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.
Prostate cancer; capromab pendetide; SPECT/CT; MDCT; prostate specific membrane antigen (PSMA)
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.
Hypoxia; 18F-FDG PET/CT imaging; carotid atherosclerosis; gene expression; HIF-1α
The aim of the current study was to assess the ability of PET imaging agents to detect early response to therapy in an orthotopic experimental rodent model of glioma. Clinically, MRI and [18F]FDG PET are routinely used but their ability to assess early therapeutic response can be limited. In this study, nude rats were implanted with U87-MG tumors orthotopically and imaged with either [18F]FDG or [18F]FLT to determine which tracer acts as the most sensitive biomarker for evaluation of treatment response in animals undergoing anti-angiogenic therapy with sunitinib, a receptor tyrosine kinase (RTK) inhibitor. Of the radiopharmaceuticals tested, [18F]FLT proved to be the most sensitive biomarker in the proliferating glioma, based on tumour-to-normal tissue radiotracer uptake (TNR ~17) in comparison to [18F]FDG (TNR ~1.7). Furthermore, [18F]FLT displayed earlier assessment of therapy efficacy, than either tumour volume measured by MRI or [18F]FDG PET imaging. Overall, longitudinal molecular imaging with [18F]FLT provides earlier detection of therapy response than either of the commonly used clinical imaging modalities potentially improving patient management.
PET; glioma; sunitinib; [18F]FLT; [18F]FDG; angiogenesis; orthotopic
18F-FDG PET/CT was compared with non-contrast chest CT in monitoring for recurrence 1-year after lobectomy of stage 1 non-small-cell lung cancer (NSCLC). For surveillance after treatment with curative intent, current (April 2012) National Comprehensive Cancer network guidelines recommend chest CT with or without contrast every 6-12 months for 2 years, then non-contrast chest CT annually. PET/CT is not currently indicated for routine follow-up. One hundred patients receiving surveillance PET/CT 1-year after lobectomy for the treatment of stage 1a or 1b NSCLC were included in the study. Exclusion criteria included the presence or interval diagnosis of a second malignancy, or surgical treatment more radical than single lobectomy. The non-contrast CT obtained from the 1-year PET/CT was interpreted by an experienced chest radiologist blinded to the PET/CT for evidence of recurrence using the following findings: pulmonary nodule, pleural effusion, pleural mass, adenopathy, and extrathoracic mass. The ecision about recurrence was made solely from the non-contrast CT without PET/CT findings. This was compared with the determination made with PET/CT. The reference standard for determination of recurrence was the multi-disciplinary tumor board who had access to all imaging and clinical data. Recurrence at 1 year was documented in 16 of 90 patients. All 16 recurrences were documented with PET/CT and 9 were found with non-contrast CT. Five of the 7 recurrences missed with non-contrast CT were extrathoracic metastases. Sensitivity of CT and PET/CT for recurrence was 56.3% and 100%, respectively (p = 0.015). Specificity of CT and PET/CT for recurrence was 95.9% and 93.2%, respectively (p = 0.62).
Lung cancer; PET/CT; non-small cell; CT; lobectomy; stage 1; lung cancer surveillance
Dynamic PET (dPET) with 18F-Deoxyglucose (FDG) provides quantitative information about distribution of the tracer in a predefined volume over time. A two-tissue compartment model can be used to obtain quantitative data regarding transport of FDG into and out of the cells, phosphorylation and dephosphorylation rate of intracellular FDG, and fractional blood volume in the target volume, also named vessel density. Aim of the study was the correlation of glucose transporters expression and hexokinases with the corresponding compartment parameters.Patients with colorectal tumors were examined with dynamic PET prior to surgery. Afterwards, tumor samples were obtained during surgery and gene expression was assessed using gene arrays. The dynamic PET data were evaluated to quantify the parameters of a two tissue compartment model for colorectal tumors using a Volume-of-Interest (VOI) technique. A multiple correlation/regression analysis was performed using glucose transporters as independent variables and k1 as the dependent variable. A correlation of r=0.7503 (p=0.03) was obtained for the transporters SLC2A1, SLC2A2, SLC2A4, SLC2A8, SLC2A9, SLC2A10 and k1. The correlation of r=0.7503 refers to an explained variance of data of 56.30 %, therefore more than 50 % of data changes are associated with the gene expression. An analysis of the hexokinases HK1-HK3 and k3 revealed a correlation coefficient of r=0.6093 (p=0.04), which is associated with an explained variance of 37.12 %. Therefore, parameters k1 and k3 reflect gene activity. The results demonstrate that k1 and k3 of the two-tissue compartment model are correlated with glucose transporters and hexokinases.
Dynamic PET; compartment model; glucose transporter; hexokinase
Disturbances of the endothelin axis have been described in tumor angiogenesis and in highly vascularized tumors, such as thyroid carcinoma. Consequently, the endothelin (ET) receptor offers a molecular target for the visualization of the endothelin system in vivo by positron emission tomography (PET). We therefore endeavoured to develop a subtype-selective ETA receptor (ETAR) radioligand by introduction of a glycosyl moiety as a hydrophilic building block into the lead compound PD156707. Employing click chemistry we synthesized the triazolyl conjugated fluoroglucosyl derivative 1 that had high selectivity for ETAR (4.5 nM) over ETBR (1.2 μM). The radiosynthesis of the glycoconjugate [18F]1 was achieved by concomitant 18F-labeling and glycosylation, providing [18F]1 in high radiochemical yields (20-25%, not corrected for decay, 70 min) and a specific activity of 41-138 GBq/μmol. Binding properties of [18F]1 were evaluated in vitro, and its biodistribution was measured in K1 thyroid carcinoma xenograft nude mice ex vivo and by molecular imaging. Although the very substantial excretion via hepatobiliary clearance was not decisively influenced by glycosylation, the 18F-glycoconjugate was more stable in blood during PET recordings than was the previously described 18F-fluoroethoxy analog. Small-animal PET imaging showed displacable binding of [18F]1 at ETAR in K1 tumors. The simple and efficient 18F-radiosynthesis together with the excellent stability make the 18F-labeled glycoconjugate [18F]1 a promising molecular tool for preclinical PET imaging studies of ETAR expression in thyroid carcinoma and other conditions with marked angiogenesis.
Endothelin receptor; angiogenesis; positron emission tomography (PET); 18F; glycosylation; thyroid carcinoma
Bone metastases of gastroenteropancreatic neuroendocrine tumors (GEP NET) can be associated with pain and a poor prognosis. Peptide receptor radionuclide therapy (PRRT) has been shown to be effective against this tumor manifestation. This study represents an update of the therapeutic assessment of PRRT with 177Lu-octreotate in GEP NET patients with bone metastases focusing on potential predictors for impaired outcome and overall survival.We retrospectively analyzed a consecutive subgroup of n=68 patients with bone metastases (BM) of GEP NET treated with 177Lu-octreotate (4 intended cycles at 3 monthly intervals; mean activity per cycle, 8.1 GBq). Baseline characteristics, including age, performance status, tumor origin, tumor load, plasma chromogranin A (CgA), and neuron-specific enolase (NSE) were analyzed regarding the impact on tumor regression (modified M.D. Anderson criteria) and survival of the patients. Survival analyses were performed using Kaplan–Meier curves, log-rank test at a significance level of p <0.05, and Cox proportional hazards model for uni- and multivariate analyses. Median follow-up was 48 months. The observed response of BMs consisted of complete remission in 2 (2.9%), partial remission in 23 (33.8%), minor response in 8 (11.8%), stable disease in 26 (38.2%), and progressive disease in 8 (13.2%) patients. Median time-to-progression (TTP) of BMs and overall survival (OS) were 35 mo (95% CI: 25-45) and 51 mo (95% CI: 38-64), respectively. Patients with responding BMs survived significantly longer than other patients (median 56 mo vs. 39 mo, p=0.034). NSE >15 ng/ml (p=0.002) and Ki67 index >10% (p=0.008) were associated with shorter overall survival. BM of GEP NET are effectively controlled by PRRT with a long median progression-free survival of approx. 3 years. Non-regression of BM, high proliferation rate and increased plasma NSE at baseline are predictive of shorter survival. However, this study confirms that poor patient condition (Karnofsky-Index ≤70%) and multifocality of BM (>10 lesions) do not affect outcome efficacy, further encouraging the use of PRRT in advanced bone metastatic disease.
Bone metastases; gastroenteropancreatic neuroendocrine tumors (GEP NET); peptide receptor radionuclide therapy (PRRT)
Molecular imaging of atherosclerotic biomarkers is critical for non-invasive detection and diagnosis of atherosclerotic plaques and therapeutic management. Fibrin and fibronectin accumulate at elevated levels in atherosclerotic plaques and are associated with atherogenesis and disease progression. Molecular imaging of these biomarkers has the potential to non-invasively characterize plaque burden. In this work, we investigated the effectiveness of a peptide-targeted macrocyclic Gd(III) chelate, CLT1-dL-(DOTA-Gd)4, specific to fibrin-fibronectin complexes for molecular MRI of atherosclerosis. Atherosclerotic plaques were induced in Apolipoprotein E-knockout (ApoE-/-) mice by feeding with high fat and cholesterol-enriched diet (HFD) for up to 30 weeks. MRI of the vessel wall in the arch aorta was performed at 10, 20 and 30 weeks after the onset of HFD. High spatial-resolution MRI was performed prior and up to 35 minutes after i.v. injection of CLT1-dL-(DOTA-Gd)4 or a nonspecific control agent at a dose of 0.1 mmol-Gd/kg. CLT1-dL-(DOTA-Gd)4 produced stronger enhancement in the atherosclerotic lesions of the aortic wall than the control at all time points in the mice. Cross sectional MR images of the aortic arch revealed progressive thickening of the atherosclerotic vessel wall in the mice on HFD for up to 30 weeks. This progression correlated well to histological staining, as well as fibrin and fibronectin immunochemical stained images. Molecular MRI with CLT1-dL-(DOTA-Gd)4 has a potential for detecting atherosclerosis and non-invasive monitoring of the progression of the plaques.
Molecular MRI; atherosclerosis; CLT1 peptide; targeted contrast agent; macrocyclic Gd(III) chelate
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.
Atherosclerosis; positron emission tomography; magnetic resonance imaging; PET/MR; hybrid scanners
Vascular endothelial growth factor receptor 2 (VEGFR2) is an important angiogenic marker over-expressed in gliomas. With the use of molecular magnetic resonance imaging (mMRI) differing levels of VEGFR2 can be characterized in vivo with in rodent gliomas varying in angiogenesis. VEGFR2 levels were assessed by intravenous administration of an anti-VEGFR2 probe (anti-VEGFR2-albumin-Gd (gadolinium)-DTPA (diethylene triamine penta acetic acid)-biotin) into C6 or RG2 glioma-bearing rats, and visualized with mMRI. A non-specific IgG was coupled to the albumin-Gd-DTPA-biotin construct as a contrast agent molecular weight control. VEGFR2 levels are heterogeneous in different regions of C6 gliomas, whereas VEGFR2 was more homogenous or evenly distributed in RG2 gliomas. RG2 gliomas have less VEGFR2 within tumor periphery and peri-necrotic (p<0.05) regions, but more VEGFR2 within tumor interior regions (p<0.01), compared to C6 gliomas. mMRI results were confirmed with fluorescence staining and mean fluorescence intensity (MFI) quantification of the anti-VEGFR2 probe in excised glioma and brain tissues, as well as detection of VEGFR2 in C6 and RG2 gliomas and corresponding contalateral brain tissues. Ex vivo VEGFR2 levels were found to be significantly higher in C6 gliomas compared to RG2 tumors (p<0.001), which corresponded with in vivo detection using the VEGFR2 probe. Immunohistochemistry staining for HIF-1α (hypoxia inducible factor 1α), which is associated with angiogenesis, indicated higher levels in RG2 (p<0.01) compared to C6 gliomas. The data suggests that C6 gliomas have angiogenesis which is associated more with large blood vessels in tumor periphery and peri-necrotic regions, and less microvascular angiogenesis within the tumor interior, compared to RG2 gliomas.
Molecular magnetic resonance imaging (mMRI); vascular endothelial growth factor receptor 2 (VEGFR2); C6 and RG2 rat gliomas; in vivo; fluorescence imaging
Focal increased lower thoracic spinal cord 18F FDG uptake is not infrequently observed as a normal physiological finding and may be confused for spinal cord metastases. This study was conducted to evaluate a possible correlation between the lower thoracic (T11-T12) spinal uptake and lower limb movements/ambulatory status of the patients as a surrogate. The primary endpoint was to identify the possible cause(s) of the normal variant focal increased thoracic spinal cord (T11-T12) 18F FDG activity and correlate it with the lower limb movements/ambulatory status of the patients. This was a retrospective analysis of PET-CT scans of 200 patients with solid and hematological malignancies. The focal relatively increased 18F FDG activity in the lower thoracic spinal cord correlated strongly with the 18F FDG intensity of the liver, bowel, C3-C5 cervical cord activity, weight of the patient and injected dose of 18F FDG. With regard to the primary endpoint, no significant correlation was found between the ambulatory status of patients in any of the groups and thoracic spine SUVmax. This could be further assessed by performing dual studies in the same patient with and without moderate to excessive leg motion. Identifying this variant focal increased 18F FDG activity can minimize errors of misdiagnosis and unnecessary further investigation.
18F FDG PET-CT; spinal cord; metastases; ambulatory status
Elastin is considered as a key player in human vascular diseases and it might contribute to the development of atherosclerosis. The elastin binding radiotracer, [18F]AlF-NOTA-EBM ([18F]2), was evaluated in a wild type mouse to determine its in vivo distribution and on human carotid atherosclerotic plaque tissues to assess its utility as a PET imaging agent for visualizing human atherosclerotic plaque lesions. The free ligand NOTA-EBM, which served as the precursor, was obtained in 25% chemical yield. The radiosynthesis of [18F]2 was accomplished by coordination of Al18F to NOTA-EBM in 8-13% decay corrected radiochemical yield (n = 7) and specific radioactivity of 59 ± 12 GBq/μmol. A dynamic in vivo PET scan in a healthy wild type mouse (C57BL/6) showed high accumulation of radioactivity in heart and lungs, organs reported to have high elastin content. Excretion of [18F]2 proceeded via the renal pathway and through the hepatobiliary system as indicated by a high uptake of radioactivity in the liver, intestines and gall bladder. In vitro autoradiography on human atherosclerotic plaque sections showed a heterogeneous distribution of [18F]2 with an elevated accumulation in stable and vulnerable atherosclerotic plaques compared to control samples of normal arteries. However, there was no statistical significance between the different plaque phenotypes and control samples. Competition experiments with 10.000-fold excess of free ligand NOTA-EBM resulted in a marked decrease of radioactivity accumulation, consistent with a target-specific ligand.
Elastin; atherosclerotic plaques; PET imaging; autoradiography; Al18F
Ultrasound can selectively and specifically visualize upregulated vascular receptors through the detection of bound microbubbles. However, most current ultrasound molecular imaging methods incur delays that result in longer acquisition times and reduced frame rates. These delays occur for two main reasons: 1) multi-pulse imaging techniques are used to differentiate microbubbles from tissue and 2) acquisition occurs after free bubble clearance (>6 minutes) in order to differentiate bound from freely circulating microbubbles. In this paper, we validate tumor imaging with a broadband single pulse molecular imaging method that is faster than the multi-pulse methods typically implemented on commercial scanners. We also combine the single pulse method with interframe filtering to selectively image targeted microbubbles without waiting for unbound bubble clearance, thereby reducing acquisition time from 10 to 2 minutes. The single pulse imaging method leverages non-linear bubble behavior by transmitting at low and receiving at high frequencies (TLRH). We implemented TLRH imaging and visualized the accumulation of intravenously administrated integrin-targeted microbubbles in a phantom and a Met-1 mouse tumor model. We found that the TLRH contrast imaging has a ~2-fold resolution improvement over standard contrast pulse sequencing (CPS) imaging. By using interframe filtering, the tumor contrast was 24.8±1.6 dB higher after the injection of integrin-targeted microbubbles than non-targeted control MBs, while echoes from regions lacking the target integrin were suppressed by 26.2±2.1 dB as compared with tumor echoes. Since real-time three-dimensional (3D) molecular imaging provides a more comprehensive view of receptor distribution, we generated 3D images of tumors to estimate their volume, and these measurements correlated well with expected tumor sizes. We conclude that TLRH combined with interframe filtering is a feasible method for 3D targeted ultrasound imaging that is faster than current multi-pulse strategies.
Targeted microbubbles; ultrasound molecular imaging; angiogenesis; 3D visualization
Omalizumab promotes clinical improvement in patients with allergic asthma, but its effect on pulmonary function is unclear. One possibility is that omalizumab improves asthma symptoms through effects on the regional distributions of ventilation, perfusion, and ventilation/perfusion matching, metrics which can be assessed with Nitrogen-13-saline Position Emission Tomography (PET). Four adults with moderate to severe uncontrolled allergic asthma underwent symptom assessment, spirometry and functional pulmonary imaging with Nitrogen-13-saline PET before and after 4-5 months of treatment with omalizumab. PET imaging was used to determine ventilation/perfusion ratios, the heterogeneity (coefficient of variation, COV) of ventilation and perfusion, and lung regions with ventilation defects. There were no significant changes in spirometry values after omalizumab treatment, but there was a trend towards an improvement in symptom scores. There was little change in the matching of ventilation and perfusion. The COV of perfusion was similar before and after omalizumab treatment. The COV of ventilation was also similar before (0.57 (0.28)) and after (0.66 (0.13)) treatment, and it was similar to previously published values for healthy subjects. There was a non-significant trend towards an increase in the extent of ventilation defects after omalizumab treatment, from 5 (15)% to 12.8 (14.7)%. Treatment of moderate to severe uncontrolled allergic asthma with omalizumab did not result in a significant improvement in ventilation and perfusion metrics assessed with functional PET imaging. The normal COV of ventilation which was unaffected by treatment supports the hypothesis that omalizumab exerts its clinical effect on lung function during allergen exposure rather than in between exacerbations.
PET functional imaging; omalizumab; Xolair; asthma; V/Q ratios
The G-protein coupled C-X-C chemokine receptor type 4 (CXCR4) is highly overexpressed in a range of cancers and is therefore an excellent biomarker for cancer imaging. To this end targeted iron oxide nanoparticles were developed and utilised for in vitro imaging of MDA-MB-231 breast cancer cells overexpressing the CXCR4 receptor. Nanoparticles comprising an iron oxide core, encapsulated in a stabilising epichlorohydrin crossed-linked dextran polymer, were conjugated to a cyclopentapeptide with affinity to the CXCR4 receptor. The particles were characterized for their size, surface charge and r2 relaxivity at 4.7 T. MR imaging of the CXCR4 receptor with targeted iron oxide nanoparticles revealed an approximately 3-fold increase in T2 signal enhancement of MDA-MB-231 cells compared to non-targeted controls. Prussian blue staining of labeled MDA-MB-231 cells revealed darker and more intense staining of the cellular membrane. This study demonstrates the potential of targeted iron oxide nanoparticles for the imaging of the CXCR4 receptor by magnetic resonance imaging (MRI).
CXCR4; iron oxide nanoparticles; tumor MRI; targeted nanoparticles; T2 imaging; cyclopentapeptide
Conventional PET methods to estimate [11C]raclopride binding potential (BP
ND) assume that endogenous dopamine concentration does not change during the scan time. However, this assumption is purposely violated in studies using pharmacological or behavioral stimuli to invoke acute dopamine release. When the assumption of steady-state dopamine is violated, conventional analysis methods may produce biased or even unusable estimates of BP
ND. To illustrate this problem, we examined the effect of scan duration on ΔBP
ND estimated by three common analysis methods (simplified reference tissue model, Logan graphical reference method, and equilibrium analysis) applied to simulated and experimental single-scan activation studies. The activation – dopamine release – in both the simulated and experimental studies was brief. Simulations showed ΔBP
ND to be highly dependent on the window of data used to determine BP
ND in the activation state. A similar pattern was seen in the data from human smoking studies. No such pattern of ΔBP
ND dependence on the window of data used was apparent in simulations where dopamine was held constant. The dependence of ΔBP
ND on the duration of data analyzed illustrates the inability of conventional methods to reliably quantify short-lived increases in endogenous dopamine.
Binding potential (BPND); transient dopamine release; model selection; scan duration; smoking; time-invariant
The definitive diagnosis of amyloidosis is made histologically with Congo red stain. Noninvasive imaging techniques for amyloidosis are beneficial for early and definite diagnosis of amyloid deposition in the body. 99mTc-aprotinin has the benefit of detecting amyloid deposits mainly in the heart, but it can also detect a wide range of lesions in other locations. The usefulness and limitations of 99mTc-Aprotinin scintigraphy for amyloid imaging were re-evaluated based on results from 25 patients (15 men and 10 women; median age, 62.9 y; range, 34-83 y). In addition, other nuclear tracers for imaging amyloidosis are discussed. Of the 25 patients with suspected amyloidosis, 19 patients were proven to have amyloid deposits by histopathological diagnosis. Major 99mTc-aprotinin positive sites were confirmed in the myocardium, thyroid, large joints, vertebrae, colon, and lungs. If 99mTc-Aprotinin images showed positive findings, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of existing amyloid deposits were 94.7, 33.3, 81.8, and 66.7%, respectively. For analysis based on biopsy region, the sensitivity, specificity, PPV, and NPV of existing amyloid deposition were 30.6, 82.6, 73.3, and 43.2%, respectively. 99mTc-Aprotinin has a high potential for diagnosis of amyloid deposition in body; however, due to its physiological uptake, its potential is limited for detection of amyloid deposits in the liver, kidney, and spleen.
99mTc-aprotinin; amyloidosis; SPECT/CT; SPECT; scintigraphy
This pilot study investigates the value of baseline total lesion glycolysis (TLG) in 18F-FDG PET/CT scans for prediction of progression-free survival (PFS) in patients with Diffuse Large B-Cell Lymphoma (DLBCL). We also evaluate the role of other quantitative parameters measured at baseline and interim PET/CT for prediction of PFS. A retrospective review (2003-2010) of patients with DLBCL who underwent 18F-FDG PET/CT before, after cycle two, and after completion of R-CHOP treatment, identified 84 patients. Twenty patients fulfilled the inclusion criteria. Standardized uptake values (SUVmax and SUVmean), total metabolic tumor volume (TMTV), and TLG were measured in baseline and interim PET/CT. Relationship between quantitative parameters and PFS was statistically analyzed using Log-rank test and univariate Cox-regression analysis. Of 20 patients (F/M: 7/13, range: 20-73 years), six patients (30%) developed recurrence after chemotherapy (mean follow-up: 51.35±17.05 months, range: 12-81 months). Results of statistical analysis showed TLG as the only discriminator of recurrence at baseline (cut-point: 704.77 g, HR: 11.21, CI: 1.29-97, P=0.02). Among the interim PET/CT parameters, SUVmean (cut -point: 2.07, HR: 6.31, CI: 1.25-31.61), SUVmax (cut-point: 2.3, HR: 6.31, CI: 1.25-31.61), and TLG (cut-point: 96.5 g, HR: 6.38, CI: 1.29 - 31.61) could all help predict PFS (P<0.05). Although not routinely reported, high baseline TLG may be a useful index to identify patients with DLBCL who are at increased risk for relapse after conventional R-CHOP. If confirmed in larger prospective studies, this may allow the selection of alternate therapeutic choices at the onset of treatment.
Diffuse large B-cell lymphoma; 18F-FDG PET/CT; progression-free survival; quantitative parameters
Manganese-enhanced magnetic resonance imaging (MRI) is a surrogate method to measure calcium content in nervous system since manganese physiologically follows calcium. Manganese is detectable in MRI and therefore visualizes structures and cell populations that actively regulate calcium. Since calcium is actively recruited for the transmission of action potentials, our purpose is to validate manganese-enhanced MRI for detection of changes in lumbar nerves related to nociception. A neuropathic pain model was created by chronic constrictive injury of the left sciatic nerve of Sprague-Dawley rats. Behavioral measurements, using von Frey’s tests, confirmed the presence of significant allodynia in the left hind limb of animals in the injured group. T1-weighted fast spin echo images were obtained of the lumbar cord and plexus of animals with injured left sciatic nerve and uninjured animals (control) scanned in a 7 Tesla magnet after intraperitoneal manganese chloride administration four weeks after surgery. Lumbar nerve roots and sciatic nerves in the injured group show increased normalized manganese-enhanced MRI signal, representing manganese enhancement, compared to the control group. In conclusion, animals with neuropathic pain in the left hind limb show increased manganese uptake in not only the injured sciatic nerve but also in the contralateral uninjured sciatic nerve on manganese-enhanced MRI in vivo. Although poorly understood, this finding corroborates ex vivo finding of bilateral nociceptive-related molecular changes in the nervous system of unilateral pain models.
Manganese-enhanced magnetic resonance imaging; chronic constrictive injury; sciatic nerve injury; neuropathic pain; animal model
The purpose of this study is to systematically evaluate the usefulness of Positron emission tomography/Magnetic resonance imaging (PET/MRI) images in a clinical setting by assessing the image quality of Positron emission tomography (PET) images using a three-segment MR attenuation correction (MRAC) versus the standard CT attenuation correction (CTAC). We prospectively studied 48 patients who had their clinically scheduled FDG-PET/CT followed by an FDG-PET/MRI. Three nuclear radiologists evaluated the image quality of CTAC vs. MRAC using a Likert scale (five-point scale). A two-sided, paired t-test was performed for comparison purposes. The image quality was further assessed by categorizing it as acceptable (equal to 4 and 5 on the five-point Likert scale) or unacceptable (equal to 1, 2, and 3 on the five-point Likert scale) quality using the McNemar test. When assessing the image quality using the Likert scale, one reader observed a significant difference between CTAC and MRAC (p=0.0015), whereas the other readers did not observe a difference (p=0.8924 and p=0.1880, respectively). When performing the grouping analysis, no significant difference was found between CTAC vs. MRAC for any of the readers (p=0.6137 for reader 1, p=1 for reader 2, and p=0.8137 for reader 3). All three readers more often reported artifacts on the MRAC images than on the CTAC images. There was no clinically significant difference in quality between PET images generated on a PET/MRI system and those from a Positron emission tomography/Computed tomography (PET/CT) system. PET images using the automatic three-segmented MR attenuation method provided diagnostic image quality. However, future research regarding the image quality obtained using different MR attenuation based methods is warranted before PET/MRI can be used clinically.
PET/CT; PET/MRI; FDG; attenuation correction; image quality; hybrid imaging
Neurofibrillary tangles (NFTs) have long been recognized as one of the pathological hallmarks in Alzheimer’s disease (AD). Recent studies, however, showed that soluble aggregated Tau species, especially hyperphosphorylated Tau oligomers, which are formed at early stage of AD prior to the formation of NFT, disrupted neural system integration. Unfortunately, little is known about Tau aggregates, and few Tau targeted imaging probe has been reported. Successful development of new imaging methods that can visualize early stages of Tau aggregation specifically will obviously be important for AD imaging, as well as understanding Tau-associated neuropathology of AD. Here, we report the first NIR ratiometric probe, CyDPA2, that targets Tau aggregates. The specificity of CyPDA2 to aggregated Tau was evaluated with in vitro hyperphosphorylated Tau proteins (pTau), as well as ex vivo Tau samples from AD human brain samples and the tauopathy transgenic mouse model, P301L. The characteristic enhancements of absorption ratio and fluorescence intensity in CyDPA2 were observed in a pTau concentration-dependent manner. In addition, fluorescence microscopy and gel staining studies demonstrated CyDPA2-labeled Tau aggregates. These data indicate that CyDPA2 is a promising imaging probe for studying Tau pathology and diagnosing AD at an early stage.
Near infrared (NIR); ratiometric; probe; Tau; Alzheimer’s disease (AD); imaging
Rats with osteoporosis were involved by combining ovariectomy (OVX) either with calcium and Vitamin D deficiency diet (Group D), or with glucocorticoid (dexamethasone) treatment (Group C). In the period of 1-12 months, dynamic PET-CT studies were performed in three groups of rats including Group D, Group C and the control Group K (sham-operated). Standardized uptake values (SUVs) were calculated, and a 2-tissue compartmental learning-machine model (calculation of K1-k4, VB and the plasma clearance of tracer to bone mineral (Ki) as well as a non-compartmental model based on the fractal dimension (FD) was used for quantitative analysis of both groups. The evaluation of PET data was performed over the lumbar spine. The correlation analysis revealed a significant linear correlation for certain dPET quantitative parameters and time up to 12 months after induction of osteoporosis. Based on the 18F-Fluoride data, we noted a significant negative correlation for K1 (the fluoride/hydroxyl exchange) in the Group C and a significant positive correlation for k3, SUV (bone metabolism) and FD in the Group K. The evaluation of the 18F-FDG data revealed a significant positive correlation for SUV (glucose metabolism) only in Group C. The correlation between the two tracers revealed significant results between K1 of 18F-Fluoride and SUV of FDG in Group K as well as between FD of 18F-Fluoride and FDG in Group D and C and between k3 of 18F-Fluoride and SUV of FDG in Group C.
dPET-CT; 18F-FDG; 18F-fluoride; osteoporosis
Positron emission tomography (PET) imaging with the glucose analog 2-deoxy-2-[18F]fluoro-D-glucose ([18F] FDG) has demonstrated clinical utility for the monitoring of brain glucose metabolism alteration in progressive neurodegenerative diseases. We examined dynamic [18F]FDG PET imaging and kinetic modeling of atlas-based regions to evaluate regional changes in the cerebral metabolic rate of glucose in the widely-used 6-hydroxydopamine (6-OHDA) rat model of Parkinson’s disease. Following a bolus injection of 18.5 ± 1 MBq [18F]FDG and a 60-minute PET scan, image-derived input functions from the vena cava and left ventricle were used with three models, including Patlak graphical analysis, to estimate the influx constant and the metabolic rate in ten brain regions. We observed statistically significant changes in [18F]FDG uptake ipsilateral to the 6-OHDA injection in the basal ganglia, olfactory bulb, and amygdala regions; and these changes are of biological relevance to the disease. These experiments provide further validation for the use of [18F]FDG PET imaging in this model for drug discovery and development.
Dynamic [18F]fluoro-D-glucose positron emission tomography; 6-hydroxydopamine; brain glucose metabolism; Parkinson’s disease
The objective of this study was to determine whether 18F-misonidazole could detect hypoxia in macroscopic and microscopic tumors in mice. In nude mice, subcutaneous xenografts and peritoneal metastases were generated utilizing human non-small cell lung cancer A549 and HTB177 cells. Animals were co-injected with 18F-misonidazole, pimonidazole and bromodeoxyuridine, and tumor perfusion was assessed by Hoechst 33342 injection. The intratumoral distribution of 18F-misonidazole was determined by micro-PET scan and autoradiography. Pimonidazole, bromodeoxyuridine and Hoechst 33342 were detected by immunohistochemistry on the autoradiography sections. Submillimeter micrometastases found to be severely hypoxic. In both peritoneal metastases and subcutaneous xenografts models, PET images displayed significant 18F-misonidazole uptake, and its distribution was non-uniform in these macroscopic subcutaneous tumors. In frozen sections, digital autoradiography and immunohistochemistry revealed similar distributions of 18F-misonidazole, pimonidazole and glucose transporter-1, in both microscopic and macroscopic tumors. Bromodeoxyuridine stained-positive proliferative regions were well perfused, as judged by Hoechst 33342, and displayed low 18F-misonidazole accumulation. 18F-misonidazole uptake was low in tumor stroma and necrotic zones as well. Microscopic non-small cell lung cancer metastases are severely hypoxic. 18F-misonidazole PET is capable to image hypoxia noninvasively not only in macroscopic tumors but also in micrometastases growing in mice. Accordingly, 18F-misonidazole may be a promising agent to detect the burden of micrometastatic diseases.
Micrometastasis; hypoxia; 18F-misonidazole; PET; autoradiography
Positron Emission Tomography (PET) and in particular gallium-68 (68Ga) applications are growing exponentially worldwide contributing to the expansion of nuclear medicine and personalized management of patients. The significance of 68Ga utility is reflected in the implementation of European Pharmacopoeia monographs. However, there is one crucial point in the monographs that might limit the use of the generators and consequently expansion of 68Ga applications and that is the limit of 0.001% of Germanium-68 (68Ge(IV)) radioactivity content in a radiopharmaceutical. We have investigated the organ distribution of 68Ge(IV) in rat and estimated human dosimetry parameters in order to provide experimental evidence for the determination and justification of the 68Ge(IV) limit. Male and female rats were injected in the tail vein with formulated [68Ge]GeCl4 in the absence or presence of [68Ga]Ga-DOTA-TOC. The tissue radioactivity distribution data was extrapolated for the estimation of human organ equivalent doses and total effective dose using Organ Level Internal Dose Assessment Code software (OLINDA/EXM). 68Ge(IV) was evenly distributed among the rat organs and fast renal excretion prevailed. Human organ equivalent dose and total effective dose estimates indicated that the kidneys were the dose-limiting organs (185±54 μSv/MBq for female and 171±38 μSv/MBq for male) and the total effective dose was 15.5±0.1 and 10.7±1.2 μSv/MBq, respectively for female and male. The results of this dosimetry study conclude that the 68Ge(IV) limit currently recommended by monographs could be increased considerably (>100 times) without exposing the patient to harm given the small absorbed doses to normal organs and fast excretion.
Positron emission tomography; 68Ga; 68Ge; dosimetry; 68Ge/68Ga generator