.. .. La-diffusion-de-thomson-rayleigh,

L. and .. .. ,

. .. La-diffusion-compton,

. .. La-création-de-paires, 105 2.2. Interaction des particules chargées lourdes avec la matière

, Collision inélastique avec les électrons : excitation, ionisation et capture électronique

A. .. Ii-:-les-dommages-cellulaires,

. .. Lésions-de-l'adn,

.. .. Réarrangements-intra-chromosomiques,

.. .. Réarrangements-inter-chromosomiques,

. .. Effets-Épigénétiques,

E. .. Bystander,

. .. Annexe-iii-:-mécanismes-de-réparation-de-l'adn, 114 6. Réparation par excision de nucléotides (Nucleotide Excision Repair, NER)

, Réparation des mésappariements de bases (Mismatch Repair, MMR)

. .. Nhej), Réparation par recombinaison homologue (RH), vol.117

A. Iv, Effectifs de souris par groupe

:. .. Bibliographie, Les dommages cellulaires

, Lésions cytoplasmiques et membranaires

, L'irradiation des acides gras membranaires peut induire la formation de résidus de phospholipides, malonedialdehyde ou 4-hydroxynonenal, à l'origine de pontages de l'Acide Désoxyribonucléique (ADN) avec les protéines de proximité comme par exemple les histones

, L'irradiation membranaire peut également être à l'origine d'une activation de la sphingomyélinase, qui va hydroxyler la sphingomyéline membranaire en céramide. Cette hydroxylation est interprétée comme un signal de mort cellulaire par la cellule et déclenchera la cascade apoptotique

, Lésions de l'ADN

. L'adn, Du fait de sa structure complexe (Figure 52), il peut présenter différents types de lésions : rupture de brin, altération des bases ou des sucres. Les mécanismes de réparation de l'ADN sont nombreux et permettent de réparer une partie de ces lésions. Cependant, une réparation aberrante peut-être à l'origine de nouvelles anomalies, Figure, vol.52

, Réparation par suture non-homologue

, Puis des polymérases µ et ? peuvent ajouter des acides nucléiques aux extrémités. Sachant que ce processus ne se base pas sur un brin matrice, il est potentiellement pourvoyeur de mutations. Enfin, une ligase relie les deux extrémités. Figure 57: mécanismes de la réparation par suture non-homologue et de la réparation par recombinaison homologue, Ce mécanisme permet de réparer les cassures double-brin (Figure 57)

, Réparation par recombinaison homologue (RH)

, Ce mécanisme permet également de réparer les cassures double-brin. A la différence de la réparation par suture non-homologue, l'utilisation de la séquence homologue à la région de cassure permet une réparation fidèle, vol.57

, Rad50, Nbs1) qui se lie aux deux extrémités de la cassure. La résection du brin d'ADN implique plusieurs protéines. Dans un premier temps, MRE11 et CtlP induisent la résection

;. Société-française-de-médecine-nucléaire and . Cancérologie, , 2018.

;. Société-française-de-médecine-nucléaire and . Cancérologie, , p.24, 2018.

, Les therapies ciblees dans le traitement du cancer en 2015-2016. Etat des lieux et enjeux, 2016.

, La Protonthérapie, indications et capacité de traitement, juin 2016, appui à la décision, 2016.

F. Binder-foucard, Estimation nationale de l'incidence et de la mortalité par cancer en France entre 1980 et 2012: étude à partir des registres des cancers du réseau Francim, 2013.

, Cancers du foie et des voies biliaires, p.24, 2012.

J. I. Yu, Initial clinical outcomes of proton beam radiotherapy for hepatocellular carcinoma, Radiat. Oncol. J, vol.36, issue.1, pp.25-34, 2018.

T. H. Kim, Phase I Dose-Escalation Study of Proton Beam Therapy for Inoperable Hepatocellular Carcinoma, Cancer Res. Treat, vol.47, issue.1, pp.34-45, 1970.

S. Apisarnthanarax, S. R. Bowen, and S. E. Combs, Proton Beam Therapy and Carbon Ion Radiotherapy for Hepatocellular Carcinoma, Semin. Radiat. Oncol, vol.28, issue.4, pp.309-320, 2018.

M. Hata, Proton Beam Therapy for Hepatocellular Carcinoma Patients with Severe Cirrhosis, Strahlenther. Onkol, vol.182, issue.12, pp.713-720, 2006.

Y. Sorin, Effectiveness of Particle Radiotherapy in Various Stages of Hepatocellular Carcinoma: A Pilot Study, Liver Cancer, vol.7, issue.4, pp.323-334, 2018.

T. Chiba, Proton Beam Therapy for Hepatocellular Carcinoma: A Retrospective Review of 162 Patients, Clin. Cancer Res, vol.11, issue.10, pp.3799-3805, 2005.

M. Mizumoto, Proton Beam Therapy for Hepatocellular Carcinoma: A Review of the University of Tsukuba Experience, Int. J. Part. Ther, vol.2, issue.4, pp.570-578, 2016.

T. C. Ling, J. I. Kang, D. A. Bush, J. D. Slater, and G. Y. Yang, Proton therapy for hepatocellular carcinoma, Chin. J. Cancer Res, vol.24, issue.4, pp.361-367, 2012.

G. S. Yoo, J. I. Yu, and H. C. Park, Proton therapy for hepatocellular carcinoma: Current knowledges and future perspectives, World J. Gastroenterol, vol.24, issue.28, pp.3090-3100, 2018.

N. N. Sanford, Protons versus Photons for Unresectable Hepatocellular Carcinoma: Liver Decompensation and Overall Survival, Int. J. Radiat. Oncol, 2019.

I. Buvat, Les limites du SUV, Médecine Nucl, vol.31, issue.4, pp.165-172, 2007.

J. W. Keyes, SUV: standard uptake or silly useless value?, J. Nucl. Med. Off. Publ. Soc. Nucl. Med, vol.36, issue.10, pp.1836-1839, 1995.

J. A. Thie, Understanding the standardized uptake value, its methods, and implications for usage, J. Nucl. Med. Off. Publ. Soc. Nucl. Med, vol.45, issue.9, pp.1431-1434, 2004.

R. Boellaard, N. C. Krak, O. S. Hoekstra, and A. A. Lammertsma, Effects of noise, image resolution, and ROI definition on the accuracy of standard uptake values: a simulation study, J. Nucl. Med. Off. Publ. Soc. Nucl. Med, vol.45, issue.9, pp.1519-1527, 2004.

O. Warburg, On respiratory impairment in cancer cells, Science, vol.124, issue.3215, pp.269-270, 1956.

E. K. Pauwels and F. J. Cleton, Positron-emission tomography with [18F]¯uorodeoxyglucose, p.11

R. Hustinx, F. Bénard, and A. Alavi, Whole-body FDG-PET imaging in the management of patients with cancer, Semin. Nucl. Med, vol.32, issue.1, pp.35-46, 2002.

Y. Yamamoto, Detection of Hepatocellular Carcinoma Using 11C-Choline PET: Comparison with 18F-FDG PET, J. Nucl. Med, vol.49, issue.8, pp.1245-1248, 2008.

J. Talbot, Detection of Hepatocellular Carcinoma with PET/CT: A Prospective Comparison of 18F-Fluorocholine and 18F-FDG in Patients with Cirrhosis or Chronic Liver Disease, J. Nucl. Med, vol.51, issue.11, pp.1699-1706, 2010.

J. Talbot, PET/CT in patients with hepatocellular carcinoma using [18F]fluorocholine: preliminary comparison with [18F]FDG PET/CT, Eur. J. Nucl. Med. Mol. Imaging, vol.33, issue.11, pp.1285-1289, 2006.

K. Chen and X. Chen, Positron Emission Tomography Imaging of Cancer Biology: Current Status and Future Prospects, Semin. Oncol, vol.38, issue.1, pp.70-86, 2011.

E. T. Mckinley, Limits of [18F]-FLT PET as a Biomarker of Proliferation in Oncology, PLoS ONE, vol.8, issue.3, 2013.

L. M. Kenny, Quantification of Cellular Proliferation in Tumor and Normal Tissues of Patients with Breast Cancer by [ 18 F]Fluorothymidine-Positron Emission Tomography Imaging: Evaluation of Analytical Methods, Cancer Res, vol.65, issue.21, pp.10104-10112, 2005.

O. Jacobson and X. Chen, Interrogating Tumor Metabolism and Tumor Microenvironments Using Molecular Positron Emission Tomography Imaging. Theranostic Approaches to Improve Therapeutics, Pharmacol. Rev, vol.65, issue.4, pp.1214-1256, 2013.

D. Soloviev, D. Lewis, D. Honess, and E. Aboagye, 18F]FLT: An imaging biomarker of tumour proliferation for assessment of tumour response to treatment, Eur. J. Cancer, vol.48, issue.4, pp.416-424, 2012.

L. Kenny, R. C. Coombes, D. M. Vigushin, A. Al-nahhas, S. Shousha et al., Imaging early changes in proliferation at 1 week post chemotherapy: a pilot study in breast cancer patients with 3?-deoxy-3?-[18F]fluorothymidine positron emission tomography, Eur. J. Nucl. Med. Mol. Imaging, vol.34, issue.9, pp.1339-1347, 2007.

B. S. Pio, Usefulness of 3?-[F-18]Fluoro-3?-deoxythymidine with Positron Emission Tomography in Predicting Breast Cancer Response to Therapy, Mol. Imaging Biol, vol.8, issue.1, pp.36-42, 2006.

A. K. Buck, Imaging Proliferation in Lung Tumors with PET: 18F-FLT Versus 18F-FDG, J. Nucl. Med, vol.44, issue.9, pp.1426-1431, 2003.

J. Schwarzenberg, 3?-Deoxy-3?-18F-Fluorothymidine PET and MRI for Early Survival Predictions in Patients with Recurrent Malignant Glioma Treated with Bevacizumab, J. Nucl. Med, vol.53, issue.1, pp.29-36, 2012.

Z. Li, Y. Yu, H. Zhang, G. Xu, and L. Chen, A meta-analysis comparing 18F-FLT PET with 18F-FDG PET for assessment of brain tumor recurrence, Nucl. Med. Commun, vol.36, issue.7, pp.695-701, 2015.

Q. Le, An Evaluation of Tumor Oxygenation and Gene Expression in Patients with Early Stage Non-Small Cell Lung Cancers, Clin. Cancer Res, vol.12, issue.5, pp.1507-1514, 2006.

J. A. Bertout, S. A. Patel, and M. C. Simon, The impact of O2 availability on human cancer, Nat. Rev. Cancer, vol.8, issue.12, pp.967-975, 2008.

N. C. Denko, Hypoxia, HIF1 and glucose metabolism in the solid tumour, Nat. Rev. Cancer, vol.8, issue.9, pp.705-713, 2008.

P. J. Blower, J. S. Lewis, and J. Zweit, Copper radionuclides and radiopharmaceuticals in nuclear medicine, Nucl. Med. Biol, vol.23, issue.8, pp.957-980, 1996.

F. Dehdashti, In vivo assessment of tumor hypoxia in lung cancer with 60Cu-ATSM, Eur. J. Nucl. Med. Mol. Imaging, vol.30, issue.6, pp.844-850, 2003.

G. Janoray, I. Barillot, and G. Calais, Évaluation de la réponse thérapeutique après radiothérapie stéréotaxique des lésions tumorales hépatiques, Cancer/Radiothérapie, vol.18, issue.4, pp.320-324, 2014.

S. Thureau, S. Mezzani-saillard, R. Modzelewski, A. Edet-sanson, B. Dubray et al., Intérêt de la TEP au FDG pour la radiothérapie des cancers bronchiques, Cancer/Radiothérapie, vol.15, issue.6-7, pp.504-508, 2011.

R. Jeraj, T. Bradshaw, and U. Simon, Molecular Imaging to Plan Radiotherapy and Evaluate Its Efficacy, J. Nucl. Med, vol.56, issue.11, pp.1752-1765, 2015.

A. Baumann, Recommandations communes avec l'AFEF, p.36

A. I. Gomaa, S. A. Khan, M. B. Toledano, I. Waked, and S. D. Taylor-robinson, Hepatocellular carcinoma: Epidemiology, risk factors and pathogenesis, World J. Gastroenterol, vol.14, issue.27, p.4300, 2008.

A. Tang, O. Hallouch, V. Chernyak, A. Kamaya, and C. B. Sirlin, Epidemiology of hepatocellular carcinoma: target population for surveillance and diagnosis, Abdom. Radiol, vol.43, issue.1, pp.13-25, 2018.

G. Fattovich, T. Stroffolini, I. Zagni, and F. Donato, Hepatocellular carcinoma in cirrhosis: incidence and risk factors, Gastroenterology, vol.127, issue.5, pp.35-50, 2004.

Y. Hoshida, B. C. Fuchs, and K. K. Tanabe, Prevention of hepatocellular carcinoma: potential targets, experimental models, and clinical challenges, p.55, 2013.

F. Turati, Alcohol and liver cancer: a systematic review and meta-analysis of prospective studies, Ann. Oncol, vol.25, issue.8, pp.1526-1535, 2014.

Y. A. Lee, C. Cohet, Y. Yang, L. Stayner, M. Hashibe et al., Meta-analysis of epidemiologic studies on cigarette smoking and liver cancer, Int. J. Epidemiol, vol.38, issue.6, pp.1497-1511, 2009.

S. D. Ryder, Guidelines for the diagnosis and treatment of hepatocellular carcinoma (HCC) in adults, Gut, vol.52, issue.90003, pp.1-8, 2003.

A. G. Singal, A. Pillai, and J. Tiro, Early Detection, Curative Treatment, and Survival Rates for Hepatocellular Carcinoma Surveillance in Patients with Cirrhosis: A Meta-analysis, PLoS Med, vol.11, issue.4, p.1001624, 2014.

H. Van-vlierberghe, BASL guidelines for the surveillance, diagnosis and treatment of hepatocellular carcinoma, Acta Gastro-Enterol. Belg, vol.67, issue.1, pp.14-25, 2004.

H. Autorité-de-santé, Recommandations professionnelles : surveillance des malades atteints de cirrhose non compliquée et prévention primaire des complications, 2007.

N. Ganne-carrié, Comment améliorer le dépistage de l'Hépatocarcinome ?, p.10

C. K. Kim, J. H. Lim, and W. J. Lee, Detection of hepatocellular carcinomas and dysplastic nodules in cirrhotic liver: accuracy of ultrasonography in transplant patients, J. Ultrasound Med, vol.20, issue.2, pp.99-104, 2001.

L. Bolondi, Screening for hepatocellular carcinoma in cirrhosis, J. Hepatol, vol.39, issue.6, pp.1076-1084, 2003.

L. Bolondi, Characterization of small nodules in cirrhosis by assessment of vascularity: The problem of hypovascular hepatocellular carcinoma, Hepatology, vol.42, issue.1, pp.27-34, 2005.

E. Caturelli, G. Ghittoni, P. Roselli, and M. Anti, Sensitivity rates in characterizing hepatocellular carcinomas, AJR Am. J. Roentgenol, vol.185, issue.4, pp.1079-1080, 2005.

, European Association for the Study of the Liver and European Organisation for Research and Treatment of Cancer, J. Hepatol, vol.56, issue.4, pp.908-943, 2012.

M. Sherman, Alphafetoprotein: an obituary, J. Hepatol, vol.34, issue.4, pp.603-605, 2001.

, Pathologic diagnosis of early hepatocellular carcinoma: A report of the international consensus group for hepatocellular neoplasia, Hepatology, vol.49, issue.2, pp.658-664, 2009.

A. Forner, Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: Prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma, Hepatology, vol.47, issue.1, pp.97-104, 2008.

T. Roskams and M. Kojiro, Pathology of early hepatocellular carcinoma: conventional and molecular diagnosis, Semin. Liver Dis, vol.30, issue.1, pp.17-25, 2010.

J. M. Llovet and J. Bruix, Novel advancements in the management of hepatocellular carcinoma in 2008, J. Hepatol, vol.48, pp.20-37, 2008.

A. Colli, Accuracy of Ultrasonography, Spiral CT, Magnetic Resonance, and Alpha-Fetoprotein in Diagnosing Hepatocellular Carcinoma: A Systematic Review. CME, Am. J. Gastroenterol, vol.101, issue.3, pp.513-523, 2006.

J. Blanc, Thésaurus National de Cancérologie Digestive, vol.7, p.11, 2019.

J. Chalaye, Positron emission tomography/computed tomography with 18F-fluorocholine improve tumor staging and treatment allocation in patients with hepatocellular carcinoma, J. Hepatol, vol.69, issue.2, pp.336-344, 2018.

K. Hasegawa, Comparison of the Therapeutic Outcomes Between Surgical Resection and Percutaneous Ablation for Small Hepatocellular Carcinoma, Ann. Surg. Oncol, vol.21, issue.S3, pp.348-355, 2014.

C. Yeh, Nonsteroidal anti-inflammatory drugs are associated with reduced risk of early hepatocellular carcinoma recurrence after curative liver resection: a nationwide cohort study, Ann. Surg, vol.261, issue.3, pp.521-526, 2015.

J. M. Llovet, J. Fuster, and J. , Intention-totreat analysis of surgical treatment for early hepatocellular carcinoma: Resection versus transplantation, Hepatology, vol.30, issue.6, pp.1434-1440, 1999.

S. Jonas, Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis, Hepatology, vol.33, issue.5, pp.1080-1086, 2001.

M. B. Schoenberg, Resection or Transplant in Early Hepatocellular Carcinoma: A Systematic Review and Meta-analysis, Dtsch. Aerzteblatt Online, 2017.

D. Grant, R. A. Fisher, M. Abecassis, G. Mccaughan, L. Wright et al., Should the liver transplant criteria for hepatocellular carcinoma be different for deceased donation and living donation?, Liver Transpl, vol.17, issue.S2, pp.133-138, 2011.

R. A. Fisher, Hepatocellular Carcinoma Recurrence and Death Following Living and Deceased Donor Liver Transplantation, Am. J. Transplant, vol.7, issue.6, pp.1601-1608, 2007.

Y. K. Cho, J. K. Kim, M. Y. Kim, H. Rhim, and J. K. Han, Systematic review of randomized trials for hepatocellular carcinoma treated with percutaneous ablation therapies, Hepatology, vol.49, issue.2, pp.453-459, 2009.

G. Germani, M. Pleguezuelo, K. Gurusamy, T. Meyer, G. Isgrò et al., Clinical outcomes of radiofrequency ablation, percutaneous alcohol and acetic acid injection for hepatocelullar carcinoma: A meta-analysis, J. Hepatol, vol.52, issue.3, pp.380-388, 2010.

C. Bouza, T. López-cuadrado, R. Alcázar, Z. Saz-parkinson, and J. M. Amate, Meta-analysis of percutaneous radiofrequency ablation versus ethanol injection in hepatocellular carcinoma, BMC Gastroenterol, vol.9, issue.1, 2009.

T. Jiang, Z. Zeng, P. Yang, and Y. Hu, Exploration of Superior Modality: Safety and Efficacy of Hypofractioned Image-Guided Intensity Modulated Radiation Therapy in Patients with Unresectable but Confined Intrahepatic Hepatocellular Carcinoma, Can. J. Gastroenterol. Hepatol, vol.2017, pp.1-8, 2017.

Y. Kuo, Volumetric intensity-modulated Arc (RapidArc) therapy for primary hepatocellular carcinoma: comparison with intensity-modulated radiotherapy and 3-D conformal radiotherapy, Radiat. Oncol, vol.6, issue.1, p.76, 2011.

J. C. and -. Cheng, Dosimetric analysis and comparison of three-dimensional conformal radiotherapy and intensity-modulated radiation therapy for patients with hepatocellular carcinoma and radiation-induced liver disease, Int. J. Radiat. Oncol, vol.56, issue.1, pp.229-234, 2003.

L. Wang, A Novel Monoclonal Antibody to Fibroblast Growth Factor 2 Effectively Inhibits Growth of Hepatocellular Carcinoma Xenografts, Mol. Cancer Ther, vol.11, issue.4, pp.864-872, 2012.

M. Feng and E. Ben-josef, Radiation Therapy for Hepatocellular Carcinoma, Semin. Radiat. Oncol, vol.21, issue.4, pp.271-277, 2011.

M. Feng, T. B. Brunner, and E. Ben-josef, Stereotactic Body Radiation Therapy for Liver Cancer: Effective Therapy With Minimal Impact on Quality of Life, Int. J. Radiat. Oncol, vol.93, issue.1, pp.26-28, 2015.

H. Kato, Results of the first prospective study of carbon ion radiotherapy for hepatocellular carcinoma with liver cirrhosis, Int. J. Radiat. Oncol, vol.59, issue.5, pp.1468-1476, 2004.

S. Dehne, Combination of Photon and Carbon Ion Irradiation with Targeted Therapy Substances Temsirolimus and Gemcitabine in Hepatocellular Carcinoma Cell Lines, Front. Oncol, vol.7, 2017.

S. E. Combs, Phase i study evaluating the treatment of patients with hepatocellular carcinoma (HCC) with carbon ion radiotherapy: The PROMETHEUS-01 trial, BMC Cancer, vol.11, issue.1, 2011.

M. Hata, Proton beam therapy for hepatocellular carcinoma with portal vein tumor thrombus, Cancer, vol.104, issue.4, pp.794-801, 2005.

R. Salem, Radioembolization for Hepatocellular Carcinoma Using Yttrium-90 Microspheres: A Comprehensive Report of Long-term Outcomes, Gastroenterology, vol.138, issue.1, pp.52-64, 2010.

L. M. Kulik, Safety and efficacy of 90Y radiotherapy for hepatocellular carcinoma with and without portal vein thrombosis, Hepatology, vol.47, issue.1, pp.71-81, 2007.

P. Hilgard, Radioembolization with yttrium-90 glass microspheres in hepatocellular carcinoma: European experience on safety and long-term survival, Hepatology, vol.52, issue.5, pp.1741-1749, 2010.

J. G. Wall, J. K. Benedetti, M. A. O'rourke, R. B. Natale, and J. S. Macdonald, Phase II trial to topotecan in hepatocellular carcinoma: A Southwest Oncology Group study, p.4

J. Taïeb, Gemcitabine plus oxaliplatin for patients with advanced hepatocellular carcinoma using two different schedules: GEMOX in Hepatocellular Carcinoma, Cancer, vol.98, issue.12, pp.2664-2670, 2003.

C. S. Fuchs, A phase II trial of gemcitabine in patients with advanced hepatocellular carcinoma, Cancer, vol.94, issue.12, pp.3186-3191, 2002.

E. M. O'reilly, A Phase II study of irinotecan in patients with advanced hepatocellular carcinoma, Cancer, vol.91, issue.1, pp.101-105, 2001.

T. Yang, Y. Lin, J. Chen, H. Wang, and C. Wang, Phase II study of gemcitabine in patients with advanced hepatocellular carcinoma, Cancer, vol.89, issue.4, pp.750-756, 2000.

A. Forner, J. M. Llovet, and J. Bruix, Hepatocellular carcinoma, Lancet Lond. Engl, vol.379, issue.9822, pp.1245-1255, 2012.
URL : https://hal.archives-ouvertes.fr/hal-01134844

G. Y. Lee, Phase II Study to Topotecan and Cisplatin in Advanced Hepatocellular Carcinoma, Korean J. Intern. Med, vol.18, issue.2, pp.104-108, 2003.

P. Chastagner, In Vivo Potentiation of Radiation Response by Topotecan in Human Rhabdomyosarcoma Xenografted into Nude Mice, p.8

J. Tannenbaum and B. T. Bennett, Russell and Burch's 3Rs Then and Now: The Need for Clarity in Definition and Purpose, J. Am. Assoc. Lab. Anim. Sci, vol.54, issue.2, p.13, 2015.

M. Gardès-albert, Espèces réactives de l'oxygène Comment l'oxygène peut-il devenir toxique ?, p.11, 2003.

E. Lartigau, S. Dewas, and L. Gras, L'effet Oxygène, une cible ancienne toujours d'actualité ?, Cancer/Radiothérapie, vol.12, issue.1, pp.42-49, 2008.

C. Borner, The Bcl-2 protein family: sensors and checkpoints for life-or-death decisions, Mol. Immunol, vol.39, issue.11, pp.615-647, 2003.

V. Gire, La sénescence : Une barrière télomérique à l'immortalité ou une réponse cellulaire aux stress physiologiques ?, médecine/sciences, vol.21, pp.491-497, 2005.

, Prescribing, recording, and reporting photon beam therapy, 2007.

J. Gueulette, Proton RBE for early intestinal tolerance in mice after fractionated irradiation, Radiother. Oncol, vol.61, issue.2, pp.177-184, 2001.

J. Gueulette, RBE variation as a function of depth in the 200-MeV proton beam produced at the National Accelerator Centre in Faure (South Africa), Radiother. Oncol, vol.42, issue.3, pp.303-309, 1997.

J. Gueulette, Relative biologic effectiveness determination in mouse intestine for scanning proton beam at Paul Scherrer Institute, Switzerland. Influence of motion, Int. J. Radiat. Oncol. Biol. Phys, vol.62, issue.3, pp.838-845, 2005.

L. E. Gerweck and S. V. Kozin, Relative biological effectiveness of proton beams in clinical therapy, Radiother. Oncol. J. Eur. Soc. Ther. Radiol. Oncol, vol.50, issue.2, pp.135-142, 1999.

H. Paganetti and M. Goitein, Radiobiological significance of beamline dependent proton energy distributions in a spread-out Bragg peak, Med. Phys, vol.27, issue.5, pp.1119-1126, 2000.

H. Paganetti, Relative biological effectiveness (RBE) values for proton beam therapy, Int. J. Radiat. Oncol. Biol. Phys, vol.53, issue.2, pp.407-421, 2002.

H. Paganetti, Proton Relative Biological Effectiveness -Uncertainties and Opportunities, Int. J. Part. Ther, vol.5, issue.1, pp.2-14, 2018.

I. L. Ibañez, Induction and rejoining of DNA double strand breaks assessed by H2AX phosphorylation in melanoma cells irradiated with proton and lithium beams, Int. J. Radiat. Oncol. Biol. Phys, vol.74, issue.4, pp.1226-1235, 2009.

V. Calugaru, C. Nauraye, G. Noël, N. Giocanti, V. Favaudon et al., Radiobiological characterization of two therapeutic proton beams with different initial energy spectra used at the Institut Curie Proton Therapy Center in Orsay, Int. J. Radiat. Oncol. Biol. Phys, vol.81, issue.4, pp.1136-1143, 2011.

M. R. Estécio, LINE-1 hypomethylation in cancer is highly variable and inversely correlated with microsatellite instability, PloS One, vol.2, issue.5, p.399, 2007.

J. G. Herman, Hypermethylation of tumor suppressor genes in cancer, Semin. Cancer Biol, vol.9, issue.5, pp.359-367, 1999.

O. Galm, J. G. Herman, and S. B. Baylin, The fundamental role of epigenetics in hematopoietic malignancies, Blood Rev, vol.20, issue.1, pp.1-13, 2006.

H. E. Carraway, Promoter hypermethylation in sentinel lymph nodes as a marker for breast cancer recurrence, Breast Cancer Res. Treat, vol.114, issue.2, pp.315-325, 2009.

A. M. Ristic-fira, Response of a Human Melanoma Cell Line to Low and High Ionizing Radiation, Ann. N. Y. Acad. Sci, vol.1095, issue.1, pp.165-174, 2007.

C. and D. Pietro, Cellular and molecular effects of protons: Apoptosis induction and potential implications for cancer therapy, Apoptosis, vol.11, issue.1, pp.57-66, 2006.

H. Narang, Differential activation of mitogen-activated protein kinases following high and low LET radiation in murine macrophage cell line, Mol. Cell. Biochem, vol.324, issue.1-2, pp.85-91, 2009.

, Proton induces apoptosis of hypoxic tumor cells by the p53-dependent and p38/JNK MAPK signaling pathways, Int. J. Oncol, 1992.

K. B. Lee, J. Lee, J. Park, T. Huh, and Y. M. Lee, Low energy proton beam induces tumor cell apoptosis through reactive oxygen species and activation of caspases, Exp. Mol. Med, vol.40, issue.1, pp.118-129, 2008.

G. H. Jang, J. Ha, T. Huh, and Y. M. Lee, Effect of proton beam on blood vessel formation in early developing zebrafish (Danio rerio) embryos, Arch. Pharm. Res, vol.31, issue.6, pp.779-785, 2008.

P. Grabham, P. Sharma, A. Bigelow, and C. Geard, Two distinct types of the inhibition of vasculogenesis by different species of charged particles, Vasc. Cell, vol.5, issue.1, p.16, 2013.

S. Girdhani, R. Sachs, and L. Hlatky, Biological effects of proton radiation: what we know and don't know, Radiat. Res, vol.179, issue.3, pp.257-272, 2013.

E. H. Kajioka, M. L. Andres, X. W. Mao, M. F. Moyers, G. A. Nelson et al., Hematological and TGF-beta variations after whole-body proton irradiation, Vivo Athens Greece, vol.14, issue.6, pp.703-708, 2000.

F. Pagès, J. Galon, M. Dieu-nosjean, E. Tartour, C. Sautès-fridman et al., Immune infiltration in human tumors: a prognostic factor that should not be ignored, Oncogene, vol.29, issue.8, pp.1093-1102, 2010.

K. N. Rithidech, P. Reungpatthanaphong, L. Honikel, A. Rusek, and S. R. Simon, Dose-rate effects of protons on in vivo activation of nuclear factor-kappa B and cytokines in mouse bone marrow cells, Radiat. Environ. Biophys, vol.49, issue.3, pp.405-419, 2010.

A. Altmeyer, Cell Death After High-LET Irradiation in Orthotopic Human Hepatocellular Carcinoma In Vivo, In Vivo, vol.25, issue.1, pp.1-9, 2011.

S. C. Heffelfinger, H. H. Hawkins, J. Barrish, L. Taylor, and G. J. Darlington, SK HEP-1: a human cell line of endothelial origin, Vitro Cell. Dev. Biol. J. Tissue Cult. Assoc, vol.28, issue.2, pp.136-142, 1992.

J. R. Eun, Hepatoma SK Hep-1 cells exhibit characteristics of oncogenic mesenchymal stem cells with highly metastatic capacity, PloS One, vol.9, issue.10, p.110744, 2014.

J. E. Glasgow and R. W. Colman, Fibronectin Synthesized by a Human Hepatoma Cell Line, Cancer Res, vol.44, issue.7, pp.3022-3028, 1984.

S. P. Flanagan, Nude', a new hairless gene with pleiotropic effects in the mouse, Genet. Res, vol.8, issue.3, pp.295-309, 1966.

B. Ng, Radiosensitization of Tumor-targeted Radioimmunotherapy with Prolonged Topotecan Infusion in Human Breast Cancer Xenografts, p.7

S. Guichard, A. Montazeri, E. Chatelut, I. Hennebelle, R. Bugat et al., Scheduledependent Activity of Topotecan in OVCAR-3 Ovarian Carcinoma Xenograft: Pharmacokinetic and Pharmacodynamic Evaluation, p.8

P. Marchand, Automated and efficient radiosynthesis of [18F]FLT using a low amount of precursor, Nucl. Med. Biol, vol.43, issue.8, pp.520-527, 2016.
URL : https://hal.archives-ouvertes.fr/hal-01412997

J. Trojan and G. Herrmann, Fluorine-18 FDG Positron Emission Tomography for Imaging of Hepatocellular Carcinoma, vol.94, p.6, 1999.

C. Ho, S. Chen, D. W. Yeung, and T. K. Cheng, Dual-Tracer PET/CT Imaging in Evaluation of Metastatic Hepatocellular Carcinoma, J. Nucl. Med, vol.48, issue.6, pp.902-909, 2007.

M. A. Khan, Positron emission tomography scanning in the evaluation of hepatocellular carcinoma, J. Hepatol, vol.32, issue.5, pp.792-797, 2000.

M. Lee, J. Y. Jeon, M. L. Neugent, J. Kim, and M. Yun, 18F-Fluorodeoxyglucose uptake on positron emission tomography/computed tomography is associated with metastasis and epithelial-mesenchymal transition in hepatocellular carcinoma, Clin. Exp. Metastasis, vol.34, issue.3-4, pp.251-260, 2017.

A. R. Haug, Imaging of primary liver tumors with positron-emission tomography, Q. J. Nucl. Med. Mol. Imaging, issue.3, 2017.

M. A. Huber, N. Kraut, and H. Beug, Molecular requirements for epithelial-mesenchymal transition during tumor progression, Curr. Opin. Cell Biol, vol.17, issue.5, pp.548-558, 2005.

C. Love, M. B. Tomas, G. G. Tronco, and C. J. Palestro, FDG PET of Infection and Inflammation, RadioGraphics, vol.25, issue.5, pp.1357-1368, 2005.

M. Revest, S. Patrat-delon, A. Devillers, P. Tattevin, and C. Michelet, Contribution of 18fluoro-deoxyglucose PET/CT for the diagnosis of infectious diseases, Médecine Mal. Infect, vol.44, issue.6, pp.251-260, 2014.
URL : https://hal.archives-ouvertes.fr/hal-01064982

Y. Chung, Diffusion-weighted MRI and 18F-FDG PET correlation with immunity in early radiotherapy response in BNL hepatocellular carcinoma mouse model: timeline validation, Eur. J. Nucl. Med. Mol. Imaging, vol.46, issue.8, pp.1733-1744, 2019.

R. J. Hicks, Early FDG-PET imaging after radical radiotherapy for non-small-cell lung cancer: Inflammatory changes in normal tissues correlate with tumor response and do not confound therapeutic response evaluation, Int. J. Radiat. Oncol, vol.60, issue.2, pp.412-418, 2004.

J. Ryu, N. C. Choi, A. J. Fischman, T. J. Lynch, and D. J. Mathisen, FDG-PET in staging and restaging non-small cell lung cancer after neoadjuvant chemoradiotherapy: correlation with histopathology, Lung Cancer, vol.35, issue.2, pp.179-187, 2002.

Z. Xiang, J. Erasmus, R. Komaki, J. D. Cox, and J. Y. Chang, FDG uptake correlates with recurrence and survival after treatment of unresectable stage III non-small cell lung cancer with high-dose proton therapy and chemotherapy, Radiat. Oncol. Lond. Engl, vol.7, p.144, 2012.

S. Girdhani, R. Sachs, and L. Hlatky, Biological Effects of Proton Radiation: What We Know and Don't Know, Radiat. Res, vol.179, issue.3, pp.257-272, 2013.

H. Wang, Monitoring early responses to irradiation with dual-tracer micro-PET in dualtumor bearing mice, World J. Gastroenterol. WJG, vol.16, issue.43, pp.5416-5423, 2010.

N. Vélez, A Semi-physiological-Based Pharmacokinetic/Pharmacodynamic Model to Describe the Effects of Topotecan on B-Lymphocyte Lineage Cells, Pharm. Res, vol.27, issue.3, pp.431-441, 2010.

F. , Imaging of Proliferation in Hepatocellular Carcinoma with the In Vivo Marker 18F-Fluorothymidine, J. Nucl. Med, vol.50, issue.9, pp.1441-1447, 2009.

S. R. Mudd, Pharmacodynamic Evaluation of Irinotecan Therapy by FDG and FLT PET/CT Imaging in a Colorectal Cancer Xenograft Model, Mol. Imaging Biol, vol.14, issue.5, pp.617-624, 2012.

M. M. Jensen and A. Kjaer, Monitoring of anti-cancer treatment with 18F-FDG and 18F-FLT PET: a comprehensive review of pre-clinical studies, p.26

B. Sanghera, FLT PET-CT in evaluation of treatment response, Indian J. Nucl. Med. IJNM Off. J. Soc. Nucl. Med. India, vol.29, issue.2, pp.65-73, 2014.

H. Keen, An Evaluation of 2-deoxy-2-[18F]Fluoro-D-Glucose and 3?-deoxy-3?-[18F]-Fluorothymidine Uptake in Human Tumor Xenograft Models, Mol. Imaging Biol, vol.14, issue.3, pp.355-365, 2012.

H. Meyer, A. Wienke, and A. Surov, Correlations Between Imaging Biomarkers and Proliferation Index Ki-67 in Lymphomas: A Systematic Review and Meta-Analysis

, Lymphoma Myeloma Leuk, vol.19, issue.6, pp.266-272, 2019.

G. Shen, H. Ma, F. Pang, P. Ren, and A. Kuang, Correlations of 18F-FDG and 18F-FLT uptake on PET with Ki-67 expression in patients with lung cancer: a meta-analysis, Acta Radiol. Stockh. Swed, vol.59, issue.2, pp.188-195, 1987.

C. and D. Pietro, Cellular and molecular effects of protons: Apoptosis induction and potential implications for cancer therapy, Apoptosis, vol.11, issue.1, pp.57-66, 2006.

H. Narang, Differential activation of mitogen-activated protein kinases following high and low LET radiation in murine macrophage cell line, Mol. Cell. Biochem, vol.324, issue.1-2, pp.85-91, 2009.

, Proton induces apoptosis of hypoxic tumor cells by the p53-dependent and p38/JNK MAPK signaling pathways, Int. J. Oncol, 1992.

K. B. Lee, J. Lee, J. Park, T. Huh, and Y. M. Lee, Low energy proton beam induces tumor cell apoptosis through reactive oxygen species and activation of caspases, Exp. Mol. Med, vol.40, issue.1, p.118, 2008.

M. Castilla-lièvre, Diagnostic value of combining <Superscript>11</Superscript>C-choline and <Superscript>18</Superscript>F-FDG PET/CT in hepatocellular carcinoma, Eur. J. Nucl. Med. Mol. Imaging, vol.43, issue.5, pp.852-859, 2016.

G. Stark, The effect of ionizing radiation on lipid membranes, Biochim. Biophys. Acta, vol.1071, issue.2, pp.103-122, 1991.

I. Corre, M. Guillonneau, and F. Paris, Membrane Signaling Induced by High Doses of Ionizing Radiation in the Endothelial Compartment. Relevance in Radiation Toxicity, Int. J. Mol. Sci, vol.14, issue.11, pp.22678-22696, 2013.

M. Tubiana, Dose-effect relationship and estimation of the carcinogenic effects of low doses of ionizing radiation: The joint report of the Académie des Sciences (Paris) and of the Académie Nationale de Médecine, Int. J. Radiat. Oncol, vol.63, issue.2, pp.317-319, 2005.

M. Tubiana, A. Aurengo, D. Averbeck, and R. Masse, Recent reports on the effect of low doses of ionizing radiation and its dose-effect relationship, Radiat. Environ. Biophys, vol.44, issue.4, pp.245-251, 2006.

I. R. Radford, Effect of radiomodifying agents on the ratios of X-ray-induced lesions in cellular DNA: use in lethal lesion determination, Int. J. Radiat. Biol. Relat. Stud. Phys. Chem. Med, vol.49, issue.4, pp.621-637, 1986.

D. T. Goodhead, Initial events in the cellular effects of ionizing radiations: clustered damage in DNA, Int. J. Radiat. Biol, vol.65, issue.1, pp.7-17, 1994.

D. T. Goodhead, Energy deposition stochastics and track structure: what about the target?, Radiat. Prot. Dosimetry, vol.122, issue.1-4, pp.3-15, 2006.

R. M. Anderson, D. L. Stevens, and D. T. Goodhead, M-FISH analysis shows that complex chromosome aberrations induced by ?-particle tracks are cumulative products of localized rearrangements, Proc. Natl. Acad. Sci, vol.99, issue.19, pp.12167-12172, 2002.

F. M. Lyng, C. B. Seymour, and C. Mothersill, Production of a signal by irradiated cells which leads to a response in unirradiated cells characteristic of initiation of apoptosis, Br. J. Cancer, vol.83, issue.9, pp.1223-1230, 2000.

, Résumé Mon travail de thèse a pour objectif de caractériser à l'aide de l'imagerie par Topographie par Emission de Positons (TEP) au 18 F-FDG et au 18 F-FLT, chez le petit animal, l'évolution de l'hépatocarcinome en cours de traitement par chimiothérapie

, Le modèle animal correspondait à une xénogreffe sous-cutanée d'une souche d'hépatocarcinome, sk-hep1, chez la souris nude. La chimiothérapie par Topotécan était administrée aux doses de 12,5mg/kg ou 6,25mg/kg. Le protocole de protonthérapie comprenait une irradiation en une fraction de 5 Gy

F. , et au 18 F-FLT étaient réalisées une fois par semaine

, Les deux types d'imagerie TEP ont montré un intérêt pour le suivi du traitement par chimiothérapie, permettant de déterminer une sous-dose de Topotécan. Pour le suivi de la protonthérapie, le 18 F-FLT était plus avantageux puisqu'il permettait d'individualiser une reprise tumorale pour les doses d'irradiation les plus faibles

, 18 F-FLT, hépatocarcinome, protonthérapie Résumé en anglais My thesis work consisted of closely monitor tumoral response of hepatocarcinoma inoculated to mice, using 18 F-FDG and 18 F-FLT PET imaging during chemotherapy

, Both 18 F-FDG and 18 F-FLT imaging permitted to follow chemotherapy efficacity, and to observe an insufficient dose of Topotecan at 6,25mg/kg. 18 F-FLT was better to observe tumoral escape with lower doses of protontherapy. Concerning proto-chemotherapy protocol, TEP imaging could not individualize significant difference in favor of potentiation. Key words : PET, 18 F-FDG, 18 F-FLT, hepatocarcinoma, Tumoral model was Sk-hep1 cells xenograft inoculate in subcutaneous tissue to female 8-week-old athymic nude mice