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Prostate cancer is the second most diagnosed cancer worldwide and its diagnosis is done through visual inspection of biopsy tissue by a pathologist, who assigns a score used by doctors to decide on the treatment. However, the scoring system, the Gleason score, is affected by a high inter and intra-observer variability, lack of standardization, and overestimation. Therefore, there is a need for new solutions that can reduce these issues and provide a more accurate diagnosis. Nowadays, high-resolution digital images of biopsy tissues can be obtained and stored. The availability of such images, called Whole Slide Images (WSI) allows the implementation of Machine and Deep learning models to assist pathologists in diagnosing prostate cancer. Multiple-Instance Learning (MIL) has been shown to reach very promising results in digital pathology and binary classification of prostate cancer slides. However, such models require large datasets to ensure good performances. This project wants to investigate the use of small sets of strongly annotated images to create new large datasets to train a MIL model. To evaluate the performance of this approach, the standard dataset is used to obtain baselines for both binary and multiclass classification tasks. For multiclassification, the International Society of Urological Pathology (ISUP) score is used, which is derived from the Gleason score. The dataset used is the publicly available PANDA. In this project, only the slides from RadboudUniversity Medical Center are used, which consists of 5160 images. The MIL model chosen is the Clustering-constrained Attention Multiple instance learning (CLAM) model, which is publicly available. The standard approach reaches a Cohen’s kappa (κ) of 0.78 and 0.59 for binary and multiclass classification respectively. To evaluate the new approach, large datasets are created starting from different set sizes. Using 500 images, the model reaches a κ of 0.72 and 0.38 respectively. While for the binary the results of the two approaches are comparable, the new approach is not beneficial for multiclass classification tasks.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23772号 / 医博第4818号 / 新制||医||1056(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 村川 泰裕, 教授 松田 文彦, 教授 篠原 隆司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Les cellules tumorales présentent des altérations de leur métabolisme, notamment le développement d'un phénotype lipogénique incluant l’augmentation de l’expression de protéines de la lipolyse. L'α/β-hydrolase domaine-6 (ABHD6), par son rôle dans l'hydrolyse des monoacylglycérols, semble être un acteur important dans le réseau lipidique de signalisation protumorigène. Des études ont révélé qu’ABHD6 est surexprimée dans l'ostéosarcome et la lignée cellulaire PC-3 du cancer de la prostate (CP), ainsi que dans les tumeurs d'Ewing. La suppression de l'expression d’ABHD6 a réduit la croissance du cancer du poumon et de ses métastases chez les souris. Ainsi, ABHD6 pourrait être un lien important entre la lipolyse et la progression du cancer. Nous émettons l'hypothèse que l'inhibition d'ABHD6 freinerait la prolifération, la migration et l’invasion des cellules du CP. Les résultats montrent que l'expression d’ABHD6 est plus élevée dans les lignées LNCaP et C4-2B que dans les lignées les plus agressives (DU145 et PC-3). L’inhibition d'ABHD6 par le KT203 a réduit la prolifération des cellules du CP avec une sensibilité plus marquée dans les LNCaP et PC-3. La perte d’expression d’ABHD6 via un pARNi affecte de façon prononcée la prolifération de l’ensemble des lignées. La migration et l'invasion des cellules PC-3 ont été notablement réduites de plus de 50 % en présence de KT203, mais cet inhibiteur n'a eu que peu d'impact sur les cellules 22Rv1 ou C4-2B. L'inhibition d'ABHD6 semble inverser l'expression des marqueurs EMT dans les cellules PC3. Ces résultats suggèrent que ABHD6 pourrait jouer un rôle dans la progression du CP. / Tumor cells alter their metabolism to adapt to increased proliferation and survival under restricted nutrient availability. These metabolic changes include accelerated glycerolipid/ fatty acid cycle that encompasses lipogenesis and lipolysis. The lipolytic enzyme a/b-hydrolase domain-6 (ABHD6), which hydrolyzes monoacylglycerols, could be a potential player in the pro- tumorigenic lipid signaling network that promotes migration, survival, and growth of cancer cells. ABHD6 is found to be elevated in several cancers including prostate cancer (PC) cell-lines. Suppression of ABHD6 expression was shown to reduce lung cancer growth and metastases in mice. The possibility that ABHD6 could be an important link between lipolysis and cancer progression is not investigated in detail. We hypothesize that ABHD6 inhibition would curtail PC cell proliferation, migration and invasion capabilities. ABHD6 expression was assessed in 22Rv1, LNCaP, C4-2B, DU145, and PC-3 PC cell-lines. The impact of ABHD6 suppression either by RNAi- knockdown or by a specific inhibitor, KT203, on PC cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) was examined. Our results show that ABHD6 expression was relatively higher in LNCaP and C4-2B, as compared to the more aggressive PC cell-lines (DU145 and PC-3). ABHD6 inhibition by KT203 reduced PC cell proliferation, more markedly in LNCaP and PC-3. However, RNAi-knockdown of ABHD6 equally reduced the proliferation of all PC cell-lines. Migration and invasion of PC-3 cells was notably decreased by more than 50% by KT203 whereas there was less effect on 22Rv1 or C4-2B cells. ABHD6 inhibition appears to reverse the expression of EMT markers in the PC-3 cells. These findings suggest that ABHD6 inhibition may prevent progression of aggressive prostate cancer.

Prostate cancer (CaP) is the second leading cause of cancer related deaths in men in the United States. Currently, androgen depletion is an essential strategy for CaP combined with surgery, chemotherapy and radiation. Hormone independent cancer stem cells escaping conventional therapy present a major therapeutic challenge. The available treatment regimens for hormone resistant CaP are only palliative and marginally increase survival. Therefore, novel strategies to eradicate CaP including stem cells are imperative. Oncolytic virus (OV) therapy is a novel approach that overcomes the limitations posed by radiation and chemotherapy. Oncolytic virotherapy of cancer is based on the use of replication competent, tumor selective viruses with limited toxicity. Newcastle Disease Virus (NDV), an avian paramyxovirus, is a safe and promising OV successfully used in many clinical trials. NDV is inherently tumor selective and cytotoxic but replication restricted in normal cells. But, systemically delivered NDV fails to reach solid tumors in therapeutic concentrations and also spreads poorly within the tumors due to barriers including complement, innate immunity and extracellular matrix. Overcoming these hurdles is paramount to realize the exceptional oncolytic efficacy of NDV. Therefore, we engineered the fusion (F) glycoprotein of NDV and generated a recombinant NDV (rNDV) cleavable exclusively by prostate specific antigen (PSA). The rNDV replicated efficiently and specifically only in prostate cancer (CaP) cells but failed to replicate in the absence of PSA. Further, PSA-cleavable rNDV caused specific lysis of androgen independent and dependent/responsive CaP cells with a mean effective concentration (EC50) ranging from 0.01 to 0.1 multiplicity of infection (MOI). PSA retargeted rNDV efficiently lysed three-dimensional prostaspheres, suggesting efficacy in vivo. Also, PSA-cleavable NDV failed to replicate in chicken embryos, indicating absence of pathogenicity to its natural host, chickens. Prostaspheres generated from DU-145 CaP cell line derived xenografts showed self-renewal, proliferative and clonogenic potential in vitro, and exhibited increased tumorigenicity in vivo. Embryonic stem and progenitor cell markers like Nanog, Nestin and CD44 were overexpressed in spheres as compared to the cell line suggesting prostaspheres comprise tumor-initiating cells from CaP. Xenograft and cell line derived prostaspheres were permissive for rNDV replication, when the fusion protein was activated by exogenous PSA. The EC50 against tumor initiating cells was 0.11-0.14 MOI, suggesting an excellent therapeutic margin for in vivo studies. PSA retargeting is likely to enhance the therapeutic index of rNDV owing to tumor restricted replication and enhanced fusogenicity. Our results suggest PSA retargeted rNDV selectively replicates and lyse PSA producing CaP cells including tumor-initiating cells and is a promising candidate for immediate Phase I/II clinical trials. / Ph. D.

Yes / The aldo-keto reductase 1C3 (AKR1C3) isoform plays a vital role in the biosynthesis of androgens and is considered an attractive target in prostate cancer (PCa). No AKR1C3-targeted agent has to date been approved for clinical use. Flufenamic acid and indomethacine are non-steroidal anti-inflammatory drugs known to inhibit AKR1C3 in a non-selective manner as COX off-target effects are also observed. Recently, we employed a scaffold hopping approach to design a new class of potent and selective AKR1C3 inhibitors based on a N-substituted hydroxylated triazole pharmacophore. Following a similar strategy, we designed a new series focused around an acidic hydroxybenzoisoxazole moiety, which was rationalised to mimic the benzoic acid role in the flufenamic scaffold. Through iterative rounds of drug design, synthesis and biological evaluation, several compounds were discovered to target AKR1C3 in a selective manner. The most promising compound of series (6) was found to be highly selective (up to 450-fold) for AKR1C3 over the 1C2 isoform with minimal COX1 and COX2 off-target effects. Other inhibitors were obtained modulating the best example of hydroxylated triazoles we previously presented. In cell-based assays, the most promising compounds of both series reduced the cell proliferation, prostate specific antigen (PSA) and testosterone production in AKR1C3-expressing 22RV1 prostate cancer cells and showed synergistic effect when assayed in combination with abiraterone and enzalutamide. Structure determination of AKR1C3 co-crystallized with one representative compound from each of the two series clearly identified both compounds in the androstenedione binding site, hence supporting the biochemical data. / University of Turin (Ricerca Locale grant 2015-2017) and Prostate Cancer UK grant S12-027.

This thesis investigates two questions: the methodological strengths and weaknesses of meta-analysis and the diagnostic performance of the Stockholm3 test for clinically significant prostate cancer. Through a systematic review and meta-analysis, we explore the robustness and limitations of meta-analysis, focusing on aspects such as bias assessment, heterogeneity, and the impact of the file-drawer problem. Applying these methods, we evaluate the Stockholm3 test’s performance, comparing it to the conventional Prostate-Specific Antigen (PSA) test. Our analysis synthesizes data from four studies consisting of 6 497 men, indicating that the Stockholm3 test offers improved diagnostic accuracy, with a higher pooled Area Under the Curve (AUC), in turn suggesting better identification of clinically significant prostate cancer. Nonetheless, the study also reveals challenges within the practice of meta-analysis, including variation among study methodologies and the presence of bias. These findings highlight the dual purpose of the research: demonstrating the utility and drawbacks of meta-analysis and validating the Stockholm3 test’s potential as a diagnostic tool. The conclusions drawn emphasize the need for continued research to enhance both meta-analytic methods and the clinical applicability of the Stockholm3 test in broader populations.

La dysfonction érectile est une complication courante des traitements du cancer de la prostate, y compris la curiethérapie. La dysfonction érectile a été associée à des marqueurs inflammatoires, notamment le rapport neutrophiles/lymphocytes (NLR). Dans ce mémoire, les interactions complexes entre la dysfonction érectile, l’inflammation et la valeur prédictive du NLR sont explorées. Plus précisément, l'étude incluse dans ce mémoire examine la valeur prédictive potentielle du NLR sur la dysfonction érectile après une curiethérapie prostatique pour le cancer de la prostate, sur la base d'une base de données maintenue de manière prospective. Les résultats montrent que le NLR de base est un prédicteur significatif de la dysfonction érectile post-curiethérapie dans les analyses univariées et multivariées, et que cet effet est plus prononcé avec un suivi plus long après curiethérapie. Par conséquent, l’inflammation systémique subclinique est un facteur potentiellement important pour prédire la toxicité sexuelle après une radiothérapie de la prostate, et le NLR est un outil potentiel pour prédire la dysfonction érectile comme complication des traitements du cancer de la prostate. De futures pistes de diagnostic et de traitements basées sur l’hypothèse inflammatoire pourraient être explorées à l’avenir sur la base de cette étude. / Erectile dysfunction is a common complication of prostate cancer treatments, including brachytherapy. Erectile dysfunction has also been association with inflammatory markers, including the neutrophil-to-lymphocyte ratio (NLR). In this memoir, the complex interactions between ED, inflammation, and the predictive value of NLR are explored. Specifically, the included study examines the potential predictive value of the NLR on erectile dysfunction after prostate brachytherapy for prostate cancer, based on a prospectively maintained database. The results show that baseline NLR is a significant predictor of post-brachytherapy erectile dysfunction on both univariate and multivariate analyses, and that this effect is more pronounced with longer follow-up after PB. Therefore, subclinical systemic inflammation is a potentially important factor for predicting sexual toxicity after prostate radiotherapy, and NLR is a potential tool to predict erectile dysfunction as a complication of prostate cancer treatments. Future avenues for diagnosis and treatments based on the inflammatory hypothesis could be explored in the future based on this study.

L'annonce d'un diagnostic de cancer déclenche systématiquement un processus de transition d'une condition de santé vers une condition de maladie. La transition est définie comme un processus adaptatif à une nouvelle situation et elle est marquée bien souvent par une détresse psychologique (Bussolari & Goodell, 2009). Ce processus est influencé par des conditions personnelles, communautaires ou sociétales pouvant le faciliter ou l'inhiber (Meleis, et al., 2000). Parmi les conditions personnelles, les perceptions de la personne de sa maladie et celles de son entourage (p.ex. : proches aidants, professionnels de la santé) exercent une influence sur son processus transitionnel ou adaptatif. Certains auteurs (Fitch, 2008) avancent l'idée que les besoins biopsychosociaux peuvent également exercer une influence sur ce processus. Des perceptions erronées de la maladie ou des besoins biopsychosociaux non comblés peuvent provoquer une détresse psychologique qui inhibe alors la transition de la personne atteinte de cancer. Dans cette vision, la présente thèse a pour objectif d'évaluer et de mieux comprendre l'expérience du cancer des personnes libanaises atteintes d'un cancer du sein ou de la prostate durant la période de transition du diagnostic au début du traitement de chimiothérapie à travers les perceptions de la maladie, les besoins biopsychosociaux et la détresse psychologique. Un cadre intégrateur incluant la théorie de la transition (Meleis et al., 2000) et le cadre des soins de soutien (Fitch, 2008) constitue les fondements théoriques de cette recherche. Il suggère que les perceptions de la maladie et les besoins biopsychosociaux sont des conditions personnelles qui ont un impact sur le vécu de la transition. Ce cadre met également l'accent sur l'influence de l'environnement ou l'entourage (p.ex. : proches aidants, professionnels de la santé) sur le vécu de la transition en lien avec les perceptions de la maladie et le soutien fourni à la personne qui vit cette transition. Pour atteindre l'objectif de l'étude, un devis mixte parallèle convergent qui comprend deux approches réalisées en deux étapes, a été utilisé. L'approche qualitative, à devis descriptif, a permis d'explorer les variables d'intérêt chez 25 personnes atteintes de cancer (14 femmes atteintes d'un cancer du sein, 11 hommes atteints d'un cancer de la prostate), ainsi que les perceptions des proches (n=25) et des professionnels de la santé (n=12), du cancer et de la détresse psychologique. L'approche quantitative, à devis corrélationnel prédictif, a permis d'évaluer les perceptions de la maladie et les besoins biopsychosociaux de 117 personnes atteintes de cancer et leur influence sur l'intensité de la détresse psychologique. Les résultats montrent que la transition du diagnostic au début du traitement représente pour la plupart des personnes atteintes de cancer un passage subi vers un état de maladie imprévue et perturbante. Pour eux, le cancer est une maladie redoutable, qui entraine des conséquences majeures et qui les accompagnera pour le reste de leur vie. Selon eux, il n'est pas contrôlable par des actions personnelles et le traitement sert à prévenir les complications négatives de la maladie (p. ex. : métastases). Depuis le diagnostic, ces personnes présentent des besoins aux niveaux pratique, physique, émotionnel, psychologique et social qui sont répondus en partie par les proches aidants et par les professionnels de la santé. Durant cette période de transition, plus de la moitié des personnes atteintes présentent un niveau modéré/élevé de détresse psychologique. Celle-ci serait associée au statut marital (vivre en couple), au type d'assurance qui couvre partiellement les coûts reliés au cancer, au fait d'avoir des personnes à charge (p. ex. : enfants, parents) à la perception du cancer comme une maladie chronique et à la présence d'une perte du poids. En conclusion, la majorité des personnes libanaises atteintes d'un cancer du sein ou de la prostate vivent une transition marquée par un niveau modéré / élevé de détresse psychologique. Cette détresse qui n'est pas identifiée ni gérée précocement dans le contexte libanais, pourrait conduire à des difficultés psychologiques sévères. Cette période de transition qui est critique dans la trajectoire de la maladie mérite donc une plus grande attention de la part des professionnels de la santé. / Announcement of a cancer diagnosis systematically triggers a process of transition from a state of health to a state of illness. Transition is defined as an adaptive process to a new situation often marked by psychological distress (Bussolari & Goodell, 2009). This process is influenced by personal, community or societal conditions that can facilitate or inhibit it (Meleis, et al., 2000). Among personal conditions, the individual's perceptions of their illness and those of people around them (e.g. caregivers, health professionals) have an influence on their transitional or adaptive process. Some authors (Fitch, 2008) suggest that biopsychosocial needs can also exert an influence on this process. Misperceptions of the illness or unmet biopsychosocial needs can cause psychological distress which then inhibits the transition of the person with cancer. Thus, the goal of the present thesis is to assess and better understand the cancer experience of Lebanese people with breast or prostate cancer during the transition period from diagnosis to the beginning of chemotherapy treatment through disease perceptions, biopsychosocial needs, and psychological distress. An integrative framework including transition theory (Meleis et al., 2000) and the supportive care framework (Fitch, 2008) underpinnings theoretical base of this research. It suggests that illness perceptions and biopsychosocial needs are personal conditions that have an impact on the experience of transition. In face of cancer, they are assessed according to a cognitive process involving, among other things, personal and cultural beliefs, knowledge, previous experiences, and goals, enabling the person to make sense of the illness and assess his/her coping resources. This framework also emphasizes the influence of the environment (e.g. family caregivers, healthcare professionals) on transition experience, in relation to perceptions of the illness and the support provided to the person going through this transition. To understand the transition of the target population and describe the cancer experience during the period of transition from diagnosis to the beginning of chemotherapy treatment, a parallel convergent mixed design was used, comprising two approaches carried out in two stages. The qualitative descriptive design explored the variables of interest in 25 people with cancer (14 women with breast cancer, 11 men with prostate cancer), as well as the illness and psychological distress perceptions of their loved ones (n=25) and healthcare providers (n=12). The quantitative predictive correlational design evaluates the illness perceptions and the biopsychosocial needs of 117 cancer people and their influence on the intensity of psychological distress. The results show that, the transition from diagnosis to the beginning of treatment is an unexpected and disruptive illness period for most cancer sufferers. Cancer is a fearsome disease, with major consequences, which may last for the rest of their lives, and which cannot be controlled by action, and treatment serves to prevent the disease's negative consequences. Since diagnosis, these people have practical, physical, emotional, psychological, and social needs that are met partially by their caregivers and healthcare professionals. During this period of transition, more than half of sufferers experience a moderate/high level of psychological distress, associated with marital status (living as a couple), type of insurance which cover partially the cost of cancer, having dependents, perception of cancer as a chronic disease and the presence of weight loss. In conclusion, the transition experience of most Lebanese people with breast or prostate cancer is marked by a moderate / high level of psychological distress. This distress, which not identified and managed early on in Lebanese context, can lead to severe psychological difficulties. This critical transition period in the disease trajectory therefore deserves greater attention from healthcare professionals.