MD Driskharroubilakouas

MD Damien Huglo

PhD Serge Mordon

PhD Maximilien Vermandel
email: m-vermandel@chru-lille.fr

Nuclear medicine for photodynamic therapy in cancer: planning, monitoring and nuclear PDT

Keywords: Photodynamic therapy, Oncology, PET, SPECT, 5-Aminolevulinic acid, PPIX Compliance with ethical standards

Photodynamic therapy (PDT) is a modality with promising results for the treatment of various cancers. PDT is increasingly included in the standard of care for different pathologies. This therapy relies on the effects of light delivered to photosensitized cells. At different stages of delivery, PDT requires imaging toplan, evaluate and monitor treatment. The contribution of molecular imaging in this context is important and continues to increase. In this article, we review the contribution of nuclear medicine imaging in oncology to PDT for planning and therapeutic monitoring purposes. Several solutions have been proposed to plan PDT from nuclear medicine imaging. For instance, photosensitizer biodistribution has been evaluated with aradiolabeled photosensitizer or with conventionalradiopharmaceuticals on positron emission tomography. The effects of PDT delivery have also been explored with specific SPECT or PET radiopharmaceuticals to evaluate the effects on cells (apoptosis, necrosis, proliferation, metabolism) or vascular damage. Finally, the synergy between photosensitizers and radiopharmaceuticals has been studied considering the Cerenkov effect to activate photosensitized cells.

Introduction

Photodynamic therapy (PDT) is apromisingstrategy for cancer therapy [START_REF] Josefsen | Unique diagnostic and therapeutic roles of porphyrins and phthalocyanines in photodynamic therapy, imaging and theranostics[END_REF][START_REF] Agostinis | Photodynamic Therapy of Cancer : An Update[END_REF] .PDT is a non-thermal treatment based on the synergy of three elements: the administration of a photosensitizer drug;light at a precise wavelength; and the presence of oxygen (Figure1). When these three components are combined, they lead to the formation of reactive oxygen species,resulting in a complex cascade of events and subsequent cell death, mainly via cytotoxic and vasculotoxicactivity.

Most of the time, PDT relies on a specific biodistribution of a photosensitizer drug to tumor cells. Amongphotosensitizer drugs, porphyrins are the most frequently used in the literature [START_REF] Debele | Drug Carrier for Photodynamic[END_REF][START_REF] Pushpan | Porphyrins in photodynamic therapy -a search for ideal photosensitizers[END_REF] .

Figure 1:Illustration of the PDT mechanism, which is initiated by the combination ofa photosensitizer,a light wave, and oxygen. PDT activation produces cytotoxic effects andfluorescence emission.

Porphyrins are macrocyclic organic compounds that have been implicated in various biological functions; the most common porphyrins areheme and chlorophyll. In addition to their interesting biological functions, they havehigh intrinsic specificity for tumors,low toxicity and favorable photophysical properties, such asfluorescence (Figure1) [START_REF] Shi | Transforming a Targeted Porphyrin Theranostic Agent into a PET Imaging Probe for Cancer[END_REF] .

PDT was initially developed for dermatological lesions, which are easily accessible to light and can be monitored by visual assessment. Based on the success of this method and despite the low penetration of light in biological tissues, apromising method has been reported for the treatment of deep tumorsusing in situ inserted optical fibers [START_REF] Bechet | Photodynamic therapy of malignant brain tumours : A complementary approach to conventional therapies[END_REF][START_REF] Quirk | Photodynamic therapy (PDT) for malignant brain tumors -where do we stand?[END_REF] . This method is referred to as interstitial photodynamic therapy (iPDT). Therefore, to assess the photosensitizerbiodistribution and monitor the therapeutic response of deep tumors, imaging is essential. Molecular imaging is a promising and prime candidate for PDT planning and monitoring, and the photosensitizer biodistribution is a relevant issue for PDT planning that radiolabeled photosensitizers or conventional PET radiopharmaceuticals may address efficiently. Molecular imaging also plays a key role in the monitoring of PDT. Radiotracers currently in use for molecular imagingmay have applications in the evaluation ofPDT effects, such as apoptosis, hypoxia, perfusion or mitochondrial viability. This article aims to present the increasing contribution of nuclear medicine imaging in oncology for the planning and monitoring of PDT and the therapeutic prospects of nuclear PDT.

Photosensitizer biodistribution for photodynamic therapy planning

PDTrelies on photosensitizer accumulation in a tumor, and some issues must be addressed prior to delivering treatment. Tumorsmay nothavesufficientphotosensitizer uptaketo enablePDT [START_REF] Floeth | Comparison of 18 F-FET PET and 5-ALA fluorescence in cerebral gliomas[END_REF][START_REF] Suzuki | Preclinical Characterization of 5-Amino-4-Oxo-[6-11 C] Hexanoic Acid as an Imaging Probe to Estimate Protoporphyrin IX Accumulation Induced by Exogenous Aminolevulinic Acid[END_REF] , or the drug accumulation may be heterogeneous. To address theseissues and provide treatment planning solutions, both thedesign ofradiolabeled photosensitizersandmolecular radiotracersalready in use clinically are relevant.

a. Radiolabeled porphyrins

Porphyrinscanberadiolabeledvia simplecomplexationchemistry with their metallo-complex chelatoras interesting biomarkers for in vivo quantitative biodistribution [START_REF] Shi | Transforming a Targeted Porphyrin Theranostic Agent into a PET Imaging Probe for Cancer[END_REF] . Radiolabeling ofporphyrins was first achieved with copper-64 in 1951 [START_REF] Waghorn | Radiolabelled porphyrins in nuclear medicine[END_REF][START_REF] Frank | The Use of Positron-Emitting Radioisotopes for the Localization of Brain Tumors[END_REF] . Hydrogen-3, carbon-14, palladium-109, sulfur-35, zinc-65, cobalt-57, andiodine-125have also been explored but are unsuitable for in vivo imaging because of their long half-lives or weak gamma photon energy. For scintigraphic imaging,neodymium-104, gallium-67, indium-111 andtechnetium-99m (99mTc), the most commonly usedisotope, have been evaluated [START_REF] Goel | Evaluation of 99mTc-labeled photosan-3, a hematoporphyrin derivative, as a potential radiopharmaceutical for tumor scintigraphy[END_REF][START_REF] Maric | Radiolabeled porphyrin vs gallium-67 citrate for the detection of human melanoma in athymic mice[END_REF][START_REF] Foster | Delineation of a transplanted malignant melanoma with indium-111-labeled porphyrin[END_REF][START_REF] Robinson | Imaging of lymph node uptake after intravenous administration of indium-111 metalloporphyrins[END_REF][START_REF] Fazaeli | Preparation and preliminary evaluation of [67Ga]tetra phenyl porphyrin complexes as possible imaging agents[END_REF][START_REF] Aboudzadeh | Production, nano-purification, radiolabeling and biodistribution study of [140Nd] 5,10,15,20-tetraphenylporphyrin complex as a possible imaging agent[END_REF][START_REF] Wang | Studies on the porphine labeled with 99mTc-pertechnetate[END_REF][START_REF] Murugesan | Preparation and biological evaluation of the new chlorin photosensitizer T3,4BCPC for detection and treatment of tumors[END_REF][START_REF] Santos | Evaluation of a 99mTc-labelled mesobisphenylporphyrin as a tumour image agent[END_REF][START_REF] Whelan | Selective incorporation of111In-labeled PHOTOFRIN by glioma tissue in vivo[END_REF] .For positron emission tomography imaging, radiolabeling with iodine-124, copper-64 and zinc-62 have been studied extensively [START_REF] Shi | Transforming a Targeted Porphyrin Theranostic Agent into a PET Imaging Probe for Cancer[END_REF][START_REF] Waghorn | Radiolabelled porphyrins in nuclear medicine[END_REF][START_REF] Bases | Attempts at tumor localization using Cu 64-labeled copper porphyrins[END_REF][START_REF] Ranyuk | PET imaging using 64Culabeled sulfophthalocyanines: Synthesis and biodistribution[END_REF][START_REF] Fazaeli | Preparation, nano purification, quality control and labeling optimization of [64Cu]-5,10,15,20-tetrakis (penta fluoro phenyl) porphyrin complex as a possible imaging agent[END_REF][START_REF] Tamura | Selective accumulation of [62Zn]-labeled glycoconjugated porphyrins as multi-functional positron emission tomography tracers in cancer cells[END_REF][START_REF] Chen | TSPO 18 kDa (PBR) targeted photosensitizers for cancer imaging (PET) and PDT[END_REF][START_REF] Pandey | Compared to Purpurinimides, the Pyropheophorbide Containing an Iodobenzyl Group showed Enhanced PDT Efficacy and Tumor Imaging (124I-PET) Ability[END_REF] .In general, radiolabeled porphyrinsaccumulate in the tumor as standard porphyrins without altering the main characteristics of the host porphyrin molecules. Consequently, labeling using metal complexes of porphyrins is the most promising method [START_REF] Shi | Transforming a Targeted Porphyrin Theranostic Agent into a PET Imaging Probe for Cancer[END_REF] . A new metal isotope well-suited forhumanPET imaging, gallium-68, is now readilyavailable. Based on the simple complexationchemistry with the porphyrin core andinexpensive germanium-68/gallium-68 radionuclide generator system, thisisotopemight become the prime isotope for radiolabeling porphyrins [START_REF] Bryden | PET/PDT theranostics: synthesis and biological evaluation of a peptide-targeted gallium porphyrin[END_REF][START_REF] Zoller | Radiolabelling and preliminary evaluation of 68Ga-tetrapyrrole derivatives as potential tracers for PET[END_REF][START_REF] Fazaeli | Development of a 68Ga-Fluorinated Porphyrin Complex as a Possible PET Imaging Agent[END_REF][START_REF] Bhadwal | Radiosynthesis and Bioevaluation of [68Ga]-Labeled 5,10,15,20-Tetra(4-methylpyridyl)-porphyrin for Possible Application as a PET Radiotracer for Tumor Imaging[END_REF] .Unfortunately, despite severalproposals forpersonalized planning of PDT [START_REF] Josefsen | Unique diagnostic and therapeutic roles of porphyrins and phthalocyanines in photodynamic therapy, imaging and theranostics[END_REF][START_REF] Shi | Transforming a Targeted Porphyrin Theranostic Agent into a PET Imaging Probe for Cancer[END_REF][START_REF] Goel | Evaluation of 99mTc-labeled photosan-3, a hematoporphyrin derivative, as a potential radiopharmaceutical for tumor scintigraphy[END_REF][START_REF] Murugesan | Preparation and biological evaluation of the new chlorin photosensitizer T3,4BCPC for detection and treatment of tumors[END_REF][START_REF] Santos | Evaluation of a 99mTc-labelled mesobisphenylporphyrin as a tumour image agent[END_REF] , radiolabeled porphyrins havenotbeen studied for theprediction or quantitative assessment of photosensitizeruptake, probably because, until recently, PDT was limited to superficial tumorsin which photosensitizer uptake is assessable by visual fluorescence.However, acommercialized photosensitizer for PDT, such as Photosan-3®(SeehofLaboratorium F&E GmbH, Wesselburenerkoog, Germany),successfully radiolabeled [START_REF] Goel | Evaluation of 99mTc-labeled photosan-3, a hematoporphyrin derivative, as a potential radiopharmaceutical for tumor scintigraphy[END_REF][START_REF] Whelan | Selective incorporation of111In-labeled PHOTOFRIN by glioma tissue in vivo[END_REF] with 99m-technetitum might be evaluated to individualize PDT treatment protocols. b. Photosensitizer prodrug: the case of 5-aminolevulinic acid 5-Aminolevulinic acid (5-ALA) is a prodrug compound that is biologically inactive and preferentiallyaccumulatesin tumor cells, whereit is transformed into protoporphyrin IX (PpIX) with ahightumor/surrounding healthy tissue ratio, particularly for glioblastoma. Hence, 5-ALA induces the selective accumulation of PpIX in tumor tissues. Consequently, 5-ALA is mainly used in clinical practice for fluorescence-guided resection of glioma to facilitate more complete resection compared with conventional surgery [START_REF] Stummer | Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial[END_REF] . Objective responses have been observed for the treatment of nonmelanoma skin cancer, gastrointestinal adenocarcinoma, bladder cancers, and gliomawith PDT using 5-ALA [START_REF] Agostinis | Photodynamic Therapy of Cancer : An Update[END_REF][START_REF] Suzuki | Preclinical Characterization of 5-Amino-4-Oxo-[6-11 C] Hexanoic Acid as an Imaging Probe to Estimate Protoporphyrin IX Accumulation Induced by Exogenous Aminolevulinic Acid[END_REF][START_REF] Khan | Evaluation of labelling conditions, quality control and biodistribution study of 99mTc-5-aminolevulinic acid (5-ALA): a potential liver imaging agent[END_REF] .Despite the high intrinsic specificity of PpIX for tumors, PpIX may be absent from the tumor or distributed heterogeneously, and an accurate assessment ofPpIX accumulationis expected topredict PDTefficacy. Although fluorescence imaging is ideal to assess the presence of PpIXafter 5-ALA administration, it is not always achievable for deep tumors. In response,radiolabeled 5-ALA compounds were recently developed. 5-Amino-4-oxo-[6-11C]hexanoic acid (11C-MALA) can be used to evaluate the quantitative accumulation and spatial distribution of 5-ALA in tumor tissues [START_REF] Suzuki | Preclinical Characterization of 5-Amino-4-Oxo-[6-11 C] Hexanoic Acid as an Imaging Probe to Estimate Protoporphyrin IX Accumulation Induced by Exogenous Aminolevulinic Acid[END_REF][START_REF] Suzuki | Synthesis of 11C-labeled retinoic acid, [11C]ATRA, via an alkenylboron precursor by Pd(0)-mediated rapid C-[11C] methylation[END_REF] , and forimproved clinicalavailability, 99m-technetium-5-aminolevulinic acidwas synthesized [START_REF] Khan | Evaluation of labelling conditions, quality control and biodistribution study of 99mTc-5-aminolevulinic acid (5-ALA): a potential liver imaging agent[END_REF] .However,the potential correlation between the tumorbiodistribution of 5-ALA and PpIX remains unclear and warrants further study.

c. Common PETradiopharmaceuticals

For certain pathologies, molecular imagingis more suitableto definetumor volumethan conventionalimaging, especially for neurosurgery or radiotherapy [START_REF] Jelercic | The role of PET-CT in radiotherapy planning of solid tumours[END_REF][START_REF] Niyazi | FET-PET for malignant glioma treatment planning[END_REF][START_REF] Nowosielski | An intra-individual comparison of MRI, [18F]-FET and [ 18F]-FLT PET in patients with high-grade gliomas[END_REF] . For example, PDT planning including 18F-fluorodeoxyglucose PET (18F-FDG PET) has been proposed for head and neck cancers [START_REF] Karakullukcu | MR and CT based treatment planning for mTHPC mediated interstitial photodynamic therapy of head and neck cancer: Description of the method[END_REF] . However, very few studies have comparedtheaccumulated amount of photosensitizer drug as a function of the target volume defined by PET imaging. Studies comparing gadoliniumdiethylenetriaminepentaacetic acid (Gd-DTPA) in Magnetic Resonance Imaging (MRI), 18Ffluoroethyl-L-tyrosine (18F-FET) PET, and 5-ALA tumorbiodistribution for glioma, glioblastoma and meningioma [START_REF] Floeth | Comparison of 18 F-FET PET and 5-ALA fluorescence in cerebral gliomas[END_REF][START_REF] Stockhammer | Association of F18-fluoroethyl-tyrosin uptake and 5-aminolevulinic acid induced fluorescence in gliomas[END_REF][START_REF] Ewelt | Finding the anaplastic focus in diffuse gliomas : The value of Gd-DTPA enhanced MRI , FET-PET , and intraoperative , ALA-derived tissue fluorescence[END_REF][START_REF] Cornelius | 5-Aminolevulinic Acid and 18 F-FET-PET as Metabolic Imaging Tools for Surgery of a Recurrent Skull Base Meningioma[END_REF][START_REF] Roessler | Intraoperative tissue fluorescence using 5aminolevolinic acid (5-ALA) is more sensitive than contrast MRI or amino acid positron emission tomography (18F-FET PET) in glioblastoma surgery[END_REF] have demonstrated that metabolic imaging with 18F-FETis superior to Gd-DPTA enhancement in MRI for predicting thedistribution of 5-ALA in glioblastoma, with a very high accuracy of 96% and a negative predictive value of 100% [START_REF] Floeth | Comparison of 18 F-FET PET and 5-ALA fluorescence in cerebral gliomas[END_REF][START_REF] Stockhammer | Association of F18-fluoroethyl-tyrosin uptake and 5-aminolevulinic acid induced fluorescence in gliomas[END_REF] . Thus,18F-FET PET is an importanttool for PDT in the brain,where the local fluorescence of PpIXcannot be observed. However, no study has compared the tumor distribution of 5-ALA to that of 3,4-dihydroxy-6-18 F-fluoro-l-phenylalanine (18F-FDOPA), although the latter exhibits abetter ratio of brain tumor/healthy tissue with Carbidopa premedicationthan 18F-FET [START_REF] Kratochwil | Intra-individual comparison of 18F-FET and 18F-DOPA in PET imaging of recurrent brain tumors[END_REF] . However, these studies also showed that the accuracy of 18F-FET to predict the 5-ALA tumor distribution decreased for low-grade glioma. These results are not due to the failure of 18F-FET PET but confirm that 5-ALA and porphyrins in generalare sensitive to tumor grade [START_REF] Floeth | Comparison of 18 F-FET PET and 5-ALA fluorescence in cerebral gliomas[END_REF] . Porphyrin accumulation depends on the type of cancer and especially on the degree of differentiation [START_REF] Suzuki | Preclinical Characterization of 5-Amino-4-Oxo-[6-11 C] Hexanoic Acid as an Imaging Probe to Estimate Protoporphyrin IX Accumulation Induced by Exogenous Aminolevulinic Acid[END_REF][START_REF] Valdés | δ$-aminolevulinic acid-induced protoporphyrin IX concentration correlates with histopathologic markers of malignancy in human gliomas: the need for quantitative fluorescence-guided resection to identify regions of increasing malignancy[END_REF] . For gliomas, 18F-FET quantitative accumulation is correlated with tumorgrade, and18F-FDGaccumulation is inversely correlated to tumor differentiation. For high-grade and dedifferentiatedtumors, the glucose metabolism observed on 18F-FDG PET may be correlated withphotosensitizer accumulation. In this context, an in vitro study demonstrated that 18F-FDG uptake before PDT can predicttreatment efficacy [START_REF] Liu | Differentiation of tumor sensitivity to photodynamic therapy and early evaluation of treatment effect by nuclear medicine techniques[END_REF] . This last point deserves further exploration.

Photodynamic therapy monitoring

Monitoring is required to evaluate the treatment response. In the early stage, monitoring enables adaptation of delivery in case of an inadequate response or the prediction of long-term response. Monitoring is generally accomplished using specific biomarkersto estimate the evolution of the disease.Tumorfluorescencecan be considereda biomarkerfor monitoringtreatment response when considering superficial tumors. However, as for the study of the biodistribution of photosensitizer drugs, fluorescence cannot be used for deep tumors. Several studies have proposed to address this problemby including metabolic imaging inPDT protocols to provide biomarkers and prognostic factorsto predicttreatment response earlier than morphological imaging [START_REF] Josefsen | Unique diagnostic and therapeutic roles of porphyrins and phthalocyanines in photodynamic therapy, imaging and theranostics[END_REF][START_REF] Shi | Transforming a Targeted Porphyrin Theranostic Agent into a PET Imaging Probe for Cancer[END_REF][START_REF] Murugesan | Preparation and biological evaluation of the new chlorin photosensitizer T3,4BCPC for detection and treatment of tumors[END_REF][START_REF] Santos | Evaluation of a 99mTc-labelled mesobisphenylporphyrin as a tumour image agent[END_REF] .

Radiolabeledporphyrinsformonitoringafter PDThave been suggested but have not been investigated further [START_REF] Josefsen | Unique diagnostic and therapeutic roles of porphyrins and phthalocyanines in photodynamic therapy, imaging and theranostics[END_REF][START_REF] Shi | Transforming a Targeted Porphyrin Theranostic Agent into a PET Imaging Probe for Cancer[END_REF][START_REF] Murugesan | Preparation and biological evaluation of the new chlorin photosensitizer T3,4BCPC for detection and treatment of tumors[END_REF][START_REF] Santos | Evaluation of a 99mTc-labelled mesobisphenylporphyrin as a tumour image agent[END_REF] . The maindrawback might betheloss ofsensitivityaftertreatmentbecause tumor cellsselectedby PDT will no longer accumulatethe photosensitizer. Consequently, monitoringusing non-specificradiotracersseemsmore appropriate and convenient.

PDT induces a selective tumor response through different mechanisms. The effectivenessand preponderance ofcertain mechanismscompared to othersis influencedby the illuminationprotocol,includingthe fluence and fractionation, bytissue oxygenation, and,obviously,by the type ofphotosensitizer drug [START_REF] Agostinis | Photodynamic Therapy of Cancer : An Update[END_REF][START_REF] Tetard | Interstitial 5-ALA photodynamic therapy and glioblastoma: Preclinical model development and preliminary results[END_REF] . The mainmechanisms areimpairment of tumor vascularization and direct cell death by apoptosis and necrosis.Therefore, different PDTeffects maybe observedwith different radiotracers.The radiotracers presented in the following are of interest for monitoring PDT. These data are from preclinical studies and depend on the tumor models and therapeutic protocols (Table 1).

a. Glucose metabolismwith 18F-fluorodesoxyglucose

The glucose analogue18F-FDGenters tumor cellsvia theoverexpressed membrane transporter GLUT and accumulates by phosphorylation in the cytoplasm.This very common radiopharmaceutical can be used to observe bothtissue perfusion in minutes followingintravenous administrationandglucose metabolism in an equilibrium state (a minimum of 15min post injection). When used afterPDT,18F-FDG PETshows the treatment responseearlier thanmorphological imaging. As early as 30 minutes and 2 h after PDT, clear decreases in tumor perfusion and glucose metabolism due to the destruction of the vascular system and direct cell death [START_REF] Lapointe | High-resolution PET imaging for in vivo monitoring of tumor response after photodynamic therapy in mice[END_REF][START_REF] Byrne A | Vascular-targeted photodynamic therapy with BF2chelated Tetraaryl-Azadipyrromethene agents: a multi-modality molecular imaging approach to therapeutic assessment[END_REF] were observed. At 24 and 48 hafterPDT,18F-FDG PET imagingshowed,inmost cases,adecrease in tumormetabolism [START_REF] Byrne A | Vascular-targeted photodynamic therapy with BF2chelated Tetraaryl-Azadipyrromethene agents: a multi-modality molecular imaging approach to therapeutic assessment[END_REF][START_REF] Smith | Mono-and tri-cationic porphyrin-monoclonal antibody conjugates: Photodynamic activity and mechanism of action[END_REF] . Although one study showed an increase in tumor metabolic activity 24 h after PDT, the type of photosensitizer drug used might be responsible for this increase. The authors suggested hypermetabolism of the photosensitizerdrug, a porphyrin-monoclonal antibody conjugate, at 24 hpostPDTvia a probable acute inflammatory response [START_REF] Smith | Mono-and tri-cationic porphyrin-monoclonal antibody conjugates: Photodynamic activity and mechanism of action[END_REF] . Finally, 36 h afterPDT, the metabolic volume on18F-FDG PETdescribed the absolute volume of the survivingtumor histological massat a resolution similar to that of MRI, revealing the early extended injury caused by PDT [START_REF] Moore | Feasibility of imaging photodynamic injury to tumours by high-resolution positron emission tomography[END_REF] The radiolabeled amino acids 18F-FET and 18F-fluorodihydroxyphenylalanine (18F-DOPA)aremainly used for studies of brain tumors, in which these amino acids accumulate with excellent contrast compared to that in healthy tissuethanks to their ability to freely cross the bloodbrain barrier and the overexpression of LATtransporters by tumor cells. No study has described the monitoring of PDT with these radiopharmaceuticals, but these amino acids are ofparticularinterestfor monitoring other treatments, especially for brain tumors. 18F-DOPA and 18F-FET are used for brain tumors inclinical practice by default with MRI, particularly to differentiate tumor progression from radionecrosis after glioma radiotherapy. Thus, radiolabeled amino acidscould certainlybeused to differentiatetumor progressionfrom the tumorphotonecrosisinducedbyPDT.

c. Tumor proliferation with 18F-fluorodeoxythymidine

18F-fluorodeoxythymidine (18F-FLT), a thymidine analogue, is trapped in cells and is phosphorylated by the cytosolic thymidine kinase-1, an enzyme of the pyrimidine salvage pathway of DNA synthesis. This radiopharmaceuticalenables imagingoftumor proliferation. In two studies,18F-FLT PETshowed an early responseto treatment with clearhypometabolism4hand 24hafterPDT [START_REF] Sugiyama | Evaluation of 3′-Deoxy-3′-18 F Fluorothymidine for Monitoring Tumor Response to Radiotherapy and Photodynamic Therapy in Mice[END_REF][START_REF] O'connor | Mechanism of cell death mediated by a BF 2chelated tetraaryl-azadipyrromethene photodynamic therapeutic: Dissection of the apoptotic pathway in vitro and in vivo[END_REF] . Interestingly,afterPDT,the decrease in metabolic proliferativeactivityobserved using 18F-FLT PETappears to bemore pronouncedthan the decreased metabolism glucose activity observed by 18F-FDG PET [START_REF] Sugiyama | Evaluation of 3′-Deoxy-3′-18 F Fluorothymidine for Monitoring Tumor Response to Radiotherapy and Photodynamic Therapy in Mice[END_REF] .

d. Membranerenewal with 11C-choline

The phosphorylation of choline is catalyzed by choline kinase, whichis overexpressed in tumor cells.Phosphorylcholineis incorporated into phosphatidylcholine, a component of the cell membrane.Thus, cholineradiolabelingpermits imagingoftumormembranerenewal. There is interest in following theearlyresponse ofprostatecancer to PDT. From 1 to 48h after therapy, PET imaging with 11C-choline revealed a marked decrease intumor 11C-choline uptake [START_REF] Fei | Choline PET for monitoring early tumor response to photodynamic therapy[END_REF][START_REF] Fei | Choline Molecular Imaging with Small animal PET for Monitoring Tumor Cellular Response to Photodynamic Therapy of Cancer[END_REF] . 11C-Choline hasnot been studiedin PDT monitoringforother cancers, and the radiolabeledforms with fluorine-18 (18Ffluoromethylcholine and 18F-fluoroethylcholine) have not been studied either.

e. Apoptosis, 64-Cu-DOTA-biotin-Sav and 99-mTc-AnnexinV

Apoptosis isa mechanism of cell deathinduced byPDT and occurs very early,within the first hourfollowingPDT [START_REF] Agostinis | Photodynamic Therapy of Cancer : An Update[END_REF] . Because it is tolerated betterdue to less tissue inflammation,apoptosis is the preferred cell death mechanism when choosing the photosensitizer drug and lighting method for PDTprotocols. There are radiotracers for theapoptosis target phosphatidylserine, which is externalized by apoptotic cells. PETimaging using 64Cu-DOTA-biotin-Sav showed clear uptake within hours following PDT, from 4.5 h post PDT.The amount of timeto reach optimal contrast after PDTdepends onthe type ofphotosensitizerdrugused and ranges from6-7 hto 10-11 hpostPDTfor two differentphotosensitizerdrugs.However,the laborious protocol required prior to theinjectionof the radiotracer,which includes pretargeting with biotinylated annexin V,followed by anavidin chase to eliminate free biotinylated products,is an important drawback of the use of this radiopharmaceutical.

Moreover,the isotope 64-copperdoes not haveideal properties for diagnostic use in humans [START_REF] Cauchon | PET imaging of apoptosis with 64Cu-labeled streptavidin following pretargeting of phosphatidylserine with biotinylated annexin-V[END_REF] . Another apoptosis radiotracer used in SPECT imaging, 99m-Tc-Annexin V, was tested for PDT. 99m-Tc-Annexin V might be well-suited for clinical use because it can beeasily preparedwithin theclinical departmentofnuclearmedicine,does notrequirepretargetingsteps,and isperfectly suitedfor human use. Excellent uptake of 99mTc-Annexin V was observed in treated tumors 2, 4 and 7 h after PDT, as confirmed by histology [START_REF] Subbarayan | A simplified method for preparation of 99mTc-annexin V and its biologic evaluation for in vivo imaging of apoptosis after photodynamic therapy[END_REF] .

f. Hypoxia with 123I-iodoazomycin arabinoside

Although more recent PET radiotracers of hypoxia are available, 123I-iodoazomycin arabinoside (123I-IAZA) isthe only radiotracer that has been studied for post-PDT monitoring. 123I-IAZA is metabolically reduced in viable cells and is inversely proportional to the intracellular oxygen concentration. 123I-IAZA exhibits significant accumulation 24h after PDT,concordant with a decrease intissue perfusion [START_REF] Moore | Measurement of PDT-induced hypoxia in Dunning prostate tumors by iodine-123-iodoazomycin arabinoside[END_REF] .

g. Perfusion and mitochondrial viability with 99mTc-hexakis-2-methoxyisobutyl isonitrileor 99mTc-hexamethylpropyleneamine oxime

The cationic complex 99mTc-hexakis-2-methyoxyisobutyl isonitrile (99mTc-MIBI) is retained by the mitochondria mainly due to its lipophilicity and charge. The uptakeof 99mTc-MIBI depends on the mitochondrion membrane potential and thus reflects mitochondrial viability.This complex was initially developed to visualize myocardial perfusion using scintigraphic imaging. The use of 99mTc-MIBI to assess tumor vascular perfusion after PDT revealed that tumor vascular perfusion decreased dramatically during the 2-h period following PDT and continued to decrease to 7% of the control value 24h later [START_REF] Chan | Efficacy and mechanism of aluminum phthalocyanine and its sulfonated derivatives mediated photodynamic therapy on murine tumors[END_REF][START_REF] Brasseur | Measurement of tumor vascular damage in mice with 99mTc-MIBI following photodynamic therapy[END_REF] .Another radiopharmaceutical for perfusion is 99mTc-hexamethylpropyleneamine oxime (99mTc-HMPAO), a liposoluble molecule that diffuses into the cell and then becomes hydrophilic and remains trapped in the cytoplasm. Tumor perfusion can be assessed to evaluate the vascular damage mechanism of PDT. Monitoring of PDT with 99mTc-HMPAO revealed maximal shut-down 8h post treatment, which persisted for at least 24h [START_REF] Moore | Measurement of PDT-induced hypoxia in Dunning prostate tumors by iodine-123-iodoazomycin arabinoside[END_REF][START_REF] Moore | Noninvasive monitoring of photodynamic therapy with 99technetium HMPAO scintigraphy[END_REF] . Regardless of tissue perfusion, 99mTc-MIBI is particularly interesting because some photosensitizers,such as Photofrin®, target the mitochondria.Therefore,99mTc-MIBI doesreveal destruction of mitochondria by the free radicals produced by PDT. The role of the mitochondria in the apoptosis mechanism could explain the apoptotic action of PDT.Accordingly, an in vitro study demonstrated that 99mTc-MIBI is superior to 18F-FDG for monitoring PDT, demonstrating a linear correlation with cell viability [START_REF] Liu | Differentiation of tumor sensitivity to photodynamic therapy and early evaluation of treatment effect by nuclear medicine techniques[END_REF] .

Author

Real time photodynamic therapy monitoring with dynamic PET

A new promising method to study tumorresponsein real timehas recently been proposed to detect transient changes in uptake during treatment. This method consists of PDT applied during a dynamic PET study, with multipleshortframes reconstructed from list-mode data and a slow continuous infusion of 18F-FDG. Because of the continuous infusion, the 18F-FDG concentration does not reach an equilibrium state, but its rate of increase is constant. Thus, the effects of the treatment are observed in real time based on the kinetics of the radiopharmaceutical [START_REF] Byrne A | Vascular-targeted photodynamic therapy with BF2chelated Tetraaryl-Azadipyrromethene agents: a multi-modality molecular imaging approach to therapeutic assessment[END_REF][START_REF] Bérard | Dynamic imaging of transient metabolic processes by small-animal PET for the evaluation of photosensitizers in photodynamic therapy of cancer[END_REF][START_REF] Cauchon | Predicting efficacy of photodynamic therapy by real-time FDG-PET in a mouse tumour model[END_REF] . As previously explained,PDTacts via different mechanismsdepending on the photosensitizer drug type. The two mainmechanismsare direct cell death andimpairment of the tumor vascularization. These mechanisms can be distinguished by real-time dynamic PET (Figure 2). Thus, damage totumor vascularizationischaracterized by a delayed drop in tumor uptakethat remains significantly lower after illumination ends. Direct cell death is characterized by a rapid reduction of 18F-FDG uptake followed by rapid restoration to more than 80% of the initial rate after illumination ends. Interestingly, thisnew method has led to the discovery of a systemic response to PDT because control tumors shielded from light alsoshowed reduced 18F-FDG uptake during the illumination phase [START_REF] Bérard | Dynamic imaging of transient metabolic processes by small-animal PET for the evaluation of photosensitizers in photodynamic therapy of cancer[END_REF] .However,othermechanismsmight have affectedthe kineticsof 18F-FDG, such as apoptosis and the inflammatory response in the tumors. Selective apoptosis is a desired response to PDT,whereas inflammation is often a side effect. Recent studies have shown that a low-fluence illumination protocol is more effective and better tolerated thanks to a greater apoptotic process and less inflammation [START_REF] Mathews | The effects of ultra low fluence rate single and repetitive photodynamic therapy on glioma spheroids[END_REF][START_REF] Lilge | Apoptosis induced in vivo by photodynamic therapy in normal brain and intracranial tumour tissue[END_REF] . Dynamic PET during PDT might also be explored to compare the metabolic responsesto low and high fluence rates but remains to be studied.

Figure 2: Illustration of the vascular damage mechanism and the direct tumor cell killing mechanism observed in real time by dynamic PET. On the left, the effect of PDT with a photosensitizer inducing vascular damage ischaracterized by a delayed drop in tumor uptake, followed by a long recovery period after the illumination ends. On the right, theeffect of PDT with a photosensitizer inducing direct cell death is characterized by a rapid reduction in 18F-FDG uptake, followed by a rapid restoration after the illumination ends 61 .

Discussion and Perspectives

Molecular imaging mightfacilitate PDT planning by predicting the quantitative biodistribution of thephotosensitizer in thetumor.In particular, a new metal isotope for PET imaging, 68-gallium,offers easy radiolabeling using its metal complexes andholds promise for PDT planning [START_REF] Shi | Transforming a Targeted Porphyrin Theranostic Agent into a PET Imaging Probe for Cancer[END_REF] . Indeed, the simple complexationchemistry of 68-gallium with the porphyrin core andgood availability asthe relatively low-cost 68-germanium/68-gallium radionuclide generator system is highly suitable for radiolabeled porphyrins [START_REF] Bryden | PET/PDT theranostics: synthesis and biological evaluation of a peptide-targeted gallium porphyrin[END_REF][START_REF] Zoller | Radiolabelling and preliminary evaluation of 68Ga-tetrapyrrole derivatives as potential tracers for PET[END_REF][START_REF] Fazaeli | Development of a 68Ga-Fluorinated Porphyrin Complex as a Possible PET Imaging Agent[END_REF][START_REF] Bhadwal | Radiosynthesis and Bioevaluation of [68Ga]-Labeled 5,10,15,20-Tetra(4-methylpyridyl)-porphyrin for Possible Application as a PET Radiotracer for Tumor Imaging[END_REF] . Given the importance of tumor oxygenation for the effectiveness of PDT, it is surprising that there has been no study of the ability of 123I-IAZA or other radiotracers of hypoxia to predict and follow the response to PDT.Imaging hypoxia prior to the delivery of PDT might be akey issuefor adapting dosimetry (fractionation scheme, fluence rate, total dose).

However, radiolabeled porphyrins might not be suitable for monitoring the effect of PDT, and nonspecificmetabolic radiotracers might be preferable. Themainmechanisms observed after PDT are damage totumor vascularization and direct cell death caused by apoptosis and necrosis. Therefore, different PDTeffects maybe observedusing different metabolic radiotracers routinely used in nuclear medicine.

Moreover, real-time 18F-FDG PET during PDT can assess PDT protocols in real time and thus enable optimizationof their duration,oxygenation, andillumination to achievepersonalized treatment. Consequently, monitoring PDT by dynamic PET could be a major advance in therapy. Thus, nuclear medicine, thanks to molecular imaging, offers interesting perspectives to optimize and personalize PDT.

However, the contribution of nuclear medicine is not limited only to PDT accompaniment but could also include PDT in deep tumorsas an alternative tointerstitial PDT. This so-called nuclear PDT relies on the Cherenkov effect as an alternative light source for PDT in deep tissue.Cherenkov radiation is an optical emission induced when charged particles move faster than the speed of light in a dielectric medium. This phenomenon is well known in the nuclear energy industry as it is responsible for the blue glow of an underwater nuclear reactor. The threshold energy of β-particles (electrons) to produce Cherenkov radiation in tissues is 0.219MeV. High-energy photons can also indirectly produce Cherenkov radiation by secondary electrons caused by photoelectric interaction or Compton scattering [START_REF] Thorek | Cerenkov imaging -a new modality for molecular imaging[END_REF] . Several isotopes used in radiopharmaceuticals emit particles with a greater energy than the threshold of 0.219MeV and thus produce Cherenkov radiation [START_REF] Gill | Computed Cerenkov luminescence yields for radionuclides used in biology and medicine[END_REF][START_REF] Liu | Molecular optical imaging with radioactive probes[END_REF][START_REF] Dothager | Cerenkov radiation energy transfer (CRET) imaging: A novel method for optical imaging of PET isotopes in biological systems[END_REF] . Several recent studies have examined Cherenkov luminescence tomography, including in small animals [START_REF] Hu | Experimental Cerenkov luminescence tomography of the mouse model with SPECT imaging validation[END_REF][START_REF] Li | Cerenkov luminescence tomography for small-animal imaging[END_REF][START_REF] Zhong | Whole-body cerenkov luminescence tomography with the finite element SP 3 method[END_REF] .Cherenkov radiation is ofparticular interest for PDT because it provides a deep light source without an invasive device. Cherenkov radiationisalso perfectly adapted to PDT with 3 major benefits: proven efficacy and better tolerance of ultra-low fluence rate excitation during PDT [START_REF] Mathews | The effects of ultra low fluence rate single and repetitive photodynamic therapy on glioma spheroids[END_REF][START_REF] Gonzales | Ultra low fluence rate photodynamic therapy : Simulation of light emitted by the Cerenkov effect[END_REF] ,with a meaningful effect at a 12 mJ/cm 2 threshold with a second-generation photosensitizer [START_REF] Hartl | Characterizing low fluence thresholds for in vitro photodynamic therapy[END_REF] ; blueluminescenceoptimal for the activation of porphyrins 1,74 (Figure 3); and light production inside the tumor.In vivo photoactivation using Cherenkov from 18FDG has been demonstrated as a proof of concept [START_REF] Ran | In vivo photoactivation without "light": Use of cherenkov radiation to overcome the penetration limit of light[END_REF] , and tumor remission was achieved using aphotosensitizeractivated by Cherenkovradiation from radionuclides [START_REF] Kotagiri | Breaking the depth dependency of phototherapy with Cerenkov radiation and low-radiance-responsive nanophotosensitizers[END_REF][START_REF] Hartl | Activating Photodynamic Therapy in vitro with Cerenkov Radiation Generated from Yttrium-90[END_REF] . Isotopes with a longer half-life and emitting particles withgreater energy, such as 90Yttrium used in clinicaloncology for the treatment of lymphoma (radioimmunotherapywith Zevalin®) and hepatocellular carcinoma (radioembolizationwith SirSpheres® or TheraSphere®), could deposit an adequate total Cherenkov light dose for PDT [START_REF] Gonzales | Ultra low fluence rate photodynamic therapy : Simulation of light emitted by the Cerenkov effect[END_REF] . Thus,the synergy between internal radiotherapy and PDTwarrants further investigation (Figure4).

Conclusion

Nuclear medicine is essential in oncology. It is an indispensable tool for a variety of current therapiesand is also an asset forPDT. The simplicity and effectiveness of porphyrinradiolabeling, its low toxicity and its accumulation intumor tissues make it a potentialtheranosticagent. The contributionof nuclear medicine is not limited to monitoring and might include the estimation of Cherenkov photosensitizeruptake in deeptumors for improved treatment planning, the identification of various biologicalmechanismsof treatment andtheir effectivenessin real time, andas an optimal Cherenkov light sourceinside deep tumors.

Figure 3 :

 3 Figure 3: Absorption spectrum of protoporphyrin IX (PpIX).

Figure 4 :

 4 Figure 4: Illustration of nuclear PDT and the synergy between internal radiotherapy and photodynamic therapy.

Radiotracer Tumor histology Photosensitizer Effect evaluated Time to significant effect Model D. Lapointe et al. 1999 47

	M.	18 F-FLT	HeLa	ATX-S10(Na)	Proliferati	24h	Mice
	Sugiyama et al. 2004 51	18 F-FDG			on Glucose	Not significant
					metabolis	24h post PDT
					m
	AE.	18 F-FLT	MDA-MB-	ADPM06	Proliferati	4h	Mice
	O'Connor		231-TGL		on
	et al. 2012 52		human
			mammary
			and U87-
			TGL human
			glioma
	B. Fei et al.	11 C-Choline	PC-3 and	Pc 4	Membran	24h	Mice
	2010 53		CWR22,		erenewal
			two human
			prostate
	B. Fei et al.	11 C-Choline	PC-3 human	Pc 4	Membran	48h	Mice
	2009 54		prostate		erenewal
	N. Cauchon	64 Cu-DOTA-	EMT6	ZnPcS2 and	Apoptosis 4.5h	Mice
	et al. 2007 55	biotin-SAv	murine	AlPcS2
			mammary
	M.	99m Tc-	RIF-1	Pc 4	Apoptosis 2h	Mice
	Subbarayan	annexin V	murine
	et al. 2003 56		fibrosarcom
			a
	RB. Moore	123 I-IAZA	R3327-AT	PII	Hypoxia	24h	Rats
	et al. 1993 57	99mTc-	rat prostate		Vascular	24h
		HMPAO			damage
	WS. Chan	99m Tc-MIBI	EMT6	AlPc, AlPcS21	Vascular	3h	Mice
	et al. 1997 58		murine	and AlPcS2	damage
			mammary
	N. Brasseur	99m Tc-MIBI	EMT6	PII	Vascular	Immediately	Mice
	et al. 1996 59	Bolus 18 F-FDG	EMT6 murine mammary murine	PII and AlPcS	Glucose metabolis damage	30min post PDT	Mice
	RB. Moore	99m Tc-	mammary R3327-AT	PII	m Vascular	8h	Rats
	AT. Byrne et al. 2009 48 et al. 1992 60	Bolus 18 F-FDG HMPAO	13762 MAT B III rat mammary prostate H rat and R3327-	ADMP06	Glucose m metabolis damage	30min	Rats
	K. Smith et	Bolus 18 F-	LoVohuman	Anti-CD104-	Glucose	24h	Mice
	al. 2010 49	FDG	colon	isothiocyanato	metabolis
			adenocarcin	porphyrin	m
			oma	conjugate

Table 1 :

 1 Preclinical studies on monitoring PDT with radiopharmaceuticals.


Trinh Thuc

Andrés Le

Yann Almansa

Simon Gousseau

Masnou

Almansa

Motion-consistent video inpainting

Keywords: Video inpainting, video restoration, patches, optical flow, video editing

MOTION-CONSISTENT VIDEO INPAINTING

Thuc Trinh Le * ‡ , Andrés Almansa † , Yann Gousseau * , Simon Masnou ‡

INTRODUCTION AND PRIOR WORKS

Video inpainting aims to fill in a missing region (an occlusion) in a video using the rest of that video to produce a "plausible" result. Video inpainting has numerous applications, ranging from restoring error concealment [START_REF] Ebdelli | Video inpainting with short-term windows: application to object removal and error concealment[END_REF] or removing undesired objects [START_REF] Granados | Background inpainting for videos with dynamic objects and a free-moving camera[END_REF] to restoring scratches or damages in vintage films [START_REF] Tang | Video inpainting on digitized vintage films via maintaining spatiotemporal continuity[END_REF]. While image inpainting has attracted much attention over the last two decades [START_REF] Bertalmío | Inpainting[END_REF], video inpainting remains an underdeveloped and challenging field due to the difficulty of dealing with complex motions, the high sensitivity of our visual system to temporal inconsistencies, and the computational complexity. Most recent methods found in the literature addresses these issues using either object-based or patch-based approaches.

Under object-based approach, a preprocessing step is required to split the video into background and foreground objects, followed by an independent reconstruction of each part and the merging of the results at the end of the algorithm. Examples which fall under this category are the layered mosaic technique of Jia et al. [START_REF] Jia | Video repairing under variable illumination using cyclic motions[END_REF], the homography-based algorithm using graph cut by Granados et al. [START_REF] Granados | Background inpainting for videos with dynamic objects and a free-moving camera[END_REF] and the posture This work was supported by the French Research Agency under Grant ANR-14-CE27-001 (MIRIAM) mapping scheme by Ling et al. [START_REF] Ling | Video object inpainting using posture mapping[END_REF]. Typically, object-based methods can provide reasonable results for reconstructing a specific object, e.g. a human. However, these techniques require some strict conditions such as periodic motion [START_REF] Jia | Video repairing under variable illumination using cyclic motions[END_REF] or user assistance [START_REF] Granados | Background inpainting for videos with dynamic objects and a free-moving camera[END_REF]. Furthermore, as the foreground and background completion procedures are performed independently, blending one with the other may cause artifacts.

In patch-based methods, patches from source regions are used to fill in the occlusion in a greedy or global fashion. Greedy methods inpaint incrementally the occlusion pixel by pixel, the reconstruction order is defined by a priority term. For example, Patwardhan et al. [START_REF] Kedar A Patwardhan | Video inpainting of occluding and occluded objects[END_REF] extend to 3D space the well-known image inpainting technique in [START_REF] Criminisi | Region filling and object removal by exemplar-based image inpainting[END_REF], whereas Daisy et al. [START_REF] Daisy | Exemplar-based video completion with geometry-guided space-time patch blending[END_REF] employ a tensor voting term to calculate the priority and focus on a geometry-guided blending technique to reduce space-time artifacts. In general, these greedy methods are very sensitive and, most importantly, do not have the capacity to reconstruct motion over a large occlusion and in a coherent way.

To ensure the global consistency, a global approach is needed. A natural strategy is to minimize a global patchbased function. In their seminal contribution [START_REF] Wexler | Space-time completion of video[END_REF], Wexler et al. pioneer the optimization of a global energy based on 3D spatio-temporal patches to preserve temporal coherency. Subsequent contributions propose various improvements. In [START_REF] Newson | Video inpainting of complex scenes[END_REF], a significant step forward is made by using the 3D Patch-Match to strengthen the coherence and speed up the patch matching. In [START_REF] Granados | How not to be seen-object removal from videos of crowded scenes[END_REF], Granados et al. focus on identifying a shift map in 3D space using graph-cut. Recently, Huang et al. [START_REF] Huang | Temporally coherent completion of dynamic video[END_REF] modify Wexler's energy by adding an optical flow term to enforce the temporal coherency. These methods not only provide very impressive results but they are also compatible with many scenarios. However, they have several drawbacks such as huge computation time [START_REF] Granados | How not to be seen-object removal from videos of crowded scenes[END_REF], inability to deal with motion within large occlusion [START_REF] Newson | Video inpainting of complex scenes[END_REF] or unpleasant artifacts [START_REF] Huang | Temporally coherent completion of dynamic video[END_REF].

In order to fix these issues, we propose a fast video inpainting technique which builds upon [START_REF] Newson | Video inpainting of complex scenes[END_REF] with three major improvements. The first and most significant advancement is the heavy use of optical flow in several stages of the algorithm. Optical flow has already been used in some previous works in video inpainting. For example, Strobel et al. [START_REF] Strobel | Flow and color inpainting for video completion[END_REF] inpaint the optical flow field first and use the result to guide the nearest neighbor search. Huang et al. [START_REF] Huang | Temporally coherent completion of dynamic video[END_REF] rely on optical flow path to find the best patches and reconstruct pixel intensities. As their method uses only 2D patches, optical flow is the only part contributing to the preservation of temporal coherency, therefore the inaccurate synthesis of optical flow will generate artifacts. Our method, on the other hand, maintains the temporal consistency by using both 3D spatio-temporal patches and an optical flow term. This term is incorporated in several stages: it is inserted in the patch distance, controls the patch shape, supports the nearest neighbor search, and serves as a guide in coarse initialization. All these stages enable us to ensure the temporal coherency and the reconstruction of objects with complex motions occluded for long time periods. The second contribution is a significant reduction in computation cost achieved by parallelizing the algorithm and modifying the patch matching process. The final improvement is the integration of a confidence map and a separation map in the pixel reconstruction step to reduce artifacts. We evaluate our method under various conditions and compare it with some other state-of-the-art approaches using their public datasets. The results can be found in a dedicated website.

PROPOSED METHOD

Overview

Our method is based on a non-local patch-based energy, in the spirit of [START_REF] Wexler | Space-time completion of video[END_REF][START_REF] Newson | Video inpainting of complex scenes[END_REF]. The energy is minimized thanks to an iterative procedure embedded in a coarse-to-fine pyramidal scheme. Our algorithm involves two core steps: the computation of a nearest neighbor field in the occlusion which approximates the patches best pairwise matches, and a reconstruction step using this field to determine the values of all occluded pixels.

Within this framework, it is essential to address many problems such as the coherent preservation of motion, the searching strategy to find the appropriate patches, the computational complexity and the border artifacts. These problems are addressed in our method by modifying patch shapes and patch metric, integrating a novel optical flow-driven initialization scheme, parallelizing the algorithm, speeding up the nearest neighbor search and enhancing the reconstruction step. These techniques will be presented in the following sections.

Energy

To handle the instability caused by camera movements, a stabilization pre-processing is performed using the method in [START_REF] Odobez | Robust multiresolution estimation of parametric motion models[END_REF]. After stabilization, we minimize a Wexler-like energy E(u, φ) to find the inpainted sequence u and the corresponding patch correspondence (or shift map) φ. Denoting W p (u) the patch centered at a pixel p in the given occlusion domain H, the shift φ(p) at p is defined as the spatial offset q-p where q is a minimizer in H c of the patch distance d(W u p , W u q ) (see below for the definition of d). The energy E associated with an image u (known outside a given occlusion domain H) and a shift map φ is defined as

E (u, φ) = p∈H d 2 W u p , W u p+φ(p)
Minimizing this energy ensures that each patch W u p centered around a pixel p in the occlusion domain H is as close as possible to its nearest neighbor W u p+φ(p) outside the occlusion (in the sense that p + φ(p) / ∈ H). We use a metric d between patches defined by:

d 2 W u p , W u q = 1 |N p | r∈Np r-p+q ∈H [α u(r) -u(r -p + q) 2 2 + β T (r)-T (r-p + q) 2 2 +γ O(r) -O(r -p+q) 2 2 ].
In this expression, N p indicates a spatio-temporal neighborhood of p. It is a parallelepiped whose shape is controlled by the optical flow vector as indicated in Figure 1. This adaptive shape, different from a classical rectangle cuboid, enables us to reduce the number of patches which contain both background and foreground data. Following [START_REF] Newson | Video inpainting of complex scenes[END_REF][START_REF] Liu | Exemplar-based image inpainting using multiscale graph cuts[END_REF], our distance incorporates texture features T = ( ∂u ∂x , ∂u ∂y ). In addition, to enhance temporal coherency, we use motion features O = (|O x |, |O y |), which is composed of the modulus of the optical flow vector coordinates. Values of weights α, β, γ must be set according to the data (automatic setting is the purpose of ongoing work).

Our energy E is high dimensional and highly non-convex, but as observed in [START_REF] Arias | Analysis of a Variational Framework for Exemplar-Based Image Inpainting[END_REF] a good local minimum can be obtained by alternate minimization w.r.t u and φ, coupled with a good initialization and a coarse-to-fine multiscale scheme. Texture and motion features in the similarity metric are key to guiding the algorithm towards a good local minimum from the coarsest scale. The general structure of our algorithm is as follows:

• Build multiscale pyramids for color u, occlusion domain H, texture features T and motion features O. • Initialization at coarsest scale (see section 2.3).

• From coarsest to finest scale do:

-Iterate until convergence: * min φ (nearest neighbor search, section 2.4). * min u (pixels reconstruction, section 2.5). * features reconstruction. -If not finest scale: Upsample φ, u, and features.

Coarse initialization

Due to the non-convexity of the functionals which are typically used in global patch-based methods, having a reliable initialization is crucial for the local minimization. Nevertheless, this step is often left unspecified in the literature, with the exception of [START_REF] Newson | Video inpainting of complex scenes[END_REF] where a greedy inpainting technique using onion peel priority is proposed at coarsest scale. Such method can produce a good initialization for small occlusions. However, it tends to wipe out moving objects in long lasting occlusions. To solve this issue, we propose to use the optical flow in the priority term, which somehow extends to space-time the 2D inpainting approach of Criminisi et al. [START_REF] Criminisi | Region filling and object removal by exemplar-based image inpainting[END_REF]. More precisely, the priority term at pixel i is defined as P r i = C i .D i , where D i is the average of the optical flow magnitude in the patch centered at i, and C i ∝ exp {-d 2 (i, H coarse )} measures how close the pixel i is to the border of the original occlusion H coarse at coarsest scale).

The coarse initialization is then obtained as follows. Starting from H = H coarse , we repeat the following procedure until there remain only "background" pixels, defined as all pixels i such that D i ≤ S, where S is an adaptive threshold obtained by Otsu's method.

• Let B = H \ (H B(0, 1)), i.e. B is the one-pixel wide outer boundary of H . Calculate P r i for i ∈ B .

• Select patch P i with highest priority term P r i , and define the region to inpaint R i = P i ∩ B . • Inpaint R i and get new occlusion region H → H \R i . Thereafter, the rest of the occlusion (i.e. background pixels) is inpainted following onion peel order.

Nearest neighbor patch search

Since its introduction by Barnes et al. [START_REF] Barnes | Patchmatch: a randomized correspondence algorithm for structural image editing[END_REF], PatchMatch has become a classical tool for approximate nearest neighbor search in patch spaces, especially in the context of image and video inpainting, not only for computational speed but also for spatial consistency. The core part of the algorithm includes a propagation step to spread out good matches and a random search step to jump out of the local optima. These two steps are repeated in several iterations. In our video inpainting context, the spatio-temporal extension of Patch-Match by Newson et al. [START_REF] Newson | Video inpainting of complex scenes[END_REF] is adopted with two important modifications to improve its efficiency:

• The first modification is a speedup of PatchMatch by parallelization, following the jump flooding technique of Barnes et al. [START_REF] Barnes | Patchmatch: a randomized correspondence algorithm for structural image editing[END_REF]. To save even more computational cost, we use a sparse grid during the random search step. For PatchMatch searching in video, it is not necessary to perform the random search step for every occluded pixel; instead, we can apply this step only for pixels on a sparse grid, without losing the efficiency. The final improvement is to use foreground/background patch clustering to reduce the search space. Combining these factors enables our PatchMatch algorithm to run 5-7 times faster than the traditional one with the same accuracy.

• The second modification is to guide the propagation step using the optical flow. From the assumption that adjacent patches are more likely to have similar nearest neighbor offsets, PatchMatch achieves a good preservation of the spatial coherency. For temporal coherency, this assumption is only valid if the background is static or in periodic motion. Otherwise, it may not hold true.

To enforce the temporal consistency, instead of propagating offsets to a fixed temporal neighbor, we propagate it following the optical flow direction. To be more formal, in the propagation step, the temporal neighbor for the patch centered at pixel (x, y, t), P (x,y,t) , is P (x+Ox,y+Oy,t+1) rather than P (x,y,t+1) where O x and O y are the optical flow components in the x and y directions.

Pixel reconstruction

In this step, all pixels in the occlusion H are reconstructed using the following weighted average:

u(p) = q∈Np s p q u (p + φ(q)) q∈Np s p q
, where the weight s p q is defined as:

s p q = exp   - d 2 W u q , W u q+φ(q) 2σ 2 p   ψ q ϕ p q .
In this expression, the first term is the original weight of [START_REF] Wexler | Space-time completion of video[END_REF] based on patches similarity. We combine it with two other factors ψ q and ϕ p q . The first one is a confidence map inspired by Fedorov et al. [START_REF] Fedorov | Variational framework for non-local inpainting[END_REF], and given by

ψ q = (1 -C 0 ) exp -d(q,H c ) σ 2 + C 0 if q ∈ H 1 otherwise
where d(q, H c ) is the distance from pixel q to the occlusion border, and C 0 , σ 2 are tuning parameters. This map is used to guide the information from the border towards the center and enables us to eliminate some border artifacts. The second term ϕ p q relies on a distinction between foreground and background pixels, obtained by thresholding the modulus of the optical flow. It is set to 1 if p and q are of same type (background or foreground), otherwise it is set to 0. Therefore, when we reconstruct background pixels, we use only background patches and similarly for foreground pixels. This is a simple way to avoid the common but undesirable effect of blending between background and foreground in the final result.

EXPERIMENTAL RESULTS

Our algorithm is implemented in Matlab with the core parts (nearest neighbor serch and pixel reconstruction) in C++. For the optical flow computation, Liu's method [START_REF] Liu | Beyond pixels: exploring new representations and applications for motion analysis[END_REF] is used.

Our method is evaluated under a wide variety of conditions, including moving objects occluded by a fixed or moving domain, static or moving camera, dynamic background, large occlusions, etc. To prove the effectivity of our method, we compare its performances with other stateof-the-art algorithms [START_REF] Newson | Video inpainting of complex scenes[END_REF][START_REF] Huang | Temporally coherent completion of dynamic video[END_REF] using their publicly available datasets. Results can be found at http://perso.enst. fr/ ˜gousseau/vid_inp_motion/.

3.1. Comparison with Huang et al. [START_REF] Huang | Temporally coherent completion of dynamic video[END_REF] In this experiment, we remove undesired objects in videos recorded with hand-held camera. The dataset used is the same as in Huang et al. [START_REF] Huang | Temporally coherent completion of dynamic video[END_REF], obtained from a recent benchmark dataset in object segmentation [START_REF] Perazzi | A benchmark dataset and evaluation methodology for video object segmentation[END_REF]. It constitutes a very challenging dataset due to the dynamic scenes, the complex camera movements, the motion blur effects and the large occlusions. The occlusion mask is constructed by dilating the ground truth using a 15x15 structuring element.

Figure 2 (a) shows some representative frames of the result. From that figure, we can see that, similar with Huang et al. [START_REF] Huang | Temporally coherent completion of dynamic video[END_REF], the spatial structure (e.g the letters in the panel) is well-preserved with our approach. Figure 2(b) shows the result as an x-t slice of the video. It can be seen that our method has the ability to preserve temporal consistency due to the combination of 3D spatio-temporal patches and dense flow field. This is also achieved in [START_REF] Huang | Temporally coherent completion of dynamic video[END_REF]; however, because only 2D patches are used in [START_REF] Huang | Temporally coherent completion of dynamic video[END_REF], the quality of the output temporal coherency strongly depends on the accuracy of the optical flow computation. Such accuracy cannot be guaranteed in several complex sequences such as mallard, drift-chicante or breakdance. Furthermore, the incorrect synthesis of optical flow may lead to several displeasing artifacts. This is reported in [START_REF] Huang | Temporally coherent completion of dynamic video[END_REF] with the sequence loulous; meanwhile, our method provides a very plausible result with that sequence.

Another advantgae of our method is its speed. While it takes Huang et al. [START_REF] Huang | Temporally coherent completion of dynamic video[END_REF] approximately 3 hours to complete one video in this dataset using 2D patches, our method takes around 50 minutes.

Comparison with Newson et al. [1]

This experiment evaluates our performance in the context of the reconstruction of moving objects. We consider several videos in which moving objects cross a fixed or a moving occlusion for a long period. Such objects can be partly or even completely occluded (sequence jumping girl) and the background can be either static or dynamic.

Representative results are illustrated in figure 3. It is clearly seen from this figure that our result outperforms that [START_REF] Newson | Video inpainting of complex scenes[END_REF] cannot reconstruct the foreground object (e.g. the boat) within a long occlusion. Our method, on the other hand, has the ability to fully reconstruct the background and foreground in a consummate manner even though the object is completely occluded. Moreover, by integrating the confident map in the reconstruction step, our result has less artifacts in the border than the one in [START_REF] Newson | Video inpainting of complex scenes[END_REF], as can be seen in figure 3 (c).

CONCLUSION

This paper presents a new video inpainting technique which shows great performance in terms of both output quality and computation time thanks to a thorough use of the optical flow, a modified patch-based energy which incorporates complex informations, a modified patch searching strategy using sparse grid and patch clustering, and finally a suitable code parallelization.

Fig. 1 .

 1 Fig. 1. Our patches are parallelepipeds with x -y skew controlled by the optical flow field.

Fig. 2 .Fig. 3 .

 23 Fig. 2. (a) some representative result frames with sequences tennis (left) and bmx-bump (right). From top to bottom: our result with occlusion mask boundary in green, our result without occlusion mask, result of Huang et al. [13]. (b) x-t slice along the profile (green line) in the sequence elephant. From top to bottom: position of the slice, occlusion mask, our result, result of Huang et al. [13].