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Background The aim of this ancillary study of the SARAH trial is to compare health-related quality of life (HRQoL) in patients with locally advanced or inoperable hepatocellular carcinoma (HCC) treated with transarterial radioembolisation (TARE) or sorafenib. Methods This study included randomised patients who received either TARE or at least one dose of sorafenib with no major deviation in the protocol and who had at least one QoL follow-up assessment in addition to the baseline evaluation. QoL was assessed from the date of randomisation using the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire, until disease progression or other reasons for stopping study participation. Data were analysed using linear mixed and time-dependent models. Results A total of 285 patients were included (122 and 163, in the TARE and sorafenib groups, respectively). Questionnaire completion rates were similar (77.5% versus 80.4%, in the TARE and sorafenib groups, respectively, p = 0.25). Longitudinal HRQoL analysis showed a significant treatment and time effects for fatigue and global health status, and significant treatment, time and treatment by time interaction effects for appetite loss, diarrhoea and social functioning. The median time to deterioration for the global health status was 3.9 months (95% confidence interval [CI] 3.7–4.3) versus 2.6 months (95% CI 2.0–3.0) in the TARE and sorafenib groups, respectively. Conclusions HRQoL was preserved longer with TARE than with sorafenib in locally advanced HCC. These data could be used to optimise management of patients with advanced or inoperable HCC.

International audience; Purpose In Selective Internal Radiation Therapy (SIRT), 99mTc-MAA SPECT images are commonly used to predict microspheres distribution but recent works used 90Y-microspheres PET images. Nevertheless, evaluation of the predictive power of 99mTc-MAA has been hampered by the lack of reliable comparisons between 99mTc-SPECT and 90Y-PET images. Our aim was to determine the “in situ” optimisation procedure in order to reliably compare 99mTc-SPECT and 90Y-PET images and achieve optimal personal dosimetry. Methods We acquired 99mTc-SPECT/CT and 90Y-PET/CT images of NEMA and Jaszczak phantoms. We found the best reconstruction parameters for quantification and for volume estimations. We determined adaptive threshold curves on the volumetric reconstruction. We copied the optimised volumes on the quantitative reconstruction, named here the “cross volumes” technique. Finally, we compared 99mTc-SPECT and 90Y-PET Dose Volume Histograms. Results Our “in situ” optimisation procedure decreased errors on volumes and quantification (from −44.2% and −15.8% to −3.4% and −3.28%, respectively, for the 26.5 mL PET phantom sphere). Moreover, 99mTc-SPECT and 90Y-PET DVHs were equivalent only after the optimisation procedure (difference in mean dose andlt;5% for the three biggest spheres). Conclusions This work showed that a preliminary “in situ” phantom study was necessary to optimise volumes and quantification of 99mTc-SPECT and 90Y-PET images and allowed to achieve a reliable comparison between patient treatment planning and post implant dosimetry, notably by the use of the “cross volumes” technique. Methodology developed in this work will enable robust evaluations of the predictive power of 99mTc-SPECT, as well as dose-response relationship and side effects in SIRT treatments. © 2017 Associazione Italiana di Fisica Medica

Tumor microenvironment is particularly enriched with extracellular ATP (eATP), but conflicting evidence has been provided on its functional effects on tumor growth and vascular remodeling. We have previously shown that high eATP concentrations exert a strong anti-migratory, antiangiogenic and normalizing activity on human tumor-derived endothelial cells (TECs). Since both metabotropic and ionotropic purinergic receptors trigger cytosolic calcium increase ([Ca2+]c), the present work investigated the properties of [Ca2+]c events elicited by high eATP in TECs and their role in anti-migratory activity. In particular, the quantitative and kinetic properties of purinergic-induced Ca2+ release from intracellular stores and Ca2+ entry from extracellular medium were investigated. The main conclusions are: (1) stimulation of TECs with high eATP triggers [Ca2+]c signals which include Ca2+ mobilization from intracellular stores (mainly ER) and Ca2+ entry through the plasma membrane, (2) the long-lasting Ca2+ influx phase requires both store-operated Ca2+ entry (SOCE) and non-SOCE components, (3) SOCE is not significantly involved in the antimigratory effect of high ATP stimulation, (4) ER is the main source for intracellular Ca2+ release by eATP: it is required for the constitutive migratory potential of TECs but is not the only determinant for the inhibitory effect of high eATP, (5) a complex interplay occurs among ER, mitochondria and lysosomes upon purinergic stimulation, (6) high eUTP is unable to inhibit TEC migration and evokes [Ca2+]c signals very similar to those described for eATP. The potential role played by store-independent Ca2+ entry and Ca2+-independent events in the regulation of TEC migration by high purinergic stimula deserves future investigation.

International audience

Purinergic signaling is involved in inflammation and cancer. Extracellular ATP accumulates in tumor interstitium, reaching hundreds micromolar concentrations, but its functional role on tumor vasculature and endothelium is unknown. Here we show that high ATP doses (>20 μM) strongly inhibit migration of endothelial cells from human breast carcinoma (BTEC), but not of normal human microvascular EC. Lower doses (1–10 μM) result ineffective. The anti-migratory activity is associated with cytoskeleton remodeling and is significantly prevented by hypoxia. Pharmacological and molecular evidences suggest a major role for P2X7R and P2Y11R in ATP-mediated inhibition of TEC migration: selective activation of these purinergic receptors by BzATP mimics the anti-migratory effect of ATP, which is in turn impaired by their pharmacological or molecular silencing. Downstream pathway includes calcium-dependent Adenilyl Cyclase 10 (AC10) recruitment, cAMP release and EPAC-1 activation. Notably, high ATP enhances TEC-mediated attraction of human pericytes, leading to a decrease of endothelial permeability, a hallmark of vessel normalization. Finally, we provide the first evidence of in vivo P2X7R expression in blood vessels of murine and human breast carcinoma. In conclusion, we have identified a purinergic pathway selectively acting as an antiangiogenic and normalizing signal for human tumor-derived vascular endothelium.

Genova et al. describe a novel non-channel function for the endogenous TRPM8 as a negative regulator of Rap1 GTPase. TRPM8 retains Rap1GDP intracellularly thus resulting in altered behavior of vascular endothelial cell adhesion and migration., Endothelial cell adhesion and migration are critical steps of the angiogenic process, whose dysfunction is associated with tumor growth and metastasis. The TRPM8 channel has recently been proposed to play a protective role in prostate cancer by impairing cell motility. However, the mechanisms by which it could influence vascular behavior are unknown. Here, we reveal a novel non-channel function for TRPM8 that unexpectedly acts as a Rap1 GTPase inhibitor, thereby inhibiting endothelial cell motility, independently of pore function. TRPM8 retains Rap1 intracellularly through direct protein–protein interaction, thus preventing its cytoplasm–plasma membrane trafficking. In turn, this mechanism impairs the activation of a major inside-out signaling pathway that triggers the conformational activation of integrin and, consequently, cell adhesion, migration, in vitro endothelial tube formation, and spheroid sprouting. Our results bring to light a novel, pore-independent molecular mechanism by which endogenous TRPM8 expression inhibits Rap1 GTPase and thus plays a critical role in the behavior of vascular endothelial cells by inhibiting migration.

Breakdown of the blood-retinal barrier (BRB), as occurs in diabetic retinopathy and other chronic retinal diseases, results in vasogenic edema and neural tissue damage, causing vision loss. Vasoinhibins are N-terminal fragments of prolactin that prevent BRB breakdown during diabetes. They modulate the expression of some transient receptor potential (TRP) family members, yet their role in regulating the TRP vanilloid subtype 4 (TRPV4) remains unknown. TRPV4 is a calcium-permeable channel involved in barrier permeability, which blockade has been shown to prevent and resolve pulmonary edema. We found TRPV4 expression in the endothelium and retinal pigment epithelium (RPE) components of the BRB, and that TRPV4-selective antagonists (RN-1734 and GSK2193874) resolve BRB breakdown in diabetic rats. Using human RPE (ARPE-19) cell monolayers and endothelial cell systems, we further observed that (i) GSK2193874 does not seem to contribute to the regulation of BRB and RPE permeability by vasoinhibins under diabetic or hyperglycemic-mimicking conditions, but that (ii) vasoinhibins can block TRPV4 to maintain BRB and endothelial permeability. Our results provide important insights into the pathogenesis of diabetic retinopathy that will further guide us toward rationally-guided new therapies: synergistic combination of selective TRPV4 blockers and vasoinhibins can be proposed to mitigate diabetes-evoked BRB breakdown.

International audience; To go further in the optimization of treatment planning in selective internal radiation therapy (SIRT), radiobiological aspects can be accounted for with the OEDIPE software and used to design fractionation protocols. Dosimetry was performed using data from 99mTc-MAA evaluations of 10 patients treated for hepatic metastases with SIRT. The maximal injectable activity (MIA) was calculated, using a tolerance criterion on BEDmean,healthyliver equal to 54 Gy2.5, for different fractionation protocols, varying the number of fractions, the repartition of activity and the time delay between fractions. OEDIPE was also used to calculate BEDmean and the EUD to the tumoral liver (TL) that would be delivered with those MIAs. Compared with a single-injection protocol, the MIA is increased on average by 23% ± 3%, 36% ± 5% and 45% ± 7% for fractionation protocols with 2, 3 and 4 equal fractions, respectively, while BEDmean,TL is increased by 15% ± 2%, 23% ± 4% and 29% ± 5%. EUDTL, calculated for one evaluation, is increased by 51%, 115% and 159% using 2, 3 and 4 equal fractions, respectively. For this evaluation, the optimal activity repartition for two-fraction protocols is (3/4-1/4) for time delays of less than 4 days, (2/3-1/3) for time delays between 4 and 6 days and (1/2-1/2) for time delays superior to 6 days. Finally, this study confirmed that OEDIPE can be regarded as a tool for treatment planning optimization and fractionation protocol design in SIRT. © 2014 EDP Sciences.

International audience; For targeted radionuclide therapies, treatment planning usually consists of the administration of standard activities without accounting for the patient-specific activity distribution, pharmacokinetics and dosimetry to organs at risk. The OEDIPE software is a user-friendly interface which has an automation level suitable for performing personalized Monte Carlo 3D dosimetry for diagnostic and therapeutic radionuclide administrations. Mean absorbed doses to regions of interest (ROIs), isodose curves superimposed on a personalized anatomical model of the patient and dose-volume histograms can be extracted from the absorbed dose 3D distribution. Moreover, to account for the differences in radiosensitivity between tumoral and healthy tissues, additional functionalities have been implemented to calculate the 3D distribution of the biologically effective dose (BED), mean BEDs to ROIs, isoBED curves and BED-volume histograms along with the Equivalent Uniform Biologically Effective Dose (EUD) to ROIs. Finally, optimization tools are available for treatment planning optimization using either the absorbed dose or BED distributions. These tools enable one to calculate the maximal injectable activity which meets tolerance criteria to organs at risk for a chosen fractionation protocol. This paper describes the functionalities available in the latest version of the OEDIPE software to perform personalized Monte Carlo dosimetry and treatment planning optimization in targeted radionuclide therapies. © 2014 EDP Sciences.

International audience; In the last decades, selective internal radiation therapy (SIRT) has become a real alternative in the treatment of unresectable hepatic cancers. In practice, the activity prescription is limited by the irradiation of organs at risk (OAR), such as the lungs and nontumoral liver (NTL). Its clinical implementation is therefore highly dependent on dosimetry. In that context, a 3-dimensional personalized dosimetry technique-personalized Monte Carlo dosimetry (PMCD)- based on patient-specific data and Monte Carlo calculations was developed and evaluated retrospectively on clinical data. Methods The PMCD method was evaluated with data from technetium human albumin macroaggregates (99mTc-MAA) evaluations of 10 patients treated for hepatic metastases. Region-of-interest outlines were drawn on CT images to create patient-specific voxel phantoms using the OEDIPE software. Normalized 3-dimensional matrices of cumulated activity were generated from 99mTc-SPECT data. Absorbed doses at the voxel scale were then obtained with the MCNPX Monte Carlo code. The maximum-injectable activity (MIA) for tolerance criteria based on either OAR mean absorbed doses (D mean) or OAR dose-volume histograms (DVHs) was determined using OEDIPE. Those MIAs were compared with the one recommended by the partition model (PM) with Dmean tolerance criteria. Finally, OEDIPE was used to evaluate the absorbed doses delivered if those activities were injected to the patient and to generate the corresponding isodose curves and DVHs. Results The MIA recommended using Dmean tolerance criteria is, in average, 27% higher with the PMCD method than with the PM. If tolerance criteria based on DVHs are used along with the PMCD, an increase of at least 40% of the MIA is conceivable, compared with the PM. For MIAs calculated with the PMCD, D mean delivered to tumoral liver (TL) ranged from 19.5 to 118 Gy for Dmean tolerance criteria whereas they ranged from 26.6 to 918 Gy with DVH tolerance criteria. Thus, using the PMCD method, which accounts for fixation heterogeneities, higher doses can be delivered to TL. Finally, absorbed doses to the lungs are not the limiting criterion for activity prescription. However, Dmean to the lungs can reach 15.0 Gy. Conclusion Besides its feasibility and applicability in clinical routine, the interest for treatment optimization of a personalized Monte Carlo dosimetry in the context of SIRT was confirmed in this study. © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Breakdown of the blood-retinal barrier (BRB), as occurs in diabetic retinopathy and other chronic retinal diseases, results in vasogenic edema and neural tissue damage, causing vision loss. Vasoinhibins are N-terminal fragments of prolactin that prevent BRB breakdown during diabetes. They modulate the expression of some transient receptor potential (TRP) family members, yet their role in regulating the TRP vanilloid subtype 4 (TRPV4) remains unknown. TRPV4 is a calcium-permeable channel involved in barrier permeability, which blockade has been shown to prevent and resolve pulmonary edema. We found TRPV4 expression in the endothelium and retinal pigment epithelium (RPE) components of the BRB, and that TRPV4-selective antagonists (RN-1734 and GSK2193874) resolve BRB breakdown in diabetic rats. Using human RPE (ARPE-19) cell monolayers and endothelial cell systems, we further observed that (i) GSK2193874 does not seem to contribute to the regulation of BRB and RPE permeability by vasoinhibins under diabetic or hyperglycemic-mimicking conditions, but that (ii) vasoinhibins can block TRPV4 to maintain BRB and endothelial permeability. Our results provide important insights into the pathogenesis of diabetic retinopathy that will further guide us toward rationally-guided new therapies: synergistic combination of selective TRPV4 blockers and vasoinhibins can be proposed to mitigate diabetes-evoked BRB breakdown.

Despite the intensive research of the last three decades into Transient Receptor Potential (TRP) cation channels, no precise and complete profiling of these channels is yet available regarding their involvement in physiopathology and carcinogenesis in particular. TRP channel activity is crucial for all the essential hallmarks of carcinogenesis such as proliferation, apoptosis, migration and angiogenesis, which is the reason why these channels have been proposed not only as clinical markers, but also as promising targets for anti-cancer therapy. However, in the majority of studies, each channel has been considered as a separate molecular entity and studied independently from the other TRPs, while a complete "transportome" of the specific stages of carcinogenesis is required for the effective use of these targets. This review focuses on the partial TRP expression profiles found in the literature and the means by which a full TRP signature could be achieved.

International audience; Different methods to calculate 90Y resin microspheres activity for Selective Internal Radiation Therapy (SIRT) were compared. Such comparison is not yet available and is needed in clinical practice to optimize patient specific treatment planning.32 99mTc-macroagregates (MAA) evaluations were performed, followed by 26 treatments. Four methods to calculate 90Y-activity were applied retrospectively three based on Body Surface Area and one based on MIRD formalism, partition model (PM). Relationships between calculated activities, lung breakthrough (LB), the activity concentration ratio between lesions and healthy liver (T/N) and tumour involvement were investigated, where lobar and whole liver treatments were analysed separately.Without attenuation correction, overestimation of LB was 65%. In any case, the estimated lungs' doses remained below 30Gy. Thus, the maximal injectable activity (MIA) is not limited by lungs' irradiation. Moreover, LB was not significantly related to T/N, neither to tumour involvement nor radiochemical purity (RP).Differences in calculated activity with the four methods were extremely large, in particular they were greater between BSA-based and PM activities for lobar treatments (from-85% to 417%) compared to whole liver treatments (from-49% to 61%). Two values of T/N ratio were identified as thresholds for BSA-based methods, healthy liver doses are much higher than 30Gy when T/Nandlt;3; for PM, tumour doses are higher than 120Gy when T/N andgt; 4. As PM accounts for uptake ratio between normal and tumour liver, this method should be employed over BSA-based methods. © 2014 Associazione Italiana di Fisica Medica.

Purpose: With a growing demand of alpha-emitting radiopharmaceuticals, especially Xofigo ({sup 223}RaCl{sub 2}) which is used in the treatment of metastatic bone disease, the optimization of dosimetry becomes necessary. Indeed, in Europe, as stated on the council directive 2013/59/euratom, exposures of target volumes for radiotherapeutic purposes shall be individually planned taking into account that doses to non-target volumes and tissues shall be as low as reasonably achievable. To that aim, the possibility of imaging {sup 223}Ra was first investigated. Methods: The experiments were conducted at the Hopital Europeen Georges Pompidou with an Infinia Hawkeye 4 gamma camera, equipped with a medium-energy collimator. Imaging parameters, such as sensibility, spatial resolution and energy spectrum, were determined using several physical phantoms with a source of 6 MBq of {sup 223}Ra. Bone metastases were modeled with a NEMA Body Phantom to investigate image degradation based on the concentration of {sup 223}Ra. Results: The acquired energy spectrum allowed to visualize several photon peaks: at 85, 154 and 270 keV. Camera sensitivity measured from the phantom study was 102.3 cps/MBq for the 85 keV ± 20 %, 89.9 cps/MBq for the 154 ± 20 % window and 65.4 cps/MBq for the 270 ± 10 % window.more » The spatial resolution (full-width at half-maximum) was respectively 1.7, 1.9 and 1.8 cm for the three energy windows. SPECT/CT images of NEMA Body Phantom without and with attenuation have permitted to determine the best reconstruction parameters. Conclusion: This study has demonstrated that it is possible to obtain clinically relevant information from images of {sup 223}Ra. All these results will be valuable to analyze biodistribution imaging of the radiopharmaceutical in the patient body and go further in the reconstruction of patient images in order to personalize the dosimetry.« less

Introduction For targeted radiation therapies, treatment planning is a real challenge. In fact, the activity that can be injected to the patient is limited by the dose to organs at risk (OARs) which has to be kept below the tolerance threshold. Therefore, a 3D dosimetric method (PMCD), based on Monte Carlo calculations, has been developed in order to personalize and optimize the activity prescription for Selective Internal Radiotherapy (SIRT) treatments. Methods The PMCD method was used with data from 10 patients treated for hepatic metastases. Using the OEDIPE software, regions of interest outlines, drawn on CT images, were used to create patient-specific voxel phantoms and 99mTc-MAA SPECT data were used to generate 3D-matrices of cumulated activity. The absorbed dose and biological effective dose (BED) were calculated at the voxel scale using the MCNPX Monte Carlo transport code and OEDIPE. The maximum injectable activity (MIA) was then calculated using OEDIPE depending on tolerance criteria on OARs based on mean absorbed doses, mean BED, Dose-Volume Histograms (DVHs) or BED-Volume Histograms (BVHs). Those MIAs were compared to the ones recommended by conventional methods: the Body Surface Area (BSA) method and the Partition Model with tolerance criteria on mean absorbed doses. Results Performing a personalized dosimetry using the PMCD method enables to increase the activity prescription while ensuring OARs’ radiation protection. Moreover, considering tolerance criteria based on DVHs further enhances treatment planning efficiency by taking advantage of the parallel characteristic of the liver and the lungs whose functions are not impaired if the level of irradiation to a fraction of the organ is kept below the tolerance threshold. Finally, tolerance criteria on mean BED and BVHs further improve treatment planning by taking into account biological considerations such as cell repair, radiosensibility or dose-rate distribution. Conclusion Besides its feasibility and applicability in clinical routine, the interest of a personalized Monte Carlo dosimetry for treatment planning in 90Y-microspheres therapies was confirmed from those patient studies.