Functional imaging and radiotherapy

peer reviewedLes progrès technologiques réalisés par l’image- rie médicale l’ont placée au centre de la prise en charge des patients oncologiques, tant au niveau du diagnostic, du pro - nostic et du suivi que dans la prise en charge thérapeutique. En effet, l’imagerie représente, à l’heure actuelle, la pierre angulaire des traitements de radiothérapie. Les objectifs du radiothérapeute sont d’irradier le plus précisément possible la tumeur à dose curative, tout en évitant les organes sains. Pour y arriver, le radiothérapeute utilise de façon routinière l’imagerie anatomique (Scanner et IRM). Depuis quelques années, le développement des différentes imageries métabo - liques et fonctionnelles, comme l’imagerie par émission de positons (PET-CT) et la résonnance magnétique fonctionnelle, ouvrent de nouvelles possibilités thérapeutiques grâce aux informations qu’elles apportent sur la biologie des tumeurs. Cet article décrit, de manière non exhaustive, les différentes imageries anatomiques et métaboliques à la disposition du radiothérapeute

Diffusion MRI for following tumor modifications after neoadjuvant radiotherapy.

Neoadjuvant radiotherapy (NeoRT) improves tumor local control and tumor resection in many cancers. The timing between the end of the NeoRT and surgery is driven by the occurrence of side effects or the tumor downsizing. Some studies demonstrated that the timing of surgery and the RT schedule could influence tumor dissemination and subsequently patient overall survival. We demonstrated the impact of NeoRT on metastatic spreading in a Scid mice model. After an irradiation of 2x5gy, we show more metastasis in the lung when the mice are operated at day 4 compared to day 11. Here, our aim is to evaluate with functional MRI (fMRI) the impact of the radiation treatment on the tumor microenvironment and subsequently to identify non-invasive markers helping to determine the best timing to perform surgery for avoiding tumor spreading

Tumor modifications recorded with IVIM and DCE-MRI after Neoadjuvant radiotherapy.

Purpose or Objective Neoadjuvant radiotherapy (NeoRT) improves tumor local control and facilitates tumor resection in many cancers. We hypothesized anti-cancer treatments (i.e. radiotherapy) modify tumor microenvironment and could potentially impact distant metastases occurrence. Previously, we developed a pre-clinical model demonstrating an impact of NeoRT schedule and the timing of surgery on metastatic spreading (Leroi et al. Oncotarget 2015). Here, we aim to identify by fMRI noninvasive markers reflecting NeoRT related tumor microenvironment modifications that could predict the best timing for performing surgery and avoiding tumor spreading. Material and Methods To briefly delineate the NeoRT model, MDA-MB 231 tumor cells implanted in the flank of SCID mice were locally irradiated with 2x5Gy when tumor reached 100mm3 and then surgically removed at different time points. We performed fMRI, Diffusion Weighted (DW) and Dynamic Contract enhancement (DCE) – MRI, before RT and every 2 days between RT and surgery. We acquired 8 slices of 1 mm thickness and 0.5 mm gap with an “in plane voxel resolution” of 0.5 mm. For DW-MRI, we performed FSEMS (Fast Spin Echo MultiSlice) sequences, with 9 different Bvalue (from 40 to 1000) and B0. We performed IVIM (IntraVoxel Incoherent Motion) analysis to obtain information on intravascular diffusion, related to perfusion (F: perfusion factor) and subsequently tumor vessels perfusion. For DCE-MRI, we performed a T1 mapping with multiple TR and DCE acquisition with 200 repetitions of 3 sec each and gadolinium IV injection after 10 repetitions. We performed semi-quantitative analysis. We validated tumor perfusion by immunochemistry with injection of FITC-dextran IV 3 min before surgery and CD31 labelling. Human Ki67 was used for lung metastases labelling and quantification. Results After the tumor irradiation, we observed a significant and transient increase at day 6 (60% of the basal value (n=6, p<0,05)) of F and D* parameters related to perfusion. The other parameters of the DW-MRI, ADC and D presented no modifications. The sham irradiated tumors used as control showed no modifications of all fMRI parameters. At the same timing, 6 days post-radiotherapy, DCE-MRI significantly demonstrated a WhashinSlope (n=13, p<0,05) increase. Immunochemistry confirmed the increase of tumor perfusion when surgery is performed at day 6. The sham irradiated tumors never demonstrated such changes. Finally, when surgery is performed on tumor increased perfusion measured by fMRI, it demonstrated a burst of lung metastasis compared to the other timings. Conclusion We showed a significant difference in perfusion-related parameters with fMRI and immunochemistry at a specific time point after NeoRT. These modifications are correlated with an increase of metastasis spreading related to surgery procedure. These results open new perspectives in the personalized medicine and MRI guided surgery timing after NeoRT

Renversement des hétérogénéités spatiale et temporelle de la perfusion tumorale identifie la tumeur tonus vasculaire comme une variable ajustable pour améliorer la prestation de drogue

peer reviewedMaturation de la vascularisation tumorale implique le recrutement de péricytes qui protègent les tubes endothéliales provenant de diverses contraintes, y compris les médicaments anti-angiogéniques. Mural cells also provide mature tumor blood vessels with the ability to either relax or contract in response to substances present in the tumor microenvironment. cellules murale également fournir d'âge mûr vaisseaux sanguins des tumeurs avec la possibilité de détendre ou se contracter en réponse à des substances présentes dans le microenvironnement de la tumeur. The observed cyclic alterations in tumor blood flow and the associated deficit in chemotherapeutic drug delivery could in part arise from this vasomodulatory influence. To test this hypothesis, we focused on endothelin-1 (ET-1), which, besides its autocrine effects on tumor cell growth, is a powerful vasoconstrictor. Les cycliques altérations observées dans la circulation sanguine des tumeurs et le déficit lié à la livraison de médicaments chimiothérapeutiques pourrait en partie résulter de cette influence vasomodulatory. Pour tester cette hypothèse, nous nous sommes concentrés sur l'endothéline-1 (ET-1), qui, outre ses effets sur la tumeur autocrine la croissance cellulaire, est un puissant vasoconstricteur. We first document that an ET A receptor antagonist induced relaxation of microdissected tumor arterioles and selectively and quantitatively increased tumor blood flow in experimental tumor models. Nous premier document qu'un antagoniste des récepteurs ET A la relaxation induite par des artérioles tumeur microdisséquées et sélectivement et quantitativement l'augmentation du débit sanguin tumorale dans des modèles expérimentaux de tumeurs. We then combined dye staining of functional vessels, fluorescent microsphere-based mapping, and magnetic resonance imaging to identify heterogeneities in tumor blood flow and to examine the reversibility of such phenomena. Nous avons ensuite combiné de la coloration des vaisseaux fonctionnels, fluorescent à base de microsphères de cartographie et d'imagerie par résonance magnétique pour identifier les hétérogénéités du débit sanguin des tumeurs et d'examiner la réversibilité de ces phénomènes. Data from all these techniques concurred to show that administration of an ET A receptor antagonist could reduce the extent of underperfused tumor areas, proving the key role of vessel tone variations in tumor blood flow heterogeneity. Les données de toutes ces techniques d'accord pour montrer que l'administration d'un antagoniste des récepteurs ET A pourrait réduire l'étendue des zones tumorales underperfused, ce qui prouve le rôle clé du navire variations des flux de ton hétérogénéité sanguins des tumeurs. We also provide evidence that ET A antagonist administration could, despite an increase in tumor interstitial fluid pressure, improve access of cyclophosphamide to the tumor compartment and significantly influence tumor growth. Nous avons également fournir la preuve que l'administration antagoniste ET A pourrait, en dépit d'une augmentation de la tumeur interstitielle pression d'un fluide, d'améliorer l'accès de cyclophosphamide dans le compartiment des tumeurs et une influence significative sur la croissance tumorale. In conclusion, tumor endogenous ET-1 production participates largely in the temporal and spatial variations in tumor blood flow. En conclusion, une tumeur ET-1 endogène de production participe largement à l'espace et les variations temporelles du flux sanguin tumoral. ET A antagonist administration may wipe out such heterogeneities, thus representing an adjuvant strategy that could improve the delivery of conventional chemotherapy to tumors. ET Une administration antagoniste peut effacer ces hétérogénéités, ce qui représente une stratégie adjuvant qui pourraient améliorer la prestation de la chimiothérapie conventionnelle des tumeurs. [Mol Cancer Ther 2006;5(6):1620–7] [Cancer Mol Il 2006; 5 (6) :1620-7]Maturation of tumor vasculature involves the recruitment of pericytes that protect the endothelial tubes from a variety of stresses, including antiangiogenic drugs. Mural cells also provide mature tumor blood vessels with the ability to either relax or contract in response to substances present in the tumor microenvironment. The observed cyclic alterations in tumor blood flow and the associated deficit in chemotherapeutic drug delivery could in part arise from this vasomodulatory influence. To test this hypothesis, we focused on endothelin-1 (ET-1), which, besides its autocrine effects on tumor cell growth, is a powerful vasoconstrictor. We first document that an ETA receptor antagonist induced relaxation of microdissected tumor arterioles and selectively and quantitatively increased tumor blood flow in experimental tumor models. We then combined dye staining of functional vessels, fluorescent microsphere-based mapping, and magnetic resonance imaging to identify heterogeneities in tumor blood flow and to examine the reversibility of such phenomena. Data from all these techniques concurred to show that administration of an ETA receptor antagonist could reduce the extent of underperfused tumor areas, proving the key role of vessel tone variations in tumor blood flow heterogeneity. We also provide evidence that ETA antagonist administration could, despite an increase in tumor interstitial fluid pressure, improve access of cyclophosphamide to the tumor compartment and significantly influence tumor growth. In conclusion, tumor endogenous ET-1 production participates largely in the temporal and spatial variations in tumor blood flow. ETA antagonist administration may wipe out such heterogeneities, thus representing an adjuvant strategy that could improve the delivery of conventional chemotherapy to tumors. [Mol Cancer Ther 2006;5(6):1620–7

Differential Biological Effects of Dietary Lipids and Irradiation on the Aorta, Aortic Valve, and the Mitral Valve

peer reviewedAimsDietary cholesterol and palmitic acid are risk factors for cardiovascular diseases (CVDs) affecting the arteries and the heart valves. The ionizing radiation that is frequently used as an anticancer treatment promotes CVD. The specific pathophysiology of these distinct disease manifestations is poorly understood. We, therefore, studied the biological effects of these dietary lipids and their cardiac irradiation on the arteries and the heart valves in the rabbit models of CVD.Methods and ResultsCholesterol-enriched diet led to the thickening of the aortic wall and the aortic valve leaflets, immune cell infiltration in the aorta, mitral and aortic valves, as well as aortic valve calcification. Numerous cells expressing α-smooth muscle actin were detected in both the mitral and aortic valves. Lard-enriched diet induced massive aorta and aortic valve calcification, with no detectable immune cell infiltration. The addition of cardiac irradiation to the cholesterol diet yielded more calcification and more immune cell infiltrates in the atheroma and the aortic valve than cholesterol alone. RNA sequencing (RNAseq) analyses of aorta and heart valves revealed that a cholesterol-enriched diet mainly triggered inflammation-related biological processes in the aorta, aortic and mitral valves, which was further enhanced by cardiac irradiation. Lard-enriched diet rather affected calcification- and muscle-related processes in the aorta and aortic valve, respectively. Neutrophil count and systemic levels of platelet factor 4 and ent-8-iso-15(S)-PGF2α were identified as early biomarkers of cholesterol-induced tissue alterations, while cardiac irradiation resulted in elevated levels of circulating nucleosomes.ConclusionDietary cholesterol, palmitic acid, and cardiac irradiation combined with a cholesterol-rich diet led to the development of distinct vascular and valvular lesions and changes in the circulating biomarkers. Hence, our study highlights unprecedented specificities related to common risk factors that underlie CVD