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1. CYRAD: a translational study assessing immune response to radiotherapy by photons or protons in postoperative head and neck cancer patients through circulating leukocyte subpopulations and cytokine levels

Author

Juliette Thariat, Thao-Nguyen Pham, Julie Coupey, Benedicte Clarisse, Jean-Michel Grellard, Nathalie Rousseau, Mathieu Césaire, and Samuel Valable

Subjects
Radiotherapy, Photons, Protons, Lymphopenia, Myeloid, Lymphoid, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Radiotherapy has both immunostimulant and immunosuppressive effects, particularly in radiation-induced lymphopenia. Proton therapy has demonstrated potential in mitigating this lymphopenia, yet the mechanisms by which different types of radiation affect the immune system function are not fully characterized. The Circulating Immunes Cells, Cytokines and Brain Radiotherapy (CYRAD) trial aims to compare the effects of postoperative X-ray and proton radiotherapy on circulating leukocyte subpopulations and cytokine levels in patients with head and neck (CNS and ear nose throat) cancer. Methods CYRAD is a prospective, non-randomized, single-center non interventional study assessing changes in the circulating leukocyte subpopulations and cytokine levels in head and neck cancer patients receiving X-ray or proton radiotherapy following tumor resection. Dosimetry parameters, including dose deposited to organs-at-risk such as the blood and cervical lymph nodes, are computed. Participants undergo 29 to 35 radiotherapy sessions over 40 to 50 days, followed by a 3-month follow-up. Blood samples are collected before starting radiotherapy (baseline), before the 11th (D15) and 30th sessions (D40), and three months after completing radiotherapy. The study will be conducted with 40 patients, in 2 groups of 20 patients per modality of radiotherapy (proton therapy and photon therapy). Statistical analyses will assess the absolute and relative relationship between variations (depletion, recovery) in immune cells, biomarkers, dosimetry parameters and early outcomes. Discussion Previous research has primarily focused on radiation-induced lymphopenia, paying less attention to the specific impacts of radiation on different lymphoid and myeloid cell types. Early studies indicate that X-ray and proton irradiation may lead to divergent outcomes in leukocyte subpopulations within the bloodstream. Based on these preliminary findings, this study aims to refine our understanding of how proton therapy can better preserve immune function in postoperative (macroscopic tumor-free) head and neck cancer patients, potentially improving treatment outcomes. Protocol version Version 2.1 dated from January 18, 2023. Trial registration The CYRAD trial is registered from October 19, 2021, at the US National Library of Medicine, ClinicalTrials.gov ID NCT05082961.

Published
2024
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2. Deformation-based morphometry: a sensitive imaging approach to detect radiation-induced brain injury?

Author

Carole Brunaud, Samuel Valable, Gwenn Ropars, Fatima-Azzahra Dwiri, Mikaël Naveau, Jérôme Toutain, Myriam Bernaudin, Thomas Freret, Marianne Léger, Omar Touzani, and Elodie A. Pérès

Subjects
Radiotherapy, Brain, Magnetic resonance imaging, Deformation-based morphometry, Macrostructural changes, Medical physics. Medical radiology. Nuclear medicine, R895-920, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Radiotherapy is a major therapeutic approach in patients with brain tumors. However, it leads to cognitive impairments. To improve the management of radiation-induced brain sequalae, deformation-based morphometry (DBM) could be relevant. Here, we analyzed the significance of DBM using Jacobian determinants (JD) obtained by non-linear registration of MRI images to detect local vulnerability of healthy cerebral tissue in an animal model of brain irradiation. Methods Rats were exposed to fractionated whole-brain irradiation (WBI, 30 Gy). A multiparametric MRI (anatomical, diffusion and vascular) study was conducted longitudinally from 1 month up to 6 months after WBI. From the registration of MRI images, macroscopic changes were analyzed by DBM and microscopic changes at the cellular and vascular levels were evaluated by quantification of cerebral blood volume (CBV) and diffusion metrics including mean diffusivity (MD). Voxel-wise comparisons were performed on the entire brain and in specific brain areas identified by DBM. Immunohistology analyses were undertaken to visualize the vessels and astrocytes. Results DBM analysis evidenced time-course of local macrostructural changes; some of which were transient and some were long lasting after WBI. DBM revealed two vulnerable brain areas, namely the corpus callosum and the cortex. DBM changes were spatially associated to microstructural alterations as revealed by both diffusion metrics and CBV changes, and confirmed by immunohistology analyses. Finally, matrix correlations demonstrated correlations between JD/MD in the early phase after WBI and JD/CBV in the late phase both in the corpus callosum and the cortex. Conclusions Brain irradiation induces local macrostructural changes detected by DBM which could be relevant to identify brain structures prone to radiation-induced tissue changes. The translation of these data in patients could represent an added value in imaging studies on brain radiotoxicity.

Published
2024
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3. Hypoxia-induced activation of NDR2 underlies brain metastases from Non-Small Cell Lung Cancer

Author

Jérôme Levallet, Tiphaine Biojout, Céline Bazille, Manon Douyère, Fatéméh Dubois, Dimitri Leite Ferreira, Jasmine Taylor, Sylvain Teulier, Jérôme Toutain, Nicolas Elie, Myriam Bernaudin, Samuel Valable, Emmanuel Bergot, and Guénaëlle Levallet

Subjects
Cytology, QH573-671
Abstract

Abstract The molecular mechanisms induced by hypoxia are misunderstood in non-small cell lung cancer (NSCLC), and above all the hypoxia and RASSF1A/Hippo signaling relationship. We confirmed that human NSCLC (n = 45) as their brain metastases (BM) counterpart are hypoxic since positive with CAIX-antibody (target gene of Hypoxia-inducible factor (HIF)). A severe and prolonged hypoxia (0.2% O2, 48 h) activated YAP (but not TAZ) in Human Bronchial Epithelial Cells (HBEC) lines by downregulating RASSF1A/kinases Hippo (except for NDR2) regardless their promoter methylation status. Subsequently, the NDR2-overactived HBEC cells exacerbated a HIF-1A, YAP and C-Jun-dependent-amoeboid migration, and mainly, support BM formation. Indeed, NDR2 is more expressed in human tumor of metastatic NSCLC than in human localized NSCLC while NDR2 silencing in HBEC lines (by shRNA) prevented the xenograft formation and growth in a lung cancer-derived BM model in mice. Collectively, our results indicated that NDR2 kinase is over-active in NSCLC by hypoxia and supports BM formation. NDR2 expression is thus a useful biomarker to predict the metastases risk in patients with NSCLC, easily measurable routinely by immunohistochemistry on tumor specimens.

Published
2023
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4. Assessment of hypoxia and oxidative-related changes in a lung-derived brain metastasis model by [64Cu][Cu(ATSM)] PET and proteomic studies

Author

Jade Fantin, Jérôme Toutain, Elodie A. Pérès, Benoit Bernay, Sarina Maya Mehani, Charly Helaine, Mickael Bourgeois, Carole Brunaud, Laurent Chazalviel, Julien Pontin, Aurélien Corroyer-Dulmont, Samuel Valable, Michel Cherel, and Myriam Bernaudin

Subjects
Brain metastasis, Lung cancer, Hypoxia, HIF, Oxidative stress, Cu-ATSM, Medical physics. Medical radiology. Nuclear medicine, R895-920
Abstract

Abstract Background Brain metastases (BM) are the most frequent malignant brain tumors. The aim of this study was to characterize the tumor microenvironment (TME) of BM and particularly hypoxia and redox state, known to play a role in tumor growth and treatment resistance with multimodal PET and MRI imaging, immunohistochemical and proteomic approaches in a human lung cancer (H2030-BrM3)-derived BM model in rats. Results First, in vitro studies confirmed that H2030-BrM3 cells respond to hypoxia with increasing expression of HIF-1, HIF-2 and their target genes. Proteomic analyses revealed, among expression changes, proteins associated with metabolism, oxidative stress, metal response and hypoxia signaling in particular in cortical BM. [64Cu][Cu(ATSM)] PET revealed a significant uptake by cortical BM (p

Published
2023
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5. Radiosensitizing Effect of PARP Inhibition on Chondrosarcoma and Chondrocyte Cells Is Dependent on Radiation LET

Author

Antoine Gilbert, Mihaela Tudor, Amandine Delaunay, Raphaël Leman, Julien Levilly, Alexandre Atkinson, Laurent Castéra, Anca Dinischiotu, Diana Iulia Savu, Samuel Valable, and François Chevalier

Subjects
carbon ion irradiation, chondrosarcoma, PARP inhibitor, DNA damages, Microbiology, QR1-502
Abstract

Chondrosarcoma is a rare malignant tumor that forms in bone and cartilage. The primary treatment involves surgical removal of the tumor with a margin of healthy tissue. Especially if complete surgical removal is not possible, radiation therapy and chemotherapy are used in conjunction with surgery, but with a generally low efficiency. Ongoing researches are focused on understanding the genetic and molecular basis of chondrosarcoma following high linear energy transfer (LET) irradiation, which may lead to treatments that are more effective. The goal of this study is to evaluate the differential effects of DNA damage repair inhibitors and high LET irradiation on chondrosarcoma versus chondrocyte cells and the LET-dependency of the effects. Two chondrosarcoma cell lines with different IDH mutation status and one chondrocyte cell line were exposed to low LET (X-ray) and high LET (carbon ion) irradiation in combination with an Olaparib PARP inhibitor. Cell survival and DNA repair mechanisms were investigated. High LET irradiation drastically reduced cell survival, with a biological efficiency three times that of low LET. Olaparib significantly inhibited PARylation in all the tested cells. A significant reduction in cell survival of both chondrosarcoma and chondrocyte cells was observed following the treatment combining Olaparib and X-ray. PARP inhibition induced an increase in PARP-1 expression and a reduced effect on the cell survival of WT IDH chondrosarcoma cells. No radiosensitizing effect was observed in cells exposed to Olaparib paired with high LET irradiation. NHEJ was activated in response to high LET irradiation, neutralizing the PARP inhibition effect in both chondrosarcoma cell lines. When high LET irradiation is not available, PARP inhibition could be used in combination with low LET irradiation, with significant radiosensitizing effects on chondrosarcoma cells. Chondrocytes may be affected by the treatment combination too, showing the need to preserve normal tissues from radiation fields when this kind of treatment is suggested.

Published
2024
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6. Beyond lymphopenia, unraveling radiation-induced leucocyte subpopulation kinetics and mechanisms through modeling approaches

Author

Thao-Nguyen Pham, Julie Coupey, Serge M. Candeias, Viktoriia Ivanova, Samuel Valable, and Juliette Thariat

Subjects
Radiotherapy, Modeling, Leucopenia, Lymphopenia, Myelosuppression, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Leucocyte subpopulations in both lymphoid and myeloid lineages have a significant impact on antitumor immune response. While radiation-induced lymphopenia is being studied extensively, radiation effects on lymphoid and myeloid subtypes have been relatively less addressed. Interactions between leucocyte subpopulations, their specific radiation sensitivity and the specific kinetics of each subpopulation can be modeled based on both experimental data and knowledge of physiological leucocyte depletion, production, proliferation, maturation and homeostasis. Modeling approaches of the leucocyte kinetics that may be used to unravel mechanisms underlying radiation induced-leucopenia and prediction of changes in cell counts and compositions after irradiation are presented in this review. The approaches described open up new possibilities for determining the influence of irradiation parameters both on a single-time point of acute effects and the subsequent recovery of leukocyte subpopulations. Utilization of these approaches to model kinetic data in post-radiotherapy states may be a useful tool for further development of new treatment strategies or for the combination of radiotherapy and immunotherapy.

Published
2023
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7. Multimodal evaluation of hypoxia in brain metastases of lung cancer and interest of hypoxia image-guided radiotherapy

Author

Aurélien Corroyer-Dulmont, Samuel Valable, Jade Fantin, Laurent Chatre, Jérôme Toutain, Sylvain Teulier, Céline Bazille, Elise Letissier, Jérôme Levallet, Didier Divoux, Méziane Ibazizène, Stéphane Guillouet, Cécile Perrio, Louisa Barré, Sébastien Serres, Nicola R. Sibson, Françoise Chapon, Guénaëlle Levallet, and Myriam Bernaudin

Subjects
Medicine, Science
Abstract

Abstract Lung cancer patients frequently develop brain metastases (BM). Despite aggressive treatment including neurosurgery and external-radiotherapy, overall survival remains poor. There is a pressing need to further characterize factors in the microenvironment of BM that may confer resistance to radiotherapy (RT), such as hypoxia. Here, hypoxia was first evaluated in 28 biopsies from patients with non‑small cell lung cancer (NSCLC) BM, using CA-IX immunostaining. Hypoxia characterization (pimonidazole, CA-IX and HIF-1α) was also performed in different preclinical NSCLC BM models induced either by intracerebral injection of tumor cells (H2030-Br3M, H1915) into the cortex and striatum, or intracardial injection of tumor cells (H2030-Br3M). Additionally, [18F]-FMISO-PET and oxygen-saturation-mapping-MRI (SatO2-MRI) were carried out in the intracerebral BM models to further characterize tumor hypoxia and evaluate the potential of Hypoxia-image-guided-RT (HIGRT). The effect of RT on proliferation of BM ([18F]-FLT-PET), tumor volume and overall survival was determined. We showed that hypoxia is a major yet heterogeneous feature of BM from lung cancer both preclinically and clinically. HIGRT, based on hypoxia heterogeneity observed between cortical and striatal metastases in the intracerebrally induced models, showed significant potential for tumor control and animal survival. These results collectively highlight hypoxia as a hallmark of BM from lung cancer and the value of HIGRT in better controlling tumor growth.

Published
2021
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8. 64Cu-ATSM/64Cu-Cl2 and their relationship to hypoxia in glioblastoma: a preclinical study

Author

Elodie A. Pérès, Jérôme Toutain, Louis-Paul Paty, Didier Divoux, Méziane Ibazizène, Stéphane Guillouet, Louisa Barré, Aurélien Vidal, Michel Cherel, Mickaël Bourgeois, Myriam Bernaudin, and Samuel Valable

Subjects
Hypoxia, Brain tumors, Cu-ATSM, PET radiotracers, Copper transporters, Medical physics. Medical radiology. Nuclear medicine, R895-920
Abstract

Abstract Background Diacetyl-bis(N4-methylthiosemicarbazone), labeled with 64Cu (64Cu-ATSM) has been suggested as a promising tracer for imaging hypoxia. However, various controversial studies highlighted potential pitfalls that may disable its use as a selective hypoxic marker. They also highlighted that the results may be tumor location dependent. Here, we first analyzed uptake of Cu-ATSM and its less lipophilic counterpart Cu-Cl2 in the tumor over time in an orthotopic glioblastoma model. An in vitro study was also conducted to investigate the hypoxia-dependent copper uptake in tumor cells. We then further performed a comprehensive ex vivo study to compare 64Cu uptake to hypoxic markers, specific cellular reactions, and also transporter expression. Methods μPET was performed 14 days (18F-FMISO), 15 days (64Cu-ATSM and 64Cu-Cl2), and 16 days (64Cu-ATSM and 64Cu-Cl2) after C6 cell inoculation. Thereafter, the brains were withdrawn for further autoradiography and immunohistochemistry. C6 cells were also grown in hypoxic workstation to analyze cellular uptake of Cu complexes in different oxygen levels. Results In vivo results showed that Cu-ASTM and Cu-Cl2 accumulated in hypoxic areas of the tumors. Cu-ATSM also stained, to a lesser extent, non-hypoxic regions, such as regions of astrogliosis, with high expression of copper transporters and in particular DMT-1 and CTR1, and also characterized by the expression of elevated astrogliosis. In vitro results show that 64Cu-ATSM showed an increase in the uptake only in severe hypoxia at 0.5 and 0.2% of oxygen while for 64Cu-Cl2, the cell retention was significantly increased at 5% and 1% of oxygen with no significant rise at lower oxygen percentages. Conclusion In the present study, we show that Cu-complexes undoubtedly accumulate in hypoxic areas of the tumors. This uptake may be the reflection of a direct dependency to a redox metabolism and also a reflection of hypoxic-induced overexpression of transporters. We also show that Cu-ATSM also stained non-hypoxic regions such as astrogliosis.

Published
2019
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9. Radioimmunotherapy for Brain Metastases: The Potential for Inflammation as a Target of Choice

Author

Aurélien Corroyer-Dulmont, Cyril Jaudet, Anne-Marie Frelin, Jade Fantin, Kathleen Weyts, Katherine A. Vallis, Nadia Falzone, Nicola R. Sibson, Michel Chérel, Françoise Kraeber-Bodéré, Alain Batalla, Stéphane Bardet, Myriam Bernaudin, and Samuel Valable

Subjects
brain metastases, radio-immunotherapy, microenvironment, alpha-particle therapy, inflammation, VCAM-1, 212Pb, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Brain metastases (BM) are frequently detected during the follow-up of patients with malignant tumors, particularly in those with advanced disease. Despite a major progress in systemic anti-cancer treatments, the average overall survival of these patients remains limited (6 months from diagnosis). Also, cognitive decline is regularly reported especially in patients treated with whole brain external beam radiotherapy (WBRT), due to the absorbed radiation dose in healthy brain tissue. New targeted therapies, for an earlier and/or more specific treatment of the tumor and its microenvironment, are needed. Radioimmunotherapy (RIT), a combination of a radionuclide to a specific antibody, appears to be a promising tool. Inflammation, which is involved in multiple steps, including the early phase, of BM development is attractive as a relevant target for RIT. This review will focus on the (1) early biomarkers of inflammation in BM pertinent for RIT, (2) state of the art studies on RIT for BM, and (3) the importance of dosimetry to RIT in BM. These two last points will be addressed in comparison to the conventional EBRT treatment, particularly with respect to the balance between tumor control and healthy tissue complications. Finally, because new diagnostic imaging techniques show a potential for the detection of BM at an early stage of the disease, we focus particularly on this therapeutic window.

Published
2021
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10. Connexin 43 and Sonic Hedgehog Pathway Interplay in Glioblastoma Cell Proliferation and Migration

Author

Filippo Torrisi, Cristiana Alberghina, Debora Lo Furno, Agata Zappalà, Samuel Valable, Giovanni Li Volti, Daniele Tibullo, Nunzio Vicario, and Rosalba Parenti

Subjects
GBM, connexin, gap junction, smoothened, GLI1, Biology (General), QH301-705.5
Abstract

Glioblastoma (GBM) represents the most common primary brain tumor within the adult population. Current therapeutic options are still limited by high rate of recurrences and signalling axes that promote GBM aggressiveness. The contribution of gap junctions (GJs) to tumor growth and progression has been proven by experimental evidence. Concomitantly, tumor microenvironment has received increasing interest as a critical process in dysregulation and homeostatic escape, finding a close link between molecular mechanisms involved in connexin 43 (CX43)-based intercellular communication and tumorigenesis. Moreover, evidence has come to suggest a crucial role of sonic hedgehog (SHH) signalling pathway in GBM proliferation, cell fate and differentiation. Herein, we used two human GBM cell lines, modulating SHH signalling and CX43-based intercellular communication in in vitro models using proliferation and migration assays. Our evidence suggests that modulation of the SHH effector smoothened (SMO), by using a known agonist (i.e., purmorphamine) and a known antagonist (i.e., cyclopamine), affects the CX43 expression levels and therefore the related functions. Moreover, SMO activation also increased cell proliferation and migration. Importantly, inhibition of CX43 channels was able to prevent SMO-induced effects. SHH pathway and CX43 interplay acts inducing tumorigenic program and supporting cell migration, likely representing druggable targets to develop new therapeutic strategies for GBM.

Published
2021
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11. Potential for Nuclear Medicine Therapy for Glioblastoma Treatment

Author

Clément Bailly, Aurelien Vidal, Coralie Bonnemaire, Françoise Kraeber-Bodéré, Michel Chérel, Amandine Pallardy, Caroline Rousseau, Emmanuel Garcion, Franck Lacoeuille, François Hindré, Samuel Valable, Myriam Bernaudin, Caroline Bodet-Milin, and Mickaël Bourgeois

Subjects
glioblastoma, nuclear medicine, cancer, radioimmunotherapy (RIT), peptide receptor radiotherapy (PRRT), radionanoparticles, Therapeutics. Pharmacology, RM1-950
Abstract

Glioblastoma is the most common malignant adult brain tumor and has a very poor patient prognosis. The mean survival for highly proliferative glioblastoma is only 10 to 14 months despite an aggressive current therapeutic approach known as Stupp’s protocol, which consists of debulking surgery followed by radiotherapy and chemotherapy. Despite several clinical trials using anti-angiogenic targeted therapies, glioblastoma medical care remains without major progress in the last decade. Recent progress in nuclear medicine, has been mainly driven by advances in biotechnologies such as radioimmunotherapy, radiopeptide therapy, and radionanoparticles, and these bring a new promising arsenal for glioblastoma therapy. For therapeutic purposes, nuclear medicine practitioners classically use β− particle emitters like 131I, 90Y, 186/188Re, or 177Lu. In the glioblastoma field, these radioisotopes are coupled with nanoparticles, monoclonal antibodies, or peptides. These radiopharmaceutical compounds have resulted in a stabilization and/or improvement of the neurological status with only transient side effects. In nuclear medicine, the glioblastoma-localized and targeted internal radiotherapy proof-of-concept stage has been successfully demonstrated using β− emitting isotopes. Similarly, α particle emitters like 213Bi, 211At, or 225Ac appear to be an innovative and interesting alternative. Indeed, α particles deliver a high proportion of their energy inside or at close proximity to the targeted cells (within a few micrometers from the emission point versus several millimeters for β− particles). This physical property is based on particle–matter interaction differences and results in α particles being highly efficient in killing tumor cells with minimal irradiation of healthy tissues and permits targeting of isolated tumor cells. The first clinical trials confirmed this idea and showed good therapeutic efficacy and less side effects, thus opening a new and promising era for glioblastoma medical care using α therapy. The objective of this literature review is focused on the developing field of nuclear medicine and aims to describe the various parameters such as targets, vectors, isotopes, or injection route (systemic and local) in relation to the clinical and preclinical results in glioblastoma pathology.

Published
2019
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12. Hypoxia Imaging and Adaptive Radiotherapy: A State-of-the-Art Approach in the Management of Glioma

Author

Michael Gérard, Aurélien Corroyer-Dulmont, Paul Lesueur, Solène Collet, Michel Chérel, Mickael Bourgeois, Dinu Stefan, Elaine Johanna Limkin, Cécile Perrio, Jean-Sébastien Guillamo, Bernard Dubray, Myriam Bernaudin, Juliette Thariat, and Samuel Valable

Subjects
glioblastoma, hypoxia, imaging, PET, MRI, radiation therapy, Medicine (General), R5-920
Abstract

Severe hypoxia [oxygen partial pressure (pO2) below 5–10 mmHg] is more frequent in glioblastoma multiforme (GBM) compared to lower-grade gliomas. Seminal studies in the 1950s demonstrated that hypoxia was associated with increased resistance to low–linear energy transfer (LET) ionizing radiation. In experimental conditions, the total radiation dose has to be multiplied by a factor of 3 to achieve the same cell lethality in anoxic situations. The presence of hypoxia in human tumors is assumed to contribute to treatment failures after radiotherapy (RT) in cancer patients. Therefore, a logical way to overcome hypoxia-induced radioresistance would be to deliver substantially higher doses of RT in hypoxic volumes delineated on pre-treatment imaging as biological target volumes (BTVs). Such an approach faces various fundamental, technical, and clinical challenges. The present review addresses several technical points related to the delineation of hypoxic zones, which include: spatial accuracy, quantitative vs. relative threshold, variations of hypoxia levels during RT, and availability of hypoxia tracers. The feasibility of hypoxia imaging as an assessment tool for early tumor response to RT and for predicting long-term outcomes is discussed. Hypoxia imaging for RT dose painting is likewise examined. As for the radiation oncologist's point of view, hypoxia maps should be converted into dose-distribution objectives for RT planning. Taking into account the physics and the radiobiology of various irradiation beams, preliminary in silico studies are required to investigate the feasibility of dose escalation in terms of normal tissue tolerance before clinical trials are undertaken.

Published
2019
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13. SRC Tyrosine Kinase Inhibitor and X-rays Combined Effect on Glioblastoma Cell Lines

Author

Filippo Torrisi, Luigi Minafra, Francesco P. Cammarata, Gaetano Savoca, Marco Calvaruso, Nunzio Vicario, Laura Maccari, Elodie A. Pérès, Hayriye Özçelik, Myriam Bernaudin, Lorenzo Botta, Giorgio Russo, Rosalba Parenti, and Samuel Valable

Subjects
Glioblastoma, ionizing radiation, hypoxia, DNA damage, combined treatments, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Glioblastoma (GBM) is one of the most lethal types of tumor due to its high recurrence level in spite of aggressive treatment regimens involving surgery, radiotherapy and chemotherapy. Hypoxia is a feature of GBM, involved in radioresistance, and is known to be at the origin of treatment failure. The aim of this work was to assess the therapeutic potential of a new targeted c-SRC inhibitor molecule, named Si306, in combination with X-rays on the human glioblastoma cell lines, comparing normoxia and hypoxia conditions. For this purpose, the dose modifying factor and oxygen enhancement ratio were calculated to evaluate the Si306 radiosensitizing effect. DNA damage and the repair capability were also studied from the kinetic of γ-H2AX immunodetection. Furthermore, motility processes being supposed to be triggered by hypoxia and irradiation, the role of c-SRC inhibition was also analyzed to evaluate the migration blockage by wound healing assay. Our results showed that inhibition of the c-SRC protein enhances the radiotherapy efficacy both in normoxic and hypoxic conditions. These data open new opportunities for GBM treatment combining radiotherapy with molecularly targeted drugs to overcome radioresistance.

Published
2020
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14. Hadrontherapy Interactions in Molecular and Cellular Biology

Author

Juliette Thariat, Samuel Valable, Carine Laurent, Siamak Haghdoost, Elodie A. Pérès, Myriam Bernaudin, François Sichel, Paul Lesueur, Mathieu Césaire, Edwige Petit, Aurélie E. Ferré, Yannick Saintigny, Sven Skog, Mihaela Tudor, Michael Gérard, Sebastien Thureau, Jean-Louis Habrand, Jacques Balosso, and François Chevalier

Subjects
cancer, radioresistance, particle therapy, hadrontherapy, hypoxia, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

The resistance of cancer cells to radiotherapy is a major issue in the curative treatment of cancer patients. This resistance can be intrinsic or acquired after irradiation and has various definitions, depending on the endpoint that is chosen in assessing the response to radiation. This phenomenon might be strengthened by the radiosensitivity of surrounding healthy tissues. Sensitive organs near the tumor that is to be treated can be affected by direct irradiation or experience nontargeted reactions, leading to early or late effects that disrupt the quality of life of patients. For several decades, new modalities of irradiation that involve accelerated particles have been available, such as proton therapy and carbon therapy, raising the possibility of specifically targeting the tumor volume. The goal of this review is to examine the up-to-date radiobiological and clinical aspects of hadrontherapy, a discipline that is maturing, with promising applications. We first describe the physical and biological advantages of particles and their application in cancer treatment. The contribution of the microenvironment and surrounding healthy tissues to tumor radioresistance is then discussed, in relation to imaging and accurate visualization of potentially resistant hypoxic areas using dedicated markers, to identify patients and tumors that could benefit from hadrontherapy over conventional irradiation. Finally, we consider combined treatment strategies to improve the particle therapy of radioresistant cancers.

Published
2019
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15. A Facile Route toward the Increase of Oxygen Content in Nanosized Zeolite by Insertion of Cerium and Fluorinated Compounds

Author

Sarah Komaty, Clément Anfray, Moussa Zaarour, Hussein Awala, Valérie Ruaux, Samuel Valable, and Svetlana Mintova

Subjects
zeolite, nanocrystals, oxygen adsorption, FTIR, fluorinated zeolite, cerium, toxicity test, Organic chemistry, QD241-441
Abstract

Enriching oxygen content within nanosized zeolite X (as synthesized Na-X) by insertion of cerium (ion exchanged Ce-X) and functionalization with bromoperfluoro-n-octane (fluorinated F-X) is reported. The materials were fully characterized by powder X-ray diffraction (XRD), dynamic light scattering (DLS), zeta potential, thermogravimetric analysis (TGA), nitrogen adsorption, and nuclear magnetic resonance (19F NMR). The O2 adsorption in the zeolite samples at various concentrations (0 to 165 Torr) at −196 °C was studied by in situ FTIR. The modification of nanosized zeolites did not alter their colloidal stability, crystallinity, porosity, and particle size distribution. The inclusion of cerium and bromoperfluoro-n-octane considerably increase the oxygen capacity by 33% for samples Ce-X and F-X in comparison to the as-synthesized Na-X zeolite. Further, toxicity tests revealed that these materials are safe, which opens the door for their implementation in medical applications, where controlled delivery of oxygen is highly desirable.

Published
2018
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17. Gadolinium-loaded LTL nanosized zeolite for efficient oxygen delivery and magnetic resonance imaging

Author

Abdallah Amedlous, Charly Hélaine, Rémy Guillet-Nicolas, Oleg Lebedev, Samuel Valable, and Svetlana Mintova

Subjects
Inorganic Chemistry
Abstract

The search for efficient gas carriers for biomedical applications presents a challenging task due to the kinetics of gas adsorption/desorption. This article presents a novel approach utilizing Gd-LTL zeolite crystals for oxygen delivery combined with an MRI study.

Published
2023

18. Supplementary Data from Molecular Mechanisms Underlying Effects of Epidermal Growth Factor Receptor Inhibition on Invasion, Proliferation, and Angiogenesis in Experimental Glioma

Author

Marc Peschanski, Eric Raymond, Jean-Jacques Parienti, Marie-France Poupon, Yannick Marie, Pascal Leuraud, Lena Marteau, Samuel Valable, Sophie de Boüard, and Jean-Sébastien Guillamo

Abstract

Supplementary Data from Molecular Mechanisms Underlying Effects of Epidermal Growth Factor Receptor Inhibition on Invasion, Proliferation, and Angiogenesis in Experimental Glioma

Published
2023

19. Data from Molecular Mechanisms Underlying Effects of Epidermal Growth Factor Receptor Inhibition on Invasion, Proliferation, and Angiogenesis in Experimental Glioma

Author

Marc Peschanski, Eric Raymond, Jean-Jacques Parienti, Marie-France Poupon, Yannick Marie, Pascal Leuraud, Lena Marteau, Samuel Valable, Sophie de Boüard, and Jean-Sébastien Guillamo

Abstract

Purpose: Epidermal growth factor receptor (EGFR) signal transduction pathways are implicated in malignant glioma aggressiveness and promote tumor cell invasion, proliferation, and angiogenesis. Nevertheless, response to EGFR tyrosine kinase inhibitor gefitinib (Iressa, ZD1839) has been disappointing in clinical trials. One potential explanation may come from the diversity of molecular alterations seen in gliomas. To validate that hypothesis, we have investigated responses to gefitinib on various tumor parameters in human malignant gliomas that exhibited different molecular alterations.Experimental Design: We used a panel of six human malignant gliomas from established xenografts characterized for their genetic (EGFR, PTEN, TP53, and CDKN2A) and molecular (EGFR, PTEN, ERK, and Akt) alterations. Tumors were treated with gefitinib (1 or 10 μmol/L) for prolonged periods (8 or 16 days) in an organotypic brain slice model that allowed quantification of invasion, proliferation, and angiogenesis.Results: In nontreated tumors, EGFR amplification was associated with profuse tumor cell invasion. After treatment, invasion was inhibited in tumors with EGFR amplification in a dose-dependent manner. Treatment had only antiproliferative effect in two of three tumors with EGFR amplification. Tumors with PTEN loss were resistant to treatment. We did not observe shrinkage of the tumors after treatment. None of the tumors had mutations of the EGFR kinase domain. Gefitinib had similar antiangiogenic effect in all of the tumors.Conclusions: Gefitinib reduces cell invasion in EGFR amplified tumors. PTEN loss of expression seems to be a determinant of resistance. Interestingly, inhibition of angiogenesis by gefitinib seems independent on the EGFR genetic status of the tumors.

Published
2023

20. Supplementary Table 1 from Inactivation of the HIF-1α/PDK3 Signaling Axis Drives Melanoma toward Mitochondrial Oxidative Metabolism and Potentiates the Therapeutic Activity of Pro-Oxidants

Author

Philippe Marchetti, Laurent Mortier, Renata Polakowska, Pierre Formstecher, Patrice Maboudou, Elisabeth Martin de Lassalle, Myriam Malet-Martino, Myriam Bernaudin, Aurélien Corroyer-Dulmont, Samuel Valable, Stéphane Balayssac, Caroline Ballot, Aurélie Jonneaux, Pierre Guerreschi, Cyril Maire, Manel Jendoubi, Yasmine Touil, Paola Corazao-Rozas, and Jérome Kluza

Abstract

PDF file - 57K, on clinical information

Published
2023

21. Supplementary Methods from Inactivation of the HIF-1α/PDK3 Signaling Axis Drives Melanoma toward Mitochondrial Oxidative Metabolism and Potentiates the Therapeutic Activity of Pro-Oxidants

Author

Philippe Marchetti, Laurent Mortier, Renata Polakowska, Pierre Formstecher, Patrice Maboudou, Elisabeth Martin de Lassalle, Myriam Malet-Martino, Myriam Bernaudin, Aurélien Corroyer-Dulmont, Samuel Valable, Stéphane Balayssac, Caroline Ballot, Aurélie Jonneaux, Pierre Guerreschi, Cyril Maire, Manel Jendoubi, Yasmine Touil, Paola Corazao-Rozas, and Jérome Kluza

Abstract

PDF file - 78K

Published
2023

22. Supplementary Figure Legends 1-5 from Inactivation of the HIF-1α/PDK3 Signaling Axis Drives Melanoma toward Mitochondrial Oxidative Metabolism and Potentiates the Therapeutic Activity of Pro-Oxidants

Author

Philippe Marchetti, Laurent Mortier, Renata Polakowska, Pierre Formstecher, Patrice Maboudou, Elisabeth Martin de Lassalle, Myriam Malet-Martino, Myriam Bernaudin, Aurélien Corroyer-Dulmont, Samuel Valable, Stéphane Balayssac, Caroline Ballot, Aurélie Jonneaux, Pierre Guerreschi, Cyril Maire, Manel Jendoubi, Yasmine Touil, Paola Corazao-Rozas, and Jérome Kluza

Abstract

PDF file - 93K

Published
2023

23. Supplementary Figure 4 from Inactivation of the HIF-1α/PDK3 Signaling Axis Drives Melanoma toward Mitochondrial Oxidative Metabolism and Potentiates the Therapeutic Activity of Pro-Oxidants

Author

Philippe Marchetti, Laurent Mortier, Renata Polakowska, Pierre Formstecher, Patrice Maboudou, Elisabeth Martin de Lassalle, Myriam Malet-Martino, Myriam Bernaudin, Aurélien Corroyer-Dulmont, Samuel Valable, Stéphane Balayssac, Caroline Ballot, Aurélie Jonneaux, Pierre Guerreschi, Cyril Maire, Manel Jendoubi, Yasmine Touil, Paola Corazao-Rozas, and Jérome Kluza

Abstract

PDF file - 415K, Showing the effect of DCA (or YC-1) plus elesclomol on ROS production in several melanoma cell lines

Published
2023

24. Supplementary Figure 3 from Inactivation of the HIF-1α/PDK3 Signaling Axis Drives Melanoma toward Mitochondrial Oxidative Metabolism and Potentiates the Therapeutic Activity of Pro-Oxidants

Author

Philippe Marchetti, Laurent Mortier, Renata Polakowska, Pierre Formstecher, Patrice Maboudou, Elisabeth Martin de Lassalle, Myriam Malet-Martino, Myriam Bernaudin, Aurélien Corroyer-Dulmont, Samuel Valable, Stéphane Balayssac, Caroline Ballot, Aurélie Jonneaux, Pierre Guerreschi, Cyril Maire, Manel Jendoubi, Yasmine Touil, Paola Corazao-Rozas, and Jérome Kluza

Abstract

PDF file - 126K, Showing the effect of YC-1 and DCA on PDH activity in A375 and LND cell lines

Published
2023

25. First-in-Man Noninvasive Initial Diagnostic Approach of Primary CNS Lymphoma Versus Glioblastoma Using PET With 18F-Fludarabine and l-[methyl-11C]Methionine

Author

Andrey Postnov, Jérôme Toutain, Igor Pronin, Samuel Valable, Fabienne Gourand, Diana Kalaeva, Nina Vikhrova, Elena Pyzhik, Stéphane Guillouet, Grigoriy Kobyakov, Ekaterina Khokholova, David Pitskhelauri, Dmitry Usachev, Sergey Maryashev, Marina Rizhova, Alexander Potapov, and Jean-Michel Derlon

Subjects
Diagnosis, Differential, Methionine, Lymphoma, Adrenal Cortex Hormones, Brain Neoplasms, Fluorodeoxyglucose F18, Positron Emission Tomography Computed Tomography, Positron-Emission Tomography, Humans, Radiology, Nuclear Medicine and imaging, General Medicine, Glioblastoma, Vidarabine
Abstract

This study sought to assess 18 F-fludarabine ( 18 F-FLUDA) PET/CT's ability in differentiating primary central nervous system lymphomas (PCNSLs) from glioblastoma multiformes (GBMs).Patients harboring either PCNSL (n = 8) before any treatment, PCNSL treated using corticosteroids (PCNSLh; n = 10), or GBM (n = 13) were investigated with conventional MRI and PET/CT, using 11 C-MET and 18 F-FLUDA. The main parameters measured with each tracer were SUV T and T/N ratios for the first 30 minutes of 11 C-MET acquisition, as well as at 3 different times after 18 F-FLUDA injection. The early 18 F-FLUDA uptake within the first minute of injection was equally considered, whereas this parameter was combined with the later uptakes to obtain R FLUDA 2 and R FLUDA 3 ratios.No significant differences in 11 C-MET uptakes were observed among PCNSL, PCNSLh, and GBM. With 18 F-FLUDA, a clear difference in dynamic GBM uptake was observed, which decreased over time after an early maximum, as compared with that of PCNSL, which steadily increased over time, PCNSLh exhibiting intermediate values. The most discriminative parameters consisting of R FLUDA 2 and R FLUDA 3 integrated the early tracer uptake (first 60 seconds), thereby provided 100% specificity and sensitivity.18 F-FLUDA was shown to likely be a promising radiopharmaceutical for differentiating PCNSL from other malignancies, although a pretreatment with corticosteroids might compromise this differential diagnostic ability. The diagnostic role of 18 F-FLUDA should be further investigating, along with its potential of defining therapeutic strategies in patients with PCNSL, while assessing the treatments' effectiveness.

Published
2022

26. Magnetic resonance imaging of hypoxia in acute stroke: a cross‐validation study against FMISO‐positron emission tomography

Author

Samuel, Valable, Toutain, Jérôme, Divoux, Didier, Chazalviel, Laurent, Corroyer-Dulmont, Aurélien, Chakhoyan, Ararat, Guillouet, Stéphane, Bernaudin, Myriam, Barbier, Emmanuel, Touzani, Omar, Imagerie et Stratégies Thérapeutiques pour les Cancers et Tissus cérébraux (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Laboratoire de Développements Méthodologiques en Tomographie par Emission de Positons (LDM-TEP), Service Hospitalier Frédéric Joliot (SHFJ), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), and Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN)

Subjects
hypoxia, [SDV]Life Sciences [q-bio], tissue oxygenation, FMISO-PET, stroke, MRI
Abstract

CERVOXY; International audience; Acute ischemic stroke results in ischemic core surrounded by a tissue at risk, named the penumbra, which is potentially salvageable. One way to differentiate the tissues is to measure the hypoxia status. The purpose of the study is to correlate the abnormal brain tissue volume derived from magnetic resonance-based imaging of brain oxygen saturation (StO2-MRI) to the [18F]FMISO positron emission tomography (PET) volume for hypoxia imaging validation, and to analyse the ability of StO2-MRI to depict the different hypoxic tissue types in the acute phase of stroke.In a pertinent model of stroke in the rat, the volume of tissue with decreased StO2-MRI signal and that with increased uptake of [18F]FMISO were equivalent and correlated (r=0.706; p=0.015). The values of StO2 in the tissue at risk were significantly greater than those quantified in the core of the lesion, and less than those of the healthy tissue (52.3±2.0%; 43.3±1.9% and 67.9±1.4%, respectively). A threshold value of StO2 of ≈60% as the cut-off for the identification of the tissue at risk was calculated. Tissue volumes with reduced StO2-MRI correlated with the final lesion (r=0.964, p

Published
2023

27. The Reactive Species Interactome in the Brain

Author

Elodie A. Pérès, Samuel Valable, Elise Malard, Myriam Bernaudin, Laurent Chatre, Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), and Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Physiology, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Context (language use), Computational biology, Oxidative phosphorylation, Biology, medicine.disease_cause, Biochemistry, Interactome, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, medicine, Humans, RSI, Molecular Biology, Reactive nitrogen species, 030304 developmental biology, General Environmental Science, chemistry.chemical_classification, 0303 health sciences, Reactive oxygen species, distress, Brain, Cell Biology, Reactive Nitrogen Species, Reactive carbonyl species, Oxidative Stress, chemistry, General Earth and Planetary Sciences, pathology, Identification (biology), eustress, Reactive Oxygen Species, Oxidation-Reduction, 030217 neurology & neurosurgery, Oxidative stress
Abstract

CERVOXY; International audience; Significance: Redox pioneer Helmut Sies attempted to explain reactive species' challenges faced by organelles, cells, tissues, and organs via three complementary definitions: (1) oxidative stress, i.e. the disturbance in the prooxidant-antioxidant defense balance in favor of the prooxidants, (2) oxidative eustress, the low physiological exposure to prooxidants, and (3) oxidative distress, the supraphysiological exposure to prooxidants. Recent Advances: Identification, concentration and interactions are the most important elements to improve our understanding of reactive species in physiology and pathology. In this context, the reactive species interactome (RSI) is a new multilevel redox regulatory system that identifies reactive species families, reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive sulfur species (RSS), and integrates their interactions with their downstream biological targets.Critical issues: We propose a united view to fully combine reactive species identification, oxidative eustress and distress, and the RSI system. In this view, we also propose including the forgotten reactive carbonyl species (RCS), an increasingly rediscovered reactive species family related to the other reactive families, and key enzymes within the RSI. We focus on brain physiology and pathology to demonstrate why this united view should be considered.Future directions: More studies are needed for an improved understanding of the contributions of reactive species through their identification, concentration, and interactions, including in the brain. Appreciating the reactive species interactome in its entirety should unveil new molecular players and mechanisms in physiology and pathology in the brain and elsewhere.

Published
2021

28. The Impact of Resampling and Denoising Deep Learning Algorithms on Radiomics in Brain Metastases MRI

Author

Ilyass Moummad, Cyril Jaudet, Alexis Lechervy, Samuel Valable, Charlotte Raboutet, Zamila Soilihi, Juliette Thariat, Nadia Falzone, Joëlle Lacroix, Alain Batalla, Aurélien Corroyer-Dulmont, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Equipe Image - Laboratoire GREYC - UMR6072, Groupe de Recherche en Informatique, Image et Instrumentation de Caen (GREYC), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Service de Radiologie [CLCC Baclesse], Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), and GenesisCare

Subjects
Cancer Research, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, deep learning, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, [SDV.CAN]Life Sciences [q-bio]/Cancer, Article, Oncology, radiomics, MRI, resampling, denoising, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, RC254-282
Abstract

Simple Summary Due to the central role of magnetic resonance Imaging (MRI) in the management of patients with cancer, waiting lists exceed clinically relevant delays. For this reason, many research groups and MRI manufacturers develop algorithms as resampling and denoising models to allow faster acquisition time without deterioration in image quality. Whereas these algorithms are available in all new MRI, it is not clear how they will impact image features as well as the validity of statistical model of radiomics which use deep images characteristics to predict treatment outcome. The aim of this study was to develop resampling and denoising deep learning (DL) models and evaluate their impact on radiomics from post-Gd-T1w-MRI brain images with brain metastases. We show that resampling and denoising DL models reconstruct low resolution and noised MRI images acquired quickly into high quality images. While fast acquisition loses most of the radiomic-features and invalidates predictive radiomic models, DL models restore these parameters. Abstract Background: Magnetic resonance imaging (MRI) is predominant in the therapeutic management of cancer patients, unfortunately, patients have to wait a long time to get an appointment for examination. Therefore, new MRI devices include deep-learning (DL) solutions to save acquisition time. However, the impact of these algorithms on intensity and texture parameters has been poorly studied. The aim of this study was to evaluate the impact of resampling and denoising DL models on radiomics. Methods: Resampling and denoising DL model was developed on 14,243 T1 brain images from 1.5T-MRI. Radiomics were extracted from 40 brain metastases from 11 patients (2049 images). A total of 104 texture features of DL images were compared to original images with paired t-test, Pearson correlation and concordance-correlation-coefficient (CCC). Results: When two times shorter image acquisition shows strong disparities with the originals concerning the radiomics, with significant differences and loss of correlation of 79.81% and 48.08%, respectively. Interestingly, DL models restore textures with 46.15% of unstable parameters and 25.96% of low CCC and without difference for the first-order intensity parameters. Conclusions: Resampling and denoising DL models reconstruct low resolution and noised MRI images acquired quickly into high quality images. While fast MRI acquisition loses most of the radiomic features, DL models restore these parameters.

Published
2022

29. Magnetic resonance imaging of hypoxia in acute stroke compared with fluorine-18 fluoromisonidazole-positron emission tomography: A cross-validation study?

Author

Samuel Valable, Jérôme Toutain, Didier Divoux, Laurent Chazalviel, Aurélien Corroyer‐Dulmont, Ararat Chakhoyan, Stéphane Guillouet, Myriam Bernaudin, Emmanuel L. Barbier, and Omar Touzani

Subjects
Molecular Medicine, Radiology, Nuclear Medicine and imaging, Spectroscopy
Abstract

Acute ischemic stroke results in an ischemic core surrounded by a tissue at risk, named the penumbra, which is potentially salvageable. One way to differentiate the tissues is to measure the hypoxia status. The purpose of the current study is to correlate the abnormal brain tissue volume derived from magnetic resonance-based imaging of brain oxygen saturation (S

Published
2022

30. Simultaneous Mapping of Vasculature, Hypoxia, and Proliferation Using Dynamic Susceptibility Contrast MRI, 18F-FMISO PET, and 18F-FLT PET in Relation to Contrast Enhancement in Newly Diagnosed Glioblastoma

Author

Samuel Valable, Solène Collet, Jean-Marc Constans, Mathieu Hatt, Jean-Sébastien Guillamo, Cécile Perrio, Ararat Chakhoyan, Dimitris Visvikis, Emmanuèle Lechapt-Zalcman, Stéphane Guillouet, J M Derlon, Myriam Bernaudin, and David Hassanein Berro

Subjects
Contrast enhancement, business.industry, media_common.quotation_subject, Newly diagnosed, 18f fmiso, Hypoxia (medical), medicine.disease, 030218 nuclear medicine & medical imaging, Peripheral, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, medicine, Contrast (vision), Radiology, Nuclear Medicine and imaging, medicine.symptom, business, Nuclear medicine, Dynamic susceptibility, media_common, Glioblastoma
Abstract

Conventional MRI plays a key role in the management of patients with high grade glioma but multiparametric MRI and PET tracers could provide further information to better characterize the tumor metabolism and heterogeneity, by identifying the regions having a high risk of recurrence. In this study, we focused on the proliferation, hypervascularization and hypoxia, all factors considered as factors of poor prognosis. They were assessed by measuring the uptake of 18F-FLT, the rCBV maps and the uptake of 18F-FMISO, respectively. For each modality, the volumes and high uptake sub-volumes (hotspots) were semi-automatically segmented and compared to contrast enhancement (CE) volume on T1w-Gd images, commonly used in the management of patient with glioblastoma. Methods: DSC MRI (31 patients), 18F-FLT PET (20 patients) and/or 18F-FMISO PET (20 patients), for a total of 31 patients, were performed on pre-operative glioblastoma patients. Volumes and hotspots were segmented on SUV maps for 18F-FLT (using FLAB) and 18F-FMISO (using mean contralateral + 3.3 SD) PET and on rCBV maps (using mean contralateral + 1.96 SD) for DSC MRI and overlaid on T1w-Gd images. For each modality, the percentage of peripheral volumes and the peripheral hotspot outside the CE volume were calculated. Results: All tumors showed high proliferation, hypervascularization and hypoxic regions. Images also showed pronounced heterogeneity of both tracers uptake and rCBV maps, within each individual case. Overlaid volumes on T1w-Gd images showed that some proliferative, hypervascularization and hypoxic regions extended beyond the CE volume but with marked differences between patients. The ranges of peripheral volume outside the CE volume were [1.6% - 155.5 %], [1.5% - 89.5%] and [3.1% - 78.0%] for 18F-FLT, rCBV and 18F-FMISO respectively. All patients had hyperproliferative hotspots outside CE volume, whereas hotspots of hypervasculature and hypoxia were mainly detected within the enhancing region. Conclusion: The spatial analysis of the multiparametric maps with the segmented volumes and hotspots provides valuable information to optimize the management and treatment of the patients with glioblastoma.

Published
2021

31. Internalization study of nanosized zeolite crystals in human glioblastoma cells

Author

Charly Helaine, Hayriye Özçelik, Sarah Komaty, Abdallah Amedlous, Sajjad Ghojavand, Didier Goux, Richard Retoux, Svetlana Mintova, Samuel Valable, Imagerie et Stratégies Thérapeutiques pour les Cancers et Tissus cérébraux (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire catalyse et spectrochimie (LCS), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Interactions Cellules Organismes Environnement (ICORE), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Laboratoire de cristallographie et sciences des matériaux (CRISMAT), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche sur les Matériaux Avancés (IRMA), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), and INCA PLBIO 11699

Subjects
Colloidal suspension, Cell uptake, Nanosized zeolite, Cytotoxicity, [SDV]Life Sciences [q-bio], Surfaces and Interfaces, General Medicine, Faujasite, Oxygen, Colloid and Surface Chemistry, Zeolites, [CHIM]Chemical Sciences, Humans, Tissue Distribution, Physical and Theoretical Chemistry, Glioblastoma, Hypoxia, Biotechnology
Abstract

CERVOXY; International audience; While the use of nanozeolites for cancer treatment holds a great promise, it also requires a better understanding of the interaction between the zeolite nanoparticles and cancer cells and notably their internalization and biodistribution. It is particularly important in situation of hypoxia, a very common situations in aggressive cancers, which may change the energetic processes required for cellular uptake. Herein, we studied, in vitro, the kinetics of the internalization process and the intracellular localization of nanosized zeolite X (FAU-X) into glioblastoma cells. In normoxic conditions, scanning electron microscopy (SEM) showed a rapid cell membrane adhesion of zeolite nanoparticles (< 5 min following application in the cell medium), occurring before an energy-dependent uptake which appeared between 1 h and 4 h. Additionally, transmission electron microscopy (TEM) and flow cytometry analyzes, confirmed that the zeolite nanoparticles accumulate over time into the cytoplasm and were mostly located into vesicles visible at least up to 6 days. Interestingly, the uptake of zeolite nanoparticles was found to be dependent on oxygen concentration, i.e. an increase in internalization in severe hypoxia (0.2 % of O2) was observed. No toxicity of zeolite FAU-X nanoparticles was detected after 24 h and 72 h. The results clearly showed that the nanosized zeolites crystals were rapidly internalized via energy-requiring mechanism by cancer cells and even more in the hypoxic conditions. Once the zeolite nanoparticles were internalized into cells, they appeared to be safe and stable and therefore, they are envisioned to be used as carrier of various compounds to target cancer cells.

Published
2022

32. Kinetics and oxygen dependence of uptake of nanozeolites by human glioblastoma cells

Author

Hélaine, C, Özçelik, Hayriye, Komaty, S., Amedlous, A., Ghojavand, Sajjad, Goux, Didier, Retoux, Richard, Mintova, Svetlana, Samuel, Valable, Imagerie et Stratégies Thérapeutiques pour les Cancers et Tissus cérébraux (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire catalyse et spectrochimie (LCS), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de cristallographie et sciences des matériaux (CRISMAT), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche sur les Matériaux Avancés (IRMA), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), and Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV]Life Sciences [q-bio]
Abstract

CERVOXY; National audience

Published
2022

33. The physical activity attenuates the brain irradiation-induced cerebral and skeletal muscle injuries in the adult rat

Author

Bécam, Julie, Ropars, Gwenn, Dwiri, Fatima-Azzahra, Toutain, Jérôme, Chazalviel, Laurent, Naveau, Mikaël, Samuel, Valable, Bernaudin, Myriam, Touzani, Omar, Pérès, Elodie A., Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Unité Support CYCERON, Normandie Université (NU)-Normandie Université (NU)-CHU Caen, and Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV]Life Sciences [q-bio]
Abstract

CERVOXY; International audience

Published
2022

34. Incorporation of trivalent cations in NaX zeolite nanocrystals for the adsorption of O2 in the presence of CO2

Author

Sarah Komaty, Michael Badawi, Ayoub Daouli, Samuel Valable, Moussa Zaarour, Svetlana Mintova, Clément Anfray, Laboratoire catalyse et spectrochimie (LCS), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Université de Lorraine (UL), Laboratoire de Physique et Chimie Théoriques (LPCT), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut de Chimie du CNRS (INC)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Denticity, Chemistry, [SDV]Life Sciences [q-bio], Inorganic chemistry, General Physics and Astronomy, Infrared spectroscopy, Ionic bonding, Sorption, 02 engineering and technology, Faujasite, engineering.material, 010402 general chemistry, 021001 nanoscience & nanotechnology, 01 natural sciences, 0104 chemical sciences, Adsorption, Physisorption, 13. Climate action, engineering, [CHIM]Chemical Sciences, Physical and Theoretical Chemistry, 0210 nano-technology, Zeolite
Abstract

CERVOXY COLL; International audience; The O2 and CO2 sorption properties of nanosized zeolite X with faujasite type structure through a partial ionic exchange of sodium (Na +) by trivalent cations (Gd 3+ and Ce 3+) were evaluated. Three faujasite samples were studied, the as-synthesized Na-X possessing Na + solely, and the modified samples Na-Gd-X and Na-Ce-X containing Gd 3+ (1.8 wt%) and Ce 3+ (0.82 wt%), respectively. Incorporating scarce amounts of trivalent cations modified the adsorption affinity of zeolites towards O2 and CO2 as demonstrated by in situ Fourier-transform infrared spectroscopy (FTIR). While Na-Ce-X encounters the highest O2 physisorption capacity, the Na-Gd-X is adsorbing the highest quantities of molecular CO2. All three samples exhibit the chemisorbed CO2 in the form of carbonates, while the Na-X stores carbonates in monodentate and polydentate forms, the Na-Gd-X and Na-Ce-X allow the formation of polydentate carbonates only. Density functional theory (DFT) calculations revealed that trivalent cations tend to adsorb gases through two cations simultaneously which explains the presence of polydentate carbonates exclusively in the corresponding modified zeolites. The DFT results confirmed the higher affinity of Na-Gd-X and Na-Ce-X nanocrystals towards O2 in the presence of CO2. The affinity of Na-Gd-X and Na-Ce-X nanocrystals towards O2 opens the door of their use as oxygen transporters for medical applications where CO2 is constantly present. The toxicity of the nanosized zeolites and their performance in O2 release are reported too.

Published
2020

35. Comparative preclinical study of the effect of proton therapy versus conventional radiotherapy on circulating leukocytes in a context of brain tumour irradiation

Author

Coupey, Julie, Pham, Thao Nguyen, Toutain, Jérôme, Hue, Erika, Hélaine, C, Saulnier, Romaric, Chazalviel, Laurent, Rousseau, Marc, Thariat, Juliette, Leblond, M.M., Samuel, Valable, Brunaud, Carole, Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), LABÉO, Pôle d’analyses et de recherche de Normandie (LABÉO), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Normandie Université (NU)-Normandie Université (NU), Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de physique corpusculaire de Caen (LPCC), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), and Normandie Université (NU)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio]
Abstract

CERVOXY; International audience

Published
2022

38. Brain Tumor Models & MRI Applications

Author

Samuel, Valable, Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), and Couteau, Florence

Subjects
[SDV] Life Sciences [q-bio], Brain tumor, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer
Abstract

CERVOXY; International audience

Published
2021

39. Comparaison de la sensibilité des astrocytes murins et humains à différentes modalités d’irradiation

Author

Pasquet, Nolwenn, Pérès, Elodie A., Petit, Edwige, Toutain, Jérôme, Bernaudin, Myriam, Samuel, Valable, Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), and Brunaud, Carole

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio]
Abstract

CERVOXY; National audience

Published
2021

40. L’activité physique réduit la cachexie observée après irradiation cérébrale chez le rat

Author

Bécam, Julie, Ropars, Gwenn, Dwiri, Fatima-Azzahra, Toutain, Jérôme, Chazalviel, Laurent, Naveau, Mikaël, Samuel, Valable, Bernaudin, Myriam, Touzani, Omar, Pérès, Elodie A., Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Unité Support CYCERON, Normandie Université (NU)-Normandie Université (NU)-CHU Caen, and Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV]Life Sciences [q-bio]
Abstract

CERVOXY; National audience

Published
2021

41. Caractérisation de l’hypoxie dans les métastases cérébrales issues de cancer du poumon : de l’approche clinique à la pré-clinique

Author

Jade, Fantin, Aurélien, Corroyer-Dulmont, Samuel, Valable, Toutain, Jérôme, Sylvain, Teulier, Céline, Bazille, Levallet, Jérôme, Françoise, Chapon, Levallet, Guénaëlle, Bernaudin, Myriam, Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Département de Pathologie [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Hôpital Côte de Nacre [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), and Brunaud, Carole

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio]
Abstract

CERVOXY; International audience

Published
2021

42. Modèle préclinique de radiotoxicité cérébrale : évaluation longitudinale et multiparamétrique des atteintes tissulaires et cognitives chez le rat adulte

Author

Pérès, Elodie A., Ropars, Gwenn, Dwiri, Fatima-Azzahra, Carole, Brunaud, Toutain, Jérôme, Naveau, Mikaël, Petit, Edwige, Samuel, Valable, Bernaudin, Myriam, Touzani, Omar, Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Unité Support CYCERON, Normandie Université (NU)-Normandie Université (NU)-CHU Caen, and Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV]Life Sciences [q-bio]
Abstract

CERVOXY; National audience

Published
2021

43. L’IRM de diffusion du muscle squelettique : une méthode pertinente pour détecter les effets à distance induits par l'irradiation cérébrale chez le rat

Author

Julie, Bécam, Gwenn, Ropars, Fatima-Azzahra, Dwiri, Jérôme, Toutain, Laurent, Chazalviel, Mikaël, Naveau, Samuel, Valable, Myriam, Bernaudin, Omar, Touzani, Elodie A., Pérès, Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Unité Support CYCERON, Normandie Université (NU)-Normandie Université (NU)-CHU Caen, and Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV]Life Sciences [q-bio]
Abstract

CERVOXY; National audience

Published
2021

44. Intérêt de l'IRM multiparamétrique pour détecter les lésions cérébrales induites par l'irradiation chez le rat

Author

Carole, Brunaud, Samuel, Valable, Fatima-Azzahra, Dwiri, Gwenn, Ropars, Jérôme, Toutain, Mikaël, Naveau, Marianne, Léger, Thomas, Freret, Myriam, Bernaudin, Omar, Touzani, Elodie A., Pérès, Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Unité Support CYCERON, Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre National de la Recherche Scientifique (CNRS), Mobilités : Vieillissement, Pathologie, Santé (COMETE), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Caen Normandie (UNICAEN), and Normandie Université (NU)-Normandie Université (NU)

Subjects
[SDV]Life Sciences [q-bio]
Abstract

CERVOXY; National audience

Published
2021

45. Cartographie simultanée de la vascularisation, de l'hypoxie et de la prolifération à l'aide de l’IRM de perfusion, la TEP au 18F-FMISO et au 18F-FLT, en relation avec la prise de contraste dans les glioblastomes

Author

Cécile Perrio, Myriam Bernaudin, Stéphane Guillouet, David Hassanein Berro, J M Derlon, Samuel Valable, Mathieu Hatt, Solène Collet, Jean-Sébastien Guillamo, Jean-Marc Constans, Ararat Chakhoyan, Emmanuèle Lechapt-Zalcman, Dimitris Visvikis, Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Service de Neurochirurgie [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Service de Neurologie [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de Neurologie [CHU Nimes] (Pôle NIRR), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Départment de Neuroradiologie [CHU Caen], Laboratoire d'Anatomie Pathologique [CHU Caen], Service de Neuropathologie [Paris], Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-GHU Paris Psychiatrie et Neurosciences, Laboratoire de Traitement de l'Information Medicale (LaTIM), Institut National de la Santé et de la Recherche Médicale (INSERM)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut Brestois Santé Agro Matière (IBSAM), and Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)

Subjects
03 medical and health sciences, 0302 clinical medicine, Radiological and Ultrasound Technology, [SDV]Life Sciences [q-bio], Radiology, Nuclear Medicine and imaging, Neurology (clinical), 030217 neurology & neurosurgery, 030218 nuclear medicine & medical imaging
Abstract

CERVOXY-LDM TEP; International audience; Introduction L'IRM conventionnelle joue un rôle clé dans la prise en charge des patients atteints de glioblastomes, cependant, l’IRM multiparamétrique et la TEP pourraient fournir des informations supplémentaires en identifiant les régions à haut risque de récidive. Dans cette étude, nous nous sommes intéressés à la prolifération, l'hypervascularisation et l'hypoxie, considérées comme des facteurs de mauvais pronostic. Elles ont été évaluées en mesurant respectivement la captation du 18F-FLT, le rCBV et la captation du 18F-FMISO et comparées à la prise de contraste (PC) sur la séquence T1w-Gd.Méthodes Une IRM de perfusion (31 patients), une TEP au 18F-FLT (20 patients) et/ou une TEP 18F-FMISO (20 patients, dont 9 ayant eu les deux radiotraceurs), ont été réalisées en préopératoire. Les volumes et les hotspots (5% max de chaque volume) ont été segmentés semi-automatiquement sur les SUV des TEP 18F-FLT et 18F-FMISO, ainsi que sur les rCBV. Le pourcentage des volumes et des hotspots en dehors de la PC, a été calculé.Résultats Toutes les tumeurs ont montré une prolifération, une hypervascularisation et des régions hypoxiques élevées. Les volumes superposés sur les images T1w-Gd ont montré que certaines régions prolifératives, d'hypervascularisation et d'hypoxie s'étendaient au-delà de la PC, mais avec des différences marquées entre les patients. Les plages de volume périphérique en dehors de la PC étaient [1,6% - 155,5%], [1,5% - 89,5%] et [3,1% - 78,0%] pour 18F-FLT, rCBV et 18F-FMISO respectivement. Tous les patients avaient des hotspots hyperprolifératifs en dehors de la PC, tandis que les hotspots d'hypervascularisation et d'hypoxie étaient principalement détectés dans la PC.Conclusion L'analyse spatiale des cartographies multimodales avec les volumes segmentés et les hotspots fournit des informations précieuses pour optimiser la prise en charge et le traitement des glioblastomes.

Published
2021

46. Caractérisation de l’hypoxie et stratégies pour lever la radiorésistance dans les glioblastomes et les métastases cérébrales

Author

Bernaudin, Myriam, Berro David, Hassanein, Collet, Solène, Corroyer-Dulmont, Aurélien, Leblond M, Marine, Emery, Evelyne, Pérès, Elodie A., Levallet, Guénaëlle, Pasquet, Nolwenn, Samuel, Valable, Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Service de Neurochirurgie [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Brunaud, Carole, Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), and Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio]
Abstract

CERVOXY; National audience; L’hypoxie est un élément central de la croissance tumorale, impliquée aussi bien dans la progression tumorale que dans la résistance aux traitements conventionnels. Nos recherches visent à aborder l’hypoxie par plusieurs approches. Tout d’abord, nous cherchons à caractériser de l’échelle préclinique à l’échelle clinique, l’hypoxie et ses relations avec les cellules tumorales mais aussi avec leur microenvironnement dont la vascularisation, l’inflammation. Pour cela, nous utilisons des marqueurs histo-moléculaires mais également l’imagerie multimodale (IRM, TEP) pour évaluer l’hétérogénéité tumorale interpatient mais également spatiale des tumeurs cérébrales primitives de haut grade mais également des métastases cérébrales (Bekaert et al., 2017; Ponte et al., 2017; Pérès et al., 2019 ; Collet S et al., 2021 ; Corroyer-Dulmont A et al., 2021). En parallèle, nous développons des stratégies visant à contourner les effets de l’hypoxie sur la résistance aux traitements et en particulier, la radiothérapie. A ce titre, nous nous intéressons à l’hadronthérapie. Ainsi, nous avons pu montrer in vitro que les ions carbone sont plus efficaces que les photons sur les cellules tumorales hypoxiques (Valable S et al., 2020). Nous évaluons l’impact de l’hadronthérapie avec ou sans traitements combinés sur le caractère souche des cellules tumorales connu pour participer à cette radiorésistance induite par l’hypoxie. Nous développons également des stratégies pour réoxygéner et/ou radiosensibiliser les tumeurs. A titre d’exemple, nous avons récemment utilisé une stratégie nanoparticulaire afin de réoxygéner les glioblastomes (Anfray et al., 2020) mais aussi apporter du gadolinium, utilisé comme agent de radiosensibilisation. Des études sont actuellement en cours pour évaluer l’efficacité de cette approche théranostique que ce soit in vitro sur les cellules tumorales mais aussi in vivo chez le rongeur.En conclusion, nos travaux de recherche combinent des approches cellulaires aux études cliniques en passant par des études précliniques afin d’identifier l’hypoxie dans différents types de tumeurs cérébrales (glioblastomes, métastases cérébrales) et de développer des stratégies visant à atténuer les effets de l’hypoxie sur la résistance aux traitements.

Published
2021

47. Simultaneous mapping of vasculature, hypoxia and proliferation using DSC-MRI, 18F-FMISO PET, and 18F-FLT PET in relation to contrast enhancement in newly diagnosed glioblastoma

Author

Collet, Solène, Guillamo, Jean Sébastien, Berro, David Hassanein, Chakhoyan, Ararat, Constans, Jean-Marc, Lechapt-Zalcman, Emmanuèle, Derlon, Jean-Michel, Hatt, Mathieu, Visvikis, Dimitris, Guillouet, Stéphane, Perrio, Cécile, Bernaudin, Myriam, Samuel, Valable, Hypoxie, physiopathologies cérébrovasculaire et tumorale (CERVOxy), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Service de Neurochirurgie [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Neurology [UCLA], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], University of California (UC)-University of California (UC), CHU Amiens-Picardie, Laboratoire d'Anatomie Pathologique [CHU Caen], Laboratoire de Traitement de l'Information Medicale (LaTIM), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Laboratoire de Développements Méthodologiques en Tomographie par Emission de Positons (LDM-TEP), Service Hospitalier Frédéric Joliot (SHFJ), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Couteau, Florence, UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), University of California-University of California-David Geffen School of Medicine [Los Angeles], University of California-University of California, Institut National de la Santé et de la Recherche Médicale (INSERM)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT)

Subjects
[SDV] Life Sciences [q-bio], Glioblastoma, PET, Vascular, [SDV]Life Sciences [q-bio], Proliferation, [CHIM] Chemical Sciences, Vasculature, [CHIM]Chemical Sciences, Oncology: Brain, Hypoxia, MRI
Abstract

CERVOXY/LDM TEP COLL; International audience; Conventional MRI plays a key role in the management of patients with high grade glioma but multiparametric MRI and PET tracers could provide further information to better characterize the tumor metabolism and heterogeneity, by identifying the regions having a high risk of recurrence. In this study, we focused on the proliferation, hypervascularization and hypoxia, all factors considered as factors of poor prognosis. They were assessed by measuring the uptake of 18F-FLT, the rCBV maps and the uptake of 18F-FMISO, respectively. For each modality, the volumes and high uptake sub-volumes (hotspots) were semi-automatically segmented and compared to contrast enhancement (CE) volume on T1w-Gd images, commonly used in the management of patient with glioblastoma. Methods: DSC MRI (31 patients), 18F-FLT PET (20 patients) and/or 18F-FMISO PET (20 patients), for a total of 31 patients, were performed on pre-operative glioblastoma patients. Volumes and hotspots were segmented on SUV maps for 18F-FLT (using FLAB) and 18F-FMISO (using mean contralateral + 3.3 SD) PET and on rCBV maps (using mean contralateral + 1.96 SD) for DSC MRI and overlaid on T1w-Gd images. For each modality, the percentage of peripheral volumes and the peripheral hotspot outside the CE volume were calculated. Results: All tumors showed high proliferation, hypervascularization and hypoxic regions. Images also showed pronounced heterogeneity of both tracers uptake and rCBV maps, within each individual case. Overlaid volumes on T1w-Gd images showed that some proliferative, hypervascularization and hypoxic regions extended beyond the CE volume but with marked differences between patients. The ranges of peripheral volume outside the CE volume were [1.6% - 155.5 %], [1.5% - 89.5%] and [3.1% - 78.0%] for 18F-FLT, rCBV and 18F-FMISO respectively. All patients had hyperproliferative hotspots outside CE volume, whereas hotspots of hypervasculature and hypoxia were mainly detected within the enhancing region. Conclusion: The spatial analysis of the multiparametric maps with the segmented volumes and hotspots provides valuable information to optimize the management and treatment of the patients with glioblastoma.

Published
2021

48. Copper exchanged FAU nanozeolite as non-toxic nitric oxide and carbon dioxide gas carrier

Author

Valentin Valtchev, Charly Hélaine, Clément Anfray, Richard Retoux, Valerie Ruaux, Sarah Komaty, Kamila Goldyn, Samuel Valable, Svetlana Mintova, Laboratoire catalyse et spectrochimie (LCS), Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut de Chimie du CNRS (INC)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de cristallographie et sciences des matériaux (CRISMAT), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche sur les Matériaux Avancés (IRMA), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), and Normandie Université (NU)-Institut de Chimie du CNRS (INC)

Subjects
biomedical applications, non-toxic, [SDV]Life Sciences [q-bio], Metal-exchanged nanozeolites, Sodium, chemistry.chemical_element, 02 engineering and technology, gas adsorption, 010402 general chemistry, 7. Clean energy, 01 natural sciences, Nitric oxide, chemistry.chemical_compound, Adsorption, [CHIM]Chemical Sciences, General Materials Science, Fourier transform infrared spectroscopy, General Chemistry, 021001 nanoscience & nanotechnology, Condensed Matter Physics, Copper, 0104 chemical sciences, chemistry, gas carrier, Mechanics of Materials, Carbon dioxide, 0210 nano-technology, Nuclear chemistry
Abstract

CERVOXY COLL; International audience; A growing interest is currently directed to find an efficient NO and CO2 gas carriers for biomedical applications. The gas adsorption properties of sodium- (Na-X) and copper- (Cu-X) containing FAU nanozeolites toward nitric oxide and carbon dioxide were studied. The materials were fully characterised by XRD, TEM, ICP, DLS and in-situ FTIR. The as-prepared Na-X showed higher gas adsorption ability towards carbon dioxide, whereas the ion-exchanged Cu-X was more efficient adsorbent with regards to nitric oxide. In addition, the cytotoxicity tests disclosed that both nanozeolites have no toxicity making them suitable for further tests in biomedical field as gas transporters.

Published
2019

49. Conférence : 'De l’oxygène pour les tumeurs cérébrales : un nouvel espoir ?'

Author

Samuel, Valable, Couteau, Florence, Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), and Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV] Life Sciences [q-bio], [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer
Abstract

CERVOXY

Published
2021

50. Ang2 overexpression optimizes the efficacy of radiochemotherapy in glioblastoma by acting in an autocrine and paracrine manner

Author

Hélaine, C, Ferré, Aurélie, Leblond, M.M., Pérès, Elodie A., Bernaudin, Myriam, Samuel, Valable, Petit, Edwige, Brunaud, Carole, Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), and Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio]
Abstract

CERVOXY; National audience

Published
2021

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