Le carcinome à cellules claires du rein (ccRCC) est une tumeur très hétérogène. Le taux de métastase est de l’ordre de 50% et les métastases des ccRCC sont peu fréquemment opérées. L’objectif de la thèse est d’une part d’analyser les facteurs prédictifs de métastases dans la tumeur primitive, et d’autre part de comparer le phénotype des tumeurs primitives et de leurs métastases dans le ccRCC par différentes approches histopathologiques et génomiques. Parmi les facteurs prédictifs de métastases, la nouvelle classification OMS/ISUP remplace l’ancienne classification de Fuhrman. L’intérêt pronostique de la nécrose tumorale est également mis en évidence. Une tumeur avec un grade donné associée à la présence de nécrose a un pronostic qui se rapproche d’une tumeur de grade plus élevé sans nécrose. Le pourcentage des cellules de grade 4 pourrait également contribuer à la stratification pronostique des patients. Une différence de survie avec un pronostic défavorable est observée pour les tumeurs dont le pourcentage des cellules de grade 4 est plus élevé (>50% vs. <10%). Au niveau moléculaire le statut du gène VHL, gène suppresseur de tumeur inactivé par un « double hit », est impliqué dans le pronostic des patients. Les ccRCC sans aucune altération de VHL sont des tumeurs plus agressives, qu’il convient d’isoler. Il existe une similarité morphologique et immunohistochimique entre les métastases et la composante de plus haut grade des tumeurs primitives correspondantes. Le profil chromosomique des métastases n’est pas totalement superposable à celui des tumeurs primitives. Il existe anomalies cytogénétiques récurrentes dans des métastases de ccRCC à des sites différents (+2p, +3q, +5, +8q, +12, +20). L’hétérogénéité tumorale retrouvée au niveau des tumeurs primitives est également retrouvée au niveau des métastases sous forme d’hétérogénéité inter- et intra-métastatique. L’analyse combinée des profils génomiques et transcriptomiques de 14 échantillons prélevés au sein d’un ccRCC primitif et de ses métastases ont permis d’identifier trois classes de clones tumoraux distincts, ne suivant aucune logique géographique. Enfin il semble exister un phénomène de multi-colonisation, qui implique non pas un, mais plusieurs clones tumoraux qui pourraient agir conjointement dans le processus métastatique. / Clear cell renal cell carcinoma (ccRCC) is a heterogeneous tumor. The metastatic rate is 50% and metastases are only rarely surgically excised. The objective of this thesis was to analyze the predictive factors of metastasis in the primary tumor on one hand; and to compare primary and metastatic phenotypes on the other hand. We combined different histopathological and genomic approaches. Considering prognostic factors, the new WHO/ISUP classification replaces the previous Fuhrman grade. The interest of tumor necrosis is also highlighted. A tumor of a certain grade with necrosis has a prognosis that is close to a tumor of higher grade without necrosis. The percentage of grade 4 cells could additionally help in stratifying patients. A significant difference in survival is observed between tumors with more than 50% grade 4 cells and tumors with less than 10%. At a molecular level, the VHL gene status (tumor suppressor gene inactivated by a double hit) could be implicated in the prognosis of patients. ccRCCs with no alteration of the gene are more aggressive tumors that need to be identified. There exists a morphological and immunohistochemical similarity between metastases and the high-grade component in corresponding primary tumors. Moreover, the chromosomal profile of metastases differs from those of the corresponding primary tumors. Recurrent cytogenetic events are observed in different metastatic sites (+2p, +3q, +5, +8q, +12, +20). The tumor heterogeneity phenomenon in primary tumors is also observed in metastases with inter- and intra- metastatic heterogeneity. The combined analysis of transcriptomic and genomic analyses of 14 specimens extracted from a single ccRCC and its metastases divided samples into three classes of sub-clones with no spatial link. We observe a multi-colonization process that implies not only one but several tumor clones that could cooperate in the metastatic process.

Gegenstand und Ziel: Einsatz des Ultraschallkontrastmittels SonoVue® zur Ermittlung der Hepatischen Transitzeit bei lebergesunden Hunden. Material und Methoden: Untersucht wurden 45 lebergesunde Hunde aus dem Patientengut der Klinik für Kleintiere der Universität Leipzig. Ausschlusskriterien waren Leber- und Herz-Kreislauferkrankungen, sowie Tumorleiden. Die Kontrastmitteluntersuchungen erfolgten am narkotisierten Tier. Das Kontrastmittel wurde intravenös appliziert. Die Zeitdifferenz zwischen Ankunft in den Leberarterien bis zum Erreichen der Lebervenen wird als Hepatische Transitzeit definiert. Die Auswertung erfolgte von zwei unabhängigen Betracht-ern, sowie einer im Ultraschallgerät installierten Analysesoftware (TIC; Time-intensity-curve). Erfasst wurden zusätzlich von jedem Patienten die Blutflussgeschwindigkeiten in der Aorta abdominalis und den Lebervenen vor und nach der Kontrastmitteluntersuchung. Ebenfalls sind die Ankunftszeiten des Kontrastmittels in den Leberarterien und Lebervenen ermittelt worden. Diese Daten wurden mit den Angaben des Alters, dem Geschlecht und dem Gewicht verglichen. Die ermittelten Ankunftszeiten des Kontrastmittels wurden mit den Blutflussgeschwindigkeiten des jeweiligen Patienten korreliert. Ergebnisse: Die Hepatische Transitzeit des Kontrastmittels SonoVue® für lebergesunde Hunde beträgt 9,82 s. Schlussfolgerungen: Die Hepatische Transitzeit des Signalverstärkers SonoVue® beim lebergesunden Hund liegt bei 9,82 s und ist damit ca. eine Sekunde kürzer als beim Men-schen. In anschließenden Studien muss bei Hunden mit nachgewiesenen Lebermetastasen die Hepatische Transitzeit ermittelt werden. Entsprechen die Ergebnisse denen aus der Human-medizin, so ist mit einer Verkürzung der Hepatischen Transitzeit zu rechnen. Insbesondere bei bekanten Primärtumor könnte mit dieser Methode eine Metastasierung früher erkannt werden.

Background: Individuals with metastatic bone disease (MBD) and multiple myeloma (MM) are commonly excluded from exercise oncology research due to safety concerns regarding potential skeletal complications including the incidence of pain, impaired mobility, pathological fracture, and spinal cord compression. However, over the past decade research has demonstrated that exercise is not only safe for this population but may offer other therapeutic benefits. To our knowledge, the specific perspectives and needs of individuals with MBD related to physical activity and exercise have not yet been explored. The objective of this study was to identify the attitudes towards and needs related to physical activity and exercise among individuals with MBD and MM. Methods: A phenomenological qualitative study utilizing a pragmatic approach to thematic analysis within a patient-oriented research framework was utilized. Semi-structured interview questions and various questionnaires were utilized to gather this descriptive information. Thematic analysis was completed using the 7-stage Framework Method, including transcription, familiarization, coding, analytical framework, and interpreting the data. Results: Of the 20 volunteer participants (90% male), four were living with MM (20%), and 16 had MBD diagnosed within 2-66 months of the study. Half of the participants did not report feeling any bone pain, with none experiencing severe bone pain, and eight (40%) experienced pain specifically with movement. Most participants engaged in a variety of physical activities and at various intensities, although 25% were found to be sedentary/insufficiently active. Five major themes emerged from the interviews including “meaning of physical activity”, “cancer care ‘exercise is medicine’ support (or lack thereof)”, “motivators to engage in physical activity”, “barriers causing a reduction in physical activity post diagnosis”, and “physical activity program preferences”. These themes encompassed a total of 32 categories and 44 subcategories, creating the overall thematic framework. Discussion: Individuals with MBD and MM do engage in regular physical activity, although differences in the frequency and intensity of exercise exist. Exercise has a recognized and valued role in their lives and health, including bone health. These patients are genuinely interested in some form of exercise program as part of their cancer care. Movement or activity modifications may be required for some based on bony lesions and fracture prevention. Differences may also be related to comorbidities, preferences, and/or abilities. While there is no “one size fits all” approach to oncology-based exercise prescription and implementation among this population, the findings of this study demonstrate that there is a strong patient-identified need to support those living with MBD and MM to engage in regular exercise in order to obtain its physical and psychological benefits. / Graduate / 2023-03-03

Recently, there has been an increase in the number of proton beam therapy (PBT) centers operating worldwide. For certain cases, proton beams have been shown to provide dosimetric and radiobiological advantages when used for cancer treatment, compared to the regular photon-beam based treatments. Under ideal circumstances, the dose given to the tissues surrounding a target can be reduced with PBT. The risk for side effects following treatment is then expected to decrease. Until present, mainly stationary targets, e.g. targets in the brain, have been treated with PBT. There is currently a growing interest to treat also target volumes in other parts of the body with PBT. However, there are sources of uncertainties, which must be more carefully considered when PBT is used, especially for PBT carried out with scanned proton beams. PBT is more sensitive to anatomical changes, e.g. organ motion or a variable gas content in the intestines, which requires that special precautions are taken prior to treating new tumour sites. In photon beam radiotherapy (RT) of moving targets, the main consequence of organ motion is the loss of sharpness of the dose gradients (dose smearing). When scanned proton beams are used, dose deformation caused by the fluctuations in the proton beam range, due to varying tissue heterogeneities (e.g., the ribs moving in and out of the beam path) and the so-called interplay effect, can be expected to impact the dose distributions in addition to the dose smearing. The dosimetric uncertainties, if not accounted for, may cause the planned and accurately calculated dose distribution to be distorted, compromising the main goal of RT of achieving the maximal local disease control while accepting certain risks for normal tissue complications. Currently there is a lack of clinical follow-up data regarding the outcome of PBT for different tumour sites, in particular for extra-cranial tumour sites in moving organs. On the other hand, the use of photon beams for this kind of cancer treatment is well-stablished. A treatment planning comparison between RT carried out with photons and with protons may provide guidelines for when PBT could be more suitable. New clinical applications of particle beams in cancer therapy can also be transferred from photon-beam treatments, for which there is a vast clinical experience. The evaluation of the different uncertainties influencing RT of different tumour sites carried out with photon- and with proton-beams, will hopefully create an understanding for the feasibility of treating cancers with scanned proton beams instead of photon beams. The comparison of two distinct RT modalities is normally performed by studying the dosimetric values obtained from the dose volume histograms (DVH). However, in dosimetric evaluations, the outcome of the treatments in terms of local disease control and healthy tissue toxicity are not estimated. In this regard, radiobiological models can be an indispensable tool for the prediction of the outcome of cancer treatments performed with different types of ionising radiation. In this thesis, different factors that should be taken into consideration in PBT, for treatments influenced by organ motion and density heterogeneities, were studied and their importance quantified. This thesis consists of three published articles (Articles I, II and III). In these reports, the dosimetric and biological evaluations of photon-beam and scanned proton-beam RT were performed and the results obtained were compared. The studies were made for two tumour sites influenced by organ motion and density changes, gastric cancer (GC) and liver metastases. For the GC cases, the impact of changes in tissue density, resulting from variable gas content (which can be observed inter-fractionally), was also studied. In this thesis, both conventional fractionations (implemented in the planning for GC treatments) and hypofractionated regimens (implemented in the planning for the liver metastases cases) were considered. In this work, it was found that proton therapy provided the possibility to reduce the irradiations of the normal tissue located near the target volumes, compared to photon beam RT. However, the effects of density changes were found to be more pronounced in the plans for PBT. Furthermore, with proton beams, the reduction of the integral dose given to the OARs resulted in reduced risks of treatment-induced secondary malignancies.

L’hétérogénéité tumorale (HT) est un trait caractéristique du cancer. Elle peut être rencontrée chez la majorité des tumeurs malignes solides, au travers de la clinique, la biologie, l’histologie, et la génétique. Au-delà de l’hétérogénéité inter-patient, on distingue l’hétérogénéité spatiale, qui regroupe l’hétérogénéité au sein de la tumeur primitive, entre tumeur primitive et métastases, entre métastases, au sein d’une métastase et l’hétérogénéité temporelle, qui fait référence à l’évolution de la tumeur au cours du temps de manière spontanée ou sous l’effet des traitements. L’HT explique la survenue inéluctable de la résistance aux thérapies anticancéreuses actuelles. L’objectif général de cette thèse était d’explorer l’hétérogénéité tumorale au plan clinique, histologique et génétique en utilisant le modèle d’hépatectomies pour métastases d’origine colo-rectales. Dans l’article 1, nous avons étudié la réponse histologique à la chimiothérapie chez des patients opérés de métastases hépatiques colo-rectales après chimiothérapie systémique ou intra-artérielle. Ainsi, nous avons montré que la réponse histologique complète était plus souvent observée après administration d’oxaliplatine par voie intra-artérielle et était associée à un meilleur pronostic. Cependant la réponse histologique complète n’est observée que chez une minorité de patients. Nous avons émis l’hypothèse qu’une réponse histologique incomplète représentent un groupe hétérogène de patients, ayant des pronostics différents. Ceci nous a conduit à proposer dans l’article 2 une méthode reproductible pour évaluer la réponse histologique, incorporant taille et nombre de nodules. La relecture des lames de pièces d’hépatectomie nous a conduit à observer une hétérogénéité de la réponse histologique au sein d’un même patient (hétérogénéité intermétastatique) et de l’aspect histologique (nécrose, fibrose). Nous avons ensuite exploré la valeur pronostique de cette hétérogénéité et chercher à identifier les facteurs prédictifs de cette hétérogénéité. Une réponse dissociée (une différence de réponse histologique > 50% entre deux nodules chez un même patient) a été observée chez 20% des patients et ne modifiait pas le pronostic. Chez les patients ayant une hétérogénéité pathologique, une discordance (mutation et absence de mutation pour les gènes KRAS, BRAF, NRAS et PI3K) entre les métastases a été mis en évidence dans 28% des patients analysés (article 3). Afin d’étudier l’hétérogénéité génétique selon le site tumoral et le type de prélèvements, nous avons utilisé les données disponibles de la plateforme de biologie moléculaire (article 4). Nous avons ainsi mis en évidence que les métastases hépatiques étaient moins souvent mutées pour KRAS, NRAS, BRAF que les tumeurs primitives ou les lésions pulmonaires. Nous avons ensuite recherché une hétérogénéité génétique intra-métastatique pour KRAS, NRAS, BRAF et PI3K au sein d’une métastase hépatique colo-rectale (article 5). Parmi les 54 patients ayant une tumeur unique analysable (2 prélèvements par tumeur), une discordance pour KRAS (N=2) et BRAF (N=1) a été mise en évidence chez 3 patients (5%). L’ensemble de ces travaux confirment que l’HT est observée à travers de nombreux points de vue. L’élaboration de nouvelles stratégies de prise en charge du cancer devra prendre compte cet aspect. / Tumor heterogeneity is a typical feature of cancer. It is observed in the majority of solid malignancies regardless of the point of view: clinical, biological, pathological, and genetic. Different levels of heterogeneity have been described: interpatient, spatial heterogeneity (within the primary tumor, between primary and distant lesion) and temporal heterogeneity (tumor evolution under the influence of treatment). Tumor heterogeneity widely explains the emergence of resistant clones to anticancer drugs. The objective of the current thesis was to explore tumor heterogeneity at a clinical, pathological and genetic level, by using the model of hepatectomy for colorectal liver metastases (CLM).In the article 1, we studied pathological response to chemotherapy in patients operated on for CLM after either systemic or intra-arterial hepatic oxaliplatin-based chemotherapy. We showed that complete pathological response was more often observed after intra-arterial chemotherapy and yield far better outcomes. However, complete response was observed in a minority of patients. We hypothesized that uncomplete pathological response encompass a large group of patients with different oncological outcomes. This lead us to propose a reproducible method (article 2) to assess pathological response, including size and number of nodules. Pathological review found heterogeneity in the response among nodules within the same patients and in the type of pathological features (necrosis, fibrosis). We then explore the prognostic value of pathological heterogeneity and sought to identify predictors of heterogeneity. A dissociated response (difference in pathological response > 50% between two nodules) was observed in XX and did not impact long-term outcomes. IN patients with dissociated response, genetic heterogeneity (mutation and no mutation for KRAS, NRAS, BRAF and PI3K) between metastases was shown in 28% of patients (article 3). To study genetic heterogeneity according to tumor location and the tumor tissue analyzed (specimen, biopsy), we used data from the department of molecular biology (article 4). We found that liver metastases were more often wild type for KRAS, NRAS, BRAF compared to lung metastases or primary tumors. In the article 5, we then sought to evaluate intrametastatic heterogeneity (KRAS, BRAF, NRAS, PI3K) within a single liver metastasis (2 samples per tumor). Among the 54 patients with single lesion analyzed, a discrepancy for KRAS (n=2) and BRAF (n=1) were observed un 3 patients (5%). This work confirms that tumor heterogeneity can be observed at various levels. Elaboration of new therapeutical strategies will have to take this aspect into consideration.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18883号 / 医博第3994号 / 新制||医||1009(附属図書館) / 31834 / 京都大学大学院医学研究科医学専攻 / (主査)教授 岩井 一宏, 教授 野田 亮, 教授 藤田 潤 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19172号 / 医博第4014号 / 新制||医||1010(附属図書館) / 32164 / 京都大学大学院医学研究科医学専攻 / (主査)教授 武藤 学, 教授 平岡 眞寛, 教授 川口 義弥 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24794号 / 医博第4986号 / 新制||医||1066(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 寺田 智祐, 教授 武藤 学, 教授 上杉 志成 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No / Background Oral administration of the omega-3 fatty acid eicosapentaenoic acid (EPA), as the free fatty acid (FFA), leads to EPA incorporation into, and reduced growth of, experimental colorectal cancer liver metastases (CRCLM). Design: We performed a Phase II double-blind, randomised, placebo-controlled trial of EPA-FFA 2 g daily in patients undergoing liver resection surgery for CRCLM. The patients took EPA-FFA (n=43) or placebo (n=45) prior to surgery. The primary end-point was the CRCLM Ki67 proliferation index (PI). Secondary end-points included safety and tolerability of EPA-FFA, tumour fatty acid content and CD31-positive vascularity. We also analysed overall survival (OS) and disease-free survival (DFS). Results The median (range) duration of EPA-FFA treatment was 30 (12–65) days. Treatment groups were well matched with no significant difference in disease burden at surgery or preoperative chemotherapy. EPA-FFA treatment was well tolerated with no excess of postoperative complications. Tumour tissue from EPA-FFA-treated patients demonstrated a 40% increase in EPA content (p=0.0008), no difference in Ki67 PI, but reduced vascularity in ‘EPA-naïve’ individuals (p=0.075). EPA-FFA also demonstrated antiangiogenic activity in vitro. In the first 18 months after CRCLM resection, EPA-FFA-treated individuals obtained OS benefit compared with placebo, although early CRC recurrence rates were similar. Conclusions EPA-FFA therapy is safe and well tolerated in patients with advanced CRC undergoing liver surgery. EPA-FFA may have antiangiogenic properties. Remarkably, limited preoperative treatment may provide postoperative OS benefit. Phase III clinical evaluation of prolonged EPA-FFA treatment in CRCLM patients is warranted. Trial Identifier: ClinicalTrials.gov NCT01070355. / The Cancer Research UK Clinical Trials Awards and Advisory Committee approved the Trial. PML and ADR were supported by Department of Health/Cancer Research UK Yorkshire Experimental Cancer Medicine Centre funding. The Trial was adopted by the UKCRN Clinical Trials Portfolio (UKCRN ID 8946) allowing West Yorkshire Comprehensive Local Research Network funding of Pharmacy costs. SLA Pharma AG funded some of the experimental work and provided EPA-FFA and placebo. SLA Pharma AG played no role in the design or execution of the Trial. Laboratory costs were also supported by the Leeds Teaching Hospitals Charitable Foundation (Rays of Hope).