Translational molecular imaging in exocrine pancreatic cancer

Effective treatment for pancreatic cancer remains challenging, particularly the treatment of pancreatic ductal adenocarcinoma (PDAC), which makes up more than 95% of all pancreatic cancers. Late diagnosis and failure of chemotherapy and radiotherapy are all too common, and many patients die soon after diagnosis. Here, we make the case for the increased use of molecular imaging in PDAC preclinical research and in patient management

Translational molecular imaging in exocrine pancreatic cancer

Effective treatment for pancreatic cancer remains challenging, particularly the treatment of pancreatic ductal adenocarcinoma (PDAC), which makes up more than 95% of all pancreatic cancers. Late diagnosis and failure of chemotherapy and radiotherapy are all too common, and many patients die soon after diagnosis. Here, we make the case for the increased use of molecular imaging in PDAC preclinical research and in patient management

Translational approach to radiopharmaceutical development

International audienceNuclear medicine, which encompasses the medical field of molecular imaging and radionuclide therapy, brings together many disciplines, and radiopharmacy requires that pharmacy, physics and medicine work together within a synergetic environment. It is undeniable that within nuclear medicine the baseline of any good procedure is the design and preparation of the radioactive pharmaceutical, referred to as the radiopharmaceutical

Differential dopamine receptor occupancy underlies L-DOPA-induced dyskinesia in a rat model of Parkinson's disease.

Dyskinesia is a major side effect of an otherwise effective L-DOPA treatment in Parkinson's patients. The prevailing view for the underlying presynaptic mechanism of L-DOPA-induced dyskinesia (LID) suggests that surges in dopamine (DA) via uncontrolled release from serotonergic terminals results in abnormally high level of extracellular striatal dopamine. Here we used high-sensitivity online microdialysis and PET imaging techniques to directly investigate DA release properties from serotonergic terminals both in the parkinsonian striatum and after neuronal transplantation in 6-OHDA lesioned rats. Although L-DOPA administration resulted in a drift in extracellular DA levels, we found no evidence for abnormally high striatal DA release from serotonin neurons. The extracellular concentration of DA remained at or below levels detected in the intact striatum. Instead, our results showed that an inefficient release pool of DA associated with low D2 receptor binding remained unchanged. Taken together, these findings suggest that differential DA receptor activation rather than excessive release could be the underlying mechanism explaining LID seen in this model. Our data have important implications for development of drugs targeting the serotonergic system to reduce DA release to manage dyskinesia in patients with Parkinson's disease

Generation of fluorescently labeled tracers – which features influence the translational potential?

International audienceGiven the increasing exploration of fluorescent tracers in the field of nuclear medicine, a need has risen for practical development guidelines that can help improve the translation aspects of fluorescent tracers. This editorial discusses the does and don'ts in developing fluorescence tracers. It has been put forward by the European Association of Nuclear Medicine (EANM) Translational Molecular Imaging & Therapy committee and has been approved by the EANM board

« New Modalities in Cancer Imaging and Therapy » XVe édition de l’atelier organisé par le réseau « Vectorisation, Imagerie, Radiothérapies » du Cancéropôle Grand-Ouest, 5–8 octobre 2022, Erquy, France

National audienceThe fifteenth edition of the international workshop organized by the "Tumour Targeting and Radiotherapies network" of the Cancéropôle Grand-Ouest focused on the latest advances in internal and external radiotherapy from different disciplinary angles: chemistry, biology, physics, and medicine. The workshop covered several deliberately diverse topics: the role of artificial intelligence, new tools for imaging and external radiotherapy, theranostic aspects, molecules and contrast agents, vectors for innovative combined therapies, and the use of alpha particles in therapy

Assessment of changes in extracellular DA levels following L-DOPA injection.

<p>Animals were subjected to on-line microdialysis measurements either under baseline conditions, or following a systemic injection of 12 mg/kg L-DOPA without any perturbation of the release sites using release-inducing drugs. Time course data is shown in A, while quantification of the two phases (4 time bins in each case) is given in panel B (Two-way ANOVA, F (7,27) = 12.15, p<0.001; followed by pairwise comparison adjusted using Bonferroni, p<0.0071). Panel C illustrates the dyskinesia rating scores obtained during the OMD experiment as the animals were sampled in awake and freely moving state. Panel D shows the integrated AIMs data from this session (One-way ANOVA, F (2,10) = 13.11, p = 0.003; followed by pairwise comparison adjusted using Bonferroni, p<0.017). Note that the dyskinesia seen in lesion and 5HT groups occur in the absence of supra-normal DA levels as detected by the probe in the striatum *: Different from baseline; +: different from intact; #: different from lesion and 5HT groups.</p

Cell Tracking in Cancer Immunotherapy

International audienceThe impressive development of cancer immunotherapy in the last few years originates from a more precise understanding of control mechanisms in the immune system leading to the discovery of new targets and new therapeutic tools. Since different stages of disease progression elicit different local and systemic inflammatory responses, the ability to longitudinally interrogate the migration and expansion of immune cells throughout the whole body will greatly facilitate disease characterization and guide selection of appropriate treatment regiments. While using radiolabeled white blood cells to detect inflammatory lesions has been a classical nuclear medicine technique for years, new non-invasive methods for monitoring the distribution and migration of biologically active cells in living organisms have emerged. They are designed to improve detection sensitivity and allow for a better preservation of cell activity and integrity. These methods include the monitoring of therapeutic cells but also of all cells related to a specific disease or therapeutic approach. Labeling of therapeutic cells for imaging may be performed in vitro, with some limitations on sensitivity and duration of observation. Alternatively, in vivo cell tracking may be performed by genetically engineering cells or mice so that may be revealed through imaging. In addition, SPECT or PET imaging based on monoclonal antibodies has been used to detect tumors in the human body for years. They may be used to detect and quantify the presence of specific cells within cancer lesions. These methods have been the object of several recent reviews that have concentrated on technical aspects, stressing the differences between direct and indirect labeling. They are briefly described here by distinguishing ex vivo (labeling cells with paramagnetic, radioactive, or fluorescent tracers) and in vivo (in vivo capture of injected radioactive, fluorescent or luminescent tracers, or by using labeled antibodies, ligands, or pre-targeted clickable substrates) imaging methods. This review focuses on cell tracking in specific therapeutic applications, namely cell therapy, and particularly CAR (Chimeric Antigen Receptor) T-cell therapy, which is a fast-growing research field with various therapeutic indications. The potential impact of imaging on the progress of these new therapeutic modalities is discussed

Anti-Tumor Efficacy of PD-L1 Targeted Alpha-Particle Therapy in a Human Melanoma Xenograft Model

International audiencePD-L1 (programmed death-ligand 1, B7-H1, CD274), the ligand for PD-1 inhibitory receptor, is expressed on various tumors, and its expression is correlated with a poor prognosis in melanoma. Anti-PD-L1 mAbs have been developed along with anti-CTLA-4 and anti-PD-1 antibodies for immune checkpoint inhibitor (ICI) therapy, and anti-PD-1 mAbs are now used as first line treatment in melanoma. However, many patients do not respond to ICI therapies, and therefore new treatment alternatives should be developed. Because of its expression on the tumor cells and on immunosuppressive cells within the tumor microenvironment, PD-L1 represents an interesting target for targeted alpha-particle therapy (TAT). We developed a TAT approach in a human melanoma xenograft model that stably expresses PD-L1 using a 213Bi-anti-human-PD-L1 mAb. Unlike treatment with unlabeled anti-human-PD-L1 mAb, TAT targeting PD-L1 significantly delayed melanoma tumor growth and improved animal survival. A slight decrease in platelets was observed, but no toxicity on red blood cells, bone marrow, liver or kidney was induced. Anti-tumor efficacy was associated with specific tumor targeting since no therapeutic effect was observed in animals bearing PD-L1 negative melanoma tumors. This study demonstrates that anti-PD-L1 antibodies may be used efficiently for TAT treatment in melanoma

Analysis of FosB induction.

<p>The numbers of FosB/δFosB -positive cells in the striatum were assessed on a single coronal section corresponding to level +1.2 mm from bregma. Digital images were taken from the dorsolateral striatum. 6OHDA lesion group and 5HT graft animals showed significant increase in the induction number of FosB/δFosB positive profiles while in DA grafts this remained very low and similar to intact striatum (Two-way ANOVA F (5,46) = 75.05, p<0.001; followed by pairwise comparison adjusted using Bonferroni, p<0.0083). *: Different from intact side and DA grafts. Scale bar in panel D represents 50 µm and applies to all panels.</p