In vivo imaging of cellular proliferation in colorectal cancer using positron emission tomography

Background and aims: Positron emission tomography (PET) using 18F labelled 2-fluoro-2-deoxy-D-glucose (18FDG) is an established imaging tool, although the recent development of a biologically stable thymidine analogue [18F] 3'-deoxy-3-fluorothymidine (18FLT) has allowed PET to image cellular proliferation by utilising the salvage pathway of DNA synthesis. In this study, we have compared uptake of 18FLT and 18FDG with MIB-1 immunohistochemistry to evaluate the role of PET in quantifying in vivo cellular proliferation in colorectal cancer (CRC). Patients and methods: Patients with resectable, primary, or recurrent CRC were prospectively studied. Thirteen lesions from 10 patients (five males, five females), median age 68 years (range 54–87), were evaluated. Patients underwent 18FDG and 18FLT PET scanning. Tracer uptake within lesions was quantified using standardised uptake values (SUVs). Histopathological examination and MIB-1 immunohistochemistry were performed on all lesions, and proliferation quantified by calculating a labelling index (% of MIB-1 positively stained nuclei within 1500 tumour cells). Results: Histology confirmed adenocarcinoma in 12 of 13 lesions; the remaining lesion was reactive. All eight extrahepatic lesions were visualised using both 18FLT and 18FDG. Three of the five resected liver metastases were also avid for 18FLT and showed high proliferation, while the remaining two lesions which demonstrated no uptake of 18FLT had correspondingly very low proliferation. There was a statistically significant positive correlation (r =0.8, p<0.01) between SUVs of the tumours visualised with 18FLT and the corresponding MIB-1 labelling indices. No such correlation was demonstrated with 18FDG avid lesions (r =0.4). Conclusions: 18FLT PET correlates with cellular proliferation markers in both primary and metastatic CRC. This technique could provide a mechanism for in vivo grading of malignancy and early prediction of response to adjuvant chemotherapy

Standardization and Validation of Brachytherapy Seeds'' Modelling Using GATE and GGEMS Monte Carlo Toolkits

Simple Summary:& nbsp;This study used GATE and GGEMS simulation toolkits, to estimate dose distribution on Brachytherapy procedures. Specific guidelines were followed as defined by the American Association of Physicists in Medicine (AAPM) as well as by the European SocieTy for Radiotherapy and Oncology (ESTRO). Several types of brachytherapy seeds were modelled and simulated, namely Low-Dose-Rate (LDR), High-Dose-Rate (HDR), and Pulsed-Dose-Rate (PDR). The basic difference between GATE and GGEMS is that GGEMS incorporates GPU capabilities, which makes the use of Monte Carlo (MC) simulations more accessible in clinical routine, by minimizing the computational time to obtain a dose map. During the validation procedure of both codes with protocol data, differences as well as uncertainties were measured within the margins defined by the guidelines. The study concluded that MC simulations may be utilized in clinical practice, to optimize dose distribution in real time, as well as to evaluate therapeutic plans.This study aims to validate GATE and GGEMS simulation toolkits for brachytherapy applications and to provide accurate models for six commercial brachytherapy seeds, which will be freely available for research purposes. The AAPM TG-43 guidelines were used for the validation of two Low Dose Rate (LDR), three High Dose Rate (HDR), and one Pulsed Dose Rate (PDR) brachytherapy seeds. Each seed was represented as a 3D model and then simulated in GATE to produce one single Phase-Space (PHSP) per seed. To test the validity of the simulations'' outcome, referenced data (provided by the TG-43) was compared with GATE results. Next, validation of the GGEMS toolkit was achieved by comparing its outcome with the GATE MC simulations, incorporating clinical data. The simulation outcomes on the radial dose function (RDF), anisotropy function (AF), and dose rate constant (DRC) for the six commercial seeds were compared with TG-43 values. The statistical uncertainty was limited to 1% for RDF, to 6% (maximum) for AF, and to 2.7% (maximum) for the DRC. GGEMS provided a good agreement with GATE when compared in different situations: (a) Homogeneous water sphere, (b) heterogeneous CT phantom, and (c) a realistic clinical case. In addition, GGEMS has the advantage of very fast simulations. For the clinical case, where TG-186 guidelines were considered, GATE required 1 h for the simulation while GGEMS needed 162 s to reach the same statistical uncertainty. This study produced accurate models and simulations of their emitted spectrum of commonly used commercial brachytherapy seeds which are freely available to the scientific community. Furthermore, GGEMS was validated as an MC GPU based tool for brachytherapy. More research is deemed necessary for the expansion of brachytherapy seed modeling

Evaluation de méthodes de segmentation bayésiennes pour l'imagerie TEP en oncologie

Ce travail se concentre sur l'étude de méthodes de segmentation statistiques pour la détermination des volumes fonctionnels dans le cadre de l'imagerie TEP avec des applications en oncologie, en particulier la radiothérapie. Nous présentons ici une comparaison des performances de différentes approches (locale et globale, « dure » et « floue ») pour des images réelles d'acquisitions TEP du fantôme IEC. Les résultats obtenus sur images simulées sont ici confirmés: la méthode locale est la mieux adaptée, et fonctionne mieux que l'approche par chaînes de Markov cachées et la méthode de référence par seuillage

Use of the GATE Monte Carlo package for dosimetry applications

6 pages, 3 figures - submitted to NIM A, presented by D. VisvikisInternational audienceOne of the roles for MC simulation studies is in the area of dosimetry. A number of different codes dedicated to dosimetry applications are available and widely used today, such as MCNP, EGSnrc and PTRAN. However, such codes do not easily facilitate the description of complicated 3D sources or emission tomography systems and associated data flow, which may be useful in different dosimetry application domains. Such problems can be overcome by the use of specific MC codes such as GATE, which is based on Geant4 libraries, providing a scripting interface with a number of advantages for the simulation of SPECT and PET systems. Despite this potential, its major disadvantage is in terms of efficiency involving long execution times for applications such as dosimetry. The strong points and disadvantages of GATE in comparison to other dosimetry specific codes are discussed and illustrated in terms of accuracy, efficiency and flexibility. A number of features, such as the use of voxelised and moving sources, as well as developments such as advanced visualisation tools and the development of dose estimation maps allowing GATE to be used for dosimetry applications are presented. In addition, different examples from dosimetry applications with GATE are given. Finally, future directions with respect to the use of GATE for dosimetry applications are outlined

GATE : a simulation toolkit for PET and SPECT

Monte Carlo simulation is an essential tool in emission tomography that can assist in the design of new medical imaging devices, the optimization of acquisition protocols, and the development or assessment of image reconstruction algorithms and correction techniques. GATE, the Geant4 Application for Tomographic Emission, encapsulates the Geant4 libraries to achieve a modular, versatile, scripted simulation toolkit adapted to the field of nuclear medicine. In particular, GATE allows the description of time-dependent phenomena such as source or detector movement, and source decay kinetics. This feature makes it possible to simulate time curves under realistic acquisition conditions and to test dynamic reconstruction algorithms. A public release of GATE licensed under the GNU Lesser General Public License can be downloaded at the address http://www-lphe.epfl.ch/GATE/

The MINDVIEW project: First results

[EN] We present the first results of the MINDVIEW project. An innovative imaging system for the human brain examination, allowing simultaneous acquisition of PET/MRI images, has been designed and constructed. It consists of a high sensitivity and high resolution PET scanner integrated in a novel, head-dedicated, radio frequency coil for a 3T MRI scanner. Preliminary measurements from the PET scanner show sensitivity 3 times higher than state-of-the-art PET systems that will allow safe repeated studies on the same patient. The achieved spatial resolution, close to 1 mm, will enable differentiation of relevant brain structures for schizophrenia. A cost-effective and simple method of radiopharmaceutical production from C-11-carbon monoxide and a mini-clean room has been demonstrated. It has been shown that C-11-raclopride has higher binding potential in a new VAAT null mutant mouse model of schizophrenia compared to wild type control animals. A significant reduction in TSPO binding has been found in gray matter in a small sample of drug-naive, first episode psychosis patients, suggesting a reduced number or an altered function of immune cells in brain at early stage schizophrenia. (c) 2018 Elsevier Masson SAS. All rights reserved.This project is funded by EU grant FP7-HEALTH-F2-2013-603002.Benlloch Baviera, JM.; González Martínez, AJ.; Pani, R.; Preziosi, E.; Jackson, C.; Murphy, J.; Barbera Ballester, J.... (2018). The MINDVIEW project: First results. European Psychiatry. 50:21-27. https://doi.org/10.1016/j.eurpsy.2018.01.002S212750Gonzalez, A. J., Gonzalez-Montoro, A., Aguilar, A., Conde, P., Canizares, G., Hernandez, L., … Benlloch, J. M. (2016). 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Journal of Psychopharmacology, 29(2), 97-115. doi:10.1177/0269881114563634Moliner, L., Correcher, C., González, A. J., Conde, P., Hernández, L., Orero, A., … Benlloch, J. M. (2013). Implementation and analysis of list mode algorithm using tubes of response on a dedicated brain and breast PET. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 702, 129-132. doi:10.1016/j.nima.2012.08.029Zelano, J., Mikulovic, S., Patra, K., Kühnemund, M., Larhammar, M., Emilsson, L., … Kullander, K. (2013). The synaptic protein encoded by the gene Slc10A4 suppresses epileptiform activity and regulates sensitivity to cholinergic chemoconvulsants. Experimental Neurology, 239, 73-81. doi:10.1016/j.expneurol.2012.09.006Antich, P., Malakhov, N., Parkey, R., Slavin, N., & Tsyganov, E. (2002). 3D position readout from thick scintillators. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 480(2-3), 782-787. doi:10.1016/s0168-9002(01)01214-1Gonzalez-Montoro, A., Benlloch, J. M., Gonzalez, A. J., Aguilar, A., Canizares, G., Conde, P., … Sanchez, F. (2017). Performance Study of a Large Monolithic LYSO PET Detector With Accurate Photon DOI Using Retroreflector Layers. IEEE Transactions on Radiation and Plasma Medical Sciences, 1(3), 229-237. doi:10.1109/trpms.2017.2692819Rahman, O., Takano, A., Amini, N., Dahl, K., Kanegawa, N., Långström, B., … Halldin, C. (2015). Synthesis of ([11C]carbonyl)raclopride and a comparison with ([11C]methyl)raclopride in a monkey PET study. Nuclear Medicine and Biology, 42(11), 893-898. doi:10.1016/j.nucmedbio.2015.07.003Howes, O. D., Kambeitz, J., Kim, E., Stahl, D., Slifstein, M., Abi-Dargham, A., & Kapur, S. (2012). The Nature of Dopamine Dysfunction in Schizophrenia and What This Means for Treatment. Archives of General Psychiatry, 69(8). doi:10.1001/archgenpsychiatry.2012.169Ling, T., Lewellen, T. K., & Miyaoka, R. S. (2007). Depth of interaction decoding of a continuous crystal detector module. Physics in Medicine and Biology, 52(8), 2213-2228. doi:10.1088/0031-9155/52/8/012González, A. J., Majewski, S., Sánchez, F., Aussenhofer, S., Aguilar, A., Conde, P., … Benlloch, J. M. (2016). The MINDView brain PET detector, feasibility study based on SiPM arrays. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 818, 82-90. doi:10.1016/j.nima.2016.02.046Wong, D. F., Waterhouse, R., Kuwabara, H., Kim, J., Brasic, J. R., Chamroonrat, W., … Mozley, P. D. (2013). 18F-FPEB, a PET Radiopharmaceutical for Quantifying Metabotropic Glutamate 5 Receptors: A First-in-Human Study of Radiochemical Safety, Biokinetics, and Radiation Dosimetry. Journal of Nuclear Medicine, 54(3), 388-396. doi:10.2967/jnumed.112.107995Jackson, C., O’Neill, K., Wall, L., & McGarvey, B. (2014). High-volume silicon photomultiplier production, performance, and reliability. Optical Engineering, 53(8), 081909. doi:10.1117/1.oe.53.8.081909Rahman, O., Långström, B., & Halldin, C. (2016). Alkyl Iodides and [11 C]CO in Nickel-Mediated Cross-Coupling Reactions: Successful Use of Alkyl Electrophiles containing a β Hydrogen Atom in Metal-Mediated [11 C]Carbonylation. ChemistrySelect, 1(10), 2498-2501. doi:10.1002/slct.201600643Sullivan, J. M., Lim, K., Labaree, D., Lin, S., McCarthy, T. J., Seibyl, J. P., … Morris, E. D. (2012). Kinetic Analysis of the Metabotropic Glutamate Subtype 5 Tracer [18F]FPEB in Bolus and Bolus-Plus-Constant-Infusion Studies in Humans. Journal of Cerebral Blood Flow & Metabolism, 33(4), 532-541. doi:10.1038/jcbfm.2012.195Levin, C. S. (2003). Detector design issues for compact nuclear emission cameras dedicated to breast imaging. 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Performance of automatic image segmentation algorithms for calculating total lesion glycolysis for early response monitoring in non-small cell lung cancer patients during concomitant chemoradiotherapy.

Background and purpose This study evaluated the use of total lesion glycolysis (TLG) determined by different automatic segmentation algorithms, for early response monitoring in non-small cell lung cancer (NSCLC) patients during concomitant chemoradiotherapy.Materials and methods Twenty-seven patients with locally advanced NSCLC treated with concomitant chemoradiotherapy underwent (18)F-fluorodeoxyglucose (FDG) PET/CT imaging before and in the second week of treatment. Segmentation of the primary tumours and lymph nodes was performed using fixed threshold segmentation at (i) 40% SUVmax (T40), (ii) 50% SUVmax (T50), (iii) relative-threshold-level (RTL), (iv) signal-to-background ratio (SBR), and (v) fuzzy locally adaptive Bayesian (FLAB) segmentation. Association of primary tumour TLG (TLGT), lymph node TLG (TLGLN), summed TLG (TLGS=TLGT+TLGLN), and relative TLG decrease (ΔTLG) with overall-survival (OS) and progression-free survival (PFS) was determined using univariate Cox regression models.Results Pretreatment TLGT was predictive for PFS and OS, irrespective of the segmentation method used. Inclusion of TLGLN improved disease and early response assessment, with pretreatment TLGS more strongly associated with PFS and OS than TLGT for all segmentation algorithms. This was also the case for ΔTLGS, which was significantly associated with PFS and OS, with the exception of RTL and T40.Conclusions ΔTLGS was significantly associated with PFS and OS, except for RTL and T40. Inclusion of TLGLN improves early treatment response monitoring during concomitant chemoradiotherapy with FDG-PET

Coronin-1C Protein and Caveolin Protein Provide Constitutive and Inducible Mechanisms of Rac1 Protein Trafficking

Sustained directional fibroblast migration requires both polarized activation of the protrusive signal, Rac1, and redistribution of inactive Rac1 from the rear of the cell so that it can be redistributed or degraded. In this work, we determine how alternative endocytic mechanisms dictate the fate of Rac1 in response to the extracellular matrix environment. We discover that both coronin-1C and caveolin retrieve Rac1 from similar locations at the rear and sides of the cell. We find that coronin-1C-mediated extraction, which is responsible for Rac1 recycling, is a constitutive process that maintains Rac1 protein levels within the cell. In the absence of coronin-1C, the effect of caveolin-mediated endocytosis, which targets Rac1 for proteasomal degradation, becomes apparent. Unlike constitutive coronin-1C-mediated trafficking, caveolin-mediated Rac1 endocytosis is induced by engagement of the fibronectin receptor syndecan-4. Such an inducible endocytic/degradation mechanism would predict that, in the presence of fibronectin, caveolin defines regions of the cell that are resistant to Rac1 activation but, in the absence of fibronectin leaves more of the membrane susceptible to Rac1 activation and protrusion. Indeed, we demonstrate that fibronectin-stimulated activation of Rac1 is accelerated in the absence of caveolin and that, when caveolin is knocked down, polarization of active Rac1 is lost in FRET experiments and culminates in shunting migration in a fibrous fibronectin matrix. Although the concept of polarized Rac1 activity in response to chemoattractants has always been apparent, our understanding of the balance between recycling and degradation explains how polarity can be maintained when the chemotactic gradient has faded

Impact of combined 18F-FDG PET/CT in head and neck tumours

To compare the interobserver agreement and degree of confidence in anatomical localisation of lesions using 2-[fluorine-18]fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) and 18F-FDG PET alone in patients with head and neck tumours. A prospective study of 24 patients (16 male, eight female, median age 59 years) with head and neck tumours was undertaken. 18F-FDG PET/CT was performed for staging purposes. 2D images were acquired over the head and neck area using a GE Discovery LS™ PET/CT scanner. 18F-FDG PET images were interpreted by three independent observers. The observers were asked to localise abnormal 18F-FDG activity to an anatomical territory and score the degree of confidence in localisation on a scale from 1 to 3 (1=exact region unknown; 2=probable; 3=definite). For all 18F-FDG-avid lesions, standardised uptake values (SUVs) were also calculated. After 3 weeks, the same exercise was carried out using 18F-FDG PET/CT images, where CT and fused volume data were made available to observers. The degree of interobserver agreement was measured in both instances. A total of six primary lesions with abnormal 18F-FDG uptake (SUV range 7.2–22) were identified on 18F-FDG PET alone and on 18F-FDG PET/CT. In all, 15 nonprimary tumour sites were identified with 18F-FDG PET only (SUV range 4.5–11.7), while 17 were identified on 18F-FDG PET/CT. Using 18F-FDG PET only, correct localisation was documented in three of six primary lesions, while 18F-FDG PET/CT correctly identified all primary sites. In nonprimary tumour sites, 18F-FDG PET/CT improved the degree of confidence in anatomical localisation by 51%. Interobserver agreement in assigning primary and nonprimary lesions to anatomical territories was moderate using 18F-FDG PET alone (kappa coefficients of 0.45 and 0.54, respectively), but almost perfect with 18F-FDG PET/CT (kappa coefficients of 0.90 and 0.93, respectively). We conclude that 18F-FDG PET/CT significantly increases interobserver agreement and confidence in disease localisation of 18F-FDG-avid lesions in patients with head and neck cancers