Radiation dosimetry and biodistribution in non-human primates of the sodium/iodide PET ligand [(18)F]-tetrafluoroborate.

BACKGROUND: [(18)F]-tetrafluoroborate is a PET radiotracer taken up by the sodium/iodide symporter (NIS). Albeit the in vivo behavior in rodents is similar to the (99m)Tc-pertechnetate, no studies exist in primates or in humans. The aims of this study were to evaluate the biodistribution of [(18)F]-tetrafluoroborate in non-human primates with PET and to estimate the absorbed dose in organs. METHODS: Whole-body PET imaging was done in a Siemens ECAT HR+ scanner in two male Macaca fascicularis monkeys. After an i.v. injection of 24.93 ± 0.05 MBq/kg of [(18)F]-tetrafluoroborate, prepared by isotopic exchange of sodium tetrafluoroborate with [(18)F]-fluoride under acidic conditions, eight sequential images from the head to the thigh (five beds) were collected for a total duration of 132 min. The whole-body emission scan was reconstructed applying attenuation and scatter corrections. After image reconstruction, three-dimensional volumes of interest (VOIs) were hand-drawn on the PET transaxial or coronal slices of the frame where the organ was most conspicuous. Time-activity curves for each VOI were obtained, and the organ residence times were calculated by integration of the time-activity curves. Human absorbed doses were estimated using the OLINDA/EXM software and the standard human model. RESULTS: [(18)F]-tetrafluoroborate was able to discriminate clearly the thyroid gland with an excellent signal-to-noise ratio. Most of the radiotracers (residence time) are localised in the organs that express NIS (stomach wall, salivary glands, thyroid, olfactory mucosa), are involved in excretion (kidneys and bladder), or reflect the vascular phase (heart and lungs). Considering the OLINDA source organs, the critical organs were the stomach wall, thyroid and bladder wall, with absorbed doses lower than 0.078 mGy/MBq. The effective dose was 0.025 mSv/MBq. CONCLUSIONS: [(18)F]-tetrafluoroborate is a very useful radiotracer for PET thyroid imaging in primates, with a characteristic biodistribution in organs expressing NIS. It delivers an effective dose slightly higher than the dose produced by (99m)Tc-pertechnetate but much lower than that produced by radioiodine in the form of (131)INa, (123)INa, or (124)INa.

[¹8F]fluorothymidine-positron emission tomography in patients with locally advanced breast cancer under bevacizumab treatment: usefulness of different quantitative methods of tumor proliferation.

OBJECTIVES: To investigate quantitative methods of tumor proliferation using 3'-[(18)F]fluoro-3'-deoxythymidine ([(18)F]FLT) PET in patients with breast cancer (BC), studied before and after one bevacizumab administration, and to correlate the [(18)F]FLT-PET uptake with the Ki67 index. MATERIAL AND METHODS: Thirty patients with newly diagnosed, untreated BC underwent a [(18)F]FLT-PET before and 14 days after bevacizumab treatment. A dynamic scan centered over the tumor began simultaneously with the injection of [(18)F]FLT (385 ± 56 MBq). Image derived input functions were obtained using regions of interest drawn on the left ventricle (LV) and descending aorta (DA). Metabolite corrected blood curves were used as input functions to obtain the kinetic Ki constant using the Patlak graphical analysis (time interval 10-60 min after injection). Maximum SUV values were derived for the intervals 40-60 min (SUV40) and 50-60 min (SUV50). PET parameters were correlated with the Ki67 index obtained staining tumor biopsies. RESULTS: [(18)F]FLT uptake parameters decreased significantly (p<0.001) after treatment: SUV50=3.09 ± 1.21 vs 2.22 ± 0.96; SUV40=3.00 ± 1.18 vs 2.14 ± 0.95, Ki_LV(10-3)=52[22-116] vs 38[13-80] and Ki_DA(10-3)=49[15-129] vs 33[11-98]. Consistency interclass correlation coefficients within SUV and within Ki were high. Changes of SUV50 and Ki_DA between baseline PET and after one bevacizumab dose PET correlated with changes in Ki67 index (r-Pearson=0.35 and 0.26, p=0.06 and 0.16, respectively). CONCLUSIONS: [(18)F]FLT-PET is useful to demonstrate proliferative changes after a dose of bevacizumab in patients with BC. Quantification of tumor proliferation by means of SUV and Ki has shown similar results, but SUV50 obtained better results. A correlation between [(18)F]FLT changes and Ki67 index was observed.

[Validation of segmentation techniques for positron emission tomography using ex-vivo images of oncological surgical specimens]. / Validación de técnicas de segmentación para la tomografía por emisión de positrones mediante imágenes ex-vivo de piezas quirúrgicas oncológicas.

OBJECTIVE: To design a novel ex-vivo acquisition technique to establish a common framework to validate different segmentation techniques for oncological PET images. To evaluate several automatic segmentation algorithms on this set of images. MATERIAL AND METHODS: In 15 patients with cancer, ex-vivo PET studies of surgical specimens removed during surgery were performed after injection of (18)F-FDG. Images were acquired in two scanners: a clinical PET/CT and a high-resolution PET scanner. Real tumor volume was determined in each patient, and a reference image was generated for segmentation of each tumor. Images were segmented with 12 automatic algorithms and with a standard method for PET (relative threshold at 42%) and results were evaluated by quantitative parameters. RESULTS: It has been possible to demonstrate by segmentation of PET images of surgical specimens that on high resolution PET images, 8 out of 12 evaluated segmentation techniques outperformed the standard method, whose value is 42%. However, none of the algorithms outperformed the standard method when applied on images from the clinical PET/CT. Due to the great interest of this set of PET images, all studies have been published on the Internet in order to provide a common framework for validation and comparison of different segmentation techniques. CONCLUSIONS: We have proposed a novel technique to validate segmentation techniques for oncological PET images, acquiring ex-vivo PET studies of surgical specimens. We have demonstrated the usefulness of this set of PET images by evaluating several automatic segmentation algorithms.

Quantitative volumetric analysis of gliomas with sequential MRI and ¹¹C-methionine PET assessment: patterns of integration in therapy planning.

PURPOSE: The aim of the study was to evaluate the volumetric integration patterns of standard MRI and (11)C-methionine positron emission tomography (PET) images in the surgery planning of gliomas and their relationship to the histological grade. METHODS: We studied 23 patients with suspected or previously treated glioma who underwent preoperative (11)C-methionine PET because MRI was imprecise in defining the surgical target contour. Images were transferred to the treatment planning system, coregistered and fused (BrainLAB). Tumour delineation was performed by (11)C-methionine PET thresholding (vPET) and manual segmentation over MRI (vMRI). A 3-D volumetric study was conducted to evaluate the contribution of each modality to tumour target volume. All cases were surgically treated and histological classification was performed according to WHO grades. Additionally, several biopsy samples were taken according to the results derived either from PET or from MRI and analysed separately. RESULTS: Fifteen patients had high-grade tumours [ten glioblastoma multiforme (GBM) and five anaplastic), whereas eight patients had low-grade tumours. Biopsies from areas with high (11)C-methionine uptake without correspondence in MRI showed tumour proliferation, including infiltrative zones, distinguishing them from dysplasia and radionecrosis. Two main PET/MRI integration patterns emerged after analysis of volumetric data: pattern vMRI-in-vPET (11/23) and pattern vPET-in-vMRI (9/23). Besides, a possible third pattern with differences in both directions (vMRI-diff-vPET) could also be observed (3/23). There was a statistically significant association between the tumour classification and integration patterns described above (p < 0.001, κ = 0.72). GBM was associated with pattern vMRI-in-vPET (9/10), low-grade with pattern vPET-in-vMRI (7/8) and anaplastic with pattern vMRI-diff-vPET (3/5). CONCLUSION: The metabolically active tumour volume observed in (11)C-methionine PET differs from the volume of MRI by showing areas of infiltrative tumour and distinguishing from non-tumour lesions. Differences in (11)C-methionine PET/MRI integration patterns can be assigned to tumour grades according to the WHO classification. This finding may improve tumour delineation and therapy planning for gliomas.

[Dual time point 18F-FDOPA PET as a tool for characterizing brain tumors]. / PET de doble fase con (18)F-FDOPA como instrumento para la caracterización de tumores cerebrales.

(18)F-FDOPA is an amino acid analogue used to evaluate presynaptic dopaminergic activity, which has aroused great interest in neuro-oncology. We have evaluated five (18)F-FDOPA PET studies of patients referred for study of parkinsonian syndrome. Two subjects had previously treated high-grade brain tumors, one nonspecific brain injury, and 2 subjects presented unexpected tumoral lesions. For all lesions SUVmax, time to SUVmax and tumor-to-normal grey matter SUVmax rate (T/N) were calculated, and 90 minutes (18)F-FDOPA kinetics were analyzed. Tumor lesions corresponded to three malignant neurocytomas, one meningioma, one pineocytoma and one intrasinusal hemangioma. Both malignant and benign tumors exhibited high uptake of (18)F-FDOPA well above the normal cortex. However, the analysis of the curve uptake displayed characteristic patterns that facilitate the characterization of tumor lesions. A dual phase maximum uptake was observed, with an early 10 minutes uptake in malignant lesions, and a late 60 to 90 minutes uptake in benign or low grade lesions.

A phase I clinical trial of thymidine kinase-based gene therapy in advanced hepatocellular carcinoma.

The aim of this phase I clinical trial was to assess the feasibility and safety of intratumoral administration of a first-generation adenoviral vector encoding herpes simplex virus thymidine kinase (HSV-TK) gene (Ad.TK) followed by systemic ganciclovir to patients with advanced hepatocellular carcinoma (HCC). Secondarily, we have analyzed its antitumor effect. Ten patients were enrolled in five dose-level cohorts that received from 10¹° to 2 × 10¹² viral particles (vp). Ad.TK was injected intratumorally and patients received up to three doses at 30-day intervals. Positron emission tomography was used to monitor TK gene expression. Ad.TK injection was feasible in 100% of cases. Treatment was well tolerated and dose-limiting toxicity was not achieved. Cumulative toxicity was not observed. Hepatic toxicity was absent even in cirrhotic patients. Fever, flu-like syndrome, pain at the injection site and pancytopenia were the most common side effects. No partial responses were observed and 60% of patients showed tumor stabilization of the injected lesion. Importantly, two patients who received the highest dose showed signs of intratumoral necrosis by imaging procedures. One of them achieved a sustained stabilization and survived for 26 months. In conclusion, Ad.TK can be safely administered by intratumoral injection to patients with HCC up to 2 × 10¹² vp per patient.

PET imaging of thymidine kinase gene expression in the liver of non-human primates following systemic delivery of an adenoviral vector.

Non-invasive in vivo imaging of transgene expression is currently providing very important means to optimize gene therapy regimes. Results in non-human primates are considered the most predictive models for the outcome in patients. In this study, we have documented that tumour and primary cell lines from human and non-human primates are comparably gene-transduced in vitro by serotype 5 adenovirus expressing HSV1-thymidine kinase. Transgene expression can be quantified in human and monkey cultured cells by positron emission tomography (PET) imaging when transduced cells are incubated with a fluoride-18 labelled penciclovir analogue. In our hands, PET images of cell cultures estimate the number of transduced cells rather than intensity of transgene expression once a threshold of TK per cell is reached. Interestingly, in vivo systemic administration of a clinical grade recombinant adenovirus expressing TK into macaques gives rise to an intense retention of the radiotracer in the liver parenchyma, providing an experimental system to visualize transgene expression that ought to be similar in human and macaques. Such imaging methodology might contribute to improve strategies based on adenoviral vectors.

Three-dimensional clinical PET in lung cancer: validation and practical strategies.

UNLABELLED: The feasibility of 3-dimensional acquisition mode for semiquantitative analysis in thoracic PET studies was compared to the conventional 2-dimensional mode. Several practical considerations were analyzed to propose an optimized scanning protocol for clinical use. METHODS: Twenty-one patients with focal thoracic abnormalities were evaluated with FDG PET. The acquisition consisted of 3 consecutive static scans for a single bed position: 3-dimensional (10 min), 2-dimensional (15 min), and 3-dimensional (5 min). On the basis of the average and maximum activity values per region of interest, standardized uptake value (SUV) normalized for total body weight (TBW), lean body mass (LBM), body surface area (BSA), and blood glucose level (PGL) were evaluated. The effect of the delay between tracer injection and PET scanning on the SUV, as well as on the relative error of the activity distribution, was studied from 40-134 min after tracer injection. RESULTS: A strong positive correlation was observed among SUVs from 2-dimensional and both 3-dimensional acquisitions. The mean SUV percentage differences between both acquisition modes were about 17%, differences that were not statistically significant when time postinjection was addressed in the analysis of covariance. SUVs provided the greatest variability and differences among studies on experimental periods up to 70 min postinjection. Indeed, the variability of 20% observed on the SUVs from 2 PET scans 13 min apart was reduced to 9% when the acquisitions started at least 70 min after tracer injection. In addition, a two-fold reduction in the relative error of the activity distribution was observed over this period of time. The reproducibility coefficient was increased from 0.87 to 0.95 before and after 70 min postinjection, respectively. No correlation was found between different normalization procedures of SUV and LBM, BSA, TBW, or height, whereas a weak correlation was found between SUV and PGL. CONCLUSION: 18F-FDG 3-dimensional PET is a realistic alternative to the gold standard 2-dimensional for clinical nonkinetic studies. A short, 5-min 3-dimensional acquisition at 70 min postinjection is proposed as the best protocol for the clinical evaluation of thoracic pathologies.

[Positron emission tomography with F-18-FDG: a new tool in the evaluation of patients with head and neck tumors]. / Tomografía de emisión de positrones con F-18-FDG: una nueva técnica en la evaluación de pacientes con neoplasias de cabeza y cuello.

INTRODUCTION: Positron emission tomography using fluoro-deoxyglucose (PET-FDG) imaging has been shown to be effective in detecting and staging malignancies based on tumor glucose metabolism. The aim of the study was to evaluate the use of PET-FDG for the detection of metastatic lesions as well as early recurrence in patients with head and neck tumors. MATERIAL AND METHODS: Eleven patients were examined with PET-FDG to study the reliability of PET in assessing regional nodal status and in identifying distant metastasis (group I) and 37 patients who had previously received curative treatment and who presented differential diagnostic problems were imaged to differentiate between scar and residual or recurrent cancer (group II). PET-FDG studies were compared to results of computed tomography (CT) in 35 patients, magnetic resonance imaging (MRI) in 4 patients and both techniques in 6 patients. RESULTS: All PET-FDG studies were positive in group I, while CT failed to detect metastatic lesions in three patients. In group II PET-FDG accurately detected recurrent disease in 22/25 patients, while CT/MRI were negative in 4 cases and equivocal in 6 cases. However, there was a false positive PET study with equivocal CT in a patient with local infection. CONCLUSION: PET-FDG was highly effective in detecting metastatic cervical lymph nodes in head and neck tumours. It was most helpful in differentiating residual or recurrent tumour from scar sequelae and it enhanced the diagnostic accuracy when CT and MRI were equivocal due to anatomical distortions.

cAMP activates transcription of the human glucocorticoid receptor gene promoter.

Glucocorticoids and cAMP regulate, either in a synergistic or additive fashion, the transcription of multiple genes, although some antagonistic effects of dexamethasone on cAMP-activated transcription have been described. The increased glucocorticoid receptor (GR) mediated response of some cell types, as a result of augmented cAMP, has been considered to be mainly due to an increased stability of GR mRNA, although other plausible explanations should not be ruled out. We studied the possibility that GR transcription itself could be affected by cAMP levels. HeLa cells were transfected with human GR (hGR) promoter constructs and their transcriptional activity determined after inducing a cAMP increase with forskolin. We found that forskolin almost doubled the transcriptional activity of the promoter construct spanning -2995 to +38 of the hGR, whereas no significant variations were observed with shorter chimeras containing sequences downstream -979. Shift mobility showed binding of CREB in vitro to a putative cAMP responsive element located at -1000, suggesting that hGR may be upregulated by cAMP at the transcriptional level, thus adding a new mechanism ascribable to this second messenger, which in conjunction with the cAMP-induced GR mRNA increased stability, would lead to a more precise control of the amount of GR protein within the cell.