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1.  Genetic engineered molecular imaging probes for applications in cell therapy: emphasis on MRI approach 
Recent advances in stem cell-based regenerative medicine, cell replacement therapy, and genome editing technologies (i.e. CRISPR-Cas 9) have sparked great interest in in vivo cell monitoring. Molecular imaging promises a unique approach to noninvasively monitor cellular and molecular phenomena, including cell survival, migration, proliferation, and even differentiation at the whole organismal level. Several imaging modalities and strategies have been explored for monitoring cell grafts in vivo. We begin this review with an introduction describing the progress in stem cell technology, with a perspective toward cell replacement therapy. The importance of molecular imaging in reporting and assessing the status of cell grafts and their relation to the local microenvironment is highlighted since the current knowledge gap is one of the major obstacles in clinical translation of stem cell therapy. Based on currently available imaging techniques, we provide a brief discussion on the pros and cons of each imaging modality used for monitoring cell grafts with particular emphasis on magnetic resonance imaging (MRI) and the reporter gene approach. Finally, we conclude with a comprehensive discussion of future directions of applying molecular imaging in regenerative medicine to emphasize further the importance of correlating cell graft conditions and clinical outcomes to advance regenerative medicine.
PMCID: PMC5069277  PMID: 27766183
In vivo cell monitoring; molecular imaging; reporter gene; magnetic resonance imaging; longitudinal monitoring; stem cell; regenerative medicine; cell tracking
2.  SUV measurement of normal vertebrae using SPECT/CT with Tc-99m methylene diphosphonate 
The purpose of this study is to perform quantitative measurement based on the standardized uptake value (SUV) of the uptake of Tc-99m methylene diphosphonate (MDP) in the normal vertebrae using a single photon emission tomography (SPECT)/computed tomography (CT) scanner. A retrospective study of patients with cancer or joint disorders was performed. We acquired data for a group of 29 patients (8 women and 21 men; mean age, 68.2 ± 6.7 years; age range, 44-87 years) undergoing bone SPECT/CT scans with Tc-99m MDP between September and October 2015. Various SUVs were calculated based on body-weight, lean-body-weight (lbw), Japanese lean-body-weight (jlbw) and Japanese bone-mineral-content (jbmc). SUVs of normal vertebrae showed a wide range of values. Among these, the maximum body-weight based SUV showed the lowest coefficient of variation. The SUVs also showed relatively small intra-subject variability. In addition, all SUVs showed moderate and significant correlation with height. Moreover, lbw-, jlbw-, and jbmc-based SUVs of men were significantly higher than those of women. In conclusions, SUVs of normal vertebrae showed a relatively large inter-individual variability and small intra-individual variability. As a quantitative imaging biomarker, SUVs might require standardization with adequate reference data for the same subject to minimize variability.
PMCID: PMC5069278  PMID: 27766184
SUV; bone; SPECT; SPECT/CT; QIBA
3.  Validation of true low-dose 18F-FDG PET of the brain 
The dosage of 18F-FDG must be sufficient to ensure adequate PET image quality. For younger patients and research controls, the lowest possible radiation dose should be used. The purpose of this study was to find a protocol for FDG-PET of the brain with reduced radiation dose and preserved quantitative characteristics. Eight patients with neurodegenerative disorders and nine controls (n=17) underwent FDG-PET/CT twice on separate occasions, first with normal-dose (3 MBq/kg), and second with low-dose (0.75 MBq/kg, 25% of the original). Five additional controls (total n=22) underwent FDG-PET twice, using normal-dose and ultra-low-dose (0.3 MBq/kg, 10% of original). All subjects underwent MRI. Ten-minute summation images were spatially normalized and intensity normalized. Regional standard uptake value ratios (SUV-r) were calculated using an automated atlas. SUV-r values from the normal- and low-dose images were compared pairwise. No clinically significant bias was found in any of the three groups. The mean absolute difference in regional SUV-r values was 0.015 (1.32%) in controls and 0.019 (1.67%) in patients. The ultra-low-dose protocol produced a slightly higher mean difference of 0.023 (2.10%). The main conclusion is that 0.75 MBq/kg (56 MBq for a 75-kg subject) is a sufficient FDG dose for evaluating regional SUV-ratios in brain PET scans in adults with or without neurodegenerative disease, resulting in a reduction of total PET/CT effective dose from 4.54 to 1.15 mSv. The ultra-low-dose (0.5 mSv) could be useful in research studies requiring serial PET in healthy controls or children.
PMCID: PMC5069279  PMID: 27766185
PET; FDG; neuroimaging; neurodegeneration; methodology
4.  Prediction of positron emission tomography/computed tomography (PET/CT) positivity in patients with high-risk primary melanoma 
Positron emission tomography/computed tomography (PET/CT) is an important tool to identify occult melanoma metastasis. To date, it is controversial which patients with primary cutaneous melanoma should have staging PET/CT. In this retrospective analysis of more than 800 consecutive patients with cutaneous melanoma, we sought to identify factors predictive of PET/CT positivity in the setting of newly-diagnosed high-risk primary melanoma to determine those patients most appropriate to undergo a PET/CT scan as part of their diagnostic work up. 167 patients with newly-diagnosed high-risk primary cutaneous melanoma underwent a PET/CT scan performed as part of their initial staging. Clinical and histologic factors were evaluated as possible predictors of melanoma metastasis identified on PET/CT scanning using both univariate and multivariate logistic regression. In all, 32 patients (19.2%) had a positive PET/CT finding of metastatic melanoma. In more than half of these patients (56.3%), PET/CT scanning identified disease that was not detectable on clinical examination. Mitotic rate, tumor thickness, lymphadenopathy, and bleeding were significantly predictive of PET/CT positivity. A combinatorial index constructed from these factors revealed a significant association between number of high-risk factors observed and prevalence of PET/CT positivity, which increased from 5.8% (with the presence of 0-2 factors) to 100.0%, when all four factors were present. These results indicate that combining clinical and histologic prognostic factors enables the identification of patients with a higher likelihood of a positive PET/CT scan.
PMCID: PMC5069280  PMID: 27766186
Melanoma; PET; PET/CT; FDG; molecular imaging; nuclear medicine; skin cancer; staging
5.  PET imaging reveals sex differences in kappa opioid receptor availability in humans, in vivo  
Opioid receptors may play critical roles in alcoholism and other addictions, addiction withdrawal, and depression and are considered pharmacological targets for treatment of these conditions. Sex differences have been demonstrated in mu (MOR) and delta (DOR) opioid receptors in humans, in vivo. In addition, sex differences have been observed in efficacy of treatment targeting kappa opioid receptors (KOR). Our goal in the present study was to compare the availability of KOR (1) between healthy control (HC) men and women. Twenty-seven subjects-18 males (M) and 9 females (F)-underwent PET scans with [11C] LY2795050, a selective kappa antagonist tracer. Partial volume correction was applied to all PET data. Volume of distribution (V T) of the tracer was estimated regionally as well as at the voxel level. V T values of males versus females were compared for 19 defined ROIs. Results at the regional and voxel levels were consistent. Males had significantly higher V T and thus a higher KOR availability than women in multiple brain regions. To our knowledge, this is the first report of sex differences in the KOR system in humans, in vivo. These findings could have implications for the treatment of pain with kappa opioid analgesics. The results may also have an impact on the diagnosis and treatment of addictive and other disorders.
PMCID: PMC5004062  PMID: 27648372
Sex differences; kappa opioid receptor system; volume of distribution; PET imaging
6.  The benefit of personalized hybrid SPECT/CT pulmonary imaging 
Hybrid pulmonary imaging in the present day has seen a fusion of various uses of CT scans, including angiography (CTAG), diagnostic CT, low dose CT (LDCT), and perfusion or ventilation scintigraphy in tomographic or planar imaging. Determining the most effective individualized test for the complete diagnostics of patients with pulmonary symptoms for various groups of patients is a major issue. The aim of the present study was to assess the effectiveness of the implementation of hybrid imaging in current methods of nuclear medicine in differential diagnostics of pulmonary embolism (PE). 326 patients were examined for symptomatology of PE. Patients were initially examined with SPECT perfusion scintigraphy. SPECT finding without sub-segmental or segmental defects was considered unproven PE but the finding of more segments or sub-segments in various lung parts was considered nearly proven PE. In the case of unclear findings, LDCT was added and in the case of a higher suspicion of PE, a ventilation examination was applied. It was possible to determine 83% of patients with the occurrence or exclusion of PE only on the basis of the perfusion SPECT examination and an X-ray or LDCT. LDCT was determined with 26% of the patients. With 41% of them, the use of LDCT resulted in an alternative diagnosis, explaining perfusion abnormalities. The research proved that use of SPECT/LDCT for differential diagnosis of lung symptoms brings about improvement in the diagnosis of pulmonary embolism or the identification of other lung diseases when lung perfusion abnormalities are recorded.
PMCID: PMC5004063  PMID: 27648373
Pulmonary embolism; ventilation-perfusion scan; SPECT/CT; hybrid imaging
7.  Feasibility of carotid artery PET/MRI in psoriasis patients 
We report our initial experience of performing integrated PET/MR imaging of the carotid arteries in psoriatic patients. Eleven patients with psoriasis and ten controls underwent carotid PET/MRI. Following injection of the FDG tracer, 3d T1w gradient echo sequence (atMR) was obtained for attenuation correction of PET data. High resolution images of carotid artery were then obtained, including pre-and post-contrast T1-w, T2-w and proton-density images as well as TOF images followed by PET imaging of the torso. From the fused axial PET/MRI, the arterial wall SUVmax and TBRmax was quantified in each slice. MRI images were also evaluated for vessel wall volume, plaque and internal composition. SUVmax and TBRmax were respectively, 1.72 ± 0.38 & 1.17 ± 0.27 in L- CCA, 1.75 ± 0.39 & 1.24 ± 0.19 in R-CCA, 1.59 ± 0.24 & 1.08 ± 0.14 in L-ICA and 1.62 ± 0.27 & 1.15 ± 0.17 in R-ICA in psoriatic patients and 1.74 ± 0.22 & 1.28 ± 0.44 in L- CCA, 1.74 ± 0.33 & 1.07 ± 0.28 in R-CCA, 1.78 ± 0.32 & 1.29 ± 0.39 in L-ICA and 1.60 ± 0.29 & 0.98 ± 0.25 in R-ICA in the controls. No discrete plaques were identified in any of the vessel segments in MRI. PET/MRI is feasible in evaluation of carotid arteries in psoriatic patients.
PMCID: PMC5004064  PMID: 27648374
Psoriasis; PET; MRI; atherosclerosis; inflammation; carotid
8.  Long-term quality assurance of [18F]-fluorodeoxyglucose (FDG) manufacturing 
Nine years of experience with 2286 commercial synthesis allowed us to deliver comprehensive information on the quality of 18F-FDG production. Semi-automated FDG production line using Cyclone 18/9 machine (IBA Belgium), TRACERLab MXFDG synthesiser (GE Health, USA) using alkalic hydrolysis, grade “A” isolator with dispensing robotic unit (Tema Sinergie, Italy), and automatic control system under GAMP5 (minus2, Slovakia) was assessed by TQM tools as highly reliable aseptic production line, fully compliant with Good Manufacturing Practice and just-in-time delivery of FDG radiopharmaceutical. Fluoride-18 is received in steady yield and of very high radioactive purity. Synthesis yields exhibited high variance connected probably with quality of disposable cassettes and chemicals sets. Most performance non-conformities within the manufacturing cycle occur at mechanical nodes of dispensing unit. The long-term monitoring of 2286 commercial synthesis indicated high reliability of automatic synthesizers. Shewhart chart and ANOVA analysis showed that minor non-compliances occurred were mostly caused by the declinations of less experienced staff from standard operation procedures, and also by quality of automatic cassettes. Only 15 syntheses were found unfinished and in 4 cases the product was out-of-specification of European Pharmacopoeia. Most vulnerable step of manufacturing was dispensing and filling in grade “A” isolator. Its cleanliness and sterility was fully controlled under the investigated period by applying hydrogen peroxide vapours (VHP). Our experience with quality assurance in the production of [18F]-fluorodeoxyglucose (FDG) at production facility of BIONT based on TRACERlab MXFDG production module can be used for bench-marking of the emerging manufacturing and automated manufacturing systems.
PMCID: PMC4965520  PMID: 27508102
(18F)-fluorodeoxyglucose (FDG); good manufacturing practice; quality assurance; quality control; total quality management
9.  A preliminary investigation into textural features of intratumoral metabolic heterogeneity in 18F-FDG PET for overall survival prognosis in patients with bulky cervical cancer treated with definitive concurrent chemoradiotherapy 
We examined the role of intratumoral metabolic heterogeneity on 18F-FDG PET during concurrent chemoradiotherapy (CCRT) in predicting survival outcomes for patients with cervical cancer. This prospective study consisted of 44 patients with bulky (≥ 4 cm) cervical cancer treated with CCRT. All patients underwent serial 18F-FDG PET studies. Primary cervical tumor standardized uptake values, metabolic tumor volume, and total lesion glycolysis (TLG) were measured in pretreatment and intra-treatment (2 weeks) PET scans. Regional textural features were analyzed using the grey level run length encoding method (GLRLM) and grey-level size zone matrix. Associations between PET parameters and overall survival (OS) were tested by Kaplan-Meier analysis and Cox regression model. In univariate analysis, pretreatment grey-level nonuniformity (GLNU) > 48 by GLRLM textural analysis and intra-treatment decline of run length nonuniformity < 55% and the decline of TLG (∆TLG) < 60% were associated with significantly worse OS. In multivariate analysis, only ∆TLG was significant (P = 0.009). Combining pretreatment with intra-treatment factors, we defined the patients with a initial GLNU > 48 and a ∆TLG ≤ 60% as the high-risk group and the other patients as the low-risk. The 5-year OS rate for the high-risk group was significantly worse than that for the low-risk group (42% vs. 81%, respectively, P = 0.001). The heterogeneity of intratumoral FDG distribution and the early temporal change in TLG may be an important predictor for OS in patients with bulky cervical cancer. This gives the opportunity to adjust individualized regimens early in the treatment course.
PMCID: PMC4965521  PMID: 27508103
Cervical cancer; chemoradiotherapy; 18F-FDG PET; texture analysis
10.  Design, construction and testing of a low-cost automated 68Gallium-labeling synthesis unit for clinical use 
The interest in 68Gallium labeled PET probes continues to increase around the world. Widespread use in Europe and Asia has led to great interest for use at numerous sites in the US. One barrier to entry is the cost of the automated synthesis units for relatively simple labeling procedures. We describe the construction and testing of a relatively low-cost automated 68Ga-labeling unit for human-use. We provide a guide for construction, including part lists and synthesis timelists to facilitate local implementation. Such inexpensive systems could help increase use around the globe and in the US in particular by removing one of the barriers to greater widespread availability. The developed automated synthesis unit reproducibly synthesized 68Ga-DOTATOC with average yield of 71 ± 8% and a radiochemical purity ≥ 95% in a synthesis time of 25 ± 1 minutes. Automated product yields are comparable to that of manual synthesis. We demonstrate in-house construction and use of a low-cost automated synthesis unit for labeling of DOTATOC and similar peptides with 68Gallium.
PMCID: PMC4965522  PMID: 27508104
68Gallium; peptide labeling; automated synthesis; DOTATOC
11.  Synthesis and pre-clinical evaluation of an 18F-labeled single-chain antibody fragment for PET imaging of epithelial ovarian cancer 
Anti-CA125 antibodies have been used in immunoassays to quantify levels of shed antigen in the serum of patients who are under surveillance for epithelial ovarian cancer (EOC). However, there is currently no molecular imaging probe in the clinic for the assessment of CA125 expression in vivo. The present study describes the development of an 18F-labeled single-chain variable fragment (scFv) for PET imaging of CA125 in preclinical EOC models. Anti-CA125 scFv was derived from MAb-B43.13 by recombinant expression of the fragment in E.coli. Fragment scFv-B43.13 was purified via immobilized metal affinity chromatography and characterized for antigen binding via immuno-staining and flow cytometry. Prosthetic group N-succinimidyl 4-[18F]fluorobenzoate ([18F]SFB) was used for radiolabeling of scFv-B43.13. Preclinical ovarian cancer models were developed based on ovarian cancer cell lines OVCAR3 (CA125-positive) and SKOV3 (CA125-negative) in NIH-III mice. The radiopharmacological profile of 18F-labeled scFv-B43.13 ([18F]FBz-scFv-B43.13) was studied with PET. [18F]FBz-scFv-B43.13 was prepared in radiochemical yields of 3.7 ± 1.8% (n = 5) at an effective specific activity of 3.88 ± 0.76 GBq/µmol (n = 5). The radiotracer demonstrated selective uptake in CA125-positive OVCAR3 cells and virtually no uptake in CA125-negative SKOV3 cells. Standardized uptake values (SUV) of radioactivity uptake in OVCAR3 tumors was 0.5 (n = 3) and 0.3 (n = 2) in SKOV3 tumors after 60 min post injection (p.i.).
PMCID: PMC4965523  PMID: 27508105
CA125; positron emission tomography; epithelial ovarian cancer; fluorine-18
12.  Development of a novel linearly-filled Derenzo microPET phantom 
Positron emission tomography (PET) phantoms are used to calibrate PET scanners so that inter-scanner and inter-isotope comparison can be made between PET datasets. Hot rod style phantoms have a hole pattern, which is filled with a positron-emitting isotope and typically involves using two radioisotope reservoirs with the pattern created with channels in between. However, this configuration is difficult to fill and requires an excess of activity and volume. Here we present an alternative design, a phantom that is linearly filled-one channel at a time. The process of fabrication of prototypes of the design is described and PET images of the prototyped phantom are also shown for a variety of commonly used radioisotopes (52Mn, 64Cu, 76Br, 124I). This design allows for a large reduction in isotope volume and required filling time making a quality assurance (QA) protocol safer, more efficient and less costly.
PMCID: PMC4965524  PMID: 27508106
Positron emission tomography (PET); quality control (QC); Derenzo phantom; rresolution; hot-rod Derenzo; microPET; 3D printing
13.  PET imaging of in vivo caspase-3/7 activity following myocardial ischemia-reperfusion injury with the radiolabeled isatin sulfonamide analogue [18F]WC-4-116 
The utility of [18F]WC-4-116, a PET tracer for imaging caspase-3 activation, was evaluated in an animal model of myocardial apoptosis. [18F]WC-4-116 was injected into rats at 3 hours after a 30 min period of ischemia induced by temporary occlusion of the left anterior descending coronary artery in Sprague-Dawley rats. [18F]WC-4-116 uptake was quantified by 1) autoradiography, 2) microPET imaging studies, and 3) post-PET biodistribution studies. MicroPET imaging also assessed uptake of the non-caspase-3-targeted tracer [18F]ICMT-18 at 3 hours postischemia. Enzyme assays and Western blotting assessed caspase-3 activation in both at-risk and not-at-risk regions. Caspase-3 enzyme activity increased in the at-risk but not in the not-at-risk myocardium. Quantitative autoradiographic analysis of [18F]WC-4-116 demonstrated nearly 2-fold higher uptake in the ischemia-reperfusion (IR) versus sham animals. [18F]WC-4-116 microPET imaging studies demonstrated that the IR animals was similarly elevated in relation to sham. [18F]ICMT-18 uptake did not increase in at-risk myocardium despite evidence of caspase-3 activation. Biodistribution studies with [18F]WC-4-116 confirmed the microPET findings. These data indicate that the caspase-3-PET tracer [18F]WC-4-116 can noninvasively image in vivo caspase activity during myocardial apoptosis and may be useful for clinical imaging in humans.
PMCID: PMC4858607  PMID: 27186438
Isatin sulfonamide analogue; apoptosis; PET; tracer; caspase
14.  Prognostic value of FDG PET/CT-based metabolic tumor volumes in metastatic triple negative breast cancer patients 
FDG PET/CT-based measures of tumor burden show promise to predict survival in patients with metastatic breast cancer, but the patient populations studied so far are heterogeneous. The reports may have been confounded by the markedly different prognosis of the various subtypes of breast cancer. The purpose of this study is to evaluate the correlation between tumor burden on FDG PET/CT and overall survival (OS) in patients within a defined population: metastatic triple negative breast cancer (MTNBC). FDG PET/CT scans of 47 consecutive MTNBC patients (54±12 years-old) with no other known malignancies were analyzed. A total 393 lesions were identified, and maximum standardized uptake value (SUVmax), mean SUV, metabolic tumor volume (MTV), total lesion number (TLN) and total lesion glycolysis (TLG), were measured and correlated with patient survival by Mantel-Cox tests and Cox regression analysis. At a median follow-up time of 12.4 months, 41 patients died with a median OS of 12.1 months. Patients with MTV less than 51.5 ml lived nearly three times longer (22 vs 7.1 months) than those with a higher MTV (χ2=21.3, P<0.0001). In a multivariate Cox regression analysis only TLN and MTV were significantly correlated with survival. Those with an MTV burden in the 75th percentile versus the 25th percentile had a hazard ratio of 6.94 (p=0.001). In patients with MTNBC, MTV appears to be a strong prognostic factor. If validated in prospective studies, MTV may be a valuable tool for risk stratification of MTNBC patients in clinical trials and to guide patient management.
PMCID: PMC4858608  PMID: 27186439
Triple-negative metastatic breast cancer; FDG PET/CT; metabolic tumor volume; breast cancer prognosis
15.  What role for radiobiphosphonates bone scintigraphy in the monitoring of an unusual bone giant cell tumor: a case report and literature review 
We report the case of 24 years old female patient, followed since ten years ago for bone giant cell tumor (GCT) of the right knee, which was complicated by pulmonary metastases. Surgical treatment and pulmonary metastasectomies have not allowed definitive cure of this disease with the appearance of metachronous bone lesions after eight years of evolution. The literature review confirms the originality of this observation: the age of the patient, the initial and metastasis locations and the occurrence of lung metastases with unfavorable prognosis. Through this clinical case, the authors highlight the role of radiobiphosphonates bone scintigraphy in detecting synchronous or metachronous bone lesions, and in monitoring of these locations under medical treatment.
PMCID: PMC4858609  PMID: 27186440
Bone giant cell tumor (GCT); radiobiphosphonates bone scintigraphy; metachronous bone lesions; lung metastases; denosumab
16.  Good manufacturing practice production of [68Ga]Ga-ABY-025 for HER2 specific breast cancer imaging 
Therapies targeting human epidermal growth factor receptor type 2 (HER2) have revolutionized breast cancer treatment, but require invasive biopsies and rigorous histopathology for optimal patient stratification. A non-invasive and quantitative diagnostic method such as positron emission tomography (PET) for the pre-therapeutic determination of the presence and density of the HER2 would significantly improve patient management efficacy and treatment cost. The essential part of the PET methodology is the production of the radiopharmaceutical in compliance with good manufacturing practice (GMP). The use of generator produced positron emitting 68Ga radionuclide would provide worldwide accessibility of the agent. GMP compliant, reliable and highly reproducible production of [68Ga]Ga-ABY-025 with control over the product peptide concentration and amount of radioactivity was accomplished within one hour. Two radiopharmaceuticals were developed differing in the total peptide content and were validated independently. The specific radioactivity could be kept similar throughout the study, and it was 6-fold higher for the low peptide content radiopharmaceutical. Intrapatient comparison of the two peptide doses allowed imaging optimization. The high peptide content decreased the uptake in healthy tissue, in particular liver, improving image contrast. The later imaging time points enhanced the contrast. The combination of high peptide content radiopharmaceutical and whole-body imaging at 2 hours post injection appeared to be optimal for routine clinical use.
PMCID: PMC4858610  PMID: 27186441
Affibody; breast cancer; clinical study; HER2; GMP; Gallium-68
17.  Metabolic characteristics distinguishing intrahepatic cholangiocarcinoma: a negative pilot study of 18F-fluorocholine PET/CT clarified by transcriptomic analysis 
PET using fluorine-18 fluorocholine (18F-fluorocholine) may detect malignancies that involve altered choline metabolism. While 18F-fluorocholine PET/CT has shown greater sensitivity for detecting hepatocellular carcinoma (HCC) than 18F-fluoro-D-deoxyglucose (FDG) PET/CT, it is not known whether it can also detect intrahepatic cholangiocarcinoma (ICC), a less common form of primary liver cancer. Clinical, radiographic, and histopathologic data from 5 patients with ICC and 23 patients with HCC from a diagnostic trial of liver 18F-fluorocholine PET/CT imaging were analyzed to preliminarily evaluate 18F-fluorocholine PET/CT for ICC. Imaging was correlated with whole-genome expression profiling to identify molecular pathways associated with tumor phenotypes. On PET/CT, all ICC tumors demonstrated low 18F-fluorocholine uptake with a significantly lower tumor to mean background uptake ratio than HCC tumors (0.69 vs. 1.64, p < 0.0001), but no corresponding significant difference in liver parenchyma uptake of 18F-fluorocholine between ICC and HCC patients (8.0 vs. 7.7, p = 0.74). Two ICC patients demonstrated increased tumor metabolism on FDG PET/CT, while immunohistochemical analysis of ICC tumors revealed overexpression of glucose transporter 1 (GLUT-1) and hexokinase indicating a hyper-glycolytic phenotype. Gene expression analysis revealed down-regulation of farnesoid-X-receptor and other lipid pathways in ICC relative to HCC, and up-regulation of glycolytic pathways and GLUT-1 by HIF1α. These results imply limited utility of 18F-fluorocholine in ICC, however, significant metabolic differences between ICC, HCC, and parenchymal liver tissue may still provide clues about the underlying liver pathology. Gene and protein expression analysis support hyperglycolysis as a more dominant metabolic trait of ICC.
PMCID: PMC4749506  PMID: 27069767
Cholangiocarcinoma; hepatocellular carcinoma; positron emission tomography; fluorocholine
18.  Revolutionizing (robot-assisted) laparoscopic gamma tracing using a drop-in gamma probe technology 
In complex (robot-assisted) laparoscopic radioguided surgery procedures, or when low activity lesions are located nearby a high activity background, the limited maneuverability of a laparoscopic gamma probe (LGP; 4 degrees of freedom (DOF)) may hinder lesion identification. We investigated a drop-in gamma probe (DIGP) technology to be inserted via a trocar, after which the laparoscopic surgical tool at hand can pick it up and maneuver it. Phantom experiments showed that distinguishing a low objective from a high background source (1:100 ratio) was only possible with the detector faced >90° from the high background source. Signal-low-objective-to-background ratios of 3.77, 2.01 and 1.84 were found for detector angles of 90°, 135° and 180°, respectively, whereas detector angles of 0° and 45° were unable to distinguish the sources. This underlines the critical role probe positioning plays. We then focused on engineering of the gripping part for optimal DIGP pick-up with a conventional laparoscopic forceps (4 DOF) or a robotic forceps (6 DOF). DIGPs with 0°, 45°, 90°, and 135° -grip orientations were designed, and their maneuverability- and scanning direction were evaluated and compared to a conventional LGP. The maneuverability- and scanning direction of the DIGP was found highest when using the robotic forceps, with the largest effective scanning direction range obtained with the 90° -grip design (0-180° versus 0-111°, 0-140°, and 37-180° for 0°, 45° and 135° -grip designs, respectively). For the laparoscopic forceps, the scan direction directly translated from the angle of the grip design with the advantage that the 135° -gripped DIGP could be faced backwards (not possible with the conventional LGP). In the ex vivo clinical setup, the surgeon rated DIGP pick-up most convenient for the 45°-grip design. Concluding, the DIGP technology was successfully introduced. Optimization of the grip design and grasping angle of the DIGP increased its utility for (robot-assisted) laparoscopic gamma tracing.
PMCID: PMC4749501  PMID: 27069762
Radioguided surgery; gamma probe; urology; interventional molecular imaging; laparoscopic surgery; robot-assisted surgery; sentinel lymph node biopsy
19.  The sensitivity and specificity of F-DOPA PET in a movement disorder clinic 
Idiopathic Parkinson’s disease (PD) is the second most common neurodegenerative disorder. Early PD may present a diagnostic challenge with broad differential diagnoses that are not associated with nigral degeneration or striatal dopamine deficiency. Therefore, the early clinical diagnosis alone may not be accurate and this reinforces the importance of functional imaging targeting the pathophysiology of the disease process. 18F-DOPA L-6-[18F] fluoro-3,4-dihydroxyphenylalnine (18F-DOPA) is a positron emission tomography (PET) agent that measures the uptake of dopamine precursors for assessment of presynaptic dopaminergic integrity and has been shown to accurately reflect the monoaminergic disturbances in PD. In this study, we aim to illustrate our local experience to determine the accuracy of 18F-DOPA PET for diagnosis of PD. We studied a total of 27 patients. A retrospective analysis was carried out for all patients that underwent 18F-DOPA PET brain scan for motor symptoms suspicious for PD between 2001-2008. Both qualitative and semi-quantitative analyses of the scans were performed. The patient’s medical records were then assessed for length of follow-up, response to levodopa, clinical course of illness, and laterality of symptoms at time of 18F-DOPA PET. The eventual diagnosis by the referring neurologist, movement disorder specialist, was used as the reference standard for further analysis. Of the 28 scans, we found that one was a false negative, 20 were true positives, and 7 were true negatives. The resultant values are Sensitivity 95.4% (95% CI: 100%-75.3%), Specificity 100% (95% CI: 100%-59.0%), PPV 100% (95% CI 100%-80.7%), and NPV 87.5% (95% CI: 99.5%-50.5%).
PMCID: PMC4749509  PMID: 27069770
18F-DOPA; flouorodopa; Parkinson’s disease; PET
20.  [11C]PiB PET in Gerstmann-Sträussler-Scheinker disease 
Gerstmann-Sträussler-Scheinker Disease (GSS) is a familial neurodegenerative disorder characterized clinically by ataxia, parkinsonism, and dementia, and neuropathologically by deposition of diffuse and amyloid plaques composed of prion protein (PrP). The purpose of this study was to evaluate if [11C]Pittsburgh Compound B (PiB) positron emission tomography (PET) is capable of detecting PrP-amyloid in PRNP gene carriers. Six individuals at risk for GSS and eight controls underwent [11C]PiB PET scans using standard methods. Approximately one year after the initial scan, each of the three asymptomatic carriers (two with PRNP P102L mutation, one with PRNP F198S mutation) underwent a second [11C]PiB PET scan. Three P102L carriers, one F198S carrier, and one non-carrier of the F198S mutation were cognitively normal, while one F198S carrier was cognitively impaired during the course of this study. No [11C]PiB uptake was observed in any subject at baseline or at follow-up. Neuropathologic study of the symptomatic individual revealed PrP-immunopositive plaques and tau-immunopositive neurofibrillary tangles in cerebral cortex, subcortical nuclei, and brainstem. PrP deposits were also numerous in the cerebellar cortex. This is the first study to investigate the ability of [11C]PiB PET to bind to PrP-amyloid in GSS F198S subjects. This finding suggests that [11C]PiB PET is not suitable for in vivo assessment of PrP-amyloid plaques in patients with GSS.
PMCID: PMC4749507  PMID: 27069768
[11C]Pittsburgh compound B (PiB) positron emission tomography (PET); Gerstmann-Sträussler-Scheinker disease (GSS); prion disease; neuroimaging; amyloid
21.  Feasibility of 68Ga-labeled Siglec-9 peptide for the imaging of acute lung inflammation: a pilot study in a porcine model of acute respiratory distress syndrome 
There is an unmet need for noninvasive, specific and quantitative imaging of inherent inflammatory activity. Vascular adhesion protein-1 (VAP-1) translocates to the luminal surface of endothelial cells upon inflammatory challenge. We hypothesized that in a porcine model of acute respiratory distress syndrome (ARDS), positron emission tomography (PET) with sialic acid-binding immunoglobulin-like lectin 9 (Siglec-9) based imaging agent targeting VAP-1 would allow quantification of regional pulmonary inflammation. ARDS was induced by lung lavages and injurious mechanical ventilation. Hemodynamics, respiratory system compliance (Crs) and blood gases were monitored. Dynamic examination using [15O]water PET-CT (10 min) was followed by dynamic (90 min) and whole-body examination using VAP-1 targeting 68Ga-labeled 1,4,7,10-tetraaza cyclododecane-1,4,7-tris-acetic acid-10-ethylene glycol-conjugated Siglec-9 motif peptide ([68Ga]Ga-DOTA-Siglec-9). The animals received an anti-VAP-1 antibody for post-mortem immunohistochemistry assay of VAP-1 receptors. Tissue samples were collected post-mortem for the radioactivity uptake, histology and immunohistochemistry assessment. Marked reduction of oxygenation and Crs, and higher degree of inflammation were observed in ARDS animals. [68Ga]Ga-DOTA-Siglec-9 PET showed significant uptake in lungs, kidneys and urinary bladder. Normalization of the net uptake rate (Ki) for the tissue perfusion resulted in 4-fold higher uptake rate of [68Ga]Ga-DOTA-Siglec-9 in the ARDS lungs. Immunohistochemistry showed positive VAP-1 signal in the injured lungs. Detection of pulmonary inflammation associated with a porcine model of ARDS was possible with [68Ga]Ga-DOTA-Siglec-9 PET when using kinetic modeling and normalization for tissue perfusion.
PMCID: PMC4749502  PMID: 27069763
68Ga; PET; lung inflammation; Siglec-9; VAP-1
22.  68Ga-DOTATOC PET and gene expression profile in patients with neuroendocrine carcinomas: strong correlation between PET tracer uptake and gene expression of somatostatin receptor subtype 2 
Somatostatin receptor expression on both protein and gene expression level was compared with in vivo 68Ga-DOTATOC PET/CT in patients with neuroendocrine carcinomas (NEC). Twenty-one patients with verified NEC who underwent a 68Ga-DOTATOC PET/CT between November 2012 and May 2014, were retrospectively included. By real-time polymerase chain reaction, we quantitatively determined the gene expression of several genes and compared with 68Ga-DOTATOC PET uptake. By immunohistochemistry we qualitatively studied the expression of assorted proteins in NEC. The median age at diagnosis was 68 years (range 41-84) years. All patients had WHO performance status 0-1. Median Ki67 index was 50% (range 20-100%). Gene expression of somatostatin receptor subtype (SSTR) 2 and Ki67 were both positively correlated to the 68Ga-DOTATOC uptake (r=0.89; p<0.0001 and r=0.5; p=0.021, respectively). Furthermore, SSTR2 and SSTR5 gene expression were strongly and positively correlated (r=0.57; p=0.006). This study as the first verifies a positive and close correlation of 68Ga-DOTATOC uptake and gene expression of SSTR2 in NEC. SSTR2 gene expression has a stronger correlation to 68Ga-DOTATOC uptake than SSTR5. In addition, the results indicate that the gene expression levels of SSTR2 and SSTR5 at large follow one another.
PMCID: PMC4749505  PMID: 27069766
Neuroendocrine carcinoma; neuroendocrine tumors; immunohistochemistry; gene expression; imaging; 68Ga-DOTATOC PET/CT; somatostatin receptor type 2; somatostatin receptor type 5; mammalian target of rapamycin; urokinase-type plasminogen activator receptor
23.  [18F]FluorThanatrace uptake as a marker of PARP1 expression and activity in breast cancer 
The nuclear enzyme PARP1 plays a central role in sensing DNA damage and facilitating repair. Tumors with BRCA1/2 mutations are highly dependent on PARP1 as an alternative mechanism for DNA repair, and PARP inhibitors generate synthetic lethality in tumors with BRCA mutations, resulting in cell cycle arrest and apoptosis. Zhou et al. recently synthesized an 18F-labeled PARP1 inhibitor ([18F]FluorThanatrace) for PET, and demonstrated high specific tracer uptake in a xenograft model of breast cancer [1]. In the current study, we characterize the level of baseline PARP expression and activity across multiple human breast cancer cell lines, including a BRCA1 mutant line. PARP expression and activity, as measured by levels of PAR and PARP1, is correlated with in vitro [18F]FluorThanatrace binding as well as tracer uptake on PET in a xenograft model of breast cancer. Radiotracer uptake in genetically-engineered mouse fibroblasts indicates [18F]FluorThanatrace is selective for PARP1 versus other PARP enzymes. This motivates further studies of [18F]FluorThanatrace as an in vivo measure of PARP1 expression and activity in patients who would benefit from PARP inhibitor therapy.
PMCID: PMC4749508  PMID: 27069769
PARP1; BRCA mutation; breast cancer
24.  Biodistribution of the radionuclides 18F-FDG, 11C-methionine, 11C-PK11195, and 68Ga-citrate in domestic juvenile female pigs and morphological and molecular imaging of the tracers in hematogenously disseminated Staphylococcus aureus lesions 
Approximately 5-7% of acute-care patients suffer from bacteremia. Bacteremia may give rise to bacterial spread to different tissues. Conventional imaging procedures as X-ray, Computed Tomography (CT), Magnetic Resonance Imaging (MRI), and ultrasound are often first-line imaging methods for identification and localization of infection. These methods are, however, not always successful. Early identification and localization of infection is critical for the appropriate and timely selection of therapy. The aim of this study was thus; a head to head comparison of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) to PET with tracers that potentially could improve uncovering of infectious lesions in soft tissues. We chose 11C-methionine, 11C-PK11195, and 68Ga-citrate as tracers and besides presenting their bio-distribution we validated their diagnostic utility in pigs with experimental bacterial infection. Four juvenile 14-15 weeks old female domestic pigs were scanned seven days after intra-arterial inoculation in the right femoral artery with a porcine strain of S. aureus using a sequential scanning protocol with 18F-FDG, 11C-methionine, 11C-PK11195 and 68Ga-citrate. This was followed by necropsy of the pigs consisting of gross pathology, histopathology and microbial examination. The pigs primarily developed lesions in lungs and neck muscles. 18F-FDG had higher infection to background ratios and accumulated in most infectious foci caused by S. aureus, while 11C-methionine and particularly 11C-PK11195 and 68Ga-citrate accumulated to a lesser extent in infectious foci. 18F-FDG-uptake was seen in the areas of inflammatory cells and to a much lesser extent in reparative infiltration surrounding necrotic regions.
PMCID: PMC4749504  PMID: 27069765
Osteomyelitis; domestic pigs; porcine; swine; Staphylococcus aureus; positron emission tomography; computed tomography; infection; 18F-FDG; 68Ga-citrate; 11C-methionine; 11C-PK11195; animal
25.  Bioluminescence imaging of estrogen receptor activity during breast cancer progression 
Estrogen receptors (ER) are known to play an important regulatory role in mammary gland development as well as in its neoplastic transformation. Although several studies highlighted the contribution of ER signaling in the breast transformation, little is known about the dynamics of ER state of activity during carcinogenesis due to the lack of appropriate models for measuring the extent of receptor signaling in time, in the same animal. To this aim, we have developed a reporter mouse model for the non-invasive in vivo imaging of ER activity: the ERE-Luc reporter mouse. ERE-Luc is a transgenic mouse generated with a firefly luciferase (Luc) reporter gene driven by a minimal promoter containing an estrogen responsive element (ERE). This model allows to measure receptor signaling in longitudinal studies by bioluminescence imaging (BLI). Here, we have induced sporadic mammary cancers by treating systemically ERE-Luc reporter mice with DMBA (9,10-dimethyl 1,2-benzanthracene) and measured receptor signaling by in vivo imaging in individual animals from early stage until a clinically palpable tumor appeared in the mouse breast. We showed that DMBA administration induces an increase of bioluminescence in the whole abdominal area 6 h after treatment, the signal rapidly disappears. Several weeks later, strong bioluminescence is observed in the area corresponding to the mammary glands. In vivo and ex vivo imaging analysis demonstrated that this bioluminescent signal is localized in the breast area undergoing neoplastic transformation. We conclude that this non-invasive assay is a novel relevant tool to identify the activation of the ER signaling prior the morphological detection of the neoplastic transformation.
PMCID: PMC4749503  PMID: 27069764
Mammary tumorigenesis; optical imaging; hormone-dependent cancer; chemical carcinogenesis

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