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1.  Simultaneous hyperpolarized 13C-pyruvate MRI and 18F-FDG-PET in cancer (hyperPET): feasibility of a new imaging concept using a clinical PET/MRI scanner 
In this paper we demonstrate, for the first time, the feasibility of a new imaging concept - combined hyperpolarized 13C-pyruvate magnetic resonance spectroscopic imaging (MRSI) and 18F-FDG-PET imaging. This procedure was performed in a clinical PET/MRI scanner with a canine cancer patient. We have named this concept hyper PET. Intravenous injection of the hyperpolarized 13C-pyruvate results in an increase of 13C-lactate, 13C-alanine and 13C-CO2 (13C-HCO3) resonance peaks relative to the tissue, disease and the metabolic state probed. Accordingly, with dynamic nuclear polarization (DNP) and use of 13C-pyruvate it is now possible to directly study the Warburg Effect through the rate of conversion of 13C-pyruvate to 13C-lactate. In this study, we combined it with 18F-FDG-PET that studies uptake of glucose in the cells. A canine cancer patient with a histology verified local recurrence of a liposarcoma on the right forepaw was imaged using a combined PET/MR clinical scanner. PET was performed as a single-bed, 10 min acquisition, 107 min post injection of 310 MBq 18F-FDG. 13C-chemical shift imaging (CSI) was performed just after FDG-PET and 30 s post injection of 23 mL hyperpolarized 13C-pyruvate. Peak heights of 13C-pyruvate and 13C-lactate were quantified using a general linear model. Anatomic 1H-MRI included axial and coronal T1 vibe, coronal T2-tse and axial T1-tse with fat saturation following gadolinium injection. In the tumor we found clearly increased 13C-lactate production, which also corresponded to high 18F-FDG uptake on PET. This is in agreement with the fact that glycolysis and production of lactate are increased in tumor cells compared to normal cells. Yet, most interestingly, also in the muscle of the forepaw of the dog high 18F-FDG uptake was observed. This was due to activity in these muscles prior to anesthesia, which was not accompanied by a similarly high 13C-lactate production. Accordingly, this clearly demonstrates how the Warburg Effect directly can be demonstrated by hyperpolarized 13C-pyruvate MRSI. This was not possible with 18F-FDG-PET imaging due to inability to discriminate between causes of increased glucose uptake. We propose that this new concept of simultaneous hyperpolarized 13C-pyruvate MRSI and PET may be highly valuable for image-based non-invasive phenotyping of tumors. This methods may be useful for treatment planning and therapy monitoring.
PMCID: PMC4299777  PMID: 25625025
Cancer; DNP; hyperpolarized; 13C-pyruvate; MR; response monitoring; 18F-FDG-PET; PET/MR; molecular imaging
2.  Feasibility of simultaneous PET/MR in diet-induced atherosclerotic minipig: a pilot study for translational imaging 
Novel hybrid 18-fluoro-deoxy-D-glucose (18F-FDG) based positron emission tomography (PET) and magnetic resonance imaging (MRI) has shown promise for characterization of atherosclerotic plaques clinically. The purpose of this study was to evaluate the method in a pre-clinical model of diet-induced atherosclerosis, based on the Göttingen minipig. Using 18F-FDG PET/MRI the goal was to develop and create a new imaging method in an in vivo animal model for translational studies of atherosclerosis. We used a strategy of multisequence MRI for optimal anatomical imaging of the abdominal aortas of the pigs (n=4): T1-weighted turbo spin-echo (T1-TSE), T2-weighted turbo spin-echo (T2-TSE) and proton density imaging with and without fat saturation. 18F-FDG PET emission data were collected from a single bed position of the abdominal aorta in 3D mode for either 10 (n=4) or 10 and 20 minutes (n=2) to measure glycolysis as given by standardized uptake values (SUV). Ex vivo en face evaluation of aortas from an atherosclerotic animal illustrated plaque distribution macroscopically, compared to a lean control animal. Although T2-TSE weighted imaging was most consistent, no one MRI sequence was preferable and superior to another for visualization and identification of the abdominal aorta. We found poor correlation between SUVs obtained from 10 and 20 minutes of reconstructed PET emission data. This can most likely be ascribed to intestinal movement. In conclusion multisequence MRI is recommended for optimal imaging of the abdominal aorta using MRI. Furthermore we found that 10 minutes of PET emission data seems adequate. This is the first study to demonstrate that the method of 18F-FDG PET/MRI is feasible in minipig models of atherosclerosis, and therefore relevant in larger prospective studies. Perspectives of the method include correlation to e.g. aortic immunohistochemistry findings and a range of genomic and proteomic analyses.
PMCID: PMC4138139  PMID: 25143863
Atherosclerosis; novel model; Göttingen minipig; positron emission tomography; magnetic resonance imaging
3.  A Catalyst for Change: The European Cancer Patient’s Bill of Rights 
The Oncologist  2014;19(3):217-224.
The European Cancer Concord is a unique patient-centered partnership that will act as a catalyst to achieve improved access to an optimal standard of cancer care and research for European citizens. In order to provide tangible benefits for European cancer patients, the partnership proposes the creation of a “European Cancer Patient’s Bill of Rights,” a patient charter that will underpin equitable access to an optimal standard of care for Europe’s citizens.
PMCID: PMC3958470  PMID: 24493667
4.  Imaging of Treatment Response to the Combination of Carboplatin and Paclitaxel in Human Ovarian Cancer Xenograft Tumors in Mice Using FDG and FLT PET 
PLoS ONE  2013;8(12):e85126.
A combination of carboplatin and paclitaxel is often used as first line chemotherapy for treatment of ovarian cancer. Therefore the use of imaging biomarkers early after initiation of treatment to determine treatment sensitivity would be valuable in order to identify responders from non-responders. In this study we describe the non-invasive PET imaging of glucose uptake and cell proliferation using 2-deoxy-2-[18F]fluoro-D-glucose (FDG) and 3’-deoxy-3’-[18F]fluorothymidine (FLT) for early assessment of treatment response in a pre-clinical mouse model of human ovarian cancer treated with carboplatin and paclitaxel.
In vivo uptake of FLT and FDG in human ovarian cancer xenografts in mice (A2780) was determined before treatment with carboplatin and paclitaxel (CaP) and repeatedday 1, 4 and 8 after treatment start. Tracer uptake was quantified using small animal PET/CT. Tracer uptake was compared with gene expression of Ki67, TK1, GLUT1, HK1 and HK2.
Tumors in the CaP group was significantly smaller than in the control group (p=0.03) on day 8. On day 4 FDG SUVmax ratio was significantly lower in the CaP group compared to the control group (105±4% vs 138±9%; p=0.002) and on day 8 the FDG SUVmax ratio was lower in the CaP compared to the control group (125±13% vs 167±13%; p=0.05). On day 1 the uptake of FLT SUVmax ratio was 89±9% in the CaP group and 109±6% in the control group; however the difference was not statistically significant (p=0.08).
Our data suggest that both FDG and FLT PET may be used for the assessment of anti-tumor effects of a combination of carboplatin and paclitaxel in the treatment of ovarian cancer. FLT provides an early and transient signal and FDG a later and more prolonged response. This underscores the importance of optimal timing between treatment and FLT or FDG imaging since treatment response may otherwise be overlooked.
PMCID: PMC3873431  PMID: 24386456
5.  Positron emission tomography in the follow-up of cutaneous malignant melanoma patients: a systematic review 
Cutaneous malignant melanoma (CMM) has a high risk of dissemination to regional lymph nodes and visceral organs. Recurrences are most frequently seen within the first 2-3 years after initial treatment, but these patients have a life-long risk of relapse. The prognosis is highly dependent on lymph node involvement and distant metastases, accentuating the importance of close surveillance to identify disease progression at an early stage, and thereby detect recurrences amenable to treatment. Positron emission tomography (PET) has already been proven useful in the staging of CMM, but the utility of PET in follow-up programs for asymptomatic patients in high risk of relapse to detect systemic recurrences has yet to be investigated. We performed a systematic literature search in PUBMED, EMBASE and the Cochrane Controlled Trials Register, and identified 7 original studies on the diagnostic value of FDG-PET in the follow-up of CMM. Sensitivity, specificity, positive and negative predictive values were calculated to examine PET’s diagnostic value in detecting relapse. The mean sensitivity of PET was 96% and the specificity was 92%. The positive and negative predictive values were, respectively, 92% and 95%. Overall, PET has a high diagnostic value and the many advantages of PET indicate utility in the routine follow-up program of CMM. However, the number of prospective studies of high quality is scarce, and as the use of PET and PET/CT is becoming more widespread and the technology is expensive, there is an urgent need for systematic assessment of the diagnostic value.
PMCID: PMC3867726  PMID: 24380042
Melanoma; follow-up; PET; PET/CT; cancer; diagnostics; skin cancer; FDG
6.  18F-FDG imaging of human atherosclerotic carotid plaques reflects gene expression of the key hypoxia marker HIF-1α 
To investigate the association between gene expression of key molecular markers of hypoxia and inflammation in atherosclerotic carotid lesions with 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) uptake as determined clinically by positron emission tomography (PET). Studies using PET have demonstrated 18F-FDG-uptake in patients with confirmed plaques of the carotid artery. Inflammatory active or “vulnerable” plaques progressively increase in bulk, develop necrotic cores, poor vessel-wall vascularization and become prone to hypoxia. We used quantitative polymerase-chain reaction (qPCR) to determine gene expression of hypoxia-inducible factor 1α (HIF-1α) and cluster of differentiation 68 (CD68) on plaques recovered by carotid endarterectomy (CEA) in 18 patients. Gene expression was compared with 18F-FDG-uptake quantified as the maximum standardized uptake value (SUVmax) on co-registered PET/computed tomography (CT) scans performed the day before CEA. Immunohistochemistry was used to validate target-gene protein expression. In univariate linear regression analysis HIF-1α was significantly correlated with 18F-FDG-uptake (SUVmax) as was CD68. A two-tailed Pearson regression model demonstrated that HIF-1α and CD68 gene expression co-variated and accordingly when entering the variables into multivariate linear regression models with SUV-values as dependent variables, HIF-1α was eliminated in the final models. 18F-FDG-uptake (SUVmax) is correlated with HIF-1α gene expression indicating an association between hypoxia and glucose metabolism in vivo. The marker of inflammation CD68 is also associated with 18F-FDG-uptake (SUVmax). As CD68 and HIF-1α gene expression co-variate their information is overlapping.
PMCID: PMC3784801  PMID: 24116346
Hypoxia; 18F-FDG PET/CT imaging; carotid atherosclerosis; gene expression; HIF-1α
7.  Feasibility of simultaneous PET/MR of the carotid artery: first clinical experience and comparison to PET/CT 
The study aimed at comparing PET/MR to PET/CT for imaging the carotid arteries in patients with known increased risk of atherosclerosis. Six HIV-positive men underwent sequential PET/MR and PET/CT of the carotid arteries after injection of 400 MBq of 18F-FDG. PET/MR was performed a median of 131 min after injection. Subsequently,PET/CT was performed. Regions of interest (ROI) were drawn slice by slice to include the carotid arteries and standardized uptake values (SUV) were calculated from both datasets independently. Quantitative comparison of 18F-FDG uptake revealed a high congruence between PET data acquired using the PET/MR system compared to the PET/CT system. The mean difference for SUVmean was -0.18 (p < 0.001) and -0.14 for SUVmax (p < 0.001) indicating a small but significant bias towards lower values using the PET/MR system. The 95% limits of agreement were -0.55 to 0.20 for SUVmean and -0.93 to 0.65 for SUVmax. The image quality of the PET/MR allowed for delineation of the carotid vessel wall. The correlations between 18F-FDG uptake from ROI including both vessel wall and vessel lumen to ROI including only the wall were strong (r = 0.98 for SUVmean and r = 1.00 for SUVmax) indicating that the luminal 18F-FDG content had minimal influence on the values. The study shows for the first time that simultaneous PET/MR of the carotid arteries is feasible in patients with increased risk of atherosclerosis. Quantification of 18F-FDG uptake correlated well between PET/MR and PET/CT despite difference in method of PET attenuation correction, reconstruction algorithm, and detector technology.
PMCID: PMC3715780  PMID: 23900769
Atherosclerosis; positron emission tomography; magnetic resonance imaging; PET/MR; hybrid scanners
8.  [18F]FDG and [18F]FLT positron emission tomography imaging following treatment with belinostat in human ovary cancer xenografts in mice 
BMC Cancer  2013;13:168.
Belinostat is a histone deacetylase inhibitor with anti-tumor effect in several pre-clinical tumor models and clinical trials. The aim of the study was to evaluate changes in cell proliferation and glucose uptake by use of 3’-deoxy-3’-[18F]fluorothymidine ([18F]FLT) and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET) following treatment with belinostat in ovarian cancer in vivo models.
In vivo uptake of [18F]FLT and [18F]FDG in human ovary cancer xenografts in mice (A2780) were studied after treatment with belinostat. Mice were divided in 2 groups receiving either belinostat (40 mg/kg ip twice daily Day 0–4 and 6–10) or vehicle. Baseline [18F]FLT or [18F]FDG scans were made before treatment (Day 0) and repeated at Day 3, 6 and 10. Tracer uptake was quantified using small animal PET/CT.
Tumors in the belinostat group had volumes that were 462 ± 62% (640 mm3) at Day 10 relative to baseline which was significantly different (P = 0.011) from the control group 769 ± 74% (926 mm3). [18F]FLT SUVmax increased from baseline to Day 10 (+30 ± 9%; P = 0.048) in the control group. No increase was observed in the treatment group. [18F]FDG SUVmean was significantly different in the treatment group compared to the control group (P = 0.0023) at Day 10. Within treatment groups [18F]FDG uptake and to a lesser extent [18F]FLT uptake at Day 3 were significantly correlated with tumor growth at Day 10.
[18F]FDG uptake early following treatment initiation predicted tumor sizes at Day 10, suggesting that [18F]FDG may be a valuable biomarker for non-invasive assessment of anti-tumor activity of belinostat.
PMCID: PMC3621527  PMID: 23548101
Positron emission tomography (PET); Belinostat; Histone deacetylase inhibitor; [18F]FLT; [18F]FDG; Computed tomography (CT)
9.  Imaging of Metastatic Lymph Nodes by X-ray Phase-Contrast Micro-Tomography 
PLoS ONE  2013;8(1):e54047.
Invasive cancer causes a change in density in the affected tissue, which can be visualized by x-ray phase-contrast tomography. However, the diagnostic value of this method has so far not been investigated in detail. Therefore, the purpose of this study was, in a blinded manner, to investigate whether malignancy could be revealed by non-invasive x-ray phase-contrast tomography in lymph nodes from breast cancer patients. Seventeen formalin-fixed paraffin-embedded lymph nodes from 10 female patients (age range 37–83 years) diagnosed with invasive ductal carcinomas were analyzed by X-ray phase-contrast tomography. Ten lymph nodes had metastatic deposits and 7 were benign. The phase-contrast images were analyzed according to standards for conventional CT images looking for characteristics usually only visible by pathological examinations. Histopathology was used as reference. The result of this study was that the diagnostic sensitivity of the image analysis for detecting malignancy was 100% and the specificity was 87%. The positive predictive value was 91% for detecting malignancy and the negative predictive value was 100%. We conclude that x-ray phase-contrast imaging can accurately detect density variations to obtain information regarding lymph node involvement previously inaccessible with standard absorption x-ray imaging.
PMCID: PMC3548812  PMID: 23349784
10.  [18F]FLT and [18F]FDG PET for Non-invasive Treatment Monitoring of the Nicotinamide Phosphoribosyltransferase Inhibitor APO866 in Human Xenografts 
PLoS ONE  2013;8(1):e53410.
APO866 is a new anti-tumor compound inhibiting nicotinamide phosphoribosyltransferase (NAMPT). APO866 has an anti-tumor effect in several pre-clinical tumor models and is currently in several clinical phase II studies. 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT) is a tracer used to assess cell proliferation in vivo. The aim of this study was non-invasively to study effect of APO866 treatment on [18F]FLT and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) uptake.
In vivo uptake of [18F]FLT and [18F]FDG in human ovary cancer xenografts in mice (A2780) was studied at various time points after APO866 treatment. Baseline [18F]FLT or [18F]FDG scans were made before treatment and repeated after 24 hours, 48 hours and 7 days. Tumor volume was followed with computed tomography (CT). Tracer uptake was quantified using small animal PET/CT. One hour after iv injection of tracer, static PET scans were performed. Imaging results were compared with Ki67 immunohistochemistry.
Tumors treated with APO866 had volumes that were 114% (24 h), 128% (48 h) and 130% (Day 7) relative to baseline volumes at Day 0. In the control group tumor volumes were 118% (24 h), 145% (48 h) and 339% (Day 7) relative to baseline volumes Day 0. Tumor volume between the treatment and control group was significantly different at Day 7 (P = 0.001). Compared to baseline, [18F]FLT SUVmax was significantly different at 24 h (P<0.001), 48 h (P<0.001) and Day 7 (P<0.001) in the APO866 group. Compared to baseline, [18F]FDG SUVmax was significantly different at Day 7 (P = 0.005) in the APO866 group.
APO866 treatment caused a significant decrease in [18F]FLT uptake 24 and 48 hours after treatment initiation. The early reductions in tumor cell proliferation preceded decrease in tumor volume. The results show the possibility to use [18F]FLT and [18F]FDG to image treatment effect early following treatment with APO866 in future clinical studies.
PMCID: PMC3537726  PMID: 23308217
11.  [18F]FLT PET for Non-Invasive Assessment of Tumor Sensitivity to Chemotherapy: Studies with Experimental Chemotherapy TP202377 in Human Cancer Xenografts in Mice 
PLoS ONE  2012;7(11):e50618.
3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT) is a tracer used to assess cell proliferation in vivo. The aim of the study was to use [18F]FLT positron emission tomography (PET) to study non-invasively early anti-proliferative effects of the experimental chemotherapeutic agent TP202377 in both sensitive and resistant tumors.
Xenografts in mice from 3 human cancer cell lines were used: the TP202377 sensitive A2780 ovary cancer cell line (n = 8–16 tumors/group), the induced resistant A2780/Top216 cell line (n = 8–12 tumors/group) and the natural resistant SW620 colon cancer cell line (n = 10 tumors/group). In vivo uptake of [18F]FLT was studied at baseline and repeated 6 hours, Day 1, and Day 6 after TP202377 treatment (40 mg/kg i.v.) was initiated. Tracer uptake was quantified using small animal PET/CT.
TP202377 (40 mg/kg at 0 hours) caused growth inhibition at Day 6 in the sensitive A2780 tumor model compared to the control group (P<0.001). In the A2780 tumor model TP202377 treatment caused significant decrease in uptake of [18F]FLT at 6 hours (-46%; P<0.001) and Day 1 (-44%; P<0.001) after treatment start compared to baseline uptake. At Day 6 uptake was comparable to baseline. Treatment with TP202377 did not influence tumor growth or [18F]FLT uptake in the resistant A2780/Top216 and SW620 tumor models. In all control groups uptake of [18F]FLT did not change. Ki67 gene expression paralleled [18F]FLT uptake.
Treatment of A2780 xenografts in mice with TP202377 (single dose i.v.) caused a significant decrease in cell proliferation assessed by [18F]FLT PET after 6 hours. Inhibition persisted at Day 1; however, cell proliferation had returned to baseline at Day 6. In the resistant A2780/Top216 and SW620 tumor models uptake of [18F]FLT did not change after treatment. With [18F]FLT PET it was possible to distinguish non-invasively between sensitive and resistant tumors already 6 hours after treatment initiation.
PMCID: PMC3511543  PMID: 23226334
12.  PET/MR in oncology: an introduction with focus on MR and future perspectives for hybrid imaging 
After more than 20 years of research, a fully integrated PET/MR scanner was launched in 2010 enabling simultaneous acquisition of PET and MR imaging. Currently, no clinical indication for combined PET/MR has been established, however the expectations are high. In this paper we will discuss some of the challenges inherent in this new technology, but focus on potential applications for simultaneous PET/MR in the field of oncology. Methods and tracers for use with the PET technology will be familiar to most readers of this journal; thus this paper aims to provide a short and basic introduction to a number of different MRI techniques, such as DWI-MR (diffusion weighted imaging MR), DCE-MR (dynamic contrast enhanced MR), MRS (MR spectroscopy) and MR for attenuation correction of PET. All MR techniques presented in this paper have shown promising results in the treatment of patients with solid tumors and could be applied together with PET increasing the amount of information about the tissues of interest. The potential clinical benefit of applying PET/MR in staging, radiotherapy planning and treatment evaluation in oncology, as well as the research perspectives for the use of PET/MR in the development of new tracers and drugs will be discussed.
PMCID: PMC3484424  PMID: 23145362
PET/MR; oncology; diagnosis; staging; therapy evaluation; radiotherapy planning; molecular imaging
13.  Brain perfusion CT compared with 15O-H2O PET in patients with primary brain tumours 
Perfusion CT (PCT) measurements of regional cerebral blood flow (rCBF) have been proposed as a fast and easy method for identifying angiogenically active tumours. In this study, quantitative PCT rCBF measurements in patients with brain tumours were compared to the gold standard PET rCBF with 15O-labelled water (15O-H2O).
On the same day within a few hours, rCBF was measured in ten adult patients with treatment-naïve primary brain tumours, twice using 15O-H2O PET and once with PCT performed over the central part of the tumour. Matching rCBF values in tumour and contralateral healthy regions of interest were compared.
PCT overestimated intratumoural blood flow in all patients with volume-weighted mean rCBF values of 28.2 ± 18.8 ml min−1 100 ml−1 for PET and 78.9 ± 41.8 ml min−1 100 ml−1 for PCT. There was a significant method by tumour grade interaction with a significant tumour grade rCBF difference for PCT of 32.9 ± 15.8 ml min−1 100 ml−1 for low-grade (WHO I + II) and 81.5 ± 15.4 ml min−1 100 ml−1 for high-grade (WHO III + IV) tumours, but not for PET. The rCBF PCT and PET correlation was only significant within tumours in two patients.
Although intratumoural blood flow measured by PCT may add valuable information on tumour grade, the method cannot substitute quantitative measurements of blood flow by PET and 15O-H2O PET in brain tumours.
PMCID: PMC3464373  PMID: 22736199
PET; Brain perfusion; Brain tumour; Oxygen radioisotopes; Perfusion CT
14.  Brain perfusion CT compared with15O-H2O-PET in healthy subjects 
EJNMMI Research  2011;1:28.
Regional cerebral blood flow [rCBF] measurements are valuable for identifying angiogenically active tumours, and perfusion computed tomography [CT] has been suggested for that purpose. This study aimed to validate rCBF measurements by perfusion CT with positron-emission tomography [PET] and15O-labelled water [15O-H2O] in healthy subjects.
RCBF was measured twice in 12 healthy subjects with15O-H2O PET and once with perfusion CT performed over the basal ganglia. Matching rCBF values in regions of interest were compared.
Measured with perfusion CT, rCBF was significantly and systematically overestimated. White matter rCBF values were 17.4 ± 2.0 (mean ± SD) mL min-1 100 g-1 for PET and 21.8 ± 3.4 mL min-1 100 g-1 for perfusion CT. Grey matter rCBF values were 48.7 ± 5.0 mL min-1 100 g-1 for PET and 71.8 ± 8.0 mL min-1 100 g-1 for perfusion CT. The overestimation of grey matter rCBF could be reduced from 47% to 20% after normalization to white matter rCBF, but the difference was still significant.
RCBF measured with perfusion CT does contain perfusion information, but neither quantitative nor relative values can substitute rCBF measured by15O-H2O PET yet. This, however, does not necessarily preclude a useful role in patient management.
PMCID: PMC3251173  PMID: 22214473
brain perfusion imaging; PET; oxygen radioisotopes; perfusion CT; healthy human subjects
15.  Surveys of current status in biomedical science grant review: funding organisations' and grant reviewers' perspectives 
BMC Medicine  2010;8:62.
The objectives of this research were (a) to describe the current status of grant review for biomedical projects and programmes from the perspectives of international funding organisations and grant reviewers, and (b) to explore funders' interest in developing uniform requirements for grant review aimed at making the processes and practices of grant review more consistent, transparent, and user friendly.
A survey to a convenience sample of 57 international public and private organisations that give grants for biomedical research was conducted. Nine participating organisations then emailed a random sample of their external reviewers an invitation to participate in a second electronic survey.
A total of 28 of 57 (49%) organisations in 19 countries responded. Organisations reported these problems as frequent or very frequent: declined review requests (16), late reports (10), administrative burden (7), difficulty finding new reviewers (4), and reviewers not following guidelines (4). The administrative burden of the process was reported to have increased over the past 5 years. In all, 17 organisations supported the idea of uniform requirements for conducting grant review and for formatting grant proposals. A total of 258/418 (62%) reviewers responded from 22 countries. Of those, 48% (123/258) said their institutions encouraged grant review, yet only 7% (17/258) were given protected time and 74% (192/258) received no academic recognition for this. Reviewers rated these factors as extremely or very important in deciding to review proposals: 51% (131/258) desire to support external fairness, 47% (120/258) professional duty, 46% (118/258) relevance of the proposal's topic, 43% (110/258) wanting to keep up to date, 40% (104/258) desire to avoid suppression of innovation. Only 16% (42/258) reported that guidance from funders was very clear. In all, 85% (220/258) had not been trained in grant review and 64% (166/258) wanted this.
Funders reported a growing workload of biomedical proposals that is getting harder to peer review. Just under half of grant reviewers take part for the good of science and professional development, but many report lack of academic and practical support and clear guidance. Around two-thirds of funders supported the development of uniform requirements for the format and peer review of proposals to help ease the current situation.
PMCID: PMC2974654  PMID: 20961441
16.  Early Detection of Response to Experimental Chemotherapeutic Top216 with [18F]FLT and [18F]FDG PET in Human Ovary Cancer Xenografts in Mice 
PLoS ONE  2010;5(9):e12965.
3′-deoxy-3′-[18F]fluorothymidine (18F-FLT) is a tracer used to assess cell proliferation in vivo. The aim of the study was to use 18F-FLT positron emission tomography (PET) to study treatment responses to a new anti-cancer compound. To do so, we studied early anti-proliferative effects of the experimental chemotherapy Top216 non-invasively by PET.
Methodology/Principal Findings
In vivo uptake of 18F-FLT in human ovary cancer xenografts in mice (A2780) was studied at various time points after Top216 treatment (50 mg/kg i.v. at 0 and 48 hours) was initiated. Baseline 18F-FLT scans were made before either Top216 (n = 7–10) or vehicle (n = 5–7) was injected and repeated after 2 and 6 hours and 1 and 5 days of treatment. A parallel study was made with 2′-deoxy-2′-[18F]fluoro-D-glucose (18F-FDG) (n = 8). Tracer uptake was quantified using small animal PET/CT. Imaging results were validated by tumor volume changes and gene-expression of Ki67 and TK1. Top216 (50 mg/kg 0 and 48 hours) inhibited the growth of the A2780 tumor compared to the control group (P<0.001). 18F-FLT uptake decreased significantly at 2 hours (−52%; P<0.001), 6 hours (−49%; P = 0.002) and Day 1 (−47%; P<0.001) after Top216 treatment. At Day 5 18F-FLT uptake was comparable to uptake in the control group. Uptake of 18F-FLT was unchanged in the control group during the experiment. In the treatment group, uptake of 18F-FDG was significantly decreased at 6 hours (−21%; P = 0.003), Day 1 (−29%; P<0.001) and Day 5 (−19%; P = 0.05) compared to baseline.
One injection with Top216 initiated a fast and significant decrease in cell-proliferation assessable by 18F-FLT after 2 hours. The early reductions in tumor cell proliferation preceded changes in tumor size. Our data indicate that 18F-FLT PET is promising for the early non-invasive assessment of chemotherapy effects in both drug development and for tailoring therapy in patients.
PMCID: PMC2945761  PMID: 20885974
17.  Cerebral FDG-PET scanning abnormalities in optimally treated HIV patients 
The long-term neurological consequences of HIV infection and treatment are not yet completely understood. In this study we examined the prevalence of cerebral metabolic abnormalities among a cohort of neurologically intact HIV patients with fully suppressed HIV viral loads. Concomitant analyses of circulating brain derived neurotrophic factor (BDNF) were performed to correlate these abnormalities with potential signs of neuro-regenerating/protective activity, and concomitant analyses of circulating tumour necrosis factor (TNF) α, interleukin (IL) 6, and soluble urokinase plasminogen activator receptor (suPAR) were performed to correlate these abnormalities with potential signs of neurodegenerative processes.
The study population consisted of HIV-positive patients known to be infected for more than 5 years and on antiretroviral (ARV) treatment for a minimum of three years with no history of virological failure, a CD4 count above 200 × 106 cells/l and no other co-morbidities. The distribution of the regional cerebral metabolic rate of glucose metabolism was measured using fluorine-18-flourodeoxyglucose positron emission tomography (FDG-PET) scanning. The PET scans were evaluated for individual pathology using Neurostat software and for group pathology using statistical parametric mapping (SPM). Circulating levels of BDNF, TNF α, IL-6 and suPAR were measured by ELISA techniques.
More than half (55%) of the patients exhibited varying severities of mesial frontal reduction in the relative metabolic rate of glucose. Compared to healthy subjects, the patients with abnormal FDG-PET scanning results had a shorter history of known HIV infection, fewer years on antiretroviral therapy and higher levels of circulating TNF α and IL-6 (p = 0.08).
A large proportion of optimally treated HIV patients exhibit cerebral FDG-PET scanning abnormalities and elevated TNF α and IL-6 levels, which may indicate imminent neuronal damage. The neuroprotective effect of early ARV treatment should be considered in future prospective follow-up studies.
PMCID: PMC2838836  PMID: 20152054
19.  Coregulation of Glucose Uptake and Vascular Endothelial Growth Factor (VEGF) in Two Small-Cell Lung Cancer (SCLC) Sublines In Vivo and In Vitro1 
Neoplasia (New York, N.Y.)  2001;3(1):80-87.
We examined the relationship between 18F- labeled 2-fluro-2-deoxy-d-glucose (FDG) uptake, and expression of glucose transporters (GLUTs) in two human small-cell lung cancer (SCLC) lines CPH 54A and CPH 54B. Changes in the expression of GLUTs and vascular endothelial growth factor (VEGF) during 12-, 18-, and 24 hours of severe hypoxia in vivo (xenografts) and in vitro (cell cultures) were recorded for both tumor lines. The two SCLC lines are subpopulations of the same patient tumor. In spite of their common genomic origin they represent consistently different metabolic and microenvironmental phenotypes as well as treatment sensitivities. There were higher levels of Glut-1 protein in 54B and a correspondingly higher FDG uptake in this tumor line (P<.001). During hypoxia a significant upregulation of in VEGF mRNA, GLUT-1 mRNA, and Glut-1 and -3 protein occurred with a distinctly different time course in the two cell lines. A similar co-upregulation of GLUT and VEGF was seen in hypoxic tumors of both lines. There were no significant changes of HIF-1α mRNA during hypoxia in either of the cell lines. A more detailed understanding of such correlations between glucose metabolism, angiogenesis, and microenvironmental phenotype of tumors, by positron emission tomography (PET) and molecular techniques might further sophisticate our interpretation of glycolytic predominance in tumors as seen by 18FFDG PET.
PMCID: PMC1505028  PMID: 11326319
VEGF; GLUT-1; hypoxia; HIF-1α; small-cell lung cancer
20.  Calibrated image-derived input functions for the determination of the metabolic uptake rate of glucose with [18F]-FDG PET 
Nuclear Medicine Communications  2014;35(4):353-361.
We investigated the use of a simple calibration method to remove bias in previously proposed approaches to image-derived input functions (IDIFs) when used to calculate the metabolic uptake rate of glucose (Km) from dynamic [18F]-FDG PET scans of the thigh. Our objective was to obtain nonbiased, low-variance Km values without blood sampling.
Materials and methods
We evaluated eight previously proposed IDIF methods. Km values derived from these IDIFs were compared with Km values calculated from the arterial blood samples (gold standard). We used linear regression to extract calibration parameters to remove bias. Following calibration, cross-validation and bootstrapping were used to estimate the mean square error and variance.
Three of the previously proposed methods failed mainly because of zero-crossings of the IDIF. The remaining five methods were improved by calibration, yielding unbiased Km values. The method with the lowest SD yielded an SD of 0.0017/min – that is, below 10% of the muscle Km value in this study.
Previously proposed IDIF methods can be improved by using a simple calibration procedure. The calibration procedure may be used in other studies, thus obviating the need for arterial blood sampling, once the calibration parameters have been established in a subgroup of participants. The method has potential for use in other parts of the body as it is robust with regard to partial volume effects.
PMCID: PMC3940375  PMID: 24335879
calibration; image-derived input function; kinetic analysis; positron emission tomography
21.  Positron emission tomography/computed tomography for optimized colon cancer staging and follow up 
Optimal management of colon cancer (CC) requires detailed assessment of extent of disease. This study prospectively investigates the diagnostic accuracy of 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography (PET/CT) for staging and detection of recurrence in primary CC.
Material and methods
PET/CT for preoperative staging was performed in 66 prospectively included patients with primary CC. Diagnostic accuracy for PET/CT and CT was analyzed. In addition to routine follow up, 42 stages I–III CC patients had postoperative PET/CT examinations every 6 months for 2 years. Serological levels of tissue inhibitor of metalloproteinase-1 (TIMP-1), carcinoembryonic antigen, and liberated domain I of urokinase plasminogen activator receptor were analyzed.
Accuracy for tumor, nodal, and metastases staging by PET/CT were 82% (95% confidence interval [CI]: 70; 91), 66% (CI: 51; 78), and 89% (CI: 79; 96); for CT the accuracy was 77% (CI: 64; 87), 60% (CI: 46; 73), and 69% (CI: 57; 80). Cumulative relapse incidences for stages I–III CC at 6, 12, 18, and 24 months were 7.1% (CI: 0; 15); 14.3% (CI: 4; 25); 19% (CI: 7; 31), and 21.4% (CI: 9; 34). PET/CT diagnosed all relapses detected during the first 2 years. High preoperative TIMP-1 levels were associated with significant hazards toward risk of recurrence and shorter overall survival.
This study indicates PET/CT as a valuable tool for staging and follow up in CC. TIMP-1 provided prognostic information potentially useful in selection of patients for intensive follow up.
PMCID: PMC3956490  PMID: 24286594
carcinoembryonic antigen; colonic neoplasms; colorectal neoplasms; neoplasm staging; positron emission tomography; prognosis; receptors; tissue inhibitor of metalloproteinase-1; urokinase plasminogen activator; X-ray computed tomography

Results 1-21 (21)