Carmen Vigil

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

PurposeThe aim of the study was to evaluate the volumetric integration patterns of standard MRI and 11C-methionine positron emission tomography (PET) images in the surgery planning of gliomas and their relationship to the histological grade.MethodsWe studied 23 patients with suspected or previously treated glioma who underwent preoperative 11C-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 11C-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.ResultsFifteen patients had high-grade tumours [ten glioblastoma multiforme (GBM) and five anaplastic), whereas eight patients had low-grade tumours. Biopsies from areas with high 11C-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).ConclusionThe metabolically active tumour volume observed in 11C-methionine PET differs from the volume of MRI by showing areas of infiltrative tumour and distinguishing from non-tumour lesions. Differences in 11C-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.

Promising Prospects for 44Sc-/47Sc-Based Theragnostics: Application of 47Sc for Radionuclide Tumor Therapy in Mice

In recent years, 47Sc has attracted attention because of its favorable decay characteristics (half-life, 3.35 d; average energy, 162 keV; Eγ, 159 keV) for therapeutic application and for SPECT imaging. The aim of the present study was to investigate the suitability of 47Sc for radionuclide therapy in a preclinical setting. For this purpose a novel DOTA-folate conjugate (cm10) with an albumin-binding entity was used. Methods: 47Sc was produced via the 46Ca(n,γ)47Ca→β−47Sc nuclear reaction at the high-flux reactor at the Institut Laue-Langevin. Separation of the 47Sc from the target material was performed by a semi-automated process using extraction chromatography and cation exchange chromatography. 47Sc-labeled cm10 was tested on folate receptor–positive KB tumor cells in vitro. Biodistribution and SPECT imaging experiments were performed in KB tumor–bearing mice. Radionuclide therapy was conducted with two groups of mice, which received either 47Sc-cm10 (10 MBq) or only saline. Tumor growth and survival time were compared between the two groups of mice. Results: Irradiation of 46Ca resulted in approximately 1.8 GBq of 47Ca, which subsequently decayed to 47Sc. Separation of 47Sc from 47Ca was obtained with 80% yield in only 10 min. The 47Sc was then available in a small volume (∼500 μL) of an ammonium acetate/HCl (pH 4.5) solution suitable for direct radiolabeling. 47Sc-cm10 was prepared with a radiochemical yield of more than 96% at a specific activity of up to 13 MBq/nmol. In vitro 47Sc-cm10 showed folate receptor–specific binding and uptake into KB tumor cells. In vivo SPECT/CT images allowed the visualization of accumulated radioactivity in KB tumors and in the kidneys. The therapy study showed a significantly delayed tumor growth in mice, which received 47Sc-cm10 (10 MBq, 10 Gy) resulting in a more than 50% increase in survival time, compared with untreated control mice. Conclusion: With this study, we demonstrated the suitability of using 47Sc for therapeutic purposes. On the basis of our recent results obtained with 44Sc-folate, the present work confirms the applicability of 44Sc/47Sc as an excellent matched pair of nuclides for PET imaging and radionuclide therapy.

Pilot Clinical Trial of Type 1 Dendritic Cells Loaded with Autologous Tumor Lysates Combined with GM-CSF, Pegylated IFN, and Cyclophosphamide for Metastatic Cancer Patients

Twenty-four patients with metastatic cancer received two cycles of four daily immunizations with monocyte-derived dendritic cells (DC). DC were incubated with preheated autologous tumor lysate and subsequently with IFN-α, TNF-α, and polyinosinic:polycytidylic acid to attain type 1 maturation. One DC dose was delivered intranodally, under ultrasound control, and the rest intradermally in the opposite thigh. Cyclophosphamide (day −7), GM-CSF (days 1–4), and pegIFN alpha-2a (days 1 and 8) completed each treatment cycle. Pretreatment with cyclophosphamide decreased regulatory T cells to levels observed in healthy subjects both in terms of percentage and in absolute counts in peripheral blood. Treatment induced sustained elevations of IL-12 in serum that correlated with the output of IL-12p70 from cultured DC from each individual. NK activity in peripheral blood was increased and also correlated with the serum concentration of IL-12p70 in each patient. Circulating endothelial cells decreased in 17 of 18 patients, and circulating tumor cells markedly dropped in 6 of 19 cases. IFN-γ–ELISPOT responses to DC plus tumor lysate were observed in 4 of 11 evaluated cases. Tracing DC migration with [111In] scintigraphy showed that intranodal injections reached deeper lymphatic chains in 61% of patients, whereas with intradermal injections a small fraction of injected DC was almost constantly shown to reach draining inguinal lymph nodes. Five patients experienced disease stabilization, but no objective responses were documented. This combinatorial immunotherapy strategy is safe and feasible, and its immunobiological effects suggest potential activity in patients with minimal residual disease. A randomized trial exploring this hypothesis is currently ongoing.

PET optimization for improved assessment and accurate quantification of 90Y-microsphere biodistribution after radioembolization

PURPOSE 90Y-microspheres are widely used for the radioembolization of metastatic liver cancer or hepatocellular carcinoma and there is a growing interest for imaging 90Y-microspheres with PET. The aim of this study is to evaluate the performance of a current generation PET/CT scanner for 90Y imaging and to optimize the PET protocol to improve the assessment and the quantification of 90Y-microsphere biodistribution after radioembolization. METHODS Data were acquired on a Biograph mCT-TrueV scanner with time of flight (TOF) and point spread function (PSF) modeling. Spatial resolution was measured with a 90Y point source. Sensitivity was evaluated using the NEMA 70 cm line source filled with 90Y. To evaluate the count rate performance, 90Y vials with activity ranging from 3.64 to 0.035 GBq were measured in the center of the field of view (CFOV). The energy spectrum was evaluated. Image quality with different reconstructions was studied using the Jaszczak phantom containing six hollow spheres (diameters: 31.3, 28.1, 21.8, 16.1, 13.3, and 10.5 mm), filled with a 207 kBq/ml 90Y concentration and a 5:1 sphere-to-background ratio. Acquisition time was adjusted to simulate the quality of a realistic clinical PET acquisition of a patient treated with SIR-Spheres®. The developed methodology was applied to ten patients after SIR-Spheres® treatment acquiring a 10 min per bed PET. RESULTS The energy spectrum showed the 90Y bremsstrahlung radiation. The 90Y transverse resolution, with filtered backprojection reconstruction, was 4.5 mm in the CFOV and degraded to 5.0 mm at 10 cm off-axis. 90Y absolute sensitivity was 0.40 kcps/MBq in the center of the field of view. Tendency of true and random rates as a function of the 90Y activity could be accurately described using linear and quadratic models, respectively. Phantom studies demonstrated that, due to low count statistics in 90Y PET acquisition, the optimal parameters for the standard OSEM+PSF reconstruction were only one iteration and a postreconstruction filter of 6 mm FWHM, for both TOF and non-TOF reconstructions. Moreover, when TOF is included, the signal to noise ratio increased and visibility achieved 100% by the experienced observers and 93.3% according to the Rose model of statistical detection. In 50% of patients, TOF allowed the visualization of 90Y radioembolized lesions not seen without TOF, confirming phantom results. Liver activity was accurately quantified, with no significant differences between reconstructed and actual delivered activity to the whole-liver [mean relative difference (10.2±14.7)%]. CONCLUSIONS Qualitative and quantitative 90Y PET imaging improved with the introduction of TOF in a PET/CT scanner, thereby allowing the visualization of microsphere deposition in lesions not visible in non-TOF images. This technique accurately quantifies the total activity delivered to the liver during radioembolization with (90)Y-microspheres and allows dose estimation.

[Dual time point 18F-FDOPA PET as a tool for characterizing brain tumors].

Abstract 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 heman- gioma. 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.

Aportación del tiempo de vuelo y de la modelización de la respuesta a una fuente puntual a las características de funcionamiento del tomógrafo PET/TAC Biograph mCT

OBJECTIVE To characterize the performance of the Biograph mCT PET/CT TrueV scanner with time of flight (TOF) and point spread function (PSF) modeling. MATERIAL AND METHODS The PET/CT scanner combines a 64-slice CT and PET scanner that incorporates in the reconstruction the TOF and PSF information. PET operating characteristics were evaluated according to the standard NEMA NU 2-2007, expanding some tests. In addition, different reconstruction algorithms were included, and the intrinsic radiation and tomographic uniformity were also evaluated. RESULTS The spatial resolution (FWHM) at 1 and 10cm was 4.4 and 5.3mm, improving to 2.6 and 2.5mm when PSF is introduced. Sensitivity was 10.9 and 10.2 Kcps/MBq at 0 and 10cm from the axis. Scatter fraction was less than 34% at low concentrations and the noise equivalent count rate (NECR) was maximal at 27.8 kBq/mL with 182 Kcps, the intrinsic radiation produced a rate of 4.42 true coincidences per second. Coefficient of variation of the volume and system uniformity were 4.7 and 0.8% respectively. The image quality test showed better results when PSF and TOF were included together. PSF improved the hot spheres contrast and background variability, while TOF improved the cold spheres contrast. CONCLUSIONS The Biograph mCT TrueV scanner has good performance characteristics. The image quality improves when the information from the PSF and the TOF is incorporated in the reconstruction.

PET de doble fase con 18F-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.

Nuclear Medicine Procedures for Treatment Evaluation and Administration

The 90Yttrium radioembolisation (RE) procedure requires the collaboration of a multidisciplinary team that includes hepatologists, oncologists, interventional radiologists and nuclear medicine specialists working together in close collaboration. To avoid toxicity to the patient, a thorough angiographic evaluation is performed to identify extrahepatic vessels that may feed the tumours (to guarantee efficacy). To mimic the microsphere application during the treatment, angiographic evaluation is accomplished with 99mTechnetium-labelled macroaggregated albumin injection into the vessel of interest, followed by imaging. Both procedures combined are essential to plan the RE therapy, and to detect and eventually occlude every collateral vessel arising from a hepatic artery that may carry microspheres to the gastrointestinal tract or other extrahepatic organs. Moreover, this approach permits the calculation of hepatopulmonary shunting, and tumour and liver tissue targeting. With this information taken together, the treatment is designed and activity is calculated to maximise the dose of radiation delivered to liver tumours while safely preserving the non-tumoural parenchyma.