Application of F-18-sodium fluoride (NaF) dynamic PET-CT (dPET-CT) for defect healing: a comparison of biomaterials in an experimental osteoporotic rat model.

BACKGROUND: The aim of the current study was to measure and compare the effect of various biomaterials for the healing of osteoporotic bone defects in the rat femur using 18F-sodium fluoride dPET-CT. MATERIAL AND METHODS: Osteoporosis was induced by ovariectomy and a calcium-restricted diet. After 3 months, rats were operated on to create a 4-mm wedge-shaped defect in the distal metaphyseal femur. Bone substitution materials of calcium phosphate cement (CPC), composites of collagen and silica, and iron foams with interconnecting pores were inserted. Strontium or bisphosphonate, which are well known for having positive effects in osteoporosis treatment, were added into the materials. Eighteen weeks after osteoporosis induction and 6 weeks following femoral surgery, dPET-CT studies scan were performed with 18F-Sodium Fluoride. Standardized uptake values (SUVs) and a 2-tissue compartmental learning-machine model (K1-k4, vessel density [VB], influx [ki]) were used for quantitative analysis. RESULTS: k3, reflecting the formation of fluoroapatite, revealed a statistically significant increase at the biomaterial-bone interface due to the Sr release from strontium-modified calcium phosphate cement (SrCPC) compared to CPC, which demonstrated enhanced new bone formation. In addition, k3 as measured in the porous scaffold silica/collagen xerogel (Sc-B30), showed a significant increase based on Wilcoxon rank-sum test (p<0.05) as compared with monolithic silica/collagen xerogel (B30) in the defect region. Furthermore, ki, reflecting the net plasma clearance of tracer to bone mineral measured in the iron foam with coating of the bisphosphonate zoledronic acid (Fe-BP), was enhanced as compared with plain iron foam (Fe) in the defect region. CONCLUSIONS: k3 was the most significant parameter for the characterization of healing processes and revealed the best differentiation between the 2 different biomaterials. PET scanning using 18F-sodium fluoride seems to be a sensitive and useful method for evaluation of bone healing after replacement with these biomaterials.

Blood eosinophil and platelet levels, proteomics patterns of trail and CXCL8 correlated with survival in bevacizumab treated metastatic colon cancers.

STrail (soluble TNF-related apoptosis-inducing-ligand) has also been observed where the cytotoxic effects of antiangiogenic agents are increased in clinical phase II and III studies when these agents are combined with TRAIL related therapies. Recent studies have shown that CXCL8 and its receptors are significantly up-regulated in CRC and act as regulators of proliferation, angiogenesis, and metastasis. sTRAIL, CXCL8, CEA, together with complete blood count parameters (hemoglobine, platelet, eosinophil, basophil, neutrophil, lymphocyte) were recorded in the beginning and every three months afterwards for a period of 4 years. The study population comprised 21 of the 42 patients with metastatic colorectal cancer (MCRC), undergoing 18 FDG-PET/CT scanning prior to treatment. Progression free survival was 262 days and overall survival was 1148 days. Overall survival was higher in patients whose Karnofsky Performance scores were above 86% (p = 0.003). Progression free survival was higher in patients whose blood eosinophil counts at 0, 6, and 9 months were higher than the mean levels of corresponding values (p-values are 0.016, 0.032, and 0.001, respectively). Another significant positive correlation was found between the platelet levels at 9 months and progression free survival (p = 0.019). There were significant changes (p < 0.05) prior to treatment and three months later for sTRAIL (p = 0.0060) and CXCL8 (p = 0.00001), based on the Wilcoxon matched pairs signed rank test. Generally, sTRAIL values increased during therapy, while a decrease was observed for CXCL8 without any significant differences for other variables.

Preliminary evaluation of different biomaterials for defect healing in an experimental osteoporotic rat model with dynamic PET-CT (dPET-CT) using F-18-sodium fluoride (NaF).

UNLABELLED: The aim of the current study was to measure and compare the effect of calcium phosphate cement (CPC) and CPC enriched with strontium (SrCPC) for the healing of osteoporotic bone defects in the rat femur using (18)F-Sodium Fluoride dPET-CT. METHODS: Osteoporosis was induced by ovariectomy and a calcium restricted diet. After three months, rats were operated to create a 4 mm defect in the distal metaphyseal femur with internal fixation. 7 Rats have been treated either with CPC (Group 2) or with SrCPC (Group 3) for bone replacement and defect healing. Furthermore, a control group of 7 rats without any biomaterial (Group 1) was used for reference. 18 weeks after osteoporosis induction and 6 weeks following femoral surgery, dPET-CT studies scan were performed with (18)F-Sodium Fluoride. SUVs and a 2-tissue compartmental learning-machine model (K1-k4, VB, influx) were used for quantitative analysis. RESULTS: VB, reflecting the fractional blood volume and k3, reflecting the formation of fluoroapatite were the most sensitive parameters for the characterisation of healing process and revealed the best differentiation for the control group and the CPC group (Group 2) as well as for the CPC with strontium carbonate group (Group 3) (p<0.05). VB was decreased by the order of Group 1, Group 2 and Group 3, while k3 was increased by the same order. Therefore, the data direct to a decreased fractional blood volume and increased fixation of fluoride in rats with these biomaterials. CONCLUSION: We found PET scanning using (18)F-Sodium Fluoride to be a sensitive and useful method for evaluation of bone healing after replacement with CPC or SrCPC.

Level of TNF-related apoptosis-inducing-ligand and CXCL8 correlated with 2-[18F]Fluoro-2-deoxy-D-glucose uptake in anti-VEGF treated colon cancers.

BACKGROUND: The changes and correlations of TRAIL (TNF-related apoptosis-inducing-ligand) and CXCL8 (IL8) prior to treatment and three months following therapy as well as the corresponding Positron emission tomography (PET/CT) (SUV(max): standardized uptake maximum values) results were evaluated. MATERIAL AND METHODS: The measurements were taken before and after treatment for comparison purposes. The study population comprised 29 patients with Metastatic Colorectal cancer (MCRC), undergoing PET/CT scanning prior to treatment. RESULTS: There were significant changes prior to treatment and three months later for sTRAIL (p=0.0080) and CXCL8 (p=0.0001)values. Generally, sTRAIL values were increasing during therapy, while a decrease was observed for CXCL8. Correlation analysis was applied to the data and revealed significant correlations for the SUV(max) in the primary tumor prior to treatment and CXCL8 prior to therapy (p=0.0303). Furthermore, significant correlations were observed for the SUV(max) and sTRAIL (p=0.0237) as well as CXCL8 (p=0.0002) three months after treatment initiation. CXCL8 prior to treatment was also correlated with the SUV three months after onset of treatment (p=0.0072). A significant correlation was noted for one combination of two variables, the SUV(max) in the metastases and CXCL8 prior to treatment (p=0.0175). These results are supported when we group the SUV(max) in the metastases following treatment into two groups with SUV(max) <5 and SUV(max) >5. CONCLUSIONS: This study provides evidence that proteomics patterns of sTRAIL and CXCL8 predict tumor response und survival in MCRC patients treated with bevacizumab and within a high concordance of FDG-PET/CT findings.

Dynamic PET with (18)F-Deoxyglucose (FDG) and quantitative assessment with a two-tissue compartment model reflect the activity of glucose transporters and hexokinases in patients with colorectal tumors.

Dynamic PET (dPET) with (18)F-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.

A case of toxic epidermal necrolysis with diverse etiologies: successful treatment with intravenous immunoglobulin and pulse prednisolone and effects on sTRAIL and sCD200 levels.

BACKGROUND: Here, we report the first case of patient with intracranial tumors (ICT) who developed a cutaneous adverse drug reaction during lansoprazole and prophylactic anticonvulsant treatment. SCORTEN is a scoring system used to predict mortality in TEN patients. If SCORTEN index is 5 or more, mortality rate is more than 90%. SCORTEN of our patient was calculated as 5. METHODS: Our patient is a 64 year-old white female, who had glioma and had been on post-op prophylactic anticonvulsant therapy. On the 3rd day post operation, lansoprazole was added to the therapy. After the first lansoprazole dose, erythematous dusky red macules occurred on extremities and trunk and on the following day confluent purpuric lesions tended to run together in 95% of the whole body including scalp, oral and genital mucosa. Nikolsky's Sign was positive on the skin. Physical examination; body temperature was 38.4 degrees C with a heart rate of 146 beats/minute and 80/50 mm Hg arterial blood pressure, Glascow Coma Scale was E1 M1e, pupillary light reflex was 2/2 +/+ and she was confused. Her biopsy resulted as toxic epidermal necrolysis. Moreover, sTRAIL and sCD200 levels of serum and blister fluid were investigated as an apoptotic marker and a negative marker for inflammation. RESULTS AND CONCLUSIONS: sTRAIL and sCD200 were evaluated both in the sera and blister fluid. sTRAIL level was lower than for healthy individuals with high levels in blister fluid; and sCD200 level was depressed by up to 10% of the normal values of healthy individuals but with high levels in the blister fluid during the active phase of the disease. After our successful treatment with human albumin, prednisolone pulse therapy, and IVIG at a dose of 400 mg/kg, she was discharged from the hospital on the 23rd day and followed up after 2 months. The increase in sTRAIL (up to two-fold) and sCD200 (up to six-fold) levels may provide useful information in understanding disease pathogenesis and monitoring treatment efficacy.

Omalizumab is effective in treating severe asthma in patients with severe cardiovascular complications and its effects on sCD200, d-dimer, CXCL8, 25-hydroxyvitamin D and IL-1ß levels.

BACKGROUND: There have been concerns about the cardiovascular safety of omalizumab. OBJECTIVES: In this study, the clinical status of the omalizumab receiving severe asthma patients and the cytokine expressions patterns were investigated. MATERIALS AND METHODS: In a pilot study described below we examined the levels of serum eosinophil cationic peptid (ECP), CD200, d-dimer, 25-hydroxyvitamin D (25(OH)D), CXCL8 and IL-1ß in asthma patients treated with anti-IgE therapy, to explore their relationship with disease activity, and the impact of anti-IgE therapy impact on those levels. Exercise stress testing and blood samples were taken at all follow up visits from the time of first diagnosis and after 20 months of treatment during the disease remission. RESULTS: Fractional exhaled nitric oxide concentrations and serum levels of sTRAIL, sCD200, D-dimer, ECP, total IgE, IL-1ß and Hs-CRP were decreased while CXCL8, 25(OH)D were increased after starting the treatment of anti-IgE. Our first case of a patient, who had both protein C and S deficiency and hence a high risk for thromboembolism, documents for the first time the safety of omalizumab for asthmatic patients with concurrent risk factors contributing to arteriothrombotic events. CONCLUSION: Omalizumab might be used carefully in patients with cardiovascular diseases.

Effects of omalizumab on eosinophil cationic peptide, 25-hydroxyvitamin-D, IL-1ß and sCD200 in cases of Samter's syndrome: 36 months follow-up.

CONTEXT: The historic triad of nasal polyposis, asthma and intolerance to aspirin and related chemicals, recently designated as Samter's syndrome, is an inflammatory condition of unknown pathogenesis. This study surveyed the levels of chosen serum eosinophil cationic peptide (ECP), soluble CD200 (SCD200), interleukin (IL)-1ß, high sensitive C-reactive protein (hs-CRP) and 25-hydroxyvitamin-D (25(OH)D) in the aspirin-induced asthmatic patients treated with anti-IgE therapy to investigate their roles in the pathogenesis of disease perpetuation and anti-IgE therapy's impact on them. METHODS: Medical history, lung function tests and measurement of fractional exhale nitric oxide concentrations were performed on the same day. Concentrations of IL-1ß and SCD200 in the serum samples were quantified using ELISA kits. Total and specific IgE and hs-CRP levels were enumerated by fluoroenzyme immunoassay. Serum levels of 25(OH)D were quantified by a radioimmunoassay. RESULTS: We had three patients of severe persistent allergic asthma with Samter's syndrome. Levels of total IgE, ECP, fractional exhale nitric oxide concentrations, SCD200, IL-1ß and hs-CRP were decreased while 25(OH)D was increased after starting the treatment of anti-IgE. CONCLUSIONS: To our knowledge, this is the first time an association between omalizumab use and Samter's syndrome has been documented. As a conclusion allergic nasal symptoms (sneezing, postnasal drip) and asthma symptoms were decreased in patients, but no change was seen on nasal polyposis development after omalizumab treatment.

Positron emission tomography as a surrogate marker for evaluation of treatment response in patients with desmoid tumors under therapy with imatinib.

We used 2-deoxy-2-[(18)F] fluoro-D-glucose (FDG) positron emission tomography (PET) to evaluate patients with desmoid tumors undergoing therapy with imatinib. The study included 22 patients with progressive disease (PD) of a biopsy proven desmoid tumor treated orally with imatinib 800 mg daily. Patients were examined using PET prior to onset of therapy and during treatment. Restaging was performed in parallel using computed tomography (CT) and/or magnetic resonance imaging (MRI). Outcome of 22 evaluable patients was as follows: five patients with partial response (PR); twelve patients with stable disease (SD) accounting for 77% with non-progressive disease; five patients showed PD. A 30% decrease of the mean average standardized uptake value (SUV) of sequential PET examinations could be demonstrated; no patient demonstrated a substantial increase in SUV. Patients with PR/SD were matched to a group of nonprogressive disease and tested versus PD. The initial average SUV and SUVmax seem to be candidates for a response prediction with an approximate P-value of 0.06553 and 0.07785, respectively. This is the first larger series of desmoid patients monitored using PET showing that early SUV changes may help to discriminate responders from nonresponders and, thus, to decide whether imatinib therapy should be continued.

Evaluation of bone remodeling with (18)F-fluoride and correlation with the glucose metabolism measured by (18)F-FDG in lumbar spine with time in an experimental nude rat model with osteoporosis using dynamic PET-CT.

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 (18)F-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 (18)F-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 (18)F-Fluoride and SUV of FDG in Group K as well as between FD of (18)F-Fluoride and FDG in Group D and C and between k3 of (18)F-Fluoride and SUV of FDG in Group C.

Evaluation of new bone formation in normal and osteoporotic rats with a 3-mm femur defect: functional assessment with dynamic PET-CT (dPET-CT) using 2-deoxy-2-[(18)F]fluoro-D-glucose ( (18)F-FDG) and (18)F-fluoride.

PURPOSE: The aim of the current study was to assess the formation of new bone in a 3-mm created defect in the femur and its adjacent bone tissue in osteoporotic and normal animals. The assessment is based on bone remodeling and glucose metabolism in a rat model with a 3-mm created defct in the femur using (18)F-fluoride and 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG) as tracers for dynamic PET-CT (dPET-CT). The (18)F-fluoride PET data were compared with those of (18)F-FDG. PROCEDURES: Osteoporosis was induced by ovariectomy and a calcium restricted diet in each rat (n = 7). Alternatively, a sham operation was performed in the control group (n = 8). After 3 months, all rats were operated to create a 3-mm defect using an oscillating saw in the distal metaphyseal femur, which was internally fixed with a metal plate. Eighteen weeks after osteoporosis induction and 6 weeks following femoral surgery, dPET-CT studies scan were performed with (18)F-FDG and (18)F-fluoride. Following PET data acquisition, standardized uptake values (SUVs) were calculated from the tracer concentration values. Then, a two-tissue compartmental learning-machine model was applied to the data for the calculation of the compartment parameters (K1-k4, VB, Ki). Furthermore, a non-compartmental model based on the fractal dimension was applied for quantitative analysis of both groups and both tracers. Finally, multivariate analysis was performed for the statistical analysis of the kinetic data. RESULTS: The values for K1 and Ki were higher in the osteoporotic rats than in the control group. Ki and K1 of (18)F-fluoride in the adjacent bone tissue differ significantly based on the Wilcoxon rank-sum test for the osteoporotic and control group (p < 0.05). The sensitivity and the negative predictive value (NPV) based on linear discriminant analysis was high with a value of 100 % for both tracers and both evaluated regions (defect and adjacent bone tissue) when comparing control and osteoporotic rats. The overall accuracy with (18)F-FDG was generally higher than that with (18)F-fluoride for both evaluated regions for the control and osteoporotic rats based on a multiparameter evaluation. CONCLUSION: In this study, the changes in tracer kinetics accurately discriminated differences in the created defect in the femur and its adjacent bone tissue between osteoporotic and control rats.

Calibration of cone beam CT using relative attenuation ratio for quantitative assessment of bone density: a small animal study.

PURPOSE: Cone beam computed tomography (CBCT) has the disadvantage of providing non-quantitative results for bone density determination. The aim of this study is to calibrate CBCT results by using an internal reference (such as muscle) for quantitatively assessing bone density. METHODS: We developed a new method using the relative attenuation ratio between two nearby materials (such as bone and muscle) for systemic error correction in CBCT that depends on the relative object position in the image volume. Phantom calibration was performed to calculate the acquired attenuation ratio in Hounsfield units (HU), comparable to the results from clinical multislice spiral computed tomography (MSCT). In addition, a small animal study with an osteoporotic rat model was evaluated to show the feasibility of this presented method to quantitatively assess bone density using a CBCT system. RESULTS: The phantom study results showed that the calibration process successfully corrected the systemic inaccuracy from CBCT, and the calibrated HU values agreed with the values measured from MSCT. In the small animal study, the quantitative bone densities assessed from the calibrated CBCT results were consistent with the results from MSCT data. CONCLUSION: A practical method to quantitatively estimate attenuation (HU) values for bone tissues from CBCT scans that are comparable to MSCT scans is proposed. The method may improve the quantification ability of CBCT scanning without any additional hardware requirements.

Tumor aggressiveness and patient outcome in cancer of the pancreas assessed by dynamic 18F-FDG PET/CT.

UNLABELLED: This study aimed to assess the role of a quantitative dynamic PET model in pancreatic cancer as a potential index of tumor aggressiveness and predictor of survival. METHODS: Seventy-one patients with (18)F-FDG-avid adenocarcinoma of the pancreas before treatment were recruited, including 27 with localized tumors (11 underwent pancreatectomy, and 16 had localized nonresectable tumors) and 44 with metastatic disease. Dynamic (18)F-FDG PET images were acquired over a 60-min period, followed by a whole-body PET/CT study. Quantitative data measurements were based on a 2-compartment model, and the following variables were calculated: VB (fractional blood volume in target area), K(1) and k(2) (kinetic membrane transport parameters), k(3) and k(4) (intracellular (18)F-FDG phosphorylation and dephosphorylation parameters, respectively), and (18)F-FDG INF (global (18)F-FDG influx). RESULTS: The single significant variable for overall survival (OS) in patients with localized disease was (18)F-FDG INF. Patients with a high (18)F-FDG INF (>0.033 min(-1)) had a median OS of 6 and 5 mo for nonresectable and resected tumors, respectively, versus 15 and 19 mo for a low (18)F-FDG INF in nonresectable and resected tumors, respectively (P < 0.04). In metastatic disease, multivariate analysis found VB, K(1), and k(3) to be significant variables for OS (P < 0.043, <0.031, and <0.009, respectively). Prognostic factors for OS in the entire group of patients that were significant at multivariate analysis were stage of disease, VB, K(1), and (18)F-FDG INF (P < 0.00035, <0.03, <0.024, and <0.008, respectively). Median OS for all patients with a high (18)F-FDG INF, low VB, and high K(1) was 3 mo, as opposed to 14 mo in patients with a low (18)F-FDG INF, high VB, and low K(1) (P < 0.021), irrespective of stage and resectability. CONCLUSION: Quantitative (18)F-FDG kinetic parameters measured by dynamic PET in newly diagnosed pancreatic cancer correlated with the aggressiveness of disease. The (18)F-FDG INF was the single most significant variable for OS in patients with localized disease, whether resectable or not.

Cilengitide affects tumor compartment, vascularization and microenvironment in experimental bone metastases as shown by longitudinal ¹8F-FDG PET and gene expression analysis.

PURPOSE: Aim of this study was to investigate the specific treatment effects of inhibiting αvß3/αvß5 integrins by cilengitide in an animal model of breast cancer bone metastases using dynamic (18)F-FDG PET and gene expression analysis. METHODS: For this purpose, nude rats bearing bone metastases were treated with cilengitide, a small molecule inhibitor of αvß3 and αvß5 integrins, from day 30 to 55 after tumor cell inoculation of MDA-MB-231 breast cancer cells (25 mg/kg, 5 days per week; n = 8 rats) and compared to control rats (n = 8). Dynamic (18)F-FDG PET data were assessed at days 30, 35 and 55 after tumor cell inoculation determining the vascular fraction VB and the metabolic variables k1-k4. At day 55, genome-wide mRNA expression analysis was performed to assess the treatment-specific expression changes from cilengitide-treated and control rats. RESULTS: In a longitudinal (18)F-FDG PET study, the vascular fraction VB was significantly decreased in bone metastases between days 30/35, 30/55 and 35/55, whereas the kinetic parameters k1 and k4 were significantly decreased between days 30/55 in skeletal lesions of treated animals. Gene expression analysis from bone metastases at day 55 revealed that tumor-produced integrins (αvß5) as well as factors relevant for angiogenesis (αvß3, VEGF, PDGF), bone resorption (PTHrP and RANKL), extracellular matrix remodeling (collagen, CD44) and bone marrow microenvironment (CXCR4) were significantly reduced upon therapy with cilengitide. CONCLUSIONS: Here, we provide evidence that cilengitide inhibits pivotal factors of all compartments of bone metastases including tumor cells, vasculature and bone microenvironment in vivo and by whole-genome transcriptome analysis.

(18)F-Deoxyglucose (FDG) kinetics evaluated by a non-compartment model based on a linear regression function using a computer based simulation: correlation with the parameters of the two-tissue compartment model.

Parametric imaging with a linear regression function of the tracer activity curve fit is a non-compartmental method, which can be used for the evaluation of dynamic PET (dPET) studies. However, the dependency of the slope of the regression function fit on the (18)F-Deoxyglucose (FDG) 2-tissue compartment parameters (vb, k1-k4) is not known yet. This study is focused on the impact of the 2-tissue compartment parameters on the slope of the curve. A data base of 1760 dynamic PET FDG studies with the corresponding 2-tissue compartment model parameter solutions were available and used to calculate synthetic time-activity data based on the 2-tissue compartment model. The input curve was calculated from the median values of the input curves of the 1760 dynamic data sets. Then, sequentially each of the five parameters (vb, k1-k4) of the 2-tissue compartment model was varied from 0.1 to 0.9 and tracer activity curves were calculated (60000 curves/parameter). A linear regression function was fitted to these curves. The comparison of the slope values of the regression function with the corresponding compartment data revealed a primary dependency on k3, which is associated with the intracellular phosphorylation of FDG. The squared correlation coefficient was high with r(2)=0.9716, which refers to 97 % explained variance of the data. k2 and vb had only a minor impact, while k1 and k4 had no impact on the slope values. The results demonstrate, that k3 has a major impact on the slope values calculated by the linear regression function.

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

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.

Multimodal hypoxia imaging and intensity modulated radiation therapy for unresectable non-small-cell lung cancer: the HIL trial.

BACKGROUND: Radiotherapy, preferably combined with chemotherapy, is the treatment standard for locally advanced, unresectable non-small cell lung cancer (NSCLC). The tumor response to different therapy protocols is variable, with hypoxia known to be a major factor that negatively influences treatment effectiveness. Visualisation of tumor hypoxia prior to the use of modern radiation therapy strategies, such as intensity modulated radiation therapy (IMRT), might allow optimized dose applications to the target volume, leading to improvement of therapy outcome. (18)F-fluoromisonidazole dynamic positron emission tomography and computed tomography ((18) F-FMISO dPET-CT) and functional magnetic resonance imaging (functional MRI) are attractive options for imaging tumor hypoxia. METHODS/DESIGN: The HIL trial is a single centre study combining multimodal hypoxia imaging with (18) F-FMISO dPET-CT and functional MRI, with intensity modulated radiation therapy (IMRT) in patients with inoperable stage III NSCLC. 15 patients will be recruited in the study. All patients undergo initial FDG PET-CT and serial (18) F-FMISO dPET-CT and functional MRI before treatment, at week 5 of radiotherapy and 6 weeks post treatment. Radiation therapy is performed as inversely planned IMRT based on 4D-CT. DISCUSSION: Primary objectives of the trial are to characterize the correlation of (18) F-FMISO dPET-CT and functional MRI for tumor hypoxia imaging in NSCLC and evaluate possible effects of radiation therapy on tumor re-oxygenation. Further objectives include the generation of data regarding the prognostic value of (18) F-FMISO dPET-CT and functional MRI for locoregional control, progression free survival and overall survival of NSCLC treated with IMRT, which will form the basis for larger clinical trials focusing on possible interactions between tumor oxygenation and radiotherapy outcome. TRIAL REGISTRATION: The ClinicalTrials.gov protocol ID is NCT01617980.

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 dynamic PET and gene array data in patients with gastrointestinal stromal tumors.

INTRODUCTION: The results obtained with dynamic PET (dPET) were compared to gene expression data obtained in patients with gastrointestinal stromal tumors (GIST). The primary aim was to assess the association of the dPET results and gene expression data. MATERIAL AND METHODS: dPET was performed following the injection of F-18-fluorodeoxyglucose (FDG) in 22 patients with GIST. All patients were examined prior to surgery for staging purpose. Compartment and noncompartment models were used for the quantitative evaluation of the dPET examinations. Gene array data were based on tumor specimen obtained by surgery after the PET examinations. RESULTS: The data analysis revealed significant correlations for the dPET parameters and the expression of zinc finger genes (znf43, znf85, znf91, znf189). Furthermore, the transport of FDG (k1) was associated with VEGF-A. The cell cycle gene cyclin-dependent kinase inhibitor 1C was correlated with the maximum tracer uptake (SUVmax) in the tumors. CONCLUSIONS: The data demonstrate a dependency of the tracer kinetics on genes associated with prognosis in GIST. Furthermore, angiogenesis and cell proliferation have an impact on the tracer uptake.