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1.  18F-click labeling of a bombesin antagonist with an alkyne-18F-ArBF3 -: in vivo PET imaging of tumors expressing the GRP-receptor 
A clickable alkyne-modified arylborimidine is rapidly converted in 15 minutes to a highly polar 18F-aryltrifluoroborate anion (18F-ArBF3 -) at high specific activity. Following labeling, the alkyne-18F-ArBF3 - was conjugated to the peptide bombesin (BBN) within 25 minutes in a second step without need for prior work-up making this one-pot-two-step method easy, user-friendly, and generally applicable. Bombesin was chosen to provide functional PET images of prostate cancer xenografts in mice of which there are few. Whereas BBN is labeled to provide some of the first in vivo tumor images based on this technique, click-labeling is recognized for its generality and broad substrate scope. Hence these results are likely to be useful for click labeling most peptides and other biomolecules.
PMCID: PMC3545365  PMID: 23342301
18F-labeling; PET imaging; click chemistry; bombesin imaging
2.  Combined SPECT and multidetector CT for prostate cancer evaluations 
111In-capromab pendetide is an imaging probe for noninvasive detection of prostate cancer dissemination, and can be difficult to interpret because of low photon statistics resulting in noisy images with limited anatomical precision. We examined if a 16-slice multidetector computed tomography (MDCT) combined with single photon emission computed tomography (SPECT) could increase the impact on the clinical management and improve confidence in SPECT image interpretations in comparison to a relatively low-mA (limited resolution) CT. 17 scans were reviewed from a SPECT combined with low-mA CT scanner; 21 scans were reviewed from a SPECT combined with 16-slice MDCT scanner. Reports of the clinical interpretations from the imaging studies, additional examinations performed by referring physicians as a follow-up to the imaging results, and long-term clinical and laboratory follow-ups were used to define confidence of the SPECT/CT readings and impact of the readings on the patient management. The impact was defined as: the occurrence of the 111In-capromab pendetide interpretation resulted in additional imaging studies or biopsies. MDCT improved the quality and confidence in the characterization of small lymph nodes with or without uptake of 111In-capromab pendetide. The increased confidence with MDCT in SPECT/CT readings was evident in all cases reviewed in this study, and the impact on the clinical management was higher (8 out of 21) using SPECT/MDCT than the impact using SPECT combined with low-mA CT (2 out of 17). The dual-modality SPECT/CT provides a quantifiable benefit when MDCT is used instead of low-mA CT, particularly for prostate cancer evaluations using 111In-capromab pendetide.
PMCID: PMC3260786  PMID: 22267999
Prostate cancer; capromab pendetide; SPECT/CT; MDCT; prostate specific membrane antigen (PSMA)
3.  The next evolution in radioguided surgery: breast cancer related sentinel node localization using a freehandSPECT-mobile gamma camera combination 
Accurate pre- and intraoperative identification of the sentinel node (SN) forms the basis of the SN biopsy procedure. Gamma tracing technologies such as a gamma probe (GP), a 2D mobile gamma camera (MGC) or 3D freehandSPECT (FHS) can be used to provide the surgeon with radioguidance to the SN(s). We reasoned that integrated use of these technologies results in the generation of a “hybrid” modality that combines the best that the individual radioguidance technologies have to offer. The sensitivity and resolvability of both 2D-MGC and 3D-FHS-MGC were studied in a phantom setup (at various source-detector depths and using varying injection site-to-SN distances), and in ten breast cancer patients scheduled for SN biopsy. Acquired 3D-FHS-MGC images were overlaid with the position of the phantom/patient. This augmented-reality overview image was then used for navigation to the hotspot/SN in virtual-reality using the GP. Obtained results were compared to conventional gamma camera lymphoscintigrams. Resolution of 3D-FHS-MGC allowed identification of the SNs at a minimum injection site (100 MBq)-to-node (1 MBq; 1%) distance of 20 mm, up to a source-detector depth of 36 mm in 2D-MGC and up to 24 mm in 3D-FHS-MGC. A clinically relevant dose of approximately 1 MBq was clearly detectable up to a depth of 60 mm in 2D-MGC and 48 mm in 3D-FHS-MGC. In all ten patients at least one SN was visualized on the lymphoscintigrams with a total of 12 SNs visualized. 3D-FHS-MGC identified 11 of 12 SNs and allowed navigation to all these visualized SNs; in one patient with two axillary SNs located closely to each other (11 mm), 3D-FHS-MGC was not able to distinguish the two SNs. In conclusion, high sensitivity detection of SNs at an injection site-to-node distance of 20 mm-and-up was possible using 3D-FHS-MGC. In patients, 3D-FHS-MGC showed highly reproducible images as compared to the conventional lymphoscintigrams.
PMCID: PMC4446392  PMID: 26069857
Sentinel node; freehandSPECT; nuclear medicine; navigation; radioguided surgery; breast cancer; mobile gamma camera
4.  In vivo inflammation imaging using a CB2R-targeted near infrared fluorescent probe 
Chronic inflammation is considered as a critical cause of a host of disorders, such as cancer, rheumatoid arthritis, atherosclerosis, and neurodegenerative diseases, although the exact mechanism is yet to be explored. Imaging tools that can specifically target inflammation are therefore important to help reveal the role of inflammation in disease progression, and allows for developing new therapeutic strategies to ultimately improve patient care. The purpose of this study was to develop a new in vivo inflammation imaging approach by targeting the cannabinoid receptor type 2 (CB2R), an emerging inflammation biomarker, using a unique near infrared (NIR) fluorescent probe. Herein, we report the first in vivo CB2R-targeted NIR inflammation imaging study using a synthetic fluorescent probe developed in our laboratory, NIR760-mbc94. In vitro binding assay and fluorescence microscopy study indicate NIR760-mbc94 specifically binds towards CB2R in mouse RAW264.7 macrophage cells. Furthermore, in vivo imaging was performed using a Complete Freund’s Adjuvant (CFA)-induced inflammation mouse model. NIR760-mbc94 successfully identified inflamed tissues and the probe uptake was blocked by a CB2R ligand, SR144528. Additionally, immunofluorescence staining in cryosectioned tissues validated the NIR760-mbc94 uptake in inflamed tissues. In conclusion, this study reports the first in vivo CB2R-targeted inflammation imaging using an NIR fluorescent probe. Specific targeting of NIR760-mbc94 has been demonstrated in macrophage cells, as well as a CFA-induced inflammation mouse model. The combined evidence indicates that NIR760-mbc94 is a promising inflammation imaging probe. Moreover, in vivo CB2R-targeted fluorescence imaging may have potential in the study of inflammation-related diseases.
PMCID: PMC4446393  PMID: 26069858
Inflammation; cannabinoid receptor; CB2; fluorescent probe; optical imaging; near infrared
5.  Dosimetry of [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 in rodents, pigs, non-human primates and human - repeated scanning in human is possible 
Quantitative PET imaging with [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 has potential use in diabetes and cancer. However, the radiation dose to the kidneys has been a concern for the possibility of repeated imaging studies in humans. Therefore, we investigated the dosimetry of [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 based on the biodistribution data in rats, pigs, non-human primates (NHP) and a human.Organ distribution of [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 in rats (Male Lewis; n=12; 30, 60, and 80 min) was measured ex vivo. The dynamic uptake of [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 in the abdomen was assessed by PET/CT scanning of pigs (male; n = 4, 0-60 min), NHP (Female; cynomolgus; n=3; 0-90 min), and human (female; n=1; 0-40, 100, 120 min).The organ distribution data in each species were extrapolated to those of a human, assuming similar distribution between the species. Residence times were assessed by trapezoidal approximation of the kinetic data. Organ doses (mGy/MBq) and the whole body effective dose (mSv/MBq), was extrapolated by using the OLINDA/EXM 1.1 software. The extrapolated human whole body effective dose was 0.017 ± 0.004 (rats), 0.014 ± 0.004 (pigs), 0.017 ± 0.004 (NHP), and 0.016 (human) mSv/MBq. The absorbed dose to the kidneys was limiting:0.33 ± 0.06 (rats), 0.28±0.05 (pigs), 0.65 ± 0.11 (NHP), and 0.28 (human) mGy/MBq, which corresponded to the maximum yearly administered amounts of 455 (rat), 536 (pig), 231 (NHP), and 536 (human) MBq before reaching the yearly kidney limiting dose of 150 mGy. More than 200 MBq of [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 can be administered yearly in a human, allowing for repeated (2-4 times) scanning. This potentially enables longitudinal clinical PET imaging studies of the GLP-1R in the pancreas, transplanted islets, or insulinoma.
PMCID: PMC4446394  PMID: 26069859
Dosimetry; [68Ga]Ga-DO3A-VS-Cys40-Exendin-4; GLP-1R; PET; islet imaging; insulinoma
6.  An anesthetic method compatible with 18F-FDG-PET studies in mice 
The purpose of this study was to establish an experimental setting and an anesthetic method compatible with future sequential studies using 18F-FDG-PET single scans, i.e. autoradiographic measurements, for the estimation of metabolic rate of glucose (MRglc) in mice. In this study we had no access to a small animal PET scanner and therefore focus was on the anesthetic setting and optimization of the input function as a preparation for the future tumor metabolic studies. Initially, four combinations of intraperitoneal (ip) anesthesia were tested on tumor bearing mice. Fentanyl-fluanisone plus diazepam yielded low and stable blood glucose levels and kept the animals sedated for approximately 2 h. The anesthesia was also tested in a longitudinal 18F-FDG study, where tumor bearing mice were anesthetized, injected with 18F-FDG, and sampled for blood, before, one day after, and 8 days after treatment with cisplatin. The animals were in good condition during the entire study period. To validate the method, average MRglc of whole brain and cerebellum in mice were calculated and compared with the literature. The average MRglc in the whole brain and cerebellum were 46.2±4.4 and 39.0±3.1 µmol 100g-1 min-1. In the present study, we have shown that an ip anesthesia with a combination of fentanyl-fluanisone and diazepam is feasible and provides stable and low blood glucose levels after a fasting period of 4 h in experiments in nude mice with xenografted human tumors. We have also verified that 18F-FDG, intraperitoneally administrated, results in an expected plasma activity uptake and clearance. The method doesn’t alter the uptake in brain which is an indirect indication that the anesthesia doesn’t alter the uptake in other organs. In combination with meticulous animal handling this set-up is reliable and future sequential tumor studies of early metabolic effects with calculation of MRglc following cytotoxic therapy are made possible.
PMCID: PMC4446395  PMID: 26069860
18F-FDG; metabolic rate of glucose (MRglc); anesthesia; mice
7.  Influence of CT-based attenuation correction on dopamine transporter SPECT with [123I]FP-CIT 
Dopamine transporter (DAT) imaging using single-photon emission computed tomography (SPECT) and 123I-labelled radiopharmaceuticals like [123I]FP-CIT is an established part in the diagnostic work-up of parkinsonism. Guidelines recommend attenuation correction (AC), either by a calculated uniform attenuation matrix (calAC) or by a measured attenuation map (nowadays done by low-dose CT; CTAC). We explored the impact of CTAC compared to conventional calAC on diagnostic accuracy and the use of DAT availability as a biomarker of nigrostriatal integrity.Integrated SPECT/CT studies with [123I]FP-CIT were performed in patients with Parkinson’s disease (PD; n = 15) and essential tremor (ET; n = 15). SPECT data was reconstructed with calAC, CTAC and without AC (noAC). Regional DAT availability was assessed by uniform volume-of-interest analyses providing striatal binding potential (BP ND) estimates. BP ND values were compared among methods and correlated with clinical parameters. Compared to calAC, both CTAC and noAC provided significantly lower, but highly linearly correlated BP ND estimates (R 2 = 0.96). Diagnostic performance to distinguish between patients with PD and those with ET was very high and did not differ between AC methods. CTAC and noAC data tended so show a stronger correlation with severity and duration of disease in PD and age in ET than did calAC. Defining the reference region on low-dose CT instead of SPECT did not consistently alter findings. [123I]FP-CIT SPECT provides a very high diagnostic accuracy for differentiation between PD and ET that is not dependent on the employed AC method. Preliminary correlations analyses suggest that BP ND estimates derived from CTAC represent a superior biomarker of nigrostriatal integrity.
PMCID: PMC4446396  PMID: 26069861
Single-photon emission computed tomography; attenuation correction; dopamine transporter; FP-CIT; Parkinson’s disease; essential tremor
8.  18F-FDG PET/CT and pain in metastatic bone cancer 
This study aims to determine if the pain intensity of patients with oncologic bone metastases (BM) correlates with metabolic activity measured by 18F-FDG PET/CT. Twenty-eight patients, ages: 21-89 years (mean: 58.8) with BM were included in the study between September 2011 to September 2013. All patients completed a detailed questionnaire regarding pain symptoms on the visual analog scale (VAS), analgesic use, and areas of chronic pain, prior to obtaining an 18F-FDG PET/CT. Pain symptoms were queried for 11 body regions including limbs, head, torso, etc. and the corresponding SUVmax of BMs within that region were modeled with the corresponding clinical data using a linear mixed effects model and a linear regression model. Overall 64 areas in the 28 subjects were found to have BM. SUVmax was found to be a significant predictor of pain intensity as measured by the VAS, with a P-value of 0.045, with a modest effect-size on linear regression of R2 of 0.11.
PMCID: PMC4446397  PMID: 26069862
18F-FDG; bone metastasis; SUV pain
9.  Quantitative carotid PET/MR imaging: clinical evaluation of MR-Attenuation correction versus CT-Attenuation correction in 18F-FDG PET/MR emission data and comparison to PET/CT 
Current PET/MR systems employ segmentation of MR images and subsequent assignment of empirical attenuation coefficients for quantitative PET reconstruction. In this study we examine the differences in the quantification of 18F-FDG uptake in the carotid arteries between PET/MR and PET/CT scanners. Five comparisons were performed to asses differences in PET quantification: i) PET/MR MR-based AC (MRAC) versus PET/MR CTAC, ii) PET/MR MRAC versus PET/CT, iii) PET/MR MRAC with carotid coil versus PET/MR MRAC without coil, iv) PET/MR MRAC scan 2 versus PET/MR MRAC scan 1, and v) PET/MR CTAC versus PET/CT. Standardized uptakes values (SUV) mean and SUV maximum were calculated for six regions-of-interests: left and right carotid arteries, left and right lungs, spine and muscle. Pearson’s Correlation and Bland-Altman plots were used to compare SUV mean and maximum within each ROI of each patient. PET/MR emission data reconstructed with MRAC versus PET/MR emission data reconstructed with CTAC had percent differences of SUV mean ranging from -2.0% (Absolute Difference, -0.02) to 7.4% (absolute difference, 0.06). Percent differences within the carotid arteries proved to correlate well with differences of SUV mean of 5.4% (Absolute Difference, 0.07) in the left carotid and 2.7% (Absolute Difference, 0.03) in the right carotid. Pearson’s correlation and Bland-Altman of PET/MR with MRAC versus PET/MR with CTAC showed high correlation between SUV mean (R2=0.80, mean difference 0.03 ± 0.18 SUV, p=0.3382), demonstrating excellent correlation within ROIs analyzed. The results of this study support the use of 18F-FDG PET/MR for quantitative measure of inflammation in the carotid arteries.
PMCID: PMC4446398  PMID: 26069863
PET/MR; attenuation correction; PET/CT; carotid arteries; cardiovascular
10.  Dosimetry of [177Lu]-DO3A-VS-Cys40-Exendin-4 – impact on the feasibility of insulinoma internal radiotherapy 
[68Ga]-DO3A-VS-Cys40-Exendin-4 has been shown to be a promising imaging candidate for targeting glucagon like peptide-1 receptor (GLP-1R). In the light of radiotheranostics and personalized medicine the 177Lu-labelled analogue is of paramount interest. In this study we have investigated the organ distribution of [177Lu]-DO3A-VS-Cys40-Exendin-4 in rat and calculated human dosimetry parameters in order to estimate the maximal acceptable administered radioactivity, and thus potential applicability of [177Lu]-DO3A-VS-Cys40-Exendin-4 for internal radiotherapy of insulinomas. Nine male and nine female Lewis rats were injected with [177Lu]-DO3A-VS-Cys40-Exendin-4 for ex vivo organ distribution study at nine time points. The estimation of human organ/total body absorbed and total effective doses was performed using Organ Level Internal Dose Assessment Code software (OLINDA/EXM 1.1). Six more rats (male: n = 3; female: n = 3) were scanned by single photon emission tomography and computed tomography (SPECT-CT). The renal function and potential cell dysfunction were monitored by creatinine ISTAT and glucose levels. The fine uptake structure of kidney and pancreas was investigated by ex vivo autoradiography. Blood clearance and washout from most of the organs was fast. The kidney was the dose-limiting organ with absorbed dose of 5.88 and 6.04 mGy/MBq, respectively for female and male. Pancreatic beta cells demonstrated radioactivity accumulation. Renal function and beta cell function remained unaffected by radiation. The absorbed dose of [177Lu]-DO3A-VS-Cys40-Exendin-4 to kidneys may limit the clinical application of the agent. However, hypothetically, kidney protection and peptidase inhibition may allow reduction of kidney absorbed dose and amplification of tumour absorbed doses.
PMCID: PMC4396004  PMID: 25973333
Lu-177; Exendin-4; dosimetry; insulinoma; imaging; radiotherapy
11.  Comparison of FDG-PET/CT images between chronic renal failure patients on hemodialysis and controls 
The whole-body 2-deoxy-2-[18F]fluoro-D-glucose (FDG) distribution in chronic renal failure (CRF) patients on hemodialysis would be different from that in subjects with normal renal function, because they lack urinary FDG excretion and remain in a constant volume overload. We evaluated the difference in the physiological uptake pattern of FDG between chronic renal failure patients on hemodialysis and control subjects. The subjects for this retrospective study consisted of 24 chronic renal failure patients on hemodialysis (HD group) and 24 age- and sex-matched control subjects (NC group). Standardized uptake values normalized by the body weight (SUVbw), ideal body weight (SUVibw), lean body mass (SUVlbm), and body surface area (SUVbsa) in the cerebellum, lungs, liver, gluteal muscles and subcutaneous fat, spleen, thoracolumbar spine, thoracic and abdominal aorta, and right atrium were calculated in positron emission tomography/computed tomography (PET/CT) images. SUVbw in the gluteal muscles, subcutaneous fat, spleen and right atrium was significantly higher in the HD group as compared to that in the NC group (p < 0.05; unpaired t test). In addition, SUVibm, SUVlbm, as well as SUVbsa in the abdominal aorta were significantly higher in the HD group as compared to those in the NC group (p < 0.05; unpaired t test). In conclusion, as compared to normal subjects, chronic renal failure patients on hemodialysis show significantly higher physiological FDG uptake in the soft tissues, spleen and blood pool.
PMCID: PMC4396005  PMID: 25973341
Chronic renal failure; hemodialysis; FDG-PET/CT; physiological uptake
12.  Imaging modality utilization trends in patients with stage III-IV oropharyngeal squamous cell carcinoma 
The objective of this study is to establish the utilization trends of CT, MRI, and FDG-PET/CT for evaluation of oropharyngeal squamous cell carcinoma (OPSCC) patients. A total of 173 patients with newly diagnosed stage III or IV OPSCC between 2003 and 2009 were included. Frequency of imaging modality use, divided into four time periods (2003-04, 2005-06, 2007-08 and 2009), was evaluated. For initial staging, percentage of PET/CT use was 64.6%, 87.5%, 94.1% and 96.3%, with an increasing trend (p < 0.001). The CT (p = 0.762) and MRI (p = 0.224) use demonstrated no change in trend. For post-treatment imaging, percentage of PET/CT use was 59.5%, 68.6%, 89.7% and 100%, with an increasing trend (p < 0.001). The CT use demonstrated a decreasing trend (p = 0.004) and MRI showed no trend change (p = 0.231). PET/CT is used with an increasing trend for initial staging and has become a central imaging modality for follow up evaluation after treatment, for advanced OPSCC.
PMCID: PMC4396006  PMID: 25973336
Oropharyngeal squamous cell carcinoma (OPSCC); PET/CT; FDG; cancer; magnetic resonance imaging (MRI)
13.  Added value of cost-utility analysis in simple diagnostic studies of accuracy: 18F-fluoromethylcholine PET/CT in prostate cancer staging 
Diagnostic studies of accuracy targeting sensitivity and specificity are commonly done in a paired design in which all modalities are applied in each patient, whereas cost-effectiveness and cost-utility analyses are usually assessed either directly alongside to or indirectly by means of stochastic modeling based on larger randomized controlled trials (RCTs). However the conduct of RCTs is hampered in an environment such as ours, in which technology is rapidly evolving. As such, there is a relatively limited number of RCTs. Therefore, we investigated as to which extent paired diagnostic studies of accuracy can be also used to shed light on economic implications when considering a new diagnostic test. We propose a simple decision tree model-based cost-utility analysis of a diagnostic test when compared to the current standard procedure and exemplify this approach with published data from lymph node staging of prostate cancer. Average procedure costs were taken from the Danish Diagnosis Related Groups Tariff in 2013 and life expectancy was estimated for an ideal 60 year old patient based on prostate cancer stage and prostatectomy or radiation and chemotherapy. Quality-adjusted life-years (QALYs) were deduced from the literature, and an incremental cost-effectiveness ratio (ICER) was used to compare lymph node dissection with respective histopathological examination (reference standard) and 18F-fluoromethylcholine positron emission tomography/computed tomography (FCH-PET/CT). Lower bounds of sensitivity and specificity of FCH-PET/CT were established at which the replacement of the reference standard by FCH-PET/CT comes with a trade-off between worse effectiveness and lower costs. Compared to the reference standard in a diagnostic accuracy study, any imperfections in accuracy of a diagnostic test imply that replacing the reference standard generates a loss in effectiveness and utility. We conclude that diagnostic studies of accuracy can be put to a more extensive use, over and above a mere indication of sensitivity and specificity of an imaging test, and that health economic considerations should be undertaken when planning a prospective diagnostic accuracy study. These endeavors will prove especially fruitful when comparing several imaging techniques with one another, or the same imaging technique using different tracers, with an independent reference standard for the evaluation of results.
PMCID: PMC4396007  PMID: 25973339
Diagnostic study; accuracy study; sensitivity; specificity; cost-effectiveness; molecular imaging; positron-emission tomography/computed tomography; 18F-fluoromethylcholine; prostate cancer; staging
14.  Differentiation of metastatic vs degenerative joint disease using semi-quantitative analysis with 18F-NaF PET/CT in castrate resistant prostate cancer patients 
Fluorine 18 Sodium Fluoride (18F-NaF) (sodium fluoride) PET/CT is a highly sensitive but is a non-specific method for identifying bone metastases. Qualitative scan interpretation using low dose CT for lesion localization is often complicated by the presence of co-existing degenerative joint disease (DJD). A semi-quantitative analysis might help in accurately differentiating benign from metastatic osseous lesions. The aim of the study was to evaluate the clinical utility of 18F-NaF PET/CT in differentiating DJD from metastatic disease in the skeleton using a qualitative analysis as well as a semi-quantitative approach using the SUVmax and to determine if there is an upper limit of SUVmax value that can reliably differentiate metastases from DJD. Baseline 18F-NaF PET/CT scans were performed for 17 castrate resistant prostate cancer patients (CRPC). A qualitative as well as semi-quantitative analysis using maximum standardized uptake value (SUVmax) based on body weight was performed for 65 metastatic and 56 DJD sites identified on the low dose CT scan acquired as a part of whole body PET/CT scan. The SUVmax range in DJD was 2.6-49.9 (mean: 6.2). The SUVmax range for metastatic lesions was 11.2-188 (mean: 160). The SUVmax value for metastatic as well as areas of DJD showed significant variation during treatment. Bone metastases showed statistically significantly higher SUVmax than DJD using a mixed effect regression model. ROC/AUC analysis was performed based on averaging the SUVs over all lesions in each subject. The AUC was found to be fairly high at 0.964 (95% CI: 0.75-0.996). The SUVmax over 50 always represented a bone metastasis and below 12 always represented a site of DJD. The results of our preliminary data show that semi-quantitative analysis is complementary to the qualitative analysis in accurately identifying DJD from metastatic disease. The cut-off SUVmax of 50 can help in differentiating DJD from bone metastases.
PMCID: PMC4396008  PMID: 25973337
F-18 NaF; castrate resistant prostate cancer; PET/CT; degenerative joint disease; bone metastases
15.  Evaluation of tumor ischemia in response to an indole-based vascular disrupting agent using BLI and 19F MRI 
Vascular disrupting agents (VDAs) have been proposed as an effective broad spectrum approach to cancer therapy, by inducing ischemia leading to hypoxia and cell death. A novel VDA (OXi8007) was recently reported to show rapid acute selective shutdown of tumor vasculature based on color-Doppler ultrasound. We have now expanded investigations to noninvasively assess perfusion and hypoxiation of orthotopic human MDA-MB-231/luc breast tumor xenografts following the administration of OXi8007 based on dynamic bioluminescence imaging (BLI) and magnetic resonance imaging (MRI). BLI showed significantly lower signal four hours after the administration of OXi8007, which was very similar to the response to combretastatin A-4P (CA4P), but the effect lasted considerably longer, with the BLI signal remaining depressed at 72 hrs. Meanwhile, control tumors exhibited minimal change. Oximetry used 19F MRI of the reporter molecule hexafluorobenzene and FREDOM (Fluorocarbon Relaxometry using Echo Planar Imaging for Dynamic Oxygen Mapping) to assess pO2 distributions during air and oxygen breathing. pO2 decreased significantly upon the administration of OXi8007 during oxygen breathing (from 122 ± 64 to 34 ± 20 Torr), with further decrease upon switching the gas to air (pO2 = 17 ± 9 Torr). pO2 maps indicated intra-tumor heterogeneity in response to OXi8007, though ultimately all tumor regions became hypoxic. Both BLI and FREDOM showed the efficacy of OXi8007. The pO2 changes measured by FREDOM may be crucial for future study of combined therapy.
PMCID: PMC4396009  PMID: 25973335
Vascular disrupting agents (VDAs); bioluminescence imaging (BLI); oximetry; hypoxia; 19F MRI; hexafluorobenzene; OXi8007; CA4P
16.  Combined use of 18F-FDG and 18F-FMISO in unresectable non-small cell lung cancer patients planned for radiotherapy: a dynamic PET/CT study 
Aim of this study was to evaluate and compare, by means of dynamic and static PET/CT, the distribution patterns and pharmacokinetics of fluorine-18 fluorodeoxyglucose (18F-FDG) and of fluorine-18-fluoromisonidazole (18F-FMISO) in non-small cell lung cancer (NSCLC) patients scheduled for intensity modulated radiation therapy (IMRT). Thirteen patients suffering from inoperable stage III NSCLC underwent PET/CTs with 18F-FDG and 18F-FMISO for tumor metabolism and hypoxia assessment accordingly. Evaluation of PET/CT studies was based on visual analysis, semi-quantitative (SUV) calculations and absolute quantitative estimations, after application of a two-tissue compartment model and a non-compartmental approach. 18F-FDG PET/CT revealed all thirteen primary lung tumors as sites of increased 18F-FDG uptake. Six patients demonstrated also in total 43 18F-FDG avid metastases; these patients were excluded from radiotherapy. 18F-MISO PET/CT demonstrated 12/13 primary lung tumors with faint tracer uptake. Only one tumor was clearly 18F-FMISO avid, (SUVaverage = 3.4, SUVmax = 5.0). Mean values for 18F-FDG, as derived from dPET/CT data, were SUVaverage = 8.9, SUVmax = 15.1, K1 = 0.23, k2 = 0.53, k3 = 0.17, k4 = 0.02, influx = 0.05 and fractal dimension (FD) = 1.25 for the primary tumors. The respective values for 18F-FMISO were SUVaverage = 1.4, SUVmax = 2.2, K1 = 0.26, k2 = 0.56, k3 = 0.06, k4 = 0.06, influx = 0.02 and FD = 1.14. No statistically significant correlation was observed between the two tracers. 18F-FDG PET/CT changed therapy management in six patients, by excluding them from planned IMRT. 18F-FMISO PET/CT revealed absence of significant tracer uptake in the majority of the 18F-FDG avid NSCLCs. Lack of correlation between the two tracers’ kinetics indicates that they reflect different molecular mechanisms and implies the discordance between increased glycolysis and hypoxia in the malignancy.
PMCID: PMC4396010  PMID: 25973334
18F-FDG; 18F-FMISO; PET/CT; non-small cell lung cancer; hypoxia
17.  Comparison of autologous 111In-leukocytes, 18F-FDG, 11C-methionine, 11C-PK11195 and 68Ga-citrate for diagnostic nuclear imaging in a juvenile porcine haematogenous staphylococcus aureus osteomyelitis model 
The aim of this study was to compare 111In-labeled leukocyte single-photon emission computed tomography (SPECT) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) to PET with tracers that potentially could improve detection of osteomyelitis. We chose 11C-methionine, 11C-PK11195 and 68Ga-citrate and validated their diagnostic utility in a porcine haematogenous osteomyelitis model. Four juvenile 14-15 weeks old female pigs were scanned seven days after intra-arterial inoculation in the right femoral artery with a porcine strain of Staphylococcus aureus using a sequential scan protocol with 18F-FDG, 68Ga-citrate, 11C-methionine, 11C-PK11195, 99mTc-Nanocoll and 111In-labelled autologous leukocytes. This was followed by necropsy of the pigs and gross pathology, histopathology and microbial examination. The pigs developed a total of five osteomyelitis lesions, five lesions characterized as abscesses/cellulitis, arthritis in three joints and five enlarged lymph nodes. None of the tracers accumulated in joints with arthritis. By comparing the 10 infectious lesions, 18F-FDG accumulated in nine, 111In-leukocytes in eight, 11C-methionine in six, 68Ga-citrate in four and 11C-PK11195 accumulated in only one lesion. Overall, 18F-FDG PET was superior to 111In-leukocyte SPECT in marking infectious and proliferative, i.e. hyperplastic, lesions. However, leukocyte SPECT was performed as early scans, approximately 6 h after injection of the leukocytes, to match the requirements of the 18 h long scan protocol. 11C-methionine and possibly 68Ga-citrate may be useful for diagnosis of soft issue lesions.
PMCID: PMC4396013  PMID: 25973338
Osteomyelitis; models; animal; domestic pigs; sus scrofa; swine; staphylococcus aureus; positron-emission tomography; tomography; emission-computed; single-photon; tomography; X-Ray computed; lnflammation; lnfection
18.  Effect of reconstruction algorithms on the accuracy of 99mTc sestamibi SPECT/CT parathyroid imaging 
The superiority of SPECT/CT over SPECT for 99mTc-sestamibi parathyroid imaging often is assumed to be due to improved lesion localization provided by the anatomic component (computed tomography) of the examination. It also is possible that this superiority may be related to the algorithms used for SPECT data reconstruction. The objective of this investigation was to determine the effect of SPECT reconstruction algorithms on the accuracy of MIBI SPECT/CT parathyroid imaging. We retrospectively analyzed preoperative MIBI SPECT/CT parathyroid imaging studies performed on 106 patients. SPECT data were reconstructed by filtered back projection (FBP) and by iterative reconstruction with corrections for collimator resolution recovery and attenuation (IRC). Two experienced readers independently graded lesion detection certainty on a 5-point scale without knowledge of each other’s readings, reconstruction methods, other test results or final diagnoses. All patients had surgical confirmation of the final diagnosis, including disease limited to the neck, and location and weight of excised lesion(s). There were 135 parathyroid lesions among the 106 patients. For FBP SPECT/CT and IRC SPECT/CT sensitivity was 76% and 90% (p = 0.003), specificity was 87% and 87% (p = 0.90), and accuracy was 83% and 88% (p = 0.04), respectively. Inter-rater agreement was significantly higher for IRC than for FBP (kappa = 0.76, “good agreement”, versus kappa = 0.58, “moderate agreement”, p < 0.0001). We conclude that the improved accuracy of MIBI SPECT/CT compared to MIBI SPECT for preoperative parathyroid lesion localization is due in part to the use of IRC for SPECT data reconstruction.
PMCID: PMC4396014  PMID: 25973340
Parathyroid; 99mTc-sestamibi; MIBI; SPECT/CT; iterative reconstruction; filtered back projection
19.  Survival after somatostatin based radiopeptide therapy with 90Y-DOTATOC vs. 90Y-DOTATOC plus 177Lu-DOTATOC in metastasized gastrinoma 
We aimed to explore the effects of 90Y-DOTATOC and 90Y-DOTATOC plus 177Lu-DOTATOC on survival of patients with metastasized gastrinoma. Patients with progressive metastasized gastrinoma were treated with repeated cycles of 90Y-DOTATOC or with cycles alternating between 90Y-DOTATOC and 177Lu-DOTATOC until tumor progression or permanent toxicity. Multivariable Cox regression analyses were used to study predictors of survival. A total of 36 patients were enrolled; 30 patients received 90Y-DOTATOC (median activity per patient 11.8GBq; range: 6.1-62.2GBq) and 6 patients received 90Y-DOTATOC plus 177Lu-DOTATOC (median activity per patient: 14.8GBq; range: 7.4-14.8GBq). Response was found in 26 patients (72.2%), including morphological (n=12, 33.3%), biochemical (n=14, 38.9%) and/or clinical response (n=6, 16.2%). A total of 21 patients (58.3%) experienced hematotoxicity grade 1/2, while 1 patient (2.8%) experienced hematotoxicity grade 3; no grade 4 hematotoxicity occurred. Furthermore, 2 patients (5.6%) developed grade 4 renal toxicity; no grade 5 renal toxicity occurred. Responders had a significantly longer median survival from time of enrollment than non-responders (45.1 months, range: 37.1-53.1 months vs. 12.6 months, range: 11.0-14.2, hazard ratio: 0.12 (0.027-0.52), p=0.005). Additionally, there was a trend towards longer median survival with 90Y-DOTATOC plus 177Lu-DOTATOC as compared to 90Y-DOTATOC alone (60.2 months, range: 19.8-100.6 months vs. 27.0 months, range: 4.0-50.0, hazard ratio: 0.21 (0.01-3.98), p=0.16). Response to 90Y-DOTATOC and 90Y-DOTATOC plus 177Lu-DOTATOC therapy is associated with a longer survival in patients with metastasized gastrinoma. Both treatment regimens are promising tools for management of progressive gastrinoma.
PMCID: PMC4299770  PMID: 25625026
Yttrium; lutetium; somatostatin; survival; gastrinoma
20.  18F-FDG-PET/CT and 18F-NaF-PET/CT in men with castrate-resistant prostate cancer 
To evaluate 18F-labeled-fluorodeoxyglucose (18F-FDG-) and 18F-labeled-sodium fluoride (18F-NaF-) positron emission tomography/computed tomography (PET/CT) as biomarkers in metastatic castrate-resistant prostate cancer (mCRPC). Nine men (53-75 years) in a phase 1 trial of abiraterone and cabozantinib had 18F-FDG-PET/CT, 18F-NaF-PET/CT and standard imaging (99mTc-labeled-methylene-diphosphonate (99mTc-MDP) bone scan and abdominal/pelvic CT) at baseline and after 8 weeks of therapy. Baseline disease was classified as widespread 18F-FDG-avid, oligometastatic 18F-FDG-avid (1 site), or non-18F-FDG-avid. Metabolic response was classified using European Organisation for Research and Treatment of Cancer (EORTC) criteria. Treatment response using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, Prostate Cancer Working Group 2 (PCWG2) guidelines and days on trial (DOT) were recorded. All men were followed for 1 year or until progression. Four men had 18F-FDG-avid disease: two with widespread (DOT 53 and 76) and two with oligometastatic disease (DOT 231 and still on trial after 742+ days). Five men had non-18F-FDG-avid disease; three remained stable or improved (2 still on trial while one discontinued for non-oncologic reasons; DOT 225-563+), and 2 progressed (DOT 285 and 532). Despite the small sample size, Kaplan-Meier analysis showed a significant difference in progression free survival (PFS) between men with widespread 18F-FDG-avid, oligometastatic 18F-FDG-avid and non-18F-FDG-avid disease (p < 0.01). All men had 18F-NaF-avid disease. Neither 18F-NaF-avid disease extent nor intensity was predictive of treatment response. 18F-FDG-PET/CT may be superior to 18F-NaF-PET/CT and standard imaging in men with mCRPC on abiraterone and cabozantinib. 18F-FDG-PET/CT may have potential to stratify men into 3 groups (widespread vs. oligometastatic 18F-FDG-avid vs. non-18F-FDG-avid mCRPC) to tailor therapy. Further evaluation is warranted.
PMCID: PMC4299771  PMID: 25625029
PET/CT; FDG; NaF; prostate cancer; bone scan
21.  Assessment of vulnerable atherosclerotic and fibrotic plaques in coronary arteries using 68Ga-DOTATATE PET/CT 
Activated macrophages which express somatostatin receptor-2 (SSTR-2) play a vital role in rupture of the vulnerable atherosclerotic plaques, which result in death. 68Ga-DOTATATE binds to somatostatin receptors 2, and therefore, can serve as potential radiotracer to detect atherosclerotic plaques. The purpose of this study was to generate preliminary data with this agent in vulnerable or fibrotic atherosclerotic plaques in the coronary arteries. We evaluated a total of 44 patients with neuroendocrine tumors (NET) who underwent 68Ga-DOTATATE PET/CT. In each subject, 7 segments in the coronary arteries were assessed, maximum SUV values and target-to-background ratios (TBRs) were calculated. The lesions detected by CT (a total of 308) were divided into 3 groups based on the Hounsfield unites (HU), and of which, 131 with HU less than 70 were classified as being normal (Control Group), 129 with HU 71-188 as fibrotic plaques (Group 2), and. 48 lesions with HU more than 188 as atherosclerotic plaques (Group 3). The mean TBR value in the normal group was 1.345 ± 0.58 while the mean TBR value in the fibrotic plaque group was 1.752 ± 1.50 (p 0.0043) and in atherosclerotic plaques group was (2.043 ± 1.76, p<0.0001). There was a significant correlation (p=0.0026) between 68Ga-DOTATATE uptake and the progression to formation of atherosclerotic plaques, based on HU. In patients with neuroendocrine tumors, 68Ga-DOTATATE PET/CT showed significantly increased uptake in the fibrotic and vulnerable atherosclerotic plaques compared to normal coronary arteries suggesting a potential role of this tracer for molecular assessment of coronary artery disease in this population.
PMCID: PMC4299775  PMID: 25625028
Atherosclerotic plaques; 68Ga-DOTATATE; somatostatin receptor; cardiovascular risk factors; macrophage
22.  Quantitative and qualitative comparison of continuous bed motion and traditional step and shoot PET/CT 
New developments in PET/CT technology have enabled the commercial availability of continuous bed motion (CBM) acquisition methods. This technology has some potential performance benefits compared to standard step and shoot (SS) imaging, however, this technology has not been assessed with regard to quantitative and image quality parameters compared to traditional SS techniques. This study seeks to compare clinically relevant quantitative and image quality parameters using CBM and SS data collection methods with the intent of providing assistance in making educated decisions regarding imaging protocol development when using CBM technology versus SS imaging.
PMCID: PMC4299776  PMID: 25625027
PET; CT; continuous bed motion; CBM
23.  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
24.  PET imaging of apoptosis in tumor-bearing mice and rabbits after paclitaxel treatment with 18F-Labeled recombinant human His10-annexin V 
Monitoring response to chemo- or radiotherapy is of great importance in clinical practice. Apoptosis imaging serves as a very useful tool for the early evaluation of tumor response. The goal of this study was PET imaging of apoptosis with 18F-labeled recombinant human annexin V linked with 10 histidine tag (18F-rh-His10-annexin V) in nude mice bearing an A549 tumor and rabbits bearing a VX2 lung cancer after paclitaxel therapy. 18F-rh-His10-annexin V was prepared by conjugation of rh-His10-annexin V with N-succinimidyl 4-[18F]fluorobenzoate. Biodistribution was determined in mice by the dissection method and small-animal PET. Single-dose paclitaxel (175 mg/m2) was used to induce apoptosis in A549 and VX2 tumor models. 18F-rh-His10-annexin V was injected into A549 mice and VX rabbits to acquire dynamic and static PET images 72 h after paclitaxel treatment. The uptake of 18F-rh-His10-annexin V in apoptotic cells 4 h after induction was 6.45±0.52 fold higher than that in non-induced cells. High focal uptake of 18F-rh-His10-annexin V was visualized in A549 (SUVmax: 0.35±0.13) and VX2 (0.41±0.23) tumor models after paclitaxel treatment, whereas lower uptake was found in the corresponding tumors before treatment (A549 SUVmax: 0.04±0.02; VX2: 0.009±0.002). The apoptotic index was 75.61±11.56% in the treated VX2 cancer, much higher than that in the untreated VX2 (8.03±2.81%). This study demonstrated the feasibility of 18F-rh-His10-annexin V for the detection of apoptosis after chemotherapy in A549 and VX2 tumor models.
PMCID: PMC4299778  PMID: 25625024
Apoptosis; molecular imaging; recombinant human His10-annexin V; tumor response
25.  Hippocampal MR spectroscopic abnormalities in a cohort of syphilitic patients with HIV and neurosyphilis infection 
Co-infection of human immunodeficiency virus (HIV) and neurosyphilis (NS) has become a rising trend, but the extent of brain damage associated with the concomitant infections remains unknown. Proton magnetic resonance spectroscopy (1H-MRS) can evaluate metabolic changes underlying early brain infections. 25 syphilitic patients (7 HIV-positive with NS; 6 HIV-positive without NS; 5 HIV-negative with NS; 7 non-HIV, non-NS) and 17 healthy controls (HC) underwent single-voxel 1H-MRS in the bilateral hippocampi. Absolute concentrations of major metabolites were measured using a 3T MRI scanner. No significant structural abnormality was detected in all patients. However, metabolic changes were found in the left hippocampus of both the HIV-positive and NS subgroups, showing significantly higher choline (Cho), creatine (Cr) and myo-inositol (mI) compared to HC. In the right hippocampus, HIV-positive subgroup showed significantly higher Cr and reduced NAA, while NS subgroup only showed significantly reduced NAA compared to HC. The non-HIV, non-NS syphilitic subgroup showed no significant difference compared to HC. Substantial metabolic changes occurred in bilateral hippocampi in HIV and NS co-infections. NAA reduction might represent early neuronal damage, while mI/Cho elevation reflects gliosis/inflammatory changes. 1H-MRS could serve as a non-invasive tool to triage patients suspected of NS for lumbar puncture in non-HIV syphilitic patients.
PMCID: PMC4299779  PMID: 25625030
HIV; neurosyphilis; co-infection; magnetic resonance spectroscopy; hippocampus

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