Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Bone is a remarkable multifunctional tissue with the ability to regenerate and remodel without generating any scar tissue. However, bone loss due to injury or diseases can be a great challenge and affect the patient significantly. Autologous bone grafting is commonly used throughout the world. Autograft both fills the void and is bone inductive, housing the particular cells that are needed for bone regeneration. However, a regenerative complement to autograft is of great interest as the use of biomaterials loaded with bioactive molecules can avoid donor site morbidity and the problem of a limited volume of material. Two such regenerative products that utilise bone morphogenetic protein (BMP)-7 and -2 have been used for more than a decade clinically. Unfortunately, several side effects have been reported, such as severe swelling due to inflammation and ectopic bone formation. Additionally, the products require open surgery and use of supra physiological doses of the BMPs due to poor localisation and retention of the growth factor. The purpose of this thesis was to harness the strong inductive capacity of the BMP-2 by optimising the carrier of this bioactive protein, thereby minimising the side effects that are associated with the clinical products and facilitating safe and localised bone regeneration. We focused on an injectable hyaluronan-based carrier developed through polymer chemistry at the University of Uppsala. The strategy was to use the body’s own regenerative pathway to stimulate and enhance bone healing in a manner similar to the natural bone-healing process. The hyaluronan-based carrier has a similar composition to the natural extracellular matrix and is degraded by resident enzymes. Earlier studies have shown improved properties when adding hydroxyapatite, a calcium phosphate that constitutes the inorganic part of the bone matrix. In Paper I, the aim was to improve the carrier by adding other forms of calcium phosphate. The results indicated that bone formation was enhanced when using nano-sized hydroxyapatite. In Paper II, we discovered the importance of crushing the material, thus enhancing permeability and enlarging the surface area. We wished to further develop the carrier system, but were lacking an animal model with relatively high throughput, facilitated access, paired data, and we were also committed to the 3Rs of refinement, reduction, and replacement. To meet these challenges, we developed and refined an animal model, and this is described in Paper III. In Paper IV, we sought to further optimise the biomaterial properties of the hydrogel through covalent bonding of bisphosphonates to the hyaluronan hydrogel. This resulted in exceptional retention of the growth factor BMP-2. In Paper V, SPECT/PET/µCT was combined as a tri-modal imaging method to allow visualisation of the biomaterial’s in situ action, in terms of drug retention, osteoblast activity and mineralisation. Finally, in Paper VI the correlation between existing in vitro results with in vivo outcomes was observed for an array of biomaterials. The study identified a surprisingly poor correlation between in vitro and in vivo assessment of biomaterials for osteogenesis.

L’objectif général de ce travail de thèse a été de caractériser in vivo, chez l’Homme, les réorganisations mnésiques retrouvées dans l’épilepsie temporo-mésiale pharmaco-résistante.Nous nous sommes appuyés sur une approche multimodale d’imagerie combinant étude de la connectivité et des réseaux d’activations mnésiques en IRMf, et étude de la consommation métabolique régionale inter-critique de glucose en TEP. Il s’agissait, notamment, de mieux comprendre la relative préservation mnésique retrouvée chez certains de ces patients, malgré l’implication du cortex temporal interne au sein de leurs réseaux épileptiques.Nos résultats, obtenus pour l’encodage d’items uniques non matériel-spécifiques, apportent des connaissances nouvelles sur l’adaptation fonctionnelle des réseaux cognitifs au sein et en dehors de la zone épileptogène, expliquant les différences de performance mnésique en reconnaissance, et leur lien possible avec les réseaux épileptiques.Ces travaux suggèrent, notamment, l’existence de ressources fonctionnelles additionnelles efficaces, à la fois locales et à distance, impliquant la voie visuelle ventrale bilatérale. Ces processus de compensation pourraient être conditionnés par les caractéristiques propres de l’atteinte primitive, et en particulier une implication différente des structures temporales internes au sein de la zone épileptogène. L’altération fonctionnelle de ce système perceptivo-mnésique pourrait induire une réorganisation inefficace plus large, sollicitant l’activation alternative des réseaux de l’attention, au niveau des régions fronto-cingulaires et pariétales. / The overall objective of this thesis was to characterize in vivo the human memory reorganization observed in medial temporal lobe epilepsy, in particular for recognition memory.We conducted a multimodal neuroimaging approach, combining the study of connectivity and memory activation networks with fMRI, and the study of inter-ictal cerebral metabolic rate of glucose with PET. We aimed to better understand the relative preservation of memory found in some patients, despite the involvement of the medial temporal lobe within their epileptic networks. Our findings, obtained for the encoding of non material-specific single items, provide new insights into the functional adaptation of cognitive networks, within and outside the epileptogenic zone, and help to explain the differences in recognition performance, and their possible relationship with epileptic networks. These studies suggest, in particular, the existence of local and remote compensatory mechanisms which are functionally effective and involve the ventral visual stream bilaterally. These could be influenced by the exact involvement of medial temporal structures within the epileptogenic zone. The impairment of this perceptive-memory system may lead to a more large-scale reorganization with the alternative activation of an inefficient network of attention-related areas involving fronto-cingulate and parietal cortices.

<p>Studija je imala za cilj da pokaže značaj primene PET/CT pregleda u planiranju radiolo&scaron;ke terapije kod pacijenata obolelih od Hočkinovog linfoma. U Vojvodini je 2009. godine prema podacima Registra za maligne neoplazme Vojvodine incidence za Hočkinov limfom iznosila 2,7 na 100 000 dok je mortalitet bio 1,1 na 100 000 stanovnika. Na osnovu dostupnih podataka Registra za maligne neoplazme Vojvodine beleži se porast incidence u protekloj deceniji. Procenat obolelih u Vojvodini u korelaciji je sa podacima koje navodi i Međunarodna agencija za istraživanje raka iz Liona (IARC). U Evropi i u Sjedinjenim Američkim Državama postoji bimodularna kriva incidence po starosti koja pokazuje maksimalne vrednosti u period između 20 i 30 godina i nakon 55. godine. S obzirom da od Hočkinovog limfoma dominantnije obolevaju mlađe osobe a da bolest ima dobru prognozu neophodno je iznaći nove načine za inicijalno određivanje stadijuma bolesti, kao i metode koje mogu da unaprede kvalitet lečenja. Jedan od načina je primena &scaron;to savremenijih dijagnostičkih metoda. PET-CT je imidžing metoda koja poslednjih godina zauzima značajno mesto u određivanju stadijuma malignih bolesti kao i u proceni odgovora na primenjenu terapiju. Fuzionisanjem skenova PET-a i CT-a dobija se PET-CT slika koja prikazuje funkcionalno stanje pojedinih tkiva i organa (PET) sa anatomskim detaljima (CT). Cilj istraživanja je bio da se utvrdi prednost PET-CT pregleda u planiranju radioterapije kod pacijenata sa supradijafragmalnom lokalizacijom bolesti. Nakon postavljanja dijagnoze Hočkinovog limfoma kod pacijenata je urađen PET-CT i planiranje radiolo&scaron;ke terapije. Zračna terapija je planirana na osnovu nalaza PET-CT-a i njegovom fuzijom sa CT-om za planiranje radiolo&scaron;kog lečenja. Dobijeni planovi su poređeni sa onim koji su rađeni standardnom 3D konformalnom tehnikom bez fuzije. Poređeni su klinički volumeni (CTV) i planirani volumen (PTV) kao i razlike u njihovoj obuhvaćenosti preskribovanom dozom. Pokazano je da postoji statistički značajna razlika u ciljnim volumenima kao i u njihovoj obuhvaćenosti. Posmatrani su takođe i rizični organi- srce, pluća, dojke, &scaron;titasta žlezda, kičmena moždina i doze koje oni prime. Dokazano je da su sa statističkom značajno&scaron;ću dozna opterećenja na navedene rizične organe manja kada se planiranje vr&scaron;i na osnovu fuzije sa PET-CT-om, te se na osnovu toga može reći da će i očekivane manifestacije kasne toksičnosti biti manje. Istraživanjem je potvrđena hipoteza da PET/CT ima veliku prednost u planiranju radioterapije jer smanjuje zapremine ciljnih volumena i doprinosi pobolj&scaron;anju kvaliteta radiolo&scaron;kog lečenja.</p> / <p>This study aimed to prove that the use of PET/CT in radiotherapy planning makes a material change in the course of the treatment of the patients with Hodgkin&#39;s lymphoma. According to the data from the Registry of malignant neoplasms in Vojvodina, incidence of Hodgkin&#39;s lymphoma in Vojvodina in 2009 was 2.7 per 100 000, while the mortality rate was 1.1 per 100 000 inhabitants. Based on the available data, the said Register recorded an increase in the incidence over the past decade. The percentage of patients who were registered in Vojvodina is in correlation with the data cited by the International Agency for Research on Cancer in Lyon (IARC).In Europe and in the United States the disease has a bi-modular distribution distribution with the highest frequency rate in persons ageing from 20-30 years and people older than 55 years. Due to the fact that the dominant Hodgkin&#39;s lymphoma affects young people and having in mind the good prognosis of the disease, it is necessary to find a new modality for the initial staging of disease and methods which can improve the quality of treatment. PET/CT is the imaging method which has in recent years had an important role in the staging of malignancies, as well in the evaluation of response to therapy. PET/CT image is obtained by fusing PET scans with CT and it show functional status of certain tissues and organs (PET) with anatomical details (CT).The object of this study was to show that PET/CT examinations are preferred imaging method in radiotherapy planning in patients with localized disease above the diaphragm. After they had been diagnosed with HL, patients underwent PET/CT scan which was later used for delineation in radiotherapy planning. In this study, radiation therapy was planned on the basis of the findings of PET /CT and its fusion with CT for planning radiological treatment. The resulting plans were compared with those made using standard 3D conformal technique without fusion. Clinical volume (CTV) and the planned volume (PTV) and the differences in their coverage with the prescription dose in both plans were also compared. The study has shown a statistically significant difference in the target volume and their coverage. In addition, the dose which receive organs at risk was also examined. It has been shown that organs at risk were exposed to lower doses when using PET/CT fusion in radiotherapy planning and consequently, less incidence of late toxicity is to be expected. The study confirmed the hypothesis that PET /CT has a great advantage in the planning of radiotherapy because it reduces the volume of the target volume and improves the quality of radiation treatment.</p>

Résumé : Le trouble de l’acquisition de la coordination (TAC), d’étiologie encore indéterminée, est une anomalie neurologique affectant environ 6% des enfants de l'âge scolaire. Le TAC se manifeste essentiellement par un déficit au niveau des exécutions motrices. Le présent travail de recherche comporte deux volets portant sur le TAC. Premièrement, une étude clinique sur 129 sujets âgés de 4 à 18 ans a permis de classifier les caractéristiques du TAC en sous-groupes cliniques. Trente-trois caractéristiques du TAC, les plus fréquemment rapportées dans la littérature, ont été recensées chez nos sujets. L'application d'évaluations statistiques a permis de faire ressortir trois classes essentielles. Le deuxième volet consistait à identifier les régions cérébrales impliquées dans une tâche motrice à l'aide de l'imagerie par la tomographie d'émission par positrons (TEP). Deux sujets avec TAC et deux sujets normaux ont été étudiés en deux séances d'imagerie TEP dont l'une au repos et l'autre en tapotant du pouce sur les doigts de la main gauche non-dominante. Les analyses du premier volet ont montré, entre autres, que le TAC touchait 3.17 garçons pour une fille, que tous les sujets étaient lents, que 47% des sujets étaient gauchers ou ambidextres alors que seulement 10% sont gauchers dans la population générale, que 26% avaient une dyspraxie verbale, et que 83% avaient été diagnostiqués anxieux. Les sujets ont été classés en trois sous-groupes: 1- maladroits et autres caractéristiques, sans problème de langage; 2- trouble de l’estime de soi et relation avec les pairs; 3- difficulté de langage. En imagerie, les structures cérébrales ont été classées selon leur captation du 18F-fluorodesoxyglucose (FDG) dans les hémisphères droit et gauche, avant et après l'activation, et en comparaison avec les sujets normaux. Trois types de structures cérébrales sont ressortis avec les statistiques: des structures activées, celles relativement non sollicitées et des structures désactivées. Il y avait plus de variations dans la captation du FDG chez les sujets avec TAC que chez les normaux. En conclusion, la caractérisation des sujets avec TAC par le diagnostic clinique et par l'imagerie peut procurer un plan de thérapie adéquat et ciblé étant donné que le TAC a un large spectre et pourrait coexister avec d'autres déficits cérébraux. / Abstract : Developmental Coordination Disorder (DCD) is a neurological abnormality affecting approximately 6% of children of school age. DCD is essentially manifested by deficit in motor executions. The present research aims two parts of DCD. First, a clinical study on 129 subjects aged 4 to 18 years old allowed to classify DCD characteristics (subtyping) in three classes. Thirty-three features of DCD, the most frequently reported in literature, have been identified in our subjects. The application of statistical clustering produced three essential classes. The second part was to identify the brain regions involved in a motor task using positron emission tomography (PET) imaging. Subjects with DCD and control subjects were studied in two PET imaging sessions at rest and then by tapping the thumb on each finger of the left non-dominant hand. The results showed, that DCD concerned 3.17 boys for one girl, all subjects were slow, 47% of the subjects were left-handed or ambidextrous while only 10% are left-handed in general population, 26% had a verbal dyspraxia, and 83% had been diagnosed with anxiety. Subjects were classified into three groups: 1- clumsy and other features without language problem; 2- self-esteem and peer relationships concern; 3- difficulty of spoken language. With PET imaging, the brain structures were classified according to their uptake of 18F-fluorodeoxyglucose (FDG) in the right and left hemispheres before and after activation, and compared with normal subjects. Three types of brain structures statistically emerged: activated structures, those relatively unsolicited and those disabled. There was more variation in uptake of FDG in patients with DCD than in control subjects. In conclusion, the characterization of subjects with DCD for clinical diagnostic and imaging can provide adequate and focused treatment plan since DCD has a broad spectrum and could coexist with other brain deficits.

Dopamine is an important neurotransmitter that is involved in several human functions such as reward, cognition, emotions and movement. Abnormalities of the neurotransmitter itself, or the dopamine receptors through which it exerts its actions, contribute to a wide range of psychiatric and neurological disorders such as Parkinson’s disease and schizophrenia. Thus far, despite the great interest and extensive research, the exact role of dopamine and the causalities of dopamine related disorders are not fully understood. Here we have developed multimodal imaging methods, to investigate the release of dopamine and the distribution of the dopamine D2-like receptor family in-vivo in healthy humans. We use the [¹¹C]PHNO PET ligand, which enables exploration of dopamine-related parameters in striatal regions, and for the first time in extrastriatal regions, that are known to be associated with distinctive functions and disorders. Our methods involve robust approaches for the manual and automated delineation of these brain regions, in terms of structural and functional organisation, using information from structural and diffusion MRI images. These data have been combined with [¹¹C]PHNO PET data for quantitative dopamine imaging. Our investigation has revealed the distribution and the relative density of the D3R and D2R sites of the dopamine D2-like receptor family, in healthy humans. In addition, we have demonstrated that the release of dopamine has a functional rather than a structural specificity and that the relative densities of the D3R and D2R sites do not drive this specificity. We have also shown that the dopamine D3R receptor is primarily distributed in regions that have a central role in reward and addiction. A finding that supports theories that assigns a primarily limbic role to the D3R.

La Tomographie par émission de positons (TEP) constitue l’une des techniques d’imagerie médicale les plus novatrices pour la visualisation in vivo des processus biologiques. Elle intervient comme technique de choix pour le diagnostic dans de nombreux domaines notamment, en oncologie, cardiologie ou encore en neurologie. La conception et l’élaboration de nouveaux radiotraceurs sont en perpétuel développement. L’utilisationd’oligonucléotides (ODN) modifiés (aptamères) possédant une grande affinité et spécificité pour une cible (gène,protéine, principe actif), comme radiotraceur pour l’imagerie in vivo apparait comme une alternative intéressante. A ce jour, quelques rares exemples d’oligonucléotides marqués, par un radioisotope, ont été décrits dans la littérature.Dans ce contexte, il a été développé deux méthodologies d’introduction du radioisotope (11C ou 18F) en dernièreétape de synthèse par chimie ‘‘click’’ pour le marquage de nucléosides et d’oligonucléotides envisagés commeradiotraceurs pour la TEP. / Positron Emission Tomography (PET) is a powerful molecular-imaging technique for physiological and biologicalinvestigations in various areas, such as oncology, cardiology, and neurosciences, as well as for drug development.Due to the increasing need of this technique for in vivo applications, there is always a demand for the developmentof new tracers and radiolabeling strategies. Furthermore, because of their excellent targeting capacities and easysynthesis along with a high level of diversity, oligonucleotides are already extensively used in vitro as ligands fornucleic acids (antisense oligonucleotides), proteins, and small related molecules (aptamer oligonucleotides). Theuse of aptamers for in vivo imaging appears especially promising, because of the wide range of possibilitiesavailable to introduce variations in their structure through defined chemical modifications. However, only fewexamples of oligonucleotide labeling for PET have been reported. In this context, we have developed twomethodological ways to introduce the radioisotope (11C, 18F), by ‘‘click’’ chemistry, at the last radiosynthesis stepin order to label nucleoside and oligonucleotide as potential radiotracers for PET.

Le syndrome de détresse respiratoire aiguë (SDRA) est caractérisé par des lésions alvéolairesdiffuses qui résultent d’une lésion de la membrane alvéolo-capillaire entrainant entre autresune réaction inflammatoire intense et une perte massive et hétérogène du volume pulmonaireaéré. La tomographie par émission de positons (TEP) et la tomographie par impédanceélectrique (TIE) sont deux techniques d’imagerie fonctionnelle permettant l’étude noninvasive, quantitative et régionale du poumon.Ce travail présente le résultat d’études expérimentales conduites dans le SDRA. Tout d’abord,nous avons comparé positivement la TIE à la TEP pour la mesure de la ventilation pulmonaireet du volume aéré. Nous avons ensuite décrit et validé une technique robuste d’obtention duvolume aéré et de la ventilation spécifique en TEP sans prélèvement invasif. Enfin, nousavons étudié en TEP l’influence de la pression expiratoire positive (PEP) et du décubitusventral (DV) sur la répartition de la ventilation, de la perfusion et de l’inflammationpulmonaires. Les poumons agressés par l’acide chlorhydrique inhalé ont une inflammationsignificativement plus élevée que le groupe contrôle. Aucune différence significatived’inflammation n’a été trouvée entre les groupes expérimentaux malgré des modificationsimportantes de la répartition de la ventilation et de la perfusion régionales lors de la mise enDV. Ces études donc ont permis le développement d’un modèle porcin stable d’agressionpulmonaire aiguë et la validation de techniques d’imagerie permettant l’étude non invasive deparamètres physiologiques importants pouvant aider au réglage de la ventilation mécanique aucours du SDRA. / Acute respiratory distress syndrome (ARDS) is characterized by diffuse alveolar damage andresulting from an increased permeability of the alveolar-capillary membrane. Of notice, thereis an intense lung inflammation. Positron emission tomography (PET) and electricalimpedance tomography (EIT) allow noninvasive assessment of pulmonary ventilation,perfusion and inflammation. We use these techniques to decipher the impairments ofventilation and inflammation throughout the lungs in an experimental model of acute lunginjury by hydrochloric acid inhalation in pigs.In a first study, we compared EIT to PET in quantifying pulmonary aerated volume andventilation, using PET as a gold standard. We found that lung ventilation and volume wereaccurately measured with EIT over a wide range of lung volume and minute ventilation. Wehave then described and validated a new model to obtain lung aerated volume and ventilationwith PET, without the requirement of gas sampling in the respiratory circuit. Finally, weconducted a controlled study with PET to evaluate the effects of positive end-expiratorypressure and body position on regional lung inflammation, ventilation and perfusion.Inflammation was significantly higher in injured groups than in control. However, there wasno significant change in inflammation across ALI groups despite significant differencebetween ventilation and perfusion repartition.We have developed in this work a stable experimental model of acute lung injury andvalidated noninvasive imaging tools allowing studying of important physiologic parametersthat could help setting up mechanical ventilation.

Les travaux présentés dans ce manuscrit ont pour objectifs la synthèse chimique de nouveaux ligands de la protéine de translocation 18 kDa (TSPO), leur évaluation in vitro et le radiomarquage isotopique des candidats les plus prometteurs par l’émetteur de positons à vie brève fluor-18 (t1/2 : 109,8 minutes). Ce travail a pour finalité le développement de nouvelles sondes moléculaires ou biomarqueurs pour l’imagerie non-invasive et atraumatique par Tomographie par Emission de Positons (TEP) de la neuroinflammation, processus reconnu dans les maladies neurodégénératives telles la maladie d’Alzheimer, de Parkinson, la sclérose en plaque et certaines maladies psychiatriques.Le radioligand de choix pour l’imagerie de la TSPO est actuellement le [18F]DPA-714, une pyrazolo[1,5-a]pyrimidine marquée au fluor-18 récemment développée au laboratoire. Cependant, cette molécule subit in vivo la perte rapide de l’atome de fluor radioactif par rupture du motif fluoroalkoxy comme démontrée lors de l’étude de son métabolisme. Mon projet de thèse a donc visé à concevoir et développer de nouveaux dérivés structurellement proches de DPA-714 (analogues) pour lesquelles la liaison entre le squelette principal et le fluor-18 serait renforcée. C’est dans ce cadre que dix-neuf composés ont été préparés et évalués pour leur affinité pour la TSPO, et que deux candidats prometteurs, DPA-C5yne et CfO-DPA-714, ont été radiomarqués au fluor-18 avec de bons rendements radiochimiques (20-30 %) et de hautes radioactivités spécifiques (50-90 GBq/µmol). Ces radioligands ont également été évalués in vivo par imagerie TEP et présentent, chez l’animal, des performances équivalentes voire légèrement supérieures à [18F]DPA-714. / The work presented in this manuscript aims to describe the synthesis of new ligands of the translocation protein 18 kDa (TSPO), their in vitro evaluation and, for the most promising candidates, their isotopic radiolabelling with the short-lived positron emitter fluorine-18 (t1/2 : 109.8 minutes). The ultimate goal of this work consists in developing new molecular probes, or biomarkers, for imaging neuroinflammation in a non-invasive and atraumatic manor using Positron Emission Tomography (PET). Neuroinflammatory processes have been identified in Alzheimer and Parkinson diseases, MS and various psychiatric pathologies.The radioligand of choice for imaging TSPO is currently [18F]DPA-714, a pyrazolo[1,5-a]pyrimidine radiolabelled with fluorine-18 which has been recently prepared in our laboratories. However, [18F]DPA-714 undergoes a rapid in vivo loss of the radioactive fluorine by cleavage of the fluoroalkoxy chain as demonstrated in metabolic studies. Therefore, my PhD project aimed to design and develop new structurally related analogues of DPA-714 where the linkage between the main backbone and the fluorine-18 would be reinforced. To this extent, nineteen compounds were prepared and their affinity towards the TSPO was evaluated. Two promising candidates, coded DPA-C5yne and CfO-DPA-714, were radiolabelled with fluorine-18 with good radiochemical yields (20-30 %) and high specific radioactivities (50-90 GBq/µmol). These radioligands were also evaluated by PET imaging at the preclinical stage and displayed equivalent or slightly improved results when compared to [18F]DPA-714.

O linfoma difuso de grandes células B (LDGCB) é o linfoma não-Hodgkin mais comum em nossa instituição (49,5%) e a classificação da Organização Mundial da Saúde reconhece vários subtipos de LDGCB com base na morfologia, imuno-histoquímica (IHQ) e perfil molecular. Metade dos pacientes permanecem incuráveis com terapia padrão baseada no anticorpo monoclonal anti-CD20 (rituximabe) e quimioterapia baseada em antraciclina. Portanto, é necessário identificar pacientes de alto risco e melhorar o seu prognóstico. Na era pré-rituximabe, a melhor maneira de identificar esse grupo de alto risco baseava-se no Índice de Prognóstico Internacional (IPI). Mais recentemente, grande interesse em subtipos moleculares e a caracterização da assinatura gênica das células malignas têm sido publicados. Pacientes com perfil de expressão gênica do centro germinativo (CG) parecem ter melhor prognóstico do que aqueles com assinatura de células B ativadas. Algoritmos IHC correspondentes foram propostos e o de Hans é o mais usado. No entanto, estes indicadores prognósticos têm sido questionados na era rituximabe. Além da classificação molecular, imagem funcional das células tumorais com 18F-fluodesoxiglucose (18F-FDG), a tomografia por emissão de pósitrons (PET/CT) tem sido recomendada ao diagnóstico e final do tratamento para aumentar a acurácia do estadiamento e avaliação de resposta. Embora alguns estudos tenham demonstrado que PET ínterim pode prognosticar a eficácia do tratamento, não há consenso e a utilização da PETi permanece controversa. O objetivo deste estudo foi investigar o impacto de fatores prognósticos clínicos, da PETi após dois ciclos de quimioterapia, e a célula de origem (CO) usando o algoritmo de Hans, como ferramentas prognósticas em pacientes tratados com R-CHOP 21. Foram analisados prospectivamente 147 pacientes. Dados clínicos estavam disponíveis em 146 casos. PETi foi realizada em 111 pacientes e 114 pacientes foram classificados em CG e NCG pelo algoritmo IHC de Hans. Com mediana de seguimento de 42,8 meses, a sobrevida global (SG), sobrevida livre de progressão (SLP) e resposta global (RG) para todos os pacientes foram 73,8%, 84,3% e 87,7%, respectivamente. IPI, R-IPI e NCCN IPI foram todos preditivos de SG. O IPI NCCN foi capaz de melhor discriminar um grupo de alto risco quando comparado ao de outros índices prognósticos clínicos. Embora PETi- tenha identificado um grupo com melhor SG (89,3% SG para PETi- versus 77,5% para a PETi+)(p = 0,04), a SLP entre os dois grupos não foi prognóstica (p=0,45), com SLP em 30 meses de 87,7%/81,2% para PETi- e PET+, respectivamente. O algoritmo de Hans não foi preditivo de SG, SLP ou RG. Associado à PETi-, ser do CG identificou um grupo de muito bom prognóstico, com SG e SLP de 100% em 48 meses. A análise univariada e multivariada revelou que, além da PETi-, o IPI, R-IPI e IPI do NCCN, juntamente com algumas variáveis que compõem este índice, foram preditivos para o SG, SLP e resposta completa. Este estudo mostrou que os fatores prognósticos clínicos são relevantes na era R-CHOP e a PETI, junto com a CO, foram capazes de identificar um subgrupo de muito bom prognóstico. Nossos resultados necessitam de confirmação / Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma in our institution (49.5%) and the World Health Organization classification recognizes several subtypes of DLBCL based on morphology, immunohistochemistry (IHC) and molecular analysis. A half of patients remain incurable with standard strategy with anti-CD20 monoclonal antibody (rituximab) and anthracycline-based chemotherapy. Therefore, it is necessary to identify high risk patients and improve their prognosis. In the pre-rituximab era, the best way to identify this high risk group was based on International Prognostic Index (IPI). More recently, lot of interest on molecular subtypes and aspects that characterize the gene signature of the malignant cells have been published. Patients with gene expression profile from germinal center (GC) seem to show better prognosis than those with Bcells activated signature. Correspondents algorithms based on IHC were proposed and Hans algorithm is the most commonly used. However these prognostic indicators have also been questioned in the rituximab era. In addition to the molecular classification, functional imaging of the tumor cells with 18F-fludeoxyglucose (18F-FDG) positron emission tomography PET/CT has been recommended at diagnosis and at the end of treatment to improve accuracy of staging and response evaluation. Although some studies have shown that interim PET may be a prognostic indicator of effectiveness of treatment, there is no agreement and the use of interim PET as a prognostic factor remains controversial. The objective of this study was to investigate the impact of clinical prognostic factors, interim imaging with 18F-FDG PET/CT after 2 cycles of treatment and cell of origin (CO) using Hans\' algorithm as prognostic tools in patients treated with R-CHOP 21. 147 DLBCL patients were analyzed prospectively and clinical data was available in 146 cases. 18 F-FDG interim PET/CT was performed in 111 patients and DLBCL was classified as GC and NGC subtype by IHC using Hans\'s algorithm in 114 patients. With a median follow-up of 42.8 months, overall survival (OS), progression free survival (PFS) and overall response (OR) for all patients were 73.8%, 84.3% and 87.7% respectively. IPI, R-IPI and NCCN IPI were all predictive of OS. NCCN IPI was able to better discriminate a high risk group comparable with other clinical prognostic indexes. Although negative iPET identified a group with better OS (89.3% OS for PETi- versus 77.5% for PETi+)(p=0.04), PFS between the two groups was not prognostic (p=0.45) with a 30 months PFS of 87.7% and 81.2%, for PETi- and PET+, respectively. Hans algorithm was not predictive for OS, PFS or OR. Instead it was, together with PETi- and CG origin, able to predict a very good prognostic group, with both 100% OS/PFS in 48 months. The univariate and multivariate analysis revealed that besides negative interim PET, IPI, R-IPI and NCCN IPI along with some variables that compose this indexes, were predictive for OS, PFS and complete response. This study showed that clinical prognostic factors are relevant in R-CHOP era and PETi, along with CO, were able to identify a very good prognostic subgroup. Our results should be confirmed in others studies