET imaging during an active navigation task in a 3D virtual-reality environment. The task was based on visual cues exclusively; no auditory cues were provided. Age-matched groups of healthy individuals, patients with MCI, and patients with AD were examined. Specific differences in the activation patterns were observed in the three groups, with stronger activation of cerebellar portions and visual association cortex in controls and stronger activation of primary visual and frontal cortical areas in patients with MCI and AD. Highly significant bilateral decrease of rCBF in task-irrelevant auditory cortical regions was detected in healthy individuals during performance of the task. This rCBF decrease was interpreted as a cross-modal inhibitory effect. It was diminished in patients with MCI and completely absent in patients with AD. A regression analysis across all individuals revealed a clear positive relation between cognitive status (mini mental state examination score) and the extent of auditory cortical deactivation.
During active navigation, a high level of movement automation and an involvement of higher-order cerebral association functions were observed in healthy controls. Conversely, in patients with MCI and AD, increased cognitive effort and attention towards movement planning, as well as stronger involvement of lower-order cerebral systems, was found. Successful cognitive performance in healthy individuals is associated with deactivation of task-irrelevant cerebral regions, whereas the development of AD appears to be characterized by a progressive impairment of cross-modal cerebral deactivation functions. These changes may cause the generally decreased ability of patients with AD to direct attention primarily to the relevant cognitive modality.
When performing a navigation task with exclusively visual clues, healthy individuals de-activate areas of the brain involved in hearing. In individuals with Alzheimer Disease, no deactivation is seen.
PMCID: PMC1216331  PMID: 16159306
25.  Radiology 
Western Journal of Medicine  1985;143(3):371-372.
PMCID: PMC1306325  PMID: 18749829

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