Leyun Pan

Impact of Angiogenesis-Related Gene Expression on the Tracer Kinetics of 18F-FDG in Colorectal Tumors

18F-FDG kinetics are primarily dependent on the expression of genes associated with glucose transporters and hexokinases but may be modulated by other genes. The dependency of 18F-FDG kinetics on angiogenesis-related gene expression was evaluated in this study. Methods: Patients with primary colorectal tumors (n = 25) were examined with PET and 18F-FDG within 2 days before surgery. Tissue specimens were obtained from the tumor and the normal colon during surgery, and gene expression was assessed using gene arrays. Results: Overall, 23 angiogenesis-related genes were identified with a tumor-to-normal ratio exceeding 1.50. Analysis revealed a significant correlation between k1 and vascular endothelial growth factor (VEGF-A, r = 0.51) and between fractal dimension and angiopoietin-2 (r = 0.48). k3 was negatively correlated with VEGF-B (r = −0.46), and a positive correlation was noted for angiopoietin-like 4 gene (r = 0.42). A multiple linear regression analysis was used for the PET parameters to predict the gene expression, and a correlation coefficient of r = 0.75 was obtained for VEGF-A and of r = 0.76 for the angiopoietin-2 expression. Thus, on the basis of these multiple correlation coefficients, angiogenesis-related gene expression contributes to about 50% of the variance of the 18F-FDG kinetic data. The global 18F-FDG uptake, as measured by the standardized uptake value and influx, was not significantly correlated with angiogenesis-associated genes. Conclusion: 18F-FDG kinetics are modulated by angiogenesis-related genes. The transport rate for 18F-FDG (k1) is higher in tumors with a higher expression of VEGF-A and angiopoietin-2. The regression functions for the PET parameters provide the possibility to predict the gene expression of VEGF-A and angiopoietin-2.

Quantitative approaches of dynamic FDG-PET and PET/CT studies (dPET/CT) for the evaluation of oncological patients.

Abstract Objectives: The use of dynamic positron emission tomography/computed tomography (dPET/CT) studies with [18F]deoxyglucose (FDG) in oncological patients is limited and primarily confined to research protocols. A more widespread application is, however, desirable, and may help to assess small therapeutic effects early after therapy as well as to differentiate borderline differences between tumour and non-tumour lesions, e.g., lipomas versus low-grade liposarcomas. The aim is to present quantification approaches that can be used for the evaluation of dPET/CT series in combination with parametric imaging and to demonstrate the feasibility with regard to tumour diagnostics and therapy management. Methods: A 60-min data acquisition and short acquisition protocols (20-min dynamic series and a static image 60 min post injection) are discussed. A combination of a modified two-tissue compartment model and non-compartmental approaches from the chaos theory (fractal dimension of the time–activity curves) are presented. Fused PET/CT images as well as regression-based parametric images fused with CT or with PET/standardised uptake value images are demonstrated for the exact placement of volumes of interest. Results: The two-tissue compartmental method results in the calculation of 5 kinetic parameters, the fractional blood volume VB (known also as the distribution volume), and the transport rates k1 to k4. Furthermore, the influx according to Patlak can be calculated from the transport rates. The fractal dimension of the time–activity curves describes the heterogeneity of the tracer distribution. The use of the regression-based parametric images of FDG helps to visualise the transport/perfusion and the transport/phosphorylation-dependent FDG uptake, and adds a new dimension to the existing conventional PET or PET/CT images. Conclusions: More sophisticated quantification methods and dedicated software as well as high computational power and faster acquisition protocols can facilitate the assessment of dPET/CT, and may find use in clinical routine, in particular for the assessment of early therapeutic effects or new treatment protocols in combination with the new generation of PET/CT scanners.

Fusion of Positron Emission Tomography (PET) and Gene Array Data: A New Approach for the Correlative Analysis of Molecular Biological and Clinical Data

The combined assessment of data obtained by positron emission tomography (PET) and gene array techniques provide new capabilities for the interpretation of kinetic tracer studies. The correlative analysis of the data helps to detect dependencies of the kinetics of radiotracer on gene expression. Furthermore, gene expression may be predicted using regression functions if a significant correlation exists, which raises new aspects regarding the interpretation of dynamic PET examinations. The development of new radiopharmaceuticals requires the knowledge of the enhanced expression of genes, especially genes controlling receptors and cell surface proteins. The GenePET program facilitates an interactive approach together with the use of key words to identify possible targets for new radiopharmaceuticals.

68Ga-PSMA-11 Dynamic PET/CT Imaging in Primary Prostate Cancer.

Purpose The aim of our study is to assess the pharmacokinetics and biodistribution of 68Ga-PSMA-11 in patients suffering from primary prostate cancer (PC) by means of dynamic and whole-body PET/CT. Materials and methods Twenty-four patients with primary, previously untreated PC were enrolled in the study. All patients underwent dynamic PET/CT (dPET/CT) scanning of the pelvis and whole-body PET/CT studies with 68Ga-PSMA-11. The evaluation of dPET/CT studies was based on qualitative evaluation, SUV calculation, and quantitative analysis based on two-tissue compartment modeling and a noncompartmental approach leading to the extraction of fractal dimension (FD). Results A total of 23/24 patients (95.8%) were 68Ga-PSMA-11 positive. In 9/24 patients (37.5%), metastatic lesions were detected. PC-associated lesions demonstrated the following mean values: SUVaverage = 14.3, SUVmax = 23.4, K1 = 0.24 (1/min), k3 = 0.34 (1/min), influx = 0.15 (1/min), and FD = 1.27. The parameters SUVaverage, SUVmax, k3, influx, and FD derived from PC-associated lesions were significantly higher than respective values derived from reference prostate tissue. Time-activity curves derived from PC-associated lesions revealed an increasing 68Ga-PSMA-11 accumulation during dynamic PET acquisition. Correlation analysis revealed a moderate but significant correlation between PSA levels and SUVaverage (r = 0.60) and SUVmax (r = 0.57), and a weak but significant correlation between Gleason score and SUVaverage (r = 0.33) and SUVmax (r = 0.28). Conclusion 68Ga-PSMA-11 PET/CT confirmed its capacity in detecting primary PC with a detection rate of 95.8%. Dynamic PET/CT studies of the pelvis revealed an increase in tracer uptake in PC-associated lesions during the 60 minutes of dynamic PET acquisition, a finding with potential applications in anti-PSMA approaches.

Shortened Acquisition Protocols for the Quantitative Assessment of the 2-Tissue-Compartment Model Using Dynamic PET/CT 18F-FDG Studies

18F-FDG kinetics are quantified by a 2-tissue-compartment model. The routine use of dynamic PET is limited because of this modalitys 1-h acquisition time. We evaluated shortened acquisition protocols up to 0–30 min regarding the accuracy for data analysis with the 2-tissue-compartment model. Methods: Full dynamic series for 0–60 min were analyzed using a 2-tissue-compartment model. The time–activity curves and the resulting parameters for the model were stored in a database. Shortened acquisition data were generated from the database using the following time intervals: 0–10, 0–16, 0–20, 0–25, and 0–30 min. Furthermore, the impact of adding a 60-min uptake value to the dynamic series was evaluated. The datasets were analyzed using dedicated software to predict the results of the full dynamic series. The software is based on a modified support vector machines (SVM) algorithm and predicts the compartment parameters of the full dynamic series. Results: The SVM-based software provides user-independent results and was accurate at predicting the compartment parameters of the full dynamic series. If a squared correlation coefficient of 0.8 (corresponding to 80% explained variance of the data) was used as a limit, a shortened acquisition of 0–16 min was accurate at predicting the 60-min 2-tissue-compartment parameters. If a limit of 0.9 (90% explained variance) was used, a dynamic series of at least 0–20 min together with the 60-min uptake values is required. Conclusion: Shortened acquisition protocols can be used to predict the parameters of the 2-tissue-compartment model. Either a dynamic PET series of 0–16 min or a combination of a dynamic PET/CT series of 0–20 min and a 60-min uptake value is accurate for analysis with a 2-tissue-compartment model.

18F-FDG dynamic PET/CT in patients with multiple myeloma: Patterns of tracer uptake and correlation with bone marrow plasma cell infiltration rate

Purpose The value of 18F-FDG PET in the diagnostic approach of multiple myeloma (MM) remains incompletely elicited. Little is known about the kinetics of 18F-FDG in the bone marrow and extramedullary sites in MM. This study aimed to evaluate quantitative data on kinetics and distribution patterns of 18F-FDG in MM patients with regard to pelvic bone marrow plasma cell infiltration. Procedures The study included 40 patients with primary MM. Dynamic PET/CT scanning of the lower lumbar spine and pelvis was performed after the administration of 18F-FDG. Whole-body PET/CT studies were performed. Sites of focal increased tracer uptake were considered as highly suggestive of myelomatous involvement after taking into account the patient history and CT findings. Bone marrow of the os ilium without pathologic tracer accumulation served as reference. The evaluation of dynamic PET/CT studies was based in addition to the conventional visual (qualitative) assessment, on semiquantitative (SUV) calculations, as well as on absolute quantitative estimations after application of a 2-tissue compartment model and a noncompartmental approach. 18F-FDG quantitative information and corresponding distribution patterns were correlated with pelvic bone marrow plasma cell infiltration. Results Fifty-two myelomatous lesions were detected in the pelvis. All parameters in suspected MM lesions ranged in significantly higher levels than in reference tissue (P < 0.01). Correlative analyses revealed that bone marrow plasma cell infiltration rate correlated significantly with SUVaverage, SUVmax, and the parameters K1, influx, and fractal dimension of 18F-FDG in reference bone marrow (P < 0.01). In addition, whole-body static PET/CT imaging demonstrated 4 patterns of tracer uptake; these are as follows: negative, focal, diffuse, and mixed (focal/diffuse) tracer uptake. Patients with a mixed pattern of radiotracer uptake had the highest mean plasma cell infiltration rate in their bone marrow, whereas those with negative PET/CT scans demonstrated the lowest bone marrow plasma cell infiltration. In total, 265 focal myeloma-indicative 18F-FDG–avid lesions were detected, 129 of which correlated with low-dose CT osteolytic findings. No significant correlation between the number of focal lesions detected in PET/CT and bone marrow infiltration was detected. Conclusions The 18F-FDG kinetic parameters K1, influx, and fractal dimension as well as SUVaverage from reference tissue correlated significantly with bone marrow malignant plasma cell infiltration rate. Patients with negative PET/CT demonstrated the lowest bone marrow infiltration by malignant plasma cells, whereas those with a mixed pattern of tracer uptake had the highest infiltration.

Dynamic PET with FDG in patients with unresectable aggressive fibromatosis: regression-based parametric images and correlation to the FDG kinetics based on a 2-tissue compartment model.

Objective Dynamic PET (dPET) studies with 18F-FDG were performed in patients with unresectable aggressive fibromatosis before imatinib therapy. The goal of the study was to evaluate the impact of regression-based parametric imaging on tumor diagnostics. A comparison between the regression-based quantitative data (slope and intercept values) with the compartmental data of FDG was performed. Methods The evaluation includes 24 patients with recurrent disease (n = 14), residual tissue (n = 2), or primary disease (n = 8), who were scheduled for palliative treatment with imatinib. Parametric images were calculated based on the dPET data by fitting a linear regression function to the time-activity data and for each voxel. Images of the slope and the intercept of the time-activity data were calculated using a dedicated software. A volume-of-interest–based analysis was also performed by applying a 2-tissue compartment model to the dPET data. The resulting parameters of the FDG kinetics [blood volume (VB), k1-k4] were compared with the volume-of-interest–based slope and intercept data. The evaluation of the parametric images was performed visually and quantitatively. Results Twenty of 24 tumors could be visualized in the SUV images with a moderate uptake, in locations that were already known from the MR images. Most (16/24) of the tumors demonstrated a clear enhancement in the intercept images, whereas 4 of them showed an intermediate enhancement and only 4 did not show any enhancement in the intercept images. In contrast, only 10 of 24 tumors demonstrated a clearly enhanced slope, 3 of them revealed a slightly enhanced slope, and 11 of the 24 patients did not demonstrate any slope enhancement within the area of the known desmoid tumors. The comparison of slope revealed the highest correlation to the SUV (r = 0.56, P < 0.05), whereas the intercept values demonstrated the highest correlation to k1 (r = 0.794, P < 0.05), followed by the fractional VB (r = 0.709, P < 0.05), followed by SUV (r = 0.630, P < 0.05). The results indicate that slope images are related to the transport/phosphorylation–dependent part of FDG, whereas intercept images are related to the transport/perfusion part of FDG. Conclusions These data demonstrate that the use of regression-based parametric imaging helps to differentiate between transport/perfusion– and transport/phosphorylation–dependent FDG uptake and demonstrate that the transport/phosphorylation rate is low in most of these tumors.

Correlation of the Ga-68-Bombesin Analog Ga-68-BZH3 with Receptors Expression in Gliomas as Measured by Quantitative Dynamic Positron Emission Tomography (dPET) and Gene Arrays

PurposeThe kinetics of Ga-68-BZH3, a Ga-68-bombesin analog, was compared to molecular biological data obtained from gene arrays in seven patients with a recurrent glioma. The primary aim of this study was the correlation of receptor expression and tracer kinetics.ProceduresDynamic positron emission tomography studies were performed and the data were analyzed by a volume-of-interest technique using a two-tissue compartment model as well as a non-compartment model. Gene array data were obtained from gene array analysis of tumor tissue samples.ResultsThe correlation analysis revealed a significant nonlinear correlation of r = 0.89 (p < 0.03) for k1 and BB2 (gastrin-releasing peptide receptor). BB1 and BB3 were not significantly correlated with k1. vb and k3 were not significantly correlated with the expression data of the receptors on the p < 0.05 level.ConclusionsThe parameter k1 is correlated with the expression of BB2 based on gene array data. The quantitative analysis of the Ga-68-BZH3 kinetics can be used to predict the receptor expression of BB2 in gliomas based on k1 of the compartment analysis. However, this study is limited to the expression data on the mRNA level and further studies are needed to assess the correlation of gene expression on the protein level.

Fractal and multifractal analysis of PET/CT images of metastatic melanoma before and after treatment with ipilimumab.

BackgroundPET/CT with F-18-fluorodeoxyglucose (FDG) images of patients suffering from metastatic melanoma have been analysed using fractal and multifractal analysis to assess the impact of monoclonal antibody ipilimumab treatment with respect to therapy outcome.ResultsThirty-one cases of patients suffering from metastatic melanoma have been scanned before and after two and after four cycles of treatment. For each patient, we calculated the fractal and multifractal dimensions using the box-counting method on the digitalised PET/CT images of all three studies to assess the therapeutic outcome. We modelled the spreading of malignant cells in the body via kinetic Monte Carlo simulations to address the dynamical evolution of the metastatic process and to predict the spatial distribution of malignant lesions. Our analysis shows that the fractal dimensions which describe the tracer dispersion in the body decrease consistently with the deterioration of the patient’s therapeutic outcome condition. In 20 out of 24 cases, the fractal analysis results match those of the treatment outcome as defined by the oncologists, while 7 cases are considered as special cases because the patients had non-tumour-related findings or side effects which affect the results. The decrease in the fractal dimensions with the deterioration of the patient conditions (in terms of disease progression) is attributed to the hierarchical localisation of the tracer which accumulates in the affected lesions and does not spread homogeneously throughout the body. Fractality emerges as a result of the migration patterns which the malignant cells follow for propagating within the body (circulatory system, lymphatic system). Analysis of the multifractal spectrum complements and supports the results of the fractal analysis. In the kinetic Monte Carlo modelling of the metastatic process, a small number of malignant cells diffuse through a fractal medium representing the blood circulatory network. Along their way, the malignant cells engender random metastases (colonies) with a small probability and, as a result, fractal spatial distributions of the metastases are formed similar to the ones observed in the PET/CT images.ConclusionsThe Monte Carlo-generated spatial distribution of metastases changes with time approaching values close to the ones recorded in the metastatic patients. Thus, we propose that fractal and multifractal analyses have potential applications in quantification of the evaluation of PET/CT images to monitor the disease evolution as well as the response to different medical treatments. The proposed approach, being operator independent, can offer new diagnostic tools in parallel to the visual location of the lesions and may improve multiparameter assessment of FDG PET/CT studies.

Comparison between 68Ga-bombesin (68Ga-BZH3) and the cRGD tetramer 68Ga-RGD4 studies in an experimental nude rat model with a neuroendocrine pancreatic tumor cell line

ObjectivesReceptor scintigraphy gains more interest for diagnosis and treatment of tumors, in particular for neuroendocrine tumors (NET). We used a pan-Bombesin analog, the peptide DOTA-PEG2-[D-tyr6, β-Ala11, Thi13, Nle14] BN(6-14) amide (BZH3). BZH3 binds to at least three receptor subtypes: the BB1 (Neuromedin B), BB2 (Gastrin-releasing peptide, GRP), and BB3. Imaging of ανβ3 integrin expression playing an important role in angiogenesis and metastasis was accomplished with a 68Ga-RGD tetramer. The purpose of this study was to investigate the kinetics and to compare both tracers in an experimental NET cell line.MethodsThis study comprised nine nude rats inoculated with the pancreatic tumor cell line AR42J. Dynamic positron emission tomography (PET) scans using 68Ga-BZH3 and 68Ga-RGD tetramer were performed (68Ga-RGD tetramer: n = 4, 68Ga-BZH3: n = 5). Standardized uptake values (SUVs) were calculated, and a two-tissue compartmental learning-machine model (calculation of K 1 - k 4 vessel density (VB) and receptor binding potential (RBP)) as well as a non-compartmental model based on the fractal dimension was used for quantitative analysis of both tracers. Multivariate analysis was used to evaluate the kinetic data.ResultsThe PET kinetic parameters showed significant differences when individual parameters were compared between groups. Significant differences were found in FD, VB, K 1, and RBP (p = 0.0275, 0.05, 0.05, and 0.0275 respectively). The 56- to 60-min SUV for 68Ga-BZH3, with a range of 0.86 to 1.29 (median, 1.19) was higher than the corresponding value for the 68Ga-RGD tetramer, with a range of 0.78 to 1.31 (median, 0.99). Furthermore, FD, VB, K 1, and RBP for 68Ga-BZH3 were generally higher than the corresponding values for the 68Ga-RGD tetramer, whereas k 3 was slightly higher for 68Ga-RGD tetramer.ConclusionsAs a parameter that reflects receptor binding, the increase of K 1 for 68Ga-BZH3 indicated higher expression of bombesin receptors than that of the ανβ3 integrin in neuroendocrine tumors. 68Ga-BZH3 seems better suited for diagnosis of NETs owing to higher global tracer uptake.