Omalizumab (anti-IgE) therapy increases blood glucose levels in severe persistent allergic asthma patients with diabetes mellitus: 18 month follow-up.

BACKGROUND: Therapeutic anti-IgE antibodies (Xolair, omalizumab) able to reduce free IgE levels and to block the binding of IgE to Fcepsilon RI without cross-linking IgE and triggering degranulation of IgE-sensitised cells have been developed. METHODS: We had two male patients of severe persistent allergic asthma with type-2 diabetes mellitus at the ages of 57 and 52 and who had suffered a side-effect of increased blood glucose level that caused a need for an extra insulin injection to control the hyperglycemia. Their asthma was not under control, frequent emergency department admissions lead us to use omalizumab treatment. Assessment of clinical changes and adverse effects were evaluated at each bimonthly patient visit including vital signs, full physical examination, details of any allergy incidents, total and specific IgE levels, serum ECP (eosinophilic cationic peptid) levels, pulmonary function test, exhaled nitric oxide concentrations, and asthma control test. RESULTS: Both patients were on week 42 - 45 of omalizumab treatment with a the dosage of 375 and 300 mg when they had the adverse reaction we reported here; they also had no other complaints. Blood levels of ECP and high sensitive CRP (hs-CRP) were decreased after starting the treatment of anti-IgE. CONCLUSIONS: To our knowledge, this is the first time an association between omalizumab use and hyperglycemia has been documented. Every vial of Xolair (150 mg) contains 145.5 mg sucrose and it might increase the blood levels of glucose in diabetics. As a conclusion the prescribing information might have been revised based on post marketing surveillance data and reported such cases indicating that different side effects may occur beyond 2 hours of the injection.

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.

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.

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.

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.

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.

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.

Incidental detection and monitoring of spontaneous recovery of sarcoidosis via fluorine-18-fluoroethyl-choline positron emission tomography/computed tomography.

We report a case of sarcoidosis detected incidentally by using fluorine-18-fluoroethylcholine- positron emission tomography/computed tomography (¹8F-FECH-PET/CT) in a 72 years old patient with prostate cancer, who had been referred for restaging after relapse indicated prostate specific antigen (PSA). The ¹8F-FECH-PET/CT examination showed a focal increased uptake in the prostate bed suggestive for local recurrence, in addition to multifocal uptake in the mediastinum matching with enlarged hilar and paratracheal lymph nodes. Histopathology revealed sarcoidosis. No treatment was recommended. Two years later the patient was referred again to us because of another recurrent PSA elevation. The second ¹8F-FECH-PET/CT showed again the previously described local recurrence, but did not show the previously described mediastinal findings nor the enlarged hilar and paratracheal lymph nodes, thus, illustrating spontaneous healing of sarcoidosis. In conclusion, this case suggests that ¹8F-FECH PET/CT study can show positive findings in sarcoidosis that were no longer detectable after two years, suggestive of spontaneous recovery.

Parametric images via dynamic 18F-fluorodeoxyglucose positron emission tomographic data acquisition in predicting midterm outcome of liver metastases secondary to gastrointestinal stromal tumours.

PURPOSE: (18)F-Fluorodeoxyglucose positron emission tomography (FDG PET) may underestimate viable tumour tissue in patients with gastrointestinal stromal tumours (GIST) treated with molecular targeted agents. The aim of the present study was to investigate the value of parametric images generated after dynamic data acquisition for the detection of active liver metastases. METHODS: The analysis included 65 dynamic FDG PET studies in 34 patients with liver metastases from GIST who were treated with imatinib or sunitinib. Parametric images of intercept and slope were calculated by dedicated software using a voxel-based linear regression of time-activity data. Intercept images represent the tracer's distribution volume and the slope its overall metabolic turnover. All images were assessed visually and semi-quantitatively. Liver disease status was established 12 months after each PET study. Dichotomous variables of visual interpretation and various quantitative parameters were entered in a statistical model of linear discriminant analysis. RESULTS: Visual analysis of slope images was more sensitive than the standard 1-h FDG uptake evaluation (70.6 vs 51.0%, p = 0.016) in detecting cases with liver disease progression (n = 51). Specificity did not differ. Combination of all variables in the discriminant analysis model correctly classified 87.7% of cases as progressive or non-progressive disease. Sensitivity was raised to 88.2%. CONCLUSION: Parametric images of intercept and slope add a new dimension to the interpretation of FDG PET studies, by isolating visually and quantifying the perfusion and phosphorylation-dependent part of tracer uptake. In treated GIST patients, integration of this information with the 1-h uptake data achieves better characterization of hepatic lesions with respect to disease activity.

A phase II study evaluating neo-/adjuvant EIA chemotherapy, surgical resection and radiotherapy in high-risk soft tissue sarcoma.

BACKGROUND: The role of chemotherapy in high-risk soft tissue sarcoma is controversial. Though many patients undergo initial curative resection, distant metastasis is a frequent event, resulting in 5-year overall survival rates of only 50-60%. Neo-adjuvant and adjuvant chemotherapy (CTX) has been applied to achieve pre-operative cytoreduction, assess chemosensitivity, and to eliminate occult metastasis. Here we report on the results of our non-randomized phase II study on neo-adjuvant treatment for high-risk STS. METHOD: Patients with potentially curative high-risk STS (size ≥ 5 cm, deep/extracompartimental localization, tumor grades II-III [FNCLCC]) were included. The protocol comprised 4 cycles of neo-adjuvant chemotherapy (EIA, etoposide 125 mg/m(2) iv days 1 and 4, ifosfamide 1500 mg/m2 iv days 1 - 4, doxorubicin 50 mg/m(2) day 1, pegfilgrastim 6 mg sc day 5), definitive surgery with intra-operative radiotherapy, adjuvant radiotherapy and 4 adjuvant cycles of EIA. RESULT: Between 06/2005 and 03/2010 a total of 50 subjects (male = 33, female = 17, median age 50.1 years) were enrolled. Median follow-up was 30.5 months. The majority of primary tumors were located in the extremities or trunk (92%), 6% originated in the abdomen/retroperitoneum. Response by RECIST criteria to neo-adjuvant CTX was 6% CR (n = 3), 24% PR (n = 12), 62% SD (n = 31) and 8% PD (n = 4). Local recurrence occurred in 3 subjects (6%). Distant metastasis was observed in 12 patients (24%). Overall survival (OS) and disease-free survival (DFS) at 2 years was 83% and 68%, respectively. Multivariate analysis failed to prove influence of resection status or grade of histological necrosis on OS or DFS. Severe toxicities included neutropenic fever (4/50), cardiac toxicity (2/50), and CNS toxicity (4/50) leading to CTX dose reductions in 4 subjects. No cases of secondary leukemias were observed so far. CONCLUSION: The current protocol is feasible for achieving local control rates, as well as OS and DFS comparable to previously published data on neo-/adjuvant chemotherapy in this setting. However, the definitive role of chemotherapy remains unclear in the absence of large, randomized trials. Therefore, the current regimen can only be recommended within a clinical study, and a possibly increased risk of secondary leukemias has to be taken into account. TRIAL REGISTRATION: ClinicalTrials.gov NCT01382030, EudraCT 2004-002501-72.

Evaluation of treatment response of cilengitide in an experimental model of breast cancer bone metastasis using dynamic PET with 18F-FDG.

The purpose of this study was the assessment of the feasibility of dynamic positron emission tomography (PET) studies with fluorine-18 fluorodeoxyglucose ((18)F-FDG) to quantify effects of the cyclic Arg-Gly-Asp peptide cilengitide, which targets the ανß 3 and ανß 5 integrin receptors in rats with breast cancer bone metastases. Rats were inoculated with MDA-MB-231 breast cancer cells, followed by the development of lytic lesions in the hind leg. Rats with lytic lesions were treated with cilengitide five times weekly on a continuous basis from days 30 to 55 after tumor cell inoculation. Dynamic PET studies with (18)F-FDG were performed in untreated (n=9), controlled (n=4) and treated rats (n=6). The data were assessed using learning-machine two-tissue compartmental analysis. The (18)F-FDG kinetic parameters obtained by two-tissue compartmental model learning-machine showed significant differences when individual parameters were compared between the control group and treated animals. Quantitative assessment of the tracer kinetics and the application of classification analysis to the data provided us with evidence to identify those tumors that demonstrated effect of cilengitide treatment. The transport rate K1 and the phosphorylation rate k3 were significantly different (P=0.033 and 0.038, respectively). Classification analysis based on support vector machines ranking feature elimination of the combination of PET parameters revealed an overall accuracy of 80.0% between treated animals and the control group. We were able to identify 83.3% treated animals compared with the control group based on k2 and VB. In conclusion, the results revealed that cilengitide treatment of experimental breast cancer bone metastases had a significant therapeutic impact on (18)F-FDG kinetics.

Positron emission tomography in patients with aggressive fibromatosis/desmoid tumours undergoing therapy with imatinib.

PURPOSE: We used (18)F-FDG PET to evaluate the FDG uptake in patients with aggressive fibromatosis (AF, also known as desmoid tumours) undergoing therapy with imatinib (imatinib mesylate, Glivec). METHODS: The pilot study included nine patients with progressive AF receiving oral treatment with imatinib at a daily dose of 800 mg. Patients were examined using PET prior to the start of therapy and during imatinib treatment. Restaging according to the Response Evaluation Criteria in Solid Tumors (RECIST) was performed in parallel using CT and/or MRI and served as reference. RESULTS: The clinical outcomes in nine evaluable patients were as follows: seven patients with stable disease, and two patients with progressive disease. A 27% decrease in the median average standardized uptake value (SUV) of the sequential PET examinations was demonstrated in all evaluable patients with three patients (33%) showing a decrease in SUV of more than 40% (48%, 52% and 54%, respectively); no patient showed a substantial increase in SUV. CONCLUSION: To our knowledge, this is the first series of AF patients undergoing treatment with imatinib and monitored using sequential PET imaging, that allows detection of SUV changes after imatinib induction, thus helping to decide whether treatment should be continued or not.

Prediction of chemotherapy outcome in patients with metastatic soft tissue sarcomas based on dynamic FDG PET (dPET) and a multiparameter analysis.

PURPOSE: Dynamic PET studies with (18)F-FDG were performed in patients with metastatic soft tissue sarcomas who received conventional chemotherapy with doxorubicin hydrochloride (Adriamycin) and ifosfamide (AI-G). The goal of the study was to evaluate the impact of full kinetic analysis and assess its value with regard to the therapy outcome based on survival data. METHODS: The evaluation included 17 patients with 29 metastatic lesions of soft tissue sarcomas, who were treated with chemotherapy consisting of an AI-G regimen prior to high-dose chemotherapy and peripheral blood stem cell transplantation where applicable. Patients were examined prior to onset of therapy and after completion of the first cycle of AI-G. Restaging data (n = 17) based on Response Evaluation Criteria in Solid Tumors were available. Survival data (n = 14) served for reference. The following parameters were retrieved from the dynamic PET studies: standardized uptake value (SUV), fractal dimension, two-compartment model with computation of k1, k2, k3, k4 (unit: 1/min), the fractional blood volume and the FDG influx calculated according to Patlak. RESULTS: The mean SUV was 6.9 prior to therapy and 4.7 after one cycle. The mean influx was 0.066 prior to therapy in comparison to 0.058 after one cycle. We dichotomized the patients according to the median survival time of 320 days into response (n = 6) and non-response (n = 8). The mean SUV was 7.6 in the group of responders and 5.4 in the group of non-responders prior to therapy. Responders revealed a mean SUV of 3.8 after therapy as compared to 5.0 SUV for non-responders. We used discriminant analysis to classify the patients into the two response groups. The classification of the non-responders was generally higher (negative predictive value > 61%) than for the responders. Finally, the combined use of the four predictor variables, namely mean SUV and k1 of both studies led to the highest accuracy of 90% for both groups. CONCLUSION: The data demonstrate that only a multiparameter analysis based on a combination of the absolute values of mean SUV and k1 of a baseline study and a follow-up study after completion of one cycle was the best combination for a group-based analysis, into response or non-response. The quantitative assessment of the FDG kinetics in tumours should be used to quantify the "inhibitory effect" of chemotherapy and to individualize treatment. The main effect of the AI-G therapy may be on angiogenesis (k1 effect) rather than on proliferation.

Parametric imaging: a promising approach for the evaluation of dynamic PET-18F-FDG studies - the DKFZ experience.

Dynamic positron emission studies (dPET) with fluorine-18-fluoro-deoxyglucose ((18)F-FDG) were performed in oncologic patients. The primary aim was to evaluate the impact of parametric imaging and assess its feasibility with regard to diagnostics and treatment management. Parametric PET images based on different algorithms have been calculated. Regression-based images, influx images according to Patlak, two-tissue compartment images as well as non-compartmental approaches, based on the fractal dimension, principal component images, and similarity mapping have been used. Our results showed that the use of parametric images is helpful to visualize quantitative parameters of the tracer kinetics and adds a new dimension to the existing conventional PET or PET/computerized tomography (CT) images. Especially, non-compartment models are computationally fast and can be applied in daily routine to gain more detailed information about the distribution of a tracer over time and space. In conclusion, it is our opinion that parametric images will gain increasing importance and find their way into clinical routine due to the improvement of the technical equipment, like computer power, faster data acquisition by new generations of PET/CT scanners and more sophisticated software for data evaluation.

The use of fluorine-18 fluorodesoxyglycose-positron emission tomography for treatment monitoring in patients with soft tissue sarcomas.

Positron emission tomography (PET) using 2-deoxy-2-[(18)F] fluoro-D-glucose ((18)F-FDG) has been used with increased frequency in the care of patients with soft tissue sarcomas to predict malignant potential of tumours, prognosis of survival and response to chemotherapy. Although there are several other PET tracers, which have found limited use in sarcomas, this review focuses on the use of (18)F-FDG, which is the most common used tracer. Recent literature and developments covering major aspects of PET imaging in the management of patients with soft tissue sarcomas will be discussed in this review with focus on treatment monitoring. Positron emission tomography cannot be used instead of histology to diagnose sarcomas, but may aid in biopsy planning. In particular, using the last generation PET/computerized tomography (CT) scanners, it is easily possible to combine morphological information provided by CT and/or magnetic resonance imaging with biological information based on PET. Imaging with PET has been shown to detect accurately primary tumours as well as lymph node and bone metastases in patients with sarcomas. In soft tissue sarcomas, changes in tumour (18)F-FDG uptake correlate significantly with histopathological response, risk of tumour recurrence and survival. In conclusion, PET is emerging as an important imaging modality in the management of patients with soft tissue sarcomas.

Quantification of pulmonary blood flow (PBF): validation of perfusion MRI and nonlinear contrast agent (CA) dose correction with H(2)15O positron emission tomography (PET).

Validation of quantification of pulmonary blood flow (PBF) with dynamic, contrast-enhanced MRI is still missing. A possible reason certainly lies in difficulties based on the nonlinear dependence of signal intensity (SI) from contrast agent (CA) concentration. Both aspects were addressed in this study. Nine healthy pigs were examined by first-pass perfusion MRI using gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) and H(2)(15)O positron emission tomography (PET) imaging. Calculations of hemodynamic parameters were based on a one-compartment model (MR) and a two-compartment model (PET). Simulations showed a significant error when assuming a linear relation between MR SI and CA dose in the arterial input function (AIF), even at low doses of 0.025 mmol/kg body weight (BW). To correct for nonlinearity, a calibration curve was calculated on the basis of the signal equation. The required accuracy of equation parameters (like longitudinal relaxation time) was evaluated. Error analysis estimates <5% over-/underestimation of the corrected SI. Comparison of PET and MR flow values yielded a significant correlation (P < 0.001) in dorsal regions where signal-to-noise ratio (SNR) was sufficient. Changes in PBF due to the correction method were significant (P < 0.001) and resulted in a better agreement: mean values (standard deviation) in units of ml/min/100 ml lung tissue were 59 (15) for PET, 112 (28) for uncorrected MRI, and 80 (21) for corrected MRI.

Early effects of FOLFOX treatment of colorectal tumour in an animal model: assessment of changes in gene expression and FDG kinetics.

PURPOSE: The very early chemotherapeutic effects of the FOLFOX (fluorouracil, folinic acid, oxaliplatin) protocol were assessed in mice implanted with a human colorectal cell line. The aim of this study was to identify changes in gene expression patterns and to detect combinations of PET parameters that may be helpful in identifying treated tumours early after chemotherapy using dynamic PET studies. METHODS: A human colorectal cell line (HCT 116) was used in nude mice. Dynamic PET studies were performed in untreated (n = 13) and treated (n = 12) animals. The data were assessed using compartmental and noncompartmental analysis. The removed tumour specimens were assessed by gene array analysis to obtain quantitative information on gene expression. RESULTS: One chemotherapeutic treatment using the FOLFOX protocol resulted in an upregulation of 2,078 gene probes by more than 25%, while 2,254 probes were downregulated following treatment. The gene array data demonstrated primarily an enhancement of genes related to apoptosis. In particular, the apoptosis antigen 1 (APO-1), p21 and the G protein-coupled receptor 87 (G-87) were 2.6- to 3.3-fold upregulated as compared to the expression in untreated animals. There was a 100% separation of untreated and treated animals on the basis of these three genes. The SUV and the FDG kinetic parameters obtained by compartmental and noncompartmental fitting were not significantly different when individual parameters were compared between groups. However, classification analysis of the combination of the PET parameters VB, K1, k3, and influx revealed an overall accuracy of 84%. We were able to identify 91.7% (11/12) of the treated animals and 76.9% (10/13) of the untreated animals correctly using the classification analysis of PET data. CONCLUSION: Even one chemotherapeutic treatment using FOLFOX has an impact on gene expression and significantly modulates FDG kinetics. Quantitative assessment of the tracer kinetics and the application of classification analysis to the data are promising tools to identify those tumours that demonstrate a chemotherapeutic effect very early following treatment.

Positron emission tomography (PET) and macromolecular delivery in vivo.

Positron emission tomography (PET) examinations with F-18-fluorodeoxyglucose (FDG) provide detailed information about the glucose-like metabolism in tissue. It is generally accepted that FDG reflects the viability of tumour cells. The kinetics of FDG is modulated by several genes, besides the glucose transporters and hexokinases. Additional specific information can be obtained non-invasively by using other tracers specific for cell membrane receptors. PET studies with radiolabelled peptides have emerged as a new diagnostic tool for imaging of certain tumour entities, like neuroendocrine tumours (NETs) and gastrointestinal stromal tumours (GISTs). This application is based on certain properties of these tumours, like the overexpression of somatostatin receptors, which can be visualised by somatostatin analogues, like 1,4,7,10-tetraazacyclododecane-N, N', N'', N'''-tetraacetic-acid-D: -Phe1-Tyr3 octreotide (DOTATOC) in NET. The overexpression of gastrin-releasing peptide (GRP) receptors can be visualised in GIST by using bombesin analogues. These peptides can be labelled by (68)Ga, which is a generator product and therefore more cost-effective than cyclotron products. (68)Ga-DOTATOC is a peptide that binds primarily to somatostatin receptor subtype 2 (SSTR2). PET studies with (68)Ga-DOTATOC are performed in patients with NET and some other tumours. (68)Ga-BZH3 ((68)Ga-Bombesin) is a peptide that binds to at least three bombesin receptor subtypes: the BB1 (also known as neuromedin B), the BB2 (also known as GRP), and the BB3 (bombesin receptor subtype 3). This bombesin analogue, (68)Ga-BZH3, is used in patients with GIST.

The impact of gene expression on 18F-FDG kinetics; a new chapter for diagnostic nuclear medicine.

Nuclear medicine procedures are the methods of choice for the assessment of the tracer kinetics in a volume over time. Fluorine-18 fluoro-deoxyglucose ((18)F-FDG) is primarily a marker of tumor viability and the kinetics of (18)F-FDG reflects major biological factors like angiogenesis and proliferation. The correct interpretation of (18)F- FDG tracer kinetics demands the knowledge about the association of quantitative positron emission tomography (PET) data and gene expression. The use of gene arrays is helpful to obtain expression data for a large number of genes from tissue samples. However, limited data are available about quantitative (18)F-FDG data and gene array results. Studies in primary liver cancer patients revealed that the (18)F-FDG uptake was associated with genes related to tumor cell adhesion and tumor invasion. We noted in patients with giant cell tumors a correlation of the (18)F-FDG uptake, as measured by the standardized uptake value (SUV) and the cell division cycle 2 (cdc2) gene expression. The effect of therapeutic interventions is dependent on the agent used for treatment. In gastrointestinal stromal tumors the change in (18)F-FDG uptake is most likely due to an antiproliferative effect. However, this may be different in other tumor types and for other treatment protocols, therefore dedicated studies of the (18)F-FDG kinetics and gene expression are needed. Based on the recent data available in colorectal tumors and gene expression, we were able to demonstrate that at least two key genes of the angiogenesis, vascular endothelial growth factor (VEGF-A) and angiopoietin-2, have a major impact on the tracer kinetics. Furthermore, regression functions for the (18)F-FDG kinetics and gene expression data facilitate the calculation of parametric images of the gene expression, reflecting the spatial distribution of angiogenesis in a colorectal tumor. Currently the development of information management systems for the prediction of clinical relevant information in individual patients is in progress to retrieve the optimum on information from individual (18)F-FDG patient examinations to support individualization of treatment management.

Quantitative, dynamic 18F-FDG-PET for the evaluation of soft tissue sarcomas: relation to differential diagnosis, tumor grading and prediction of prognosis.

The purpose of this study was to evaluate soft tissue sarcomas by dynamic (18)F-FDG-PET studies, and to establish an index of kinetic parameters for evaluation of their malignancy, histological grade and prognosis, after surgical resection. One hundred and seventeen patients including 79 with histologically proven soft tissue malignancies, 14 with primary benign soft tissue tumors and 24 with postoperative scar tissues were examined. The (18)F-FDG studies were accomplished as a dynamic series for 60 min. The evaluation of the (18)F-FDG kinetics was performed using the following parameters: standardized uptake value (SUV), global influx (Ki), computation of transport constants (k1-k4) with consideration of the vascular fraction (VB) according to a two tissue compartment model, and fractal dimension (FD) based on the box-counting procedure (non-compartmental model). Discriminant analysis (DA) was used for data evaluation. Multivariate analysis was performed to assess the predictive value of each kinetic parameter on survival. Our results showed that in the primary cases (n=46), SUV, k1, Ki and FD were higher in sarcomas than benign tumors. The diagnostic sensitivity of 62.50%, a specificity of 92.86%, and an accuracy of 71.74% were achieved by using the combination of k1 and SUV as input variables for DA. In the postoperative cases (n=71), SUV, VB, k3, Ki, and FD were higher in recurrent lesions than in scar tissues. DA revealed a sensitivity of 80.85%, a specificity of 87.50%, and an accuracy of 83.10% by using the combination of SUV, Ki and FD. In liposarcoma patients (n=32), SUV and FD were higher in GII,III tumors as compared with GI. DA led to a sensitivity of 86.96%, a specificity of 55.56%, and an accuracy of 78.13% by using the combination of SUV and FD. By multivariate analysis of primary soft tissue sarcomas (n=26) after surgical resection, groups with k3>0.025 (P<0.0026) or FD>1.25 (P<0.0162) had significantly poor prognosis. In conclusion, the evaluation of full (18)F-FDG kinetics provides important information for the diagnosis of malignant lesions, histological grading and prognosis of soft tissue sarcomas.